Pharmacology of Antibacterial agents

CHEMOTHERAPY
Chemotherapy Compiled by Birhanu G. 1

Chemotherapy
 Use of chemical agents (natural/synthetic) to destroy or
inhibit the growth of infective agents &/or cancerous cells
 Antibiotics: s/ces produced by µorganisms to suppress
the growth & replication or kill other µorganisms
 N.B.: now antibiotics are synthesized in the laboratory

Chemotherapy
Antiparasitics
Antihelminthics
Antiprotozoals
Antimicrobials Antibacterials
Antifungals
AntiviralsAntineoplastics

Use of Anti-infective Agents
✍ Prophylactic therapy
✍ Empiric therapy
✍ Definitive therapy: identification of pathogen & sensitivity
test
☞Goal: selective toxicity

Antibacterial Agents: ABX
☞ Can be:
 Narrow spectrum: INH, Cloxacillin, Naldixic acid, Pen-G
 Broad spectrum: CAPH, TTCs, Rifamycins, FQs
 Bactericidal:
 Penicillin, cephalosporins, vancomycin, FQs, aminoglycosides,
metronidazole
✍ MBC: the lowest concentration of ABX reduces the viability of
the initial bacterium inoculum by ≥99.9%
✍ Can be determined from broth dilution MIC

 Bacteriostatic:
 TTCs, macrolides, amphenicols, lincosamides,
 Aminocyclitoles, sulphonamides
✍ Never confuse these terms with potency levels of the drugs or
efficacy: narrow are weak, broad are strong

MOA of ABX

 Drug resistance: unresponsiveness of µ-organism to
antimicrobial agents
 Can be innate/acquired
☞ Origin of Drug Resistance
 Chromosomal mutation & selection: vertical
 Acquisition of chromosomal or extra chromosomal
material/horizontal/
 Conjugation: sexual reproduction
 Transduction: phages
 Transformation: taking genetic material from env’t or dead
bacteriaChemotherapy Compiled by Birhanu G. 11

Mechanisms of Bacterial Resistance

Delaying the emergence of resistance
✍ Antimicrobials should be employed only when actually needed
✍ Narrow agents should be employed whenever possible
✍ Newer antibiotics should be reserved

Systematic Approach for Selection of Antimicrobials
✍ Confirm the presence of infection
☞Careful history & physical examination
☞Signs and symptoms
☞Predisposing factors
✍ Identification of the pathogen
☞Collection of infected material
☞Stains, serology, culture and sensitivity
✍ Host & Drug factors

Patient specific considerations
 Age: causative agents, contraindication
 Disruption of host defenses(immunity):
 Compromised → cidal
 Site of infection
 History of recent antimicrobial use
 Antimicrobial allergies
 Renal and/or hepatic function
 Concomitant administration of other medications
 Pregnant & nursing women and compliance

Drug-specific considerations
 Spectrum of activity
 Effects on nontargeted microbial flora
 Appropriate dose
 Pharmacokinetic & Pharmacodynamic properties
 Adverse-effect & drug-interaction profile
 Cost

Antimicrobial drug combination
 Indication
 Severe infection of unknown etiology
 Mixed infection
 Prevention of resistance
 Decreased toxicity
 Enhanced action: penicillin + aminoglycoside = synergism

Disadvantages of antimicrobial combination
 Increase risk of allergy
 Antagonism of antimicrobial effect: TTC + penicillin
 Increase risk of super infection
 Increased cost

Cell wall synthesis
inhibitors
-lactams
Penicillins
Cephalosporins
Carbapenems
Monobactams
Fosfomycin
Cycloserine
Bacitracin: poly peptides
Glycopeptides: Vancomycin

BETA-LACTAM ANTIBIOTICS

Most commonly used β-lactams

 The penicillin nucleus, 6-aminopenicillanic acid (6-APA),
consists of 3 components:
 A thiazolidine ring: five-member
 The β-lactam ring & a side chain
 Cephalosporin nucleus, 7-aminocephalosporanic acid (7-ACA)
contains:
 A six-member dihydrothiazide ring,
 β-lactam ring & a side chain

PENICILLINS
 MOA:
 Bacterial cell wall is cross-linked polymer of polysaccharides &
pentapeptides
 Irreversibly acetylate membrane-binding proteins; PBPs or
transpeptidases/transamidases → inhibit transpeptidation
reactions involved in the cross-linking
 β-lactam ring structurally mimics the D-alanine-D-alanine
portion of the peptidoglycan: suicide substrates of PBPs

 β-lactam ABX are known to bind & inhibit inhibitors of
autolysins → activation of autolysins: destruction of the
existing cell wall
✍ For maximum effectiveness, they require actively proliferating
microorganisms
✍ Little or no effect on bacteria that are not growing & dividing

NARROW SPECTRUM PENICILLINS
Natural Penicillins: Penicillin G, Pen.V
 Active against:
 G+ve cocci & bacilli: except penicillinase producing µbes
 G-ve cocci: N.menigitidis, N.gonorrhea
 Which have slightly larger porins
 G-ve bacilli: have narrow porins, not effective
 Spirochetes: T.pallidum, Borrelia, Leptospira

Therapeutic uses
 Drug of choice for G+ve cocci;
 Pneumonia or meningitis by Streptococcus pneumonia
 Pharyngitis by Streptococcus pyogenes
 Infective endocarditis by Streptococcus viridians
 Infection caused by G+ve bacilli:
 Gangrene by Cl. perfringes
 Tetanus by Cl. tetani
 Anthrax by B. anthracis

Therapeutic uses…
 First choice for meningitis by N. meningitids
 Drug of choice for the treatment of syphilis
 Prophylactic applications;
 Syphilis in sexual partners
 Benzathine pen.G monthly for life in recurrent rheumatic fever
 Bacterial endocarditis

Pharmacokinetics
 Pen.-G is available as salts: Na+, K+, Procaine, Benzathine
 Pen.-G: orally ineffective due to the acid
 Procaine & Benzathine salts are intermediate & long acting
respectively
 Both absorbed from the muscle slowly & referred to as
repository forms of Pen G
 Distributes well to most tissues; inflammation distribution
into CSF, joints & eye
 Penicillin is eliminated by tubular secretion [90%].
 Excretion delayed by probenecidChemotherapy Compiled by Birhanu G. 30

PHENOXYMETHYL PENICILLIN: PENICILLIN-V
 Acid stable: given orally
 Used in streptococcal pharyngitis, prophylaxis of rheumatic
fever; GABHS

VERY NARROW SPECTRUM: -LACTAMASE RESISTANT
Cloxacillin, Dicloxacillin, Oxacillin, Methicillin, Nafcillin
 Also called anti-staphylococcal penicillins
 They have bulky side chains that protect the -lactam ring
Can’t get access to G-ve due to bulky size: drawback
 Use: in S.aureus & Staph.epidermdis infections
 Emergence of staphylococcal strains (MRSA): Vancomycin
VRSA: FQs, Linezolid

