INFECTIOUS DISEASES powerpoint by doc eva

INFECTIOUS DISEASES
Ma. Eva C. San Juan, MSPharm, Ed.D, PhD

a.
 A. Anti-infective agents treat infection
 suppressing or destroying the causative microorganisms—bacteria,
mycobacteria, fungi, protozoa, or viruses.
 Anti-infective agents from natural substances - antibiotics;
 From synthetic substances are called antimicrobials.

B. Indications.
 Confirm infection by history and physical examination, signs and
symptoms and predisposing factors.
 Anti-infective agents should be used only when
1. A signifi cant infection
2. prophylactic therapy

C. Gram stain microbiological culturing,
and susceptibility tests
C. Gram stain, microbiological culturing, and susceptibility
tests should be performed before antiinfective therapy is
initiated.
Test materials must be obtained by a method that avoids
contamination of the specimen by the patient’s own
flora.

1. Gram stain.
causative agent is gram positive or gram negative
 choice of drug therapy.
 a. Gram-positive microorganisms stain blue or purple.
b. Gram-negative microorganisms stain red or rose-pink.
 c. Fungi may also be identified by gram stain

2. Microbiological cultures.
To identify the specifi c causative agent, specimens of
body fl uids or infected tissue are collected for analysis.

3. Susceptibility tests.
 determine microbial
susceptibility to a given
drug and thus can be
used to predict whether
the drug will combat the
infection effectively.

a. Microdilution method.
 The drug is diluted serially in various media containing the test microorganism.
 (1) Th e lowest drug concentration that prevents microbial growth aft er 18 to 24 hrs of
incubation is called the minimum inhibitory concentration (MIC).
 (2) Th e lowest drug concentration that reduces bacterial density by 99.9% is called the
minimum bactericidal concentration (MBC).
 (3) Breakpoint concentrations of antibiotics are used to characterize antibiotic activity:
 The interpretive categories are susceptible, moderately susceptible (intermediate), and
resistant.
 Th ese concentrations are determined by considering pharmacokinetics, serum and tissue
concentrations following normal doses, and the population distribution of MICs of a group of
bacteria for a given drug.

b. Kirby–Bauer disk diffusion technique
 less expensive but less reliable than the microdilution method; however,
provides qualitative susceptibility information.
 (1) Filter paper disks impregnated with specific drug quantities are
placed on the surface of agar plates streaked with a microorganism
culture. After 18 hrs, the size of a clear inhibition zone is determined; drug
activity against the test strain is then correlated to zone size.
 (2) The Kirby–Bauer technique does not reliably predict therapeutic eff
ectiveness against certain microorganisms (e.g., Staphylococcus aureus,
Shigella).

D. Choice of agent.
 1. Pharmacological properties include the drug’s ability to reach
the infection site and to attain a desired level in the target tissue.
 2. Spectrum of activity. To treat an infectious disease eff ectively, an
anti-infective drug must be active against the causative pathogen.
 Susceptibility testing or clinical experience in treating a given
infection may suggest the effectiveness of a particular drug.

3. Patient factors (IFAUA)
 a. Immunological status.
 b. Presence of a foreign body.
 c. Age.
 d. Underlying disease
 e. History of drug allergy or adverse drug reactions
 f. Pregnancy and lactation.
 . g. Genetic traits

a. Immunological status.
A patient with impaired immune mechanisms may require
a drug that rapidly destroys pathogens (i.e., bactericidal
agent) rather than one that merely suppresses a
pathogen’s growth or reproduction (i.e., bacteriostatic
agent).

b. Presence of a foreign body.
anti-infective therapy effectiveness is reduced in patients
whith prosthetic joints or valves, cardiac pacemakers, and
various internal shunts.

c. Age.
 pharmacokinetic properties of drugsvary widely patients’ age.
 young and very old- , drug metabolism and excretion decreases.
 Elderly patients- increased risk of suffering ototoxicity -
aminoglycosides.

d. Underlying disease
 (1) Preexisting kidney or liver disease increases nephrotoxicity or
hepatotoxicity RISK
 (2) Patients with central nervous system (CNS) disorders -
neurotoxicity (motor seizures) -penicillin therapy.
 (3) Patients with neuromuscular disorders (e.g., myasthenia gravis) -
increased risk for neuromuscular blockade with aminoglycoside or
polymyxin B therapy.

e. History of drug allergy or adverse drug
reactions
 previous allergic or other untoward reactions - higher risk of
experiencing the same reaction
 Except in life-threatening situations, patients who have had serious
allergic reactions to penicillin, for example, should not receive the
drug again.

f. Pregnancy and lactation.
 Risk vs Benefit
 (1) Pregnancy can increase the risk of adverse drug eff ects for both mother and
fetus. Also, plasma drug concentrations tend to decrease in pregnant women,
reducing a drug’s therapeutic effectiveness.
 (2) Most drugs, including antibiotics, appear in the breast milk of nursing mothers
and may cause adverse eff ects in infants.
 For example, sulfonamides may lead to toxic bilirubin accumulation in a
newborn’s brain
 KERNICTERUS

. g. Genetic traits
 (1) Sulfonamides may cause hemolytic anemia in patients with
glucose-6-phosphate dehydrogenase (G6PD) deficiency.
 (2) Patients who rapidly metabolize drugs (i.e., rapid acetylators)
may develop hepatitis when receiving the antitubercular drug
isoniazid.

E. Empiric therapy.
 In serious or life-threatening disease, anti-infective therapy must begin before the
infecting organism has been identifi ed.
 In this case, the choice of drug (or drugs) is based on clinical experience,
suggesting that a particular agent is eff ective in a given setting.
 1. A broad-spectrum antibiotic usually is the most appropriate choice until the
specifi c organism has been determined.
 2. In all cases, culture specimens must be obtained before therapy begins.

F. Multiple antibiotic therapy.
 A combination of drugs should be given only when clinical
experience has shown such therapy to be more eff ective than
single-agent therapy in a particular setting.
 A multiple-agent regimen can increase the risk of toxic drug effects
and, in a few cases, may result in drug antagonism and subsequent
therapeutic ineffectiveness.

Indications for multiple-agent therapy
include
 1. Need for increased antibiotic eff ectiveness. Th e synergistic
(intensifi ed) eff ect of two or more agents may allow a dosage
reduction or a faster or enhanced drug eff ect.
 2. Treatment of an infection caused by multiple pathogens (e.g.,
intra-abdominal infection)
 3. Prevention of proliferation of drug-resistant organisms (e.g.,
during treatment of tuberculosis

G. Duration of anti-infective therapy.
 To achieve the therapeutic goal, anti-infective therapy must continue for a suffi cient
duration.
 1. Acute uncomplicated infection. Treatment generally should continue until the patient
has been afebrile and asymptomatic for at least 72 hrs.
 2. Chronic infection (e.g., endocarditis, osteomyelitis). Treatment may require a longer
duration (4 to 6 weeks) with follow-up culture analyses to assess therapeutic effectiveness.

H. Monitoring therapeutic effectiveness.
 1. Fever curve. An important assessment tool, the fever curve may be a reliable indication of response to
therapy. Defervescence usually indicates favorable response.
 2. White blood cell (WBC) count. In the initial stage of infection, the neutrophil count from a peripheral blood
smear may rise above normal (neutrophilia), and immature neutrophil forms (“bands”) may appear (“left shift ”).
In patients who are elderly, debilitated, or suff ering overwhelming infection, the WBC count may be normal or
subnormal.
 3. Radiographic findings. Small eff usions, abscesses, or cavities that appear on radiographs indicate the focus of
infection.
 4. Pain and inflammation (as evidenced by swelling, erythema, and tenderness) may occur when the infection is
superfi cial or within a joint or bone, also indicating a possible focus of infection.
 5. Erythrocyte sedimentation rate (ESR or “sed rate”). Large elevations in ESR are associated with acute or chronic
infection, particularly endocarditis, chronic osteomyelitis, and intra-abdominal infections. A normal ESR does not
exclude infection; more oft en, ESR is elevated as a result of noninfectious causes such as collagen vascular
disease.
 6. Serum complement concentrations, particularly the C3 component, are oft en reduced in serious infections
because of consumption during the host defense process.

Causes of therapeutic ineffectiveness
include the following:
 1. Misdiagnosis. Th e isolated organism may have been misidentifi ed by the laboratory or may not be the
causative agent for infection (e.g., the patient may have an unsuspected infection).
 2. Improper drug regimen. Th e drug dosage, administration route, dosing frequency, or duration of therapy may
be inadequate or inappropriate.
 3. Inappropriate choice of antibiotic agent. As discussed in I.D, patient factors and the pharmacological
properties and spectrum of activity of a given drug must be considered when planning anti-infective drug therapy.
 4. Microbial resistance. By acquiring resistance to a specifi c antibiotic, microorganisms can survive in the drug’s
presence. Many gonococcal strains, for instance, now resist penicillin. Drug resistance is particularly common in
geographical areas in which a specifi c drug has been used excessively (and perhaps improperly).
 5. Unrealistic expectations.
 6. Infection by two or more types of microorganisms. If not detected initially, an additional cause of infection may
lead to therapeutic failure.

Causes of in-effectiveness….
 5. Unrealistic expectations. Antibiotics are ineffective in certain circumstances.
 a. Patients with conditions that require surgical drainage
 b. Fever should not be treated with anti-infective drugs unless infection has been identifi
ed as the cause. Although fever frequently signifi es infection, it sometimes stems from
noninfectious conditions (e.g., drug reactions, phlebitis, neoplasms, metabolic disorders,
arthritis). Th ese conditions do not respond to antibiotics. One exception to this position is
neutropenic cancer patients; such patients with no signs or symptoms of infection other
than fever are widely treated with antimicrobial agents.

J. Antimicrobial prophylaxis for surgery
 Antibiotic prophylaxis is a short course of antibiotic administered before there is clinical
evidence of infection.
 2. General considerations
 a. Timing. Th e antibiotic should be administered to ensure that appropriate antibiotic
levels are available at the site of contamination before the incision. Initiation of prophylaxis
is oft en at induction of anesthesia, within 1 hr or just before the surgical incision. Th is
ensures peak serum and tissue antibiotic levels.

b. Duration
 . Prophylaxis should be maintained for the duration of surgery. Long
surgical procedures (e.g., 3 hrs) may require additional doses. Th
ere is little evidence to support continuation of prophylaxis beyond
24 hrs.

 d. Route of administration. Intravenous (IV) or intramuscular (IM)
routes are preferred to guarantee good serum and tissue levels at
the time of incision

c. Antibiotic spectrum should be
appropriate for the usual pathogens.
 (1) In general, fi rst-generation cephalosporins (e.g., cefazolin) are
the drugs of choice for most procedures and patients. Th ese agents
have an appropriate spectrum, a low frequency of side eff ects, a
favorable half-life, and a low cost.
 (2) Vancomycin is a suitable alternative in penicillin-sensitive
patients and in situations in which methicillin-resistant S. aureus is a
concern..

II. ANTIBACTERIAL AGENTS
 A. Defi nition and classifi cation.
 Used to treat infections caused by bacteria, antibacterial agents fall into several major categories:
aminoglycosides, carbapenems, cephalosporins, erythromycins, penicillins (including various subgroups),
sulfonamides, tetracyclines, fl uoroquinolones, metronidazole (see V.C.2.b), urinary tract antiseptics, and
miscellaneous anti-infectives (Table 36-1).
 B. Aminoglycosides. Th ese drugs, containing amino sugars, are used primarily in infections caused by
gram-negative enterobacteria and in suspected sepsis.
 Th ey have little activity against anaerobic and facultative organisms.
 Th e toxic potential of these drugs limits their use. Major aminoglycosides include amikacin (Amikin),
gentamicin (Garamycin), kanamycin, neomycin, netilmicin, streptomycin, and tobramycin (Nebcin). 1.
Mechanism of action.
 Aminoglycosides are bactericidal; they inhibit bacterial protein synthesis by binding to and impeding the
function of the 30S ribosomal subunit.
 (Some aminoglycosides also bind to the 50S ribosomal subunit.) Th eir mechanism of action is not fully
known.

2. Spectrum of activity
 a. Streptomycin is active against both gram-positive and gram-negative bacteria. However, widespread resistance to this
drug has restricted its use to the organisms that cause plague and tularemia, gram-positive streptococci (given in
combination with penicillin), and Mycobacterium tuberculosis (given in combination with other antitubercular agents as
described in VI.C.2).
 b. Amikacin, kanamycin, gentamicin, tobramycin, neomycin, and netilmicin are active against many gram-negative
bacteria (e.g., Proteus, Serratia, and Pseudomonas organisms).
 (1) Gentamicin is active against some Staphylococcus strains; it is more active than tobramycin against Serratia organisms.
 (2) Amikacin is the broadest spectrum aminoglycoside with activity against most aerobic gram-negative bacilli as well as
many anaerobic gram-negative bacterial strains that resist gentamicin and tobramycin. It is also active against M.
tuberculosis and Mycobacterium avium-intracellulare (MAI).
 (3) Tobramycin may be more active against Pseudomonas aeruginosa than gentamicin. (
 4) Netilmicin may be active against gentamicin-resistant organisms; it appears to be less ototoxic than other
aminoglycosides.
 (5) Neomycin, in addition to its activity against such gram-negative organisms as Escherichia coli and Klebsiella
pneumoniae, is active against several gram-positive organisms (e.g., S. aureus). P. aeruginosa and most streptococci are
now neomycin resistant.

4. Precautions and monitoring eff ects.
 Aminoglycosides can cause serious adverse eff ects. To prevent or minimize such problems, blood drug concentrations and
blood urea nitrogen (BUN) and serum creatinine levels should be monitored during therapy.
 a. Ototoxicity. Aminoglycosides can cause vestibular or auditory damage. Th e relative ototoxicity is as follows:
streptomycin kanamycin amikacin gentamicin tobramycin netilmicin
 (1) Gentamicin and streptomycin cause primarily vestibular damage (manifested by tinnitus, vertigo, and ataxia). Such
damage may be bilateral and irreversible.
 (2) Amikacin, kanamycin, and neomycin cause mainly auditory damage (hearing loss).
 (3) Tobramycin can result in both vestibular and auditory damage.
 b. Nephrotoxicity. Because aminoglycosides accumulate in the proximal tubule, mild renal dysfunction develops in up to
25% of patients receiving these drugs for several days or more. Usually, this adverse eff ect is reversible. Use of once-daily
administration (ODA) has been reported in the literature to be as eff ective and less nephrotoxic than traditional dosing.
 (1) Neomycin is the most nephrotoxic aminoglycoside; streptomycin is the least nephrotoxic. Gentamicin and tobramycin
are nephrotoxic to approximately the same degree.
 (2) Risk factors for increased nephrotoxic eff ects include the following: (a) Preexisting renal disease (b) Previous or
prolonged aminoglycoside therapy (c) Concurrent administration of another nephrotoxic drug(d) Impaired renal fl ow
unrelated to renal disease (e.g., from hypotension, severe hepatic disease)
 (3) Trough levels 2 g/mL for gentamicin and tobramycin and 10 g/mL for amikacin are associated with nephrotoxicity.

 c. Neuromuscular blockade. Th is problem may arise in patients receiving high-dose aminoglycoside
therapy.
 (1) Risk factors for neuromuscular blockade include the following: (a) Concurrent administration of a
neuromuscular blocking agent or an anesthetic (b) Preexisting hypocalcemia or myasthenia gravis (c)
Intraperitoneal or rapid IV drug administration
 (2) Apnea and respiratory depression may be reversed with administration of calcium or an
anticholinesterase. d. Hypersensitivity and local reactions are rare adverse eff ects of aminoglycosides.
 e. Th erapeutic levels
 (1) Gentamicin and tobramycin peak at 6 to 10 g/mL for traditional dosing; when using the ODA
method, the peak is 16 to 20 g/mL or 8 to 10 times the MIC of targeted bacteria. Th eir trough level is 0.5
to 1.5 g/mL for traditional or once-daily regimens.
 (2) Amikacin peaks at 25 to 30 g/mL. Th e trough level is 5 to 8 g/mL. 5. Signifi cant interactions a. IV
loop diuretics can result in increased ototoxicity. b. Other aminoglycosides, cisplatin, and amphotericin
B can cause increased nephrotoxicity when given concurrently with streptomycin.

C. Carbapenems.
 Th ese agents are -lactams that contain a fused -lactam ring and a fi ve-membered ring system that diff ers from
penicillins in being unsaturated and containing a carbon atom instead of a sulfur atom.
 Th e class has a broader spectrum of activity than do most -lactams. Formerly known as thienamycin, imipenem
(Primaxin) was the fi rst carbapenem compound introduced in the United States, followed by meropenem (Merrem)
and, most recently, ertapenem (Invanz) and doripenem (Doribax).
 Because it is inhibited by renal dipeptidases, imipenem must be combined with cilastatin sodium, a dipeptidase
inhibitor (cilastatin is not required with the others because these are not sensitive to renal dipeptidase).
 1. Mechanism of action. Carbapenems are bactericidal, inhibiting bacterial cell wall synthesis. 2. Spectrum of
activity. Th ese drugs have the broadest spectrum of all -lactam antibiotics. Th e group is active against most gram-
positive cocci (including many enterococci), gram-negative rods (including many P. aeruginosa strains), and
anaerobes. Th is class has good activity against many bacterial strains that resist other antibiotics. Ertapenem has a
narrower spectrum of a ctivity than the other carbapenems. It has little or no activity against P. aeruginosa and
Acinetobacter. Th ese -lactam antibiotics resist destruction by most -lactamases

3. Carbapenems Therapeutic uses.
 Carbapenems are most valued in the treatment of severe infections caused by drug-resistant
organisms susceptible to these agents.
 Th ese agents are eff ective against urinary tract and lower respiratory infections; intra-
abdominal and gynecological infections; and skin, soft tissue, bone, and joint infections.
 4. Precautions and monitoring eff ects
 a. Carbapenems may cause nausea, vomiting, diarrhea, and pseudomembranous colitis.
 b. Seizures, dizziness, and hypotension may develop; seizures appear less frequently with
meropenem or ertapenem (1.5% of patients receiving imipenem vs. 0.5% of those receiving
meropenem or ertapenem).
 c. Patients who are allergic to penicillin or cephalosporins may suff er cross-sensitivity reactions
during carbapenem therapy.

D. Cephalosporins.
 These agents are known as -lactam antibiotics because their chemical structure consists of a -lactam ring adjoined to a
thiazolidine ring. Cephalosporins generally are classifi ed in four major groups based mainly on their spectrum of activity
(Table 36-2).
 1. Mechanism of action.
 Cephalosporins are bactericidal; they inhibit bacterial cell wall synthesis, reducing cell wall stability and thus causing
membrane lysis.
 2. Spectrum of activity
 a. First-generation cephalosporins are active against most gram-positive cocci (except enterococci) as well as enteric
aerobic gram-negative bacilli (e.g., E. coli, K. pneumoniae, Proteus mirabilis
 b. Second-generation cephalosporins are active against the organisms covered by fi rst-generation cephalosporins and
have extended gram-negative coverage, including -lactamase–producing strains of Haemophilus infl uenzae.
 c. Th ird-generation cephalosporins have wider activity against most gram-negative bacteria, for example, Enterobacter,
Citrobacter, Serratia, Providencia, Neisseria, and Haemophilus organisms, including -lactamase–producing strains. Some
members have antipseudomonal activity.
 d. Fourth-generation cephalosporins include cefepime (Maxipime) and ceft aroline (Tefl aro). However, their designation as
a fourth-generation cephalosporin is debatable.

 Cefepime is highly resistant to -lactamases and has a low propensity for selection of -lactam– resistant
mutant strains.
 It shows evidence of greater activity versus gram-positive cocci, Enterobacteriaceae, and Pseudomonas
than third-generation cephalosporins.
 Ceftaroline has extended coverage of gram-positive bacteria including methicillin-resistant
Staphylococcus aureus (MRSA), multidrug-resistant Streptococcus pneumonia (MDRSP), and common
gramnegative bacteria. However, it has poor activity against anaerobes; atypical bacteria; and
Stenotrophomonas, Acinetobacter, and Pseudomonas species. It is not stable against several -l
actamases.
 e. Each generation of cephalosporin has shift ed toward increased gram-negative activity but has lost
activity toward gram-positive organisms.
 Fourth-generation agents should have improved activity toward gram-positive organisms (including
MRSA) over third-generation agents, as well as greater aerobic and anaerobic gram-negative coverage.

3. Therapeutic uses
 a. First-generation cephalosporins commonly are administered to treat serious Klebsiella infections and
gram-positive and some gram-negative infections in patients with mild penicillin allergy. Th ese agents
also are used widely in perioperative prophylaxis. For most other indications, they are not the preferred
drugs.
 b. Second-generation cephalosporins are valuable in the treatment of urinary tract infections resulting
from E. coli organisms, acute otitis media, sinusitis, and gonococcal disease caused by organisms that
resist other agents.
 (1) Cefaclor (Ceclor) is useful in otitis media and sinusitis in patients who are allergic to ampicillin and
amoxicillin. Cefprozil (Cefzil), a second-generation cephalosporin can be administered twice daily but
off ers no important spectrum diff erences.
 (2) Cefoxitin (Mefoxin) is therapeutic for mixed aerobic–anaerobic infections, such as intraabdominal
infection. Th e cefotetan (Cefotan) spectrum is similar, but this agent can be given twice daily.
 (3) Cefuroxime (Zinacef) is commonly administered for outpatient community-acquired pneumonia.

c. Third-generation cephalosporins
 penetrate the cerebrospinal fl uid (CSF) and thus are valuable in the treatment of
meningitis caused by such organisms as meningococci, pneumococci, H. infl uenzae,
and enteric gram-negative bacilli.
 (1) treat sepsis of unknown origin in immunosuppressed patients and to treat fever in
neutropenic immunosuppressed patients (given in combination with an aminoglycoside).
 (2) useful in infections caused by many organisms resistant to older cephalosporins.
 (3) administered as empiric therapy for life-threatening infection in which resistant
organisms .
 (4) Initial therapy of mixed bacterial infections (e.g., sepsis) commonly involves third
generation cephalosporins.

. The fourth-generation agent, cefepime
 d. treatment of urinary tract infections, uncomplicated skin and skin
structure infections, pneumonia, and empiric use in febrile
neutropenic patients.
 Cefepime has a spectrum of activity similar to third-generation
agents but is more resistant to some -lactamases.
 Ceftaroline is approved only for the treatment of community-
acquired bacterial pneumonia and acute bacterial skin and skin
structure infections caused by susceptible isolates.

4. Precautions and monitoring eff ects
 a. Because all cephalosporins (except cefoperazone) are eliminated renally, doses must be adjusted for
patients with renal impairment.
 b. Cross-sensitivity with penicillin has been reported in up to 10% of patients receiving cephalosporins.
More recent information indicates that true cross-reactivity is rare.
 c. Cephalosporins can cause hypersensitivity reactions similar to those resulting from penicillin (see II.F.1.e.
[1]). Manifestations include fever, maculopapular rash, anaphylaxis, and hemolytic anemia.
 d. Other adverse eff ects include nausea, vomiting, diarrhea, superinfection, nephrotoxicity, and
Clostridium diffi cile–induced colitis; with cefoperazone, cefmetazole, and cefotetan, bleeding diatheses
may occur. Bleeding can be reversed by vitamin K administration.
 e. Cephalosporins may cause false-positive glycosuria results on tests using the copper-reduction method.
 f. Ceft riaxone now contraindicated in newborns receiving concurrent administration of
calciumcontaining solutions or products due to risk of fatal precipitation in lungs and kidneys. New
warning added also stating that ceft riaxone and IV calcium-containing solutions should not be
administered within 48 hrs of each other

5. Signifi cant interactions
 a. Probenecid may impair the excretion of cephalosporins (except ceftazidime), causing increased
cephalosporin levels and possible toxicity.
 b. Alcohol consumption may result in a disulfiram-type reaction in patients receiving cefmetazole,
cefotetan, and cefoperazone. ( si tetan naa sa metazole kay nay pera
 c. Plasma concentrations of cefaclor extended-release tablets, cefdinir, and cefpodoxime may be
reduced by coadministration with antacids.
 d. H2-antagonists may reduce plasma levels of cefpodoxime and cefuroxime.
 e. Iron supplements and iron-fortified foods reduce absorption of cefdinir by 80% and 30%, respectively.

E. Erythromycins.
 Th e chemical structure of these macrolide antibiotics is characterized by a lactone ring to which sugars
are attached. Erythromycin base and the estolate, ethylsuccinate, and stearate salts are given orally;
erythromycin lactobionate and gluceptate are given parenterally.
 1. Mechanism of action. Erythromycins may be bactericidal or bacteriostatic; they bind to the 50S
ribosomal subunit, inhibiting bacterial protein synthesis.
 2. Spectrum of activity. Erythromycins are active against many gram-positive organisms, including
streptococci (e.g., Streptococcus pneumoniae), and Corynebacterium and Neisseria species as well as
some strains of Mycoplasma, Legionella, Treponema, and Bordetella. Some Staphylococcus aureus
strains that resist penicillin G are susceptible to erythromycins.

