Pharmacology 1.2

1. Anti-infective agents
Sept, 2022

2. Introduction
• The term anti-infective is broadly used to
include agents that are active against
infectious microorganisms:
– Bacteria: antibacterial agents
– Fungi: antifungal agents
– Viruses: antiviral agents
– Parasites: antihelmintics, antiprotozoal agents

3. Antibacterial agents

4. Introduction
• Microbial resistance poses a big challenge to the use of
antimicrobial drugs.
• Mechanisms
– Cell wall synthesis inhibitors:
• production of antibiotic-inactivating enzymes,
• changes in the structure of target receptors,
• increased efflux via drug transporters, and
• decreases in the permeability of microbes’ cellular membranes to
antibiotics.
– Strategies to counter:
• use of adjunctive agents that can protect against antibiotic
inactivation,
• the use of antibiotic combinations,
• the introduction of new (and often expensive) chemical derivatives of
established antibiotics, and
• efforts to avoid the indiscriminate use or misuse of antibiotics.

5. • Categories:
– Beta-Lactam Antibiotics & Other Cell Wall
Synthesis Inhibitors
– Chloramphenicol, Tetracyclines, Macrolides,
Clindamycin, Streptogramins, & Linezolid
– Aminoglycosides
– Sulfonamides, Trimethoprim, & Fluoroquinolones
– Antimycobacterial Drugs

6. Beta-Lactam Antibiotics & Other Cell
Wall Synthesis Inhibitors
• Major bacterial cell wall inhibitors.
– Penicillins and
– cephalosporins
• The above possess the unusual 4-member ring that is common to
all their members, hence the name beta-lactams
• The beta-lactams include some of the most effective, widely used,
and well-tolerated agents available for the treatment of microbial
infections.
• Other cell wall inhibitors (not beta lactams):
– Vancomycin, fosfomycin, and bacitracin also inhibit cell wall synthesis
• But not nearly as important as the beta-lactam drugs.
• The selective toxicity of the drugs in this category is mainly due to
specific actions on the synthesis of a cellular structure that is
unique to the microorganism.

7. • Important terminologies: refer to
Pharmacology: Examination & Board Review,
9e > Part VIII. Chemotherapeutic Drugs >
Chapter 43. Beta-Lactam Antibiotics & Other
Cell Wall Synthesis Inhibitors >

8. Penicillins
Chemistry
• Derivatives of 6-aminopenicillanic acid:
– possess a beta-lactam ring structure that is essential
for antibacterial activity.
Classification
• Penicillin subclasses:
– additional chemical substituents conferring
differences in
• antimicrobial activity,
• susceptibility to acid and enzymatic hydrolysis, and
• biodisposition.

9. • Classification done on basis of antibacterial spectrum
and susceptibility or resistance to beta lactam
inactivating enzymes (beta lactamase/penicillinase):
1. Narrow-Spectrum Penicillinase-Susceptible Agents:
• Pennicilin G, penicillin V
• Greatest activity against gram-positive organisms, gram-negative
cocci, and non-beta-lactamase-producing anaerobes
• little activity against gram-negative rods
• susceptible to hydrolysis by beta-lactamases
2. Very-Narrow-Spectrum Penicillinase-Resistant Drugs:
• methicillin (prototype) nafcillin, oxacillin
• resistant to staphylococcal beta-lactamases
• active against staphylococci and streptococci but inactive against
enterococci, anaerobic bacteria, and gram-negative cocci and rods.

10. 3. Wider-Spectrum Penicillinase-Susceptible Drugs:
• Aminopenicillins: amoxicillin, ampicillin
• Carboxypenicillins (antipseudomonal): Carbenicillin
(obsolete), ticarcillin
• Ureidopenicillins: piperacillin, mezlocillin, and azlocillin
• Drugs in this class retain the spectrum of activity of penicillin
G,
– But have greater activity against gram-negative bacteria due to
their enhanced ability to penetrate the gram-negative outer
membrane
– they are inactivated by beta-lactamases

11. Mechanism of action:
• Beta-lactam antibiotics are bactericidal drugs.
– inhibit cell wall synthesis by the following steps
(Figure 43–1):
• (1) binding of the drug to specific enzymes (penicillin-
binding proteins[PBPs]) located in the bacterial
cytoplasmic membrane;
• (2) inhibition of the transpeptidation reaction that
cross-links the linear peptidoglycan chain constituents
of the cell wall; and
• (3) activation of autolytic enzymes that cause lesions in
the bacterial cell wall.
– Refer to figure 43–1

12. Resistance to penicillins
1. Inactivation/hydrolysis of the beta-lactam ring beta-lactamase results in loss of
antibacterial activity.
• beta-lactamases (penicillinases) are produced by most staphylococci and many
gram-negative organisms is a major mechanism of bacterial resistance.
• Inhibitors of these bacterial enzymes:
– clavulanic acid,
– sulbactam,
– Tazobactam
– The above are often used in combination with penicillins to prevent their inactivation.
2. Structural change in target PBPs is another mechanism of resistance and is
responsible for methicillin resistance in staphylococci and for resistance to
penicillin G in pneumococci (eg, PRSP, penicillin resistant Streptococcus
pneumoniae) and enterococci.
3. In some gram-negative rods (eg, Pseudomonas aeruginosa), changes in the porin
structures in the outer cell wall membrane may contribute to resistance by
impeding access of penicillins to PBPs.

13. Pharmacokinetics:
• Absorption and mode of administration:
– Absorption of orally administered drug differs greatly for
different penicillins, depending in part on their acid stability and
protein binding
– Absorption of most oral penicillins (amoxicillin being an
exception) is impaired by food, and the drugs should be
administered at least 1-2 hours before or after a meal.
– Penicillin G
• Benzylpenicillin -IV
• Procaine benzylpenicillin (procaine penicillin), IM
• Benzathine benzylpenicillin (benzathine penicillin), IM
– Phenoxymethylpenicillin (penicillin V): Oral
– Other oral penicillins: Flucloxacillin, Dicloxacillin, ampicillin,
amoxicillin

14. • Penicillins are widely distributed in body fluids and tissues with
exception of the eye, the prostate, and the central nervous system
where penetration is poor;
– However, with active inflammation of the meninges, penicillins easily
cross the blood brain barrier hence making them suitable for
treatment of bacterial meningitis caused by susceptible organisms
• Penicillins are polar compounds and are not metabolized
extensively;
• They are usually excreted unchanged in the urine via glomerular
filtration and tubular secretion; the latter process is inhibited by
probenecid.
– Nafcillin is excreted mainly in the bile and ampicillin undergoes
enterohepatic cycling.
– The plasma half-lives of most penicillins vary from 30 min to 1 h.
– Procaine and benzathine forms of penicillin G are administered
intramuscularly and have long plasma half-lives because the active
drug is released very slowly into the bloodstream.

15. Clinical Uses
1. Narrow-Spectrum Penicillinase-Susceptible Agents (Pen G and Family)
– have a limited spectrum of antibacterial activity and are susceptible to beta-
lactamases.
• Clinical uses;
– include therapy of infections caused by common:
• streptococci,
• meningococci,
• gram-positive bacilli, and
• spirochetes.
– Many strains of pneumococci are now resistant to penicillins (penicillin-
resistant Streptococcus pneumoniae [PRSP] strains).
– Most strains of Staphylococcus aureus and a significant number of strains of
Neisseria gonorrhoeae are resistant via production of beta-lactamases.
– Syphilis :
– Although no longer suitable for treatment of gonorrhea, penicillin G remains the drug of
choice for syphilis.
– Activity against enterococci is enhanced by aminoglycoside antibiotics.
– Penicillin V is an oral drug used mainly in oropharyngeal infections.

