Chapter 35 · Module 9

Glycopeptides and Lipopeptides

Vancomycin, second-generation glycopeptides, and daptomycin — mechanisms, monitoring, and critical clinical rules

Abbreviations: MRSA = methicillin-resistant Staphylococcus aureus | VRE = vancomycin-resistant Enterococcus | TDM = therapeutic drug monitoring | AUC = area under the concentration-time curve | MIC = minimum inhibitory concentration | ABSSSI = acute bacterial skin and skin structure infection | CPK = creatine phosphokinase | VISA = vancomycin-intermediate S. aureus | VRSA = vancomycin-resistant S. aureus

Vancomycin

Mechanism & Spectrum

Vancomycin

Mechanism

Binds D-Ala-D-Ala terminus of peptidoglycan precursor (lipid II)
Blocks transglycosylation and transpeptidation → bactericidal
Large molecule (1,450 Da) → cannot penetrate Gram-negative outer membrane
Unaffected by penicillin-binding protein mutations → active vs. MRSA

Spectrum (Gram-positive only)

MRSA, methicillin-susceptible S. aureus, coagulase-negative staphylococci
S. pneumoniae, streptococci, E. faecalis
Oral: local activity only → C. difficile (no systemic levels)

Pharmacokinetics & TDM

Dosing and Monitoring

Pharmacokinetics

IV only for systemic infections; oral = local GI action only
~50% protein bound; limited CSF penetration
Eliminated by glomerular filtration — dose-adjust in renal impairment

AUC-Guided TDM (current standard)

Target AUC/MIC: 400–600 mg-h/L for MRSA
Bayesian software + 2 timed samples preferred
Replaced trough-only monitoring (imprecise; excess nephrotoxicity)
MIC ≥2 → consider alternative agents

Adverse Effects

Key Toxicities

Nephrotoxicity

Proximal tubular injury; exposure-dependent
Vancomycin + piperacillin-tazobactam → significantly higher AKI risk
Generally reversible; monitor creatinine

Red Man Syndrome

Rate-dependent histamine release; NOT IgE-mediated
Flushing, erythema, pruritus (face, neck, upper torso)
Slow infusion + diphenhydramine → prevents; not a true allergy

Ototoxicity

Uncommon alone; risk increases with aminoglycosides

Resistance

VISA and VRSA

VISA (Intermediate)

Cell wall thickening via regulatory gene mutations
More D-Ala-D-Ala targets → vancomycin must saturate more sites
Arises after prolonged vancomycin exposure

VRSA (High-Level Resistance)

vanA gene acquired from VRE via conjugation
D-Ala-D-Ala replaced by D-Ala-D-Lac → eliminates binding
Rare; requires alternative agents (linezolid, daptomycin)

Second-Generation Glycopeptides

Agent	Half-Life / Dosing	Approved For	Key Feature	Caution
Teicoplanin	70–100 h / once daily	Gram-positive infections (not US)	IM or IV; less red man syndrome	TDM required; vanA susceptible
Dalbavancin	~14–15 days / 1–2 doses	ABSSSI (MRSA)	No TDM; enables OPAT	Dose-adjust if CrCl <30
Oritavancin	~245 h / single dose	ABSSSI	Triple mechanism; partial vanA activity	Interferes with coagulation assays ×120 h
Telavancin	~8 h / once daily IV	HABP/VABP, cSSSI	D-Ala-D-Ala + membrane depolarization	Black box: nephrotoxicity; teratogenic

Daptomycin

Mechanism, Spectrum & PK

Daptomycin

Mechanism

Ca²⁺-dependent membrane insertion → depolarization
Collapses transmembrane potential → arrests DNA, RNA, protein synthesis
Bactericidal; no cross-resistance with cell wall or ribosomal agents

Spectrum

MRSA, MSSA, VRE, VISA, VRSA
Key use: VRE bacteremia, MRSA bacteremia/endocarditis

Pharmacokinetics

IV once daily; ~90% protein bound; low volume of distribution
Renal elimination; dose-adjust if CrCl <30 mL/min

Adverse Effects & Resistance

Key Risks

Skeletal Muscle Toxicity

Myopathy, CPK elevation; rarely rhabdomyolysis
Monitor CPK weekly; stop if >5× ULN with symptoms or >10× ULN
Suspend statins during therapy
Eosinophilic pneumonia: rare paradoxical pulmonary toxicity

See-Saw Effect (Resistance)

VISA cell wall thickening → daptomycin also cannot reach membrane
Vancomycin MIC ↑ parallels daptomycin MIC ↑
Test susceptibility before using as salvage after vancomycin failure

Critical Rule — Daptomycin and Pneumonia

Pulmonary surfactant inactivates daptomycin completely. In vitro susceptibility is irrelevant for pulmonary infections. Never use daptomycin for pneumonia regardless of the organism or susceptibility report. Use linezolid or vancomycin for MRSA pneumonia.