3. Th erapeutic usesof Erythromycins
 A. are the preferred drugs for the treatment of Mycoplasma pneumoniae and Campylobacter infections, Legionnaires
disease, chlamydial infections, diphtheria, and pertussis.
 B. In patients with penicillin allergy, erythromycins are important alternatives in the treatment of pneumococcal
pneumonia, S. aureus infections, syphilis, and gonorrhea.
 c. Erythromycins may be given prophylactically before dental procedures to prevent bacterial endocarditis.
 4. Precautions and monitoring parameters
 a. Gastrointestinal (GI) distress (e.g., nausea, vomiting, diarrhea, epigastric discomfort) may occur with all erythromycin
forms and are the most common adverse eff ects.
 b. Allergic reactions (rare) may present as skin eruptions, fever, and eosinophilia.
 c. Cholestatic hepatitis may arise in patients treated for 1 week or longer with erythromycin estolate; symptoms usually
disappear within a few days aft er drug therapy ends. Th ere have been infrequent reports of hepatotoxicity with other
salts of erythromycin.
 d. IM injections of more than 100 mg produce severe pain persisting for hours. e. Transient hearing impairment may
develop with high-dose erythromycin therapy.

5. Signifi cant interactions of Erythromycin
 A. inhibits the hepatic metabolism of theophylline, causes toxic accumulation.
 b. Erythromycin interferes with the metabolism of digoxin, corticosteroids, carbamazepine, cyclosporin,
and lovastatin, possibly potentiating the eff ect and toxicity of these drugs.
 c. Clarithromycin (Biaxin) may potentiate oral anticoagulants (monitor prothrombin time), increase
cyclosporine levels with increased toxicity, and increase digoxin and theophylline levels.
 d. Coadministration of clarithromycin and cisapride may increase risk of serious cardiac arrhythmias;
coadministration is contraindicated.
 e. Sudden deaths have been reported when clarithromycin was added to ongoing pimozide therapy;
coadministration is contraindicated.

6. Alternatives to erythromycin
 a. Clarithromycin and azithromycin (Zithromax) are semisynthetic macrolide antibiotics. Th ese expensive but well-tolerated
alternatives to erythromycin are administered once daily.
 (1) Clarithromycin
 (a) Spectrum of activity. Clarithromycin is more active than erythromycin against staphylococci and streptococci. In addition to
activity against other organisms c overed by erythromycin, it is also active in vitro against MAI, Toxoplasma gondii, and
Cryptosporidium spp.
 (b) Therapeutic uses.
 indicated for the prevention of Mycobacterium avium complex (MAC) infection and is useful in otitis media, sinusitis, mycoplasmal
pneumonia, and pharyngitis.
 Clarithromycin is also used with proton pump inhibitors (PPIs) for Helicobacter pylori eradication.
 2) Azithromycin
 (a) Spectrum of activity. Azithromycin is less active than erythromycin against grampositive cocci but more active against H. infl
uenzae and other gram-negative o rganisms. Azithromycin concentrates within cells, and tissue levels are higher than serum levels.
 (b) Th erapeutic uses. Th is agent is useful in nongonococcal urethritis caused by chlamydia, lower respiratory tract infections,
Mycobacterium avium-intracellulare (MAC or MAI) infection and prophylaxis, pharyngitis, pelvic infl ammatory disease, and
Legionnaires disease. Azithromycin is also indicated for pediatric use.

F. Penicillins
 1. Natural penicillins. As with cephalosporins and all other penicillins, natural penicillins are
 -lactam antibiotics. Among the most important antibiotics, natural penicillins are the
preferred drugs in the treatment of many infectious diseases.
 a. Available agents (1) Penicillin G sodium and potassium salts can be administered orally,
intravenously, or intramuscularly.
 (2) Penicillin V (Pen-Vee K), a soluble drug form, is administered orally.
 (3) Penicillin G procaine and penicillin G benzathine are repository drug forms.
Administered intramuscularly, these insoluble salts allow slow drug absorption from the
injection site and thus have a longer duration of action (12 to 24 hrs).
 b. Mechanism of action. Penicillins are bactericidal; they inhibit bacterial cell wall
synthesis in a manner similar to that of the cephalosporins.

c. Spectrum of activity
 (1) Natural penicillins are highly active against gram-positive cocci and against some
gramnegative cocci.
 (2) Penicillin G is 5 to 10 times more active than penicillin V against gram-negative
organisms and some anaerobic organisms.
 (3) Because natural penicillins are readily hydrolyzed by penicillinases (-lactamases), they
are ineff ective against S. aureus and other organisms that resist penicillin.

d. Th erapeutic uses (1) Penicillin G
 infections caused by penicillin-susceptible S. pneumoniae organisms, including (
 a) Pneumonia (b) Arthritis (c) Meningitis (d) Peritonitis (e) Pericarditis (f) Osteomyelitis (g) Mastoiditis
 (2) Penicillins G and V -against other streptococcal infections, such as pharyngitis, otitis media, sinusitis, and
bacteremia.
 (3) Penicillin G is the preferred agent in gonococcal infections, syphilis, anthrax, actinomycosis, gas gangrene, and
Listeria infections.
 (4) Administered when an oral penicillin is needed, penicillin V is most useful in skin, soft tissue, and mild respiratory
infections.
 (5) Penicillin G procaine is eff ective against syphilis and uncomplicated gonorrhea.
 (6) Used to treat syphilis infections outside the CNS, penicillin G benzathine also is eff ective against group A -
hemolytic streptococcal infections.
 (7) Penicillins G and V may be used prophylactically to prevent streptococcal infection, rheumatic fever, and
neonatal gonorrheal ophthalmia. Patients with valvular heart disease may receive these drugs preoperatively.
 (8) Th ere is emerging resistance to penicillin G by S. pneumoniae in some areas of the United States. Th e
alternative therapy is vancomycin

e. Precautions and monitoring eff ects
 (1) Hypersensitivity reactions. Th ese occur in up to 10% of patients receiving penicillin. Manifestations range
from mild rash to anaphylaxis.
 (a) Th e rash may be urticarial, vesicular, bullous, scarlatiniform, or maculopapular. Rarely, thrombopenic
purpura develops.
 (b) Anaphylaxis is a life-threatening reaction that most commonly occurs with parenteral administration.
 Signs and symptoms include severe hypotension, bronchoconstriction, nausea, vomiting, abdominal pain,
and extreme weakness. (
 c) Other manifestations of hypersensitivity reactions include fever, eosinophilia, angioedema, and serum
sickness.
 (d) Before penicillin therapy begins, the patient’s history should be evaluated for reactions to penicillin. A
positive history places the patient at heightened risk for a subsequent reaction. In most cases, such patients
should receive a substitute antibiotic. (However, hypersensitivity reactions may occur even in patients with a
negative h istory.)
 (2) Other adverse eff ects of natural penicillins include GI distress (e.g., nausea, diarrhea), bone marrow
suppression (e.g., impaired platelet aggregation, agranulocytosis), and superinfection. With high-dose
therapy, seizures may occur, particularly in patients with renal impairment.

f. Significant interactions
 (1) Probenecid increases blood levels of natural penicillins and may be given concurrently
for this purpose.
 (2) Antibiotic antagonism occurs when erythromycins, tetracyclines, or chloramphenicol is
given within 1 hr of the administration of penicillin. Th e clinical signifi cance of such
antagonism is not clear.
 (3) With penicillin G procaine and benzathine, precaution must be used in patients with a
history of hypersensitivity reactions to penicillins because prolonged reactions may o ccur.
Intravascular injection should be avoided. Procaine hypersensitivity is a contraindication to
the use of procaine penicillin G.
 (4) Parenteral products contain either potassium (1.7 mEq/million units) or sodium (2 mEq/
million units).

2. Penicillinase-resistant penicillins.
 Th ese penicillins are not hydrolyzed by staphylococcal penicillinases (-lactamases).
 Th ese agents include methicillin, nafcillin, and the isoxazolyl penicillins—dicloxacillin
(Dynapen) and oxacillin.
 a. Mechanism of action (see II.F.1.b)
 b. Spectrum of activity. Because these penicillins resist penicillinases, they are active
against staphylococci that produce these enzymes.

c. Therapeutic uses
 (1) Penicillinase-resistant penicillins are used solely in staphylococcal infections resulting
from organisms that resist natural penicillins.
 (2) Th ese agents are less potent than natural penicillins against organisms susceptible to
natural penicillins and thus make poor substitutes in the treatment of infections caused by
these organisms.
 3) Nafcillin is excreted by the liver and thus may be useful in treating staphylococcal
infections in patients with renal impairment.
 (4) Oxacillin and dicloxacillin are most valuable in long-term therapy of serious
staphylococcal infections (e.g., endocarditis, osteomyelitis) and in the treatment of minor
staphylococcal infections of the skin and soft tissues.

d. Precautions and monitoring eff ects
 (1) As with all penicillins, the penicillinase-resistant group can cause hypersensitivity
reactions (see II.F.1.e.[1]).
 (2) Methicillin may cause nephrotoxicity and interstitial nephritis.
 (3) Oxacillin may be hepatotoxic.
 (4) Complete cross-resistance exists among the penicillinase-resistant penicillins.

e. Signifi cant interactions.
 Probenecid increases blood levels of these penicillins and may be
given concurrently for that purpose.

3. Aminopenicillins.
 Th is penicillin group includes the semisynthetic agents ampicillin and amoxicillin (Amoxil).
 Because of their wider antibacterial spectrum, these drugs are also known as broad-spectrum penicillins.
 b. Spectrum of activity. Aminopenicillins have a spectrum that is similar to but broader than that of the
natural and penicillinase-resistant penicillins. Easily destroyed by staphylococcal penicillinases,
aminopenicillins are ineff ective against most staphylococcal organisms. Against most bacteria sensitive
to penicillin G, aminopenicillins are slightly less eff ective than this agent.
 c. Th erapeutic uses. Aminopenicillins are used to treat gonococcal infections, upper respiratory
infections, uncomplicated urinary tract infections, and otitis media caused by susceptible organisms.
 (1) For infections resulting from penicillin-resistant organisms, ampicillin may be given in combination with
sulbactam (Unasyn).
 (2) Amoxicillin is less eff ective than ampicillin against shigellosis.
 (3) Amoxicillin is more eff ective against S. aureus, Klebsiella, and Bacteroides fragilis infections when
administered in combination with clavulanic acid—amoxicillin/potassium clavulanate (Augmentin)
because clavulanic acid inactivates penicillinases.

 (1) Hypersensitivity reactions may occur (see II.F.1.e.[1]). (
 2) Diarrhea is most common with ampicillin.
 (3) In addition to the urticarial hypersensitivity rash seen with all penicillins, ampicillin and
amoxicillin frequently cause a generalized erythematous, maculopapular rash. (Th is
occurs in 5% to 10% of patients receiving ampicillin.)

4. Extended-spectrum penicillins.
 Th ese agents have the widest antibacterial spectrum of all penicillins. Also called antipseudomonal penicillins, this group
includes the carboxypenicillin (e.g., ticarcillin) and the ureidopenicillin (e.g., piperacillin).
 b. Spectrum of activity. Th ese drugs have a spectrum similar to that of the aminopenicillins but also are eff ective against
Klebsiella and Enterobacter spp., some B. fragilis organisms, and indole-positive Proteus and Pseudomonas organisms.
 (1) Ticarcillin is active against P. aeruginosa. Combined with clavulanic acid (Timentin), ticarcillin has enhanced activity against
organisms that resist ticarcillin alone.
 (2) Piperacillin is more active than ticarcillin against Pseudomonas organisms.
 (3) Piperacillin and tazobactam (Zosyn). Tazobactam is a -lactamase inhibitor that expands the spectrum of activity to include
some organisms not sensitive to piperacillin alone (if resistance is the result of -lactamase production), including strains of
staphylococci, Haemophilus, Bacteroides, and Enterobacteriaceae. Generally, tazobactam does not enhance activity against
Pseudomonas.
 c. Th erapeutic uses. Extended-spectrum penicillins are used mainly to treat serious infections caused by gram-negative
organisms (e.g., sepsis; pneumonia; infections of the abdomen, bone, and soft tissues). Piperacillin/tazobactam is eff ective in
the treatment of nosocomial pneumonia.
 d. Precautions and monitoring eff ects (1) Hypersensitivity reactions may occur (see II.F.1.e.[1]). (2) Ticarcillin may cause
hypokalemia. (3) Th e high sodium content of ticarcillin may pose a danger to patients with heart failure (HF). (4) All inhibit
platelet aggregation, which may result in bleeding. e. Signifi cant interactions (see II.F.2.e)

G. Sulfonamides.
 Derivatives of sulfanilamide, these agents were the fi rst drugs to prevent and cure human
bacterial infection successfully. Although their current usefulness is limited by the introduction of
more eff ective antibiotics and the emergence of resistant bacterial strains, sulfonamides remain
the drugs of choice for certain infections. Th e major sulfonamides are sulfadiazine,
sulfamethoxazole, sulfisoxazole, and sulfamethizole.
 1. Mechanism of action. Sulfonamides are bacteriostatic; they suppress bacterial growth by
triggering a mechanism that blocks folic acid synthesis, thereby forcing bacteria to synthesize
their own folic acid.
 2. Spectrum of activity. Sulfonamides are broad-spectrum agents with activity against many
gram-positive organisms (e.g., S. pyogenes, S. pneumoniae) and certain gram-negative
organisms (e.g., H. infl uenzae, E. coli, P. mirabilis). Th ey also are eff ective against certain strains
of Chlamydia trachomatis, Nocardia, Actinomyces, and Bacillus anthracis.

 3. Th erapeutic uses
 a. Sulfonamides most oft en are used to treat urinary tract infections caused by E. coli, including acute and
chronic cystitis and chronic upper urinary tract infections.
 b. Th ese agents have value in the treatment of nocardiosis, trachoma and inclusion conjunctivitis, and
dermatitis herpetiformis.
 c. Sulfadiazine may be administered in combination with pyrimethamine to treat toxoplasmosis.
 d. Sulfamethoxazole may be given in combination with trimethoprim (Bactrim) ( COTRIMOXAZOLE )to treat such
infections as Pneumocystis carinii pneumonia, Shigella enteritis, Serratia sepsis, urinary tract infections, respiratory
infections, and gonococcal urethritis. It is the drug of choice in the treatment of Stenotrophomonas maltophilia.
 e. Sulfi soxazole is sometimes used in combination with erythromycin ethylsuccinate to treat acute otitis media
caused by H. infl uenzae organisms. For the initial treatment of uncomplicated urinary tract infections, sulfi
soxazole may be given in combination with phenazopyridine for relief of symptoms of pain, burning, or urgency.
 f. Prophylactic sulfonamide therapy has been used successfully to prevent streptococcal infections and
rheumatic fever recurrences.


4. Sulfonamides Precautions and
monitoring effects
 a. Sulfonamides may cause blood dyscrasias (e.g., hemolytic anemia—particularly in patients with
G6PD defi ciency, aplastic anemia, thrombocytopenia, agranulocytosis, and eosinophilia).
 b. Hypersensitivity reactions to sulfonamides probably result from sensitization and most commonly
involve the skin and mucous membranes. Manifestations include various types of skin rash,
exfoliative dermatitis, and photosensitivity. Drug fever and serum sickness also may develop.
 c. Crystalluria and hematuria may occur, possibly leading to urinary tract obstruction. (A dequate fl
uid intake and urine alkalinization can prevent or minimize this risk.) Sulfonamides should be used
cautiously in patients with renal impairment.
 d. Life-threatening hepatitis caused by drug toxicity or sensitization is a rare adverse eff ect. Signs
and symptoms include headache, nausea, vomiting, and jaundice.
 e. AIDS patients have increased frequency of cutaneous hypersensitivity reactions to
sulfamethoxazole.
 5. Significant interactions. Sulfonamides may potentiate the effects of phenytoin, oral
anticoagulants, and sulfonylureas

H. Tetracyclines.
 These broad-spectrum agents are eff ective against certain bacterial strains that resist other
antibiotics. Nonetheless, they are the preferred drugs in only a few situations. Th e major
tetracyclines include demeclocycline (Declomycin), doxycycline (Vibramycin), minocycline
(Minocin), and oxytetracycline (Terramycin).
 1. Mechanism of action. Tetracyclines are bacteriostatic; they inhibit bacterial protein synthesis by
binding to the 30S ribosomal subunit.
 2. Spectrum of activity. Tetracyclines are active against gram-negative and gram-positive
organisms, spirochetes, Mycoplasma and Chlamydia organisms, rickettsial species, and certain p
rotozoa.
 a. Pseudomonas and Proteus organisms are now resistant to tetracyclines. Many coliform bacteria,
pneumococci, staphylococci, streptococci, and Shigella strains are increasingly resistant.
 b. Cross-resistance within the tetracycline group is extensive.

3. Tetracyclines Therapeutic uses
 a. Tetracyclines are the agents of choice in rickettsial (Rocky Mountain spotted fever),
chlamydial, and mycoplasmal infections; amebiasis; and bacillary infections (e.g.,
cholera, brucellosis, tularemia, some Salmonella and Shigella infections).
 b. Tetracyclines are useful alternatives to penicillin in the treatment of anthrax, syphilis,
gonorrhea, Lyme disease, nocardiosis, and H. infl uenzae respiratory infections.
 c. Oral or topical tetracycline may be administered as a treatment for acne.
 d. Doxycycline is highly eff ective in the prophylaxis of “traveler’s diarrhea” (commonly
caused by E. coli).
 Because the drug is excreted mainly in the feces, it is the safest tetracycline for the
treatment of extrarenal infections in patients with renal impairment.
 e. Demeclocycline is used commonly as an adjunctive agent to treat the syndrome of
inappropriate antidiuretic hormone (SIADH) secretion.

4. Tetracyclines Precautions and
monitoring effects
 a. GI distress (e.g., diarrhea, abdominal discomfort, nausea, anorexia) is a common adverse eff ect of tetracyclines. Th is
problem can be minimized by administering the drug with food or temporarily decreasing the dosage.
 b. Skin rash, urticaria, and generalized exfoliative dermatitis signify a hypersensitivity reaction. Rarely, angioedema and
anaphylaxis occur.
 c. Cross-sensitivity within the tetracycline group is common.
 d. Phototoxic reactions (severe skin lesions) can develop with exposure to sunlight. Th is reaction is most common with
demeclocycline and doxycycline.
 e. Tetracyclines may cause hepatotoxicity, particularly in pregnant women. Manifestations include jaundice, acidosis, and
fatty liver infi ltration.
 f. Renally impaired patients may experience a signifi cant increase in BUN secondary to catabolic eff ects of tetracyclines.
 g. Tetracyclines may induce permanent tooth discoloration, tooth enamel defects, and retarded bone growth in infants
and children.
 h. Use of outdated and degraded tetracyclines can lead to renal tubular dysfunction, possibly resulting in renal failure.
 i. Minocycline can cause vestibular toxicity (e.g., ataxia, dizziness, nausea, vomiting). j. IV tetracyclines are irritating and
may cause phlebitis.

5. Tetracyclines Significant interactions
 a. Dairy products and other foods, iron preparations, and antacids and laxatives
containing aluminum, calcium, or magnesium can cause reduced tetracycline
absorption. Absorption of doxycycline is not inhibited by these factors.
 b. Methoxyfl urane may exacerbate the tetracyclines’ nephrotoxic eff ects.
 c. Barbiturates and phenytoin decrease the antibiotic eff ectiveness of
tetracyclines.
 d. Demeclocycline antagonizes the action of antidiuretic hormone (ADH) and
may be given as a diuretic in patients with SIADH.

I. Fluoroquinolones
 I. Fluoroquinolones - related to nalidixic
 include ciprofloxacin (Cipro), norfl oxacin (Noroxin), ofl oxacin (Floxin), moxifl oxacin (Avelox), levofl
oxacin (Levaquin), and gemifl oxacin (Factive). Th ey are bactericidal for growing bacteria.
 1. Mechanism of action. Fluoroquinolones inhibit DNA gyrase.
 2. Spectrum of activity. Fluoroquinolones are highly active against enteric gram-negative bacilli,
Salmonella, Shigella, Campylobacter, Haemophilus, and Neisseria.
 a. Ciprofloxacin has activity against P. aeruginosa, but the fluoroquinolones as a group have variable
activity against non–P. aeruginosa. Ciprofl oxacin is active against some anaerobes; it has moderate
activity against M. tuberculosis.
 b. Gram-positive organisms are less susceptible than gram-negative organisms but usually are
sensitive, except for Enterococcus faecalis and methicillin-resistant staphylococci.
 c. Ofloxacin has the greatest activity against Chlamydia.

3. Therapeutic uses of fluoroquinolones
 a. Norfloxacin is indicated for the oral treatment of urinary tract infections, uncomplicated
gonococcal infections, and prostatitis.
 b. Ciprofl oxacin, ofl oxacin, and levofl oxacin are available orally and intravenously. Ciprofl oxacin
is approved for use in urinary tract infections; lower respiratory infections; sinusitis; bone, joint, and skin
structure infections; empiric use in febrile neutropenic patients; typhoid fever; urethral and cervical
gonococcal infections; and infectious diarrhea. Ofl oxacin is approved for use in lower respiratory
infections, uncomplicated gonococcal and chlamydial cervicitis and urethritis, skin and skin structure
infections, prostatitis, and urinary tract infections.
 c. Levofl oxacin is approved for the treatment of urinary tract infections. Gemifl oxacin, moxifl
oxacin, and levofl oxacin are also used in lower respiratory tract infections. Gemifl oxacin is only
available orally.
 d. Moxifl oxacin is approved for the treatment of complicated intra-abdominal infections but should
not be used for urinary tract infections.

3. Therapeutic uses Fluoroqinolones
 a. Norfl oxacin is indicated for the oral treatment of urinary tract infections, uncomplicated gonococcal
infections, and prostatitis.
 b. Ciprofloxacin, ofloxacin, and levofloxacin are available orally and intravenously. Ciprofloxacin is
approved for use in urinary tract infections; lower respiratory infections; sinusitis; bone, joint, and skin
structure infections; empiric use in febrile neutropenic patients; typhoid fever; urethral and cervical
gonococcal infections; and infectious diarrhea. Ofloxacin is approved for use in lower respiratory
infections, uncomplicated gonococcal and chlamydial cervicitis and urethritis, skin and skin structure
infections, prostatitis, and urinary tract infections.
 c. Levofloxacin is approved for the treatment of urinary tract infections.
 Gemifloxacin, moxifloxacin, and levofloxacin are also used in lower respiratory tract infections.
 Gemifloxacin is only available orally.
 d. Moxifloxacin is approved for the treatment of complicated intra-abdominal infections but should not
be used for urinary tract infections.

4. FQs Precautions and monitoring effects
 a. Occasional adverse eff ects include nausea, dyspepsia, headache,
dizziness, insomnia, cardiac QT prolongation, arthropathy, tendonitis, CNS
eff ects, photosensitivity, and hypoglycemia.
 b. Infrequent adverse eff ects include rash, urticaria, leukopenia, and
elevated liver enzymes. Crystalluria occurs with high doses at alkaline pH.
c. Th e FDA has added a black box warning about the increased risk of
developing tendinitis and tendon rupture in patients taking this class of
medications.

5. FQs Significant interactions
 a. Ciprofl oxacin has been shown to increase theophylline levels. Variable eff ects on theophylline
levels have been reported from other members of the group. In patients requiring fl uoroquinolones,
theophylline levels should be monitored.
 b. Antacids and sucralfate and divalent or trivalent cations such as iron decrease the absorption of fl
uoroquinolones.
 c. Fluoroquinolones may increase prothrombin times in patients receiving warfarin.
 d. Concurrent use with nonsteroidal anti-infl ammatory drugs (NSAIDs) may increase the risk of CNS
stimulation (seizures).
 e. Fluoroquinolones may produce prolonged QT interval when administered with antiarrhythmic
agents. Some fl uoroquinolones (i.e., gemifl oxacin, moxifl oxacin) should be avoided in patients with
known prolongation of the QTC interval, with uncorrected hypocalcemia, or who are receiving class
IA or class III antiarrhythmic drugs.
 f. Some fl uoroquinolones have been reported to enhance the eff ects of oral anticoagulants.
 g. Hyperglycemia and hypoglycemia have been reported in patients receiving quinolones and an
antidiabetic agent. Blood glucose monitoring is recommended in such patients.

J. Urinary tract antiseptics.
 Concentrating in the renal tubules and bladder, these agents exert local antibacterial eff ects; most do not
achieve blood levels high enough to treat systemic infections. However, some new quinolone derivatives, such as
ciprofl oxacin and ofl oxacin, are valuable in the treatment of certain infections outside the urinary tract (see
II.I.3.b).
 1. Mechanism of action
 a. Methenamine is hydrolyzed to ammonia and formaldehyde in acidic urine; formaldehyde is antibacterial
against gram-positive and gram-negative organisms. Mandelic and hippuric acids, with which methenamine is
combined, provide supplementary antibacterial action.
 b. Nitrofurantoin is bacteriostatic; in high concentrations, it may be bactericidal. Presumably, it disrupts bacterial
enzyme systems.
 c. Quinolones. Nalidixic acid and its analogs and derivatives—oxolinic acid, norfl oxacin, cinoxacin, ciprofl oxacin,
and others—interfere with DNA gyrase and inhibit DNA synthesis during bacterial replication.
 d. Fosfomycin tromethamine is bactericidal in the urine at therapeutic doses. Th e bactericidal action is because
of its inactivation of the enzyme enolpyruvyl transferase, thereby blocking the condensation of uridine
diphosphate-N-acetylglucosamine with p-enolpyruvate, one of the fi rst steps in bacterial cell wall synthesis

2. Methenamine Spectrum of activity
 a. Methenamine is active against both gram-positive and gram-negative organisms (e.g.,
Enterobacter, Klebsiella, Proteus, P. aeruginosa, S. aureus).
 b. Nitrofurantoin is active against many gram-positive and gram-negative organisms, including
some strains of E. coli, S. aureus, Proteus, Enterobacter, and Klebsiella.
 c. Quinolones (see II.I.2) (1) Nalidixic acid and oxolinic acid are active against most gram-
negative organisms that cause urinary tract infections, including P. mirabilis, E. coli, Klebsiella,
and Enterobacter organisms. Th ese drugs are not eff ective against Pseudomonas organisms. (2)
Norfl oxacin is active against E. coli, Enterobacter, Klebsiella, Proteus, P. aeruginosa, S. aureus,
Citrobacter, and some Streptococcus organisms.
 (3) Cinoxacin is active against E. coli, Klebsiella, P. mirabilis, Proteus vulgaris, Proteus m organii,
Serratia, and Citrobacter organisms.