 Methicillin
 Acid labile; allergic reaction; severe interstitial nephritis
 Only for drug sensitivity testing: nephrotoxicity
 Nafcillin
 Erratic & incomplete absorption from PO, so; IM or IV
 S/E: Neutropenia, Nephritis (less severe)
 Isoxazolyl Penicillins: Oxacillin, Cloxacillin, Dicloxacillin
 Acid stable; orally & parenterally administered
 Absorption affected by food

BROAD SPECTRUM
 AMINOPENICILLINS
 Ampicillin, Amoxicillin, Bacampicillin, Pivampicillin
 Antimicrobial spectrum as penicillin G; plus G-ve bacilli:
 They can enter via porins
 Spectrum: HELPS to clear enterococci (G-ve)
 Acid stable: can be administered PO
 Ineffective against -lactamase producing bacteria
 Need to be combined with -lactamase inhibitors
 Can’t cover P.aeruginosa: has tight/few porins

Therapeutic uses
 Ampicillin: can be given PO & parenterally
 Meningitis: L.monocytogenes; with 3rd gen Cephalosporin
 Pneumonia (G-ve) with gentamycin
 Hepatic encephalopathy: reducing NH3 production
 Especially in azotemic patients, since neomycin is not safe
 Bile (biliary tract infection)

 Amoxicillin:
 Pharyngitis, otitis media, tonsillitis, bronchitis, CAP,
sinusitis
 UTI: cystitis, pyelonephritis
 PUD (H. pylori): triple/dual therapy
 Severe dental abscess with spreading cellulitis
 Anthrax: postexposure inhalational prophylaxis
 IE prophylaxis: 2 g PO 30-60’ before dental procedure
 Lyme disease (off-label)
 Chlamydial infection in pregnant: off-labelChemotherapy Compiled by Birhanu G. 36

 Amoxicillin
 Oral absorption is better than ampicillin: food doesn’t affect
 Incidence of diarrhea is less than ampicillin
 Less active against shigella
 Bacampicillin: prodrug of ampicillin

 ANTIPSEUDUOMONAL PENICILLINS
 Carboxypenicillins: Carbenicillin, Ticarcillin
 Carbenicillin
 Active against p.aeruginosa & indole positive proteus
 Neither penicillinase nor acid resistant: very small R-chain
 Carbenicillin Indanyl Sodium: the only PO
 Indanyl ester of carbenicillin: acid stable (PO)
 After absorption, rapidly converted to carbenicillin by
hydrolysis of the ester linkage
 The active moiety excreted rapidly in the urine, where it
achieves effective concentrations: UTI by ProteusChemotherapy Compiled by Birhanu G. 38

 Ticarcillin
 2-4 times more potent against pseudomonas
 Ureidopenicillins: Piperacillin, Mezlocillin, Azlocillin
 Spectrum: P. aeruginosa, Enterobacteriaceae (non β-lactamase
producing), Bacteroides, E. faecalis
 Piperacillin-tazobactam: has the broadest antibacterial
spectrum of the penicillins: methicillin-susceptible S. aureus,
H. influenzae, B. fragilis, E. coli, Klebsiella

 -lactamase inhibitors: Clavulinic Acid, Sulbactam, Tazobactam
 Inhibits bacterial -lactamases
 Most active against -lactamase produced by: S. aureus,
H.influenza, some enterobacteriaceae, Bacteroid spp.
 Chromosomal -lactamases of Serratia spp, Enterobacter spp,
P. aeruginosa are not inhibited

 Amoxicillin-clavulinic acid combo: augmentin®, Enhancin®
 Available in 4:1 combination.
 250-750mg amoxicillin & 62.5-125mg clavulinic acid
 Use:
 Skin infection: streptococci, staphylococci.
 Acute otitis media: H.infleunza, M.catarrhalis
 Sinusitis, Lower RTI
 Diabetic foot infection: staphylococci, aerobic & anaerobic G-ve

 Ampicillin-Sulbactam combo: Unasym®
 Combination is available 1:0.5
 Same spectrum of augmentin: used in mixed infection
 Piperacillin-tozabactam combo: Zosyn®
 Equivalent or superior to 3rd generation cephalosporin
 Ticarcillin-clavulanic acid combo: Timentin®
 750 mg + 50 mg: in 0.8 g Timentin OR 1.5 g + 100 mg: in 1.6
g OR 3 g + 200 mg: in 3.2 g
 For: Klebsiella, E.coli, S aureus, P.aeruginosa, H.influenzae,
Enterobacter, Citrobacter, serratia marcescens, Bacteroides
fragilis, Staphylococus epidermidisChemotherapy Compiled by Birhanu G. 42

Resistance to Penicillins
 Innate/Natural/: all cells w/c have no peptidoglycan
 Fungi: cell wall is made of chitin
 Mycobacteria: cell wall is mycolic acid/thick waxy layer/
 Mycoplasma: have no cell wall
 Pseudomonas: have no porins for Pen-G
 Chlamydia: obligate intracellular µbe: penicillin can’t enter
 Viruses: have no cell wall
 All human cells: have no cell wall; SAFEST ABX

 Acquired:
 -lactamase production: chromosomal or plasmid mediated
 The gene for -lactamase is present in plasmids: can be
transferred to other bacteria w/c were initially non resistant
 Plasmid mediated/conjugation/; the most dangerous: rapid
 A bacterium can transfer plasmids for many bacteria

 Chromosomal mediated: mutation & selection i.e vertical
 Acquisition of chromosomal material/horizontal/
 Transduction: phages
 Transformation: taking genetic material from env’t or dead
bacteria

 Acquired…
 Alteration of porins: dev’t of tight porins
 Due to mutation of the gene  permeability
 Efflux (active) pump: less common
 Alteration of PBPs (trans peptidases): due to mutation of the
gene that codes for trans peptidases: most common

Drug Interactions:
 Aminoglycosides: synergism
Inactive precipitate is formed if mixed in one container
 Probenecid: inhibits the secretion of penicillins by competing
for active tubular secretion via the organic acid transporter
 Bacteriostatic antibiotics: due to antagonism
 Ampicillin and oral contraceptives;
 Decreased enterohepatic circulation

Adverse effects
 The safest drugs: no monitoring
 Hypersensitivity reaction: pencillioc acid act as a hapten
 Type-I: IgE mediated /immediate hypersensitivity
 IgE-mediated degranulation of mast cells
 Anaphylactic shock is the most dangerous
 Need of skin test for the suspect penicillin

