Five agents, one core mechanism

Mechanism of action

How glycopeptides bind D-Ala-D-Ala

• Five hydrogen bonds between the glycopeptide peptide backbone and the terminal D-Ala-D-Ala carbonyl/amino groups
• Binding affinity: K_D ≈ 10⁻⁶ M for vancomycin
• This molecular “lid” sterically blocks transglycosylase and transpeptidase access
• Substitution to D-Ala-D-lactate (VanA, VanB, VanD, VanM) removes one critical H-bond → affinity ↓ ~1000×
• Substitution to D-Ala-D-serine (VanC, VanE, VanG) reduces affinity ~7×

Why lipoglycopeptides act differently

Vancomycin structure

• Tricyclic glycopeptide, MW ~1,449 Da
• Heptapeptide backbone + two attached sugars (vancosamine, glucose)
• Peptide backbone binds D-Ala-D-Ala via five hydrogen bonds
• High-affinity binding defines class activity but limits target flexibility

A potted history

• Isolated 1953 from Amycolatopsis orientalis in Borneo soil
• FDA approval 1958 for penicillin-resistant S. aureus
• Early lots: “Mississippi mud” — impurities caused ototoxicity and nephrotoxicity
• Use dropped after methicillin (1960) and the new β-lactams arrived
• Re-emergence in the 1980s with rising MRSA prevalence → use went from ~2 tonnes/yr (1984) to >11 tonnes/yr (1996) in the US alone

Vancomycin spectrum

Active against (gram-positives, dividing):

• Staphylococcus aureus — MSSA, MRSA, hVISA (partially), VISA (reduced)
• Coagulase-negative staphylococci
• Streptococci (groups A–G, S. pneumoniae, viridans)
• Enterococci (susceptible strains; VRE = resistant)
• Listeria monocytogenes, Corynebacterium jeikeium
• Clostridioides difficile, Cutibacterium acnes

Not active: gram-negatives, mycobacteria, fungi

Vancomycin tissue penetration

→ Limitations underlie use of adjunctive intraventricular, intraperitoneal, intravitreal routes.

VRE epidemiology

• Globally widespread, predominantly VanA and VanB phenotypes in Enterococcus faecium
• NHSN data (US, 2011–2014): VRE accounted for 28% of HAI enterococcal isolates
• EARS-Net 2019 (EU): enormous regional variation — <1% (Nordic) to >50% (some Eastern European countries) for E. faecium
• Latin America VENOUS-I cohort: dominant clones differ from US/EU

EARS-Net data
Vancomycin-resistant Enterococci in Europe

VRE mechanisms — the van gene clusters

The key trick: substitution of D-Ala-D-Ala with D-Ala-D-lactate or D-Ala-D-serine at the peptidoglycan terminus reduces vancomycin affinity by ~1000-fold (lactate) or ~7-fold (serine).

VDE — vancomycin-dependent enterococci

hVISA, VISA, VRSA — the definitions

VISA mechanism — the “clogging” model

VRSA — the rare event

• Acquisition of the enterococcal vanA operon by MRSA, usually in patients with concomitant VRE infection
• Conjugative transfer in vivo demonstrated experimentally and in clinical isolates
• First US case 2002; total ~16 confirmed US cases as of 2023
• Most isolates: high-level resistance (MIC ≥32 μg/mL) but susceptible to linezolid, daptomycin, ceftaroline, oritavancin

MIC “creep” and clinical failure

• Multiple cohorts: MRSA bacteraemia with vancomycin MIC at the upper end of susceptibility (1.5–2 μg/mL by Etest) linked to higher failure, persistence, and mortality
• Cochrane meta-analysis confirmed association but emphasised heterogeneity of testing methods
• IDSA 2011 MRSA guidelines: consider alternative agent if persistent bacteraemia despite adequate exposure OR MIC >2 μg/mL

Pharmacodynamic target: AUC/MIC ≥ 400

• In vivo and clinical data: AUC₂₄ / MIC ≥ 400 correlates with clinical response and microbiologic eradication in MRSA
• AUC > 600 mg·h/L correlates with nephrotoxicity
• Therapeutic window for serious MRSA infections: AUC 400–600

Why trough monitoring isn’t enough

2020 ASHP/IDSA/PIDS/SIDP guidelines — key points

• For serious MRSA infections (bacteraemia, endocarditis, pneumonia, meningitis, osteomyelitis):
  • AUC₂₄ target 400–600 (assuming MIC ≤1 mg/L by BMD)
  • Bayesian-derived AUC preferred; first-order equations from two timed concentrations acceptable
  • Loading dose 25–30 mg/kg (actual body weight) for severely ill patients
• For non-serious infections: trough-based monitoring may still be acceptable