3. Methenamine Therapeutic uses
 a. Methenamine and nitrofurantoin are used to prevent and treat
urinary tract infections.
 b. Quinolones are administered to treat urinary tract infections;
some also are used in such diseases as osteomyelitis and respiratory
tract infections.
 c. Fosfomycin is indicated for treatment of uncomplicated urinary
tract infection (acute cystitis) in women caused by susceptible
strains of E. coli or E. faecalis.

4. Methenamine Precautions and
monitoring effects
 a. Methenamine may cause nausea, vomiting, and diarrhea; in high doses, it may lead to
urinary tract irritation (e.g., dysuria, frequency, hematuria, albuminuria). Skin rash also may
develop.
 b. Nitrofurantoin may cause various adverse eff ects.
 (1) GI distress (e.g., nausea, vomiting, diarrhea) is relatively common. (
 2) Hypersensitivity reactions to nitrofurantoin may involve the skin, lungs, blood, or liver;
manifestations include fever, chills, hepatitis, jaundice, leukopenia, hemolytic anemia,
granulocytopenia, and pneumonitis.
 (3) Adverse CNS eff ects include headache, vertigo, and dizziness. Polyneuropathy may
develop with high doses or in patients with renal impairment.

 c. Quinolones
 (1) Nalidixic acid and oxolinic acid may cause nausea; vomiting; abdominal
pain; urticaria; pruritus; skin rash; fever; eosinophilia; and CNS eff ects such as
headache, dizziness, confusion, vertigo, drowsiness, and weakness.
 (2) Cinoxacin may induce nausea, vomiting, diarrhea, headache, insomnia, skin
rash, pruritus, and urticaria.

5. Methenamine Significant interactions
 a. Th e eff ects of methenamine are inhibited by alkalinizing agents
and are antagonized by acetazolamide.
 b. Nitrofurantoin absorption is decreased by magnesium-
containing antacids. Nitrofurantoin blood levels are increased and
urine levels decreased by sulfi npyrazone and probenecid, leading
to increased toxicity and reduced therapeutic eff ectiveness.
 c. Quinolones (1) Cinoxacin urine levels are decreased by
probenecid, reducing therapeutic eff ectiveness. (2) Norfl oxacin is
rendered less eff ective by antacids.

K. Miscellaneous antibacterial agents
 1. Aztreonam (Azactam). Th is agent was the fi rst commercially available monobactam
(monocyclic -lactam compound).
 It resembles the aminoglycosides in its effi against many gramnegative organisms but does
not cause nephrotoxicity or ototoxicity.
 Other advantages of this drug include its ability to preserve the body’s normal gram-positive
and anaerobic fl ora, activity against many gentamicin-resistant organisms, and lack of
cross-allergenicity with penicillin.
 a. Mechanism of action. Aztreonam is bactericidal; it inhibits bacterial cell wall synthesis.
 b. Spectrum of activity. Th is drug is active against many gram-negative organisms,
including Enterobacter and some strains of P. aeruginosa. c. Th erapeutic uses. Aztreonam is
therapeutic for urinary tract infections, septicemia, skin infections, lower respiratory tract
infections, and intra-abdominal infections resulting from gram-negative organisms. Increased
incidence of P. aeruginosa resistant to aztreonam has been reported. d. Precautions and
monitoring eff ects (1) Aztreonam sometimes causes nausea, vomiting, and diarrhea. (2)
Liver enzymes may increase transiently during aztreonam therapy. (3) Th is drug may induce
skin rash.

2. Chloramphenicol.
 A nitrobenzene derivative, this drug has broad activity against rickettsia as well as many gram-positive and gram-
negative organisms.
 It also is eff ective against many ampicillin-resistant strains of H. infl uenzae. a. Mechanism of action.
 Chloramphenicol is primarily bacteriostatic, although it may be bactericidal against a few bacterial strains.
 b. Spectrum of activity. Th is agent is active against rickettsia and a wide range of bacteria, including H. infl uenzae,
Salmonella typhi, Neisseria meningitidis, Bordetella pertussis, Clostridium, B. fragilis, S. pyogenes, and S. pneumoniae.
 c. Th erapeutic uses. Because of its toxic side eff ects, chloramphenicol is used only to suppress infections that cannot
be treated eff ectively with other antibiotics. Such infections typically include
 (1) Typhoid fever
 (2) Meningococcal infections in cephalosporin-allergic patients
 (3) Serious H. infl uenzae infections, particularly in cephalosporin-allergic patients
 (4) Anaerobic infections (e.g., those originating in the pelvis or intestines)
 (5) Anaerobic or mixed infections of the CNS
 (6) Rickettsial infections in pregnant patients, tetracycline-allergic patients, and renally i mpaired patients

d. Chloramphenicol Precautions and
monitoring effects
 (1) Chloramphenicol can cause bone marrow suppression (dose-related) with resulting pancytopenia;
rarely, the drug leads to aplastic anemia (not related to dose).
 (2) Hypersensitivity reactions may include skin rash and, in extremely rare cases, angioe dema or
anaphylaxis.
 (3) Chloramphenicol therapy may lead to gray baby syndrome in neonates (especially p remature
infants).
 Th is dangerous reaction, which stems partly from inadequate liver detoxifi cation of the drug, is
manifested by vomiting, gray cyanosis, rapid and irregular respirations, vasomotor collapse, and in
some cases death

. e. Chlormaphenicol Significant
interactions
 (1) Chloramphenicol inhibits the metabolism of phenytoin, tolbutamide,
chlorpropamide, and dicumarol, leading to prolonged action and
intensified eff ect of these drugs.
 (2) Phenobarbital shortens chloramphenicol’s half-life, thereby
reducing its therapeutic eff ectiveness.
 (3) Penicillins can cause antibiotic antagonism.
 (4) Acetaminophen elevates chloramphenicol levels and may cause
toxicity

3. Clindamycin (Cleocin).
 Th is agent has essentially replaced lincomycin, the drug from which it is derived. It is used to treat skin,
respiratory tract, and soft tissue infections caused by staphylococci, pneumococci, and streptococci.
a. Mechanism of action.
 Clindamycin is bacteriostatic;
 it binds to the 50S ribosomal subunit, thereby suppressing bacterial protein synthesis. b. Spectrum of
activity. Th is agent is active against most gram-positive and many anaerobic organisms, including B.
fragilis.
 c. Th erapeutic uses. Because of its marked toxicity, clindamycin is used only against infections for
which it has proven to be the most eff ective drug. Typically, such infections include abdominal and
female genitourinary tract infections caused by B. fragilis.
 d. Precautions and monitoring eff ects (1) Clindamycin may cause rash, nausea, vomiting, diarrhea,
and pseudomembranous colitis as evidenced by fever, abdominal pain, and bloody stools. (2) Blood
dyscrasias (e.g., eosinophilia, thrombocytopenia, leukopenia) may occur. e. Signifi cant interactions.
Clindamycin may potentiate the eff ects of neuromuscular blocking agents.

4. Dapsone.
 A member of the sulfone class, this drug is the primary agent in the treatment of all forms of leprosy.
 a. Mechanism of action. Dapsone is bacteriostatic for Mycobacterium leprae; its mechanism of action probably resembles
that of the sulfonamides.
 b. Spectrum of activity. Th is drug is active against M. leprae; however, drug resistance develops in up to 40% of patients.
 Dapsone also has some activity against P. carinii organisms and the malarial parasite Plasmodium.
 c. Therapeutic uses (1) Dapsone is the drug of choice for treating leprosy. (2) Th is agent may be used to treat dermatitis
herpetiformis, a skin disorder. (3) Maloprim, a dapsone–pyrimethamine product, is valuable in the prophylaxis and treatment
of malaria. (4) Dapsone, with or without trimethoprim, is used for prophylaxis of P. carinii pneumonia in patients with AIDS.
 d. Precautions and monitoring eff ects (1) Hemolytic anemia can occur with daily doses 200 mg. Other adverse
hematological eff ects include methemoglobinemia and leukopenia. (2) Nausea, vomiting, and anorexia may develop. (3)
Adverse CNS eff ects include headache, dizziness, nervousness, lethargy, paresthesias, and psychosis. (4) Dapsone
occasionally results in a potentially lethal mononucleosis-like syndrome. (5) Paradoxically, this drug sometimes exacerbates
leprosy. (6) Other adverse eff ects include skin rash, peripheral neuropathy, blurred vision, tinnitus, hepatitis, and cholestatic
jaundice.
 e. Signifi cant interactions. Probenecid elevates blood levels of dapsone, possibly resulting in toxicity.

5. Clofazimine
 5. Clofazimine is phenazine dye with antimycobacterial and anti-infl ammatory activity. a. Mechanism of action.
 Clofazimine appears to bind preferentially to mycobacterial DNA, inhibiting replication and growth. It is
bactericidal against M. leprae, and it appears to be bacteriostatic against MAI.
 b. Spectrum of activity. Clofazimine is active against various mycobacteria, including M. leprae, M. tuberculosis,
and MAI.
 c. Th erapeutic uses. Clofazimine is used to treat leprosy and a variety of atypical Mycobacterium infections.
 d. Precautions and monitoring eff ects
 (1) Pigmentation (pink to brownish) occurs in 75% to 100% of patients within a few weeks. Th is skin discoloration
has led to severe depression (and suicide).
 (2) Urine, sweat, and other body fl uids may be discolored.
 (3) Other eff ects include ichthyosis and dryness of skin (8% to 28%), rash and pruritus (1% to 5%), and GI
intolerance (e.g., abdominal/epigastric pain, diarrhea, nausea, vomiting) in 40% to 50% of patients.
 Clofazimine should be taken with food.

6. Daptomycin (Cubicin)
 6. Daptomycin (Cubicin) is a unique lipopeptide antibiotic with clinical activity in the treatment of resistant
gram-positive infections.
 a. Mechanism of action. Daptomycin is bactericidal; unlike other antibiotics, it binds to the bacterial cell
membrane, causing depolarization of the membrane potential leading to inhibition of RNA, DNA, and
protein synthesis.
 b. Spectrum of activity. Th is drug is active against vancomycin-susceptible E. faecium and S. a ureus
(including methicillin-resistant strains) as well as other aerobic gram-positive bacteria.
 c. Th erapeutic uses. Daptomycin is indicated for the treatment of complicated skin and skin structure
infections and intravascular line and S. aureus bacteremia. It is not indicated for the treatment of
pneumonia.
 (1) Reported side eff ects are generally mild and self-limiting and include constipation, abnormal liver
function tests, and renal failure.
 (2) Cases of myalgia and/or muscle weakness, exacerbations of myasthenia gravis, and increases in
creatine phosphokinase (CPK) have been reported.

7. Fidaxomicin (Dificid)
 is the fi rst of a new class of antibiotics called macrocycles.
 a. Mechanism of action. Fidaxomicin is bactericidal against C. difficile in vitro, inhibiting RNA synthesis
by RNA polymerases.
 b. Spectrum of activity. Fidaxomicin eradicates C. difficile selectively with minimal disruption to normal
GI flora.
 c. Therapeutic uses. To reduce the development of drug-resistant bacteria and maintain the
effectiveness of fi daxomicin and other antibacterial drugs, fi daxomicin should be used only to treat
infections that are proven or strongly suspected to be caused by Clostridium diffi cile. Fidaxomicin is
indicated in adults ( 18 years of age) for treatment of C. diffi cile–associated diarrhea (CDAD).
 d. Precautions and monitoring eff ects. Because there is minimal systemic absorption of fi daxomicin, it
is not eff ective for treatment of systemic infections. Th e most common adverse reactions are nausea
(11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and
neutropenia (2%).

8. Linezolid (Zyvox)
 is a synthetic oxazolidinone that has clinical use in the treatment of
infections caused by aerobic gram-positive bacteria.
 a. Mechanism of action.
Linezolid is bacteriostatic against Enterococci and Staphylococci, and
bactericidal against Streptococci.
Linezolid binds to the 23S ribosomal RNA of the 50S subunit and thus inhibits
protein synthesis.

Linezolid
 b. Spectrum of activity.
 Th e drug is active against vancomycin-resistant Enterococcus faecium and S. aureus (methicillin-susceptible and -
resistant strains) as well as other aerobic grampositive bacteria.
 C. Th erapeutic uses. Linezolid is indicated for treatment of infections caused by vancomycin resistant E. faecium,
nosocomial pneumonia caused by methicillin-susceptible and -r esistant strains of S. aureus, community-acquired
pneumonia caused by penicillin- susceptible strains of S. pneumoniae, and skin and skin structure infections owing to
these organisms.
 d. Precautions and monitoring effects
 (1) Safety data are limited. Adverse eff ects generally are minor (e.g., gastrointestinal complaints, headache, rash).
 (2) Th rombocytopenia or a signifi cant reduction in platelet count has been reported (2.4%) and is related to duration of
therapy. Monitor platelets in patients with risk of bleeding, preexisting thrombocytopenia, platelet disorders (including
those caused by concurrent medications) and in patients receiving linezolid lasting longer than 2 weeks.
 (3) Myelosuppression owing to direct bone marrow suppression has been reported rarely.
 e. Signifi cant interactions. Patients receiving concomitant therapy with adrenergic or serotonergic agents or consuming
more than 100 mg of tyramine a day may experience an enhancement of the drug’s eff ect or serotonin syndrome.

9. Quinupristin/dalfopristin (Synercid)
 is an intravenous streptogramin antibiotic composed of two chemically distinct compounds.
 a. Mechanism of action. Quinupristin binds to the 50S subunit, and dalfopristin binds tightly to the 70S ribosomal particle.
 b. Spectrum of activity. Synercid has activity against Staphylococci spp., including resistant strains. Th is combination has
better activity against E. faecium than Enterococcus faecalis and is also active against some gram-negative organisms
and anaerobes; activity has not been shown against Enterobacteriaceae.
 c. Th erapeutic uses. It is used for treatment of vancomycin-resistant E. faecium (VREF) bacteremia and skin and skin
structure infections caused by S. aureus and S. pyogenes.
 (1) Reported side eff ects are generally mild and infusion related: pain, erythema, or itching at the infusion site; increases
in pulse and diastolic pressure; headache; nausea or vomiting; and diarrhea. It may increase liver function tests slightly.
 (2) Drug interactions are a result of cytochrome P450 3A4 inhibition. Potential drug interactions include cyclosporin,
nifedipine, and midazolam.
 (3) Concomitant use of medications that may prolong QTc interval should be avoided.
 (4) Mild to life-threatening pseudomembranous colitis has been reported.

10. Rifaximin.
 Is a semisynthetic antibiotic that is structurally related to rifamycin.
 a. Mechanism of action. It inhibits bacterial RNA synthesis by binding to the subunit of bacterial DNA-
dependent RNA polymerase.
 b. Spectrum of activity. Th is nonsystemically absorbed drug has activity against both enterotoxigenic
and enteroaggregative strains of Escherichia coli.
 c. Therapeutic uses. Rifaximin is used in the treatment of travelers diarrhea with noninvasive strains of E.
coli and prophylaxis of hepatic encephalopathy. High resistance rates have been reported aft er 5
days of treatment.
 d. Precautions and monitoring eff ects. Because of its limited systemic absorption, adverse eff ects are
few but include constipation, vomiting, fl atulence, and headache.

11. Spectinomycin ( Trobicin)
 An aminocyclitol agent related to the aminoglycosides, this antibiotic is useful against
penicillin-resistant strains of gonorrhea.
 a. Mechanism of action. Spectinomycin is bacteriostatic; it selectively inhibits protein synthesis
by binding to the 30S ribosomal subunit.
 b. Spectrum of activity. Th is agent is active against various gram-negative organisms.
 c. Therapeutic uses. Spectinomycin is used only to treat gonococcal infections in patients with
penicillin allergy or when such infection stems from penicillinase-producing gonococci (PPNG).
 d. Precautions and monitoring eff ects. Because spectinomycin is given only as a single-dose IM
injection, it causes few adverse eff ects. Nausea, vomiting, urticaria, chills, dizziness, and
insomnia occur rarely.

12. Telavancin (Vibativ)
 is the fi rst of a new class of antimicrobials known as the lipoglycopeptides. It is a semisynthetic
derivative of vancomycin.
 a. Mechanism of action. Telavancin is bacteriocidal; it inhibits peptidoglycan and cell wall synthesis as
well as disrupts membrane potential.
 b. Spectrum of activity. Th is drug is active against gram-positive bacteria, including MRSA and
vancomycin-susceptible Enterococcus faecalis (VREF).
 c. Th erapeutic uses. Telavancin is indicated for the treatment of complicated skin and skin structure
infections caused by susceptible gram-positive bacteria, including MRSA.
 d. Precautions and monitoring eff ects (1) Taste disturbance, nausea and vomiting, and foamy urine
were the most common side eff ects. (2) Nephrotoxicity and QT prolongation have been reported in
patients. (3) Use of telavancin should be avoided in pregnant women.

13. Telithromycin (Ketek)
 is the fi rst of a new class of antimicrobials called the ketolides. It is an oral semisynthetic derivative of erythromycin.
 a. Mechanism of action. Telithromycin may be bactericidal or bacteriostatic; it inhibits bacterial protein synthesis.
 b. Spectrum of activity. Th is drug is active against many aerobic and anaerobic gram-positive organisms, including
multidrug-resistant S. pneumoniae, some gram-negative organisms, as well as atypical pathogens.
 c. Th erapeutic uses. Telithromycin is indicated for the treatment of mild to moderate community-acquired
pneumonia only. Th e FDA removed the previous two approved indications and added a black box warning.
 d. Precautions and monitoring eff ects (1) GI eff ects (including diarrhea, nausea, and vomiting) were the most
common side eff ects followed by dizziness and visual disturbances (such as diplopia and blurred and abnormal
vision); serious liver toxicity has been reported. (2) Cross-sensitivity with the other macrolides occurs. (3)
Concomitant use of drugs or conditions that may prolong the QTc interval should be avoided. (4) Contraindicated
in patients with myasthenia gravis, hepatitis, or jaundice.
 e. Signifi cant interactions (1) Coadministration of telithromycin with either cisapride or pimozide is contraindicated.
(2) Concomitant administration of drugs metabolized by cytochrome P450 3A4 in patients with telithromycin should
be closely monitored. (3) Patients on bepridil, mesoridazine, terfenadine, thioridazine, or ziprasidone should not be
prescribed telithromycin owing to the high potential for toxicity. (4) Th is agent has a high potential to interact with
many drugs. Check product information for the most current interaction information.

14. Tigecycline (Tygacil).
 An intravenous glycylcycline antibiotic developed as a semisynthetic analogue of tetracycline with a broad
spectrum of activity.
 a. Mechanism of action. Tigecycline is bacteriostatic; it inhibits bacterial protein synthesis by reversibly binding to
the 30S ribosome subunit.
 b. Spectrum of activity. Th e drug is active against vancomycin-susceptible E. faecalis, methicillin-resistant S.
epidermidis, and S. aureus (methicillin-susceptible and -resistant strains) as well as some gram-negative aerobes
and anaerobes.
 c. Th erapeutic uses. Tigecycline is indicated for the treatment of complicated intra-abdominal infections caused
by E. coli, vancomycin-susceptible E. faecalis, S. aureus (methicillinsusceptible strains only) and B. fragilis. Also
indicated for the treatment of complicated skin and skin structure infections caused by E. faecalis (vancomycin-
susceptible strains), S. pyogenes and S. aureus (methicillin-susceptible and -resistant strains).
 d. Precautions and monitoring eff ects (1) Safety data are limited. Side eff ects are generally mild with GI
disturbances—for example, nausea (22% to 35%) and vomiting (13% to 19%)—the most commonly reported. Th e
mechanism of these reactions is uncertain. (2) May cause permanent discoloration of the teeth similar to the
tetracyclines. (3) Caution in patients with a history of hypersensitivity reactions to tetracyclines. (4) Phototoxic
reactions, pancreatitis, and increases in BUN may occur.

e. Significant interactions.
 Closely monitor the prothrombin time or international sensitivity index (INR) in patients on warfarin
during concomitant administration of tigecycline.

15. Trimethoprim.
 A substituted pyrimidine, trimethoprim is most commonly combined with s ulfamethoxazole (a sulfonamide
discussed in II.G) in a preparation called co-trimoxazole. However, it may be used alone for certain urinary tract
infections.
 a. Mechanism of action. Trimethoprim inhibits dihydrofolate reductase, thus blocking bacterial synthesis of folic acid.
 b. Spectrum of activity (1) Trimethoprim is active against most gram-negative and gram-positive organisms. H
owever, drug resistance may develop when this drug is used alone.
 (2) Trimethoprim–sulfamethoxazole is active against a variety of organisms, including Streptococcus pneumoniae,
N. meningitidis, and Corynebacterium diphtheriae; some strains of Staphylococcus aureus, Staphylococcus
epidermidis, P. mirabilis, Enterobacter, Salmonella, Shigella, Serratia, and Klebsiella spp.; and Escherichia coli.
 (3) Th e trimethoprim–sulfamethoxazole combination is synergistic; many organisms resistant to one component are
susceptible to the combination.
 c. Th erapeutic uses (1) Trimethoprim may be used alone or in combination with sulfamethoxazole to treat
uncomplicated urinary tract infections caused by Escherichia coli, P. mirabilis, and Klebsiella and Enterobacter
organisms. (2) Trimethoprim–sulfamethoxazole is therapeutic for acute gonococcal urethritis, acute exacerbation of
chronic bronchitis, shigellosis, and Salmonella infections. (3) Trimethoprim–sulfamethoxazole may be given as
prophylactic or suppressive therapy in P. carinii pneumonia. It is the drug of choice for the treatment of
Stenotrophomonas maltophilia infections.

 (1) Most adverse eff ects involve the skin (possibly from sensitization). Th ese include rash,
pruritus, and exfoliative dermatitis.
 (2) Rarely, trimethoprim–sulfamethoxazole causes blood dyscrasias (e.g., acute hemolytic
anemia, leukopenia, thrombocytopenia, methemoglobinemia, agranulocytosis, aplastic
anemia).
 (3) Adverse GI eff ects including nausea, vomiting, and epigastric distress glossitis may o
ccur.
 (4) Neonates may develop kernicterus.
 (5) Patients with AIDS sometimes suff er fever, rash, malaise, and pancytopenia during
trimethoprim therapy.

16. Vancomycin.
 This glycopeptide destroys most gram-positive organisms.
 a. Mechanism of action. Vancomycin is bactericidal; it inhibits bacterial cell wall synthesis.
 b. Spectrum of activity. Th is drug is active against most gram-positive organisms, including
methicillin-resistant strains of S. aureus and Enterococci.
 c. Th erapeutic uses. Vancomycin usually is reserved for serious infections, especially those
caused by methicillin-resistant staphylococci. It is particularly useful in patients who are allergic
to penicillin or cephalosporins. Typical uses include endocarditis, osteomyelitis, and
staphylococcal pneumonia. (1) Oral vancomycin is valuable in the treatment of antibiotic-
induced pseudomembranous colitis caused by C. diffi cile or S. aureus enterocolitis. Because
vancomycin is not a bsorbed aft er oral administration, it is not useful for systemic infections.
Because of resistance, the Centers for Disease Control and Prevention (CDC) recommend
vancomycin as the second choice to metronidazole for C. diffi cile infections. (2) Because 1 g
provides adequate blood levels for 7 to 10 days, IV vancomycin is particularly useful in the
treatment of anephric patients with gram-positive bacterial infections.

vancomycin
 d. Precautions and monitoring eff ects (1) Ototoxicity may arise; nephrotoxicity is rare but
can occur with high doses. (2) Vancomycin may cause hypersensitivity reactions,
manifested by such symptoms as anaphylaxis and skin rash. (3) Th erapeutic levels peak at
20 to 40 g/mL. Th e trough is 15 g/mL.
 (4) Red man’s syndrome may occur. Th is is facial fl ushing and hypotension owing to too
rapid infusion of the drug. Infusion should be over a minimum of 60 mins for a 1-g dose. (5)
IV solutions are very irritating to the vein. e. Vancomycin-resistant enterococci. A few
strains of vancomycin-resistant enterococci are susceptible to teicoplanin (investigational
by Hoechst Marion Roussel), linezolid (Zyvox), or quinupristin/dalfopristin (Synercid). Th ese
agents may be useful for multiple-drug–resistant E. faecium.


