Review
Susceptibility relationship between vancomycin and daptomycin in Staphylococcus aureus: facts and assumptions

https://doi.org/10.1016/S1473-3099(09)70200-2Get rights and content

Summary

The decrease in vancomycin treatment efficacy that is accompanying increases in vancomycin minimum inhibitory concentration (MIC) within the susceptible range (so-called MIC creep) has led to the suggestion that vancomycin is losing its potency in treating serious Staphylococcus aureus infections. Understanding the clinical importance of the microbiological effects of glycopeptides on bacterial lipopeptides and lipoglycopeptides will be crucial in treating serious meticillin-resistant S aureus infections. We review the observed effects of reduced glycopeptide susceptibility on the activities of daptomycin in S aureus in vitro and in vivo. Factors associated with loss of susceptibility and ways to reduce the risk of resistance to daptomycin are reviewed, including the importance of prompt mechanical reduction of bacterial inoculum through surgery or through potent or combination antibiotic therapy, as well as optimisation of daptomycin pharmacodynamic exposure.

Introduction

Although parenteral vancomycin has been approved for use since 1958, its use did not increase worldwide until the mid-1980s,1 largely as a result of empirical and directed therapy against meticillin-resistant Staphylococcus aureus (MRSA) infections.2, 3 Because of limited choices, clinicians have relied on vancomycin alone for many years in the management of serious MRSA infections and have enjoyed a substantial period without vancomycin resistance appearing in S aureus.4, 5 Vancomycin resistance among S aureus, as it is at present defined microbiologically, remains rare. In fact, despite millions of S aureus isolates being testing throughout the world since vancomycin was approved, only nine cases of vancomycin-resistant S aureus (VRSA; defined by a vancomycin minimum inhibitory concentration [MIC] of 16 mg/L or greater) have been identified to date (M J Rybak, Wayne State University, Detroit, MI, USA, personal communication).6 Vancomycin-intermediate S aureus (VISA; defined by a vancomycin MIC of 4–8 mg/L) isolates were present in only two of over 5300 clinical S aureus isolates assessed in a recently published surveillance programme of antimicrobial resistance.7 As of 2007, about 100 cases of VISA isolates have been reported worldwide.8 However, increasing data suggest that vancomycin is losing its clinical and microbiological potency against S aureus, as shown by increases in vancomycin MIC to within the susceptible range. Reduced vancomycin treatment efficacy of MRSA bacteraemia and pneumonia has been shown in several studies by MICs at the upper limit of susceptibility.9, 10, 11, 12, 13, 14, 15 Accumulating data suggest that the definition of vancomycin susceptibility needs further evaluation in serious MRSA infections such as pneumonia and bacteraemia.

Although not supported by data, reduced vancomycin efficacy in bacteraemia and pneumonia, as indicated by vancomycin MICs at the upper limit of susceptibility, might indirectly imply that clinicians should consider early alternative therapy if these organisms are identified, or patients should be treated empirically if they have a high likelihood of harbouring such organisms on the basis of comorbidities, local susceptibility profiles, or recent glycopeptide exposure.16 However, no data have shown that alternative antibiotics would result in better outcomes. For example, no head-to-head comparisons exist for vancomycin against either linezolid for pneumonia or daptomycin for bacteraemia in cases in which MRSA has a vancomycin MIC of 2 mg/L. In a recent study of daptomycin versus comparator drug for MRSA bacteraemia,17 only 16% of the MRSA had vancomycin MICs of at least 1 mg/L. In this prospective trial, the vancomycin treatment success rate was 14% (one of seven) for the seven cases of S aureus bacteraemia with vancomycin MICs of 2 mg/L (two by central laboratory testing and five additional by local laboratory testing).17 Furthermore, increased costs and the microbiological effects seen in vitro with the activity of daptomycin and other lipopeptides against S aureus with increased vancomycin MICs might leave many clinicians perplexed as to how best to manage serious infections by MRSA if the vancomycin MIC is 2 mg/L.

Understanding the clinical importance of the microbiological effects of glycopeptides on bacterial lipopeptides and lipoglycopeptides will be crucial to maximise their benefit for patients with serious MRSA infections in an era with reduced development of new antimicrobials. The goal of this Review is to directly address the effect of reduced glycopeptide susceptibility on the activity of daptomycin, in the context of published data in vitro and in vivo. Specifically, we address the activity of daptomycin against S aureus with reduced glycopeptide susceptibility, ranging from susceptible strains with vancomycin MICs of 2 mg/L to VISA and VRSA.

