(4) Antibacterials IV (Other Cell-Wall Active Agents)

What do β-lactams do?

interfere with peptidoglycan cross-linking

Main drugs covered:

• Glycopeptides → vancomycin

• Lipoglycopeptides (reference only)

  • dalbavancin

  • telavancin

  • oritavancin

• Daptomycin (membrane)

• Fosfomycin (cell wall)

• Cycloserine (cell wall)

• Bacitracin (cell wall)

• Polymyxins / colistin (membrane)

GLYCOPEPTIDES — VANCOMYCIN

Key concept

• Very large / bulky molecule

• Cannot fit through Gram-negative porins

• Vancomycin = Gram-positive only

GLYCOPEPTIDES — VANCOMYCIN

Activity

• Bactericidal for Gram-positive organisms

• Works against:

  • MRSA

  • Enterococcus faecium / faecalis

  • C. difficile

GLYCOPEPTIDES — VANCOMYCIN

Important clinical pearl

• For C. difficile:

  • must be given orally

  • because infection is in gut

GLYCOPEPTIDES — VANCOMYCIN

Important use pearl

• Do NOT use vanco for MSSA if anti-staph penicillin can be used

  • anti-staph penicillins work better / easier on patient

GLYCOPEPTIDES — VANCOMYCIN

Distribution / PK

• widely distributed

• enters CSF (7–30%)

• 90% renal excretion

• kidney dysfunction → half life can be 6–10 days

GLYCOPEPTIDES — VANCOMYCIN

Clinical uses

• bloodstream infections

• endocarditis

• meningitis (with cefotaxime / ceftriaxone / rifampin)

• oral for C. diff

GLYCOPEPTIDES — VANCOMYCIN

Adverse effects

• nephrotoxicity / ototoxicity (rare)

• red man / red neck syndrome:

  • histamine release

  • prevent with slow IV infusion

• other rare:

  • rash

  • phlebitis

  • neutropenia

VANCOMYCIN MECHANISM

MOA

• binds D-Ala-D-Ala on peptidoglycan pentapeptide

• strict requirement for two alanines

• blocks:

  • transglycosylation

  • cross-linking

• weakens wall → lysis

VANCOMYCIN MECHANISM

Resistance

VRE

VRSA

VISA / GISA

VANCOMYCIN MECHANISM - Resistance

VRE

• enterococci acquired van genes

• change target:

  • D-Ala-D-Lactate

• vanco cannot bind

VANCOMYCIN MECHANISM - Resistance

VRSA

• rare

• slow emergence because:

  • many genes needed

  • hard to transfer all at once

VANCOMYCIN MECHANISM - Resistance

VISA / GISA

• thicker cell wall traps drug

DAPTOMYCIN

Key

• cyclic lipopeptide

• Gram-positive only

• active against:

  • VRE

  • VRSA

  • skin infections

  • bacteremia

  • endocarditis

DAPTOMYCIN

Important PK

• IV once daily

• renal clearance

DAPTOMYCIN

Huge exam pearl

• Daptomycin cannot be used for pneumonia

  • pulmonary surfactant in lungs inactivates drug

DAPTOMYCIN

MOA

• calcium-dependent insertion into membrane

• causes membrane depolarization

• potassium efflux

• bacterial death

DAPTOMYCIN

Important concept

• concentration-dependent bactericidal

FOSFOMYCIN

Key

• analog of phosphoenolpyruvate

FOSFOMYCIN

MOA

• inhibits MurA enzyme

• blocks first step of peptidoglycan synthesis

• blocks formation of NAM

FOSFOMYCIN

Activity

• Gram positive + Gram negative

• oral available

• IV used globally (not in U.S.)

• active drug excreted in urine

FOSFOMYCIN

Main use

• UTI

• MDR urinary pathogens

FOSFOMYCIN

Resistance

1. transporter mutation

• glpT / uhpT mutations

• drug cannot enter cell

2. drug-modifying enzymes

• FosA

✅ ON EXAM ⭐

• Resistance can occur by blocked uptake

 CYCLOSERINE

Key

• structural analog of D-alanine

CYCLOSERINE

MOA

• inhibits incorporation of D-alanine into pentapeptide

• inhibits alanine racemase

CYCLOSERINE

Activity

• Gram positive

• Gram negative

• M. tuberculosis

 CYCLOSERINE

Main use

mostly TB

 CYCLOSERINE

PK

• widely distributed

• renal excretion

 CYCLOSERINE

Toxicity

• CNS toxicity:

  • headache

  • tremor

  • psychosis

  • seizures

BACITRACIN

Key

• cyclic peptide mixture

• very large molecule

• Gram-positive only

BACITRACIN

MOA

• inhibits cell wall formation

• blocks dephosphorylation of lipid carrier

• prevents peptidoglycan subunit transfer across membrane

BACITRACIN

Important use

• topical only Why?

• highly nephrotoxic if systemic

BACITRACIN

Common combinations

• often with:

  • polymyxin

  • neomycin

BACITRACIN

Example:

Neosporin

 POLYMYXINS / COLISTIN

Key

• membrane-active drugs

• Gram-negative only

 POLYMYXINS / COLISTIN

Drugs

• polymyxin B

• colistin (polymyxin E)

POLYMYXINS / COLISTIN

Spectrum

• Acinetobacter

• Pseudomonas

• MDR Enterobacteriaceae

POLYMYXINS / COLISTIN

Important

• old “last resort” drug

• brought back due to resistance crisis

POLYMYXINS / COLISTIN

Toxicity

• nephrotoxicity

• neurotoxicity

POLYMYXINS / COLISTIN

Use

topical or systemic

POLYMYXIN MECHANISM

Why only Gram-negative?

• binds LPS in outer membrane

• Gram-positive do NOT have LPS

 POLYMYXIN MECHANISM

MOA

• inserts into outer membrane

• disrupts phospholipid structure

• damages outer + inner membrane

• causes lysis

 POLYMYXIN MECHANISM

Important

rapidly bactericidal

POLYMYXIN RESISTANCE

Big resistance pearl

• resistance rising due to increased use

 POLYMYXIN RESISTANCE

• plasmid-mediated resistance gene

• modifies lipid A

• prevents polymyxin binding

POLYMYXIN RESISTANCE

Important story

• first major reports in China (farm animals + hospitals)

• now worldwide