III. SYSTEMIC ANTIFUNGAL AGENTS
 A.Th ese agents treat systemic and local fungal (mycotic) infections—diseases that resist treatment with
antibacterial drugs. B. Amphotericin B (Fungizone). Th is polyene antifungal antibiotic is therapeutic for
various fungal infections that frequently proved fatal before the drug became available. It is used
increasingly in the empiric treatment of severely immunocompromised patients in certain clinical situations.
 1. Mechanism of action. Amphotericin B is both fungistatic in clinically obtained concentrations and may
be fungicidal in the presence of susceptible organisms. It binds to sterols in the fungal cell membrane,
thereby increasing membrane permeability and permitting leakage of intracellular contents. Other
mechanisms may be involved as well.
 2. Spectrum of activity.
 Amphotericin B is a broad-spectrum antifungal agent with activity against Aspergillus, Blastomyces,
Candida spp. (albicans, krusei tropicalis, and glabrata), Cryptococcus, Coccidioides, Histoplasma,
Paracoccidioides, Phycomycetes (mucor), and Sporothrix.
 It is also useful against some protozoa such as Leishmania, Naegleria, and Acanthamoeba.


3. Therapeutic uses. Amphotericin B
 3. Therapeutic uses. Amphotericin B is the most eff ective antifungal agent in the treatment of systemic fungal
infections, especially in immunocompromised patients.
 a. It is the treatment of choice for pulmonary Aspergillus infections; Blastomyces infections, which are life-threatening
with AIDS or CNS involvement; deep-organ infections with
 Candida; Coccidioides infections with severe pulmonary involvement or with disseminated nonmeningeal
immunocompetent or immunocompromised patients; all Cryptococcus infections; disseminated Histoplasma
infections involving CNS or immunosuppressed patients; Malassezia furfur fungemia; pulmonary and extrapulmonary
Phycomycetes (mucormycosis); Penicillium marneff ei; and extracutaneous Sporothrix.
 b. Th is agent may be used to treat coccidioidal arthritis.
 c. Topical preparations are given to eradicate cutaneous and mucocutaneous candidiasis.
 d. It may be used as empiric therapy in febrile, neutropenic patients.
 e. It is used as secondary prophylaxis of fungal infections in HIV-positive patients, guarding against recurrence of
infection.
 f. It may be used prophylactically in neutropenic cancer patients and bone marrow transplant or solid-organ
transplant patients to reduce the incidence of Aspergillus and Candida infections.

 4. Precautions and monitoring eff ects. Because amphotericin B can cause many serious adverse eff ects, it should
be administered in a hospital setting—at least during the initial therapeutic stage.
 Th e adverse eff ects are divided into infusion reactions and others
 . a. Infusion reactions occur while the drug is being administered and include fever, shaking chills, hypotension,
anorexia, nausea, vomiting, headache, dyspnea, and tachypnea. Premedication with acetaminophen and
diphenhydramine has been helpful in prophylaxing against infusion reactions. In addition, hydrocortisone 10 to 50
mg may be added to the infusion as prophylaxis against infusion-related reactions. Meperidine 25 to 50 mg IV is eff
ective treatment of active shaking chills/rigors. Meperidine is also eff ective in prophylaxis of rigors.
 b. Nephrotoxicity frequently occurs. Dosage adjustment or drug discontinuation or changing to a liposomal
amphotericin B product may be necessary as renal impairment progresses.
 c. Electrolyte abnormalities, including hypokalemia, hypomagnesemia, and hypocalcemia, are common. Monitor
and replace electrolytes as needed.
 d. Normocytic, normochromic anemia will develop over long-term use (10 weeks). Monitor hematocrit periodically.
 e. Bronchospasm, wheezing, and anaphylaxis or anaphylactoid reactions have occurred. A test dose of 1 mg of
amphotericin B is oft en administered before infusion of large quantities of the drug.

 f. Phlebitis or thrombophlebitis is reported with conventional amphotericin B. Heparin (500 to 1000 U) can
be added to the infusion to aid in prevention.
 g. CNS eff ects include headache, peripheral neuropathy, malaise, depression, seizure, myasthenia,
and hallucinations.
 h. Elevated liver transaminases, aspartate aminotransferase (AST), alanine aminotransferase (ALT),
alkaline phosphatase, bilirubin, -glutamyltransferase (GGT), and lactate dehydrogenase (LDH) may
occur.
 i. Amphotericin B parenteral use should be mixed only in dextrose 5% in water (D5W) and should be
protected from light. 5. Signifi cant interactions.
 Other nephrotoxic drugs (aminoglycosides, capreomycin, colistin, cisplatin, cyclosporine, methoxyfl
urane, pentamidine, polymyxin B, and vancomycin) may cause additive nephrotoxicity

amphotericin B cholesterol sulfate complex (A
mphotec), and liposomal amphotericin B
(AmBisome)
 amphotericin B cholesterol sulfate complex (A mphotec), and liposomal
amphotericin B (AmBisome) off er alternative formulations of amphotericin B for
the treatment of severe fungal infections in patients who are intolerant of or
whose disease is refractory to conventional treatment.

C. Echinocandins.
 Th ree echinocandins are approved in the United States: caspofungin (Cancidas), micafungin (Mycamine), and anidulafungin
(Eraxis).
 Th ese agents have a broad spectrum of activity against Candida species with micafungin and anidulafungin having similar
MICs that are generally lower than the MIC of caspofungin.
 1. Mechanism of action. Caspofungin works by causing fungal cell wall lysis. By being a noncompetitive inhibitor of (1,3)
synthase, which is an essential component of fungal cell wall synthesis, it causes osmotic instability within the fungus and fungal
cell wall lysis.
 2. Spectrum of activity. Echinocandins have fungicidal activity against Candida species and fungistatic activity against
Aspergillus species. All three agents in this class appear to have good activity in vitro for most isolates of Candida species,
including those that are either Amphotericin-B or fl uconazole and itraconazole-resistant, such as C. glabrata.
 3. Th erapeutic uses. All three agents are indicated for the treatment of esophageal candidiasis.
 a. Caspofungin and anidulafungin are also indicated for the treatment of candidemia and other infections caused by
Candida species, including intra-abdominal abscesses and peritonitis.
 b. Caspofungin may also be used for the treatment of candidal pleural space infections, empiric treatment of presumed
fungal infections in neutropenic patients, and treatment of invasive aspergillosis in patients refractory to or intolerant of other
antifungals (i.e., amphotericin B, itraconazole
 c. Micafungin is indicated for the prophylaxis of candidal infections in patients undergoing hematopoietic stem cell
transplantation (HSCT).

 Although this class has adverse events associated with its use, the overall toxicity profi le is signifi cantly better than that of amphotericin B.
 a. Infusion vein complications (not defi ned by manufacturer) and thrombophlebitis have been seen on infusion of caspofungin.
 b. Hematological decreases in hemoglobin and hematocrit may occur; however, the incidence does not diff er from that of having a
fungal disease.
 c. Headache may occur.
 d. Slight decreases in serum potassium may occur, but nowhere near the magnitude of that caused by amphotericin B.
 e. Anorexia, nausea, vomiting, and diarrhea have occurred.
 f. Rare increases in serum creatinine; however, there have been no reported cases of nephrotoxicity.
 g. Possible slight increases in serum aminotransferases
 h. Allergic reactions occur in 5% of patients and anaphylaxis in 2% of patients.
 i. Pregnancy category C embryotoxic reactions have occurred in animals.
 5. Signifi cant interactions
 a. When cyclosporine is combined with caspofungin, clinically signifi cant rises in ALT were observed. Serum transaminases should be
monitored, and this combination should be avoided in patients with preexisting liver disease.
 b. When used in combination, carbamazepine, nelfi navir, nevirapine, phenytoin, and rifampin increases the clearance of caspofungin.
Higher doses of caspofungin (70 mg every day) should be considered when this combination is administered.
 c. Tacrolimus clearance will be increased when the combination is used; monitor tacrolimus serum levels closely.

D. Flucytosine (Ancobon).
 Th is fluorinated pyrimidine usually is given in combination with amphotericin B.
 1. Mechanism of action. Flucytosine penetrates fungal cells and is converted to fl uorouracil, a
metabolic antagonist. Incorporated into the RNA of the fungal cell, fl ucytosine causes defective
protein synthesis. It is either fungistatic or fungicidal, depending on the concentration of the drug.
 2. Spectrum of activity. Th is drug is primarily active against Cryptococcus and Candida. It is most
commonly used in conjunction with amphotericin B. Fungal resistance against fl ucytosine alone has
been well documented. Flucytosine may also possess some activity against chromomycosis and
some strains of Aspergillus (in vitro testing only).
 3. Th erapeutic uses. Flucytosine is adjunctively used with amphotericin B for severe systemic
infections (e.g., septicemia, endocarditis, pulmonary and urinary tract infections, meningitis). Use of fl
ucytosine alone is not recommended.

Flucytosine
 a. Frequent adverse eff ects include GI intolerance with nausea, vomiting, and diarrhea.
 b. Occasional adverse reactions are more severe and include marrow suppression with
leukopenia or thrombocytopenia (dose related, especially with renal failure or concurrent
amphotericin B use). Confusion, rash, hepatitis, enterocolitis, headache, and
photosensitivity reactions can also occur.
 c. Rare reactions include hallucinations, blood dyscrasias with agranulocytosis and
pancytopenia, fatal hepatitis, anaphylaxis, and anemia.
 d. Flucytosine may cause a markedly false elevation of serum creatinine if an Ektachem
analyzer is used.
 5. Signifi cant interactions. Benefi cial drug interactions occur with fl ucytosine. Flucytosine
has demonstrated synergy with amphotericin B and fl uconazole against Cryptococcus
and Candida spp.

E. Griseofulvin (Fulvicin).
 Produced from Penicillium griseofulvin Dierckx, this drug is deposited in the skin, bound to keratin.
 1. Mechanism of action. Th is agent is fungistatic; it inhibits fungal cell activity by interfering with mitotic
spindle structure. Its mechanism of action is similar to colchicine.
 2. Spectrum of activity. Griseofulvin is active against various strains of Microsporum, Epidermophyton,
and Trichophyton
 . 3. Th erapeutic uses. Griseofulvin is eff ective in tinea infections of the skin, hair, and nails (including
athlete’s foot, jock itch, and ringworm) caused by Microsporum, Epidermophyton, and Trichophyton.
a. Generally, this agent is given only for infections that do not respond to topical antifungal agents. b.
Griseofulvin is available only in oral form.
 c. It possesses vasodilatory activity and may be used in Raynaud disease.
 d. It may be used to treat gout.

 4. Precautions and monitoring eff ects a. Griseofulvin rarely results in serious adverse eff ects. However, the
following problems have been reported.
 (1) Common: headache, fatigue, confusion, impaired performance, syncope, and lethargy, which generally
resolve with continued use
 (2) Occasional: leukopenia, neutropenia, and granulocytopenia
 (3) Rare: serum sickness, angioedema, urticaria, erythema, and hepatotoxicity b. Th e dosage depends on
the particle size of the product: 250 mg of ultramicrosize (Fulvicin P/G) is equivalent in therapeutic eff ects to
500 mg of microsize (Fulvicin U/F).
 5. Signifi cant interactions
 a. Griseofulvin may increase the metabolism of warfarin, leading to decreased prothrombin time.
 b. Barbiturates may reduce griseofulvin absorption.
 c. Alcohol consumption may cause tachycardia and fl ushing.
 d. Oral contraceptives may cause amenorrhea or increased breakthrough bleeding.

F. Imidazoles.
 Th e substituted imidazole derivatives ketoconazole (Nizoral), miconazole (M onistat), fl uconazole (Difl
ucan), itraconazole (Sporanox), voriconazole (Vfend) and posaconazole (N oxafi l) are valuable in the
treatment of a wide range of systemic fungal infections.
 1. Mechanism of action. Imidazoles inhibit sterol synthesis in fungal cell membranes and increase cell wall
permeability; this in turn makes the cell more vulnerable to osmotic pressure. Th ese agents are fungistatic.
 2. Spectrum of activity. Th ese agents are active against many fungi, including yeasts, dermatophytes,
actinomycetes, and some Phycomycetes.
 3. Th erapeutic uses a. Ketoconazole, an oral agent, successfully treats many fungal infections that
previously y ielded only to parenteral agents.
 (1) It is therapeutic for systemic and vaginal candidiasis, mucocandidiasis, candiduria, oral thrush,
histoplasmosis, coccidioidomycosis, chromomycosis, dermatophytosis (tinea), and paracoccidioidomycosis.
 (2) Because ketoconazole is slow acting and requires a long duration of therapy (up to 6 months for some
chronic infections), it is less eff ective than other antifungal agents for the treatment of severe and acute
systemic infections.

 b. Miconazole, primarily administered as a topical agent, the parenteral form has been discontinued
in the United States. It was a relatively toxic formulation which has been replaced by other members
of this class (e.g., fl uconazole).
 (1) Topical miconazole is highly eff ective in vulvovaginal candidiasis, ringworm, and other skin
infections.
 c. Fluconazole. Available in oral and parenteral forms, fl uconazole can be used against systemic
and CNS infections involving Cryptococcus and Candida. Candida oropharyngeal infection and
esophagitis may also be treated with fl uconazole. Aspergillus, Coccidioides, and Histoplasma have
demonstrated in vitro sensitivity.
 d. Itraconazole is available as an oral agent with activity against systemic and invasive pulmonary
aspergillosis without the hematological toxicity of amphotericin B. Other deep mycotic infections
susceptible to itraconazole include blastomycosis, coccidioidomycosis, cryptococcosis, and
histoplasmosis

. e. Voriconazole.
 Voriconazole is available as both an intravenous and an oral agent
for the treatment of fungal infections involving invasive aspergillosis,
Scedosporium apiospermum, and Fusarium spp., including those
species that are refractory to other therapy

. f. Posaconazole.
 Available as an oral suspension indicated for the prevention of invasive infections
caused by Aspergillus and Candida species in patients receiving HSCT or with
neutropenis.
 Posaconazole may also be used to treat invasive fungal infections in patients
who have previously failed or are intolerant to other antifungals.

 a. Ketoconazole may cause nausea, vomiting, diarrhea, abdominal pain, and constipation. Rarely, it
leads to headache, dizziness, gynecomastia, and fatal hepatotoxicity.
 b. Fluconazole commonly causes GI disturbances (e.g., nausea, vomiting, epigastric pain, diarrhea).
Reversible elevations in serum aminotransferase, exfoliative skin reactions, and headaches have
been reported.
 c. Itraconazole may cause nausea, vomiting, hypertriglyceridemia, hypokalemia, rash, and
elevations in liver enzymes.
 d. Voriconazole. Visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis,
peripheral edema, abdominal pain, and respiratory disorders rarely occurred. Liver function test
abnormalities have occurred.
 e. Posaconazole. Most common adverse events have been nausea and headache. Rash, dry skin,
taste disturbances, abdominal pain, dizziness, hypokalemia, thrombocytopenia, and fl ushing can
occur. Posaconazole can cause abnormalities in liver function and has been associated with
prolongation of the QT interval.

5. Significant interactions
 a. Both ketoconazole and miconazole may enhance the anticoagulant eff ect of warfarin.
 b. Ketoconazole may antagonize the antibiotic eff ects of amphotericin B.
 c. Fluconazole has been shown to elevate serum levels of phenytoin, cyclosporine, warfarin, and
sulfonylureas. Concurrent hepatic enzyme inducers, such as rifampin, have resulted in increased
elimination of both fl uconazole and itraconazole.
 d. Coadministration of itraconazole or ketoconazole with astemizole or terfenadine may result in
increased astemizole or terfenadine levels, possibly leading to life-threatening dysrhythmias and
death. Torsades des POintes
 e. Both ketoconazole and itraconazole need the presence of stomach acid for adequate
absorption. Use with antacids, H2-blockers, or proton pump inhibitors is contraindicated.

 f. Concomitant use of imidazole antifungal agents with cisapride may result in increased
concentrations of cisapride, which has been associated with adverse cardiac events such as
torsades de pointes leading to sudden death.
 g. Voriconazole. Cytochrome P450 2C19 is the major enzyme involved in metabolism. Vo
riconazole inhibits cytochrome P450 2C19, 2C9, and 3A4. Any medication that is metabolized via
these routes may be affected, and monitoring of blood levels (if appropriate) or clinical signs and
symptoms is necessary when taking concomitant medications.
 h. Posaconazole serum levels are reduced by concurrent administration with cimetidine,
phenytoin or rifabutin; avoid concomitant use if possible. Posaconazole may increase
concentrations of cyclosporine, tacrolimus, rifabutin, midazolam, and phenytoin; dosage
adjustments may be required.
 (1) Food increases the oral bioavailability; take posaconazole with a full meal or liquid nutritional
supplement

G. Nystatin (Mycostatin).
 A polyene antibiotic, nystatin has a chemical structure similar to that of amphotericin B.
 1. Mechanism of action. Nystatin is fungicidal and fungistatic; binding to sterols in the fungal cell
membrane, it increases membrane permeability and permits leakage of intracellular contents.
 2. Spectrum of activity. Nystatin is active primarily against Candida spp.
 3. Th erapeutic uses a. Th is drug is used primarily as a topical agent in vaginal and oral Candida
infections. b. Oral nystatin is therapeutic for Candida infections of the GI tract, especially oral and
esophageal infections; because the drug is not readily absorbed, it maintains good local activity.
 4. Precautions and monitoring eff ects. Oral nystatin occasionally causes GI distress (e.g., nausea,
vomiting, diarrhea). Rarely, hypersensitivity reactions occur.

H. Terbinafine (Lamisil)
 is a synthetic allylamine with structure and activity related to naftifi ne.
 1. Mechanism of action. Terbinafi ne inhibits squalene monooxygenase, leading to an interruption of fungal
sterol biosynthesis. Terbinafi ne may be fungicidal or fungistatic, depending on drug concentration and
species.
 2. Spectrum of activity. Terbinafi ne has activity against dermatophytic fungi (Trichophyton,
 Microsporum, and Epidermophyton), fi lamentous fungi (Aspergillus), and dimorphic fungi ( Blastomyces). It
may also possess some activity against yeasts.
 3. Th erapeutic uses a. Oral terbinafi ne is useful against infections of the toenail and fi ngernail
(onychomycosis, tinea unguium). Time to cure is reduced over imidazole antifungals for these indications. It is
useful in patients who may not tolerate the adverse eff ect profi le of imidazole antifungals. b. It is also used in
tinea capitis and tinea corporis infections.
 4. Precautions and monitoring eff ects. Adverse eff ects include taste or ocular disturbances, symptomatic
hepatobiliary dysfunction, decrease in lymphocyte count and neutropenia, and serious skin reactions.


IV. TOPICAL ANTIFUNGAL AGENTS
 A. Defi nition. Th ese agents are for topical use for fungal infections. B. Amphotericin B (Fungizone) is
available as a 3% cream or lotion or an oral suspension that is not absorbed through the GI tract.
 1. Mechanism of action. See III.B.1.
 2. Spectrum of activity. See III.B.2.
 3. Th erapeutic uses. Amphotericin B is used for oropharyngeal candidiasis, cutaneous and
mucocutaneous candidal infections, or as a local irrigant for the bladder and intrapleural or
intraperitoneal areas.
 4. Precautions and monitoring eff ects. Compared with systemic administration, the topical
formulations have relatively low toxicity. a. Dry skin and local irritation with erythema, pruritus, or
burning, along with mild skin discoloration, has occurred with the lotion and cream. b. Rash and GI
eff ects (e.g., nausea, vomiting, steatorrhea, diarrhea) tend to occur with the suspension. In addition,
there have been case reports of urticaria, angioedema, Stevens–Johnson syndrome, and toxic
epidermal necrolysis.

C. Butenafine (Mentax)
 is a synthetic benzylamine related to the allylamine antifungal agents (n aft ifi ne, terbinafi ne).
 1. Mechanism of action. Butenafi ne alters fungal membrane permeability and growth inhibition,
interferes with sterol biosynthesis by allowing squalene to accumulate within the cell, and may be
fungicidal in certain concentrations against susceptible organisms such as the dermatophytes.
 2. Spectrum of activity. Butenafine is active against Trichophyton rubrum, T. mentagrophytes,
Microsporum canis, Sporothrix schenckii, and yeasts, including Candida parapsilosis and C. albicans.
 3. Th erapeutic uses. Th e 1% cream is used in dermatophytoses, including tinea corporis, tinea cruris,
and tinea pedis.
 4. Precautions and monitoring eff ects. If clinical improvement of fungal infection does not improve aft
er the treatment period, the diagnosis should be reevaluated.

D. Butoconazole (Mycelex)
 is an azole antifungal cream available for vaginal use.
 1. Mechanism of action. Butoconazole has fungistatic activity against susceptible organisms. Th e drug interferes with
membrane permeability, secondary metabolic eff ects, and growth inhibition. Butoconazole contains antibacterial eff ects
against some gram-positive organisms.
 2. Spectrum of activity. Butoconazole is active against dermatophytes (Trichophyton concentricum, T. mentagrophytes, T.
rubrum, T. tonsurans, Epidermophyton fl occosum, M. canis, M. gypseum), yeasts (C. albicans, C. glabrata), and some
gram-positive organisms (S. aureus, E. faecalis, and S. pyogenes).
 3. Th erapeutic uses. A 2% cream is used for vulvovaginal candidiasis and complicated, recurrent vulvovaginal candidiasis.
 a. Vulvovaginal burning and itching are the most common; however, their incidence is low. Headache; itching of fi ngers;
urinary frequency and burning; and vulvovaginal discharge, irritation, soreness, stinging, odor, and swelling rarely occur.
 b. Butoconazole may damage birth-control devices such as condoms and diaphragms, leading to inadequate
protection. Consider alternative methods of birth control.
 c. Tampon use should be avoided with the use of butoconazole.

E. Ciclopirox (Loprox)
 is a synthetic antifungal agent that is chemically unrelated to any other antifungal agent. Th e
ethanolamine contained in ciclopirox appears to enhance epidermal penetration.
 1. Mechanism of action. Ciclopirox causes intracellular depletion of amino acids and ions necessary
for normal cellular function.
 2. Spectrum of activity. Ciclopirox is active against dermatophytes, yeasts, some gram-positive and
gram-negative bacteria, Mycoplasma, and Trichomonas vaginalis. Specifi cally, ciclopirox has a ctivity
against T. mentagrophytes, T. rubrum, E. fl occosum, M. canis, M. furfur, and C. albicans.
 3. Th erapeutic uses. Ciclopirox is used topically for the treatment of tinea pedis, tinea cruris, tinea
corporis, tinea versicolor (from Malassezia), and cutaneous candidiasis (moniliasis) from C. a lbicans.
 4. Precautions and monitoring eff ects. Local irritation manifested by erythema, pruritus, burning,
blistering, swelling, and oozing has occurred. If this occurs, ciclopirox should be discontinued.

F. Clioquinol (formerly iodochlorhydroxyquin)
 is a topical antifungal in a 3% ointment that can be used alone or in combination with
hydrocortisone.
 1. Mechanism of action. Unknown
 2. Spectrum of activity. It is active against dermatophytic fungi.
 3. Th erapeutic uses. It is used topically against the following: a. Tinea pedis and tinea cruris (ringworm
infections) b. Previously used to treat diaper rash; however, it is no longer recommended, and use in
children 2 years of age is contraindicated
 4. Precautions and monitoring eff ects a. Local irritation, rash, and sensitivity reactions are common.
b. Systemic absorption aft er topical application may occur. c. High doses of clioquinol over long
periods have been associated with oculotoxic /neurotoxic eff ects, including optic neuritis, optic
atrophy, and subacute myelo-optic neuropathy.

G. Clotrimazole (Lotrimin)
 is an azole antifungal agent that is an imidazole derivative. It is related to other azole antifungal agents, such as butoconazole,
econazole, ketoconazole, miconazole, oxiconazole, sulconazole, and tioconazole.
 1. Mechanism of action. Clotrimazole alters fungal cell membrane permeability by binding with phospholipids in the membrane.
 2. Spectrum of activity. It is active against yeasts, dermatophytes (T. rubrum, T. mentagrophytes, E. fl occosum, M. canis), and
some gram-positive bacteria. At higher concentrations, clotrimazole inhibits M. furfur, Aspergillus fumigatus, C. albicans, and
some strains of S. aureus, S. pyogenes, Proteus vulgaris, and Salmonella. At very high concentrations, clotrimazole has an eff ect
on Sporothrix, Cryptococcus, Cephalosporium, Fusarium, and T. vaginalis.
 a. Th e lozenges, which are administered fi ve times per day, are useful in treating oropharyngeal candidiasis. Lozenges are also
used for primary prophylaxis of mucocutaneous candidiasis in HIV-infected infants or children with severe immunosuppression.
 b. Th e cream, lotion, or solution is used to treat dermatophytoses, superfi cial mycoses, and cutaneous candidiasis. c.
Intravaginal dosage forms are useful in treating vulvovaginal candidiasis.
 4. Precautions and monitoring eff ects a. Cutaneous reactions with topical administration may include blistering, erythema,
edema, pruritus, burning, stinging, peeling, skin fi ssures, and general irritation. b. Th e vaginal tablets are associated with mild
burning, skin rash, itching, vulval irritation, lower abdominal cramps, bloating, slight cramping, vaginal soreness during
intercourse, and an increase in urinary frequency. c. Cross-sensitization occurs with imidazole; however, it is unpredictable. d.
Abnormal liver function tests (elevated AST) have occurred in patients taking the lozenges.