 Type-II: IgG mediated
 Penicillin metabolites alter RBC membrane proteins →
 IgG mediated RBC destruction: penicillin associated hemolytic
anemia
 Type-III:
 Body produces Ab against penicillin
 Ag-Ab complex mediated complement activation
 Ag-Ab interacts & activates complement system → neutrophil
activation →
 Vasculitis: skin rash, glomerulonephritis, pericarditis, pleuritis,
generalized lymphadenopathy, polyarthritisChemotherapy Compiled by Birhanu G. 50

 Maculopapular rash: Ampicillin, direct toxicity especially in
patients with infectious mononucleosis due to EBV
 Diarrhea: due to PO Ampicillin
 Development of Clostridium difficile 
 Bloody diarrhea due to damage of GIT mucosa (Pseudo
membranous colitis)

 Nephritis: naficillin, methicillin (not in clinical use)
 Neurotoxicity: GABAergic inhibition  seizure
So, not given intrathecally
 Inhibition of platelet function: Piperacillin, Ticarcillin,
carbencillin
 Neutropenia
 Cation toxicity: since they are given as a salt of Na or K

CEPHALOSPORINS
Pharmacodynamics:
 Inhibition of bacterial transpeptidases
 Bactericidal

CLASSIFICATION

1st Generation Cephalosporins
 Relatively narrow spectrum (G+ve bacteria)
Selected 1st generation Cephalosporins;

2nd Generation Cephalosporins
 True Cephalosporins: Cefaclor, Cefamandole, Cefonicid,
Cefuroxime, Cefprozil, Cefpodoxime, Loracarbef & Ceforanide.
 Have high activity against: H.infleunza, N.meningitidis,
N.gonorhoeae
 Cephamycins: Cefoxitin, Cefmetazole, Cefotetan.
 Antibacterial against selected enterobacteriaceae; most
active against B.fragilis.

3rd Generation Cephalosporins
 Cefotaxime, Ceftriaxone, Ceftazidime, Cefoperazone,
Cefixime, Ceftizoxime.
 Less active than 1st generation against G+ve cocci.
 More active against Enterobacteriaceae.
 Antipseudomonal activity from Cefoperazone & Ceftazidime

 Ceftriaxone: most potent;t1/2=8hrsonce daily dose
 High efficacy in bacterial meningitis, multiresistant typhoid
fever, complicated UTI, Abdominal sepsis, Septicaemias
 Ceftazidime: excellent activity against G-ve: p.aeruginosa
 Penetrate CSF & DOC in meningitis due to p.aeruginosa;
given parenterally.
 Cefoperazone: strong against pseudomonas; high ppb
 Do not reliable penetrate into CSF.
 Indicated in severe urinary, respiratory, biliary infection and
septicaemia

4th Gen. Cephalosporins: Cefepime, Cefpirome
 Rapidly cross the outer membrane of G-ve.
 More resistant to hydrolysis [chromosomal -lactamase:
produced by enterobacter] & lactamases that inactivate 3rd
generation
 Active against Enterobacteriaceae, P. aeruginosa, H. influenza
& Neisseria spp.

Advanced Generation: Ceftaroline
 Broad spectrum
 Administered IV as a Prodrug, Ceftaroline fosamil
 Active against MRSA
 Used for the tXt of complicated skin & skin structure
infections and CAP
 The unique structure allows Ceftaroline to bind to PBP2a
found with MRSA and PBP2x found with Streptococcus
pneumoniae

 In addition to its broad G+ve activity, it also has similar G-ve
activity to the 3rd Gen. cephalosporin; Ceftriaxone
 Active against:
P. aeruginosa,
Extended spectrum β-lactamase (ESBL)-producing
Enterobacteriaceae,
Acinetobacter baumannii.
 The twice-daily dosing regimen also limits use outside of an
institutional setting

Adverse effects
 Allergic reactions
 Antibiotic-associated colitis: super infection.
 Bleeding: hypoprothrombinemia (methylthioterazole/MTT
containing group, 3rd generation)
 Cefoperazone, Cefotetan, Cefamandole, Cefmetazole
 Local effects: thrombophlebitis from IV injection

Drug interaction
 Probenecid
 Alcohol: Cephalosporins with MTT have disulfiram like rxn.
 Drugs that promote bleeding

Other -lactam Antibiotics
 Carbapenems: Ertapenem, Imipenem, Meropenem, Doripenem
 Imipenem, with Cilastatin: Primaxin
 MOA: Inhibit bacterial trans peptidases
– -lactamase resistant
Imipenem (IV)
 Antimicrobial spectrum: G+ve and G-ve including P.
aeruginosa; & anaerobes
 Distributed in CSF; metabolized in renal tubule by
dehydropeptidases which can be inhibited by cilastatin

Adverse effect
 GIT: NVD in rapid IV infusion
 CNS: Seizure
 Hypersensitivity reaction
Therapeutic use
 Serious hospital acquired infection
 Treatment of mixed infections [aerobic & anaerobic].

 MONOBACTAMS: Aztreonam
 Isolated from Chromobacterium violaceum
MOA:
 Bind to PBP inhibit cell wall synthesis.
 Antimicrobial spectrum: narrow (G-ve aerobic bacteria: H.
Influenza, N. Meningitides, & pseudomonas).
 -Lactamase resistant; no cross sensitivity with other -
lactam
 Used as substitute to Aminoglycosides in UT, lower RT, skin &
soft tissue infection

FOSFOMYCIN: bactericidal
 Inhibits the first cytoplasmic step in cell wall biosynthesis
 Covalently binds with UDP-N-acetylglucosamine
enolpyruvyl transferase (MurA);
 Involved in the formation of the peptidoglycan precursor
UDP N-acetylmuramic acid (UDPMurNAc)

 Fosfomycin uses two mechanisms for cellular entry;
 L-alphaglycerophosphate & hexose-6-phosphate
transporter systems
 Fosfomycin reduces adherence of bacteria to urinary
epithelial cells
 It also suppresses PAF receptors in respiratory epithelial
cells → reducing adhesion of S.pneumoniae &
H.influenzaeChemotherapy Compiled by Birhanu G. 70

 Has oral & parenteral forms
 Dose:
 3g Stat PO (FDA) for uncomplicated UTI, OR
 3g Q10 days for UTI prophylaxis
 The oral formulation is a powder (fosfomycin tromethamine) &
 BA is approximately 40%, with a t1/2 of 5-8 h
 Distribution: low in blood but highly concentrated in urine
 ADR: well tolerated; GI distress, vaginitis, headache, dizziness

CYCLOSERINE
 D-4-amino-3-isoxazolidone
 Broad-spectrum, produced by Streptococcus orchidaceous

 MOA:
 Acts within the cytoplasm to prevent the formation of D-
alanine-D-alanine
 It does this by mimicking the structure of D-alanine &
inhibiting;
 L-alanine racemase: racemizing L-alanine to D-alanine
 D-alanine-D-alanine ligase: linking the 2 D-alanine units
together

