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Open Access

Peer-reviewed

Research Article

Comparative effectiveness of daptomycin versus vancomycin among patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections: A systematic literature review and meta-analysis

  • Yau Adamu,

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing

    Current address: Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA, United States of America

    Affiliation Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Bayero University, Kano, Nigeria

    ⨯
  • Mireia Puig-Asensio,

    Roles Conceptualization, Data curation, Investigation, Methodology, Resources, Software, Supervision, Validation, Visualization, Writing – review & editing

    Current address: Department of Infectious Diseases, Bellvitge University Hospital, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC; CB21/13/00009), Instituto de Salud Carlos III, Madrid, Spain

    Affiliation Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America

    ⨯
  • Bashir Dabo,

    Roles Data curation, Investigation, Methodology, Resources, Validation, Visualization, Writing – review & editing

    Affiliation College of Public Health, University of South Florida, Tampa, Florida, United States of America

    ⨯
  • Marin L. Schweizer

    Roles Conceptualization, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – review & editing

    marin.schweizer-looby@va.gov

    Affiliation Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States of America

    ⨯

Abstract

Background

In the treatment of methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSIs), vancomycin stands as the prevalent therapeutic agent. Daptomycin remains an alternative antibiotic to treat MRSA BSIs in cases where vancomycin proves ineffective. However, studies have conflicted on whether daptomycin is more effective than vancomycin among patients with MRSA BSI.

Objective

To compare the effectiveness of daptomycin and vancomycin for the prevention of mortality among adult patients with MRSA BSI.

Methods

Systematic searches of databases were performed, including Embase, PubMed, Web of Science, and Cochrane Library. The Newcastle Ottawa Scale (NOS) and Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) were used to assess the quality of individual observational and randomized control studies, respectively. Pooled odd ratios were calculated using random effects models.

Results

Twenty studies were included based on a priori set inclusion and exclusion criteria. Daptomycin treatment was associated with non-significant lower mortality odds, compared to vancomycin treatment (OR = 0.81; 95% CI, 0.62, 1.06). Sub-analyses based on the time patients were switched from another anti-MRSA treatment to daptomycin demonstrated that switching to daptomycin within 3 or 5 days was significantly associated with 55% and 45% decreased odds of all-cause mortality, respectively. However, switching to daptomycin any time after five days of treatment was not significantly associated with lower odds of mortality. Stratified analysis based on vancomycin minimum inhibitory concentration (MIC) revealed that daptomycin treatment among patients infected with MRSA strains with MIC≥1 mg/L was significantly associated with 40% lower odds of mortality compared to vancomycin treatment.

Conclusion

Compared with vancomycin, an early switch from vancomycin to daptomycin was significantly associated with lower odds of mortality. In contrast, switching to daptomycin at any time only showed a trend towards reduced mortality, with a non-significant association. Therefore, the efficacy of early daptomycin use over vancomycin against mortality among MRSA BSIs patients may add evidence to the existing literature in support of switching to daptomycin early over remaining on vancomycin. More randomized and prospective studies are needed to assess this association.

Citation: Adamu Y, Puig-Asensio M, Dabo B, Schweizer ML (2024) Comparative effectiveness of daptomycin versus vancomycin among patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections: A systematic literature review and meta-analysis. PLoS ONE 19(2): e0293423. https://doi.org/10.1371/journal.pone.0293423

Editor: Mohamed O. Ahmed, University of Tripoli, LIBYA

Received: May 8, 2023; Accepted: October 12, 2023; Published: February 21, 2024

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Methicillin-resistant Staphylococcus aureus (MRSA) infections continued to be a significant public health challenge in the United States, with reported mortality ranging from 20% to 30% [1, 2]. Vancomycin has been the first-line antibiotic for the treatment of MRSA infections, particularly bloodstream infections (BSIs) [3]. However, the available evidence demonstrates challenges regarding its safety profile as well as tissue penetration and slow killing time [4, 5]. Clinical failures in vancomycin treated MRSA patients have been associated with strains of MRSA that are less susceptible to vancomycin as measured by higher vancomycin minimum inhibitory concentrations (MICs) [6]. Alternative antibiotics to treat MRSA BSI are recommended when vancomycin MIC is greater than 2mg/L [6–8].