H. Econazole (Spectazole)
 is an azole antifungal agent that is an imidazole derivative.
 1. Mechanism of action. Econazole alters cell membranes and increases
permeability (like many other azole agents).
 2. Spectrum of activity. Econazole is active against dermatophytes, yeasts, some
gram-positive bacteria, and T. vaginalis.
 3. Th erapeutic uses a. Th e 1% topical cream, lotion, or solution is useful in
treating dermatophytoses and cutaneous candidiasis (tinea corporis and tinea
cruris). b. Econazole is also used to treat pityriasis (tinea) versicolor (M. furfur).
 4. Precautions and monitoring effects. In general, there is a low incidence of
toxicity. Topically, a patient may experience burning, stinging sensations, pruritus,
and erythema (aft er 2 to 4 days).

I. Gentian violet
 is a dye that possesses the ability to kill fungi, yeasts, and some gram-positive bacteria.
 1. Mechanism of action. None known
 2. Spectrum of activity. Gentian violet is active against Candida, Epidermophyton, Cryptococcus,
Trichophyton, and some Staphylococcus spp.
 3. Therapeutic uses. It is used to treat cutaneous C. albicans infections (monilia or thrush).
 a. Gentian violet may cause irritation or sensitivity reactions or possibly ulceration of the mucous
membranes. If the solution is swallowed, esophagitis, laryngitis, or tracheitis may occur.
 b. Skin tattooing may occur if gentian violet is applied to granulation tissue.
 c. Gentian violet should not be used in areas of extensive ulceration.
 d. This drug is a dye and will stain clothing

J. Ketoconazole (Nizoral)
 is an imidazole-derived antifungal drug that is available topically as a cream and a shampoo.
 3. Therapeutic uses
 a. Th e 2% topical cream is used in treating tinea corporis, tinea cruris, and tinea pedis caused by the dermatophytes (E. fl
occosum, T. mentagrophytes, and T. rubrum).
 b. It is used for cutaneous candidiasis.
 c. The 2% topical cream or 2% shampoo may be used in treating tinea versicolor (M. furfur). Selenium-based shampoos may also
be useful in this area.
 d. The 2% topical cream is useful against seborrheic dermatitis. The 2% shampoo is useful in reducing scaling caused by dandruff .
 e. When combined with a steroid, ketoconazole is useful in treating the following: atopic dermatitis, diaper rash, eczema,
folliculitis, impetigo, intertrigo, lichenoid dermatitis, and psoriasis.
 f. An ophthalmic suspension can be extemporaneously prepared to treat fungal keratitis.
 4. Precautions and monitoring effects
 a. Reactions from the 2% topical cream include local irritation, pruritus, and stinging. Contact dermatitis is possible and occurs with
other imidazole derivatives.
 b. Th e 2% shampoo may lead to increased hair loss, irritation, abnormal hair texture, scalp pustules, dry skin, pruritus, and oiliness or
dryness of hair and scalp. It may in addition straighten otherwise curly hair.

K. Miconazole (Monistat)
 is an imidazole-derived antifungal drug that is available topically as a 2% aerosol, 2% aerosol powder, 2% cream, a kit, 2% powder and
2% tincture, 2% vaginal cream, and 100 mg and 200 mg vaginal suppositories.
 3. Therapeutic uses.
 Miconazole is advantageous over other agents such as nystatin and tolnaft ate in that its activity covers dermatophytes as well as
Candida.
 a. Topical use is eff ective against tinea pedis, tinea cruris, and tinea corporis caused by dermatophytes (T. mentagrophytes, T. rubrum,
and E. fl occosum).
 b. It is also eff ective against tinea versicolor from M. furfur.
 c. Like other imidazole derivatives, it is useful in treating cutaneous fungal infections.
 d. Th e vaginal cream and vaginal suppositories are eff ective in treating vulvovaginal candidiasis.
 4. Precautions and monitoring parameters
 a. Topical creams have caused local irritation and burning.
 b. Vaginal preparations have led to vulvovaginal burning, itching, irritation, pelvic cramps, vaginal burning, headache, hives, and skin
rash.
 c. If vulvovaginal candidiasis persists for longer than 3 days, seek further medical attention.
 d. Tampons should be avoided in patients using vaginal suppositories or cream; sanitary pads should be substituted.
 e. Vaginal suppositories are manufactured from a vegetable oil base that may interact with latex products. Avoid using diaphragms or
condoms concurrently with suppositories. Seek an alternative form of birth control.

L. Naftifine (Naftin)
 is a synthetic allylamine similar to terbinafi ne. It is available as a 1% topical cream and a 1% topical gel.
 1. Mechanism of action. Naft ifi ne is fungistatic and interferes with sterol biosynthesis by accumulating
squalene in the fungal cell. Naft ifi ne also possesses some local anti-infl ammatory activity.
 2. Spectrum of activity a. Naft ifi ne is active against T. mentagrophytes, T. rubrum, T. tonsurans,
Trichophyton verrucosum, Trichophyton violaceum, E. fl occosum, Microsporum audouinii, M. canis, and
M. gypseum. b. C. albicans, Candida krusei, Candida parapsilosis, and Candida tropicalis are aff
ected by naft ifi ne; however, the concentrations of naft ifi ne vary for Candida killing, depending on
the s pecies. c. In vitro activity has been demonstrated against Aspergillus fl avus and Aspergillus
fumigatus. Others include Sporothrix schenckii, Cryptococcus neoformans, Petriellidium boydii,
Blastomyces dermatitidis, and Histoplasma capsulatum.
 3. Th erapeutic uses. Naft ifi ne is active against dermatophytoses and cutaneous candidiasis. a. It is also
used to treat tinea cruris, tinea pedis, tinea corporis, and tinea manus (T. mentagrophytes, T. rubrum, T.
verrucosum, T. violaceum, E. fl occosum, or M. canis). b. It is also useful in treating tinea unguium
(onychomycosis).
 4. Precautions and monitoring eff ects. Transient burning and stinging

M. Nystatin (Mycostatin).
 A polyene antibiotic, nystatin has a chemical structure similar to that of
amphotericin B. It is available as an oral suspension, tablet, lozenge, topical
cream, ointment, topical powder, and vaginal tablet.
 1. Mechanism of action. Nystatin is fungicidal and fungistatic; binding to sterols in
the fungal cell membrane, it increases membrane permeability and permits
leakage of intracellular c ontents.
 2. Spectrum of activity. Nystatin is active primarily against Candida spp.
 3. Th erapeutic uses. Th is drug is used primarily as a topical agent in vaginal and
oral Candida i nfections.
 4. Precautions and monitoring effects. Irritation has occurred in extremely rare
instances.

N. Oxiconazole (Oxistat
 is an imidazole-derived antifungal drug that is available as a 1% topical cream or 1%
topical lotion.
 1. Mechanism of action. See III.E.1.
 2. Spectrum of activity. See III.E.2.
 a. Th e 1% cream or lotion is useful in treating tinea cruris, tinea corporis, tinea manus, and
tinea pedis from dermatophytes.
 b. Oxiconazole is also eff ective against tinea versicolor caused by M. furfur.
 4. Precautions and monitoring eff ects. Adverse eff ects are rare and are confi ned to local
irritation.

O. Sulconazole (Exelderm)
 is an imidazole-derived antifungal drug that is available as a 1% topical cream and a 1% topical
solution.
 1. Mechanism of action (see III.E.1). Th e antibacterial eff ects exerted by sulconazole are thought to
be the result of a direct physicochemical eff ect on the destruction of unsaturated fatty acids
present in bacterial cell membranes.
 2. Spectrum of activity a. Sulconazole has activity against dermatophytes, including E. fl occosum,
M. audouinii, M. canis, M. gypseum, T. mentagrophytes, T. rubrum, T. tonsurans, and T. violaceum. It
also has activity against M. furfur. b. Sulconazole also has activity against selected gram-positive
aerobes (S. aureus, S. epidermidis, Staphylococcus saprophyticus, E. faecalis, Micrococcus luteus,
and Bacillus subtilis) and anaerobes (Clostridium and Propionibacterium acnes, Clostridium
perfringens, Clostridium tetani, and Clostridium botulinum).

P. Terbinafi ne (Lamisil AT)
 a. Th e 1% topical cream or 1% topical solution is useful in treating tinea corporis and tinea
cruris.
 b. Th e 1% topical cream has been studied for use against tinea pedis; the solution has not
been evaluated for this indication.
 c. Th e 1% cream is useful against tinea versicolor (M. furfur).
 d. Th ere is not an approved indication for cutaneous candidiasis; however, sulconazole
1% is as eff ective as miconazole 2% or clotrimazole 1% in treating cutaneous candidiasis.
 e. Sulconazole is useful in treating infections caused by bacteria such as impetigo (S.
pyogenes) and ecthyma (S. aureus).
 4. Precautions and monitoring eff ects. Adverse reactions include local eff ects such as
burning and irritation, skin edema, dryness, scaling, fi ssuring, cracking, generalized red
papules, and severe eczema.

P. Terbinafi ne (Lamisil AT)
 is a synthetic allylamine available as a 1% cream with structure and activity related to naft
ifi ne.
 1. Mechanism of action. Terbinafi ne inhibits squalene monooxygenase, leading to an
interruption of fungal sterol biosynthesis. Terbinafi ne may be fungicidal or fungistatic,
depending on drug concentration and species.
 2. Spectrum of activity. Terbinafi ne has activity against dermatophytic fungi
(Trichophyton, Microsporum, and Epidermophyton), fi lamentous fungi (Aspergillus), and
dimorphic fungi (Blastomyces). It may also possess some activity against yeasts.
 3. Th erapeutic uses. It is useful for tinea pedis, tinea corporis, and tinea cruris.
 4. Precautions and monitoring eff ects. It can cause local irritation.

Q. Terconazole (Terazol 7)
 is an imidazole-derived antifungal drug that is available as a 0.4% and 0.8% vaginal
cream and an 80-mg vaginal suppository.
 1. Mechanism of action. It is fungicidal against C. albicans. Like other imidazole agents,
terconazole alters cellular membranes, resulting in increased membrane permeability.
 2. Spectrum of activity. It is active against dermatophytes; yeasts; and, at high
concentrations, gram-positive and gram-negative bacteria.
 3. Th erapeutic uses are for complicated and uncomplicated vulvovaginal candidiasis.

 Adverse reactions include burning, pruritus, irritation, headache, body pain, and pain of female genitalia. R.
Tioconazole (Vagistat-1) is an imidazole-derived antifungal drug that is available as a 6.5% vaginal ointment.
 1. Mechanism of action. Tioconazole is fungicidal against C. albicans. Like other imidazole agents,
tioconazole alters cellular membranes, resulting in increased membrane permeability.
 2. Spectrum of activity a. Activity against fungi includes most strains of Candida and the dermatophytes. Th
ere is also activity against Aspergillus and C. neoformans. b. Tioconazole is active against the following
aerobic gram-positive bacteria: Gardnerella vaginalis, Corynebacterium minutissimum, E. faecalis, S. aureus,
S. epidermidis, and some Streptococci spp. Gram-negative bacteria: it is active against H. pylori,
Haemophilus ducreyi, Moraxella catarrhalis, Neisseria gonorrhoeae, and N. meningitidis. c. Other organisms
that tioconazole has activity against are T. vaginalis, Lymphogranuloma venereum, and Chlamydia
trachomatis.
 3. Th erapeutic uses. Tioconazole is used for simple and complicated vulvovaginal candidiasis. Other uses
have been explored; however, topical creams for use in those scenarios are not available in the United
States.
 4. Precautions and monitoring eff ects. Local irritation has been manifested as vulvovaginal burning, vaginitis,
and pruritus.

S. Tolnaftate (Tinactin)
 is available topically as a 1% aerosol, 1% powder, 1% cream, and 1% solution.
 1. Mechanism of action. It may distort hyphae and stunt mycelial growth in
susceptible fungi.
 2. Spectrum of activity. Tolnaft ate may be either fungistatic or fungicidal to the
following organisms: M. gypseum, M. canis, M. audouinii, Microsporum
japonicum, T. rubrum, T. mentagrophytes, Trichophyton schoenleinii, T. tonsurans,
E. fl occosum, Aspergillus niger, C. albicans, C. neoformans, and A. fumigatus.
 3. Th erapeutic uses. Tolnaft ate is used for dermatophytoses and tinea versicolor.
4. Precautions and monitoring eff ects. Th ere may be slight local irritation.


V. ANTIPROTOZOAL AGENTS
 A. Classification. These drugs fall into two main categories: antimalarial agents, used to treat
malaria infection, and amebicides and trichomonacides, used to treat amebic and
trichomonal infections.
 B. Antimalarial agents. Still a leading cause of illness and death in tropical and subtropical
countries, malaria results from infection by any of four species of the protozoal genus
Plasmodium.
 Antimalarial agents are selectively active during diff erent phases of the protozoan life cycle.
 Major antimalarial drugs include chloroquine (Aralen), hydroxychloroquine (Plaquenil),
primaquine, pyrimethamine (Daraprim), quinine, and mefl oquine (Lariam). In addition, three
combination brands are available: sulfadoxine plus pyrimethamine (Fansidar), atovaquone
plus proguanil (Malarone), and artemether plus lumefantrine (Coartem).

1. Mechanism of action
 a. Chloroquine and hydroxychloroquine bind to and alter the properties
of microbial and mammalian DNA.
 b. Th e mechanism of action of primaquine, quinine, Fansidar, and mefl
oquine is unknown.
 c. Pyrimethamine impedes folic acid reduction by inhibiting the enzyme
dihydrofolate r eductase.

2. Spectrum of activity
 a. Chloroquine and hydroxychloroquine are suppressive blood schizonticidal
agents and are active against the asexual erythrocyte forms of Plasmodium
vivax and Plasmodium falciparum and gametocytes of P. vivax, Plasmodium
malariae, and Plasmodium ovale.
 b. Primaquine, a curative agent, is active against liver forms of P. vivax and P.
ovale and the primary exoerythrocytic forms of P. falciparum.
 c. Pyrimethamine is active against chloroquine-resistant strains of P. falciparum
and some strains of P. vivax.
 d. Quinine, a generalized protoplasmic poison, is toxic to a wide range of
organisms. In malaria, this drug has both suppressive and curative action against
chloroquine-resistant strains.

e. Fansidar (sulfadoxine plus
pyrimethamine)
 is a blood schizonticidal agent that is active against the
erythrocytic forms of susceptible plasmodia.
 It is also active against T. gondii.

f. Malarone (atovaquone plus proguanil)
 is active against the erythrocytic and exoerythrocytic forms of
Plasmodium spp.

g. Mefloquine
 g. Mefloquine is a blood schizonticidal agent that is active against
P. falciparum (both chloroquine-susceptible and -resistant strains)
and P. vivax

. h. Coartem
is a fi xed dose oral combination of artemether (20 mg),
an artemisinin derivative, and lumefantrine (120 mg), two
antimalarials.
Both components are blood schizontocides active
against P. falciparum

3. Therapeutic uses
 a. Chloroquine is the preferred agent used to suppress malaria symptoms and to terminate
acute malaria attacks resulting from P. falciparum and P. malariae infections. (1) It is more
potent and less toxic than quinine. (2) Except where drug-resistant P. falciparum strains are
prevalent, chloroquine is the most useful antimalarial agent.
 b. Hydroxychloroquine is used as an alternative to chloroquine in patients who cannot tolerate
chloroquine or when chloroquine is unavailable.
 c. Primaquine is used to cure relapses of P. vivax and P. ovale malaria and to prevent malaria in
exposed persons returning from regions where malaria is endemic.
 d. Pyrimethamine is eff ective in the prevention and treatment of chloroquine-resistant strains of
P. falciparum. It is now used almost exclusively in combination with a sulfonamide or sulfone.
 e. Quinine (1) Quinine sulfate, an oral form, is therapeutic for acute malaria caused by
chloroquineresistant strains. (2) Quinine dihydrochloride, a parenteral form, is used in severe
cases of chloroquine- resistant malaria (it is available only from the CDC). (3) Quinine is almost
always given in combination with another antimalarial agent

f. Fansidar
 (1) Fansidar is used for the suppression or prophylaxis of chloroquine-
resistant P. falciparum malaria.
 (2) It has been used for the prophylaxis of P. carinii infections in AIDS
patients unable to tolerate cotrimoxazole (trimethoprim–
sulfamethoxazole).

g. Mefloquine
is indicated for the treatment of acute malaria and the
prevention of P. falciparum and P. vivax infections.

 h. Coartem is indicated for treatment of acute, uncomplicated malaria
infections due to
 Plasmodium falciparum in patients of 5 kg body weight and above.
 i. Malarone
 (1) Prophylaxis of P. falciparum malaria, including areas where chloroquine
resistance has been reported.
 (2) Treatment of acute, uncomplicated P. falciparum malaria.
 Th is combination has been shown to be eff ective in regions where the drugs
chloroquine, halofantrine, mefl oquine, and amodiaquine may have
unacceptable failure rates, presumably because of drug resistance.

 a. Chloroquine and hydroxychloroquine
 (1) Because these drugs concentrate in the liver, they should be used cautiously in patients
with hepatic disease. (
 2) Chloroquine must be administered with extreme caution in patients with neurological,
hematological, or severe GI disorders.
 (3) Visual disturbances, headache, skin rash, and GI distress have been reported

b. Primaquine
 (1) Th is agent is contraindicated in patients with rheumatoid arthritis and lupus
erythematosus and in those receiving other potentially hemolytic drugs or bone
marrow suppressants.
 (2) Primaquine may cause agranulocytosis, granulocytopenia, and mild anemia.
In patients with G6PD defi ciency, it may cause hemolytic anemia.
 (3) Abdominal cramps, nausea, vomiting, and epigastric distress sometimes
occur.

d. Quinine
 (1) Quinine is contraindicated in patients with G6PD defi ciency,
tinnitus, and optic neuritis.
 (2) Quinine overdose or hypersensitivity reactions may be fatal.
Manifestations of quinine poisoning include visual and hearing
disturbances; GI symptoms (e.g., nausea, vomiting); hot, fl ushed
skin; headache; fever; syncope; confusion; shallow, then depressed,
respirations; and cardiovascular collapse.
 (3) Quinine must be used cautiously in patients with atrial fi brillation.
(4) Renal damage and anuria have been reported.

e. Fansidar
 (1) Severe, sometimes fatal, hypersensitivity reactions have occurred. In
most cases, death resulted from severe cutaneous reactions, including
erythema multiforme, Stevens– Johnson syndrome, and toxic epidermal
necrolysis.
 (2) Adverse hematological and hepatic eff ects as seen with sulfonamides
have been reported.

f. Mefloquine
 (1) Concomitant use of mefloquine with quinine, quinidine, or -
adrenergic blockade may produce electrocardiographic
abnormalities or cardiac arrest. Torsades des pointes
 (2) Concomitant use of mefloquine and quinine or chloroquine may
increase the risk of convulsions.

g. Coartem
 (1) Coartem tablets should be taken with food.
 (2) Avoid use in patients with known QT prolongation, those with
hypokalemia or hypomagnesemia, and those taking other drugs
that prolong the QT interval.
 (3) Th e most common adverse reactions in adults ( 30%) are
headache, anorexia, dizziness, asthenia, arthralgia, and myalgia.
Th e most common adverse reactions in children ( 12%) are pyrexia,
cough, vomiting, anorexia, and headache.

h. Malarone
 (1) Concomitant administration with tetracycline has been
associated with 40% reduction in plasma concentrations of
atovaquone. Similarly, concurrent rifampin is known to reduce
atovaquone levels by 50%.
 (2) Take malarone with food or milk.

1. Mechanism of action
 a. Diloxanide, a dichloroacetamide derivative, is amebicidal; its mechanism of action is unknown. (Not available
commercially but can be compounded by Panorama Compounding Pharmacy, Van Nuys, CA—per Medical
Letter 8/04.)
 b. Metronidazole is a synthetic compound with direct amebicidal and trichomonacidal action; it works at both
intestinal and extraintestinal sites. Its mechanism of action involves disruption of the helical structure of DNA.
 c. Nitazoxanide is designated by the U.S. Food and Drug Administration (FDA) as an orphan drug. Its antiprotozoal
activity is believed to be the result of interference with the pyruvate: ferredoxin oxidoreductase (PFOR) enzyme-
dependent electron transfer reaction essential for energy metabolism.
 d. Quinacrine is an acridine derivative that inhibits DNA metabolism.
 e. Iodoquinol is a luminal or contact amebicide that is eff ective against the trophozoites of Entamoeba
histolytica located in the lumen of the large intestine.
 f. Paromomycin is a poorly absorbed amebicidal aminoglycoside whose mechanism of action parallels other
aminoglycosides (i.e., protein synthesis inhibitor). It is also eff ective against enteric bacteria Salmonella and
Shigella.
 g. Tinidazole precise mechanism of action is unknown.

2. Diloxanide Spectrum of activity and
therapeutic uses
 (1) Th is drug is used to treat asymptomatic carriers of amebic and
Giardia cysts.
 (2) Diloxanide is therapeutic for invasive and extraintestinal
amebiasis (given in combination with a systemic or mixed
amebicide).
 (3) Diloxanide is not eff ective as single-agent therapy for
extraintestinal amebiasis

b. Metronidazole
 (1) Th is agent is the preferred drug in amebic dysentery, giardiasis, and trichomoniasis.
 (2) Metronidazole also is active against all anaerobic cocci and gram-negative
anaerobic bacilli.
 (3) Th is agent is the treatment of choice by the CDC for the treatment of C. diffi cile c
olitis infections owing to the emerging use of broad-spectrum antibiotics. Th is therapy is c
ost-eff ective.

 c. Quinacrine is useful in the treatment of giardiasis and tapeworms.
 d. Iodoquinol is indicated for treatment of intestinal amebiasis. It is active against the protozoa E.
histolytica.
 e. Nitazoxanide is indicated for treatment of diarrhea caused by Cryptosporidium parvum and
Giardia lamblia in children.
 f. Paromomycin is indicated for acute and chronic intestinal amebiasis; it is not useful for
extraintestinal amebiasis because it is not absorbed. Paromomycin has been used for Dientamoeba
fragilis, Taenia saginata, Dipylidium caninum, and Hymenolepis nana.
 g. Tinidazole is a second-generation synthetic nitroimidazole active against trichomoniasis, Giardia
duodenalis/G. lamblia, and E. histolytica.

3. DiloxanidePrecautions and monitoring
effects
 a. Diloxanide rarely causes serious adverse eff ects. Vomiting, fl atulence, and pruritus have
been reported.
 b. Metronidazole
 (1) Th e most common adverse eff ects of this drug are nausea, epigastric distress, and d
iarrhea.
 (2) Metronidazole is carcinogenic in mice and should not be used unnecessarily.
 (3) Headache, vomiting, metallic taste, and stomatitis have been reported.
 (4) Occasionally, neurological reactions (e.g., ataxia, peripheral neuropathy, seizures)
develop.
 (5) A disulfi ram-type reaction may occur with concurrent ethanol use.

c. Quinacrine
 (1) Th is drug frequently causes dizziness, headache, nausea, and vomiting.
Nervousness and seizures also have been reported.
 (2) Quinacrine should not be taken in combination with primaquine because this
may increase primaquine toxicity.
 (3) Quinacrine should be administered with extreme caution in patients with
psoriasis because it may cause marked exacerbation of this disease.

d. Iodoquinol
 may produce optic neuritis or atrophy or peripheral neuropathy
with highdose, long-term use.
 Protein-bound iodine levels may be increased during treatment
and may interfere with the results of thyroid tests for 6 months after
treatment.
 Iodoquinol should not be used in patients who are hypersensitive to
8-hydroxy-quinolone (e.g., i odoquinol, iodochlorhydroxyquin) or
iodine-containing agents or in patients with h epatic disorders.

e. Paromomycin
 may cause nausea, cramping, and diarrhea at high doses ( 3
g/day).
 Inadvertent absorption through ulcerative bowel lesions may result
in ototoxicity or renal damage.

f. Nitazoxanide
 may cause abdominal pain, diarrhea, vomiting, headache, flatulence,
fever, eye discoloration, rhinitis, and discolored urine.

g. Tinidazole
 may produce metallic taste, nausea, anorexia, dyspepsia,
vomiting, weakness, dizziness, and headache

D. Pentamidine isethionate (Pentam 300
 is an aromatic diamide antiprotozoal agent.
 It can be administered intramuscularly, intravenously, or by
inhalation.
 1. Mechanism of action is not fully understood, but in vitro studies
indicate interference with nuclear metabolism and inhibition of
DNA, RNA, phospholipid, and protein synthesis.

2. Pentamidine Therapeutic uses
a. Pentamidine is indicated for the prevention and
treatment of infections caused by P. carinii.
b. Unlabeled uses include treatment of trypanosomiasis,
visceral leishmaniasis, and babesiosis.

 a. Nephrotoxicity, bronchospasm, and cough are the most common eff ects produced by intravenous or
inhaled pentamidine.
 b. Severe hypotension may occur aft er a parenteral dose of pentamidine. Cardiorespiratory arrest can
occur aft er a single rapid infusion of the drug.
 c. Pain, erythema, and tenderness may occur aft er an IM administration of the drug. Th is can be
minimized by using the Z-track technique of drug administration. Phlebitis may occur following IV
administration.
 d. Hypoglycemia may occur with initial administration of drug via the IV, IM, or i nhalational route. After the
patient has been on the drug for a period, hyperglycemia will result. The effect of the drug may actually
induce a reversible insulin-dependent diabetes mellitus.
 e. Leukopenia and thrombocytopenia, which can be severe, occur occasionally.
 f. Pentamidine may result in elevated liver function tests, AST, and ALT.
 g. GI eff ects can also occur, including nausea, vomiting, abdominal discomfort, pain, diarrhea, and
dysgeusia.
 h. Neurological eff ects can occur with parenteral administration and may include dizziness, tremors,
confusion, anxiety, insomnia, and seizures.
 i. Hypocalcemia and fever have also been reported and may be severe at times.

