Meropenem, Colistin, and Linezolid

1. MEROPENEM

Drug Class

Mechanism of Action

Antimicrobial Spectrum

• More active against gram-negative organisms (Enterobacterales, P. aeruginosa, Acinetobacter)
• Slightly less active against gram-positives, particularly Enterococcus

ADME

• Route: IV only (not absorbed orally)
• Half-life: ~1 hour; renally cleared
• Extended infusion: Infusing over 3 hours (instead of 30 min) maximizes time above MIC - useful for low-level resistant pathogens (PK/PD optimization)
• Renal dose adjustment: Required

Therapeutic Uses

• Hospital-acquired/nosocomial infections when resistant pathogens are suspected
• Preferred carbapenem for CNS infections (meningitis) - less epileptogenic than imipenem
• Intra-abdominal, respiratory, urinary tract, skin/soft tissue infections in hospitalized patients
• Meropenem/vaborbactam (2g/2g q8h) - reserved for MDR gram-negative pathogens including KPC-producing organisms

Key Adverse Effects

• Nausea, vomiting (less common than imipenem)
• Seizures - lower risk than imipenem, hence preferred for meningitis
• Drug interaction: Meropenem (and other carbapenems) markedly reduces serum valproic acid levels - do NOT co-administer
• β-lactam cross-allergy: Most patients allergic to penicillins can safely receive carbapenems; those with severe immediate-type reactions need test-dose protocol

Resistance

2. COLISTIN (Polymyxin E)

Drug Class

Formulations

• Colistimethate sodium (CMS) - prodrug, used for IV/inhaled administration
• Colistin sulfate (base) - active form, used topically/orally for gut decontamination
• CMS is hydrolyzed slowly in the bloodstream to active colistin sulfate

Mechanism of Action

1. Interact with phospholipids of gram-negative outer membranes
2. Bind to the lipid A portion of lipopolysaccharide (LPS/endotoxin)
3. Disrupt membrane integrity → membrane permeabilization → cell death (bactericidal)

Antimicrobial Spectrum

ADME

• Not absorbed orally (oral use = gut decontamination only)
• IV route: CMS prodrug given IV; slow conversion to active colistin in blood
• Significant interpatient variability in active drug levels due to competing renal elimination of CMS vs. nonrenal clearance of active colistin
• Renal dose adjustment mandatory for CMS
• Inhaled CMS: used adjunctively for VAP (better PK than inhaled polymyxin B)
• Can be given intrathecally/intraventricularily for CNS infections

Dosing (Goldman-Cecil guideline)

• Loading dose: 300 mg CMS, then maintenance 150-180 mg q12h, with adjustments for renal function

Therapeutic Uses

• Extensively drug-resistant (XDR) / carbapenem-resistant gram-negative infections: Acinetobacter baumannii, Klebsiella pneumoniae, P. aeruginosa
• Hospital-acquired/ventilator-associated pneumonia (HAP/VAP) - inhaled colistin often added to IV therapy
• Always used in combination (with carbapenems, rifampin, or other agents) to prevent resistance emergence and improve efficacy
• NOT a first-line agent - reserved for when other options are exhausted

Key Adverse Effects

• Nephrotoxicity: Primary dose-limiting toxicity. Acute kidney injury (AKI) in up to 50-60% of patients via renal tubular cell damage. Narrow therapeutic window. Daily creatinine monitoring required.
• Neurotoxicity: Paresthesias, peripheral numbness, tingling, slurred speech, muscle weakness, apnea, vertigo
• Neuromuscular blockade possible - overdose can cause apnea
• Polymyxin B has modestly lower nephrotoxicity compared to CMS

Resistance

• Resistance among normally susceptible isolates is uncommon but emergence during treatment is documented, especially in XDR Acinetobacter and Klebsiella
• MCR genes (plasmid-mediated colistin resistance) are a growing global concern

3. LINEZOLID

Drug Class

Mechanism of Action

1. Binds to the 50S ribosomal subunit (specifically the peptidyl transferase center/23S rRNA)
2. Blocks the positioning and formation of the N-formylmethionyl-tRNA initiation complex
3. Prevents assembly of the 70S ribosome (30S + 50S) needed to start translation
4. This is distinct from other protein synthesis inhibitors (e.g., macrolides, tetracyclines, aminoglycosides act at different steps)

Antimicrobial Spectrum

ADME

• Oral bioavailability: ~100% - one of the key advantages; oral = IV dosing is equivalent
• Excellent tissue penetration including CSF/CNS
• Wide distribution into tissues and fluids

Dosing

• 600 mg IV or PO q12h for most serious infections (skin/soft tissue, pneumonia, bacteremia)
• Tedizolid: 200 mg once daily (lower dose due to greater potency)

Therapeutic Uses

• MRSA infections: Pneumonia (especially HAP/VAP), skin and soft tissue infections, bacteremia
• VRE infections: Serious infections when vancomycin cannot be used
• Complicated SSTIs (skin and soft-tissue infections)
• MDR tuberculosis (XDR-TB): Active in vitro and in clinical use (second-line)
• CNS infections caused by resistant gram-positives (excellent CNS penetration)

Key Adverse Effects

Drug Interactions (Critical)

• SSRIs/SNRIs → Serotonin syndrome (major interaction)
• Sympathomimetics → Hypertensive crisis (MAOI effect)
• Tyramine-containing foods → Hypertensive reaction

Resistance

• Mutations in 23S rRNA of the 50S subunit - most common mechanism
• cfr gene (methylation of 23S rRNA) - transferable resistance, emerging concern
• Tedizolid retains activity against some linezolid-resistant enterococci

Summary Comparison Table