 Spectrum: both G-ve & G+ve
 Against MAC, MTB, Enterococci, S. aureus, S. epidermidis,
Nocardia & Chlamydia
 Salmonella, Shigella, E. coli, Klebsiella, Enterobacter, Serratia,
Citrobacter, Proteus mirabilis, L.monocytogenes, Neisseria
gonorrhoeae, Aerococcus urinae, H.pylori

BACITRACIN
 An antibiotic produced by the Tracy-I strain of Bacillus subtilis
 Bacitracins are a group of polypeptide antibiotics; multiple
components have been demonstrated in the commercial pdts
 The major constituent is bacitracin A; its probable structural
formula is:

✍ BACITRACIN:
 Inhibits the recycling of pyrophosphobactoprenol to the inner
leaflet
 Bactoprenol is a lipid synthesized by 3 d/t species of
lactobacilli. It is a hydrophobic C55 isoprenoid.
 BPP transports NAM & NAG across the cell membrane during
the synthesis of peptidoglycan, by flipping the repeating
monomer units from the cytoplasm to the periplasm
 Bactoprenol remains in the membrane at all times
 Since it is associated with severe nephrotoxicity, not given
systemically rather used topicallyChemotherapy Compiled by Birhanu G. 76

 Clinical Use:
 Alone or in combination with polymyxin or neomycin: Rx of
mixed skin, wound or mucous membrane infections
 Adverse Effects:
 Significant nephrotoxicity: systemic administration
 Skin sensitization: on topical use

VANCOMYCIN
 A tricyclic glycopeptide antibiotic produced by Streptococcus
orientalis
 MOA:
 Binding to peptidoglycan pentapeptide  Transglycosylase
inhibition  inhibition of elongation of peptidoglycan
(glycosylation)  no cross linking

 Spectrum:
 Against G+ve: MRSA, MRSE & Cl.difficile
 PKs: not absorbed orally; given IV except antibiotic induced
colitis
 Resistance: alteration of the D-alanyl-D-alanine target to D-alanyl-
D-lactate or D-alanyl D-serine, to w/c vancomycin can’t bind
 VRSA: FQs, linezolid, streptogramins; quinupristin/dalfopristin

PROTEIN SYNTHESIS INHIBITORS
 Bactericidal: Aminoglycosides
 Bacteriostatic:
 Aminocyclitols
 Tetracyclines & Amphenicols: broad spectrum
 Macrolides: moderate spectrum
 Lincosamides, Streptogramins (Quinupristin,
Dalfopristin), Oxazolidinones (Linezolid, Tedizolid,
Sutezolid): narrow spectrum
 Mupirocin: G-ve & G+ve

PROTEIN SYNTHESIS
Simplified schematic of mRNA translationChemotherapy Compiled by Birhanu G. 83

Protein synthesis inhibitors
 Substances that stops or slows the growth or proliferation of
cells by blocking the generation of new proteins
 Act at the ribosome level (either the ribosome itself or the
translation factor), taking advantages of the major d/ces b/n
prokaryotic & eukaryotic ribosome structures
 Toxins: ricin also function via protein synthesis inhibition
Ricin acts at the eukaryotic 60S

Mechanism
 Work at d/t stages of prokaryotic mRNA translation into
proteins, like;
 Initiation
 Elongation: aminoacyl tRNA entry, proofreading, peptidyl
transfer & ribosomal translocation &
 Termination

Aminoglycosides
 Streptomycin, Gentamicin, Kanamycin, Amikacin,
Tobramycin, Sisomycin, Neomycin, Paramomycin,…
 General properties:
 Composed of two or more amino sugars connected by a
glycoside linkage
 At physiological pH, they are polycations
 Are water soluble, stable in solution
 Interact chemically with -lactam antibiotics

MOA:
 Transport of aminoglycosides through outer membrane
by passive diffusion via porins; then they are actively
transported across the cell membrane
 Low extracellular pH & anaerobic conditions inhibit
transport by reducing the gradient

MOA…
 The drug binds to 30s rRNA irreversibly 
 Interference with the initiation complex of peptide
formation;
 Misreading of mRNA, w/c causes incorporation of
incorrect amino acids into the peptide & results in a non
functional or toxic protein;
 Breakup of polysomes into non functional monosomesChemotherapy Compiled by Birhanu G. 88

Effects of aminoglycosides on protein synthesis

 Antimicrobial spectrum
 Aerobic, gram-negative organisms
 Pseudomonas, Klebsiella, E.coli, others
 Pharmacokinetics
 Absorbed very poorly from intact GIT: IM & IV
 Distribution limited to ECF;
 Bind to renal tissue  nephrotoxicity
 Penetrate to perilymph & endolymph of inner ear 
ototoxicity
 Eliminated primarily by kidney

ONCE DAILY DOSING
 2-3 equally divided doses (traditional)
 Once daily dosing may be preferred in certain situations,
since they have PAE & conc. dependent killing
 Once daily dose;
 Efficacious as traditional multiple dose method
 Lower but not eliminate: nephrotoxicity & ototoxicity
 Simple, less time consuming & cost effective
 Does not worsen neuromuscular function
 Exceptions: in pts with Enterococcal endocarditis; further
study in pediatricsChemotherapy Compiled by Birhanu G. 93

Therapeutic uses
 Against G-ve enteric bacteria in bacterimia & sepsis; TB
 In combination with -lactam antibiotic to increase
coverage(G+ve) & synergism

Aminoglycosides…

Adverse Effects
 Ototoxicity
 Cochlear toxicity: tinnitus, high frequency hearing loss
– Neomycin, Kanamycin, Amikacin
 Vestibular toxicity: vertigo, ataxia, loss of balance
– Streptomycin & Gentamycine
 Nephrotoxicity: injure cells of proximal renal tubule
 Risk factors: older pts, renal disease, large doses, frequent
dosing interval, concomitant drugs: Vancomycin, Frusemide,
Clindamycin, Piperacillin, Cephalothin, Foscarnet

 Neuromuscular blockade: rarely
 Weakness of respiratory musculature
 Risk is amplified in pts with tubocurarine, succinylcholine
Aminoglycosides prevent internalization of Ca2+ in
presynaptic axon  decrease release of acetylcholine
 Skin rash

Aminocyclitols: Spectinomycin
 Structurally related to aminoglycosides
 It lacks amino sugars & glycosidic bonds
 MOA: binds with 30s sub unit of rRNA
 Active in vitro against many G+ve & G-ve
 Used almost solely as an alternative treatment for drug-
resistant gonorrhea or gonorrhea in penicillin-allergic pts
 The majority of gonococcal isolates are inhibited by 6
mcg/mL of Spectinomycin