E. Atovaquone (Mepron)
 is a hydroxynaphthoquinone initially synthesized as an antimalarial drug.
 1. Mechanism of action. Atovaquone blocks mitochondrial electron transport at complex III of the
respiratory chain of protozoa, resulting in inhibition of pyrimidine synthesis.
 2. Spectrum of activity. It is active against P. carinii, T. gondii, C. parvum, P. falciparum, isosporidia, and
microsporidia.
 3. Th erapeutic uses. Atovaquone is used for second-line treatment of mild to moderate P. carinii
pneumonia in patients intolerant of co-trimoxazole or other sulfonamides or who are nonresponsive to
co-trimoxazole.
 4. Precautions and monitoring eff ects a. Oral absorption signifi cantly increases when administered
with food (especially a high-fat meal). b. Rash, nausea, diarrhea, headache, fever, abdominal pain,
dizziness, and elevated liver function tests commonly are reported.
 5. Signifi cant interactions. Atovaquone is highly bound to plasma protein. It should be used with
caution when administered with other highly protein-bound drugs with a narrow therapeutic range.

F. Eflornithine HCl (Ornidyl).
 Th is is an IV antiprotozoal agent. Its activity has been attributed to the inhibition of the enzyme
ornithine decarboxylase.
 1. Mechanism of action. Th is is a specifi c, enzyme-activated, irreversible inhibitor of ornithine
decarboxylase.
 2. Spectrum of activity and therapeutic uses. Efl ornithine is active in the treatment of the
meningoencephalitic stage of Trypanosoma brucei gambiense (sleeping sickness).
 a. Myelosuppression is the most frequent serious side eff ect.
 b. Seizures occur in about 8% of treated patients.
 c. Cases of hearing impairment have been reported.

VI. ANTITUBERCULAR AGENTS
 A. Defi nition and classifi cation.
 Drugs used to treat tuberculosis suppress or kill the slow-growing mycobacteria that cause this disease.
 Antitubercular agents fall into two main categories:
 fi rst-line and second-line drugs. Because the causative organisms tend to develop resistance to any
single drug, combination drug therapy has become standard in the treatment of tuberculosis.
 1. Th e incidence of tuberculosis in the United States is increasing owing to shift s in populations
considered to be endemic for tuberculosis, the rise in HIV-positive patients, and drug resistance.
 2. Agents chosen for therapy must eradicate mycobacterium. First-line agents available include
isoniazid, ethambutol, pyrazinamide, rifampin, rifabutin, and rifapentine. Combination ch emotherapy
is essential. Agents showing the lowest incidence of resistance (isoniazid, rifampin) are usually used in
combination with pyrazinamide or ethambutol. 3. Choice of therapy depends on many patients and
disease factors (e.g., duration of therapy needed, likelihood of drug resistance, and HIV status).

B. First-line.
 Th ese drugs, isoniazid, ethambutol, rifampin, rifabutin, rifapentine, and pyrazinamide, usually off er the greatest eff
ectiveness with the least toxicity; they are successful in most tuberculosis patients.
 At least three to four drug combinations are recommended. Th e CDC recommends daily treatment with isoniazid,
rifampin, pyrazinamide, and ethambutol for the initial phase of 2 months, followed by a continuation phase of
isoniazid and rifampin for 4 to 5 months (Table 36-4).
 1. Ethambutol (Myambutol) is a synthetic water-based compound.
 a. Mechanism of action. Th is drug is bacteriostatic. Its precise mechanism of action is unknown; however, it has
demonstrated activity only against susceptible bacteria actively undergoing cell division.
 b. Spectrum of activity and therapeutic uses. Ethambutol is active against many M. tuberculosis strains as well as
many other mycobacterial species. However, drug resistance develops fairly rapidly when it is used alone. In most
cases, ethambutol is given adjunctively in combination with isoniazid or rifampin for tuberculosis. It is also useful in
combination with other agents such as clarithromycin or azithromycin and rifabutin in treating MAC.
 c. Precautions and monitoring eff ects. Rarely, ethambutol causes such adverse eff ects as reversible dose-related
( 15 mg/kg/day) optic neuritis, drug fever, abdominal pain, headache, dizziness, and confusion. Liver function tests
should be periodically monitored. Visual testing and renal function (reduce dose with impairment) should also be
monitored.

2. Isoniazid (Nydrazid)
 2. Isoniazid (Nydrazid) is a hydrazide of isonicotinic acid. Th e mainstay of antitubercular therapy, this drug
should be included (if tolerated) in all therapeutic regimens.
 a. Mechanism of action. Isoniazid is bacteriostatic for resting bacilli and bactericidal for rapidly dividing
organisms. Its mechanism of action is not fully known; the drug probably disrupts bacterial cell wall synthesis
by inhibiting mycolic acid synthesis.
 b. Spectrum of activity. Isoniazid has activity only against organisms in the genus Mycobacterium. More
specifi cally, it has demonstrated activity against M. tuberculosis, Mycobacterium bovis, and select strains of
Mycobacterium kansasii.
 c. Therapeutic uses
 (1) Th e most widely used antitubercular agent, isoniazid should be given in combination with other
antitubercular drugs (such as rifampin, ethambutol, and pyrazinamide) to prevent drug resistance in
tuberculosis.
 (2) Treatment of latent infection (previously referred to as preventive therapy of chemoprophylaxis). Isoniazid
may be administered alone for up to 1 year in adults or children who have a positive tuberculin test result
but lack active lesions

 (1) Th e most common adverse eff ects of isoniazid are skin rash, fever, jaundice, and p eripheral
neuritis.
 (2) Hepatitis, an occasional reaction, can be severe and, in some cases, fatal. Th e risk of hepatitis
increases with the patient’s age and rises with alcohol abuse. Monitor liver function tests.
 (3) Blood dyscrasias (e.g., agranulocytosis, aplastic or hemolytic anemia, thrombocytopenia) may
occur. Monitor complete blood count (CBC) routinely.
 (4) Adverse GI eff ects include nausea, vomiting, and epigastric distress.
 (5) CNS toxicity may result from pyridoxine defi ciency. Signs and symptoms include insomnia,
restlessness, hyperrefl exia, and convulsions. Pyridoxine 15 to 50 mg/day should be administered to
patients taking isoniazid to minimize the peripheral neuropathy associated with its use (especially in
patients with diabetes, HIV, uremia, alcoholism, malnutrition, pregnancy, or seizure disorder).

e. Signifi cant interactions
 (1) With concurrent phenytoin therapy, blood levels of both phenytoin and isoniazid may increase,
possibly causing toxicity.
 (2) Aluminum-containing antacids may reduce isoniazid absorption.
 (3) Concurrent carbamazepine therapy may increase the risk of hepatitis.
 (4) Use of isoniazid with other antitubercular agents, such as cycloserine or ethionamide, may cause
additive nervous system eff ects.
 (5) Th ere is the potential for the serotonin syndrome to exist when isoniazid is used in combination with
selective serotonin reuptake inhibitors or in patients taking meperidine. Isoniazid has been shown to
have some monoamine oxidase (MAO)–inhibiting activity.

3. Rifampin (Rimactane)
 3. Rifampin (Rimactane) is a complex macrocyclic agent.
 a. Mechanism of action. Th is drug is bactericidal; it impairs bacterial RNA synthesis by b inding to DNA-
dependent RNA polymerase.
 b. Spectrum of activity. Rifampin has activity against most mycobacterial strains. In addition, rifampin
has activity against many other organisms, including N. meningitidis, S. aureus, H. infl uenzae, Legionella
pneumophila, and C. trachomatis.
 c. Th erapeutic uses (1) In recommended combinations for treatment of active tuberculosis (2)
Prophylactic rifampin is eff ective when administered to carriers of N. meningitidis disease and
chemoprophylaxis of patients with H. infl uenzae type b organisms. (3) Rifampin may be used in
combination with dapsone for the treatment of leprosy.
 d. Precautions and monitoring eff ects (1) Serious hepatotoxicity may result from rifampin therapy. Liver
function tests should be routinely conducted. (2) In rare cases, this drug induces an infl uenza-like
syndrome. (3) Other adverse eff ects include skin rash, drowsiness, headache, fatigue, confusion,
nausea, vomiting, and abdominal pain. (4) Rifampin colors urine, sweat, tears, saliva, and feces
orange-red.

e. Signifi cant interactions
 (1) Rifampin induces hepatic microsomal cytochrome P450 isoenzymes and thus may d
ecrease the therapeutic eff ectiveness of corticosteroids, warfarin, oral contraceptives,
quinidine, digitoxin, protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors,
ketoconazole, verapamil, methadone, oral antidiabetic agents, cyclosporine, dapsone,
chloramphenicol, and barbiturates.
 (2) Probenecid may increase blood levels of rifampin.
 (3) Aminosalicylic acid may impair absorption of rifampin secondary to bentonite, an
excipient used in preparation of aminosalicylic granules.
 f. Th e newer rifamycins, rifabutin (Mycobutin) and rifapentine (Prift in) may be substituted
for rifampin in special situations, for example, intolerance or serious drug interactions.

4. Rifabutin (Mycobutin)
 is an antimycobacterial agent that is similar to rifampin, with activity against both tubercular and
nontubercular mycobacterial, and off ers no clear advantage over rifampin.
 a. Mechanism of action. In addition to its antimycobacterial activity against tubercular and nontubercular
mycobacterial, rifabutin has been reported to inhibit reverse transcriptase and block the in vitro infectivity
and replication of HIV.
 b. Th erapeutic uses. Rifabutin is indicated for the prevention of disseminated MAI complex disease in
patients with advanced HIV infections.
 c. Precautions and monitoring eff ects. Th e use of rifabutin has resulted in mild elevation of liver enzymes
and thrombocytopenia.
 d. Signifi cant interactions (1) Rifabutin antagonizes and potentially negates the immune response mediated
by the bacillus Calmette–Guérin (BCG) vaccine. (2) Rifabutin may increase the clearance of drugs by
inducing hepatic microsomal enzymes, but does so to a lesser extent than rifampin. Th e concentrations of
the following drugs may be reduced while taking rifabutin: cyclosporine, zidovudine, prednisone, digitoxin,
quinidine, ketoconazole, protease inhibitors, propranolol, phenytoin, sulfonylureas, and warfarin. Serum
cyclosporine levels should be monitored in patients receiving both agents.

5. Rifapentine (Prift in)
 is a long-acting rifamycin-derivative and has a similar profi le of microbiological activity to rifampin. It is
usually administered once or twice weekly.
 a. Mechanism of action. Rifapentine is bactericidal against intracellular and extracellular M. tuberculosis
at therapeutic levels.
 b. Spectrum of activity and therapeutic uses. Indicated for treatment of primary tuberculosis.
Rifapentine should always be used in conjunction with 1 other antituberculosis drug to which the isolate
is susceptible.
 c. Precautions and monitoring effects. Rifapentine induces cytochrome P450 isoenzymes 3A4 and
2C8/9 responsible for inactivation of certain calcium channel–blocking agents (verapamil, diltiazem,
nifedipine), antifungals (ketoconazole, fluconazole, itraconazole), sulfonylurea antidiabetic agents,
methadone, corticosteroids, cardiac glycosides, certain antiarrhythmic agents (disopyramide,
mexiletine, quinidine, tocainide), quinine, dapsone, chloramphenicol, clarithromycin, doxycycline,
fluoroquinolones, transcriptase inhibitor cyclosporin, tacrolimus, and warfarin. Concomitant use of
rifapentine with these drugs may decrease plasma concentrations, and dosage adjustments may be r
equired.

6. Pyrazinamide
 is a pyrazine analog of nicotinamide.
 a. Mechanism of action. Th is drug is bactericidal and/or bacteriostatic, depending on the cell
concentration achieved.
 b. Spectrum of activity and therapeutic uses. Pyrazinamide is a highly specifi c agent and has
activity only against M. tuberculosis. Pyrazinamide is used as a primary agent with isoniazid and
rifampin for at least 2 months, followed by isoniazid and rifampin.
 c. Precautions and monitoring eff ects. Th is agent may result in hepatotoxicity and, rarely,
hepatic necrosis resulting in death. Anorexia, nausea, vomiting, malaise, and fever have been
reported. Hyperuricemia may result in gouty exacerbations. Both liver function tests and uric acid
levels should routinely be monitored.

C. Second-line agents.
 Th ese agents include aminosalicylic acid (Paser), capreomycin (Capastat), c ycloserine (Seromycin),
ethionamide (Trecator-SC), quinolones (ciprofl oxacin, ofl oxacin, levofl oxacin, sparfl oxacin),
streptomycin, and kanamycin. Second-line drugs are mainly substituted or added to preferred therapy
owing to intolerance or drug resistance. Th ese agents are less eff ective, more toxic, and are used in
combination with primary agents.
 1. Mechanism of action a. Aminosalicylic acid is bacteriostatic; it probably inhibits the enzymes
responsible for folic acid synthesis. b. Cycloserine can be bacteriostatic or bactericidal, depending on
its concentration at the infection site; it impairs amino acid use, thereby inhibiting bacterial cell wall
synthesis. c. Th e mechanism of action of capreomycin (bacteriostatic), ethionamide (bactericidal),
and pyrazinamide (bactericidal) is unknown.
 2. Spectrum of activity and therapeutic uses. Second-line antitubercular agents are active against
various microorganisms, including M. tuberculosis. Th ese agents generally are reserved for patients with
extensive extrapulmonary or drug-resistant disease or for patients who need retreatment. Th ese drugs
are almost always administered in combination.

C. Second-line agents
 a. Adverse eff ects of aminosalicylic acid include leukopenia, agranulocytopenia,
thrombocytopenia, hemolytic anemia, mononucleosis-like syndrome, malaise, joint pain,
fever, and skin rash.
 b. Capreomycin and streptomycin are ototoxic and nephrotoxic; they should not be
administered together.
 c. Cycloserine may cause adverse CNS eff ects including headache, suicidal and
psychotic tendencies, hyperirritability, confusion, paranoia, and nervousness.
 d. Ethionamide may induce nausea, vomiting, orthostatic hypotension, metallic taste,
epigastric distress, and peripheral neuropathy.
 e. Streptomycin -ototoxicity

D. Alternative agents
 1. Rifater. A combination of rifampin 120 mg, isoniazid 50 mg, and pyrazinamide 300 mg in
one tablet is used in patients expected to have low compliance with tuberculosis drug
therapy.
 One disadvantage - five to six tablets daily, which may reduce compliance.
 2. Quinolones. Ciprofloxacin and levofloxacin - tuberculosis therapy. Levofoxacin is
preferred owing to increased serum concentrations. Levofloxacin is usually used in
combination with other tuberculosis agents for active treatment. For prophylaxis,
levofloxacin is combined with pyrazinamide.
 3. Macrolides. Clarithromycin and azithromycin - limited activity against M. t uberculosis.

VII. ANTIVIRAL AGENTS
 A. treat viral infections by affecting viral replication.
 Obligate , intracellular parasites - injure host as well as viral cells.
 active against either DNA or RNA viruses, some (e.g., adefovir, ribavirin) are active against both.
 B. DNA viruses. Currently approved antiviral therapies against the Herpesviridae family of DNA
viruses—herpes simplex virus 1 and 2 (HSV-1, HSV-2), varicella zoster virus (VZV), cytomegalovirus
(CMV)—are virustatic and arrest DNA synthesis by inhibiting viral DNA polymerase.
 Many of these agents are prodrugs and require viral and host cellular enzymes (e.g., thymidine,
deoxyguanosine kinase) to phosphorylate them into the active triphosphate form before exerting
their antiviral activity.
 mechanism of resistance is a deficiency or structural alteration in viral thymidine kinase
 Some of these agents also demonstrate activity against RNA viruses, including hepatitis C and HIV.

1. Acyclovir (Zovirax)
 is a synthetic acyclic analog of guanosine with activity against various
herpes viruses.
 a. Mechanism of action.
 Acyclovir monophosphate is phosphorylated to the triphosphate, where it
becomes incorporated into viral DNA and inhibits viral replication.
 b. Spectrum of activity- active against herpes viruses, particularly HSV-1, HSV-
2, VZV, and chickenpox (varicella).

c. Therapeutic uses (1) Acyclovir
 (1) Acyclovir -treat initial and recurrent HSV-1 and HSV-2 infections and for acute treatment of herpes
zoster (shingles) and chickenpox. It is also used orally for long-term suppression of genital HSV
infections.
 (2) available in topical, oral, and IV forms. Topical acyclovir is applied directly on herpes lesions in
recurrent herpes labialis (cold sores). It is not recommended for use on genital herpes lesions due to
poor efficacy.
 (3) Acyclovir may be administered intravenously in the treatment of initial and recurrent
mucocutaneous HSV infection and VZV infection in immunocompromised patients as well as in the
treatment of HSV infections that are disseminated or affect the central nervous system.

d. Acyclovir Precautions and monitoring
effects
 (1) Oral acyclovir may induce nausea, vomiting, diarrhea, and headache.
 (2) IV administration may cause dose-dependent renal impairment, crystalline nephropathy,
neurological eff ects (e.g., lethargy, confusion, tremors, agitation, seizures, coma,
obtundation), hypotension, rash, itching, and phlebitis at the injection site.
 (3) Local discomfort and pruritus may result from topical administration.
 (4) Acyclovir is removed by hemodialysis. Doses should be adjusted in renal impairment and
hemodialysis.
 e. Significant interactions.
 Probenecid reduces the renal clearance of acyclovir, resulting in increases in acyclovir half-life
and serum concentration.
 Acyclovir may decrease plasma concentrations of phenytoin and valproic acid.

2. Adefovir dipivoxil (Hepsera)
 is a phosphonate nucleotide analog with activity against various DNA and RNA viruses.
 a. Mechanism of action. Adefovir is phosphorylated to the active diphosphate form by cellular
kinases. It is then incorporated into viral DNA, resulting in termination of replication.
 b. Spectrum of activity and therapeutic uses
 (1) Adefovir is active against hepatitis B virus (including lamivudine-resistant strains), herpes viruses,
and HIV.
 (2) However, adefovir is approved for use only for treatment of chronic hepatitis B infection in
adults with evidence of active viral replication with persistently elevated liver function tests or
histologically active disease.

c. Adefovir Precautions and monitoring eff ects
 (1) Severe acute hepatitis exacerbations have occurred in patients who
discontinue therapy (black box warning). If therapy is discontinued, liver function
tests must be monitored closely.
 (2) Nephrotoxicity has been reported with adefovir, especially in patients with
underlying renal dysfunction or those taking concomitant nephrotoxins (black
box warning).
 (3) rash, GI disturbances, headache, and weakness.
(4) Dose adjustment is required for renal insufficiency.

3. Amantadine (Symmetrel)
 is a synthetic tricyclic amine with a unique chemical structure similar to
rimantadine. It demonstrates activity against infl uenza A viral infection.
 a. Mechanism of action. Amantadine inhibits replication of the influenza A
virus by interfering with viral attachment and uncoating.
 b. Spectrum of activity and therapeutic uses
 (1) Due to increasing rates of resistance, amantadine is no longer
recommended for prophylaxis or treatment of influenza A virus.
 2) This drug may also be used to treat parkinsonism as well as drug-induced
extrapyramidal symptoms.

c. Amantadine Precautions and
monitoring effects
 (1) ataxia, nightmares, and insomnia. Other CNS eff ects include
depression, confusion, dizziness, fatigue, anxiety, and headache.
 Elderly patients may be at increased risk of CNS adverse reactions.
Patients with a history of seizures or psychiatric disorders should be
monitored closely during therapy.
 (2) Anticholinergic reactions (e.g., dry mouth, blurred vision) have
been reported.
 (3) Dosage adjustment is needed for patients with impaired renal
function.

4. Cidofovir (Vistide)
 is a synthetic acyclic purine nucleoside phosphonate derivative.
 a. Mechanism of action. Cidofovir diphosphate suppresses CMV replication
by selective inhibition of viral DNA synthesis.
 b. Spectrum of activity. In vitro activity has been demonstrated against CMV,
VZV, Epstein– Barr virus (EBV), and HSV-1 and HSV-2. Controlled clinical studies
are limited to patients with AIDS and CMV retinitis.
 c. Th erapeutic use includes the treatment, but not the cure, of CMV retinitis in
patients with AIDS.

d. Cidofovir Precautions and monitoring
effects
 (1) Cases of acute renal failure leading to dialysis or death have occurred (black box w
arning). It is also carcinogenic and teratogenic.
 (2) Avoid using this drug in patients with serum creatinine 1.5 mg/dL or creatinine clearance
(CrCl) 55 mL/min or in patients who are receiving (or have received in the past 7 days)
nephrotoxic agents.
 (3) Cidofovir is contraindicated in patients with a history of severe hypersensitivity to
probenecid or sulfa-containing medications.
 (4) Th e dose-limiting toxicity of cidofovir is nephrotoxicity; neutropenia, peripheral
neuropathy, and diarrhea are common adverse eff ects.
 (5) Probenecid must be administered before and aft er each cidofovir dose. Th e patient
must be hydrated with 1 L of normal saline before infusing.
 Note: Cidofovir is available only in IV form.

5. Entecavir (Baraclude)
 is a carbocyclic analog of guanosine used for treatment of chronic hepatitis
B infection.
 a. Mechanism of action. Once phosphorylated to the active triphosphate
form, entecavir inhibits hepatitis B viral polymerase and ultimately halts
hepatitis B DNA synthesis.
 b. Spectrum of activity. Entecavir exhibits activity against hepatitis B virus,
including lamivudine-resistant strains. Development of HIV resistance to
nucleoside reverse transcriptase inhibitors is possible if entecavir is used
without antiretroviral treatment in HIV and hepatitis B virus coinfection.

c. Entecavir Therapeutic uses
 (1) Entecavir is approved for treatment of chronic hepatitis B infection
in adults with evidence of active viral replication and persistent
elevations in liver function tests or histologically active disease.
 (2) It is eff ective for patients who have failed treatment with
lamivudine owing to resistance development.
 (3) Entecavir is not recommended for use in patients with hepatitis B
virus infection who are coinfected with HIV and are not receiving
antiretroviral therapy.

d. Entecavir Precautions and monitoring
effects
 (1) Severe acute exacerbations of hepatitis B have been observed in
patients who discontinue therapy, necessitating close monitoring (black box
warning).
 (2) Common adverse eff ects include dizziness, fatigue, headache, and
nausea.
 (3) Dose adjustment is required for renal insuffi ciency.
 (4) Counsel patients to take entecavir on an empty stomach.

6. Famciclovir (Famvir)
 is a prodrug of the antiviral agent penciclovir.
 a. Mechanism of action. Famciclovir is rapidly phosphorylated in virus-infected cells by viral
thymidine kinase to penciclovir monophosphate. Penciclovir is a competitive inhibitor of viral
DNA polymerase and prevents viral replication by inhibition of herpes virus DNA s ynthesis.
 b. Spectrum of activity and therapeutic uses (1) Famciclovir has activity against HSV-1, HSV-2,
and VZV. Th e drug is indicated for management of acute herpes zoster (shingles) and oral
and genital herpes. (2) Th erapy must be promptly initiated as soon as herpes zoster is
diagnosed (within 48 to 72 hrs), at a dose of 500 mg every 8 hrs for 7 days.
 c. Precautions and monitoring eff ects (1) Common adverse events include fatigue, GI
complaints (nausea, diarrhea, vomiting, constipation), and anorexia. Headache is also
commonly reported. (2) Dose adjustment is necessary in patients with renal dysfunction.
Famciclovir is removed by hemodialysis.

