Chloramphenicol
Mechanism & Spectrum
Chloramphenicol
Mechanism
- Binds 23S rRNA at peptidyl transferase center on 50S subunit
- Blocks peptide bond formation — halts elongation
- Bacteriostatic (bactericidal vs. H. influenzae, N. meningitidis, S. pneumoniae)
Spectrum
- Gram-positive, Gram-negative, anaerobes, rickettsiae
- Active vs. Salmonella typhi, Bacteroides fragilis
- No reliable activity vs. MRSA or Pseudomonas aeruginosa
Pharmacokinetics
Key Properties
CNS Penetration
- CSF: 30–50% of plasma even without meningitis
- Rises toward plasma levels with meningeal inflammation
- Best CNS penetration among protein synthesis inhibitors
Metabolism
- Hepatic glucuronidation → inactive glucuronide
- Immature in neonates → accumulation → gray baby syndrome
- Reduce dose in hepatic impairment; monitor serum levels
Toxicity
Two Bone Marrow Toxicities
Reversible Suppression
- Dose-dependent; plasma levels >25 mcg/mL
- All cell lines; fully reversible on stopping
- Prevented by monitoring
Aplastic Anemia (Idiosyncratic)
- Unrelated to dose or plasma level
- ~1 in 30,000 courses; onset weeks–months after exposure
- Irreversible; mortality >50% without transplant
- Cannot be predicted or prevented by monitoring
Drug Interactions & Clinical Role
CYP Inhibition & Indications
Drug Interactions
- Inhibits CYP2C19 (major), CYP2C9, CYP3A4
- ↑ phenytoin levels → toxicity
- ↑ warfarin effect → bleeding risk
Modern Systemic Use
- Meningitis: severe beta-lactam allergy
- Brain abscess (CNS penetration + anaerobic coverage)
- Typhoid: multidrug-resistant S. typhi
- Topical: bacterial conjunctivitis (safe)
Oxazolidinones: Linezolid and Tedizolid
Mechanism & Spectrum
Oxazolidinones
Mechanism — Unique
- Block 70S initiation complex assembly (pre-elongation)
- Bind 23S rRNA on 50S; prevent 30S + 50S joining
- No cross-resistance with macrolides, lincosamides, or chloramphenicol
Spectrum (Gram-positive only)
- MRSA, vancomycin-resistant S. aureus, VRE
- Penicillin-resistant S. pneumoniae, streptococci
- Linezolid: also active vs. Mycobacterium tuberculosis
- No Gram-negative activity
Pharmacokinetics
Linezolid vs. Tedizolid
Linezolid
- ~100% oral bioavailability — IV = oral, complete interchangeability
- Non-CYP metabolism → no CYP-based drug interactions
- No dose adjustment for renal impairment
- Dosing: twice daily
Tedizolid (Prodrug)
- Converted by plasma phosphatases to active form
- Half-life ~12 h → once-daily dosing
- 4–8× more potent than linezolid (lower daily dose)
- Less myelosuppression than linezolid
Linezolid Adverse Effects and Resistance
Adverse Effects
Mitochondrial Inhibition + MAO Inhibition
Myelosuppression (reversible)
- Thrombocytopenia most common (appears after ~2 weeks)
- Fully reversible on stopping; monitor CBC weekly if >2 weeks
- Tedizolid: significantly less myelosuppression
Serotonin Syndrome
- Linezolid = reversible nonselective MAO inhibitor
- Avoid with SSRIs, SNRIs, TCAs, meperidine, tramadol
- Triad: mental status changes + autonomic instability + neuromuscular signs
Neuropathy (prolonged courses)
- Peripheral: stocking-glove paresthesias — may be irreversible
- Optic: visual loss, color vision loss — may be permanent
- Monitor monthly if course >4 weeks
Clinical Niche & Resistance
Indications and Resistance
Use Linezolid For
- MRSA pneumonia (superior to vancomycin — ZEPHYR trial)
- MRSA skin/soft tissue infections
- VRE infections
- MRSA osteomyelitis (oral step-down advantage)
Do NOT Use For
- MRSA bacteremia or endocarditis — bacteriostatic; use vancomycin or daptomycin
Resistance
- 23S rRNA point mutations (reduced drug binding)
- cfr gene: rRNA methyltransferase → cross-resistance with chloramphenicol
- Tedizolid active vs. single-mutation isolates; inactive vs. cfr-positive
Key Distinction
Both chloramphenicol and linezolid inhibit mitochondrial protein synthesis, producing reversible bone marrow suppression. Chloramphenicol also causes aplastic anemia — an idiosyncratic, unpredictable, dose-independent reaction that linezolid does not. Linezolid also inhibits MAO, creating serotonin syndrome risk that chloramphenicol does not share.