16. 2. Very-Narrow-Spectrum Penicillinase-Resistant
Drugs
– primary use is in the treatment of known or
suspected staphylococcal infections.
– Methicillin-resistant (MR) staphylococci (S aureus
[MRSA] and S epidermidis [MRSE]) are resistant to
all penicillins and are often resistant to multiple
antimicrobial drugs.

17. 3. Wider-Spectrum Penicillinase-Susceptible Drugs
• Aminopenicillins (Ampicillin and Amoxicillin)
– has a wider spectrum of antibacterial activity than penicillin G but remains
susceptible to penicillinases.
– Their clinical uses include indications similar to penicillin G as well as
infections resulting from:
• enterococci,
• Listeria monocytogenes,
• Escherichia coli,
• Proteus mirabilis,
• Haemophilus influenzae, and Moraxella catarrhalis, although resistant strains occur.
– When used in combination with inhibitors of penicillinases (eg, clavulanic
acid), their antibacterial activity is often enhanced.
– In enterococcal and listerial infections, ampicillin is synergistic with
aminoglycosides.
• Carboxypenicillins (Ticarcillin) and Ureidopenicillins (piperacillin)
– Both classes of drugs have activity against several gram-negative rods,
including Pseudomonas, Enterobacter, and in some cases Klebsiella species.
– They have synergistic actions when used with aminoglycosides against such
organisms.
– They are all susceptible to penicillinases and are often used in combination
with penicillinase inhibitors (eg, tazobactam and clavulanic acid) to enhance
their activity.

18. Adverse effects
• Though most penicillins are generally not toxic, adverse
events may occur in form of:
– Allergy:
• Presentation: urticaria, severe pruritus, fever, joint swelling,
hemolytic anemia, nephritis, and anaphylaxis
• About 5–10% of persons with a history of penicillin reaction have
an allergic response when given a penicillin again.
• Methicillin causes interstitial nephritis, and nafcillin is associated
with neutropenia.
• Antigenic determinants include degradation products of penicillins
such as penicilloic acid.
• Complete cross-allergenicity between different penicillins should
be assumed.
• Ampicillin frequently causes maculopapular skin rash that does
not appear to be an allergic reaction.

19. – Gastrointestinal Disturbances
• Nausea and diarrhea may occur with oral penicillins,
especially with ampicillin.
• Gastrointestinal upsets may be caused by direct
irritation or by overgrowth of gram-positive organisms
or yeasts.
• Ampicillin has been implicated in pseudomembranous
colitis.

20. Cephalosporins
Chemistry
• The cephalosporins are derivatives of 7-aminocephalosporanic acid and
contain the beta-lactam ring structure.
• Many members of this group are in clinical use.
Mechanism of action:
• Cephalosporins bind to PBPs on bacterial cell membranes to inhibit
bacterial cell wall synthesis by mechanisms similar to those of the
penicillins.
• Cephalosporins are bactericidal against susceptible organisms.
• Structural differences from penicillins render cephalosporins less
susceptible to penicillinases produced by staphylococci,
– but many bacteria are resistant through the production of other beta-
lactamases that can inactivate cephalosporins.
• Resistance can also result from decreases in membrane permeability to
cephalosporins and from changes in PBPs.
• Methicillin-resistant staphylococci are also resistant to cephalosporins.

21. Pharmacokinetics
• Several cephalosporins are available for oral use, but
most are administered parenterally.
• Some Cephalosporins (those with side chains may
undergo hepatic metabolism), but the major
elimination mechanism for drugs in this class is renal
excretion via active tubular secretion.
• Cefoperazone and ceftriaxone are excreted mainly in
the bile.
• Most first- and second-generation cephalosporins do
not enter the cerebrospinal fluid even when the
meninges are inflamed.

22. Classification
• Cephalosporins vary in their antibacterial
activity and are designated:
– first-,
– second-,
– third-, or
– fourth-generation drugs
– The above categorization is based on the order of their
introduction into clinical use.

23. First-Generation Drugs
First-Generation Drugs:
– cefadroxil,
– cefazolin,
– cephalexin,
– cephalothin,
– cephapirin, and cephradine

24. First-Generation Drugs
• Antibacterial spectrum:
– very active against gram-positive cocci, including
pneumococci, streptococci, and staphylococci.
– These cephalosporins are not active against
methicillin-resistant strains of staphylococci
– Escherichia coli, Klebsiella pneumoniae, and
Proteus mirabilis are often sensitive,
• but activity against Pseudomonas aeruginosa, indole-
positive Proteus, Enterobacter, Serratia marcescens,
Citrobacter, and Acinetobacter is poor

25. First-Generation Drugs
• Clinical uses
– Although the first-generation cephalosporins have a
broad spectrum of activity and are relatively nontoxic,
they are rarely the drug of choice for any infection.
– Oral drugs may be used for the treatment of:
• urinary tract infections,
• minor staphylococcal lesions,
• minor polymicrobial infections such as cellulitis or soft tissue
abscess
– Cefazolin penetrates well into most tissues hence a
drug of choice for surgical prophylaxis

26. First-Generation Drugs
• Dosage forms:
– Oral:
• Cephalexin, cephradine, and cefadroxil are absorbed
from the gut to a variable extent.
– Parenteral:
• Cefazolin is almost the only first-generation parenteral
cephalosporin now in use

27. Second-Generation Drugs
• Drugs:
– Cefaclor,
– cefamandole,
– cefonicid,
– cefuroxime,
– cefprozil,
– loracarbef, and ceforanide and
– the structurally related cephamycins:
• cefoxitin, cefmetazole, cefotetan
• This is a heterogeneous group of drugs with marked
individual differences in activity, pharmacokinetics, and
toxicity

28. Second-Generation Drugs
• Antibacterial spectrum:
– have slightly less activity against gram-positive
organisms than the first-generation drugs but
have an extended gram-negative coverage
– Klebsiella (including those resistant to cephalothin)
are usually sensitive.
– Cefamandole, cefuroxime, cefonicid, ceforanide,
and cefaclor are active against H influenzae but
not against Serratia or B fragilis.

29. • Dosage forms
– Oral: Cefaclor, cefuroxime axetil, cefprozil, and
loracarbef
– Parenteral: cefonicid, cefoxitin, cefotetan or
ceforanide, cefprozil
Second-Generation Drugs

30. • Clinical uses:
– Second generation cephalosporins are useful in
treatment of:
• infections caused by Bacteroides fragilis ( cefotetan,
cefoxitin )
• sinus, ear, and respiratory infections caused by H
influenzae or M catarrhalis (cefamandole, cefuroxime,
cefaclor ).
Second-Generation Drugs

31. Third-Generation Drugs
• Drugs:
– cefixime,
– cefoperazone,
– cefotaxime,
– cefpodoxime,
– ceftazidime,
– ceftizoxime, and
– ceftriaxone.

