2. Introduction
• Antimicrobial drugs have caused a dramatic change not
only of the treatment of infectious diseases but of a
fate of mankind
• Looking back on the history of human diseases, infectious
diseases have accounted for a very large proportion of
diseases as a whole
• Microorganisms were found to be responsible for a
variety of infectious diseases that had been plaguing
humanity from ancient days
• Accordingly, chemotherapy aimed at the causative
organisms was developed as the main therapeutic
strategy
2
3. Definition of terms
• Anti-infective agents:
– are drugs that are designed to act selectively on foreign
organisms that have invaded and infected the body
• Chemotherapy:
– is the use of chemicals against invading organisms (i.e.
bacteria).The term is used for both treatment of cancer and
treatment of infection
• Antibiotic:
– is a chemical that is produced by one microorganism and has the
ability to harm other microbes, also include synthetic agents (eg.
Sulfa drugs)
• Antimicrobial agent:
– is a chemical substance derived from a biological source or
produced by chemical synthesis that kills or inhibits the growth
of microorganisms 3
4. • Selective toxicity:
– is the ability of a drug to injure a target cell or organism without
injuring other cells or organisms that are in intimate contact
• Narrow spectrum anti-infectives:
– affect only a few bacterial types
– E.g., The early penicillin drugs
• Broad-spectrum anti-infectives:
– affect many bacteria
– E.g., Imipenem
• Bactericidal Drugs:
– Antibiotics that can aggressively cause bacterial death.
– Penicillins, Cephalosphorins, Metronidazole, Aminoglycosides,
Vancomycin
• Bacteriostatic drugs:
– Anti-infectives that interfere with the ability of the cell to
reproduce/replicate without killing them
– E.g., Tetracyclines, chloramphenicol
4
6. 2. Classification By Mechanism Of Action
• Drugs that inhibit bacterial cell wall synthesis or activate
enzymes that disrupt the cell wall
• Drugs that increase cell membrane permeability (causing
leakage of intracellular material)
• Drugs that inhibit bacterial protein synthesis
• Drugs that inhibit bacterial synthesis of nucleic acids
• Antimetabolites (disruption of specific biochemichal
reactions--> decrease in the synthesis of essential cell
constituents) 6
9. Inhibitors of Bacterial Cell Wall Synthesis
• Also called Cell wall active agents
• Include;
– Cycloserine (anti-TB drug)
– Bacitracin
– vancomycin
– Β-lactams
• Penicillins
• Cephalosporins
• Monobactams
• Carbapenems
9
10. Bacterial Cell Wall Structure and Function
• Peptidoglycan, named for its peptide and sugar composition, is
a three-dimensional meshwork of peptide–cross-linked sugar
polymers that surrounds the bacterial cell just outside its
cytoplasmic membrane
• Peptidoglycan is also known as murein , after the Latin murus
(wall)
• Nearly all clinically important bacteria produce peptidoglycan
– Mycoplasma pneumoniae have no cell wall
• Peptidoglycan
– critically important for the survival of bacteria, which
experience large fluctuations in osmotic pressure depending
on their environment
10
11. Bacterial Cell Wall cont…
• The peptidoglycan layers
– wrapped around the cell
– provide the tensile strength required to withstand high
turgor pressures that would otherwise cause the plasma
membrane to rupture
• Since peptidoglycan is essential for bacterial survival, its
biosynthesis is a major target for antibiotics
• The largest and most widely used class of bacterial cell wall
synthesis inhibitors,
– the beta-lactam antibiotics,
– inhibit the transpeptidase enzymes that mediate peptide
cross-linking
11
13. β-Lactam Antibiotics
• Contains the β-lactam ring essential for the antibacterial
activity
13
Figure: The structure of
cephalosporins
Figure: The structure of
penicillins
14. β-Lactam Antibiotics: Mechanism of Action
• Cross-linking of adjacent peptidoglycan (murein) strands,
– The final reaction in bacterial cell wall synthesis
– A transpeptidation reaction
• Catalyzed by enzyme transpeptidase (also called Penicillin
Binding Protein, PBPs)
• Transpeptidation reaction:
– Bacterial transpeptidases cleave the terminal D-alanine from a
pentapeptide on one peptidoglycan strand and then cross-link it
with the pentapeptide of another peptidoglycan strand
• The cross-linked peptidoglycan (murein) strands,
– give structural integrity to cell walls
– permit bacteria to survive environments that do not match the
organism’s internal osmotic pressure
14
15. Mechanism of Action cont…
• The β-lactam antibiotics
– structurally resemble the terminal D-Ala-D-Ala in the
pentapeptides on peptidoglycan (murein)
• Bacterial transpeptidases
– Covalently bind the β-lactam antibiotics at the enzyme
active site,
– The resultant acyl enzyme molecule is stable and inactive
• The intact β-lactam ring is required for antibiotic action
• When β-lactam antibiotics inactivate PBPs
– structurally weakened cell wall,
– aberrant morphological form,
– cell lysis, and death of bacteria
15
16. • A number of microorganisms have evolved mechanisms to
overcome the inhibitory actions of the β-lactam antibiotics
• Four major mechanisms of resistance:
– inactivation of the β-lactam ring,
– alteration of PBPs,
– reduction of antibiotic access to PBPs, and
– elaboration of antibiotic efflux mechanisms
• The most important mechanism of resistance is hydrolysis of
the β-lactam ring by β-lactamases (penicillinases and
cephalosporinases)
• Many bacteria (Staphylococcus aureus, Neisseria
gonorrhoeae, Enterobacteriaceae,Haemophilus influenzae)
possess β-lactamases
16
Mechanisms Of Resistance to β-lactams
17. Mechanisms Of Resistance cont…
• The β- lactamases
– evolved from PBPs and acquired the capacity to bind β-
lactam antibiotics
– hydrolyze the β-lactam ring
• Some bacteria have chromosomal (inducible) genes for β-
lactamases
• Other bacteria acquire β-lactamase genes via plasmids or
transposons (via conjugation)
• Transfer of β-lactamase genes between bacterial species
– proliferation of resistant organisms
– result in clinically important adverse consequences
• β-lactamase inhibitors:
– clavulanic acid, sulbactam, and tazobactam.
17
18. Mechanisms Of Resistance cont…
• Chemical inhibition of β-lactamases, however, is not a
permanent solution to antibiotic resistance,
– since some β-lactamases such as, the cephalosporinases
produced by Citrobacter spp., Enterobacter spp., and
Pseudomonas aeruginosa are resistant to clavulanic acid,
tazobactam, or sulbactam
Alteration of PBPs:
• Resistant bacteria, usually gram-positive organisms, produce
PBPs with low affinity for β-lactam antibiotics.
• Mutations on bacterial PBPs:
– involved in the mechanism for β-lactam resistance in
Streptococcus pneumoniae, Enterococcus faecium, and
methicillin-resistant S. aureus (MRSA).
18
19. Penicillins
• A large group of bactericidal compounds
• Subdivided and classified by their chemical structure and
spectrum of activity
• β-lactam ring fused with a thiazolidine nucleus
– The structure common to all penicillins
• The antimicrobial activity of penicillin resides in the β-lactam
ring
• Splitting of the β-lactam ring by either acid hydrolysis or β-
lactamases results in the formation of penicilloic acid,
– a product without antibiotic activity
• Addition of various side chains (R) to the basic penicillin
molecule,
– Gives compounds with the same mechanism of action but
with different chemical and biological properties
19
20. Penicillins cont…
• Penicillins may be classified into four groups:
– Natural penicillins (G and V) (narrow spectrum)
– Antistaphylococcal (penicillinase-resistant)
penicillins (very narrow spectrum),
– Aminopenicillins (extended spectrum), and
– Antipseudomonal penicillins (very extended
spectrum).
20
21. Natural Penicillins
Penicillin G (benzylpenicillin)
– an acid-labile compound, poor absorption from GIT
– Most appropriate for IM or IV therapy
– Low concentrations appear in breast milk and CSF
– inflamed meninges,
• CSF conce. approximate 5% of the serum conc.
– inflamed joints,
• Conce. of the drug approach serum levels.
– Excreted by the kidneys,
• 90% via tubular secretion, 10% by glomerular filtration
– Half-life = 30 minutes
– Probenecid
• blocks tubular secretion
• used to increase the serum conce. and prolong the half-
life 21
22. Clinical uses of penicillin G
Include;
– Endocarditis caused by S. viridans (or Streptococcus
bovis),
– pharyngitis (group A β-hemolytic streptococci),
– cat bite cellulitis (Pasteurella multocida), and
– Syphilis (Treponema pallidum).