 Strains of gonococci may be resistant to spectinomycin, but
there is no cross-resistance with other drugs used in
gonorrhea
 Spectinomycin is rapidly absorbed after IM injection
 A single dose of 40 mg/kg up to a maximum of 2 g is given
 Side effects:
 Pain at the injection site &, occasionally, fever & nausea
 Rarely nephrotoxicity & anemia

Tetracyclines
 Oxytetracycline, Tetracycline, Demeclocycline,
Doxycycline, Minocycline
 Antimicrobial spectrum: broad
 G+ve & G-ve aerobic & anaerobic bacteria
 Spirochetes, Mycoplasma, Rickettsia, Chlamydia & some
protozoa
 Glycylcyclines (Tigecycline):
 Related to TTCs in their MOA as well as spectrum

MOA:
 Enter microorganism by passive & active transport
Act by binding 30s ribosome reversibly  block the binding
of aminoacyl t-RNA to A site on the mRNA-ribosome
complex/Elongation (tRNA delivery)
Tetracyclines prevent stable binding of the EF-Tu-tRNA-GTP
ternary complex to the ribosome and inhibit accommodation
of A-tRNAs upon EF-Tu-dependent GTP hydrolysis

Pharmacokinetics

Adverse Effects
 GI Irritation: oral therapy  burning, cramps & NVD
 Super infection
 Effect on bone & teeth;
 Yellow or brown discoloration of teeth
 Hypoplasia of enamel
 Suppression of long bone growth in infants
Doxycycline bind less with Ca2+  less frequent dental
changes

 Liver toxicity
 Kidney toxicity: in kidney impairment except doxycycline
 Photosensitization: especially demeclocycline induce
sensitivity to sunlight or ultraviolet light, particularly in
fair-skinned persons
 Vestibular reactions: vertigo, nausea & vomiting
 >100mg doses of doxycycline; 200-400mg of Minocycline

Macrolides
 Macro cyclic lactone ring to which deoxysugar is attached
 Erythromycin, Clarithromycin, Azithromycin
 MOA:
 Binding to 50s rRNA  inhibiting peptidyl transfer,
ribosomal translocation (transpeptidation), premature
dissociation of peptidyl t-rRNA from the ribosome 
inhibition of protein synthesis
 Usually bacteriostatic, may be -cidal @ high dose

Erythromycin
 Decreased by stomach acid  enteric coating
 Stearate & esters: fairly acid resistant  better absorbed
 Estolate salt best absorbed orally
 Administration: topical, PO, IM, IV
 Excretion: primarily bile & faces

Clarithromycin
 Similar with erythromycin with respect to antibacterial
activity & drug interaction except:
 More active against M. avium complex
 Also against M. leprae, H.pylori, Toxoplasma gondii

Azithromycin
 Semisynthetic derivative of Erythromycin
 Have better oral absorption
 Longer t1/2
 Fewer GI side effects
 Are expensive

 Azithromycin is similar to clarithromycin except:
✍ Less active against staphylo-& strepto-cocci
✍ Slightly more active against H. influenza
✍ Highly active against Chlamydia
✍ Long t1/2 [3days] permit once daily dosing
✍ Free of drug interaction

Therapeutic uses

 Adverse Effects
 GI effects: ANVD
 Liver toxicity: estolate salts cause acute cholestatic
hepatitis due to hypersensitivity reaction
 Drug Interaction
 Erythromycin metabolized to form inactive complexes
with CYP450  ↑level of Terfenadine or Astemizole
 ↑BA of digoxin by interfering with its inactivation in gut
flora

Lincosamides: Clindamycin
 MOA: inhibition of protein synthesis via binding to 50s rRNA
 Usually bacteriostatic
 Therapeutic use:
 Infections that involve B.fragilis & penicillin resistant
anaerobic bacteria
 With aminoglycosides/ Cephalosporins to treat penetrating
wounds of the abdomen
 Infections of female genital tract;
 Pelvic abscess, aspiration pneumonia (anaerobes above the
diaphragm)Chemotherapy Compiled by Birhanu G. 119

 Recommended instead of erythromycin for prophylaxis of
endocarditis
 Clindamycin + Primaquine in TXt of moderate or severe PCP
alternative to Cotrimoxazole
 Clindamycin + Pyrimethamine for AIDS related toxoplasmosis
 Adverse effects:
 Nausea,
 Diarrhea &
 Skin rashes
 Clindamycin associated colitis

Amphenicoles: Chloramphenicol (CAPH), MOA:
 Binds to specific nucleotides within the 50S ribosome, w/c
inhibits peptidyl transferase activity & peptide bonding
 Inhibit both bacterial & mitochondrial ribosomes (but not
cytoplasmic)
 Suppresses synthesis of important enzymes: cytochromes
a + a3 & b  suppresses mitochondrial respiration 
oxidative stress (mitochondrial toxicity)Chemotherapy Compiled by Birhanu G. 122

 MOA:…
 Inhibition of mitochondrial function is thought to be the
mechanism underlying dose-dependent reversible bone
marrow suppression
 Reactive metabolites of CAPH may be mutagenic  dev’t of
aplastic anemia

 Drug Class: Antibiotic (broad spectrum & bacteriostatic)
 Indications:
 Rarely used in US b/c of aplastic anemia
 A “treatment of last choice” for MDR: vancomycin-
resistant Enterococcus
Used in developing countries: inexpensive & effective
 Broad spectrum: N.meningitidis, C.perfringens,
Bacteroides, H.influenzae (bactericidal effect in this
sensitive organism), Salmonella typhi & Rickettsia

ADRs:
 GI disturbance: NVD
 Bone marrow suppression: dose-dependent & reversible
 Aplastic anemia: idiosyncratic, rare, lethal
 Gray baby syndrome: ed conjugation & excretion
 Vomiting, limb body tone, gray skin color
 Cyanosis: blue lips & skin
 Hypotension, cardiovascular collapse
 Superinfection

 Drug Interactions:
 CAF inhibits some of the hepatic mixed-function
oxidases
 Blocks the metabolism of drugs: warfarin & phenytoin
Elevating their conc. & potentiating their effects

Summary

NUCLEIC ACID SYNTHESIS INHIBITORS
 Indirect inhibitors: antimetabolites
 Sulfonamides, trimethoprim, pyrimethamine
 Activity & clinical uses:
 Sulfonamides alone limited in use b/c of multiple resistance
 Sulfasalazine is a prodrug used in ulcerative colitis & RA
 Ag sulfadiazine used in burns

 Pharmacokinetics:
 Sulfonamides are hepatically acetylated (conjugation)
 Renally excreted metabolites cause crystalluria (older
drugs)
 High protein binding:
Drug interaction
Kernicterus in neonates: avoid in third trimester

