Daptomycin and streptogramins

Russell E. Lewis

2026-05-29

Daptomycin and Streptogramins






Russell E. Lewis, Pharm.D., FCCP
Associate Professor of Infectious Diseases


{{< fa solid envelope size=1x >}} russelledward.lewis@unipd.it
Slides and course materials: www.idpadovaid.com

Learning Objectives


After this lecture, you should be able to:

  1. Describe the mechanism of action of daptomycin
  2. Understand daptomycin’s spectrum of activity and susceptibility testing
  3. Explain mechanisms of daptomycin resistance
  4. Apply appropriate dosing for different clinical scenarios
  5. Recognize adverse effects and monitoring requirements
  6. Identify clinical indications for daptomycin use

Part 1: Daptomycin basics

What is Daptomycin?


  • Cyclic lipopeptide antibiotic (1620.67 Da)
  • Produced by Streptomyces roseosporus
  • Discovered in the 1980s- Eli Lilly
  • FDA approved: 2003 (US), 2006 (Europe)

Chemical Structure


Mechanism of Action

(Jung et al., 2004; Müller et al., 2016; Pogliano et al., 2012; Silverman et al., 2003)

Key Feature: Bactericidal without lysis


  • Kills bacteria without significant cell lysis
  • Results in reduced inflammatory response
  • Less release of proinflammatory mediators
  • Potential advantage in severe infections

(Silverman et al., 2003)

Part 2: Antimicrobial spectrum

Spectrum of activity


Active against:

  • Staphylococcus aureus (MSSA, MRSA, VISA)
  • Coagulase-negative staphylococci
  • Enterococcus faecalis and E. faecium (including VRE)
  • Streptococci
  • Some gram-positive anaerobes

Organisms with variable/No activity


Variable activity:

  • Actinomyces spp. (MIC90 4-32 μg/mL)
  • Lactobacillus spp.
  • Some clostridial species

No activity:

  • Gram-negative organisms
  • Pulmonary infections (surfactant inactivation!)

Susceptibility testing challenges


Warning

Calcium-supplemented Mueller-Hinton broth is REQUIRED (50 μg/mL calcium concentration)

  • Disk diffusion: NOT recommended
  • Etest: Variable reproducibility
  • Broth microdilution: Preferred method
  • Significant interlaboratory variability exists

(Campeau et al., 2018; Humphries et al., 2011)

Susceptibility breakpoints


Organism Susceptible Intermediate Resistant
Staphylococci ≤1 μg/mL - >1 μg/mL
Streptococci ≤1 μg/mL - >1 μg/mL
E. faecalis (FDA) ≤4 μg/mL - -
E. faecium (CLSI 2019) - 2-4 μg/mL (SDD) ≥8 μg/mL

(Clinical and Laboratory Standards Institute, 2019)

Part 3: Resistance Mechanisms

Resistance is uncommon but…


  • In vitro- resistance after serial passage is uncommon
  • Clinical resistance emerges during therapy
  • 6% of patients in pivotal bacteremia trial developed elevated MICs
  • Risk factors:
    • Deep-seated/undrained infections
    • Prior vancomycin exposure
    • Inadequate dosing

(Fowler et al., 2006; Sakoulas et al., 2006; Silverman et al., 2001)

Phenotypic changes in resistant strains


  • Enhanced membrane fluidity
  • Increased positive surface charge
  • Resistance to depolarization
  • Reduced phosphatidylglycerol content
  • Increased pigment production
  • Decreased daptomycin binding

(Mishra et al., 2012; Sakoulas et al., 2006)

Genetic basis (S. aureus)


Key genes implicated:

  1. mprF - LPG synthase/flippase → increased surface charge
  2. yycFG/walKR - Cell envelope homeostasis
  3. vraSR - Cell wall stress response
  4. dlt operon - D-alanylation of teichoic acids
  5. pgsA/cls - Phospholipid metabolism



(Arias et al., 2011a; Howden et al., 2011; Peleg et al., 2012; Yang et al., 2010, 2009)

The “Seesaw effect”


Clinical Pearl

Daptomycin resistance often leads to increased β-lactam susceptibility

  • Basis for daptomycin + β-lactam combinations
  • Demonstrated in vitro and in animal models
  • Multiple β-lactams effective (oxacillin, ceftaroline, etc.)
  • May prevent emergence of resistance