PENICILLIN UNITS:
– The activity of penicillin G was originally defined in
units
– Crystalline sodium penicillin G contains approximately
1600 units per mg (1 unit = 0.6 mcg; 1 million units of
penicillin = 0.6 g)
22
23. Penicillin G cont…
• Depot intramuscular formulations of penicillin G,
– procaine penicillin and benzathine penicillin,
– decreased solubility, delayed absorption, and a prolonged
half-life
• Procaine penicillin:
– Drug is detectable 24 hours after injection, and
• Benzathine penicillin:
– low levels (0.003 units/mL) are detectable 4 weeks after
injection
• penicillin G depot formulations,
– individualize treatment to clinical and microbial conditions
• Depot formulations are inappropriate for meningitis
– Aim of therapy in meningitis is to achieve high CSF
antibiotic conce. rapidly
23
24. Penicillin G cont…
• Intravenous penicillin G
– first choice for therapy of meningitis caused by
susceptible S. pneumoniae
• Depot formulation of benzathine penicillin G
– for rheumatic fever prophylaxis
• Penicillin V
– orally administered phenoxymethyl congener of
penicillin G
– have an antibacterial spectrum of activity that is
similar to that of penicillin G
– used to treat streptococcal infections when oral
therapy is appropriate and desirable
24
26. Antistaphylococcal (penicillinase-resistant)
Penicillins
• Nafcillin, oxacillin, cloxacillin, and dicloxacillin
• More resistant to bacterial β-lactamases than is penicillin G
• Effective against streptococci and penicillinase-producing
staphylococci
– used mostly for skin and soft-tissue infections or
documented methicillin-sensitive S. aureus infections
• Lack activity against Gram-negative bacteria,
– Unable to pass through G-negative bacterial porins due to
size
• Methicillin,
– no longer marketed because of interstitial nephritis
– similar to nafcillin and oxacillin
26
27. Antistaphylococcal cont…
• For historical reasons, staphylococci resistant to oxacillin or
nafcillin are labeled methicillin resistant
– Methicillin resistance Staphylococcus aureus (MRSA)
• Many hospitals are reservoirs for MRSA and methicillin-
resistant Staphylococcus epidermidis (MRSE).
– These nosocomial pathogens are resistant in vitro to all β-lactam
antibiotics
• Nafcillin (IM, IV)
– T1/2 = 0.8 to 1.2 hrs
– Primarily cleared by biliary excretion
• Oxacillin (IM, IV)
– T1/2 = 0.4 to 0.7 hrs
– Eliminated by both the kidney and biliary excretion
• No dosage adjustment is required for these drugs in renal
failure
27
28. Antistaphylococcal cont…
• Indications for nafcillin or oxacillin include,
– severe staphylococcal infections like cellulitis, empyema,
endocarditis, osteomyelitis, pneumonia, septic arthritis
• Cloxacillin and dicloxacillin:
– Comparable alternatives for oral therapy
– Eliminated by both the kidney and biliary excretion
• No dosage adjustment is required for these drugs in
renal failure
• T1/2 = 0.5 to 0.8 hrs
• Indications for cloxacillin or dicloxacillin include,
– clinically mild staphylococcal infections like impetigo
28
29. Aminopenicillins (extended spectrum)
• Include, Ampicillin and Amoxicillin
– Effective against a variety of Gram-positive cocci, Gram-
negative cocci such as Neisseria gonorrhoeae and N.
meningitis , and Gram-negative rods such as E. coli and
Haemophilus influenzae, but their spectrum is limited by
sensitivity to most β-lactamases
– Have similar pharmacokinetics
– Both have good oral bioavailability
– T1/2; ampicillin= 1.1 to 1.5 hrs, amoxicillin = 1.4 to 2.0 hrs.
– Ampicillin achieves therapeutic concentrations in the CSF
only during inflammation
• Effective treatment for meningitis caused by Listeria
monocytogenes
29
30. Aminopenicillins cont…
• Amoxicillin does not reach adequate concentrations in the
CNS,
– not appropriate for meningitis therapy
• Other indications for ampicillin include serious infections like
enterococcal endocarditis and pneumonia caused by β-
lactamase-negative H. influenzae
• Amoxicillin oral therapy:
– appropriate for clinically acute nonserious bacterial
infections like otitis media and sinusitis
• Amoxicillin also has use in multidrug regimens for the
eradication of Helicobacter pylori in duodenal and gastric
ulcers
30
31. Antipseudomonal Penicillins (very extended
spectrum)
• Mezlocillin, piperacillin, Carbenicillin, azlocillin and ticarcillin
– Achieve only low concentrations in the CSF,
• not among the drugs of first choice for meningitis
therapy
– Undergo renal elimination
– Have comparable spectra of activity against many gram-
positive and gram-negative pathogens, including most
anaerobes
– Mezlocillin, piperacillin, and ticarcillin;
• have similar clinical outcomes in patients with known or
suspected P. aeruginosa infections
– Inactivated by β-lactamase (may be combined with β-
lactamase inhibitors)
31
32. β-Lactamase Inhibitor Combinations
• Several formulations combine a β-lactam antibiotic with a β-
lactamase inhibitor (ampicillin-sulbactam [Unasyn], ticarcillin-
clavulanic acid [Timentin], piperacillin-tazobactam [Zosyn], and
amoxicillin–clavulanic acid [Augmentin])
• All of the β-lactamase inhibitor combinations except amoxicillin-
clavulanic acid are parenteral formulations
• Elimination of the combination drugs occurs primarily by renal
excretion.
– require dose adjustments in patients with renal insufficiency
• Combination significantly broadens the spectrum of antibacterial
activity against β-lactamase-producing organisms
• These drugs have clinical use in treating infections with known or
suspected mixed bacterial flora, such as biliary infections, diabetic
foot ulcers, endomyometritis, and peritonitis
32
33. β-Lactam Antibiotics in Pregnancy
• All of the penicillin antibiotics are classified by FDA in
pregnancy category B
• Obstetricians frequently prescribe,
– ampicillin, penicillin G, and penicillin V
– because they are effective against the infections
most frequently encountered in caring for pregnant
women (e.g., upper respiratory and lower urinary tract
infections).
33
34. Adverse Effects to Penicillins
• Penicillins are considered among the safest antibiotics
• Anaphylaxis
– a serious, rare allergic response with an occurrence rate
between 0.004% and 0.015% of penicillin courses
• Allergic reactions to penicillin
– immunoglobulin (Ig) E–mediated type I immune responses
– Symptoms include urticaria, pruritus, bronchospasm,
angioedema, laryngeal edema, and hypotension
• Allergic cross-reactivity between β-lactam antibiotics is
significant
• Diarrhea: common with extended spectrum
• Neurotoxicity
• Nephritis
34
35. Cephalosporins
• Semisynthetic antibiotics derived from products of various
microorganisms, including Cephalosporium and Streptomyces.
• β-lactam ring
– associated with antibacterial activity
• The different pharmacological, pharmacokinetic, and
antibacterial properties of individual cephalosporins
– Variation in substitution (R)
• More resistant to β-lactamase than penicillins
• cephalosporinases (β-lactamases specific for the
cephalosporins)
• Resistance to cephalosporins also results from modification of
microbial PBPs
35
36. Antibacterial Spectrum
• Cephalosporins are classified into generations according to
their antibacterial spectrum and stability to β-lactamases
• The first-generation cephalosporins:
– active against streptococci, methicillin-sensitive S. aureus,
and a few gram-negative bacilli
– Broad spectrum especially against Gm+ve organisms
– Not effective against pseudomonas
– Resistant to β-lactamase enzyme
– Do not cross the meninges so not effective in meningitis
– E.g. cefadroxil, cefazolin, cephalexin, cephalothin,
cephapirin
36
Figure: The structure of
cephalosporins.
37. Antibacterial Spectrum cont…
• The second-generation cephalosporins:
– have greater stability against β-lactamase
inactivation
– possess a broader spectrum of activity to
include gram-positive cocci, gram-ve
organisms, and anaerobes.
– Do not penetrate meninges
E.g. cefaclor, cefamandole, cefonicid,
cefuroxime
37
38. Antibacterial Spectrum cont…
• The extended-spectrum, or third-
generation, cephalosporins
– high degree of potency and β-lactamase stability
– broader spectrum of action against many common
gram-ve bacteria and anaerobes while retaining
good activity against streptococci
– Less active against staph. than the earlier
generations
– greatest activity against P. aeruginosa.
– Cross BBB (most agents)
E.g. cefoperazone, cefotaxime, ceftazidime,
ceftizoxime, ceftriaxone
38
39. Antibacterial Spectrum cont…
• Cefepime:
− has been called a fourth-generation cephalosporin
− because of its great in vitro activity against several
gram-positive and gram-negative organisms
• The distinction between third and fourth generation may
be irrelevant clinically
• None of the cephalosporins adequately treats infections
caused by
− Enterococcus faecalis,
− E. faecium,
− MRSA, or
− L. monocytogenes.
39
40. Pharmacokinetics
• Concomitant ingestion of food reduces the bioavailability of
some cephalosporins, e.g., cefaclor,
– taken to an empty stomach
• Distribute in satisfactory concentrations to most tissues
except the CNS
• Only cefepime, cefuroxime, cefotaxime, ceftriaxone, and
ceftazidime achieve therapeutic concentrations in CSF
• Cefotaxime and ceftriaxone
– antibiotics of first choice for the empirical treatment of
brain abscess and meningitis
40
41. Pharmacokinetics cont…
• Variation in the protein binding among the cephalosporins
• Urinary excretion:
– the major elimination path for most cephalosporins.
– Dose adjustment in patients with renal failure
• Biliary elimination is important for some cephalosporins.
– Cefmetazole, cefoperazone, cefoxitin, and
ceftriaxone
41
43. Clinical Uses of Cephalosporins
• The first-generation cephalosporins have activity against
most of the bacterial pathogens that colonize skin and
infect wounds
– useful in antimicrobial prophylaxis before surgery
• Second-generation cephalosporins
– cefoxitin and cefotetan have good anaerobic activity,
• prophylaxis of lower abdominal and gynecological
infection
• Third-generation cephalosporins
– broad spectrum, used in wide range of infections
including,
• Lyme disease (Borrelia sp.), pneumonia, peritonitis,
and sepsis syndrome.