Section snippets

Daptomycin mechanisms of action and resistance

Daptomycin, a cyclic lipopeptide derived from the fermentation product of Streptomyces roseosporus, is active against a wide spectrum of clinically relevant Gram-positive pathogens, including MRSA.18 It has proven clinical effectiveness in the treatment of complicated skin and skin structure infections and S aureus bacteraemia, including right-sided infective endocarditis.17, 19 Daptomycin retains its in-vitro potency against antibiotic-resistant Gram-positive bacteria such as S aureus,

Daptomycin activity against S aureus

Surveillance studies in the USA, Canada, and Europe have shown that the incidence of daptomycin non-susceptible S aureus is uncommon. A recent broth microdilution survey of the activity of daptomycin against 6710 consecutively collected Gram-positive organisms in US and Canadian hospitals showed a 99·9% susceptibility in S aureus (MIC 1·0 mg/L or less).30 Castanheira and colleagues30 did not notice the so-called MIC creep to daptomycin. Likewise, a Canadian National Intensive Care Unit study31

Common links in loss of daptomycin susceptibility

Given the importance of preserving our antimicrobial repertoire in an era when efforts towards the development of new antimicrobials is shrinking, it is important to examine the clinical features associated with loss of daptomycin susceptibility. Most of these patients had deep-seated infections associated with a high burden of infecting organisms, commonly with the presence of a biomedical device or dead tissue with poor blood perfusion. Rather than proceeding rapidly to reduce the bacterial

Suboptimum pharmacodynamics and the mutant selection window hypothesis

Dong and colleagues51 and Zhao and Drlica52 have established the concept of the mutant selection window (MSW), an antimicrobial concentration range above the MIC and the mutation prevention concentration (MPC), within which bacterial populations are enriched with more resistant forms. Pharmacodynamic modelling experiments in vitro have confirmed this property for fluoroquinolones, glycopeptides, and daptomycin, providing a foundation on which the loss of susceptibility to these antimicrobials

Vancomycin susceptibility and its effects on daptomycin activity

Increased vancomycin treatment failures have been reported in several studies with vancomycin-susceptible MRSA with MICs of 2 mg/L compared with 1 mg/L or less.9, 10, 11, 12, 13, 14 These increases in treatment failure might be the result of higher frequencies of heteroresistance to vancomycin (hVISA) among isolates with vancomycin MICs of 2 mg/L.58 A recent investigation of daptomycin activity against vancomycin-susceptible MRSA from bloodstream isolates found daptomycin susceptibility to be

Effects of vancomycin exposure on daptomycin activity and efficacy

The well-documented relation between vancomycin and daptomycin susceptibilities in vitro has raised the question of whether prior vancomycin exposure would attenuate daptomycin activity.26, 27, 65, 67, 69 After all, in the real world, many patients would be given daptomycin for S aureus infection after an empirical or unsuccessful trial of vancomycin. We have previously studied the in-vitro activities of daptomycin and vancomycin on initial MRSA bloodstream isolates, stratified by whether the

Minimising the risk of daptomycin susceptibility loss

Studies in vitro suggest that the selection of daptomycin non-susceptible mutants might be avoided or limited (figure 2). Optimising bacterial exposure to daptomycin at the site of infection might allow maximum killing and prevent the emergence of drug-resistant mutants. A rabbit mixed infection model of aortic valve endocarditis due to MRSA with daptomycin-susceptible (MIC 0·5 mg/L) and non-susceptible MRSA (MIC 2·0 mg/L) found that a higher dose of daptomycin might be more effective against

Conclusions

We have discussed the concepts of daptomycin heteroresistance in S aureus that serve as the foundation for mutation selection, particularly if bacteria are present in large densities. We have highlighted the in-vitro, animal, and clinical data that provide our understanding of the relation between the activities of daptomycin and vancomycin. Although these antibiotics have distinct mechanisms of action, the potency of their activities against S aureus is clearly linked in VISA isolates.

Search strategy and selection criteria

Data for this Review were identified through a Medline search, references from relevant articles, and through searches of the extensive files of the authors. Search terms were “daptomycin resistance”, “daptomycin resistant”, “vancomycin resistance”, “vancomycin resistant”, “daptomycin vancomycin”, “glycopeptide resistance”, “glycopeptide resistant”, and “aureus”. Only English language papers were reviewed and no date limits were used.

References (76)

  • PC Appelbaum

    Microbiology of antibiotic resistance in Staphylococcus aureus

    Clin Infect Dis

    (2007)
  • PA Moise et al.

