Antibacterial Agents

Mechanisms
INHIBITORS OF CELL-WALL SYNTHESIS
All cell-wall synthesis inhibitors are bactericidal.
They are divided into B-lactam and non-B-lactam drugs.

Penicillin
• Penicillins interact
with cytoplasmic
membrane-binding
proteins (PBPs) to
inhibit
transpeptidation
reactions involved in
cross-linking, the final
steps in cell-wall
synthesis
Properties of Penicillins
Penicillins
General considerations:
• – Activity enhanced if used in combination with beta-lactamase
inhibitors (clavulanic acid, sulbactam)
• – Synergy with aminoglycosides against pseudomonal and
enterococcal species
Pharmacokinetics:
• – Most are eliminated via active tubular secretion; dose reduction
needed only in major renal dysfunction
• – Nafcillin and oxacillin eliminated largely in bile; ampicillin undergoes
enterohepatic cycling, but excreted by the kidney

Side effects:
• – Hypersensitivity, GI distress
Cephalosporins-Subgroups and antimicrobial
activity
First generation: Spectrum: gram-positive cocci (E.coli, Klebsiella pneumoniae)
cefazolin,cephalexi Common use in surgical prophylaxis
n Pharmacokinetics: none enter CNS

Second generation:
cefotetan, cefaclor, Spectrum: ↑ gram-negative coverage, including some anaerobes
cefuroxime, Pharmacokinetics: no drugs enter the CNS, except cefuroxime
cefoxitin

Third generation: Spectrum: gram-positive and gram-negative cocci (Neisseria gonorrhoea), plus
ceftriaxone (IM) many gram-negative rods
and cefotaxime
(parenteral) and Pharmacokinetics: most enter CNS; important in empiric management of
cefixime (oral) meningitis and sepsis

Fourth generation: Even wider spectrum, Resistant to most beta-lactamases

cefepime(IV) Pharmacokinetics: Ceftriaxone is largely eliminated in the bile
 Mechanism of action:
• indirectly preventing transpeptidation involved in elongation of
peptidoglycan chains.
• Does not interfere with PBPs

Spectrum: MRSA, enterococci, Clostridium difficile

Resistance:
Vancomycin
• Vancomycin-resistant staphylococcal (VRSA) and enterococcal
(VRE) strains emerging
• Enterococcal resistance involves change in the muramyl
pentapeptide “target,” such that the terminal D-ala is replaced by
D-lactate
Pharmacokinetics:
• Used IV and orally (not absorbed) in colitis
• Enters most tissues (e.g., bone), but not CNS
• Eliminated by renal filtration (important to decrease dose in renal
dysfunction)
Side effects:
• “Red man syndrome” (histamine release)
• Ototoxicity (usually permanent, additive with other drugs)
• Nephrotoxicity (mild, but additive with other drugs)
INHIBITORS OF
BACTERIAL PROTEIN
SYNTHESIS
Aminoglycosides
Activity and clinical
Pharmacokinetics: Side effects:
uses:
• Bactericidal, useful • Are polar compounds, • Nephrotoxicity (6 to
spectrum includes not absorbed orally or 7% incidence) includes
gram-negative rods; widely distributed into proteinuria,
tissues hypokalaemia,
• Renal elimination acidosis, and acute
proportional to GFR, tubular necrosis—
and major dose usually reversible.
reduction needed in • Ototoxicity (2%
renal dysfunction incidence) from cell
damage; includes
deafness (irreversible)
and vestibular
dysfunction.
 Activity and clinical uses:

• Bacteriostatic drugs, “Broad-spectrum”

antibiotics, with good activity versus
chlamydial and mycoplasma species, H.
pylori (GI ulcers), Rickettsia.

Tetracyclin Side effects:

es • Tooth enamel dysplasia and possible ↓

bone growth in children
• Phototoxicity
• GI distress, superinfections leading to
candidiasis or colitis
• Vestibular dysfunction
• Have caused liver dysfunction during
pregnancy at very high doses
(contraindicated)
Chloramphenicol
Activity and clinical
Pharmacokinetics: Side effects:
uses:
• Bacteriostatic with a • Orally effective, with • Dose-dependent
wide spectrum of good tissue bone marrow
activity distribution, suppression
• Currently a backup including CSF common; aplastic
drug for infections • Metabolized by anaemia rare
due to Salmonella hepatic • “Gray baby”
typhi, B. fragilis, glucuronidation, and syndrome in
Rickettsia, and dose reductions are neonates (↓
possibly in bacterial needed in liver glucuronosyltransfer
meningitis dysfunction and in ase)
neonates
• Inhibition of
cytochrome P450
Macrolides: erythromycin, azithromycin,
clarithromycin