43
44. Adverse Effects of Cephalosporins
• The cephalosporins have good safety profiles
• Hypersensitivity reactions
– Should not be used in patients that had anaphylactic
reaction with penicillin
• Local irritation: severe pain after IM injection and
thrombophlebitis after IV injection
• Nephrotoxicity especially when used with aminoglycosides
• Superinfections with Clostridium difficile, enterococci, MRSA,
P. aeruginosa, and Candida albicans
• Bleeding
– inhibits production of active vitamin K.
– Antiplatelet effects.
44
45. Carbapenems
• Include: Imipenem, meropenem and ertapenem
• Broadest spectrum β-lactams
• Effective against gm +ve and –ve organisms especially
pennicillinase producing organisms and anaerobes
(Important in empiric therapy)
• Resistant to β-lactamase
Imipenem
• broadest spectrum of all of the β-lactam antibiotics
• active against most gram+ve, gram-ve, and anaerobic
bacteria
• more potent against E. faecalis, B. fragilis, and P.
aeruginosa than 3rd generation cephalosporins
45
46. Imipenem cont…
• Imipenem–cilastatin
– only available for IM or IV
• Cilastatin
– inhibitor of dehydropeptidase I
• Dehydropeptidase I
– The enzyme present in renal tubules, converts imipenem to
an inactive nephrotoxic metabolite
• To decrease metabolic clearance, imipenem is combined with
cilastatin
• one of the drugs of first choice for the empirical therapy of
many polymicrobial pulmonary, intraabdominal, and soft
tissue infections
Imipenem adverse effects:
• Extensive cross allergy with penicillin
• Seizures
46
47. Monobactams
• Are monocyclic β-lactams (monobactams)
• natural monobactams have little antimicrobial activity
E.g Aztreonam, Azactam
Aztreonam
• A synthetic derivative
• has excellent activity against gram-ve organisms,
including P. aeruginosa
• has low affinity for PBPs in streptococci, staphylococci,
and anaerobes
– no significant activity against gram-positive bacteria
or anaerobes
• stable to most β–lactamases
47
48. Aztreonam cont…
• is not bioavailable after oral administration
– Parenteral administration
• achieve therapeutic concentrations in CSF in the presence of
inflamed meninges
– an alternative antibiotic to the cephalosporins for the
therapy of meningitis caused by gram-negative bacilli
• may be used as a substitute for an aminoglycoside in the
treatment of infections caused by susceptible gram-negative
organisms
• Most of the adverse effects of aztreonam
– local reactions at the site of injection
– rarely causes allergic reactions in patients with a history
of type I hypersensitivity to other β-lactam antibiotics
48
49. Glycopeptides: Vancomycin
Vancomycin, oritavancin, dalbavancin, telavancin
Vancomycin:
• a complex tricyclic glycopeptide antibiotic produced by
Streptomyces orientalis,
• Mechanism of action
– inhibitor of cell wall synthesis
– prevent polymerization of the linear peptidoglycan by
peptidoglycan synthase
• Bactericidal in vitro
• narrow-spectrum agent
• active against gram-positive organisms
• Not effective against gram-negative rods, mycobacteria
49
50. Vancomycin cont…
• poorly absorbed from the GIT.
• Given by IV except for the treatment of staphylococcal
enterocolitis and pseudomembranous colitis
• half-life is 5 to 11 hours
• With impaired renal function, the half-life is 7 to 9 days
• cross inflamed but not normal meninges
– can be used in the treatment of meningitis with
susceptible organisms
• Renal excretion is predominant, only small amounts
appear in the stool
50
51. Clinical Uses of Vancomycin
• Display excellent activity against staphylococci and
streptococci, but because of;
– wide availability of equally effective and less toxic drugs,
– second-line drugs in the treatment of most infections.
• MRSA infections, unless resistant to vancomycin.
– Staphylococcus epidermidis infections associated with the
use of intravascular catheters.
• Staphylococcal enterocolitis and endocarditis.
• Enterococci that are resistant to vancomycin are emerging as
major nosocomial pathogens.
• Limit the use of vancomycin to treatment of serious
infections caused by MRSA
– Because of fear of resistance development
51
52. Adverse Effects of Vancomycin
• Ototoxicity,
– the major adverse effect
– may result in tinnitus, high-tone hearing loss, and
deafness in extreme instances
• chills, fever, and a maculopapular skin rash often involving
the head and upper thorax (red man syndrome).
– Because of histamine release.
• rarely nephrotoxic when used alone
52
53. Bacitracin
• So named because it was first identified in a species of
Bacillus,
• A peptide antibiotic
• Bactoprenyl phosphate (BPP)
– Carrier lipid responsible for synthesis and export of
murein monomer
• Bacitracin form a complex with bactoprenyl diphosphate
– inhibits dephosphorylation and render BPP useless for
further rounds
• Active against gram-positive cocci (Staphylococcus
aureus, streptococci), a few gram-negative organisms,
and one anaerobe, Clostridium difficile.
53
54. Bacitracin cont…
• Due to its significant kidney, neurological, and bone
marrow toxicity,
– not used systemically
• most commonly used topically for superficial dermal or
ophthalmologic infections
• not absorbed orally,
– remains within the gut lumen and is occasionally
administered orally to treat Clostridium difficile
colitis or to eradicate vancomycin- resistant
enterococci (VRE) in the GIT.
54
56. Aminoglycosides
• Are hydrophilic, polycationic, amine-containing carbohydrates
• usually composed of three to five rings
• The polycationic aminoglycoside chemical structure
– results in a binding both to the anionic outer bacterial
membrane and to anionic phospholipids in the cell
membranes of mammalian renal proximal tubular cells.
• Bactericidal effects and renal toxicity
• Because of their hydrophilicity,
– transport across the hydrophobic lipid bilayer of
eukaryotic cell membranes is impeded
• Not orally bioavailable
• Include: amikacin, gentamicin, kanamycin, netilmicin,
neomycin, streptomycin, paromomycin and tobramycin
56
58. Mechanism Of Antibacterial Action
• Involve two possibly synergistic effects:
First, the positively charged aminoglycoside binds to
negatively charged sites on the outer bacterial
membrane,
disrupting membrane integrity
accounts for the rapid concentration-dependent
bactericidal effect
Second, aminoglycosides bind to various sites on
bacterial 30S ribosomal subunits,
disrupting the initiation of protein synthesis and
inducing errors in the translation of mRNA to
peptides
58
59. Mechanism Of Antibacterial Action cont…
• Have a postantibiotic effect;
– likely due to ribosome disruption
– Ribosomal regeneration requires time to synthesize
new ribosomes
• postantibiotic effect explains why aminoglycosides can
be given in single daily doses despite their short half-life
• Penetration of aminoglycosides through the outer
bacterial membrane occurs by:
– outer membrane disruption
– diffusion through outer membrane porins
59
60. Mechanism Of Antibacterial Resistance
• Three recognized mechanisms:
(1) Production of a transferase enzyme or enzymes
which inactivate the aminoglycoside by adenylylation,
acetylation, or phosphorylation
• The most important mechanism
(2) There is impaired entry of aminoglycoside into the
cell
– mutation or deletion of a porin protein or proteins
involved in transport and maintenance of the
electrochemical gradient
(3) The receptor protein on the 30S ribosomal subunit
may be deleted or altered as a result of a mutation
60
61. Pharmacokinetics
• Both the rate and extent of GI absorption of individual
aminoglycosides are generally quite low
• The systemic bioavailability of the aminoglycosides is low
across other membranes as well
– E.g., gentamicin is poorly absorbed from a topical
ophthalmic preparation
• Neomycin bioavailability across intact skin is also low,
– absorption across damaged skin can be significant:
nephrotoxicity can occur in burn patients treated with
topical neomycin.
61
62. Pharmacokinetics cont…
• Most of the enzymes that catalyze the metabolism of
foreign compounds are found inside cells
• As aminoglycosides do not penetrate most cells,
– do not undergo any significant metabolism
• cleared by the kidneys and can be recovered in the urine
• clearance is approximately equal to that of the
glomerular filtration rate,
– high urine concentrations;
– contribute to the efficacy in urinary tract infections.
62
63. Clinical Uses of Aminoglycosides
1. Serious Gram-Negative Bacillary Infections:
Gentamicin is most commonly used to treat serious infections
due to
gram-negative aerobic bacilli, such as Escherichia coli and
Klebsiella pneumoniae, and
Proteus, Serratia, Acinetobacter, Citrobacter, and
Enterobacter spp
Often used in combination with β-lactams in the initial
empirical therapy of sepsis and of fever in
immunocompromised patients
ensure adequate antibiotic coverage
exploit their synergistic antibiotic activity
These drugs should not, however, be injected simultaneously,
β-lactams can chemically inactivate the aminoglycosides.