32. Third-Generation Drugs
• Antibacterial spectrum:
– Have increased activity against gram-negative
organisms resistant to other beta-lactam drugs
– Most are active against Providencia, Serratia
marcescens, and beta-lactamase-producing strains
of H influenzae and Neisseria;
• they are less active against Enterobacter strains that
produce extended-spectrum beta-lactamases

33. Third-Generation Drugs
• Pharmacokinetic features:
– All drugs in this class (except cefoperazone and
cefixime) penetrate body fluids and tissues well
including the blood-brain barrier
– Most preparations are parenteral; though cefixime
can be given orally

34. Third-Generation Drugs
Clinical uses:
• Drugs in this subclass should usually be reserved for treatment of
serious infections.
– Penicillin-resistant pneumococci (PRSP strains):
• Ceftriaxone and cefotaxime are currently the most active cephalosporins
against penicillin-resistant pneumococci (PRSP strains), but resistance is
reported
– Gonorrhea:
• Ceftriaxone (as a single 125 mg injection) and cefixime (as a single 400 mg
oral dose) are first-line drugs for treatment of gonorrhea now that many
strains of N gonorrhoeae are resistant to penicillin
– Acute otitis media:
• a single injection of ceftriaxone is usually as effective as a 10-day course of
treatment with amoxicillin.
– Meningitis,
• including meningitis caused by pneumococci, meningococci, H influenzae, and
susceptible enteric gram-negative rods, but not by Listeria monocytogenes.
• They should be used in combination with an aminoglycoside for treatment of
meningitis caused by P aeruginosa

35. Fourth-Generation Drugs
• Drugs:
– Cefepime
• The drug is more resistant to beta-lactamases produced
by gram-negative organisms, including:
– Enterobacter, Haemophilus,
– Neisseria, and
– some penicillin-resistant pneumococci.
• Cefepime combines the gram-positive activity of first-
generation agents with the wider gram-negative
spectrum of third-generation cephalosporins.
• Others: cefluprenam, cefozopran, cefpirome

36. Adverse effects of cephalosporins
• Allergy
– Cephalosporins cause a range of allergic reactions from
skin rashes to anaphylactic shock.
– These reactions occur less frequently with cephalosporins
than with penicillins.
– Complete cross-hypersensitivity between different
cephalosporins should be assumed.
– Cross-reactivity between penicillins and cephalosporins is
incomplete (5–10%),
• so penicillin-allergic patients are sometimes treated successfully
with a cephalosporin.
• However, patients with a history of anaphylaxis to penicillins
should not be treated with a cephalosporin.

37. Adverse effects of cephalosporins
• Toxicity:
– Cephalosporins may cause pain at intramuscular
injection sites and phlebitis after intravenous
administration.
– They may increase the nephrotoxicity of
aminoglycosides when the two are administered
together.
• Drugs containing a methylthiotetrazole group (eg,
cefamandole, cefoperazone, cefotetan) may
cause hypoprothrombinemia and disulfiram-like
reactions with ethanol.

38. Other Beta-Lactam Drugs
• Monobactams :
– Contain a monocyclic beta-lactam ring
– They are resistant to beta-lactamases produced by certain gram-
negative rods, including Klebsiella, Pseudomonas, and Serratia
– Example: Aztreonam- inhibit cell wall synthesis
• It has no activity against gram positive bacteria and anaerobes
• Carbapenems:
– chemically different from penicillins
• but retaining the beta-lactam ring structure with low susceptibility to
beta-lactamases
– They have wide activity against gram-positive cocci (including
some penicillin-resistant pneumococci), gram-negative rods, and
anaerobes
– Examples: Imipenem, Meropenem, and Ertapenem

39. Beta-Lactamase Inhibitors
– Clavulanic acid,
– sulbactam, and
– tazobactam
• They are used in fixed combinations with certain
hydrolyzable penicillins.

40. Other Cell Wall or Membrane-Active Agents
• Vancomycin:
– Vancomycin has a narrow spectrum of activity and is used
for serious infections caused by drug-resistant gram-
positive organisms, including methicillin-resistant
staphylococci (MRSA),
• and in combination with a third-generation cephalosporin such as
ceftriaxone for treatment of infections due to penicillin-resistant
pneumococci (PRSP).
• Others:
– Fosfomycin
– Bacitracin
– Cycloserine
– Daptomycin

41. – Inhibitors of bacterial protein synthesis:
• Bacteriostatic inhibitors of bacterial protein synthesis:
– Chloramphenicol, Tetracyclines, Macrolides, Clindamycin,
Streptogramins, & Linezolid
• Aminoglycosides- bactericidal inhibitors of protein synthesis
– Act in a concentration dependent mode
– Sulfonamides, Trimethoprim:
• Antifolate: bacteriostatic inhibitors of folic acid synthesis
• E.g Trimethoprim Plus Sulfamethoxazole (co-trimoxazole )
– Fluoroquinolones:
• inhibitors of bacterial DNA synthesis
– Antimycobacterial Drugs:
• Varied modes of action
Other antibacterial agents

42. Inhibitors of bacterial protein synthesis
• Antibiotics acting by selective inhibition of bacterial
protein synthesis:
– Chloramphenicol,
– Tetracyclines,
– Macrolides,
– Clindamycin
– Aminoglycosides
• Mechanisms of protein synthesis in microorganisms
differ to those of mammalian cells:
– Bacteria have 70S ribosomes, whereas
– mammalian cells have 80S ribosomes

43. Inhibitors of bacterial protein synthesis
• Inhibitors of microbial protein synthesis considerably
vary in chemical structures and spectrum of
antimicrobial activity:
– Chloramphenicol, tetracyclines, and the aminoglycosides
• The first drugs to be introduced in this category
• Overused due to their broad spectrum of antibacterial activity and
low toxicities, hence emergence of resistance
– Macrolides:
• Erythromycin; an older macrolide antibiotic, with a narrower
spectrum of action;
– but continues to be active against several important pathogens.
• Azithromycin and clarithromycin; semisynthetic macrolides, have
some distinctive properties compared with erythromycin, as does
clindamycin.
– Newer inhibitors of microbial protein synthesis:
• streptogramins, linezolid, telithromycin, and tigecycline (a
tetracycline analog)
• These have activity against certain bacteria that have developed
resistance to older antibiotics

44. Inhibitors of bacterial protein synthesis
Mechanisms of Action
• Chloramphenicol, Tetracyclines, Macrolides and
Clindamycin are bacteriostatic inhibitors of
protein synthesis acting at the ribosomal level
(Figure 44–1).
• All of these antibiotics bind on the 50S ribosomal
subunit; except
– Tetracyclines which binds on the 30S ribosomal
subunit
• Refer to Figure 44-1 for details on the specific
mechanisms

45. Chloramphenicol
Classification and Pharmacokinetics
• Chloramphenicol
– Possesses a simple and distinctive structure,
– remains the only drug in this chemical class
• Administered both orally as well as parenterally
– After oral administration, the drug is rapidly and completely absorbed
– It is widely distributed; readily crossing the placental and blood-brain
barriers.
• Most of the drug is inactivated in the liver either by conjugation with
glucuronic acid through the action of glucuronosyltransferase or by
reduction
• Active chloramphenicol (about 10% of the total dose administered)
and its inactive degradation products (about 90% of the total) are
eliminated in the urine
• A small amount of active drug is excreted into bile and feces and may
undergo enterohepatic cycling

46. Chloramphenicol
Antimicrobial Activity
• Has a wide spectrum of antimicrobial activity
– usually bacteriostatic.
• However, it has bactericidal action against some strains of:
– Haemophilus influenzae,
– Neisseria meningitidis, and
– Bacteroides.
» It is not active against Chlamydia species.
• Resistance:
– plasmid-mediated, through;
• the formation of acetyltransferases that inactivate the drug.
– Low-level resistance to chloramphenicol may emerge from
large populations of chloramphenicol-susceptible cells by
selection of mutants that are less permeable to the drug

47. Chloramphenicol
Clinical Uses
• Chloramphenicol has very few uses as a systemic drug
owing to its toxicity.
• A backup drug for:
– severe infections caused by Salmonella species
– for the treatment of pneumococcal and meningococcal
meningitis in beta-lactam–sensitive persons.
• Sometimes used for rickettsial diseases and for
infections caused by anaerobes such as Bacteroides
fragilis.
• The drug is commonly used as a
– topical antimicrobial agent

48. Chloramphenicol
Adverse reactions:
• Gastrointestinal Disturbances
– These conditions may occur from direct irritation and from superinfections,
especially candidiasis.
• Bone Marrow
– Dose-dependent (but reversible) inhibition of red cell maturation leading to a
decrease in circulating erythrocytes.
– Aplastic anemia:
• a rare idiosyncratic reaction which is usually irreversible and may be fatal (approximately
1 case in 25,000–40,000 patients treated).
• Gray Baby Syndrome
– occurs in infants and is characterized by:
• decreased red blood cells, cyanosis, and cardiovascular collapse.
– Premature neonates, who are deficient in hepatic glucuronosyltransferase are
sensitive to doses of chloramphenicol, which would be tolerated in older
infants.