Daptomycin, a lipopeptide antibiotic, is one of the alternative antibiotics recommended for treatment of MRSA BSI with high vancomycin MIC and treatment failure [8]. However, the use of daptomycin as an alternate anti-MRSA antibiotic is limited by issues associated with cost and antibiotic stewardship [9–11]. The use of daptomycin to treat MRSA BSIs in situations of vancomycin treatment failure has been increasing [12]. Moreover, the recent approval of generic daptomycin by the Food and Drug Administration (FDA) may lower the cost of daptomycin, leading to increased frequency of daptomycin use [13]. The cost of daptomycin treatment may also be comparable to vancomycin considering that vancomycin therapy requires AUC and trough-based therapeutic drug monitoring [14, 15]. A survey conducted among infectious disease physicians showed that 71% of the participating physicians used daptomycin to treat at least one MRSA BSI patient each year [16].

Several studies have been published comparing the effects of daptomycin versus vancomycin on preventing all-cause mortality in MRSA BSI patients. The inconsistency of the available results does not provide clear guidance to physicians on when to use daptomycin and when to switch from vancomycin to daptomycin for optimal treatment of MRSA BSI. The objective of this study was to compare the effectiveness of daptomycin versus vancomycin for the prevention of mortality, clinical failure and persistent bacteremia among adult patients with MRSA BSIs.

Materials and methods

Protocol development

This meta-analysis was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines [17, 18]. In addition, the study’s research question was formulated following the Population, Intervention, Comparator, and Outcomes (PICO) model, where the population of interest were adult patients with MRSA BSI, the Intervention/Exposure was defined as daptomycin use either initially or switch from vancomycin, and the comparator was vancomycin [19, 20]. The primary outcome was all-cause mortality. Mortality was defined as all-cause mortality measured after MRSA infected patients were followed-up for differing lengths of time, including in-hospital, 14-days, 30-days, 42-days, or 60-days after at least 48 hours of vancomycin or daptomycin therapy. The secondary outcomes were clinical failure and persistent bacteremia. Clinical failure as defined by the included studies. These definitions included a composite of all-cause mortality, 7-day clinical or microbiologic failure, failure at end of treatment (EOT), MRSA BSI relapse, new or worsening signs and symptoms of infection while receiving MRSA therapy, failure to eradicate the organism from the bloodstream at the end of at least 7 days of primary therapy, and treatment switch due to poor evolution or death during treatment. Persistent bacteremia as defined by included studies and included persistent positive MRSA blood cultures ≥5 days after the start of drug of interest (vancomycin or daptomycin) or from index blood culture during therapy, positive MRSA blood cultures within 14 days before cessation of therapy, and positive MRSA blood cultures ≥7 days after diagnosis while receiving effective treatment for ≥ 5 days.

Search strategy

A systematic electronic literature search was conducted into the PubMed, EMBASE, Cochrane Library, and Web of Science databases from their inception up to the 7th of July 2023. The bibliographies of the included studies were examined to identify additional studies. A search strategy was conducted using the following terms without language restriction to find articles that were relevant to this study; ‘Vancomycin’ AND ’methicillin resistant Staphylococcus aureus’ AND ‘Daptomycin’. Study selection was conducted based on a priori inclusion and exclusion criteria. Authors were contacted to retrieve additional information not published in the original article. The inclusion criteria were Randomized Control Trials (RCTs), cohort, and case control studies reporting information on mortality comparing daptomycin versus vancomycin use in adult patients with MRSA BSI. The detailed exclusion criteria are listed in Fig 1. Briefly, excluded studies were case reports, case series, studies without sufficient information on the exposure of interest, comparator, or primary outcome among patients with MRSA BSI.