63
64. Clinical Uses of Aminoglycosides cont…
• Pseudomonas aeruginosa
– more likely than other gram-negative bacilli to exhibit
resistance to gentamicin
– However, Pseudomonas spp. resistant to gentamicin
may be susceptible to amikacin or tobramycin
• Streptomycin is the drug of choice for patients with
pneumonia due to Yersinia pestis (plague) or Francisella
tularensis (tularemia)
64
65. 2. Eradication of Facultative Gut Flora
• A combination of neomycin and non-absorbable erythromycin
base;
– given orally prior to colorectal surgery
– reduce the incidence of postoperative wound infection
• Orally administered neomycin is sometimes used to suppress
the facultative flora of the gut in patients with hepatic
encephalopathy
• Neomycin is often combined with other antibiotics, such as
polymyxin B and bacitracin, in topical preparations to prevent
any infection of minor skin abrasions, burns, and cuts
3. Endocarditis
• Gentamicin or streptomycin with penicillin in enterococcal
endocarditis 65
66. 4. Meningitis
• The degree of penetration of the aminoglycosides into
CSF is proportional to the degree of inflammation of the
meninges
• Best combined with the β-lactams or other antibiotics in
the treatment of meningitis
5. Tuberculosis
• increased prevalence of mycobacterial resistance to
standard antibiotic chemotherapy,
– Increased use of aminoglycosides
• Streptomycin:
– in the initial therapy of severe or disseminated
tuberculosis, common in immunocompromised patients.
66
67. 6. Ophthalmological Infection
• very high concentrations of gentamicin achieved in the
conjunctival sac,
– effective against nearly all of the typical bacterial
pathogens that cause conjunctivitis.
• High-dose of gentamicin for treating bacterial
ophthalmic keratitis.
7. Gonococcal Urethritis
• Spectinomycin:
– antibiotic chemically related to the aminoglycosides,
– occasionally used to treat uncomplicated gonococcal
urethritis in patients who are allergic to β-lactam.
67
68. Adverse Effects of Aminoglycosides
• Cause nephrotoxicity,
• Relative nephrotoxicity of the various aminoglycosides
– correlated with the number of amine groups that each
contains;
– neomycin is the most nephrotoxic and streptomycin is
the least
• Concurrent use with loop diuretics (eg, furosemide) or
other nephrotoxic antimicrobial agents (eg, vancomycin
or amphotericin) can potentiate nephrotoxicity and
should be avoided if possible.
• Even severe aminoglycoside-induced nephrotoxicity is
nearly always reversible upon prompt discontinuation of
the drug
68
69. Adverse Effects of Aminoglycosides cont…
• Aminoglycosides accumulate in otolymph and can cause
both vestibular and auditory ototoxicity,
– Both can be irreversible
• Can cause neuromuscular junction blockade by displacing
Ca from NMJ,
– inhibiting the Ca-dependent prejunctional release of
acetylcholine and blocking postsynaptic acetylcholine
receptor binding
– Care in patients with myasthenia gravis, hypocalcemia,
or after the use of a NMJ blocking agent
– can be reversed by administration of IV calcium.
69
70. Macrolides
• Consist of a large lactone ring to which sugars are
attached
• Include erythromycin, clarithromycin, azithromycin
Mechanism of Action:
• bind to the 50S ribosomal subunit of bacteria but not to
the 80S mammalian ribosome;
– accounts for its selective toxicity
• Block protein synthesis
• Macrolides are bacteriostatic
• May be bactericidal at higher doses
70
72. Antibacterial Spectrum of Macrolides
• Effective against a number of organisms, including
– Mycoplasma spp.,
– H. influenzae,
– Streptococcus spp. (including S. pyogenes and S.
pneumoniae),
– staphylococci, gonococci,
– Legionella pneumophila
• There has been increasing resistance of S. pneumoniae
to macrolides
• Clarithromycin is very active against:
– H. influenzae, Legionella, and Mycobacterium avium-
intracellulare 72
73. Antibacterial Spectrum of Macrolides cont…
• Azithromycin is superior against
– Branhamella, Neisseria, and H. influenzae
• Clarithromycin and azithromycin have significant activity
against Mycobacterium avium complex (MAC),
– drugs of choice in treating disseminated MAC
• Both azithromycin and clarithromycin
– used prophylactically in AIDS patients to prevent
disseminated MAC
• T1/2
– erythromycin = 1.4 hours,
– clarithromycin = 3 to 7 hours
– azithromycin = 68 hours 73
74. Clinical Uses
• Although erythromycin is a well-established antibiotic,
there are relatively few primary indications for its use
• Indications include:
– treatment of Mycoplasma pneumoniae infections,
– eradication of Corynebacterium diphtheriae from
pharyngeal carriers,
– chlamydial infections, chlamydial conjunctivitis,
– Campylobacter enteritis
• Erythromycin:
– effective in the treatment and prevention of S.
pyogenes and other streptococcal infections,
– but not effective in more resistant fecal streptococci.
74
75. Clinical Uses cont…
• Staphylococci are generally susceptible to erythromycin,
– suitable alternative for the penicillin-hypersensitive
individual
• It is a second-line drug for the treatment of gonorrhea
and syphilis
• Erythromycin
– Used for treatment of middle ear and sinus
infections, including H. influenzae,
• Erythromycin-resistant S. pneumoniae is a concern.
75
76. Lincosamides
• The lincosamide family of antibiotics includes lincomycin
and clindamycin,
Mechanism of Action
• bind to the 50S ribosomal subunit at a binding site close
to or overlapping the binding sites for chloramphenicol
and erythromycin
– inhibit protein synthesis
76
77. Pharmacokinetics
• Food does not interfere with the absorption
• 90% is protein bound
• penetrate most tissues well, including bone.
• Used in bone and joint infections caused by susceptible
organisms
• do not readily penetrate the normal or inflamed meninges
• pass readily through the placental barrier
• half-life is 2 to 2.5 hours.
• Metabolized by the liver, and 90% of the inactivated
drug is excreted in the urine.
77
78. Clinical Uses
Clindamycin
• highly active against staphylococci and streptococci.
• However, the adverse reaction of pseudomembranous
colitis
– limited its use to individuals who are unable to
tolerate other antibiotics and to the treatment of
penicillin-resistant anaerobic bacterial infections
• excellent activity topically against Corynebacterium
acnes
• excellent activity against anaerobic bacteria
– but have potentially life-threatening adverse
reactions and should not be used without good
justification
78
79. Adverse Effects
• The major adverse reactions reported are
– Hypersensitivity rashes and diarrhea
• Hepatotoxicity and bone marrow suppression
• It is important to differentiate between GI irritation
and pseudomembranous colitis
• The colitis results in
– mucosal ulceration
– bleeding and may necessitate colectomy
• Rarely fatal
79
80. Tetracyclines
• Include: tetracycline, chlortetracycline, and
oxytetracycline, demeclocycline and methacycline,
minocycline and doxycycline
• All tetracyclines have a similar mechanism of action,
– But have different chemical structures
• Structural analogues synthesized
– to improve pharmacokinetic properties and
antimicrobial activity
80
81. Mechanism of action
• Tetracyclines bind to the 30S ribosome:
• prevent the binding of aminoacyl transfer RNA (tRNA)
to the A site (acceptor site) on the 50S ribosomal unit
• The tetracyclines affect both eukaryotic and
prokaryotic cells but are selectively toxic for bacteria,
– readily penetrate microbial membranes and
accumulate in the cytoplasm through an energy-
dependent tetracycline transport system that is
absent from mammalian cells
81
82. Mechanisms of Resistance to
Tetracyclines
• Three mechanisms of resistance have been described:
(1) impaired influx or increased efflux by an active
transport protein pump
(2) ribosome protection due to production of proteins that
interfere with tetracycline binding to the ribosome
(3) enzymatic inactivation
• The most important of these are production of an efflux
pump and ribosomal protection
82
83. Antibacterial Spectrum
• Tetracyclines display broad-spectrum activity
• Bacteriostatic antibiotics
• are effective against both gram-positive and gram-
negative bacteria,
– Rickettsia, Coxiella, Mycoplasma, and Chlamydia spp..
• Tetracycline resistance has increased among
pneumococci and gonococci
• All tetracyclines have a similar spectrum of in vitro
activity
– Minocycline more active
– Oxytetracycline and tetracycline are somewhat less
active than other members of this group
83
84. Pharmacokinetics
• Partially absorbed from the stomach and upper GI tract.
• Food impairs absorption of all tetracyclines except
doxycycline and minocycline
• Tetracyclines form insoluble chelates with calcium ,
magnesium, and other metal ions,
– their simultaneous administration with milk (calcium),
magnesium hydroxide, aluminum hydroxide, or iron will
interfere with absorption
• Incompletely absorbed tetracyclines remaining in the
intestine.
– may inhibit sensitive intestinal microorganisms and alter
the normal intestinal flora.
• Penetrate the uninflamed meninges
• cross the placental barrier. 84
85. Pharmacokinetics cont…
• Various congeners differ in their half-lives and their
protein binding ability:
short acting: (t1/2 = 6–8 hours)
• tetracycline, chlortetracycline, and oxytetracycline,
intermediate acting: (t1/2 = 12 hours)
• demeclocycline and methacycline, and
long acting: (t1/2= 16–18 hrs )
• minocycline and doxycycline.
85
86. Pharmacokinetics cont…
• Tetracyclines are concentrated in the bile
• Bile concentrations
– up to five times those of the plasma
• Doxycycline, minocycline, and chlortetracycline
– excreted primarily in the feces
• The other tetracyclines
– eliminated primarily in the urine by glomerular
filtration
86
87. Clinical Uses
• Little difference in clinical response among the various
tetracyclines
• Their use restricted in pregnancy and in patients under
the age of 8 years
• Doxycycline,
– longer half-life and
– lack of nephrotoxicity,
• choice for patients with preexisting renal disease
or those who are at risk for developing renal
insufficiency
• Lack of nephrotoxicity
– related mainly to biliary excretion
87
88. Clinical Uses cont…
• Doxycycline
– first-line agent in the prophylaxis of anthrax after
exposure.