• Activity and clinical uses: wide-spectrum antibiotics

• Gram-positive cocci
• Atypical organisms (Chlamydia, Mycoplasma)
• Legionella pneumophila
• Campylobacter jejuni
• Mycobacterium avium-intracellulare (MAC)
• H. pylori
• Pharmacokinetics: inhibit cytochrome P450s
• Side effects:
• Gastrointestinal distress (erythromycin, azithromycin > clarithromycin) due to
stimulation of motilin receptors
• Reversible deafness at high doses
• Increased QT interval
INHIBITORS OF NUCLEIC ACID SYNTHESIS :
Quinolones
Drugs: ciprofloxacin, levofloxacin, and other “−floxacins”

Mechanisms of action:
• Quinolones are bactericidal and interfere with DNA synthesis
• Inhibit topoisomerase II (DNA gyrase) and topoisomerase IV (responsible for separation of replicated DNA during
cell division)
Activity and clinical uses:
• Urinary tract infections (UTIs) and other gram (-), especially in cases of drug resistance
• Drug-resistant pneumococci(levofloxacin)

Pharmacokinetics:
• Iron, calcium limit their absorption
• Eliminated mainly by kidney by filtration and active secretion (inhibited by probenecid)
• Reduce dose in renal dysfunction

Side effects:
• Tendonitis, tendon rupture, nerve damage (peripheral neuropathy)
• Phototoxicity, rashes
• CNS effects (insomnia, dizziness, headache)
• Contraindicated in pregnancy and in children
Features of
Antitubercul
ar Drugs
Antifungal
Agents
 Polyenes (Amphotericin B, Nystatin)

Activity and clinical

Mechanisms: Pharmacokinetics: Side effects:
uses:
• Amphoteric • Amphotericin B • Amp B given by • Fever, chills,
compounds with (Amp B) has wide slow IV infusion: muscle rigor,
both polar and fungicidal poor penetration hypotension
nonpolar structural spectrum; into the CNS • Nephrotoxicity and
components: • Nystatin (too toxic • Slow clearance anaemia
interact with for systemic use): (half-life >2 weeks)
ergosterol in used topically for via both
fungal membranes localized infections metabolism and
to form artificial (e.g., candidiasis) renal elimination
“pores,” which
disrupt membrane
permeability
• Resistant fungal
strains appear to
have low
ergosterol content
in their cell
membranes
 Azoles (Ketoconazole, Fluconazole,
Itraconazole, Voriconazole)

• Mechanism:
• “Azoles” are fungicidal and interfere with the synthesis of ergosterol by inhibiting 14-
α-demethylase, a fungal P450 enzyme, which converts lanosterol to ergosterol
• Activity and clinical uses:
• Mucocutaneous candidiasis or dermatophytosis
• Prophylaxis and suppression in cryptococcal meningitis
• Blastomycoses, sporotrichoses, aspergillosis
• Pharmacokinetics:
• Effective orally
• Absorption of ketoconazole ↓ by antacids
• Absorption of itraconazole ↑ by food
• Only fluconazole penetrates into the CSF and can be used in meningeal infection;
• Side effects: decreased synthesis of steroids, including cortisol and testosterone →↓ libido,
gynecomastia, menstrual irregularities; increased liver function tests and rare
hepatotoxicity
ANTIVIRAL
DRUG
Many antiviral drugs are
antimetabolites which resemble
the structure of naturally
occurring purine and pyrimidine
bases or their nucleoside forms.
Antimetabolites are usually
prodrugs requiring metabolic
activation by host- cell or viral
enzymes; such bioactivation
involves phosphorylation
reactions catalysed by kinases.
 Acyclovir
Mechanisms of action:
• Monophosphorylated by viral thymidine kinase (TK), then further bioactivated by host-cell
kinases to the triphosphate
• Acyclovir-triphosphate is both a substrate for and inhibitor of viral DNA polymerase
• When incorporated into the DNA molecule, acts as a chain terminator because it lacks the
equivalent of a ribosyl 3′ hydroxyl group

Activity and clinical uses:

• Activity includes herpes simplex virus (HSV) and varicella-zoster virus (VZV)
• There are topical, oral, and IV forms; has a short half-life
• Reduces symptoms if used early in chickenpox; prophylactic in immunocompromised patients.

Side effects: minor with oral use, more obvious with IV; crystalluria
(maintain full hydration) and neurotoxicity (agitation, headache, confusion).