    Vancomycin in vitro bactericidal activity and its relationship to efficacy in clearance of methicillin-resistant Staphylococcus aureus bacteremia

    Antimicrob Agents Chemother

    (2007)
  • G Sakoulas et al.

    Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia

    J Clin Microbiol

    (2004)
  • PA Moise-Broder et al.

    Accessory gene regulator group II polymorphism in methicillin-resistant Staphylococcus aureus is predictive of failure of vancomycin therapy

    Clin Infect Dis

    (2004)
  • LK Hidayat et al.

    High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity

    Arch Intern Med

    (2006)
  • A Soriano et al.

    Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia

    Clin Infect Dis

    (2008)
  • TP Lodise et al.

    Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin

    Antimicrob Agents Chemother

    (2008)
  • PA Moise et al.

    Microbiological effects of prior vancomycin use in patients with methicillin-resistant Staphylococcus aureus bacteraemia

    J Antimicrob Chemother

    (2008)
  • VG Fowler et al.

    Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus

    N Engl J Med

    (2006)
  • JN Steenbergen et al.

    Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections

    J Antimicrob Chemother

    (2005)
  • RD Arbeit et al.

    The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections

    Clin Infect Dis

    (2004)
  • CF Carpenter et al.

    Daptomycin: another novel agent for treating infections due to drug-resistant Gram-positive pathogens

    Clin Infect Dis

    (2004)
  • I Jenkins

    Linezolid- and vancomycin-resistant Enterococcus faecium endocarditis: successful treatment with tigecycline and daptomycin

    J Hosp Med

    (2007)
  • JH Lakey et al.

    Fluorescence indicates a calcium-dependent interaction between the lipopeptide antibiotic LY146032 and phospholipid membranes

    Biochemistry

    (1988)
  • JA Silverman et al.

    Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus

    Antimicrob Agents Chemother

    (2003)
  • JA Silverman et al.

    Resistance studies with daptomycin

    Antimicrob Agents Chemother

    (2001)
  • L Friedman et al.

    Genetic changes that correlate with reduced susceptibility to daptomycin in Staphylococcus aureus

    Antimicrob Agents Chemother

    (2006)
  • MM Mwangi et al.

    Tracking the in vivo evolution of multidrug resistance in Staphylococcus aureus by whole-genome sequencing

    Proc Natl Acad Sci USA

    (2007)
  • SK Pillai et al.

    Daptomycin nonsusceptibility in Staphylococcus aureus with reduced vancomycin susceptibility is independent of alterations in MprF

    Antimicrob Agents Chemother

    (2007)
  • K Julian et al.

    Characterization of a daptomycin-nonsusceptible vancomycin-intermediate Staphylococcus aureus strain in a patient with endocarditis

    Antimicrob Agents Chemother

    (2007)
  • T Jones et al.

    Failures in clinical treatment of Staphylococcus aureus infection with daptomycin are associated with alterations in surface charge, membrane phospholipid asymmetry, and drug binding

    Antimicrob Agents Chemother

    (2008)
  • GG Zhanel et al.

    Antimicrobial-resistant pathogens in intensive care units in Canada: results of the Canadian National Intensive Care Unit (CAN-ICU) Study, 2005–2006

    Antimicrob Agents Chemother

    (2008)
  • MK Hayden et al.

    Development of daptomycin resistance in vivo in methicillin-resistant Staphylococcus aureus

    J Clin Microbiol

    (2005)
  • D Hirschwerk et al.

    Diminished susceptibility to daptomycin accompanied by clinical failure in a patient with methicillin-resistant Staphylococcus aureus bacteremia

    Infect Control Hosp Epidemiol

    (2006)
  • A Mangili et al.

    Daptomycin-resistant, methicillin-resistant Staphylococcus aureus bacteremia

    Clin Infect Dis

    (2005)
  • FM Marty et al.

    Emergence of a clinical daptomycin-resistant Staphylococcus aureus isolate during treatment of methicillin-resistant Staphylococcus aureus bacteremia and osteomyelitis

    J Clin Microbiol

    (2006)
  • DJ Skiest

    Treatment failure resulting from resistance of Staphylococcus aureus to daptomycin

    J Clin Microbiol

    (2006)
  • HR Vikram et al.

    Clinical progression of methicillin-resistant Staphylococcus aureus vertebral osteomyelitis associated with reduced susceptibility to daptomycin

    J Clin Microbiol

    (2005)
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