– choice for the primary stage of Lyme disease in adults
and children older than 8 years
• Tetracyclines are still the drugs of choice for
treatment of:
– cholera,
– diseases caused by Rickettsia and Coxiella,
– granuloma inguinale,
– relapsing fever,
– chlamydial diseases (trachoma, lymphogranuloma
venereum), and
– nonspecific urethritis
88
89. Clinical Uses cont…
• They are also effective in the treatment:
– brucellosis, tularemia,
– infections caused by Pasteurella and Mycoplasma spp.
• Tetracyclines no longer can be entirely relied on in the
treatment of streptococcal infections;
– 40% of Streptococcus pyogenes and
– 10% of Streptococcus pneumoniae
• are resistant.
89
90. Adverse Effects
• Oral admin. - nausea, vomiting, epigastric burning,
stomatitis, and glossitis, due to
– gastric irritation
– Modification of gut flora.
• IV injection.
– phlebitis.
• Hepatotoxicity
• Renal dysfunction
• Staining of both the deciduous and permanent teeth and
retardation of bone growth can occur if tetracyclines
are administered after the fourth month of gestation or
if they are given to children less than 8 years of age.
90
91. Chloramphenicol
Mechanism of Action
• A nitrobenzene derivative
• Inhibit protein synthesis by binding to the 50S
ribosomal subunit
• Resistance to chloramphenicol:
– changes in the ribosome-binding site results in a
decreased affinity for the drug,
– decreased permeability, and
– Chloramphenicol acetyltransferase, a plasmid-encoded
enzyme that inactivates the drug.
91
92. Antibacterial Spectrum
• Chloramphenicol is a broad-spectrum bacteriostatic.
• Effective against gram-positive and gram-negative
bacteria, including:
– Rickettsia, Mycoplasma, and Chlamydia spp.
– Most anaerobic bacteria, including Bacteroides
fragilis.
92
93. Pharmacokinetics
Chloramphenicol is rapidly and completely absorbed from
GIT
not affected by food ingestion or metal ions.
half-life = 1.5 to 3.5 hours.
60% bound to serum albumin,
penetrates the brain.
crosses the placental barrier.
inactivated in the liver by glucuronosyltransferase and is
rapidly excreted (80–90% of dose) in the urine.
About 5 to 10% excreted unchanged.
93
94. Clinical Uses
• Potentially fatal nature of chloramphenicol-induced
bone marrow suppression:
– restricts its use to a few life-threatening infections
in which the benefits outweigh the risks.
• No justification for its use in treating minor infections.
• No longer recognized as the treatment of choice for any
bacterial infection.
• Since effective CSF levels are obtained,
– a choice for treatment of specific bacterial causes of
meningitis:
• Haemophilus influenzae, Neisseria meningitidis, and
S. pneumoniae.
• Effective against H. influenzae–related arthritis,
osteomyelitis, and epiglottitis.
94
95. Clinical Uses cont…
• Development of β-lactamase-producing strains of H.
influenzae:
– increased the use of chloramphenicol.
• However, advent of 3rd -generation cephalosporins such
as ceftriaxone and cefotaxime,
– Decreased chloramphenicol use.
• A major treatment of typhoid and paratyphoid fever in
developing countries
• Widely used for the topical treatment of eye infections.
– B/c of its extreme broad spectrum and ability to
penetrate ocular tissue
– But use is declining because of its toxicity.
95
96. Clinical Uses cont…
• Alternative to tetracycline for rickettsial diseases,
– especially in children younger than 8 years
• Used to treat vancomycin-resistant enterococci
• Used in the treatment of serious anaerobic infections
caused by penicillin-resistant bacteria, such as B. fragilis
• Clindamycin and metronidazole are now preferred for
treatment of anaerobic infections.
96
97. Adverse Effects
Gray baby syndrome:
• Newborn infants cannot adequately conjugate
chloramphenicol to form the glucuronide;
• high levels of free chloramphenicol may accumulate and
cause a potentially fatal toxic reaction when given
dosages above 50 mg/kg/d
• This syndrome is characterized by
– abdominal distention, vomiting, flaccidity,
hypothermia, gray color, shock, and collapse
• The mortality rate is high
• The syndrome also has been observed in older children
and is associated with high serum levels of
chloramphenicol 97
98. Adverse Effects cont…
Bone marrow depression.
• The most publicized adverse affects.
• dose related and is seen most frequently when daily
doses exceed 4 g.
• Characterized by:
– anemia, sometimes with leukopenia or
thrombocytopenia,
• reversible on discontinuation.
• Aplastic anemia
– occurs in only about 1 in 24,000 to 40,000 cases of
treatment.
– not a dose-related response, although can occur in
prolonged use.
– is usually fatal.
• The mechanism is not known. 98
100. Drugs Used in Tuberculosis
• Tuberculosis remains the most important communicable disease in
the world
• Currently, increase in cases of tuberculosis,
– there is also a progressive increase in multidrug-resistant (MDR)
tuberculosis
• It is caused by Mycobacterium species
• They have the ability to remain dormant in the body but viable and
capable of causing disease
a major therapeutic challenge
• The mycobacteria are slow-growing intracellular organisms
– require the administration of a combination of drugs for extended
periods to achieve effective therapy and to prevent the emergence of
resistance
100
101. Key Concepts In The Treatment Of
Tuberculosis
• Selection of drugs must consider risk of adverse
reactions
• Three basic concepts in TB treatment are as follows:
(1) Regimens must contain multiple drugs to which the
organism is susceptible
(2) Drugs must be taken regularly
(3) Drug therapy must continue for a sufficient time
Traditionally, antituberculosis drugs are classified as:
First-line drugs
Second line drugs
101
102. First-line drugs:
superior in efficacy and possess an acceptable degree of toxicity
Include: isoniazid, rifampin, pyrazinamide, ethambutol, and
streptomycin
Most patients with TB can be treated successfully with these
drugs
Second-line drugs
more toxic and less effective
indicated only when the Mycobacterium tuberculosis is resistant
to the first-line agents
Therapy with second-line agents may have to be prolonged
beyond the standard period of treatment, depending on the
microbiological response to therapy
Include: cycloserine, ethionamide, aminosalicylic acid,
rifabutin, quinolones, capreomycin, Amikacin, Clofazimine
102
103. First-line Antituberculosis Drugs
Isoniazid (isonicotinic acid hydrazide, or INH)
• the most active drug for the treatment of tuberculosis caused by
susceptible strains
• A synthetic agent
– Isoniazid is a prodrug that is activated by KatG, the mycobacterial
catalase-peroxidase
Mechanism of Action
– active against susceptible bacteria only when cells undergoing cell
division
– inhibit the synthesis of mycolic acids
– active drug binds to Fatty acid synthetase 2 (FAS2).
• blocks mycolic acid synthesis
– Is bactericidal against actively growing M. tuberculosis and
– bacteriostatic against non-replicating organisms
103
104. Isoniazid cont…
Pharmacokinetic Properties
– Readily absorbed from GIT
– does not bind to serum proteins
– diffuses readily into all body fluids and cells, including the
tuberculosis lesions
– acetylated to acetyl isoniazid by N-acetyl-transferase
– half-lives bn 1 hour and 3 hours
104
105. Isoniazid cont…
Clinical Uses
– Isoniazid is among the safest and most active mycobactericidal
agents
– Therapeutic and prophylactic regimens for susceptible
tuberculosis infections
– Included in all first-line drug combinations for use in all types of
tuberculous infections
Adverse Effects
– Related to dosage and duration of therapy
– Isoniazid-induced hepatitis and peripheral neuropathy
• two major untoward effects
105
106. Rifampin
• Rifampin is a semisynthetic macrocyclic antibiotic
produced from Streptomyces mediterranei
• A large lipid soluble molecule
• bactericidal for both intracellular and extracellular
microorganisms
MOA:
– Rifampin binds strongly to the β-subunit of bacterial
DNA-dependent RNA polymerase and thereby
inhibits RNA synthesis
– Rifampin does not affect mammalian polymerases
• It is active against M. tuberculosis, Staphylococcus
aureus, Neisseria meningitis, Haemophilus influenzae,
Chlamydiae, and certain viruses 106
107. Clinical Uses of Rifampin
First-line antitubercular drug
used in the treatment of all forms of pulmonary and
extra- pulmonary tuberculosis
alternative to isoniazid in the treatment of latent
tuberculosis infection
may be combined with an antileprosy agent for the
treatment of leprosy
Prophylaxis in contacts of children with Haemophilus
influenza type b disease
Meningitis
107
108. Adverse Reactions
The most commonly observed side effects:
nausea, vomiting, headache, dizziness, and fatigue.
