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.
ReviewSusceptibility relationship between vancomycin and daptomycin in Staphylococcus aureus: facts and assumptions
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
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Persistent methicillin-resistant Staphylococcus aureus bacteremia owing to placental abscess
2018, Journal of Infection and ChemotherapyIn vitro susceptibility of methicillin-resistant Staphylococcus aureus isolates from skin and soft tissue infections to vancomycin, daptomycin, linezolid and tedizolid
2017, Brazilian Journal of Infectious DiseasesCitation Excerpt :Besides, clinical outcomes with vancomycin depend of bacterial load at site of infection, and higher rates of nephrotoxicity are associated with high-dose therapy.38 Daptomycin is an alternative to vancomycin for patients with MRSA infections, but some authors have recommended to use high doses to minimize the emergence of elevated MIC values, which has been associated with an increase in the vancomycin MIC and the heteroresistant phenotype (hVISA).39,40 Interestingly, in this study the activity of tedizolid was maintained in strains isolated from patients with different characteristics including an age range between 15 and 89 years old, different comorbidities and previous antimicrobial use.
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