(Dhand et al., 2011; Mehta et al., 2012)

Enterococcal resistance


  • LiaFSR system is central to resistance
  • Homologue of VraTSR in staphylococci
  • Cell envelope stress response system
  • Additional mutations in gdpD, cls genes
  • Resistance can emerge WITHOUT prior exposure

(Arias et al., 2011b; Khan et al., 2019; Tran et al., 2013)

Part 4: Pharmacokinetics

Key PK parameters


Parameter Value
Half-life 7.3-9.6 hours
Protein binding 90-93%
Volume of distribution 92-117 mL/kg
Elimination Renal (unchanged)

(Benvenuto et al., 2006; Dvorchik et al., 2003)

Peak concentrations by dose


Dose (mg/kg) Peak (μg/mL) AUC (μg·hr/mL)
4 ~55 ~500
6 ~86 ~750
8 ~116 ~850
10 ~130 -
12 ~165 -

(Benvenuto et al., 2006; Dvorchik et al., 2003; Louie et al., 2001)

Tissue penetration


Good penetration:

  • Skin/soft tissue (~68% of plasma)
  • Cardiac vegetations (~50% of serum)

Poor penetration:

  • CNS (~2-6%)
  • Bone (variable)
  • Lungs (inactivated by surfactant!)

(Cottagnoud et al., 2004; Lee et al., 2008; Traunmüller et al., 2010; Wise et al., 2002)

Part 5: Dosing

FDA-EMA approved dosing


Indication Dose Route
ABSSSI 4 mg/kg q24h IV
Bacteremia/Right-sided endocarditis 6 mg/kg q24h IV



BUT…



Experts recommend 8-12 mg/kg/day for serious infections!

(Arbeit et al., 2004; Falcone et al., 2013; Fowler et al., 2006; Kullar et al., 2013)

Renal dose adjustment


CrCl Dose Adjustment
≥30 mL/min No adjustment
<30 mL/min Every 48 hours
Hemodialysis After HD, q48h
CRRT Variable - consider TDM

For patients on CRRT, there’s no uniform recommendation. Drug monitoring may be helpful. Some suggest 8 mg/kg q48h for CVVHDF. Monitor CPK more frequently in renal impairment.

(Khadzhynov et al., 2011; Kielstein et al., 2014; US Food and Drug Administration, 2020)

Special populations


  • Obesity: No dose adjustment (use actual body weight)
  • Hepatic impairment: No adjustment (Child-Pugh B)
  • Pediatrics: FDA-approved, age-based dosing
  • Pregnancy: Category B (insufficient human data)

(Ardura et al., 2007; Gonzalez et al., 2017; US Food and Drug Administration, 2020)

Part 6: Adverse effects

Muscle toxicity (Primary Concern)


  • CPK elevation (dose and duration dependent)
  • Mechanism: Direct membrane toxicity to myofibers
  • Risk factors:
    • Cmin ≥24.3 mg/L
    • Concurrent statin use
    • Renal impairment
    • Duration >7 days

(Bhavnani et al., 2010; Dare et al., 2018; McConnell et al., 2017)

CPK monitoring & management


When to Stop Daptomycin

  • CPK >1000 units/L WITH symptoms
  • CPK >2000 units/L (10× ULN) even without symptoms


Monitor:

  • Baseline CPK before starting
  • Weekly CPK (more often in renal impairment)
  • Weekly in patients on statins

(Arbeit et al., 2004; Bhavnani et al., 2010; Fowler et al., 2006)

Other adverse effects


Effect Frequency Notes
Eosinophilic pneumonia Rare After ~10 days; stop drug
Peripheral neuropathy 9% vs 2% Usually mild, reversible
GI symptoms Common Similar to comparators
Renal/hepatic Rare May be protective vs aminoglycosides


(Fowler et al., 2006; Silverman et al., 2007)

Drug Interactions


Minimal CYP450 interactions (not metabolized hepatically)

Monitor closely with:

  • Statins - increased CPK risk
  • PT/INR assays - may cause false elevation

(Dare et al., 2018; McConnell et al., 2017)

Part 7: Clinical applications

FDA-approved Indications


  1. ABSSSI (Acute Bacterial Skin & Skin Structure Infections)
    • S. aureus (MSSA, MRSA)
    • Streptococcus pyogenes
    • E. faecalis (vancomycin-susceptible)
  2. S. aureus bacteremia & right-sided endocarditis