Therapeutic uses
UTI: Sulfisoxazole: high solubility, achieve effective
concentration & less expensive
 Bacteria;
 G+ve: Nocardia, Listeria (back up), community acquired
MRSA, Strep.
 G-ve: E.coli, Salmonella, Shigella, H.influenzae
 Fungus: PCP (back-up drugs: pentamidine & atovaquone)
 Protozoa: T.gondii: sulfadiazine + pyrimethamine

Therapeutic uses….
 Trachoma: Sulfacetamide
 Sulphadiazine/Sulfadoxine + Pyrimethamine OR
(FANSIDAR®=Sulfadoxine + Pyrimethamine): to treat
toxoplasmosis
 Ulcerative colitis: sulfasalazine

Adverse effects
 Hypersensitivity reactions: Sulphur content
 Mild: rash, fever, photosensitivity
 Severe: SJS; lesion of skin & mucus membrane, fever,
malaise & toxemia
 Hematologic effect
 Hemolytic anemia: G6PDH deficiency
 Agranulocytosis: leucopenia & thrombocytopenia

 Kernicterus: displacing bilirubin from plasma protein 
crosses the BBB; avoid in 3rd trimester & < 2 months age
 Renal damage: they form crystal urea
 Trimethoprim or pyrimethamine:
Bone marrow suppression: leukopenia

COTRIMOXAZOLE: TMP + SMX
 Trimethoprim & Sulphamethoxazole: to  resistance
 Shows synergism  Cidal
 Selected because of similarity in pharmacokinetics
 MOA: inhibition of two sequential steps

 Therapeutic Uses
 UTI: caused by E.coli, Klebsiella, Enterobacter, P.mirabilis
 PCP: Txt of choice
 Drug of choice for shigellosis
 Other infections;
 Acute otitis media & chronic bronchitis: H. infleunza,
S.pneumonia
 Urethritis & pharyngitis due to penicillinase producing N.
gonorrhoe
 Alternative to CAPH for typhoid fever

 TMP concentrates in the relatively acidic milieu of prostate &
vaginal fluids  effective
 TMP (1part) & SMX (5part)
 Adverse effects
 Dermatologic
 GI: NV & stomatitis
 Hematologic: megaloblastic anemia; leukopenia;
thrombocytopenia
 HIV pts with PCP: drug induced fever, rashes, diarrhea

Direct Inhibitors of Nucleic Acid Synthesis
 Quinolones, FQs & Rifamycins
 Naldixic acid, Ciprofloxacin, Levofloxacin, "-floxacins”
 MOA:
 Block DNA replication by inhibit the ligase domains of;
 Topoisomerase II (DNA gyrase): in G-ve bacteria  relaxation
of super coiled DNA  DNA strand breakage &
 Topoisomerase IV: G+ve bacteria  impacts chromosomal
stabilization during cell division, thus interfering with the
separation of newly replicated DNA

Antimicrobial Spectrum
 Norfloxacin is the least active of FQs against G+ve & G-ve
 Ciprofloxacin, Enoxacin, Lemofloxacin, Ofloxacin, Pefloxacin,
Levo-, Moxi-, Gemi- & Gati-floxacin:
 Excellent against G-ve: pseudomonas, enterobacteriaceae,
haemophilus spp., Neisseria spp., Campylobacter
 Moderate to good against G+ve: methicillin susceptible strains
of staph; streptococci & enterococci tend to be less susceptible
 FQs also have activity against Mycoplasma & Chlamdiae;
Legionella spp. & Mycobacteria

Pharmacokinetics
 Absorption: well absorbed, food does not reduce absorption
 Distribution: Vd is high
 Concentration in prostate, kidney, bile, lung, neutrophils/
macrophages exceed serum concentration.
 Elimination
 Ofloxacin & lomefloxacin: predominantly by kidney.
 Pefloxacin, sparfloxacin, trovafloxacin: nonrenal pathway.
 Most others have mixed excretion: renal & nonrenal

Drug interaction
 With di or trivalent cations: cation-quinolone complex
 Inhibit CYP1A2: increase serum methylxanthine
 Can elevate levels of warfarin [PT time monitored]

Therapeutic uses
 UTI: complicated & uncomplicated, prostatitis
 GIT infection:
 Diarrhea caused by shigella, salmonella, toxigenic E.coli,
campylobacter
 Peritonitis
 STIs: N.gonorrhea, C.trachomatis, H.ducreyi

Therapeutic uses…
 RTIs:
 RTI: H.influenzae, M.catarrhalis & Enteric G-ve
 Atypical pneumonia: M.pneumoniae, C.pneumoniae,
L.pneumoniae
 Exacerbation of chronic bronchitis
 Skin & soft tissue infection
 Others: mycobacterial (TB), for nontubercular mycobacteria,
typhoid fever

Adverse effect
 GIT: ANV & abdominal discomfort
 CNS: headache, dizziness, insomnia
 Cartilage deterioration in immature animals:
 Not recommended in child 18yrs; & lactating & pregnant
woman

 RIFAMYCINS: Rifampin, Rifapentine & Rifabutin
☞ See Antimycobacterial Agents
 MISCELLANEOUS: Metronidazole
☞ See anti-protozoal drugs

Summary of Resistance

Antimycobacterial Agents

Drugs For the Treatment of Mycobacterial infection
 Mycobacterium infection continues to be difficult to treat;
 Slow & rapid growing microbe
 Can also be dormant; resistant to many drugs
 Cell wall: Greek mycos; waxy appearance (lipid rich)
 Efflux pumps: the cell membrane is rich in ABC permeases
 Location in host;
 Needs prolonged treatment
 Drug toxicity & poor patient compliance
 High risk of emergency of resistant bacteria

 The objective of therapy is: to eliminate symptoms & prevent
relapse
 So, must kill actively dividing & resting mycobacteria
 Since the response to chemotherapy is slow: Rx is prolonged
 Combination of drugs: to prevent the emergence of resistance
TB resistance can be:
 Mono drug resistance
 Multi drug resistance (MDR-TB)
 Extensively drug resistance (XDR-TB)
 Total drug resistance – TDR-TB: India, Iran, Italy

ANTIMYCOBACTERIAL DRUGS
☞Superior efficacy & acceptable toxicity;
 Rifamycins: Rifampin, Rifapentine, Rifabutin
 Pyrazinamide: 25 mg/kg/d
 Isoniazid: 300 mg/day
 Ethambutol: 15-25 mg/kg/d
Dosage: adult dose in normal renal function

 Aminoglycosides: Streptomycin, Amikacin, Kanamycin
 Bedaquiline
 Bicyclic Nitroimidazoles: Delaminid, Pretomanid
 Capreomycin
 Clofazimine
 Fluoroquinolones: ciprofloxacin, levofloxacin

 Ethionamide
 Para-aminosalicylic Acid: PAS
 Cycloserine
 β-Lactam Antibiotics for the Treatment of TB
 Macrolides
 Dapsone
 Oxazolidinones: Linezolid, Tedizolid, Sutezolid