49. Chloramphenicol
Drug Interactions
• Chloramphenicol inhibits hepatic drug-
metabolizing enzymes,
– thus increasing the elimination half-lives of some
drugs including:
• phenytoin,
• tolbutamide
• and warfarin.

50. Tetracyclines
Classification
• Broad-spectrum bacteriostatic antibiotics;
– Show minor differences in their activities against specific
organisms.
• Drugs:
– Tetracycline (prototype)
– Chlortetracycline
– Oxytetracycline
– Doxycycline
– Minocycline
– Demeclocycline
– Methacycline
– Tigecycline

51. Tetracyclines
Pharmacokinetics
• Variable oral absorption, usually impaired by;
– foods and multivalent cations (calcium, iron, aluminum).
• Have a wide tissue distribution and cross the placental barrier;
– Distribution in the CNS is however poor ( 10-25% of the concentration in serum)
• The mode of excretion of tetracyclines is both through urine and bile
– All undergo enterohepatic cycling.
• Unlike other tetracyclines that are eliminated primarily in the urine,
– Doxycycline and tigecycline are excreted mainly in feces
• Based on half life, tetracyclines can be classified into three categories:
– Short acting (half life: 6-8 hrs)- tetracycline, chlortetracycline,, oxytetracycline
– Intermediate acting (half life: 12 hrs)- demeclocycline and methacycline
– Long acting ( half life: 16-18 hrs)- doxycycline and minocycline
• Tigecycline is poorly absorbed orally and therefore formulated only for IV
use,
– It is eliminated in the bile and has a half-life of 30–36 h.

52. Tetracyclines
Antibacterial Activity
• Broad-spectrum with activity against gram-positive and
gram-negative bacteria;
– Including species of Rickettsia, Chlamydia, Mycoplasma,
and some protozoa.
• Resistance is widespread:
– the development of mechanisms (efflux pumps) for active
extrusion of tetracyclines and the formation of ribosomal
protection proteins that interfere with tetracycline binding.
– These mechanisms do not confer resistance to tigecycline
in most organisms, with the exception of the multidrug
efflux pumps of Proteus and Pseudomonas species.

53. Clinical Uses
• Primary Uses
– Tetracyclines are recommended in the treatment of infections caused
by:
• Mycoplasma pneumoniae (in adults),
• chlamydiae,
• Rickettsiae,
• vibrios,
• and some spirochetes.
– Doxycycline is currently an alternative to macrolides in the initial
treatment of community-acquired pneumonia.
• Secondary Uses:
– Tetracyclines are alternative drugs in the treatment of syphilis.
– They are also used in:
• the treatment of respiratory infections caused by susceptible organisms,
• for prophylaxis against infection in chronic bronchitis,
• in the treatment of leptospirosis, and
• in the treatment of acne.
Tetracyclines

54. • Selective Uses
– Specific tetracyclines are used in the treatment of:
• gastrointestinal ulcers caused by Helicobacter pylori
(tetracycline),
• in Lyme disease (doxycycline),
• and in the meningococcal carrier state (minocycline).
• Doxycycline is also used for the prevention of malaria and in
the treatment of amebiasis.
• Demeclocycline inhibits the renal actions of antidiuretic
hormone (ADH) and is used in the management of patients
with ADH-secreting tumors (Chapter 15).
• Brucellosis (Doxycycline)
• Trachoma (chlamydia trachomatis)- tetracycline
Tetracyclines

55. Tigecycline (a derivative of minocycline)
• Unique features include a broad spectrum of
action that includes organisms resistant to
standard tetracyclines.
• The antimicrobial activity of tigecycline includes:
– gram-positive cocci resistant to methicillin (MRSA
strains) and vancomycin (vancomycin resistant
enterococci-VRE strains),
– beta-lactamase–producing gram-negative bacteria,
anaerobes, chlamydiae, and mycobacteria.
• The drug is formulated only for intravenous use.
Tetracyclines

56. Adverse reactions
• Gastrointestinal Disturbances
– Effects on the gastrointestinal system range from mild nausea and diarrhea to severe,
possibly life-threatening enterocolitis;
• Disturbances in the normal flora may lead to candidiasis (oral and vaginal) and, more rarely, to
bacterial superinfections with S aureus or Clostridium difficile.
• Bony Structures and Teeth
– Fetal exposure to tetracyclines may lead to tooth enamel dysplasia and irregularities in
bone growth. Although usually contraindicated in pregnancy, there may be situations in
which the benefit of tetracyclines outweigh the risk.
– Treatment of younger children may cause enamel dysplasia and crown deformation
when permanent teeth appear.
• Hepatic Toxicity
– High doses of tetracyclines, especially in pregnant patients and those with preexisting
hepatic disease, may impair liver function and lead to hepatic necrosis.
• Renal Toxicity
– Older tetracyclines are associated with Fanconi's syndrome: One form of renal tubular
acidosis developing as a result of decreased reabsorption of bicarbonate in the proximal
tubules
– Though not directly nephrotoxic, tetracyclines may exacerbate preexisting renal
dysfunction.
Tetracyclines

57. • Photosensitivity
– Tetracyclines, especially demeclocycline, may
cause enhanced skin sensitivity to ultraviolet light.
• Vestibular Toxicity
– Dose-dependent reversible dizziness and vertigo
have been reported with doxycycline and
minocycline.
Tetracyclines

58. Macrolides
Classification and Pharmacokinetics
• The macrolide antibiotics:
– Erythromycin,
– Azithromycin, and
– Clarithromycin
• These are large cyclic lactone ring structures with attached sugars.
• The drugs have good oral bioavailability, but azithromycin
absorption is impeded by food.
• Macrolides distribute to most body tissues,
– but azithromycin is unique in that the levels achieved in tissues and in
phagocytes are considerably higher than those in the plasma.
• Elimination:
– Erythromycin: via biliary excretion half life 2 h
– Clarithromycin: via hepatic metabolism and urinary excretion of intact
drug; half life 2 h .
– Azithromycin: mainly via urine as unchanged drug. half-life 2–4 days

59. Antibacterial Activity
• Erythromycin has activity against many species of:
– Campylobacter,
– Chlamydia,
– Mycoplasma,
– Legionella,
– gram-positive cocci, and some gram-negative organisms.
• Azithromycin and clarithromycin spectrum similar to
erythromycin;
– but include greater activity against species of Chlamydia
,Mycobacterium avium complex, and Toxoplasma.
• Azithromycin is also effective in gonorrhea, as an
alternative to ceftriaxone and in syphilis, as an
alternative to penicillin G.
Macrolides

60. Macrolides
• Resistance to the macrolides in gram-positive
organisms involves:
– efflux pump mechanisms and the production of a
methylase that adds a methyl group to the ribosomal
binding site.
– Cross-resistance between individual macrolides is
complete.
– In the case of methylase-producing microbial strains, there
is partial cross-resistance with other drugs that bind to the
same ribosomal site as macrolides, including clindamycin
and streptogramins.
• Resistance in Enterobacteriaceae is the result of
formation of drug-metabolizing esterases.