Hepatitis
strongly induces most cytochrome P450 isoforms (CYPs 1A2,
2C9, 2C19, 2D6, and 3A4) ---increased metabolism of many
drugs
Imparts a harmless red-orange color to
urine, feces, saliva, sweat, tears, and contact
lenses
Patients should be advised of such discoloration
of body fluids
108
109. Pyrazinamide
• Pyrazinamide is a synthetic analogue of nicotinamide
• Inhibit the enzyme fatty acid synthetase 1 (FAS1)
• FAS1
– Catalyzes the formation of long, saturated hydrocarbon chains
required for synthesis of mycolic acid
• Pyrazinamide inhibits mycolic acid biosynthesis
– Bactericidal
• requires an acidic environment, such as that found in the
phagolysosomes, to express its tuberculocidal activity
– highly effective on intracellular mycobacteria
• half-life is 9 to 10 hours
• The drug and its metabolites:
– excreted primarily by renal glomerular filtration
109
110. Pyrazinamide cont…
Clinical Uses
• Front-line drug used in conjunction with isoniazid and
rifampin in short-course (i.e., 6-month) regimens as a
"sterilizing" agent; active against residual intracellular
organisms that may cause relapse
Adverse Reactions
• Hepatotoxicity
– the major concern in 15% of pyrazinamide recipients
• can inhibit excretion of urates, resulting in
hyperuricemia
– Nearly all patients on it develop hyperuricemia and
possibly acute gouty arthritis
• Nausea, vomiting, anorexia, drug fever, and malaise
110
111. Ethambutol
• Water-soluble, heat-stable compound
• Acts by inhibition of arabinosyl transferase enzymes that are
involved in cell wall biosynthesis (synthesis of NAG-
arabinogalactan)
• Nearly all strains of M. tuberculosis and M. kansasii and most
strains of Mycobacterium avium-intracellulare are sensitive to
ethambutol
• Well absorbed orally
• Half-life= 3 to 4 hours
• Widely distributed in all body fluids, including CSF, even in the
absence of inflammation
111
112. Streptomycin
• An aminoglycoside antibiotic
• was the first drug shown to reduce tuberculosis
mortality
• bactericidal against M. tuberculosis in vitro
• is inactive against intracellular organisms
– Highly polar
• Most M. tuberculosis strains, M. kansasii and M. avium-
intracellulare are sensitive
• About 80% of strains that are resistant to isoniazid and
rifampin are also resistant to streptomycin
112
113. Streptomycin cont…
Indicated as a fourth drug in combination with isoniazid,
rifampin, and pyrazinamide in patients at high risk for
drug resistance
Also used in the treatment of streptomycin-susceptible
MDR tuberculosis
Adverse effects:
Ototoxicity and nephrotoxicity are the major concerns during
administration of streptomycin and other aminoglycosides
The toxic effects are dose related
increase with age and underlying renal insufficiency
113
114. Second-line Antituberculous Drugs
Para-aminosalicyclic Acid (PAS)
• PAS, like the sulfonamides, is a structural analogue of PABA
• Is a folate synthesis antagonist
– interferes with the incorporation of PABA into folic acid
• Bacteriostatic
• The antibacterial activity is highly specific for M. tuberculosis;
– not effective against other mycobacterium species
• Use of PAS has diminished over the years following:
– introduction of more effective drugs, such as rifampin and
ethambutol
• At present, therapy with PAS is limited to the treatment of
MDR tuberculosis
114
115. Ethionamide
• A derivative of isonicotinic acid and is chemically related
to isoniazid
• A secondary agent used in combination when primary
agents are ineffective or contraindicated
• a bacteriostatic antituberculosis agent
• Its exact mechanism of action is unknown
– but is believed to involve inhibition of mycolic acid
synthesis
• poorly water soluble and available only in oral form
• Well absorbed orally
115
116. Cycloserine
• A broad-spectrum antibiotic produced by Streptomyces
orchidaceus
• inhibits bacterial protein synthesis
• Active against M. tuberculosis, Escherichia coli, S. aureus,
Enterococcus, Nocardia, and Chlamydia spp.
• used in the treatment of MDR tuberculosis
• Used also in renal tuberculosis,
– since most of the drug is excreted unchanged in the urine
• Neurological symptoms, appear in the first week of therapy,
– dizziness, confusion, irritability, psychotic behavioral
changes, and even suicidal ideation
– contraindicated in patients with underlying psychiatric and
seizure disorders
116
117. Rifabutin
• An antibiotic related to rifampin, shares its mechanism of action,
that is, inhibition of RNA polymerase
• has significant activity in vitro and in vivo against M. avium-
intracellular complex (MAC)
• Active against M. tuberculosis, including some rifampin-resistant
strains, such as M. leprae and M. fortuitum
• High lipophilicity,
– achieves a 5- to 10-fold higher concentration in tissues than
in plasma
• Half-life range of 16 to 96 hours
• Clinical use of rifabutin has increased in recent years,
– especially in the treatment of HIV infection
• Is a substrate and less potent inducer of cytochrome 450
enzymes
117
118. Amikacin and Kanamycin
• Have been used in the treatment of tuberculosis
• Amikacin
– very active against several mycobacterium species
– however, it is expensive and has significant toxicity
– considered in the treatment of MDR tuberculosis
after streptomycin and capreomycin
– Also used in the treatment of disseminated MAC in
AIDS patients
• No cross-resistance between streptomycin and other
aminoglycosides;
• Most M. tuberculosis strains that are resistant to
streptomycin are sensitive to kanamycin
118
119. Clofazimine
• Has some activity against M. tuberculosis
• Its precise mechanism of action is unknown but may
involve mycobacterial DNA binding
• used as a last resort drug for the treatment of MDR
tuberculosis
• primarily used in the treatment of M. leprae and M.
avium-intracellulare
119
120. Quinolones: Ciprofloxacin, Levofloxacin and
Ofloxacin
• Most of the fluoroquinolones antibiotics have activity
against M. tuberculosis and M. avium-intracellulare
• Ciprofloxacin, ofloxacin, and levofloxacin inhibit 90% of
the strains of susceptible tubercular bacilli
• Levofloxacin is preferred because,
– approved for once-daily use
• The quinolones act by inhibition of bacterial DNA gyrase
• Quinolones are important recent additions to the
therapeutic agents used against M. tuberculosis,
especially in MDR strains
120
121. Combination Chemotherapy of
Tuberculosis
• Two phases;
– the intensive phase, which lasts 8 weeks & makes the
patients noninfectious; and,
– the continuation phase, which lasts 4 to 6 months
• Clears the body from the mycobacterium
• During the intensive phase of DOTs (direct observation
therapy), the drugs must be collected daily and must be
swallowed under the direct observation of a health
worker
• During the continuation phase, the drugs must be
collected every month and self-administered by the
patient
121
122. TREATMENT OF MALARIA
Four species of protozoal parasite called plasmodium typically cause
human malaria:
Plasmodium falciparum
P vivax
P malariae,
P ovale.
A fifth species, P knowlesi, is primarily a pathogen of monkeys, but
has recently been recognized to cause illness, including severe
disease, in humans in Asia
Although all of the species may cause significant illness, P. falciparum
is responsible for the majority of serious complications and deaths
Drug resistance is an important therapeutic problem, most notably
with P falciparum
123. PARASITE LIFE CYCLE
An infected female Anopheline mosquito inoculates plasmodium
sporozoites to initiate human infection.
Circulating sporozoites rapidly invade liver cells, and exoerythrocytic
stage tissue schizonts mature in the liver
Merozoites are subsequently released from the liver and invade
erythrocytes
Only erythrocytic parasites cause clinical illness
Repeated cycles of infection can lead to the infection of many
erythrocytes and serious disease
Sexual stage gametocytes also develop in erythrocytes before being
taken up by mosquitoes, where they develop into infective
sporozoites
124.
125.
126. Anti-malarial Drugs may be selected for:-
Prevention of clinical attacks --- Chemoprophylaxis
Treatment of clinical attack
Radical cure
127. Classification of Anti-malarial Drugs according to Site of
action
1.Tissue Hepatic Schizonticides /Acting on Hepatic
cycle/
a. Drug effective against primary tissue forms-- Pre-
erythrocytic stage / for Causal prophylaxis
. Proguanil
b. Drug effective against developing or dormant tissue
forms/ for Terminal prophylaxis or Radical cure
. Primaquine
128. 2.Blood Schizonticides / Drug acting on Erythrocytic
parasites/ for Suppressive cure
a. Rapidly acting Blood schizonticides
Chloroquine
Amodiaquine
Piperaquine
Quinine
Mefloquine
Halofantrine
Artemisinin (Qinghaosu) & its derivatives i.e.
Artemether, Artesunate, dihydroartemisinin
129. b. Slower acting Blood schizonticides
Proguanil
Doxycycline
Pyrimethamine
3. Gametocides/ Against sexual Erythrocytic
forms
Primaquine --- Against P. falciparum
Chloroquine, Quinine --- Against P. Vivax, P. Ovale.
They kill sexual forms & prevent transmission to
mosquitoes
132. Chloroquine
Most widely used anti-malarial, blood schizonticide
Source: Synthetic drug.
chemistry: 4-Aminoquinoline.