7. Foscarnet (Foscavir)
 is a synthetic pyrophosphate analog that directly inhibits enzymes involved in viral DNA
synthesis without incorporation into viral DNA. It is a broad-spectrum antiviral agent
and is an option in cases of acyclovir or ganciclovir resistance.
 a. Mechanism of action (1) Viral DNA replication requires the addition of
deoxynucleoside triphosphates at the end of the DNA strand by DNA polymerase and
the subsequent cleavage of pyrophosphate from the newly attached nucleotide.
 Foscarnet binds noncompetitively to DNA polymerase to form an inactive complex
and prevents pyrophosphate cleavage. Viral DNA chain elongation is thus terminated.
 (2) Foscarnet is also active against HIV. It is a noncompetitive, reversible inhibitor of HIV
reverse transcriptase, the enzyme responsible for converting viral RNA to viral DNA.

b. Foscarnet Spectrum of activity and
therapeutic uses.
 Foscarnet has in vitro activity against HSV-1 and HSV-2, CMV, VZV, EBV DNA
polymerases, infl uenza polymerase, and HIV reverse transcriptase. Th erapeutically,
the drug is used to treat CMV disease as well as acyclovirresistant HSV and VZV
infections.
 (1) Foscarnet is an alternative to ganciclovir and valganciclovir for treatment of CMV
infection in immunocompromised patients. Foscarnet causes less hematologic toxicity
than ganciclovir in patients who have received allogeneic stem cell transplants. An
initial induction therapy lasts 2 to 3 weeks. Maintenance therapy is needed to prevent
relapse.
 (2) Foscarnet is indicated for the treatment of acyclovir-resistant mucocutaneous HSV
in immunocompromised patients. It is not, however, a cure for HSV infections. (3)
Foscarnet is able to cross the blood–brain barrier

c. Precautions and monitoring eff ects
 (1) IV foscarnet is highly nephrotoxic, causing acute tubular necrosis. Th e incidence of
acute renal failure can be markedly reduced if adequate hydration and daily monitoring
of BUN and serum creatinine are maintained throughout therapy.
 (2) Other common adverse eff ects include electrolyte abnormalities (e.g.,
hypocalcemia, hypomagnesemia, hypophosphatemia and hyperphosphatemia,
hypokalemia), anemia, fever, headache, and seizures.
 (3) Dose adjustment for renal dysfunction is required. Foscarnet is removed by
hemodialysis.
 (4) Foscarnet must be administered using an infusion pump over at least 1.5 to 2 hrs. Do
not administer the drug as an IV bolus.
 d. Signifi cant interactions (1) Concomitant nephrotoxins (aminoglycosides, amphotericin
B, etc.) increase the risk of renal toxicity. (2) Foscarnet is exclusively eliminated by
glomerular fi ltration; concurrent nephrotoxic agents should be avoided whenever
possible.

8. Ganciclovir (Cytovene)
 is a synthetic purine nucleoside analog that is approved for the treatment
and prophylaxis of CMV infections in immunocompromised patients (e.g.,
HIV-positive patients, transplant recipients).
 a. Mechanism of action. Aft er conversion to ganciclovir triphosphate,
ganciclovir is incorporated into viral DNA, which inhibits viral DNA
polymerase, thereby terminating viral r eplication.
 b. Spectrum of activity. Ganciclovir has in vitro activity against HSV-1 and
HSV-2, VZV, EBV, and CMV (owing to its enhanced ability to penetrate host
cells).


c. Ganciclovir Therapeutic uses.
 It is indicated for treatment of CMV retinitis in patients with HIV/AIDS. It is also used for
prophylaxis of CMV infection in HIV-positive patients (secondary prophylaxis) and
transplant recipients at risk for CMV disease.
 (1) Conversion into the triphosphate form is greater in infected host cells, even though
drug penetration occurs in both uninfected and infected cells.
 (2) Inhibitory concentrations for the viral DNA polymerase are lower than those for the host
cellular polymerase.
 (3) It is available in oral and IV formulations as well as an intraocular implant. Although the
oral formulation is approved for prevention and maintenance treatment of CMV, its poor
bioavailability has limited its use. Valganciclovir has become the drug of choice for these
indications, owing to its markedly improved bioavailability.

d. Gancyclovir Precautions and
monitoring eff ects
 (1) Ganciclovir has a black box warning concerning increased potential
for neutropenia, anemia, and thrombocytopenia. It is also teratogenic,
carcinogenic, and mutagenic.
 (2) Adverse eff ects commonly include fever, rash, and GI disturbances.
Phlebitis and pain may occur at the site of infusion.
 (3) Because ganciclovir is cleared by glomerular fi ltration and tubular
secretion, renal function and adequate hydration should be monitored.
Doses should be adjusted in cases of renal impairment and hemodialysis.
 (4) Solutions of ganciclovir are extremely alkaline. Avoid direct contact
with skin.


e. Ganciclovir Significant interactions
 (1) Probenecid may increase ganciclovir concentrations and
possibly toxicity.
 (2) Use of zidovudine, azathioprine, or mycophenolate mofetil in
combination with ganciclovir may result in neutropenia; careful
monitoring of neutrophil count is required when these are taken
concurrently with ganciclovir.
 (3) Imipenem–cilastatin in combination with ganciclovir may
increase the potential for seizures.

9. Oseltamivir (Tamifl u)
 is pharmacologically similar to zanamivir but structurally diff erent. Both of
these agents are in a class known as the neuraminidase inhibitors and have
a unique mechanism of action.
 a. Mechanism of action. Oseltamivir is a prodrug that must be hydrolyzed to
oseltamivir carboxylate in vivo to exert its antiviral activity. It is a potent
selective inhibitor of the infl uenza virus enzyme, neuraminidase. Inhibition of
this enzyme prevents viral replication and spread to other host cells.
 b. Spectrum of activity. Th is agent is active against both infl uenza A and B
viruses. It is one of the preferred agents for use against the 2009 H1N1 strain of
infl uenza.

c.Oseltamivir Therapeutic uses
 (1) It is approved for the symptomatic treatment of infl uenza A and B
infections in patients 1 year of age and older who present with symptoms
within 48 hrs.
 (2) Oseltamivir has been shown to decrease the duration of symptoms by 1 to
2 days if taken within 48 hrs of onset of viral symptoms.
 (3) It is also approved for the prophylaxis of infl uenza infections in patients 1
year of age and older. Dosing recommendations are available for prevention
and treatment of H1N1 infl uenza in children younger than 1 year of age.
Note: Th e infl uenza virus vaccine is still the gold standard for prophylaxis.
 (4) Oseltamivir demonstrates some activity against strains of avian infl uenza,
making it a possible option for treatment and prophylaxis.

d. Oseltamivir Precautions and monitoring
effects
 (1) Th e most common adverse eff ects are nausea and vomiting. Th ere
have been postmarketing reports of self-injury and delirium (mostly in Japan)
among pediatric patients. Close monitoring for abnormal behavior is
recommended.
 (2) Dosage adjustments are required for patients with impaired renal
function.
 (3) Cross-resistance between oseltamivir and zanamivir has been reported.
 (4) Dosing errors have resulted when prescribers dosed oseltamivir
suspension in mL instead of mg. Be sure to verify and communicate doses in
mg only.

10. Ribavirin (Rebetol, Copegus)
 is a synthetic nucleoside analog.
 a. Mechanism of action. Ribavirin may inhibit RNA and DNA synthesis by depleting intracellular
nucleotide reserves.
 b. Spectrum of activity. Th is agent is active in vitro against a broad spectrum of DNA and RNA viruses,
including infl uenza A and B, RSV, herpes simplex, and hepatitis C virus.
 c. Th erapeutic uses. Th e aerosolized form of ribavirin is no longer recommended for treatment of RSV in
infants and children, owing to inconsistent clinical benefi ts observed in clinical trials. Combination
therapy with oral ribavirin and subcutaneous interferon-alpha is eff ective in treatment of non-
genotype1 chronic hepatitis C.

d. Ribavirin Precautions and monitoring eff ects
 (1) Common adverse eff ects of oral ribavirin include hemolytic anemia
(black box warning) and GI disturbances. Hemoglobin and hematocrit
should be monitored carefully, especially during the fi rst 4 weeks of
treatment.
 (2) Ribavirin is teratogenic; its use is contraindicated in pregnancy and
in the male partners of pregnant women.
 (3) Ribavirin should be avoided in patients with a CrCl 50 mL/min.
 (4) Ribavirin should never be used as monotherapy in treatment of
chronic hepatitis C.

11. Rimantadine (Flumadine)
 is a synthetic antiviral agent and an
-methyl derivative of amantadine that blocks the early step in the
replication of the infl uenza A virus.
 a. Mechanism of action. Rimantadine inhibits the early viral replication
cycle, possibly inhibiting the uncoating of the virus. It has the same
mechanism of action and spectrum of activity as amantadine.
 b. Spectrum of activity and therapeutic uses (1) Due to increasing rates of
resistance, rimantadine is no longer recommended for prophylaxis or
treatment of infl uenza A virus. (2) Infl uenza vaccination is the method of
choice for prevention of infl uenza infection.

c. Rimantadine Precautions and
monitoring effects
 (1) Rimantadine may increase the incidence of seizure in patients
with seizure disorder.
 (2) Th e most frequent adverse reactions include GI disturbance
(e.g., nausea, vomiting, anorexia) and CNS toxicity (e.g., insomnia,
dizziness, headache), which are less than those observed with
amantadine.
 (3) Dose reductions are recommended in patients with hepatic or
renal dysfunction

12. Telbivudine (Tyzeka)
 is a synthetic thymidine nucleoside analog used for treatment of chronic hepatitis B
infection.
 a. Mechanism of action. Telbivudine is phosphorylated into the active triphosphate form
that inhibits hepatitis B viral DNA polymerase, with ultimate termination of the DNA chain
and inhibition of viral replication.
 b. Spectrum of activity (1) Telbivudine exhibits activity against hepatitis B virus but not HIV.
(2) Th ere is a high incidence of cross-resistance between lamivudine-resistant hepatitis B
virus and telbivudine.
 c. Th erapeutic uses (1) Telbivudine is indicated for treatment of chronic hepatitis B
infection in adults with active v iral replication and persistent elevations in liver function
tests or histologically active disease. (2) When compared with lamivudine, telbivudine
produced a greater virologic response in controlled clinical trials.

d. Telbivudine Precautions and monitoring
effects
 (1) Th ere is a black box warning regarding severe exacerbations of
hepatitis B in patients discontinuing therapy, requiring close
monitoring.
 (2) Common adverse eff ects include elevations in creatine
phosphokinase, headache, fatigue, nausea, and vomiting.
 (3) Dosage adjustment is required in patients with renal insuffi
ciency. (4) May be taken without regard to meals.

13. Valacyclovir (Valtrex)
 is the l-valyl ester prodrug of the antiviral agent acyclovir.
 a. Mechanism of action. Valacyclovir is rapidly converted to acyclovir. Acyclovir is selective for the
thymidine kinase enzyme, beginning the conversion of acyclovir to acyclovir triphosphate, stopping
the replication of herpes viral DNA.
 b. Spectrum of activity and therapeutic uses (1) Valacyclovir is active against HSV-1, HSV-2, and VZV.
(2) Th is agent is used for the acute treatment of herpes zoster (shingles), herpes labialis (cold sores),
and genital herpes in immunocompetent adults. It is also eff ective for suppression of recurrent
episodes of genital herpes in immunocompetent and HIV-infected people as well as reduction of
transmission of genital herpes. (3) Advantages over acyclovir include oral dosing of only once to three
times daily and a ttainment of higher plasma concentrations than oral acyclovir. A disadvantage is
that there is no IV form available.

c. Valacyclovir Precautions and
monitoring effects
 (1) Valacyclovir has caused thrombotic thrombocytopenic
purpura/hemolytic uremic syndrome in immunocompromised individuals,
including those with advanced HIV and transplant recipients.
 (2) Begin therapy within 72 hrs of herpes zoster rash onset.
 (3) Most commonly reported adverse reactions are mild and include nausea,
headache, and vomiting. Dosage adjustment is needed in patients with
renal dysfunction.

14. Valganciclovir (Valcyte)
 is the l-valyl ester prodrug of the antiviral agent ganciclovir.
 a. Mechanism of action. Valganciclovir is converted in vivo to ganciclovir. Aft er
conversion to the active form, ganciclovir triphosphate, ganciclovir is incorporated into
viral DNA, which inhibits viral DNA polymerase, thereby terminating viral replication.
 b. Spectrum of activity and therapeutic uses (1) For in vitro activity, see VII.B.8.b. (2)
Valganciclovir is indicated for the treatment of CMV retinitis in patients with AIDS and for
prevention of CMV aft er transplantation of kidney, heart, and kidney-pancreas. It is not
indicated for liver transplant recipients, due to an increased risk of tissue-invasive CMV as
compared with ganciclovir. (3) Th e markedly improved bioavailability of valganciclovir
over oral ganciclovir has resulted in the widespread use of valganciclovir for treatment and
prevention of CMV disease.

c. Precautions and monitoring eff ects
 (1) Same black box warnings as for ganciclovir.
 (2) Doses should be adjusted in cases of renal impairment. Do not use in hemodialysis
patients; ganciclovir must be used.
 (3) Only available orally. Do not substitute doses of oral valganciclovir 1:1 for oral
ganciclovir; they are not equivalent.
 (4) A potential carcinogen and teratogen; common adverse eff ects are the same as for
g anciclovir.
 (5) If the tablet is broken, avoid contact with skin owing to teratogenic and carcinogenic
potential.
 (6) Be aware of the potential for errors as a result of the look-alike and sound-alike names
of valganciclovir and valacyclovir.

15. Zanamivir (Relenza)
 is the fi rst of a class of antiviral agents called neuraminidase inhibitors a
pproved by the FDA for the treatment of infl uenza A and B infections in
adults and children at least 7 years of age. It is also indicated for prevention
of infl uenza in adults and children at least 5 years of age.
 a. Mechanism of action. Zanamivir inhibits replication of the infl uenza A and
B viruses by selective inhibition of the infl uenza virus neuraminidase
enzyme.

b. Zanamivir Spectrum of activity, Therapeutic
Uses, Precautions and Monitoring Effects
 Th is agent is active against both the infl uenza A and B viruses. It
demonstrates activity against avian infl uenza in animal studies. It is one of
the preferred agents for use against the 2009 H1N1 strain of infl uenza.
 c. Th erapeutic uses (1) It is approved for the treatment of uncomplicated infl
uenza A and B infection for patients who have been symptomatic for 48 hrs.
It is also indicated for infl uenza prophylaxis. (2) Zanamivir is approved for oral
inhalation use only, using the Diskhaler device provided by the manufacturer.
(3) Zanamivir may be considered for prevention or treatment of avian and
swine (H1N1) infl uenza. (4) Shown to decrease duration of symptoms by
approximately 1.5 days if taken within 48 hrs of onset of viral symptoms.
 .

d. Zanamivir Precautions and monitoring
effects
 (1) Th e use of zanamivir is not recommended in patients with a history of
asthma or c hronic obstructive pulmonary disease, owing to the risk of
bronchospasm and acute decline in lung function.
 (2) Th e most common adverse eff ects were mild and included diarrhea,
nausea, and vomiting. Th e incidence of these was no diff erent than
placebo.
 (3) Do not puncture the Rotadisk blister until immediately before
administering the dose to ensure full dosage. Manual dexterity required for
this device.
 (4) Do not use in a nebulizer or mechanical ventilator

C. 6 classes of antiretroviral agents
against HIV (RNA virus)
1) active against HIV and include the nucleoside reverse transcriptase
inhibitors (NRTIs) abacavir, didanosine, emtricitabine, lamivudine,
stavudine, and zidovudine;
2) the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir disoproxil
fumarate;
3) the nonnucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine,
efavirenz, etravirine, nevirapine, and rilpivirine and the
4) protease inhibitors (PIs) atazanavir, darunavir, fosamprenavir, indinavir,
lopinavir/ritonavir, nelfi navir, ritonavir, saquinavir, and tipranavir;
5) the fusion inhibitor enfuvirtide; the entry inhibitor maraviroc;
6) and the integrase inhibitor raltegravir.

 2. virustatic and require lifelong therapy, use in various combinations known as potent
combination antiretroviral therapy.
 a. Appropriate combinations include those that have demonstrated effi cacy and safety in
controlled clinical trials (Table 36-6).
 b. Monotherapy with any single antiretroviral agent is unacceptable in the treatment of HIV
infection owing to rapid development of viral resistance.
 c. Before designing a treatment plan, a CD4 cell count, an HIV RNA level (viral load),
genotypic resistance testing, along with baseline lab values (e.g., basic chemistry, complete
blood count, etc.) should be obtained to determine if treatment should be initiated. Aft er
starting therapy, repeat these measurements in 2 to 8 weeks, followed by every 3 to 6
months once undetectable.
 d. A minimum of 0.5 to log10 copies/mL decline in HIV RNA levels should be seen aft er the fi
rst 2 to 8 weeks of therapy for clinical response; a subsequent decrease to undetectable
levels should be achieved by 12 to 24 weeks.

3. Reverse transcriptase inhibitors
 3. Reverse transcriptase inhibitors are classifi ed as either nucleosides or nucleotides. Th ese
agents are competitive inhibitors of reverse transcriptase, which leads to chain termination
when i ncorporated into the viral DNA chain.
 Th ey are inactive until phosphorylated by human cellular kinases into the active
triphosphate metabolite.
 Each agent has a corresponding three-letter acronym as well as a brand name.
 With the exception of abacavir, each agent in this class of antiretrovirals requires dosage
adjustment in patients with renal dysfunction.
 All agents in this class have a black box warning concerning the potential for
development of lactic acidosis and severe hepatomegaly with steatosis.

(2) Spectrum of activity and therapeutic
uses.
 a. Abacavir (ABC; Ziagen) is a synthetic carbocyclic nucleoside
analog indicated for the treatment of both adult and pediatric patients
with HIV.
 Abacavir is approved for use in adults and children 3 months of age
only in combination with other antiretroviral agents.
 (a) Abacavir is available alone or coformulated as a combination
tablet with lamivudine and zidovudine (Trizivir), which is dosed twice
daily.
 (b) Abacavir is also available in a combination tablet with lamivudine
(Epzicom) which is dosed once daily.

3) Abacavir Precautions and monitoring
effects
 ( (a) Abacavir has a black box warning for a life-threatening hypersensitivity reaction that can lead to
death. It occurs in approximately 5% of patients taking this drug, typically within the fi rst 6 weeks of
therapy.
 Th is reaction involves respiratory symptoms, fever, rash, and GI complaints.
 Reexposure following these symptoms can mimic anaphylaxis and may result in death. Th erefore,
rechallenge is contraindicated.
 A medication guide describing this reaction should be dispensed with each new prescription and refi ll
of abacavir-containing products. Th e HLA-B*5701 screening test should be used prior to initiating
therapy to determine if a patient is at risk for having this reaction.
 (b) Th ere are cohort studies indicating increased risk of myocardial infarction with abacavir; however,
this has not been shown in other studies, and this remains a controversial association. (4) Signifi cant
interactions
 . Alcohol increases the area under the curve (AUC) of abacavir by 41%.

b. Didanosine (ddI; Videx),
 a synthetic purine analog, inhibits HIV replication and has a longer intracellular half-life ( 20 hrs) than
zidovudine (7 hrs).
 (1) Mechanism of action. See VII.C.3.
 (2) Spectrum of activity and therapeutic uses. Didanosine is approved for the treatment of adults and
children only in combination with other antiretroviral agents.

3) Precautions and monitoring effects of
Didanosine
 ( (a) Didanosine can cause reversible peripheral neuropathy and acute, potentially lethal pancreatitis (black
box warning). Serum triglycerides should be monitored, and didanosine should be withheld when initiating
potential pancreatitis-inducing agents (e.g., IV pentamidine, sulfonamides). Transiently elevated serum
amylase may not refl ect pancreatitis.
 (b) Didanosine has been associated with noncirrhotic portal hypertension, with some patients presenting with
esophageal varices.
 (c) Other adverse eff ects include headache, diarrhea, nausea, and hyperuricemia ( because didanosine is
catalyzed to uric acid).
 (d) Didanosine is available in an enteric-coated capsule or buff ered oral tablet formulation to prevent
degradation at acidic pH. It must be taken on an empty stomach.
 (e) Do not use in combination with stavudine because of additive potential for toxicity.
 (f) Do not use the combination regimen of didanosine and tenofovir in treatment-naive patients, owing to
high rates of early virologic failure and toxicity.
 (4) Signifi cant interactions. Pancreatitis-inducing drugs, alcohol, and those known to cause peripheral
neuropathy should not be used with didanosine. Ribavirin should not be coadministered with didanosine.

c. Emtricitabine (FTC; Emtriva)
 is a synthetic nucleoside analog structurally related to lamivudine with activity
against HIV infection.
 (1) Mechanism of action. See VII.C.3.
 (2) Spectrum of activity and therapeutic uses. Emtricitabine is indicated for
use in HIVinfected adults and children in combination with other antiretroviral
agents. It is available by itself or as a combination tablet with tenofovir
(Truvada), as a combination tablet with tenofovir and efavirenz (Atripla), and
as a combination tablet with tenofovir and rilpivirine (Complera). Although it
demonstrates activity against hepatitis B virus, it is not approved for use in
treatment of this infection. Emtricitabine and tenofovir are approved for daily
use in combination to prevent HIV infection in HIV-negative men who have
sex with men.

(3) Emtricitabine Precautions and
monitoring effects
 (a) Adverse eff ects most commonly observed in clinical trials were mild-
moderate and include headache, rash, diarrhea, and nausea.
Hyperpigmentation of the palms or soles may occur.
 (b) Serious acute exacerbations of hepatitis B have been documented in
HIV/hepatitis B coinfected patients who discontinued therapy with
emtricitabine (black box w arning); therefore, liver function tests should be
monitored for several months aft er discontinuation.
 (c) Do not use in combination with lamivudine, due to similar resistance
profi les and no additional benefi ts.
 (4) Significant interactions. None have been identifi ed.

d. Lamivudine (3TC; Epivir)
 is a synthetic nucleoside analog with activity against HIV and hepatitis B virus.
 Spectrum of activity and therapeutic uses.
 Lamivudine is indicated for use in HIVpositive adults and children 3 months of age in
combination with other antiretroviral agents.
 It is also used in a lower dosage for the treatment of chronic hepatitis B in patients
with active liver infl ammation and evidence of hepatitis B viral replication.
 (a) Lamivudine is available alone or within a twice daily combination tablet
containing lamivudine, zidovudine, and abacavir (Trizivir).
 (b) Lamivudine is also available as a combination tablet with abacavir (Epzicom)
and zidovudine (Combivir).

(3) Lamivudine Precautions and
monitoring effects
 (a) Reported adverse reactions are minor and include headache, fatigue,
and GI reactions such as nausea, vomiting, and diarrhea. CNS toxicity
includes neuropathy, dizziness, and insomnia.
 (b) Do not use in combination with emtricitabine, due to similar resistance
profi les and no additional benefi ts.
 (c) Lamivudine has the same black box warning regarding acute
exacerbations of hepatitis B as emtricitabine (see VII.C.3.c).
 (4) Significant interactions. Coadministration with co-trimoxazole results in
increased lamivudine levels. No dose adjustment is required

e. Stavudine (d4T; Zerit)
 is a synthetic thymidine nucleoside analog that is active against HIV.
 (2) Spectrum of activity and therapeutic uses. Stavudine is indicated for use in
combination with other antiretroviral agents in adults and children of all ages.
 (3) Precautions and monitoring eff ects
 (a) Th e major toxicity with stavudine is a dose related, but reversible
peripheral neuropathy occurring in up to 21% of patients.
 (b) Other adverse eff ects include headache, rash, diarrhea, nausea, and
vomiting.
 (c) Fatal episodes of pancreatitis have been reported.
 (4) Signifi cant interactions. Do not use in combination with zidovudine.

f. Tenofovir disoproxil fumarate (TDF;
Viread)
is an acyclic nucleoside phosphonate diester analog
(nucleotide) with antiviral activity against HIV and hepatitis B
virus.
(1) Mechanism of action. Tenofovir (a prodrug) is rapidly
hydrolyzed by plasma esterases to tenofovir, with subsequent
conversion to the active tenofovir diphosphate.
Note: NtRTIs are active as the diphosphate, unlike the NRTIs,
which require conversion to the triphosphate.

(2) Spectrum of activity and therapeutic
uses.
Tenofovir is approved for use in combination with other
antiretroviral agents for the treatment of HIV in adults.
It is also available as a once daily combination tablet
containing tenofovir and emtricitabine (Truvada) as well
as tenofovir, emtricitabine, and efavirenz (Atripla) and
tenofovir, emtricitabine, and rilpivirine (Complera).
 Tenofovir and emtricitabine are approved for daily use in
combination to prevent HIV infection in HIV-negative men
who have sex with men.

(3) Precautions and monitoring eff ects
(a) Minor adverse eff ects have been reported in clinical trials. Th
ese include complaints of diarrhea, nausea, vomiting,
headache, and asthenia.
(b) Additional adverse eff ects observed during postmarketing
surveillance include renal insuffi ciency and decreases in bone
mineral density.
(c) Tenofovir has the same black box warning that emtricitabine
has for patients with concomitant hepatitis B (see VII.C.3.c).
(d) Dose adjustment is required for renal insuffi ciency.

(4) Signifi cant interactions (a) Tenofovir
increases didanosine serum concentrations, resulting in
increased risk of toxicity.
Additionally, there is a high rate of early virologic failure and
development of resistance mutations.
Th us, this combination is not recommended for use.
(b) Tenofovir decreases serum concentrations of atazanavir.
When these two agents are used together, ritonavir must be
added to the regimen.

g. Zidovudine (AZT; Retrovir
 ) is a synthetic thymidine analog. Th is agent was the fi rst available drug for the treatment
of HIV infection. (1) Mechanism of action. See VII.C.3. (2) Spectrum of activity and
therapeutic uses (a) Zidovudine is indicated in the treatment of adults and children for the
treatment of HIV. (b) It is indicated for the prevention of maternal–fetal HIV transmission.
(c) Zidovudine is available as oral capsules, tablets, and solution as well as an IV s olution.
(d) Oral zidovudine is also available as a coformulation with lamivudine (Combivir) and
with lamivudine and abacavir (Trizivir).