61. Clinical Uses
• Erythromycin is effective in the treatment of infections
caused by:
– M pneumoniae,
– Corynebacterium,
– Campylobacter jejuni,Chlamydia trachomatis,
– Chlamydophila pneumoniae,
– Legionella pneumophila,
– Ureaplasma urealyticum, and
– Bordetella pertussis.
• The drug is also active against gram-positive cocci (but not
penicillin-resistant Streptococcus pneumoniae [PRSP] strains)
and
– beta-lactamase–producing staphylococci (but not methicillin-
resistant S aureus [MRSA] strains).
Macrolides

62. Macrolides
• Azithromycin has a similar spectrum of activity
– but is more active against H influenzae, Moraxella catarrhalis,
and Neisseria.
– Because of its long half-life, a single dose of azithromycin is
effective in the treatment of urogenital infections caused by C
trachomatis, and a 4-day course of treatment has been effective
in community-acquired pneumonia.
• Clarithromycin
– has almost the same spectrum of antimicrobial activity and
clinical uses as erythromycin.
– The drug is also used for prophylaxis against and treatment of
M avium complex and as a component of drug regimens for
ulcers caused by H pylori.

63. Adverse reactions:
• Common adverse effects associated with macrolides:
– gastrointestinal irritation (common) via stimulation of motilin
receptors,
– skin rashes, and
– eosinophilia.
– Note: the above are more common with erythromycin
compared to the others
• Hepatitis:
– A hypersensitivity-based acute cholestatic hepatitis may occur
with erythromycin estolate.
– Hepatitis is rare in children, but there is an increased risk with
erythromycin estolate in the pregnant patient.
Macrolides

64. Drug interactions:
• Erythromycin and clarithromycin inhibit several forms of hepatic
cytochrome P450 and can increase the plasma levels of many drugs,
including:
– anticoagulants,
– carbamazepine,
– cisapride,
– digoxin, and
– theophylline.
• The lactone ring structure of azithromycin is slightly different from
that of other macrolides, and drug interactions are uncommon
because azithromycin does not inhibit hepatic cytochrome P450.
Macrolides

65. Clindamycin
Classification and Pharmacokinetics
• Clindamycin inhibits bacterial protein synthesis via a
mechanism similar to that of the macrolides,
– although it is not chemically related.
• Resistance:
– Mechanisms of resistance include:
• methylation of the binding site on the 50S ribosomal subunit and
enzymatic inactivation.
– Gram-negative aerobes are intrinsically resistant because of
poor penetration of clindamycin through the outer membrane.
– Cross-resistance between clindamycin and macrolides is
common.
• Good tissue penetration occurs after oral absorption.
• Clindamycin undergoes hepatic metabolism,
– and both intact drug and metabolites are eliminated by biliary
and renal excretion.

66. Clinical Use and Toxicity:
• Uses:
– treatment of severe infections caused by certain anaerobes such as
Bacteroides.
– backup drug against gram-positive cocci (it is active against community-
acquired strains of methicillin-resistant S aureus) and is recommended
for prophylaxis of endocarditis in valvular disease patients who are
allergic to penicillin.
– The drug is also active against Pneumocystis jiroveci and is used in
combination with pyrimethamine for AIDS-related toxoplasmosis.
• Toxicity:
– gastrointestinal irritation,
– skin rashes,
– neutropenia,
– hepatic dysfunction,
– and possible superinfections such as C difficile pseudomembranous
colitis.
Clindamycin

67. Telithromycin
• Telithromycin is a ketolide structurally related to macrolides.
• The drug has the same mechanism of action as erythromycin and a similar
spectrum of antimicrobial activity.
– However, some macrolide-resistant strains are susceptible to telithromycin
because it binds more tightly to ribosomes and is a poor substrate for bacterial
efflux pumps that mediate resistance.
• The drug can be used in community-acquired pneumonia including
infections caused by multidrug-resistant organisms.
• Telithromycin is given orally once daily and is eliminated in bile and urine.
• The adverse effects of telithromycin include:
– hepatic dysfunction and prolongation of the QTc interval.
– The drug is an inhibitor of the CYP3A4 drug-metabolizing system.
• CYP3A4 is a member of the cytochrome p450 group of enzymes

68. Streptogramins
• Streptogramins are bactericidal; bind to 50s
ribosomal subunit
– Example- Quinupristin-dalfopristin
• Antibacterial activity:
– penicillin-resistant pneumococci,
– methicillin-resistant (MRSA) and
– vancomycin-resistant staphylococci (VRSA), and
resistant Enterococcus faecium;
• Enterococcus faecalis is intrinsically resistant via an efflux
transport system.
• Administered intravenously, the drugs may cause
pain and an arthralgia-myalgia syndrome.

69. • Streptogramins are potent inhibitors of
CYP3A4 and increase plasma levels of many
drugs, including:
– astemizole,
– cisapride,
– cyclosporine,
– diazepam,
– nonnucleoside reverse transcriptase inhibitors,
– and warfarin.
Streptogramins

70. Linezolid
• The first of a novel class of antibiotics (oxazolidinones),
linezolid is active against:
– drug-resistant gram-positive cocci, including strains
resistant to penicillins (eg, MRSA, PRSP)
– vancomycin (eg, VRE).
– L monocytogenes and corynebacteria.
• Linezolid binds to a unique site located on the 23S
ribosomal RNA of the 50S ribosomal subunit,
– and there is currently no cross-resistance with other
protein synthesis inhibitors.
• Resistance (rare to date) involves a decreased affinity
of linezolid for its binding site.

71. • Linezolid is available in both oral and parenteral
formulations and should be reserved for
treatment of infections caused by multidrug-
resistant gram-positive bacteria.
• The drug is metabolized by the liver and has an
elimination half-life of 4–6 h.
• Thrombocytopenia and neutropenia occur, most
commonly in immunosuppressed patients.
• Linezolid has been implicated in the serotonin
syndrome when used in patients taking selective
serotonin reuptake inhibitors (SSRIs).
Linezolid

72. Aminoglycosides
Introduction:
• Minimal inhibitory concentration (MIC) should
be attained through multiple daily antibiotic
dosage in rx of microbial infxns
• For many antibiotics (e.g penicillins) the micro-
organism killing action is time-dependent;
– in vivo efficacy is directly related to time above
MIC and becomes independent of concentration
once the MIC has been reached

73. • Characteristics of aminoglycosides:
– Concentration-dependent killing action:
• As the plasma level is increased above the MIC, some
antibiotics (e.g. aminoglycosides) kill an increasing
proportion of bacteria and do so at a more rapid rate
– Postantibiotic effect: killing action continues even
when their plasma levels have declined below
measurable levels
– Toxicity is lower with a single large dose than multiple
small doses
The above characteristics form the basis for single
high dosing for aminoglycosides
Aminoglycosides

74. Mechanism of Action
• Aminoglycosides are bactericidal inhibitors of protein synthesis.
– Their penetration through the bacterial cell envelope is partly
dependent on oxygen-dependent active transport, and they have
minimal activity against strict anaerobes.
• Aminoglycoside transport is enhanced by cell wall synthesis
inhibitors, which may be the basis for their antimicrobial synergism.
• The drugs interfere with protein synthesis by binding to the 30S
ribosomal subunit (Figure 45–1). Inhibition of protein synthesis
occurs in three ways:
– (1) they block formation of the initiation complex;
– (2) they cause misreading of the code on the mRNA template; and
– (3) they inhibit translocation
Aminoglycosides

75. • Drugs:
– Gentamicin
– Amikacin
– Tobramycin
– Streptomycin
– Kanamycin
– Netilmicin
– Spectinomycin
Aminoglycosides

76. Pharmacokinetics
• Aminoglycosides are structurally related amino sugars attached by
glycosidic linkages.
• They are polar compounds, not absorbed after oral administration
and must be given intramuscularly, or intravenously for systemic
effect.
• They have limited tissue penetration and do not readily cross the
blood-brain barrier.
• Glomerular filtration is the major mode of excretion, and plasma
levels of these drugs are greatly affected by changes in renal
function.
– Excretion of aminoglycosides is directly proportional to creatinine
clearance.
– With normal renal function, the elimination half-life of aminoglycosides
is 2–3 h.
Aminoglycosides