Vancomycin in special populations

• Neonates / VLBW infants: weight- and PMA-based dosing; AUC monitoring increasingly available; hearing screening recommended after prolonged courses
• Children: AUC₂₄ target 400–600 for serious MRSA; Bayesian tools especially useful given inter-patient variability
• Pregnancy: category B/C; minimal transplacental passage in ex vivo models; therapeutic fetal concentrations reached in overt amnionitis; no demonstrated teratogenicity in second/third trimester
• Obesity: dose by actual body weight, but cap loading at 3 g; obese patients often achieve higher AUC than non-obese at same mg/kg
• Elderly: heightened nephrotoxicity risk; use lower trough/AUC targets where clinically acceptable

Vancomycin dosing summary

Local administration

• Intraperitoneal (CAPD peritonitis): 15–30 mg/kg in long dwell (≥6 h) every 5–7 days
• Intraventricular (ventriculitis, shunt infection): 5 mg (slit ventricles), 10 mg (normal), 15–20 mg (enlarged); reduce 60% in infants
• Intraocular (endophthalmitis): 1 mg intravitreal
• Oral (C. difficile): 125 mg q6h × 10 days (fulminant: 500 mg q6h + IV metronidazole)

Vancomycin infusion (red-man) syndrome

Nephrotoxicity

Risk factors (additive):

• AUC > 650 mg·h/L (≈ trough ≥ 15 mg/L)
• Concomitant nephrotoxins, possibly piperacillin-tazobactam
• Duration >14 days
• Pre-existing renal disease, advanced age, obesity, sepsis, hypovolaemia

Mechanisms: oxidative tubular injury, immune-mediated interstitial nephritis, intratubular cast obstruction

Other adverse effects

• Ototoxicity: rare with modern preparations; cumulative dose- and duration-related; very-low-birthweight infants at higher risk
• Neutropenia: 1–2% short courses, 12–13% with prolonged therapy
• Thrombocytopenia: rare; can be immune-mediated
• Rash / drug fever: 3% / 2%; DRESS and SJS/TEN rare but reported
• Linear IgA bullous dermatosis: classic vancomycin association
• C. difficile colitis from IV vancomycin (paradoxically reported)

Preventing vancomycin AKI

• AUC-guided dosing with target 400–600 mg·h/L
• Avoid concomitant nephrotoxins (consider avoiding piperacillin-tazobactam — use cefepime or carbapenem if combination needed)
• Maintain euvolaemia; correct hypovolaemia before high-dose courses
• Reassess need for vancomycin daily; de-escalate if MRSA ruled out
• Consider continuous infusion in critically ill patients
• For high-risk patients, consider alternative agent (daptomycin, linezolid, ceftaroline) if MRSA confirmed

MRSA bacteraemia and endocarditis

• Vancomycin remains first-line when daptomycin not appropriate
• AUC-guided dosing; loading dose for severe disease
• Consider alternative agent if:
  • Persistent bacteraemia ≥ 7 days despite adequate exposure
  • MIC > 2 μg/mL
  • Endovascular source not controlled
• Alternatives: daptomycin (high dose ≥8 mg/kg), ceftaroline, daptomycin + ceftaroline, dalbavancin (off-label)

MRSA pneumonia

• Vancomycin and linezolid both recommended first-line in IDSA/ATS HAP/VAP guidelines
• Linezolid: higher epithelial lining fluid concentration; reduced renal toxicity
• Most randomised trials: clinical equivalence
• For necrotising pneumonia or PVL-positive strains, linezolid often preferred (toxin suppression)

Persistent MRSA bacteraemia — alternatives

• Daptomycin ≥ 8 mg/kg (high-dose to reduce resistance emergence)
• Daptomycin + ceftaroline combination — synergy in vitro; observational survival benefit in persistent bacteraemia
• Daptomycin + β-lactam (oxacillin, nafcillin, anti-staphylococcal penicillin) — “seesaw effect”
• Ceftaroline monotherapy — option for daptomycin-non-susceptible
• Linezolid — “bacteriostatic,” generally not first choice for bacteraemia but role in refractory cases
• Investigational: oritavancin or dalbavancin for off-label bacteraemia / endocarditis continuation