ISONIAZID (INH/Isonicotinic hydrazide)-H
 H enters bacilli by passive diffusion
 The drug is not directly toxic to the bacillus but must be
activated to its toxic form within the bacillus by KatG
 KatG catalyzes the production from H of an isonicotinoyl
radical that subsequently interacts with mycobacterial
NAD & NAPD to produce a dozen adducts: nicotinoyl-NAD
isomer, nicotinoyl-NADP isomer

 Nicotinoyl-NAD isomer, inhibits the activities of enoyl acyl
carrier protein reductase (InhA) & KasA → inhibits
synthesis of mycolic acid → cell death
 Nicotinoyl-NADP isomer, potently inhibits mycobacterial
DHFR, thereby interfering with nucleic acid synthesis

 Other products of KatG activation of H:
 Superoxide, H2O2, alkyl hydroperoxides, & the NO radical
May also contribute to the mycobactericidal effects of H
 M.TB especially sensitive to damage from these radicals
b/c the bacilli have a defect in the central regulator of the
oxidative stress response, oxyR

☞Backup defense against radicals is provided by alkyl
hydroperoxide reductase (encoded by ahpC), w/c
detoxifies organic peroxides
☞Increased expression of ahpC reduces H effectiveness

Metabolism & activation of Isoniazid

 Absorption: well after PO or IM
 Distributed widely: CSF  20% of plasma conc.
 Increased in meningeal inflammation
 Metabolized by acetylation: fast acetylators: hepatotoxicity,
slow acetylation: peripheral neuropathy
 Acetylation status does not generally affect the outcome with
daily therapy
 Therapeutic Uses
 Component of all TB chemotherapeutic regimens
 Alone is used to prevent TBChemotherapy Compiled by Birhanu G. 167

Adverse effects
 Allergic reactions: fever, skin rashes
 Direct toxicities:
 Drug induced hepatitis: high risk age, rifampin, alcohol
 Peripheral neuropathy:
 Due to relative vit-B6 deficiency: promotes excretion
 Likely to occur in slow acetylators & pts with predisposing
factor: malnutrition, alcoholism, diabetes, AIDS & uremia
 Reversed by administration of vitamin B6
 Convulsion, optic neuritis, psychosis  reversed by vit-B6

Drug interaction
 H is a potent inhibitor of CYP2C19 & CYP3A & a weak
inhibitor of CYP2D6
 H induces CYP2E1

RIFAMYCINS: Rifampin, Rifapentine & Rifabutin
 RIFAMPICIN/RIFAMPIN: R
 MOA: binds to the β subunit of DNA-dependent RNA
polymerase (rpoB) to form a stable drug-enzyme complex 
suppresses chain formation in RNA synthesis  cidal
 Well absorbed, distributed throughout the body
 Excreted mainly through liver into bile

Therapeutic uses
 Mycobacterial infection:
 TB: cidal for intra & extracellular bacteria
 In TB prevention as an alternative to H
 Leprosy
 Atypical mycobacteria
 Prophylaxis in contacts of children with H.influenzae type b
disease (meningitis)

Therapeutic uses…
 In combination with other agents;
 To eradicate staphylococcal carriage
 For Rx of serious staphylococcal infections;
 Osteomyelitis
 Prosthetic valve endocarditis

Adverse effects
 Hepatitis
 Hypersensitivity reactions
 Fever, flushing, pruritus
 Thrombocytopenia
 Interstitial nephritis
 Miscellaneous ADR: harmless orange color appearing in
urine, saliva, tears, sweat & soft contact lenses
 GI upset

ETHAMBUTOL(E)
 MOA:
 Inhibits mycobacterial arabinosyl transferase-III, encoded by
the emb AB gene
 Arabinosyl transferases are involved in the polymerization
reaction of arabinoglycan (arabinogalactan biosynthesis), an
essential component of the mycobacterial cell wall
  bacteriostatic

 Therapeutic use: TB
 Adverse effects
 Retrobulbar neuritis (optic neuritis)
Loss of visual acuity & red-green color blindness
 GI intolerance
 Hyperuricemia due to deceased uric acid excretion

PYRAZINAMIDE (Z)
 Synthetic pyrazine analogue of nicotinamide
 Converted to pyrazinoic acid, active form of drug
 Largely bacteriostatic,
 But can be cidal on actively replicating mycobacteria

 Pyrazinamide is activated by acidic conditions: 5-6 pH
 Proposed MCZs:
 Z passively diffuses into mycobacterial cells
 M. TB pyrazinamidase deaminates Z to pyrazinoic acid
(POA−)
 POA− passively diffused to the extracellular acidic milieu
 POA− is protonated to the uncharged form; POAH
 POAH (lipid-soluble) reenters the bacillus & accumulates
due to a deficient efflux pump

 Acidification of the intracellular milieu is believed to
inhibit enzyme function & collapse the transmembrane
proton motive force, thereby killing the bacteria
 Inhibitors of energy metabolism or reduced energy
production states lead to enhanced Z effect

 Other targets of Z:
 Ribosomal protein S1 in the trans-translation process, so
that toxic proteins due to stress accumulate & kill the
bacteria
 An aspartate decarboxylase involved in making precursors
needed for pantothenate & CoA biosynthesis in persistent
M. tuberculosis

 Therapeutic use: for RX of TB only
 Sterilizing agent in intensive phase of therapy
 Allows total duration of therapy to be shortened to 6 months
 M.bovis & M.leprae are innately resistant to Pyrazinamide
 Adverse effects
 GI intolerance,
 Joint pains (arthralgia),
 The most hepatotoxic agent
 Hyperuricemia

Mechanisms of resistance of Mycobacteria

ANTI-TB DRUGS
 Drugs available in FDC in Ethiopia:
ERHZ: 275/150/75/400 mg, RHZ: 150/75/400 mg
RH: 150/75 mg, EH: 400/150 mg
 TB medicines available as loose form are:
 Ethambutol 400mg,
 Isoniazid 300mg,
 Streptomycin sulphate vials 1gm

PHASES OF CHEMOTHERAPY
 There are two phases:
1. Intensive (initial) phase(IP)
 Consists of 4 or more drugs
 Duration: 8 wks for new cases & 12 wks for re-treatment
 The drugs must be swallowed daily under DOT
 Rapid killing of actively growing & semi dormant bacilli
 It renders the patient non infectious ( 2wks)
 Protects against the development of resistance

2. Continuation phase
 Immediately follows the intensive phase
 Consists of 2 or 3 drugs
 Duration is 4 – 6 months
 Except for re-treatment cases drugs must be collected every
month
 Eliminates bacilli that are still multiplying
 Reduces failures and relapses