77. • Dosage adjustments must be made in renal
insufficiency to prevent toxic accumulation.
• Monitoring of plasma levels of aminoglycosides is
important for safe and effective dosage selection
and adjustment.
• For traditional dosing regimens (2 or 3 times
daily), peak serum levels are measured 30–60
min after administration and trough levels just
before the next dose.
– With once-daily dosing, peak levels are less important
since they will naturally be high.
Aminoglycosides

78. Resistance:
• the primary mechanism of resistance to
aminoglycosides, especially in gram-negative
bacteria, involves
– the plasmid-mediated formation of inactivating
enzymes (group transferases)
• Other mechanisms:
• changes in porin protein structure that lead to impaired entry
of aminoglycoside into the cell
• Impaired binding of the drug on the target site due to
alteration in the structure of the receptor protein in the 30S
ribosomal sub unit
Aminoglycosides

79. Clinical Uses:
• Aminoglycosides vary in their activities against
specific organisms, particularly gram-negative
rods:
• Gentamicin, tobramycin, and amikacin:
– treatment of serious infections caused by:
• aerobic gram-negative bacteria, including Escherichia coli and
Enterobacter, Klebsiella, Proteus
– Also active against strains of Haemophilus influenzae,
Moraxella catarrhalis, and Shigella species,
– although they are not drugs of choice for infections caused by
these organisms
• In most cases, aminoglycosides are used in combination with
a beta-lactam antibiotic
Aminoglycosides

80. • Streptomycin:
– Enterococcal carditis (in combination with
penicillins).
– Tuberculosis,
– Plague, and
– Tularemia
• Neomycin and kanamycin:
– Have a high toxic potential;
• Hence use limited to topical or oral use
– e.g., to eliminate bowel flora.
Aminoglycosides

81. • Netilmicin
– treatment of serious infections caused by organisms
resistant to the other aminoglycosides.
– However, it is no longer available in the United States.
• Spectinomycin
– an aminocyclitol related to the aminoglycosides.
– Its sole use is as a backup drug,
• administered intramuscularly as a single dose for the treatment of
gonorrhea, most commonly used in patients allergic to beta-
lactams.
• There is no cross-resistance with other drugs used in gonorrhea.
– Spectinomycin may cause pain at the injection site.
Aminoglycosides

82. Adverse reactions:
• Ototoxicity
– Auditory or vestibular damage (or both) may occur with any
aminoglycoside and may be irreversible.
– Auditory impairment is more likely with amikacin and
kanamycin;
– vestibular dysfunction is more likely with gentamicin and
tobramycin.
– Ototoxicity risk is proportional to the plasma levels and thus is
especially high if dosage is not appropriately modified in a
patient with renal dysfunction. Ototoxicity may be increased by
the use of loop diuretics.
– Because ototoxicity has been reported after fetal exposure, the
aminoglycosides are contraindicated in pregnancy unless their
potential benefits are judged to outweigh risk.
Aminoglycosides

83. • Nephrotoxicity:
– Renal toxicity usually takes the form of acute
tubular necrosis.
– This adverse effect, which is often reversible, is
more common in elderly patients and in those
concurrently receiving amphotericin B,
cephalosporins, or vancomycin.
• Gentamicin and tobramycin are the most nephrotoxic.
Aminoglycosides

84. • Neuromuscular blockade:
– Though rare, a curare-like block (inhibition of nicotinic
acetylcholine receptors at the neuromuscular junction)
may occur at high doses of aminoglycosides and may result
in respiratory paralysis.
– It is usually reversible by treatment with calcium and
neostigmine, but ventilatory support may be required.
• Skin reactions:
– Allergic skin reactions may occur in patients, and contact
dermatitis may occur in personnel handling the drug.
– Neomycin is the agent most likely to cause this adverse
effect.
Aminoglycosides

85. Sulfonamides, Trimethoprim, &
Fluoroquinolones
• Sulfonamides and trimethoprim (antifolate
drugs):
– antimetabolites selectively toxic to microorganisms
because they interfere with folic acid synthesis.
– Sulfonamides continue to be used selectively as
individual antimicrobial agents, although resistance is
common.
– The combination of a sulfonamide with trimethoprim
results in sequential blockade of folic acid synthesis,
thus producing a synergistic action against a wide
spectrum of microorganisms;
• resistance occurs but has been relatively slow in
development

86. • Fluoroquinolones:
– selectively inhibit microbial nucleic acid
metabolism,
– have a broad spectrum of antimicrobial activity
that includes many common pathogens.
– Emergence of resistance associated with the older
antibiotics is present in this class,
• but countered to some extent by the introduction of
newer fluoroquinolones with expanded activity against
common pathogenic organisms.

87. Sulphonamides
Introduction and features:
• The sulfonamides are weakly acidic compounds that have a common
chemical nucleus resembling p-aminobenzoic acid (PABA).
• Members of this group differ mainly in their pharmacokinetic
properties and clinical uses.
• Pharmacokinetic features:
– modest tissue penetration,
– hepatic metabolism, and excretion of both intact drug and acetylated
metabolites in the urine.
– Solubility may be decreased in acidic urine, resulting in precipitation of
the drug or its metabolites.
– Because of the solubility limitation, a combination of 3 separate
sulfonamides ( triple sulfa ) has been used to reduce the likelihood that
any one drug will precipitate.
– Sulfonamides bind to plasma proteins at sites shared by bilirubin and by
other drugs

88. Sulphonamides
Classification:
Mode of administration:
• Oral absorbable agents: Sulfisoxazole,
sulfamethoxazole, sulfadiazine, sulfadoxine
• Oral nonabsorbable agents: Sulfasalazine
• Topical agents: Sodium sulfacetamide, silver
sulfadiazine
Oral absorbable sulphonamides further sub
classified on basis of duration of action:
• short-acting (eg, sulfisoxazole),
• intermediate-acting (eg, sulfamethoxazole),
• long-acting (eg, sulfadoxine).

89. Mechanisms of Action:
• The sulfonamides are bacteriostatic inhibitors of folic
acid synthesis.
– Act as antimetabolites of PABA,
• they are competitive inhibitors of dihydropteroate synthase (Figure
46–1).
– They can also act as substrates for this enzyme, resulting in
the synthesis of nonfunctional forms of folic acid.
• The selective toxicity of sulfonamides results from the
inability of mammalian cells to synthesize folic acid;
– they must use preformed folic acid that is present in the
diet.
Refer to FIGURE 46–1
Sulphonamides

90. Sulphonamides
Clinical uses:
• The sulfonamides are active against:
– gram-positive and gram-negative organisms, Chlamydia, and
Nocardia.
• Specific members of the sulfonamide group are used by the
following routes for the conditions indicated:
– Simple Urinary Tract Infections: Oral (eg, triple sulfa,
sulfisoxazole).
– Ocular Infections: Topical (eg, sulfacetamide).
– Burn Infections: Topical (eg, mafenide, silver sulfadiazine).
– Ulcerative Colitis, Rheumatoid Arthritis: Oral (eg, sulfasalazine).
– Toxoplasmosis: Oral sulfadiazine plus pyrimethamine (a
dihydrofolate reductase inhibitor) plus folinic acid.

91. Sulphonamides
Adverse drug reactions:
• Hypersensitivity
– Allergic reactions, including skin rashes and fever, occur
commonly.
– Cross-allergenicity between the individual sulfonamides
should be assumed and may also occur with chemically
related drugs (eg, oral hypoglycemics, thiazides).
– Exfoliative dermatitis, polyarteritis nodosa, and Stevens-
Johnson syndrome have occurred rarely.
• Gastrointestinal
– Nausea, vomiting, and diarrhea occur commonly.
• Hepatotoxicity:
– Mild hepatic dysfunction can occur, but hepatitis is
uncommon.

