Vancomycin, Daptomycin & Polymyxins

Vancomycin: mechanism and uses

Mechanism. Vancomycin is a large glycopeptide that binds the D-Ala-D-Ala terminus of peptidoglycan precursors, blocking transglycosylation (chain elongation) and cross-linking. Because it grabs the substrate rather than an enzyme, β-lactamases and the PBP2a of MRSA are irrelevant. It is too bulky to cross the gram-negative outer membrane, so it is gram-positive only: bactericidal against staphylococci, bacteriostatic against enterococci.

IV uses. MRSA bacteremia, endocarditis, osteomyelitis and pneumonia; methicillin-resistant S. epidermidis on catheters and prosthetic material; penicillin-resistant pneumococci, which is why it joins ceftriaxone in empiric meningitis therapy; and ampicillin-resistant enterococci. Against MSSA it kills more slowly than nafcillin or cefazolin, so therapy is switched once susceptibility is known.

Oral vancomycin. Taken by mouth it is essentially unabsorbed and reaches high colonic concentrations, making it a first-line treatment for C. difficile colitis alongside fidaxomicin. IV vancomycin is not excreted into the colonic lumen and does not treat C. difficile.

Vancomycin: toxicity, dosing and resistance

Kidney injury. Nephrotoxicity (acute tubular injury) is the main dose-limiting problem; risk rises with high exposure, long courses and co-nephrotoxins, especially piperacillin-tazobactam and aminoglycosides. Ototoxicity is rare; thrombophlebitis occurs at peripheral IV sites; DRESS (fever, rash, eosinophilia and organ injury weeks into therapy) and neutropenia appear with prolonged courses.

Flushing, pruritus and erythema of the face, neck and upper torso during a fast infusion, sometimes with hypotension, is the vancomycin infusion reaction (formerly "red man syndrome"): direct, non-IgE mast-cell degranulation with histamine release. Stop, then restart more slowly after an antihistamine; it is not an allergy and does not bar future use.

Dosing. Doses are adjusted to an AUC/MIC target of about 400–600, now preferred over trough-only monitoring, to balance efficacy against kidney injury.

Resistance. vanA and vanB operons make precursors ending in D-Ala-D-Lac, which vancomycin binds about 1000-fold less avidly. This defines VRE (mostly E. faecium), treated with daptomycin or linezolid, and the rare VRSA that acquired the genes from enterococci. VISA strains instead thicken their cell walls and trap the drug.

Daptomycin

Mechanism. A cyclic lipopeptide that, in a calcium-dependent step, inserts into the gram-positive cytoplasmic membrane and oligomerizes. Potassium leaks out, the membrane depolarizes, and DNA, RNA and protein synthesis stop. Killing is rapid and concentration-dependent; the drug cannot cross the gram-negative outer membrane.

Uses. MRSA and VRE bacteremia, right-sided (tricuspid) endocarditis and complicated skin and soft tissue infections.

Never use daptomycin for pneumonia: pulmonary surfactant binds and inactivates it. MRSA pneumonia is treated with vancomycin or linezolid.

Toxicity. CK elevation, myopathy and occasionally rhabdomyolysis, so CK is checked weekly and statins are paused. Acute eosinophilic pneumonia (fever, dyspnea, infiltrates, eosinophils in bronchoalveolar lavage fluid) is uncommon but classic and resolves after withdrawal.

Polymyxins

Mechanism. Polymyxin B and colistin (polymyxin E) are cationic polypeptides with a fatty-acid tail. They bind the anionic lipid A of LPS, displace the Mg²⁺ and Ca²⁺ that bridge neighboring LPS molecules, and act as detergents on the outer and then inner membrane, causing leakage and death. Proteus and Serratia are intrinsically resistant.

Uses. Systemic polymyxins are last-resort agents for multidrug-resistant Pseudomonas, Acinetobacter and carbapenem-resistant Enterobacterales; colistin is given IV as the inactive prodrug colistimethate. Topical polymyxin B is combined with bacitracin and neomycin in triple-antibiotic ointments.

Toxicity. Nephrotoxicity (acute tubular necrosis) is common and dose-limiting. Neurotoxicity brings perioral and limb paresthesias and dizziness; neuromuscular blockade can cause respiratory arrest, especially with aminoglycosides, paralytic agents or myasthenia gravis.

Resistance. The plasmid gene mcr-1 encodes an enzyme that adds phosphoethanolamine to lipid A, reducing its negative charge; because it transfers between bacteria, it threatens this last line of therapy.

Fosfomycin, bacitracin and the cell-wall pathway

Fosfomycin. A phosphoenolpyruvate analog that irreversibly inhibits MurA, the first committed step of peptidoglycan synthesis. A single 3 g oral dose treats uncomplicated cystitis, keeping urine levels high for days, and it often stays active against ESBL-producing E. coli.

Bacitracin. It prevents recycling of the bactoprenol lipid carrier that ferries precursors across the membrane. It is used only topically, for superficial gram-positive skin infections, because systemic use is nephrotoxic.