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Fig 1. A PRISMA diagram showing the study selection process.

https://doi.org/10.1371/journal.pone.0293423.g001

Study selection and data collection

The titles, abstracts and full-text articles were screened for inclusion. The abstracted data from selected articles included: 1) first author and year of publication; 2) study design and study duration; 3) population characteristics; 4) country in which the study was conducted; 5) exposure characteristics; 6) presence of MRSA-associated endocarditis; 7) end point of assessment including mortality, persistent bacteremia, and clinical failure; and 8) confounders adjusted for in the study (Fig 1). These data were collected independently by two authors (YA and BD) using data abstraction forms. The disagreements were resolved in meetings by consensus. When multiple studies described the same population, the study with the most details and the lowest risk of bias was included. Where one study reported different mortality rates based on follow-up duration (i.e., in-hospital vs 30-days vs 60-days), the shortest duration of follow-up was included [21].

Quality assessment

The quality of individual observational studies was assessed using the Newcastle Ottawa Scale (NOS) based on selection, comparability, outcomes in cohort studies, or exposure in case-control studies. Studies with quality scores of 6 or more were classified as moderate to high quality publications [22]. RCTs were assessed using the Revised Cochrane risk-of-bias tool for randomized trials [23].

Data analysis

The pooled odd ratios with corresponding 95% CIs were calculated using random effects models. To explore the source(s) of heterogeneity and robustness of the study findings, subgroup analyses were performed based on the study design, duration of follow-up, vancomycin MIC and switch time from vancomycin to daptomycin. Also, sub-group analyses were conducted based on patients with endocarditis, and patients treated with other additional anti-MRSA antibiotics. Statistical heterogeneity was measured using the I-square statistic test. Publication bias was investigated using R functions, “regtest” and “ranktest” to perform Egger’s regression test for funnel plot asymmetry using RStudio. The data presented were analyzed using Excel, RevMan software version 5.4.1 and Rstudio.

Results

Study characteristics

Twenty studies out of the 2,182 articles identified were included in the meta-analysis (Fig 1). Nine were matched retrospective cohort studies, six were unmatched retrospective cohort studies, one case-control study, one combined prospective and retrospective study designs, and one quasi-experimental study. The remaining two were RCTs. The characteristics of the studies included are summarized in Table 1.

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Table 1. Main characteristics of the included studies.

https://doi.org/10.1371/journal.pone.0293423.t001

Study population

Twenty studies reported the effectiveness of daptomycin compared with vancomycin in terms of mortality. Of the 9,523 adults with MRSA BSI, 1,527 (16.03%) and 7,996 (83.97%) were treated with daptomycin and vancomycin, respectively. The age range of the patients was 21 to 91 years. The majority of studies included MRSA strains with vancomycin MIC >1 mg/L, four studies enrolled only patients infected with MRSA BSI strains with vancomycin MIC between 1 and 2 mg/L [24–27]. However, 50% to 94% of strains in three studies had vancomycin MIC above 2 mg/L and 16% to 20% of strains from two studies had vancomycin MIC ≥2 mg/L [27–31]. Among the sixteen studies with available data, the percentage of endocarditis patients from individual studies ranged from 2.9% to 100% (Table 1). One study excluded all patients with endocarditis [24], while another study exclusively recruited endocarditis patients [32].

Exposure and outcome assessment

Receipt of daptomycin was defined as either the initial receipt of daptomycin treatment or switching from another anti-MRSA treatment to daptomycin and continued daptomycin for at least 72 hours. Four studies evaluated the initial receipt of daptomycin without switching [24, 25, 33, 34]. The remaining observational studies evaluated patients who were switched to daptomycin within 3 days, within 5 days, or within 10 days [26–30, 35–38]. Some studies mentioned switching to daptomycin at any time or after five days [27, 28, 36–38]. One study had no statement about initial use or switching time [39]. Reasons for switching to daptomycin are reported in Table 1. Most studies administered the recommended daptomycin dose of 6 mg/kg/day and increased it to 8–10 mg/kg/day based on clinical prognosis [24, 26, 30, 33, 35]. About 80% of the included studies with available information on daptomycin dose started with a dose of 6 mg/kg/day, and only three studies used higher doses of 8–10 mg/kg/day, 9.2 mg/kg/day, or 10 mg/kg/day [5, 32, 35]. The exposure to the comparator vancomycin was based on receiving vancomycin for at least 48 hours after MRSA blood culture and remaining on vancomycin for at least 72 hours. Ten studies reported mean vancomycin trough levels within 12–20 mg/L (Table 1). However, Usery et al. reported vancomycin trough levels below the recommended value of 15 mg/L in 35% of the vancomycin arm [31]. Nine studies included patients who received additional anti-MRSA agents other than vancomycin. This ranged from 4.5% to 91% of patients in the vancomycin arm and 1.2% to 37% of patients in the daptomycin arm [26–28, 30, 32, 33, 36–38]. The proportion of patients with other added anti-MRSA antibiotics were comparable between vancomycin and daptomycin arms, except for the Fowler et al. study where 91% of the vancomycin-treated patients had combination therapy, whereas none of the daptomycin patients received combination therapy [33]. A similar study was excluded because it was from the same population [40].