92. • Hematotoxicity
– Although such effects are rare, sulfonamides can
cause granulocytopenia, thrombocytopenia, and
aplastic anemia.
– Acute hemolysis may occur in persons with
glucose-6-phosphate dehydrogenase deficiency.
• Nephrotoxicity
– Sulfonamides may precipitate in the urine at acidic
pH, causing crystalluria and hematuria.

93. Drug Interactions:
• Competition with warfarin and methotrexate
for plasma protein binding transiently
increases the plasma levels of these drugs.
• Sulfonamides can displace bilirubin from
plasma proteins, with the risk of kernicterus in
the neonate if used in the third trimester of
pregnancy.

94. Trimethoprim
• Features/mechanism of action:
– a selective inhibitor of bacterial dihydrofolate
reductase that prevents formation of the active
tetrahydro form of folic acid
– Bacterial dihydrofolate reductase is 4–5 orders of
magnitude more sensitive to inhibition by
trimethoprim than the mammalian enzyme.
– Trimethoprim is usually given as a combination with
sulphonamides due to their synergistic sequential
blockade of bacterial folic acid synthesis:
• Co-trimoxazole- Trimethoprim-Sulfamethoxazole (TMP-
SMZ)

95. • Toxicity of Trimethoprim
– may cause the predictable adverse effects of an antifolate
drug;
• megaloblastic anemia,
• leukopenia, and
• granulocytopenia.
– These effects are usually ameliorated by supplementary
folinic acid.
– The combination of TMP-SMZ may cause any of the
adverse effects associated with the sulfonamides.
– AIDS patients given TMP-SMZ have a high incidence of
adverse effects, including fever, rashes, leukopenia, and
diarrhea

96. Trimethoprim- Sulphamethoxazole (TMZ-SMZ)
• When the 2 drugs are used in combination,
antimicrobial synergy results from the
sequential blockade of folate synthesis (Figure
46–1). The drug combination is bactericidal
against susceptible organisms.
• Clinical uses:
Useful in treatment of:
– urinary tract infections
– Respiratory infections
– Ear infections

97. – sinus infections caused by Haemophilus influenzae and
Moraxella catarrhalis.
– Opportunistic infections in the immunocompromised
patient: drug of choice for:
• Aeromonas hydrophila
• Pneumocystis pneumonia. An intravenous formulation is
available for patients unable to take the drug by mouth and is
used for treatment of severe pneumocystis pneumonia and for
gram-negative sepsis.
– Nocardiosis (drug of choice)
– cholera (possible backup drug) ,
– typhoid fever,
– shigellosis,
– infections caused by methicillin-resistant staphylococci
and Listeria monocytogenes.

98. Fluoroquinolones (quinolones)
Most quinolones are synthetic fluorinated analogs
of nalidixic acid
Classification:
• Fluoroquinolines are classified by "generation"
based on their antimicrobial spectrum of activity:
1st, 2nd and 3rd generation
– first-generation fluoroquinolone: Norfloxacin,
• has activity against the common pathogens that cause
urinary tract infections.
– second-generation fluoroquinolones: Ciprofloxacin
and ofloxacin
• have greater activity against gram-negative bacteria and are
also active against the gonococcus, many gram-positive
cocci, mycobacteria, and agents of atypical pneumonia
(Mycoplasma pneumoniae, Chlamydophila pneumoniae).

99. – Third-generation fluoroquinolones: levofloxacin,
gemifloxacin, and moxifloxacin
• are slightly less active than ciprofloxacin and ofloxacin
against gram-negative bacteria but have greater activity
against gram-positive cocci, including S pneumoniae and
some strains of enterococci and methicillin-resistant
Staphylococcus aureus (MRSA).
• commonly referred to as "respiratory fluoroquinolones."
• The most recently introduced drugs (eg, gemifloxacin,
moxifloxacin) are the broadest-spectrum
fluoroquinolones introduced to date, with enhanced
activity against anaerobes.
Fluoroquinolones (quinolones)

100. Fluoroquinolones (quinolones)
Mechanism of Action
• The fluoroquinolones interfere with bacterial DNA synthesis
by inhibiting:
– topoisomerase II (DNA gyrase), especially in gram-negative
organisms and
– topoisomerase IV, especially in gram-positive organisms
• DNA gyrase is required for the relaxation of supercoiled
DNA,
– a step required for normal transcription and duplication
• Topoisomerase IV catalyzes separation of replicated
chromosomal DNA during cell division.
• Quinolones are usually bactericidal against susceptible
organisms
• Like aminoglycosides, they have post antibiotic effect

101. Resistance:
• This has emerged rapidly in second-generation
fluoroquinolones,
– especially in Campylobacter jejuni and gonococci,
but also in gram-positive cocci (eg, MRSA),
Pseudomonas aeruginosa and Serratia species.
– Mechanisms of resistance include:
• decreased intracellular accumulation of the drug via
the production of efflux pumps or changes in porin
structure (in gram-negative bacteria).
Fluoroquinolones (quinolones)

102. Fluoroquinolones (quinolones)
Clinical Use:
• urogenital and gastrointestinal tracts infections
caused by:
– gram-negative organisms, including:
• gonococci,
• E coli,
• Klebsiella pneumoniae,
• Campylobacter jejuni, Enterobacter, Pseudomonas aeruginosa,
Salmonella, and Shigella species.
• Respiratory tract infections
• Skin infections
• Soft tissue infections,
– their effectiveness on the above (respiratory tract
infections, skin infections and soft tissue infections) is
now variable because of the emergence of resistance.

103. • Gonorohoea:
– Ciprofloxacin and ofloxacin in single oral doses
have been used as alternatives to ceftriaxone or
cefixime in gonorrhea, but they are not currently
recommended because resistance is now
common.
• Chlamydia trachomatis:
– Ofloxacin eradicates Chlamydia trachomatis, but a
7-d course of treatment is required.
Fluoroquinolones (quinolones)

104. • Community-acquired pneumonia,
– Levofloxacin has activity against organisms associated with
community pneumonia including chlamydiae, mycoplasma, and
legionella
– Gemifloxacin and moxifloxacin have the widest spectrum of
activity, which includes both gram-positive and gram-negative
organisms, atypical pneumonia agents, and some anaerobic
bacteria.
• Fluoroquinolones have also been used in the:
– meningococcal carrier state
– treatment of tuberculosis
– prophylactic management of neutropenic patients.
Fluoroquinolones (quinolones)

105. Fluoroquinolones (quinolones)
Adverse reactions:
• Gastrointestinal distress (the most common adverse effect).
• skin rashes,
• headache,
• dizziness,
• insomnia,
• abnormal liver function tests,
• phototoxicity,
• both tendinitis and tendon rupture.
• Opportunistic infections caused by C albicans and streptococci have
occurred.
• The fluoroquinolones are not recommended for children or
pregnant women because they may damage growing cartilage and
cause arthropathy.

106. Fluoroquinolones (quinolones)
• Drug interactions:
– Fluoroquinolones may increase the plasma levels
of theophylline and other methylxanthines,
enhancing their toxicity.
– Newer fluoroquinolones (gemifloxacin,
levofloxacin, moxifloxacin) prolong the QTc
interval.
• They should be avoided in patients with known QTc
prolongation and those on certain antiarrhythmic drugs
or other drugs that increase the QTc interval.

107. Antimycobacterial Drugs
Introduction
• Challenges in treatment of infections caused by Mycobacterium
tuberculosis, M leprae, and M avium-intracellulare :
– (1) limited information about the mechanisms of antimycobacterial
drug actions;
– (2) the development of resistance;
– (3) the intracellular location of mycobacteria;
– (4) the chronic nature of mycobacterial disease, which requires
protracted drug treatment and is associated with drug toxicities; and
– (5) patient compliance.
• Chemotherapy of mycobacterial infections almost always involves
the use of drug combinations to delay the emergence of resistance
and to enhance antimycobacterial efficacy.