(3) Precautions and monitoring eff ects (a)
Zidovudine
 can cause severe bone marrow suppression, including macrocytic anemia
and neutropenia aft er the fi rst few weeks to months of therapy. Th e risk is
increased in patients with preexisting bone marrow suppression or who are
taking concomitant medications that cause bone marrow suppression.
 (b) Erythropoietin can be considered as an adjunctive therapy in patients
with zidovudine-induced anemia, in cases for which it cannot be
discontinued.
 (c) Other adverse eff ects include headache, malaise, seizures, anxiety,
fever, and rash. (d) Prolonged use may lead to symptomatic myopathy

. (4)Zidovudine Signifi cant interactions
(a) Co-trimoxazole, atovaquone, valproic acid,
methadone, and probenecid may increase zidovudine
concentrations, causing increased risk of zidovudine
toxicity.
 (b) Other cytotoxic drugs, such as ganciclovir, dapsone,
ribavirin, and interferonalpha, can cause additive bone
marrow suppression.
(c) Rifabutin and rifampin may decrease levels of
zidovudine.

4. Nonnucleoside reverse transcriptase
inhibitors (NNRTIs
 Th e NNRTI class binds directly to and produces a noncompetitive inhibition of the HIV
reverse transcriptase, leading to chain termination.
 Th ese agents are indicated for use in adults and pediatric patients in combination with
NRTIs or possibly protease inhibitors (PIs).
 Efavirenz is the preferred NNRTI for initial treatment, whereas the others are currently
recommended as alternatives. NNRTI-based regimens provide potent antiviral activity with
less pill burden than many PI-based regimens.
 All NNRTIs may cause rash and hepatotoxicity; patients should be monitored closely for
these adverse e ff ects. a. Delavirdine (Rescriptor)
 (2) Spectrum of activity and therapeutic uses. Delavirdine is approved for use in adults in
the treatment of HIV in combination with other antiretroviral agents. Its use has fallen out of
favor owing to its three times daily dosing schedule.

(3) NNRTIs Precautions and monitoring effects
(a) In clinical trials, 4.3% of patients discontinued
delavirdine because of rash. Cases of Stevens–Johnson
syndrome have been reported.
 (b) Other adverse eff ects include headache and
nausea.

(4) NNRTIs Significant interactions
(a) Th e concentrations of the following medications are greatly
increased by delavirdine and must be avoided: alprazolam,
midazolam, triazolam, simvastatin, lovastatin, rifabutin, and
cisapride.
(b) Decreased delavirdine concentrations result when it is
administered with St. John’s wort, carbamazepine, phenobarbital,
phenytoin, or rifampin. Concomitant use should be avoided.
(c) Because delavirdine requires an acidic GI tract for optimal
absorption, its use should be avoided with proton pump inhibitors
and H2-receptor antagonists.

b. Efavirenz (Sustiva)
 (2) Spectrum of activity and therapeutic uses.
 Efavirenz is approved for use in combination with other antiretroviral agents for the treatment of HIV
infection in adults and pediatric patients. One advantage over other NNRTIs is its once-daily dosing. It
is available alone or as a combination tablet with tenofovir and emtricitabine (Atripla).
 (a) Most common adverse eff ects are CNS-related (52%), including insomnia, dizziness, drowsiness,
nightmares, and hallucinations, necessitating a bedtime dosing to minimize these eff ects. Th ese eff
ects typically subside aft er 2 to 4 weeks of treatment.
 (b) Owing to its teratogenic eff ects, efavirenz should be avoided in the fi rst trimester of pregnancy
and in women of childbearing potential who wish to conceive or who are using unreliable
contraception.
 (c) Other adverse eff ects include rash, increased transaminases, and GI disturbances.
 (d) False-positive results may occur with screening tests for cannabinoids and benzodiazepines.

(4) Signifi cant interactions (a) Efavirenz
 induces and inhibits the cytochrome P450 3A4 isoenzyme system. It should
not be used concomitantly with cisapride, midazolam, triazolam, or ergot
d erivatives.
 (b) St. John’s wort decreases efavirenz concentrations and should be
avoided.
 (c) Efavirenz decreases methadone AUC by 52%; patients should be
monitored for opiate withdrawal and have their doses titrated
accordingly.
 (d) Efavirenz decreases levonorgestrel concentrations, resulting in possible
decreased eff ectiveness of emergency postcoital contraception.

c. Etravirine (Intelence)
 (2) Spectrum of activity and therapeutic uses. Etravirine is indicated for use
in combination with at least two additional antiretroviral agents in
treatment-experienced adults who demonstrate viral replication and
documented resistance to other NNRTIs. It is not for use in treatment-naive
patients. (
 3) Precautions and monitoring eff ects (a) Adverse eff ects include nausea
and rash. Hypersensitivity reactions have occurred, resulting in rash,
constitutional symptoms, and possible hepatic failure. (b) Because food
increases the absorption of etravirine by 50%, it should be taken following a
meal.

(4) Signifi cant interactions (a) Etravirine
 induces and inhibits a variety of cytochrome P450 isoenzymes. It should
not be used concomitantly with carbamazepine, phenobarbital,
phenytoin, unboosted PIs, atazanavir/ritonavir, fosamprenavir/ritonavir,
tipranavir/ritonavir, ritonavir, or other NNRTIs.
 (b) St. John’s wort and rifampin decrease etravirine concentrations and
should be avoided.
 (c) Etravirine may decrease serum concentrations of phosphodiesterase
Type 5 (PDE 5) inhibitors used for erectile dysfunction, requiring a dosage
increase.
 (d) Etravirine may decrease clopidogrel activation and should not be
used c onc omitantly.

d. Nevirapine (Viramune)
 was the fi rst NNRTI approved for use by the FDA for the treatment of HIV infection. (1) Mechanism of action.
See VII.C.3.
 (2) Spectrum of activity and therapeutic uses. Nevirapine is indicated in combination with other antiretrovirals
in adult and pediatric HIV patients. An extended-release tablet became available in early 2011.
 (3) Precautions and monitoring eff ects (a) Nevirapine has the highest incidence of Stevens–Johnson
syndrome of all NNRTIs. (b) Symptomatic hepatitis, including fatal hepatic necrosis, has been observed with
nevirapine (black box warning). Th e frequency of this adverse eff ect is i ncreased in women with pre-
nevirapine CD4 counts 250 cells/mm3 and men with CD4 counts 400 cells/mm3. Nevirapine should not be
initiated in these patients. (c) Other adverse eff ects include fever, nausea, and headache. (d) To decrease
the frequency of adverse eff ects, a 2-week dose escalation is required.
 (4) Signifi cant interactions (a) Nevirapine induces cytochrome P450 3A4, resulting in decreased
concentrations of oral contraceptives, efavirenz, atazanavir ritonavir, and ketoconazole. Th ese
combinations should be avoided. (b) Use of rifampin and St. John’s wort should be avoided, as they
decrease the serum concentrations of nevirapine. (c) Methadone concentrations decrease signifi cantly with
nevirapine, oft en necessitating a dose increase.

e. Rilpivirine (Edurant)
 (2) Spectrum of activity and therapeutic uses. Rilpivirine is approved for use in combination with
other antiretroviral agents for the treatment of HIV infection in treatment-naïve adults. It is available
alone and as a combination tablet with tenofovir and emtricitabine (Complera).
 (a) In clinical trials, virologic failure was more likely with rilpivirine in those patients with high viral
loads (e.g.: 100,000 copies/mL) as compared to those with viral loads 100,000 copies/mL. Th
erefore, it is especially important to consider the patient’s baseline viral load prior to initiating
therapy with rilpivirine.
 (b) In clinical trials, virologic failure with rilpivirine was more likely to result in resistance to other
NNRTIs as compared to efavirenz.
 (c) In order to improve absorption, rilpivirine should be taken with a meal.
 (d) Most common adverse eff ects are nausea, dizziness, insomnia, headache, and rash. Th e
incidence of rash and CNS adverse eff ects is lower than efavirenz.

(4) Significant interactions of Rilpivirine
(Edurant)
 (a) At therapeutic doses, rilpivirine does not inhibit or induce the CYP450
isoenzyme system.
 (b) Since rilpivirine is a substrate of CYP450 3A4, concomitant use with
inducers of this enzyme system, including rifampin, carbamazepine,
phenobarbital, phenytoin, dexamethasone, and St. John’s wort should be
avoided.
 (c) Because rilpivirine requires an acidic GI tract for optimal absorption, its
use should be avoided with proton pump inhibitors. If other acid
suppressants are used with rilpivirine, the doses should be separated by as
much time as possible (e.g: 12 hours before or 4 hours aft er rilpivirine
dosing).

5. Protease inhibitors (PIs).
 The PIs competitively inhibit the viral protease enzyme, preventing the enzyme from cleaving the
gag and gag-pol polyproteins necessary for virion roduction.
 PIs are used in combination with other antiretroviral agents, including other PIs, to s uppress HIV
replication.
 All of the PIs are cytochrome P450 inhibitors; ritonavir is the most potent i nhibitor. All PIs are
contraindicated with numerous drugs, including simvastatin, lovastatin, rifampin, cisapride,
pimozide, midazolam, triazolam, ergots, alfuzosin, salmeterol, and St. John’s wort.
 Concomitant therapy with antiepileptic drugs, erectile dysfunction drugs, colchicine, and azole
antifungals must be undertaken with caution. Most PIs interact with warfarin, necessitating close INR
monitoring and warfarin dosage adjustment.
 Owing to the wide array of drug interactions with PIs, always assess medication profiles carefully for
drug interactions before initiation. Many PIs require dose adjustment for hepatic insufficiency.

a. Atazanavir (Reyataz)
 (2) Spectrum of activity and therapeutic uses. Atazanavir is a component of
preferred and alternative PI-based regimens for HIV. It is dosed once daily.
 (a) Atazanavir may prolong the PR interval and possibly cause fi rst-degree AV
block. Caution should be used in patients with underlying conduction defects
or in those taking concomitant medications that prolong the PR interval.
 (b) Other adverse eff ects include fat maldistribution, hyperglycemia, and
indirect hyperbilirubinemia. Atazanavir may increase lipids when used with
ritonavir booster doses. Rash may occur in up to 20% of patients. (c) Dose
adjustment is required for hepatic insuffi ciency.

(4) Significant interactions (see VII.C.5).
Atazanavir
 is the most problematic of all PIs in terms of drug interactions.
 (a) Because atazanavir requires an acidic GI tract for optimal absorption, concomitant use of
proton pump inhibitors is contraindicated when used without ritonavir booster doses or in PI-
experienced patients. In PI-naive patients, atazanavir/ ritonavir may be used with proton
pump inhibitors in a dosage equivalent to no more than o meprazole 20 mg daily. Dosing of
the proton pump inhibitor should be separated by 12 hrs from the atazanavir/ritonavir. If other
acid suppressants are used with a tazanavir, the doses must be separated by as much time as
possible (up to 12 hrs apart).
 (b) Atazanavir substantially increases concentrations of clarithromycin, resulting in possible
QTc prolongation. Th e dose of clarithromycin should be decreased by 50%, or alternative
therapy considered.
 (c) Concentrations of buprenorphine and its active metabolite are substantially i ncreased by
atazanavir; concomitant use with unboosted atazanavir must be avoided.

b. Darunavir (Prezista)
 2) Spectrum of activity and therapeutic uses. Darunavir is the newest PI to receive FDA
approval for the treatment of HIV. It is considered a preferred PI for use in treatment-naive
patients. Its dosing is dependent on treatment experience and number of resistance
mutations present.
 (a) Darunavir must be coadministered with ritonavir.
 (b) Because darunavir contains a sulfonamide moiety, cross-reactivity may occur in s ulfa-
allergic patients.
 (c) Adverse eff ects include nausea, increased amylase, hepatotoxicity, hyperlipidemia,
hyperglycemia, and rash.

(3) Precautions and monitoring effects of
Darunavir (Prezista)
 (a) Fosamprenavir may be dosed once daily in treatment-naive
patients. PI-experienced patients require twice daily dosing. In most
cases, fosamprenavir is administered with low-dose ritonavir.
 (b) Adverse eff ects include hyperlipidemia, hyperglycemia, fat
maldistribution, rash, and GI disturbances.

d. Indinavir (Crixivan)
 (2) Spectrum of activity and therapeutic uses. Indinavir, in combination with ritonavir, is no longer
recommended as part of regimen for patients receiving initial treatment for HIV due to a high
incidence of nephrolithiasis.
 (a) Because indinavir may cause nephrolithiasis (kidney stones), patients should be instructed to
drink at least 1.5 L of water daily to prevent this adverse eff ect.
 (b) Indinavir can cause indirect hyperbilirubinemia. Combination therapy with atazanavir is not
recommended owing to the potential for additive eff ects.
 (c) Other adverse eff ects include hyperglycemia, hyperlipidemia, fat maldistribution, headache,
and GI intolerance.
 (d) Dose adjustment is required for hepatic insufficiency.
 (4) Signifi cant interactions
 Vitamin C in doses 1 g daily decreases indinavir concentrations. Caution patients not to exceed the
recommended daily allowance for vitamin C.

e. Lopinavir/ritonavir (Kaletra)
 ( (2) Spectrum of activity and therapeutic uses. Th is product is available as a
coformulation of lopinavir with a “booster” dose of ritonavir, which inhibits
lopinavir metabolism and results in higher serum concentrations.
 Lopinavir/ritonavir is an alternative PI used in regimens for treatment-naive
patients due to its risk of GI adverse eff ects and hyperlipidemia. It is the
preferred PI in pregnancy.


(3) Precautions and monitoring effects (a)
Lopinavir/ritonavir
 (a) is formulated as a fi lm-coated tablet that does not require
refrigeration. It is also available as an oral solution containing 42%
alcohol.
 (b) Adverse eff ects include GI intolerance, hyperlipidemia,
hyperglycemia, fat maldistribution, PR interval prolongation, and
pancreatitis.

(4) Significant interactions of Lopinavir /
ritonavir
 (a) Lopinavir/ritonavir decreases methadone concentrations, possibly
necessitating a methadone dose increase to prevent opiate withdrawal.
 (b) Concomitant administration with voriconazole is contraindicated
because of the risk of decreased voriconazole effi cacy.
 (c) Concomitant administration with efavirenz or nevirapine requires
increased doses of lopinavir/ritonavir due to enzyme induction.
 (d) Once daily dosing of lopinavir/ritonavir should not be used in patients
receiving carbamazepine, phenytoin, or phenobarbital, due to induction of
lopinavir/ritonavir metabolism.

f. Nelfi navir (Viracept)
 (2) Spectrum of activity and therapeutic uses. Nelfi navir is not generally
recommended for treatment of HIV infection due to inferior virologic effi
cacy. Unlike the other PIs, it is never used in combination with ritonavir.
 (3) Precautions and monitoring eff ects (a) Diarrhea is commonly
reported with nelfi navir. Th is can oft en be managed with
antidiarrheals. (b) Other adverse eff ects are similar to those with
lopinavir/ritonavir. (c) Use caution with look-alike, sound-alike names
(nelfi navir and nevirapine).
 (4) Signifi cant interactions (see VII.C.5). Nelfi navir decreases
methadone concentrations, necessitating increased monitoring and
dose adjustment if indicated.

g. Ritonavir (Norvir)
 (2) Spectrum of activity and therapeutic uses. Ritonavir is not used
as the sole PI in a PI-based regimen owing to its poor tolerability
and high pill burden when administered in full doses.
 Alternatively, it is used in low doses as a pharmacokinetic boosting
agent with other PIs. Because it is such a potent cytochrome P450
enzyme inhibitor, ritonavir markedly increases the serum
concentrations of other PIs, resulting in higher concentrations with
improved viral suppression.

(3) Precautions and monitoring eff ects
 (a) Capsules should be refrigerated before dispensing. Capsules then may be
stored at room temperature for up to 30 days. A tablet formulation is also
available that does not require refrigeration and should be taken with food.
 (b) Oral solution should not be refrigerated.
 (c) Adverse eff ects include GI intolerance, circumoral paresthesias, h
yperlipidemia, h yperglycemia, fat maldistribution, increased liver function
tests, and taste p erversion.
 (4) Signifi cant interactions (see VII.C.5). Many drug interactions occur with
ritonavir b ecause it is such a potent inhibitor of so many cytochrome P450
isoenzymes. Always refer to proper resources to assess for drug interactions.

h. Saquinavir (Invirase)
 (2) Spectrum of activity and therapeutic uses.
 Use of saquinavir without booster doses of ritonavir is not
recommended because of the poor bioavailability of saquinavir.
 Because saquinavir/ritonavir has been associated with signifi cant
QTc prolongation, its use should be avoided in patients with
pretreatment QT intervals 450 msec, refractory hypokalemia or
hypomagnesemia, presence of or at risk for complete heart block,
and concomitant medications that prolong QT interval.
 Th us, its use is greatly limited as compared with other PIs.

(3) Precautions and monitoring effects/
Significant Interactions of Saquinavir/ritonavir
 (a) Saquinavir/ritonavir prolongs the PR and QT intervals; cases of
torsades de pointes have been reported.
 A baseline electrocardiogram (ECG) should be obtained prior to
treatment.
 (b) Other adverse eff ects are similar to lopinavir/ritonavir.
 (4) Significant interactions. Saquinavir/ritonavir increases
concentrations of trazodone and may result in prolonged QT
interval. Concomitant use is contraindicated.

. Tipranavir (Aptivus)
(2) Spectrum of activity and therapeutic uses.
Th e use of tipranavir is limited to highly treatment-
experienced patients with HIV who are resistant to other PIs as
well as to other classes of antiretrovirals.

(3) Precautions and monitoring effects of
Tipranavir
 (a) Owing to the poor bioavailability of tipranavir, it must be coadministered with ritonavir.
 (b) Capsules must be refrigerated. Once dispensed, they are stable at room temperature
for up to 60 days.
 (c) Tipranavir has been associated with clinical hepatitis and fatal hepatic decompensation
(black box warning). Liver function tests should be monitored closely, especially in patients
with underlying liver disease.
 (d) Rarely, there have been reports of fatal and nonfatal intracranial hemorrhage with
tipranavir (black box warning).
 (e) Because the structure of tipranavir contains a sulfonamide moiety, cross-reactivity may
occur in sulfa-allergic patients.
 (f) Other adverse effects include rash, hyperlipidemia, hyperglycemia, and fat m
aldistribution

6. Fusion inhibitors.
 Enfuvirtide (T-20; Fuzeon) is the fi rst and only member of this class of a
ntiretrovirals.
 a. Mechanism of action. Enfuvirtide inhibits the entry of HIV into CD4 cells by
interfering with the fusion of viral and cellular membranes.
 b. Spectrum of activity and therapeutic uses. Enfuvirtide is primarily used in
highly treatment-experienced patients with extensive viral resistance. It is not
recommended for use as initial therapy in treatment-naive patients, as it has
not been studied in this population.

c. Precautions and monitoring effects of
Enfuvirtide
 (1) Enfuvirtide is injected subcutaneously twice daily. Local injection site
reactions occur in almost all patients, including pain, redness, pruritus, and
nodules.
 (2) Other adverse eff ects include hypersensitivity reactions and increased
rate of bacterial pneumonia.
 (3) No dose adjustment is necessary for renal impairment.
 d. Significant interactions. no significant drug interactions with enfuvirtide.

7. Entry inhibitor. Maraviroc (Selzentry)
 is the fi rst and only member of this class of antiretroviral therapy.
 a. Mechanism of action. Maraviroc is a chemokine receptor 5 (CCR5)
coreceptor antagonist. It binds to the CCR5 receptor on the CD4 cell
membrane, preventing entry of the virus into the cell.
 b. Spectrum of activity and therapeutic uses. Maraviroc is used along with
other antiretrovirals in adult patients who are infected with HIV that binds to
the CCR5 receptor.

c. Maraviroc Precautions and monitoring
eff ects
 (1) Hepatotoxicity was observed during clinical trials with maraviroc (black
box warning). Th is may be preceded by a systemic allergic reaction.
Patients should be evaluated immediately if either occurs.
 (2) Use caution in patients with liver disease or cardiovascular risk factors.
 (3) Adverse eff ects include cough, rash, fever, musculoskeletal symptoms,
dizziness, abdominal pain, and orthostatic hypotension.
 (4) Not recommended for use in patients with severe or end-stage renal
disease unless clinically warranted.

d. Maraviroc Significant interactions
 (a) When used with cytochrome P450 inhibitors, such as PIs (except
tipranavir/ ritonavir), delavirdine, ketoconazole, itraconazole, and
clarithromycin, administer maraviroc 150 mg twice daily.
 (b) When used with cytochrome P450 inducers (such as carbamazepine,
phenobarbital, phenytoin, efavirenz, and rifampin) without a strong
cytochrome P450 inhibitor, administer maraviroc 600 mg twice daily.
 (c) When used with other medications, including tipranavir/ritonavir,
nevirapine, NRTIs, raltegravir, and enfuvirtide, administer maraviroc 300 mg
twice daily.
 Concomitant administration with St. John’s wort or rifapentine is not
recommended due to reduction in maraviroc serum concentrations.

8. Integrase inhibitor.
 is the first and only member of this class of antiretroviral therapy.
 a. Mechanism of action. Raltegravir inhibits the viral enzyme integrase,
thereby preventing the insertion of HIV genetic material into the CD4 cell
genome and halting the viral replication process.
 b. Spectrum of activity and therapeutic uses. Raltegravir is used along with
other antiretrovirals as a preferred agent in treatment-naïve patients with HIV infection.


Raltegravir (Isentress)
 (1) Because elevations in creatine kinase, along with myopathy and
rhabdomyolysis, may o ccur with raltegravir, use with caution in
patients who are receiving concomitant medications that may
cause these adverse eff ects.
 (2) Th e most common adverse effects include nausea, diarrhea,
headache, and fever.

 d. Significant interactions. Because rifampin decreases the serum concentration of
raltegravir, the dose of raltegravir should be increased to 800 mg twice daily when used c
oncomitantly.

D. Hepatitis C virus (RNA virus):
 Direct-acting antiviral (DAA) agents
 1. DAA use in combination with interferon alfa and ribavirin for the
management of genotype 1 hepatitis C virus (HCV) infection; these
include a. boceprevir and b. telaprevir.
 The combination improved sustained virologic response rates and the
possibility of a shorter duration of treatment for patients with genotype 1
HCV infection.

DAA
 2. These agents are inhibitors of the HCV nonstructural 3/4A (NS3/4A)
serine protease, an enzyme required for viral replication and virion
assembly.
 a. Monotherapy – unacceptable- development of resistance with
subsequent virologic failure occurs rapidly.
 b. used only for treatment of genotype 1 HCV infection, in combination
with interferon alfa and ribavirin.
 c. Limited data exists for use of these agents in patients coinfected with
HCV and HIV

3. Boceprevir (Victrelis)
 b. Spectrum of activity and therapeutic uses. Boceprevir is approved for use
in adults with genotype 1 HCV infection who are treatment-naïve or who
have failed prior treatment with interferon and ribavirin.
 It is added to interferon alfa and ribavirin following 4 weeks of t reatment
with those two agents.
 The total treatment duration of this three drug regimen varies from 24-44
weeks, depending upon the patient’s previous history of HCV treatment,
HCV viral load measurements, and presence of cirrhosis.


Boceprevir
 (1) must be administered every 7-9 hours with a meal or light snack. Patients
should be counseled on how to avoid missing or delaying doses in order to
optimize the eff ectiveness of this agent.
 (2) No dosage adjustments are necessary for renal or hepatic impairment.
 (3) Common adverse eff ects include headache, nausea, anemia, and taste
disturbances.

d. Significant interactions
of Boceprevir
 (1) is a substrate and strong inhibitor of CYP450 3A4/5, resulting in
numerous drug-drug interactions.
 Avoid concomitant use with alfuzosin, rifampin, phenobarbital,
carbamazepine, phenytoin, ergot alkaloids, St. John’s wort,
simvastatin, lovastatin, drosperinone, triazolam, and oral
midazolam.
 (2) Careful review of concomitant medications is required during
treatment with boceprevir, so that appropriate monitoring can be
performed.

4. Telaprevir (Incivek)
 b. Spectrum of activity and therapeutic uses.
 Telaprevir is approved for use in adults with genotype 1 HCV infection who
are treatment-naïve or who have not responded to prior treatment with
interferon-based therapy, including prior null responders, partial
responders, and relapsers.
 It is added to interferon alfa and ribavirin at the start of therapy and
continued for the fi rst 12 weeks of treatment, depending upon response.
 The interferon and ribavirin are then continued for an additional 12 or 36
weeks, depending upon the virologic response observed.


Telaprevir
 (1) must be administered every 7–9 hours with a meal or snack containing at least 20 grams
of fat. Th e product labeling and educational materials provided with this agent include
numerous examples of these food combinations.
 (2) No dosage adjustment is necessary for renal impairment.
 (3) Use of telaprevir is not recommended in moderate to severe hepatic impairment, owing
to a lack of pharmacokinetic data in this population.
 (4) Adverse effects include rash, anemia, nausea, diarrhea, rectal discomfort, dysgeusia,
and fatigue.

d. Significant interactions of Telaprevir
 (1) Telaprevir is a substrate and strong inhibitor of CYP450 3A, resulting in
numerous drugdrug interactions.
 Avoid concomitant use with alfuzosin, rifampin, ergot alkaloids, St. John’s
wort, simvastatin, lovastatin, triazolam, and oral midazolam.
 (2) Careful review of concomitant medications is required during
treatment with telaprevir, so that appropriate monitoring can be
performed.

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