The primary outcome, all-cause mortality, was measured after patients were followed-up for differing lengths of time. Thirteen studies reported 30-day mortality, four reported 60-day mortality, eight reported in-hospital mortality, two reported 14-day mortality, and one reported 42-day mortality. Other reported outcomes included clinical failure and persistent bacteremia/microbiological failure as defined by the authors (Table 1).

Quality assessment

Thirteen out of 18 observational studies were of moderate to high quality based on the NOS quality scale, with scores of 6 to 8 points [25–31, 36–39, 41, 42]. The remaining observational studies scored less than 6 points on NOS scale (S1 Table in S2 File) [5, 32, 34, 35, 43, 44]. One of the two RCTs had a high risk-of-bias in the overall bias assessment (S1 Table in S2 File) because it was terminated before the intended study period due to low enrollment [24]. The other RCT (Randomized Control Trials) was of low risk of bias for most domains and high-risk-of-bias in the overall assessment because it had a high-risk-of-bias in the domain called intended intervention [33].

Quantitative synthesis

Pooled all-cause mortality.

The analysis of 20 included studies demonstrated that the overall pooled odds of all-cause mortality were 19% lower among those who received daptomycin compared to those who received vancomycin, although this difference was not statistically significant (OR = 0.81; 95% CI: 0.62, 1.06) Fig 2 and Table 2). The I2 value from pooling all studies was 21% (p = 0.12), suggesting low heterogeneity [45–47] (Table 2). Removing very small studies (i.e., involving less than 10 patients per arm) from the meta-analysis did not change the pooled odds of all-cause mortality (OR = 0.86; 95% CI, 0.70, 1.08) (S2 Table in S2 File). Sub-analyses were conducted based on variables that are relevant to clinical practice, including vancomycin MICs, switching time from one anti-MRSA antibiotic to another, follow-up duration before death, endocarditis, and using additional antibiotics [16, 21].

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Fig 2. Forest plots of all included studies comparing the effects of daptomycin versus vancomycin on prevention of any reported all-cause mortality primary outcome.

https://doi.org/10.1371/journal.pone.0293423.g002

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Table 2. Subgroup analysis and heterogeneity results for mortality.

Summarized results of subgroup analysis of all-cause Mortality based daptomycin switch time, endocarditis, use of additional anti-MRSA agent, and vancomycin MIC.

https://doi.org/10.1371/journal.pone.0293423.t002

Sub-analysis of 9 studies that either used daptomycin as a first-line agent or switched to daptomycin within 3 days after positive blood culture demonstrated statistically significant 53% lower odds of mortality among the daptomycin group compared to the vancomycin group (I2 = 0%). Similarly, switching to daptomycin within 5 days was associated with significantly decreased mortality (Table 2 and S1 Fig 1S in S1 File). However, switching any time during treatment was not statistically significantly associated with decreased all-cause mortality (OR = 0.87; 95% CI, 0.70, 1.08) (Table 2 and S1 Fig 1S in S1 File). The stratified analysis of mortality based on the duration of follow-up did not change the results (Table 2 and S1 Fig 2S in S1 File).