108. Classification:
• Drugs in treatment of tuberculosis:
– First line:
• Isoniazid (INH),
• Pyrazinamide,
• Rifamycins (Rifampicin, rifabutin, rifapentine),
• Streptomycin,
• Ethambutol
– Second line (Alternative drugs):
• Amikacin,
• Ciprofloxacin, ofloxacin
• Ethionamide,
• p-Aminosalicylic acid (PAS)
Antimycobacterial Drugs

109. • Drugs in treatment of atypical tuberculosis:
–Drugs for major infections
–Drugs for minor infections
• Drugs for treatment of leprosy:
–Sulfones:
• Dapsone
• Acedapsone
Antimycobacterial Drugs

110. First line Drugs for Tuberculosis
Isoniazid (INH)
• Mechanism of action:
– Requires bioactivation;
– Bactericidal
– inhibits mycolic acid synthesis;
• Resistance:
– Linked to mutation of genes that code for proteins
involved in:
• activation of INH
• Binding the drug to inhibit mycolic acid synthesis
• Clinical use:
– primary drug for (Latent TB Infection) LTBI and a
primary drug for use in combinations

111. • Pharmacokinetics:
– Oral and IV forms;
– Well distributed in tissues including CNS
– hepatic clearance ( varies among fast and slow
acetylators);
• Adverse reactions:
– Hepatotoxicity,
– peripheral neuropathy (use pyridoxine);
– hemolysis in G6PDH deficiency
• Drug interactions:
– inhibits metabolism of carbamazepine, pheytoin and
warfarin
First Line Drugs for Tuberculosis

112. Rifamycins
– Rifampin (RIF)
– Rifabutin
– Rifapentine
• Mechanism of action:
– Inhibit DNA-dependent RNA polymerase;
– bactericidal;
• Resistance: emerges rapidly when the drug is used
alone
• Clinical uses:
– RIF is an optional drug for LTBI, a primary drug used in
combinations for active TB
• Pharmacokinetics:
– Rifampin (oral, IV); others oral;
– enterohepatic cycling with some metabolism;
First Line Drugs for Tuberculosis

113. • Adverse reactions:
– Rash, nephritis, cholestasis, thrombocytopenia; flu-
like syndrome with intermittent dosing
• Drug interactions:
– induced formation of CYP450 by RIF leads to
decreased efficacy of many drugs;
• anticonvulsants, contraceptive steroids, cyclosporine,
ketoconazole, methadone, terbinafine, and warfarin
– Rifabutin causes less drug interactions compared to
RIF;
– Rifabutin is effective as an antimicrobial agent and is
preferable in treatment of TB in AIDS patients
First Line Drugs for Tuberculosis

114. Ethambutol (ETB):
• Mechanism of action:
– Inhibits formation of arabinoglycan, a component of
mycobacterial cell wall;
– Bacteriostatic
• Resistance: emerges rapidly if drug is used alone;
• Clinical use:
– component of many drug combination regimens for active
TB
• Pharmacokinetics:
– Orally administered
– Well distributed in tissues including CNS
– renal elimination with a large fraction of the drug excreted
unchanged; reduce dose in renal dysfunction
First Line Drugs for Tuberculosis

115. • Adverse reactions:
– Dose-dependent visual disturbances, reversible on
discontinuance;
– headache,
– confusion,
– hyperuricemia
– peripheral neuritis
First Line Drugs for Tuberculosis

116. Pyrazinamide (PYR)
• Mechanism not known, but requires bioactivation via
hydrolytic enzymes (mycobacterial pyrazinamidase) to
form pyrazoic acid (active)
– Bacteriostatic;
• Pharmacokinetics:
– Given orally
– penetrates most body tissues, including the CNS
– both hepatic and renal elimination (reduce dose in
dysfunction)
• Clinical use;
– component of many drug combination regimens for active
TB
First Line Drugs for Tuberculosis

117. • Adverse reactions
– Polyarthralgia (40% incidence),
– hyperuricemia,
– myalgia,
– maculopapular rash,
– porphyria, and photosensitivity;
Avoid in pregnancy
First Line Drugs for Tuberculosis

118. Streptomycin
• An aminoglycoside
• Use currently increasing due to growing prevalence of
drug-resistant strains of M tuberculosis.
• Streptomycin is used principally in drug combinations for
the treatment of:
– life-threatening tuberculous disease, including
• meningitis,
• miliary dissemination,
• and severe organ tuberculosis.
• The pharmacodynamic and pharmacokinetic properties
of streptomycin are similar to those of other
aminoglycosides
First Line Drugs for Tuberculosis

119. • Used for cases resistant to first-line agents;
• Considered second-line drugs because they
are no more effective, and their toxicities are
often more serious than those of the major
drugs.
They include:
• Amikacin
– Indicated for streptomycin-resistant or multidrug-
resistant mycobacterial strains.
– Should be used in combination drug regimens to
prevent resistance.
Alternative (Second Line) Drugs for Tuberculosis

120. Alternative (Second Line) Drugs for Tuberculosis
• Ciprofloxacin and ofloxacin:
– Active against strains of M tuberculosis resistant to
first-line agents.
• Ethionamide:
– a congener of (chemically related) INH, but cross-
resistance does not occur.
– The major disadvantage of ethionamide is severe
gastrointestinal irritation and adverse neurologic
effects at doses needed to achieve effective
plasma levels.

121. • p-Aminosalicylic acid (PAS)
– rarely used because primary resistance is common
– Cause gastrointestinal irritation, peptic ulceration,
hypersensitivity reactions, and effects on kidney, liver,
and thyroid function.
• Other drugs of limited use because of their
toxicity include:
– capreomycin (ototoxicity, renal dysfunction) and
– cycloserine (peripheral neuropathy, CNS dysfunction).
Alternative (Second Line) Drugs for Tuberculosis

122. Antitubercular Drug Regimens
Standard Regimens
• Empiric treatment of pulmonary TB (in most
areas of <4% INH resistance),
– an initial 3-drug regimen of:
• INH,
• rifampin,
• and pyrazinamide.
– If the organisms are fully susceptible (and the patient
is HIV-negative),
• pyrazinamide can be discontinued after 2 mo and treatment
continued for a further 4 mo with a 2-drug regimen.

123. Alternative Regimens
• Alternative regimens in cases of fully
susceptible organisms include:
– INH + rifampin for 9 mo, or
– INH + ETB for 18 mo.
• Intermittent (2 or 3 x weekly) high-dose 4-
drug regimens are also effective.
Antitubercular Drug Regimens

124. Resistance
• INH is the most prone to resistance
• INH resistance >4%;
– the initial drug regimen should include:
• ethambutol or streptomycin.
– Tuberculosis resistant only to INH (the most
common form of resistance) can be treated for 6
mo with a regimen of:
• RIF + pyrazinamide + ethambutol or streptomycin.
Antitubercular Drug Regimens

125. • Multidrug-resistant organisms (resistant to
both INH and rifampin):
– 3 or more drugs to which the organism is
susceptible for a period of more than 18 mo,
• including 12 mo after sputum cultures become
negative.
Antitubercular Drug Regimens

126. Drugs for Atypical Mycobacterial Infections
• Mycobacterium avium complex (MAC):
• a cause of disseminated infections in AIDS patients.
– Prophylaxis of MAC in AIDS patients:
• clarithromycin or azithromycin with or without rifabutin
is recommended for primary prophylaxis in patients
with CD4 counts less than 50/L.
– Treatment of MAC:
• azithromycin or clarithromycin with ethambutol and
rifabutin

127. Bibliography
– Anthony J. Trevor, Bertram G. Katzung & Susan B.
Masters (2013) Pharmacology- Examination And
Board Review 10th ed., McGraw Hill, Lange
– Katzung B.G (2007) Basic & Clinical Pharmacology,
11th ed, McGraw Hill, Lange