(Arbeit et al., 2004; Fowler et al., 2006)

Off-label uses


  • VRE infections (bacteremia, endocarditis)
  • Left-sided endocarditis (with other agents)
  • Osteomyelitis
  • Prosthetic joint infections
  • CNS infections (limited data)

When to consider daptomycin


  • MRSA with vancomycin MIC ≥1.5-2 μg/mL
  • Vancomycin failure or intolerance
  • VRE infections
  • Concern for nephrotoxicity
  • Desire for once-daily dosing

(Kullar et al., 2011; Moore et al., 2012; Murray et al., 2013)

When NOT to use daptomycin


Important

NEVER use for pneumonia!

Also avoid:

  • Known daptomycin-resistant organism
  • Prior daptomycin failure
  • Active rhabdomyolysis
  • Untreated source of infection

Part 8: Combination therapy strategies

Rationale for Combinations


  1. Prevent emergence of resistance
  2. Exploit the seesaw effect
  3. Enhance bactericidal activity
  4. Treat complicated/deep-seated infections

(Dhand et al., 2011; Mehta et al., 2012; Sakoulas et al., 2014a)

Daptomycin + β-lactam


Best supported combination:

  • Oxacillin/nafcillin
  • Ceftaroline (excellent data)
  • Ceftriaxone, cefotaxime
  • Ertapenem
  • Even ampicillin-sulbactam

(Barber et al., 2015; Dhand et al., 2011; Mehta et al., 2012; Sakoulas et al., 2014b)

Other combinations

Other combinations


Partner Evidence Comment
Gentamicin In vitro synergy Nephrotoxicity concern
Rifampin Variable May be antagonistic
Fosfomycin Emerging data Limited availability
Trimethoprim-sulfamethoxazole Case reports For MRSA

(Credito et al., 2007; Rose et al., 2012)

Case example: Persistent MRSA bacteremia

Case example: Persistent MRSA bacteremia


Scenario: Day 7 of vancomycin, blood cultures still positive

Approach: 1. Switch to high-dose daptomycin (8-10 mg/kg) 2. Add β-lactam (ceftaroline or oxacillin) 3. Ensure source control 4. Monitor CPK closely

(Dhand et al., 2011; Fowler et al., 2006; Kullar et al., 2013)

Part 9: Quinupristin-Dalfopristin (Brief Overview)

Quinupristin-dalfopristin basics


  • Streptogramin B (30%) + Streptogramin A (70%)
  • Trade name: Synercid
  • Target: 50S ribosomal subunit
  • Limited clinical use due to:
    • Central line requirement
    • Arthralgias/myalgias
    • Infusion site reactions
    • Limited availability

Quinupristin-dalfopristin spectrum & dosing


Active against:

  • Most gram-positives EXCEPT E. faecalis
  • Some gram-negatives (H. influenzae, M. catarrhalis)

Dosing: 7.5 mg/kg IV q12h (1-hour infusion)

No renal adjustment needed

Quinupristin-dalfopristin: Why it’s rarely used


  • Arthralgias/myalgias (up to 50%)
  • Severe infusion site reactions
  • Requires central venous access
  • CYP3A4 drug interactions
  • Limited availability in US
  • Better alternatives exist (linezolid, daptomycin)

Summary & Key Takeaways

Daptomycin key points


  1. Calcium-dependent cyclic lipopeptide
  2. Bactericidal without cell lysis
  3. Spectrum similar to vancomycin but active against VISA/VRE
  4. Never use for pneumonia (surfactant inactivation)
  5. Monitor CPK - stop if elevated with symptoms
  6. Use high doses (8-12 mg/kg) for serious infections

Clinical pearls


Tip

  • Consider daptomycin when vancomycin MIC ≥1.5-2 μg/mL
  • Add β-lactam for persistent bacteremia
  • The “seesaw effect” makes β-lactam combinations logical
  • Renal dosing: extend interval, don’t reduce dose
  • Check CPK baseline and weekly; more often with renal impairment or statins

Questions to Consider


  1. Why can’t daptomycin be used for pneumonia?
  2. What is the seesaw effect and how is it clinically useful?
  3. When should you suspect daptomycin resistance?
  4. What CPK level should prompt discontinuation?
  5. Why is high-dose daptomycin preferred for serious infections?

References


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