VRE bacteraemia — treatment choices

Bacterial meningitis

• Empirical: vancomycin + 3rd-generation cephalosporin (cefotaxime or ceftriaxone) in adults
• Rationale: penicillin-resistant S. pneumoniae coverage
• Add ampicillin for Listeria if age >50 or immunocompromised
• Add dexamethasone for suspected pneumococcal meningitis

C. difficile infection

• Oral vancomycin 125 mg q6h × 10 days
  • first-line for non-fulminant initial episode (IDSA/SHEA 2021)
• Fidaxomicin preferred when available (lower recurrence)
• Recurrent CDI: tapering/pulsed oral vancomycin OR fidaxomicin OR bezlotoxumab adjunct
• Fulminant disease: vancomycin 500 mg q6h PO + metronidazole 500 mg IV q8h ± rectal vancomycin

Teicoplanin — distinguishing features

• Glycopeptide complex from Actinoplanes teichomyceticus
• Lipophilic side chain → high protein binding (~90–95%), long half-life
• Spectrum largely overlaps vancomycin
• Higher MIC in some staphylococcal species (notably S. haemolyticus)
• VanA: resistant; VanB: susceptible (no induction)
• Not available in the United States

Teicoplanin TDM — the critical detail

Maintenance: 6 mg/kg/day after loading. Always load — half-life is too long to wait for steady state.

Teicoplanin — practical pearls

• Trough monitoring on day 4 (steady state after loading)
• Can be given IM bolus when IV access difficult
• Can give entire daily dose as slow bolus IV (no 60-minute infusion needed)
• Reduced red-neck syndrome vs vancomycin
• For VanB enterococcal endocarditis, teicoplanin remains a legitimate option
• Continued therapy at home (OPAT): once-daily dosing supports this

Teicoplanin clinical use cases

Where teicoplanin shines:

• Outpatient continuation therapy (once-daily dosing, IM or IV bolus possible)
• Patients intolerant of vancomycin (red-neck, less nephrotoxicity)
• VanB enterococcal infection
• Settings where AUC monitoring not feasible (trough-based TDM is simpler)

Caveats:

• Inferior to vancomycin in early endocarditis trials at low doses
• With aggressive loading and target-trough maintenance, modern outcomes comparable

Three drugs, three personalities

Telavancin mechanism and spectrum

• Vancomycin parent + decylaminoethyl tail (membrane-anchor) + phosphonomethylaminomethyl group
• Dual mechanism: D-Ala-D-Ala binding + membrane depolarisation
• 4–8× lower MICs than vancomycin against susceptible S. aureus
• Activity preserved against most VISA, hVISA
• Inactive against VRSA, VanA enterococci

Telavancin — the boxed warnings

Plus: coagulation assay interference — PT, aPTT, INR, ACT spuriously prolonged. Draw before next dose for accurate result.

Telavancin clinical evidence

• ABSSSI (ATLAS 1 and 2): non-inferior to vancomycin; cure 88.3% vs 87.1%, and 90.6% vs 86.4% in MRSA subgroup
• HAP/VAP (ATTAIN 1 and 2): non-inferior to vancomycin overall; higher mortality in the subgroup with CrCl <50 mL/min
• Approved indications (US): cSSSI, HAP/VAP caused by S. aureus when alternatives are inappropriate

Dalbavancin — defining feature is half-life

• Parent: A40926 (teicoplanin-like glycopeptide), modified with lipophilic side chain
• t½ ~346 hours (~14 days); ~33% of drug still in plasma at 14 days
• Binds D-Ala-D-Ala with enhanced dimerisation
• Activity: MRSA, MSSA, CoNS, streptococci, vancomycin-susceptible enterococci
• Activity reduced against VISA; inactive against VRSA, VanA enterococci

Dalbavancin — clinical trial backbone

• DISCOVER 1 and 2 (Boucher 2014): two-dose regimen (1000 mg + 500 mg/wk) non-inferior to vancomycin → linezolid for ABSSSI
• DUR001-303 (Dunne 2016): single-dose 1500 mg non-inferior to two-dose regimen
• Rappo 2018: randomized comparator-controlled trial for adult osteomyelitis — high cure rates with two-dose dalbavancin
• DOTS (Turner 2025): RCT, dalbavancin (days 1 + 8) vs standard IV therapy for completion treatment in complicated S. aureus bacteraemia after blood-culture clearance — not superior but noninferior; comparable safety
• Vertebral osteomyelitis (open-label cohort): efficacious; growing real-world experience

DOTS — Pharmacokinetic data

Population PK model (n = 97, 640 samples): 3-compartment, zero-order input, first-order elimination

• Protein binding >99% in 92.3% of paired samples — substantially higher than previously estimated (~93%)
• Unbound concentrations linked to total via power function: C_U(t) = A × C_T(t)^K

DOTS PK — covariate effects on disposition

All covariates entered as power functions on the respective parameter.

