Chapter 35 · Module 10

Metronidazole, Clindamycin, and Miscellaneous Agents

Anaerobic and protozoal coverage, toxin suppression, urinary tract agents, and last-resort polymyxins

Abbreviations: TMP-SMX = trimethoprim-sulfamethoxazole | MRSA = methicillin-resistant Staphylococcus aureus | CA-MRSA = community-acquired MRSA | MLSB = macrolide-lincosamide-streptogramin B | UTI = urinary tract infection | PCP = Pneumocystis jirovecii pneumonia | ESBL = extended-spectrum beta-lactamase

Metronidazole

Mechanism & Spectrum

Metronidazole

Mechanism

Reductive activation by anaerobic ferredoxin enzymes
Generates free radicals → DNA strand breaks → bactericidal
Inactive in aerobic organisms (wrong redox potential)

Spectrum

All major anaerobes: B. fragilis, C. difficile, C. perfringens, Fusobacterium
Protozoa: T. vaginalis, Giardia, E. histolytica
No aerobic activity

Adverse Effects & Interactions

Key Toxicities

Disulfiram-Like Reaction

Inhibits aldehyde dehydrogenase → acetaldehyde accumulates
Avoid all alcohol during therapy and 48 h after

Neurological (Prolonged Use)

Peripheral neuropathy — may be irreversible
CNS toxicity: ataxia, encephalopathy (reversible MRI pattern)

Drug Interactions

Inhibits CYP2C9 → ↑ warfarin effect (monitor INR)
↓ Renal lithium clearance → lithium toxicity risk

Clindamycin

Mechanism, Spectrum & PK

Clindamycin

Mechanism

Binds 50S at peptidyl transferase center → bacteriostatic
Also suppresses toxin production at sub-inhibitory concentrations
Add to beta-lactam in necrotizing fasciitis / toxic shock syndrome

Spectrum

CA-MRSA (check D-zone), MSSA, streptococci
Most Gram-positive anaerobes; many B. fragilis (resistance increasing)
No Gram-negative aerobic activity; C. difficile intrinsically resistant

Pharmacokinetics

~90% oral bioavailability; excellent bone/joint/soft tissue penetration
Poor CNS penetration — not for CNS infections

Adverse Effects & Resistance

Key Risks

C. difficile Colitis

Among highest-risk antibiotics for C. difficile
Evaluate any diarrhea during or weeks after therapy

MLSB Resistance

Constitutive: high-level resistance to macrolides, clindamycin, strep B
Inducible: appears susceptible in vitro but fails in vivo
D-zone test: blunted zone near erythromycin disk = inducible resistance
Positive D-zone → do NOT use clindamycin

Miscellaneous Agents

Agent	Mechanism	Key Indications	Key Adverse Effects	Caution
Fosfomycin	Inhibits MurA (first step peptidoglycan synthesis)	Uncomplicated cystitis (E. coli, E. faecalis); ESBL strains	Generally well tolerated	UTI only — no systemic tissue levels
Nitrofurantoin	Multi-target reduction products (DNA, RNA, ribosomes)	Uncomplicated cystitis only	Pulmonary toxicity (acute or chronic fibrosis); hepatotoxicity	Never for pyelonephritis; avoid if CrCl <30
TMP-SMX	Sequential DHPS + DHFR block → folate synthesis inhibited	UTI, CA-MRSA skin, PCP prophylaxis/treatment, Nocardia	Hypersensitivity rash, hyperkalemia, ↑ creatinine, myelosuppression	Stevens-Johnson risk; sulfonamide allergy
Polymyxins	Bind LPS → outer and inner membrane disruption	Carbapenem-resistant Acinetobacter, Pseudomonas, CRE	Nephrotoxicity (major), neurotoxicity	Last-resort only; not empiric; colistin = prodrug

Critical Rules

Nitrofurantoin is for lower UTI only — never pyelonephritis. Metronidazole is no longer first-line for C. difficile — use vancomycin or fidaxomicin. D-zone positive MRSA → do not use clindamycin. Polymyxins are last-resort agents — never empiric, never for susceptible organisms.