1. New Patients
 New patients presumed or known to have drug-susceptible
TB, pulmonary TB: 2HRZE/4HR
Alternatives:
 2HRZE/4(HR)3: a daily IP followed by thrice weekly
continuation phase, provided that each dose is DOT OR
 2(HRZE)3/4(HR)3: thrice weekly dosing throughout therapy,
provided that every dose is directly observed and the patient
is NOT living with HIV or living in an HIV-prevalent setting
 Settings with high levels of H resistance in new patients:
2HRZE/4HREChemotherapy Compiled by Birhanu G. 185

2. Previously Treated Patients
 Specimens for culture & drug susceptibility testing (DST)
should be obtained from all previously treated TB patients at
or before the start of treatment
 DST should be performed for at least for R & H
 Recommendation: 2HRZE(S)/1HRZE/5HRE

Special population
 Co-Management of HIV and Active TB Disease
 It is recommended that TB patients who are living with
HIV should receive at least the same duration of TB
treatment as HIV negative TB patients
 TB tXt should be started first, followed by ART as soon as
possible and within the first 8 wks of starting TB tXt
 The recommended first-line ART regimens for TB patients
are those that contain efavirenz (EFV)

 Pregnancy
 With the exception of streptomycin, the 1st line anti-TB drugs
are safe for use in pregnancy: streptomycin is ototoxic to the
fetus & should not be used during pregnancy
 TB and Leprosy
 R will be common to both regimens and it must be given in
the doses required for TB

 Treatment of patients with renal failure
 Avoid streptomycin & Ethambutol
 Give 2RHZ/4RH
 Treatment of patients known liver disease
 Do not give Pyrazinamide because this is the most hepatotoxic
anti-TB drug
 Recommended regimens: 2SERH/6EH or 2SEH/10EH

 Treatment of Extrapulmonary TB
 Of the EPTB, lymphatic, pleural & bone or joint disease are
most common, while pericardial, meningeal & disseminated
(miliary) forms are more likely to result in a fatal outcome
 TB meningitis: 9-12 months of treatment
 TB of bones or joints: 9 months of treatment

Bicyclic Nitroimidazoles
 Delaminid, Pretomanid: pro-drugs
 Being used in the treatment of X-DR & MDR-TB
 Are in clinical trials for use in drug-susceptible TB
 Delamanid: dihydro-nitroimidazooxazole derivative
 Activated by the enzyme deazaflavin dependent
nitroreductase (Rv3547)
 Forms a reactive intermediate metabolite that inhibits
mycolic acid production

 Pretomanid
 Activated by the bacteria via a nitroreduction step that
requires, a specific G6PDX, FGD1 & the reduced deazaflavin
cofactor F420 encoded by Rv3547
 Has two mechanisms of action;
 1st, under aerobic conditions it inhibits M. TB mycolic acid &
protein synthesis at the step b/n hydroxymycolate &
ketomycolate

 2nd, in NRPB, it generates reactive nitrogen species such
as NO via its des-nitro metabolite, which then augment
the kill of intracellular NRPB by the innate immune
system
 In addition, direct poisoning of the respiratory complex in
the NRPB leads to ATP depletion

Bedaquiline
 A cationic amphiphilic drug, which may account for its
high accumulation in tissues
 Acts by targeting subunit c of the ATP synthase of M.TB
→ inhibition of the proton pump activity of the ATP
synthase
Targets bacillary energy metabolism

Ethionamide
 A congener of thioisonicotinamide
☞Mycobacterial EthaA, NADPH-specific, FAD-containing
monooxygenase, converts ethionamide to a sulfoxide &
then to 2-ethyl-4-aminopyridine
☞A closely related & transient intermediate is the active
antibiotic

 Ethionamide inhibits mycobacterial growth by inhibiting
the activity of the inhA gene product, the enoyl-ACP
reductase of fatty acid synthase II
 As INH: inhibition of mycolic acid biosynthesis &
consequent impairment of cell wall synthesis

Para-aminosalicylic Acid: PAS
 A structural analogue of PABA, the substrate of
dihydropteroate synthase (folP1/P2)
 PAS is a competitive inhibitor folP1, but in vitro the
inhibitory activity against folP1 is very poor
 However, mutation of the thymidylate synthase gene
(thyA) results in resistance to PAS, but only 37%
 Unidentified actions of PAS likely play more important
roles in its anti-TB effects

Capreomycin
 A cyclic peptide antibiotic obtained from Streptomyces
capreolus
 Consists of 4 active components: capreomycins IA, IB,
IIA & IIB
 Clinically used agent contains primarily IA & IB
 MOA: protein synthesis inhibition

 Show cross-resistance with kanamycin & neomycin
 Shouldn’t be administered with other drugs that damage
cranial nerve VIII
 Given for MDR-TB
 Recommended daily dose is 1 g (no more than 20 mg/kg)
per day for 60-120 days, followed by 1 g two or three
times a week

Drugs active against atypical Mycobacterium
 M.avium: cause disseminated TB in late stages of AIDS
 Azithromycin or Clarithromycin + Ethambutol: well tolerated
regimen
 Rifabutin & Clarithromycin: prevent M.avium complex
bacterimia in AIDS patients

ANTILEPROTIC DRUGS
 Leprosy(Hansen’s disease) caused by M.leprae
There are two types of leprosy;
1. Lepromatous Leprosy
 Severe, rapidly progress
 Marked ulceration
 Tissue destruction & nerve damage
 TXt lasts at least 2yrs with Dapsone + R + Clofazimine

2. Tuberculoid Leprosy
 Mild infection
 Slow in progress & loss of sensation
 Rx lasts 6 months (Dapsone + Rifampicin)

DAPSONE/SULFONES
 Dapsone: DDS, diamino-diphenylsulfone
 The primary drug: effective, low in toxicity & inexpensive
 MOA: inhibition of folate synthesis
 PK: given orally, well absorbed, widely distributed
 Enterohepatic recycling
 Excreted as metabolites renally
 Adverse effects
 Rashes, GI disturbance
 Show erythema nodusom: inflammatory reaction

CLOFAZIMINE: weakly bactericidal
 Possible MOA include:
 Membrane disruption
 Inhibition of mycobacterial phospholipase A2
 Inhibition of microbial K+ transport
 Generation of hydrogen peroxide
 Interference with the bacterial electron transport chain
 It has also anti-inflammatory effects via inhibition of
macrophages, T cells, neutrophils & complement

 Used together with or as an alternative to Dapsone in sulfone
resistant leprosy or when patients are intolerant to sulfones
 A common dosage is 100 mg/d orally
Adverse effects
 Red brown to nearly black discoloration of the skin &
conjunctiva
 GI intolerance (occasionally)

RX of mycobacterial infections other than TB, leprosy & MAC

Reading assignment
Immuno-pharmacology
 Immuno-modulators: activators, suppressants

Pharmacology of Antibacterial agents

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