133. Pharmacokinetics:
Orally as Chloroquine phosphate & I/M / I/V injection as
Chloroquine sulphate
• Absorption: well & almost complete from GIT but ↓ses by
antacids containing Calcium & Magnesium
• Distribution: Rapid & wide. Concentrated in RBCs, liver,
spleen, kidney, lung, melanin containing tissues. It also
penetrates into the CNS & traverses placenta
• PPB: 50% & extensively tissue bound specially to melanin
containing tissues
• t½: 1-2days
134. MOA of Chloroquine as Antimalarial
It is highly effective blood schizonticide
Moderate gametocide for P. vivax, P. ovale &
P. malariea
No effect on liver stages of malarial
parasites
135. MOA : Chloroquine probably acts as follows:
• Chloroquine is a weak base, it is concentrated in
parasite’ s food vacuoles by ion trapping
• Malarial Parasites utilize hemoglobin as food, it is
broken down in to heme which is toxic but it is
polymerized into harmless hemozoin by enzyme
heam polymerase
Chloroquine prevents biocrystallization of heme into
Hemozoin, by inhibiting HAEM POLYMERASE
Increased pH & accumulation of toxic heme, produces
oxidative damage to the membranes, leading to lysis
of both the Malarial Parasites & RBCs.
136.
137. Resistance to chloroquine
Very common in P. falciparum
Uncommon but increasing in P. vivax
In P. falciparum, it has been correlated with
mutations in a transporter, PfCRT
There is decreased accumulation of drug .
It can be reversed by verapamil, desipramine
and chlorpheniramine , clinical value not
established
138. Therapeutic uses
• Acute attack of Malaria-
Effective, safe & cost effective
DOC for non-falciparum & sensitive falciparum Malaria.
Terminates fever rapidly in 24-48hrs
Clears parasitemia in 48-72 hrs
Safe in pregnancy & young children
• Chemoprophylaxis of Malaria
• Hepatic amebiasis / abscess
Concentrated in liver kills trophozoits of E. histolytica
• Rheumatoid Arthritis
139. Adverse Effects
A/E are minimal with low doses for chemoprophylaxis.
After oral doses for Acute attack of Malaria:
Common A/E
Pruritis (primarily in Africans) sometimes with Urticaria
Nausea, vomiting ,Abdominal Pain, Anorexia
Headache
Blurring of vision
140. AMODIAQUINE
• Closely related to chloroquine
• MOA & MOR similar to chloroquine
• Low cost, limited toxicity
A/E: Rare-- Agranulocytosis, aplastic anemia &
hepatotoxicity
Therapeutic Uses:
Treatment of malaria with chloroquine resistant P.
falciparum in combination :
Amodiaquine with Artesunate (Coarsucam).
It is first line therapy in many African countries
• Amodiaquine with Sulfadoxine -Pyrimethamine
Not used for prophylaxis– increased toxicity with long
term use
141. Piperaquine
• Chemically it is Bisquinoline
• Piperaquine was used for treatment of malaria from
1970s-1980s in China, the use waned due to
resistance
• Now it is combined with Dihydroartemisinins
• Piperaquine & Dihydroartemisinins (Artikin)– first
line therapy for falciparum malaria , without apparent
resistance
• It has longer half life—28day– so longer period of
post treatment prophylaxis than other combinations
of artemisinins
142. Artimisinin (Qinghaosu) & its Derivatives
• Artemisinin: It is Sesquiterpene lactone
endoperoxide, active compound of a Herbal medicine
used in China for 2000 yrs
Insoluble --- only used orally
• Analogs: Artisunate & Artemether
• Artesunate :Water soluble, useful for oral I/V,
I/M & rectal administration
• Artemether :Lipid soluble, useful for oral I/M &
rectal administration
• Dihydroartimisinin :Water soluble, useful for oral
administration
143. Ph. Kinetics of Artemisinin( Qinghaosu) & its
Analogs:
Abs.: Given orally well & almost complete from
GIT
t ½: 1-3 hrs
Dist.: Rapid & wide, some tissue binding
Met : in liver Artesunate & Artemether metabolized
to active metabolite dihydroartimisinin
144. MOA:
• Rapidly acting blood schizonticide against all four
species of MP
•No effect on hepatic stages
•They act by producing free radicals due to iron
catalyzed cleavage of the artemisinin endoperoxide
bridge in the parasite food vacuole
145. Therapeutic Uses
1. Treatment of uncomplicated P. falciparum malaria
Combination is preferred as standard treatment:
Artemether in combination with lumefantrine
Artesunate in combination with Mefloquine / Amodiaquine
/ Sulfadoxine-Pyrimethamine
Dihydroartemisinins with Piperaquine (Artikin)
2. Treatment of complicated P. falciparum malaria
I/V Artemether & Artesunate
I/V Artemether has efficacy like Quinine & I/V Artisunate
is even superior--- in clinical trials
3. Not useful for prophylaxis – short half life
146. Adverse Effects
• Nausea, Vomiting, Diarrhea & dizziness
• Rare toxicities: Neutropenia, anemia, hemolysis,
elevated liver enzymes & Allergic reactions
• Irreversible neurotoxicity in animals at high doses
• Teratogenic in animals
• However WHO has recommended use of I/V
artisunate in pregnancy, for treatment of severe
Falciparum malaria
147. Quinine & Quninidine
Blood schizonticides
Source:
Quinine: Natural alkaloid, Bark of Cinchona
Quinidine: dextrorotatory stereoisomer of quinine
Chemistry: Quinoline methanol
MOA:Exact MOA not known
Rapidly acting Blood schizonticide. , highly effective against four
species of human M. Parasites
Gameticidal: against p vivax and P ovale but not p falciparum.
Resistance:
• Common in some areas .It is increasing.
148. Therapeutic Uses
1. Severe P. falciparum malaria (cerebral Malaria)–
Quinidine is preferred over Quinine, Parenterally
2. P. falciparum malaria resistant to Chloroquine,
orally Quinine sulfate in combination with Doxycycline
/Clindamycin
3. Prophylaxis of malaria – generally not used
149. Adverse Effects
1.Cinchonism: ---- Dose related
a. Mild cases: Tinnitis, headache , Nausea, Dizziness,
Flushing , visual disturbances
b. Severe case: More marked visual & auditory
disturbances, Vomiting ,Diarrhoea
2. Haematological disturbances
Haemolytic anaemia (in G6PD deficiency)
Leucopenia, agranulocytosis ,thrombocytopenia
3. Hypersensitivity reactions:
Skin rashes, urticaria, angioedema , bronchospasm
4. Abortion– as they stimulate uterine contractions
150. Contraindications & cautions:
Underlying visual & auditory disturbances
Discontinue on severe Cinchonism
G6PD deficient patient
Cardiac abnormalities
C/I with Mefloquine
Dose reduction in renal insufficiency
152. Primaquine
Synthetic 8-Aminoquinoline
Given orally
Its metabolites can produce hemolysis, specially in G-6
phosphate –dehydrogenase deficiency
Tissue schizonticide against dormant hypnozoit liver forms of P.
vivax & P. ovale
Gametocide for all 4 species
Exact MOA unknown
153. Clinical uses of Primaquine
• Radical cure of acute Vivax & Ovale Malaria.-- drug
of choice provided G6PD status is normal
• Terminal prophylaxis of Vivax & Ovale
• Gameticidal: To disrupt transmission , rendering P.
falciparum gametocytes non-infective for Malarial
Parasites
• Not recommended for routine chemoprophylaxis
154. Adverse Effects
GIT upsets
Haemolytic anaemia & Methaemoglobinaemia
(in G6PD deficiency)
Rarely Leucopenia, agranulocytosis & Cardiac
arrhythmias
Contra indications & cautions:
NEVER given parenterally--- marked hypotension
Patients with myelosuppression
Pregnancy
G6PD status should be checked
156. Introduction
• Viral infections are among the leading causes of
morbidity and mortality worldwide
• The persistence AIDS epidemic makes this painfully
clear
• Despite advances in anti-HIV drug therapies, AIDS
continues to be a common cause of death, particularly in
some African nations, where as many as one person in
five is infected with HIV
– lack of an effective vaccine against HIV,
– too expensive anti-HIV drugs
• Despite this discouraging statistic,
– drugs available to combat viruses have been
instrumental in saving millions of lives each year and in
improving the quality of life for countless others with
viral illnesses
156
157. Introduction cont…
• Viruses are obligate intracellular parasites that use many
of the host cell’s biochemical mechanisms and products
to sustain their viability
• A mature virus (virion) can exist outside a host cell and
still retain its infective properties
• However, to reproduce, the virus must enter the host
cell, take over the host cell’s mechanisms for nucleic acid
and protein synthesis, and direct the host cell to make
new viral particles
157
158. Classification of Viruses
• Viruses are composed of one or more strands of a nucleic
acid (core) enclosed by a protein coat (capsid).
• Many viruses possess an outer envelope of protein or
lipoprotein
• Viral cores can contain either DNA or RNA; thus, viruses
may be classified as DNA viruses or RNA viruses.