DOTS PK — exposure–response: day 22 concentration

• Among 93 evaluable patients, 72 (77.4%) achieved clinical success at day 70
• Total day 22 concentration >32 µg/mL identified as optimal cut point:

• No increase in serious adverse events in the higher-exposure group (26.7% vs 42.9%; difference −16.2 pp, 95% CI −36.2 to 3.8)
• Effect consistent across subgroups: MRSA/MSSA, bacteraemia duration, deep-seated infection

DOTS PK — unbound exposure and late complications

• 73% of unbound samples below quantification by day 42; 98% by day 70
• All infectious complications occurred after day 40 — temporally coinciding with declining unbound exposure
• Unbound exposure–response associations were attenuated compared with total concentrations
  • Narrow dynamic range of unbound concentrations (protein binding >99%)
  • Many later samples near the lower limit of quantification (0.05 µg/mL)

Clinical implication: total day 22 concentration is a more practical and stable surrogate for sustained systemic exposure in this population

DOTS PK — implications for TDM and dosing

• Most patients receiving two 1500 mg doses do not achieve day 22 concentrations >32 µg/mL
  • Mean day 22 concentration: 29.0 µg/mL; only 32.3% were above the threshold
• Patients below the threshold still had success rates numerically comparable to standard IV therapy
• However: exploratory data suggest some patients may benefit from a third dose between days 22–40
  • Guided by low day 22 concentration (TDM approach)
  • Or applied empirically in patients at risk for lower exposure (high weight, high CrCl, low albumin)

Dalbavancin in people who inject drugs (PWID)

• Increasingly used for S. aureus bacteraemia and right-sided endocarditis in PWID
• Single 1500 mg dose covers ~2 weeks of therapy without IV access
• Observational cohorts: outcomes comparable to standard IV therapy in selected patients
• Caveats: requires careful selection (source controlled, no metastatic complications)
• DOTS (Turner 2025) included right-sided native valve endocarditis; showed noninferiority to standard IV therapy — first RCT data in this population
• Dedicated left-sided or prosthetic valve endocarditis RCT data remain absent; further trials needed

Dalbavancin — practical use

• ABSSSI: 1500 mg IV × 1 OR 1000 mg + 500 mg one week later
• Osteomyelitis (off-label): 1500 mg + 1500 mg one week later
• Bacteraemia / endocarditis (off-label): variable regimens, often paired with initial vancomycin/daptomycin then dalbavancin for continuation
• Pediatric ABSSSI: <6 y 22.5 mg/kg; 6–<18 y 18 mg/kg (max 1500 mg)
• 30-minute infusion; 500 mg vials in 5% dextrose, 1–5 mg/mL
• No renal or hepatic adjustment (modest renal clearance reduction in severe impairment but no formal adjustment recommended)
• AEs: nausea, headache, diarrhoea, mild ALT elevation; well tolerated

Oritavancin — the triple-mechanism agent

Oritavancin clinical evidence

• SOLO I and SOLO II (Corey 2014, 2015): single 1200 mg dose non-inferior to twice-daily vancomycin × 7–10 days for ABSSSI
• Approved indication: ABSSSI caused by susceptible gram-positive organisms
• Off-label uses (open-label cohorts):
  • Acute osteomyelitis (Van Hise 2020 — two-year multicentre cohort, good outcomes with weekly or biweekly oritavancin)
  • Prosthetic joint infection
  • Bacteraemia, including VRE bacteraemia
• Two formulations: Orbactiv/Tenkasi (3 h infusion) and Kimyrsa (1 h infusion)

Oritavancin — the coagulation problem

Oritavancin in prosthetic joint infection

• Open-label cohorts: single- or multiple-dose oritavancin for PJI when surgical control achieved
• Particularly attractive for staphylococcal and enterococcal PJI requiring prolonged therapy
• One protocol: 1200 mg IV → 1200 mg in 1 week → maintenance every 4 weeks for chronic suppression
• Evidence base: case series and small open-label cohorts; no RCT yet
• Antimicrobial stewardship implication: requires explicit protocol and follow-up