• Examples of DNA viruses and the diseases that they
produce include
– Adenoviruses (colds, conjunctivitis);
– Hepadna viruses (hepatitis B);
– Herpes viruses (cytomegalovirus, chickenpox,
shingles);
– Papilloma viruses (warts); and
– poxviruses (smallpox)
158
161. Viral Replication
• Although the specific details of replication vary among
types of viruses, the overall process can be described as
follows:
(1) attachment of the virus to receptors on the host cell surface;
(2) entry of the virus through the host cell membrane;
(3) uncoating of viral nucleic acid;
(4) synthesis of early regulatory proteins, eg, nucleic acid
polymerases;
(5) synthesis of new viral RNA or DNA;
(6) synthesis of late, structural proteins;
(7) assembly (maturation) of viral particles; and
(8) release from the cell
• Antiviral agents can potentially target any of these steps
161
163. Overview of Antiviral Therapy
• Three basic approaches are used to control viral diseases:
– vaccination,
– antiviral chemotherapy, and
– stimulation of host resistance mechanisms
• Vaccination has been used successfully to prevent measles, rubella,
mumps, poliomyelitis, yellow fever, smallpox, chickenpox, and
hepatitis B
• The usefulness of vaccines appears to be limited (e.g., HIV)
• Vaccines have little or no use once the infection has been
established because they cannot prevent the spread of active
infections within the host
163
164. Overview of Antiviral Therapy cont…
• Passive immunization with human immune globulin, equine
antiserum, or antiserum from vaccinated humans
– Can be used to assist the body’s own defense
mechanisms
• The chemotherapy of viral infections may involve
interference with any or all of the steps in the viral
replication cycle
• Because viral replication and host cell processes are so
intimately linked, the main problem in the chemotherapy
of viruses is finding a drug that is selectively toxic to
the virus
164
166. The HIV Epidemic Unfolds
• HIV isolated in 1984 - Luc Montanier (Pasteur Institute,
Paris) and Robert Gallo (NIH, Bethesda, USA)
• HIV diagnostic tests developed in 1985
• First antiretroviral drug, zidovudine, developed in 1986
• Exploding pandemic
– Has infected more than 50 million people around the
world
– Has killed over 22 million people
166
167. Classification of HIV
• Retrovirus: single stranded RNA transcribed to
double stranded DNA by reverse transcriptase
• Integrates into host genome
• Can lie dormant within a cell for many years,
especially in resting (memory) CD4+ T4 lymphocytes
• HIV type (distinguished genetically)
– HIV-1 -> worldwide pandemic (~ 40 M people)
– HIV-2 -> isolated in West Africa; causes AIDS
much more slowly than HIV-1 but otherwise
clinically similar
167
171. How HIV Enters Cells
• There are three crucial steps for entry of HIV into the
CD4 T cell:
1. Binding of HIV via the gp120 envelope protein to the
CD4 receptor (attachment),
2. Binding to coreceptors via conformational changes to
gp120, and finally
3. Fusion of virus and cell
• In addition to the CD4 receptor, HIV requires
coreceptors for entry into the target cell
• The two most important ones are CXCR4 and CCR5
• HIV variants mainly using CCR5 are referred to as R5
viruses; those using CXCR4 are referred to as X4 viruses
171
172. How HIV Enters Cells cont…
• When the virus enters the blood, it binds a protein on its
surface (gp120) to a CD4 receptor and co-receptors
(CXCR4 or CCR5) on the CD4 cell
• Then gp120 shifts to expose gp41
• Once exposed, gp41 pierces the CD4 cell and pulls it in
close enough to allow viral-cell fusion
• Binding of virus to cell surface results in fusion of viral
envelope with cell membrane
• Viral core is released into cell cytoplasm
172
173. HIV and Cellular Receptors
Seyoum G. Adall, ANTIVIRAL DRUGS 173
174. Viral-host Dynamics
• About 1010 (10 billion) virions are produced daily
• Average life-span of an HIV virion in plasma is ~6 hours
• Average life-span of an HIV-infected CD4 lymphocytes
is ~1.6 days
• HIV can lie dormant within a cell for many years,
especially in resting (memory) CD4 cells, unlike other
retroviruses
• The extremely high rates of viral replication results in
every possible point mutation in the viral genome arising
daily
• In any given patient, the virus usually varies by 1-6% in
the env gene, for example
174
175. HIV Life Cycle and Sites for Therapeutic Intervention
175
176. Classes of Antiretrovirals
• Fusion inhibitors
– Prevents fusion of the virus into a CD4 cell by preventing
conformational change needed to allow virus to enter a CD4 cell
• Nucleoside reverse transcriptase inhibitors (NRTIs) or nukes
(zidovudine, lamivudine)
– Mimic naturally occurring nucleosides
– Blocks viral DNA construction as they deceive reverse
transcriptase
• Non- nucleoside reverse transcriptase inhibitors (NNRTIs) or
non-nukes (Nevirapine or Efavirenz)
– Bind to the reverse transcriptase enzyme
• Protease inhibitors (PIs) (Indinavir or lopinavir)
– Prevent cleavage of the protease chain
176
178. NRTI Mechanism of Action
• NRTIs must first undergo intracellular phosphorylation
to be active
• NRTIs inhibit the viral reverse transcriptase enzyme
– Enzyme responsible for transcribing viral RNA into
double stranded DNA
• NRTIs mimic other nucleosides and are incorporated into
the DNA strand
• They prevent the addition of the natural nucleosides into
the DNA strand
• This halts the production of new virions
178
179. NRTI Class Side Effects
• Nausea
• Headache
• Peripheral Neuropathy
• Lipoatrophy
• Pancreatitis
• Lactic Acidosis
– d4T > ddI > ZDV
– Rare with ABC, TDF, 3TC and FTC
179
180. NRTI Mitochondrial Toxicity
• Inhibition of mitochondrial DNA polymerase-
– oxidative metabolism,
ATP generation
• Implicated in lactic acidosis
• Other possible manifestations:
– Neuropathy (d4T, ddI)
– Lipoatrophy (d4T)
– Pancreatitis (ddI)
– Myopathy (ZDV)
– Cardiomyopathy (d4T, ZDV)
180
181. Facial Lipoatrophy: may be due to mitochondrial
toxicity
Not reversible, occur commonly with stavudine
181
Facial Lipoatrophy:
184. NNRTI Mechanism of Action cont…
• NNRTIs also inhibit the viral reverse transcriptase
enzyme but have a different mechanism of action
compared to NRTIs
• NNRTIs bind directly to the reverse transcriptase
enzyme
– Inhibit viral DNA synthesis
• Unlike the NRTI agents, NNRTIs neither compete with
nucleoside triphosphates nor require phosphorylation to
be active
• All are substrates for CYP3A4 and can act as inducers
(nevirapine), inhibitors (delavirdine), or mixed inducers
and inhibitors (efavirenz) 184
185. Efavirenz
• should be taken on an empty stomach because high-fat
meal increase toxicity
• metabolized by CYP3A4 and CYP2B6 to inactive
metabolites
• It is highly bound to albumin (~ 99%)
• The principal adverse effects: dizziness, drowsiness,
insomnia, headache, confusion, amnesia, agitation,
delusions, depression, nightmares, euphoria and Skin rash
• Should be avoided in pregnant women
• It is both inducer and an inhibitor of CYP3A4
• Contraindicated in pregnancy!!
– Known to cause birth defects 185
186. Nevirapine
• oral bioavailability (90%) is not food-dependent
• It is extensively metabolized by the CYP3A isoform
• When initiating therapy, gradual dose escalation
over 14 days is recommended to decrease the
incidence of rash
• Hepatotoxicity occurs in about 4% of patients
• a moderate inducer of CYP3A metabolism
• Rash occurs in approximately 17% of patients
186
190. Protease Inhibitors (PIs) cont…
• Protease inhibitors – prevent viral protease enzyme from
cleaving the polyprotein precursor to viral coat protein
and reduces activation of critical viral proteins/enzymes
• Thus new virons are formed, but are defective and
cannot infect other cells
• Use of PIs is associated with a syndrome of
redistribution and accumulation of body fat that
results in central obesity to the exception of atazanavir
190
194. PI Mechanism of Action
• Protease enzyme is responsible for cleaving (cutting up)
larger polyproteins into structural proteins and reverse
transcriptase enzyme
• Protease is needed to form a fully mature, functional
virus that is able to replicate and produce more virus
• Protease inhibitors prevent this enzyme from doing its
job in the later steps of the viral life cycle
194
195. PI Class Side Effects
• Metabolic Disorders
– Hepatotoxicities
– Hyperglycemia, insulin resistance
– Lipid abnormalities
– Fat redistribution
• Bone Disorders
• GI intolerance
• Drug interactions
• CYP450 3A4 Inhibition
– RTV > IDV = NFV = APV >SQV
195
196. Fusion Inhibitors
• Include: Enfuvirtide, Maraviroc
• Inhibits entry of HIV into the CD4 cell
• Enfuvirtide binds to glycoprotein gp41 (a protein on the viral
membrane)
– prevents a change in the shape of the membrane protein and
prevents fusion of the virus and the CD4 cell membrane
– blocks entry into the cell
• Unfortunately, Enfuvirtide is only active when injected
subcutaneously
• This aspect (in addition to its high cost) severely limits it use in the
correctional setting
• Enfuvirtide lacks cross-resistance to the other currently approved
antiretroviral drug classes 196
197. Maraviroc
• First in new class of agents, CCR5 inhibitors
• Approved August 6th, 2007
• Maraviroc binds to the CCR5 receptor on the membrane of human
cells such as CD4 cells
– prevents the interaction of HIV-1 gp120 and human CCR5 which
is necessary for entry into the cell.
• Does not prevent HIV-1 entry into CXCR4-tropic or dual-tropic cells
• Indicated (in combination with other ARVs) treatment-experienced
adult HIV-infected patients
• Not recommended in patients who have dual/mixed tropic or CXCR4-
tropic virus
• Use of maraviroc should be based on treatment history and tropism
assay results
197
198. Intergrase Inhibitors:
RALTEGRAVIR
• A pyrimidinone analog that binds and inhibits the
enzyme integrase
– It inhibits strand transfer
• Bioavailability does not appear to be food-
dependent
• Metabolized by glucuronidation
198