Oritavancin — other cautions

• CYP450 interactions: weak inhibitor (CYP2C9, CYP2C19), weak inducer (CYP3A4, CYP2D6) — monitor narrow-therapeutic-index substrates
• No dose adjustment for renal or hepatic impairment (mild-to-moderate)
• Adverse events: headache, nausea, vomiting, diarrhoea, mild ALT elevation, infusion reactions (flushing, pruritus)

When to use lipoglycopeptides

Strong rationale:

• ABSSSI requiring inpatient gram-positive cover but suitable for early discharge / ED treatment
• Patients with poor adherence to oral step-down or unable to take oral
• Difficult IV access where prolonged IV not feasible
• VRE bacteraemia / VanA enterococcal infection — oritavancin specifically
• Outpatient continuation of osteomyelitis or endocarditis therapy (off-label)

Weaker rationale (think twice):

• Routine ABSSSI in patients who can take oral cephalexin/clindamycin/doxycycline
• Hospital-acquired infections where source control isn’t established
• Patients with concurrent need for IV unfractionated heparin (avoid oritavancin)

Pharmacoeconomics — when does cost make sense?

• Acquisition cost: dalbavancin €1500–2500 per 1500 mg dose; oritavancin €2500–3500 per 1200 mg dose (varies by country)
• Per-day hospital ward cost: €500–1500 in most European systems
• Breakeven: ~2–3 hospital days avoided per single-dose lipoglycopeptide
• Cost-effective when:
  • Avoiding admission entirely for ABSSSI
  • Discharging early from bacteraemia
  • Replacing prolonged OPAT IV course
• Less cost-effective when displacing inexpensive oral options

Resistance and surveillance concerns

• Long tissue persistence of dalbavancin and oritavancin → prolonged sub-MIC exposure in vivo
• Theoretical concern for selection of resistance, particularly enterococci
• To date, no large-scale resistance emergence documented in surveillance (SENTRY, ATLAS)
• Vigilance warranted as use expands; reporting of unusual MIC patterns essential

Decision framework — empirical gram-positive cover

Case 1 — MRSA bacteraemia with rising creatinine

55-year-old man, T2DM, admitted with right-sided infective endocarditis, MRSA bacteraemia. Day 5 of vancomycin (trough 18 mg/L, AUC 580). Creatinine has risen from 0.9 → 1.6 mg/dL. Blood cultures still positive at 96 h.

What do you do?

• Switch to daptomycin 8–10 mg/kg?
• Add ceftaroline?
• Continue vancomycin and accept renal injury?
• Image to look for missed focus?

Case 2 — ABSSSI in IV drug user

32-year-old woman, active opioid injection use, presents with extensive cellulitis of forearm at injection site. Stable, no systemic features. MRSA likely. Refusing admission, no IV access available, unreliable for outpatient appointments.

What’s your antibiotic strategy?

• Standard oral cephalexin → outpatient?
• IV vancomycin via PICC?
• Single-dose dalbavancin 1500 mg in ED?
• Single-dose oritavancin 1200 mg in ED?

Case 3 — VanA VRE bacteraemia

68-year-old, post-cardiac surgery, in ICU on day 21. New fever with positive blood cultures: E. faecium VanA phenotype. Patient has acute kidney injury (CrCl 30 mL/min) and is on dual antiplatelet therapy.

Treatment options?

• Linezolid 600 mg q12h
• Daptomycin 10 mg/kg (renally adjusted)
• Oritavancin single-dose
• Tigecycline

Questions to think about

• For your hospital, what is the local prevalence of MRSA, hVISA, VRE phenotypes? How does this change your empirical choices?
• Is your lab equipped to flag MIC creep or to perform PAP-AUC for suspected hVISA?
• Does your antimicrobial stewardship programme have a protocol for single-dose dalbavancin in the ED? What patient-selection criteria would you build in?
• For your next vancomycin patient, will you use trough-based or AUC-based dosing? What tool will you use?

Key references

• Murray BE, Arias CA, Nannini EC. Glycopeptides and lipoglycopeptides. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 9th ed., 2025.
• Rybak MJ et al. Therapeutic monitoring of vancomycin for serious MRSA infections: A revised consensus guideline by ASHP/IDSA/PIDS/SIDP. Am J Health-Syst Pharm. 2020.
• Liu C et al. Clinical practice guidelines by IDSA for the treatment of MRSA infections in adults and children. Clin Infect Dis. 2011.
• Kalil AC et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: IDSA/ATS guidelines. Clin Infect Dis. 2016.
• Shariati A et al. Global prevalence of vancomycin-resistant, intermediate, and heterogeneously vancomycin-intermediate S. aureus: systematic review and meta-analysis. Sci Rep. 2020.