Further subgroup analysis was performed based on vancomycin MIC levels of the infecting MRSA strains. Pooling studies that restricted enrollment to only patients with MRSA strains with vancomycin MIC ≥1 showed a significant 40% lower odds of mortality among daptomycin users compared to vancomycin users (OR = 0.60; 95% CI: 0.36, 0.99). Similarly, pooling studies that restricted enrollment to patients with MRSA strains with vancomycin MIC of 1 to 2 mg/L was associated with 71% lower odds of mortality among daptomycin users compared to vancomycin users (OR 0.29; 95% CI: 0.17, 0.50). Next, a sub-analysis of studies that excluded patients with MRSA strains with vancomycin MICs >2 resulted in significant 30% lower odds of mortality in daptomycin treated patients compared to non-daptomycin treatment (OR = 0.70; 95% CI: 0.51, 0.97) (Table 2). However, the lower odds of mortality associated with the daptomycin group disappeared among studies that included patients with any VAN MIC (Table 2 and S1 Fig 3S in S1 File).

A sub-analysis of the 9 studies that used additional anti-MRSA antibiotics together with vancomycin or daptomycin revealed lower odds of mortality among the daptomycin treated patients compared to vancomycin (OR = 0.65; 95% CI, 0.43, 0.96), with I2 = 43% (Table 2 and S1 Fig 4S in S1 File). The remaining sub-analyses yielded non-significant results (S1 Figs 5S and 6S in S1 File).

Clinical failure.

When pooling the 14 studies that evaluated clinical failure, daptomycin use was significantly associated with 38% lower odds of clinical failure (OR = 0.62; 95% CI, 0.41, 0.94) (Fig 3A). The I2 value was 82% (p <0.01), suggesting high heterogeneity. Stratified analysis based on switch time indicated significant associations. Switching to daptomycin within 3 days and switching within 5 days were significantly linked with 64% and 61% decreased odds of clinical failure, compared to staying on vancomycin (Table 3). However, switching treatment to daptomycin at any time after 5 days of treatment did not yield a significant reduction in clinical failure compared to staying on vancomycin (OR = 1.03; 95% CI, 0.66, 1.61). In contrast, the subgroup analysis based on the switch time failed to explain the heterogeneity observed (Table 3 and S2 Fig 1S in S1 File). In the sub-analysis of studies evaluating patients infected with MRSA strains exhibiting an MIC of ≥1 mg/L, daptomycin-treated patients had significantly reduced odds of clinical failure in comparison to those who received non-daptomycin treatments, akin to the observed effect on mortality rates.

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Fig 3.

Forest plots of all included studies comparing the effects of daptomycin versus vancomycin on prevention of clinical failure (A) and persistent bacteremia (B) secondary outcomes.

https://doi.org/10.1371/journal.pone.0293423.g003

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Table 3. Pooled results of stratified subgroup analysis for secondary outcomes: Clinical failure and persistent bacteremia.

Summarized results of subgroup analysis of Clinical Failure and Persistent Bacteremia outcomes based on daptomycin switch time, endocarditis, use of additional anti-MRSA agent, and vancomycin MIC.

https://doi.org/10.1371/journal.pone.0293423.t003

Further sub-analysis of the 3 studies that enrolled patients with vancomycin MIC 1 to 2 mg/L found a significant association between daptomycin use and lower odds of clinical failure compared to vancomycin (OR = 0.35; 95% CI, 0.18, 0.68). In contrast, sub-analysis among studies the enrolled patients with any MIC resulted in a non-significant association between daptomycin use and clinical failure in MRSA BSI patients (OR = 0.77; 95% CI, 0.48, 1.23). However, the association became significant after removing all studies with MRSA strains that had vancomycin MIC ≥ 2 (Table 3 and S2 Fig 2S in S1 File). The remaining sub-analyses results are available in S2 Figs 3S and 4S in S1 File).

Persistent bacteremia.

Pooling the 16 studies with information on persistent bacteremia showed that daptomycin use was significantly associated with 32% lower odds of persistent bacteremia compared to vancomycin use among MRSA BSI patients (OR = 0.68; 95% CI, 0.52, 0.88) with lower heterogeneity between the studies (I2 = 25%, p = 0.17) (Fig 3B). Similarly, findings from stratified analyses based on switch time demonstrated that switching to daptomycin within 3 or 5 days after initial blood culture or using daptomycin as the initial choice were significantly associated with lower odds of persistent bacteremia compared to remaining on vancomycin (Table 3 and S3 Fig 1S in S1 File). Switching to daptomycin any time after 5 days was not statistically associated with lower odds of persistent bacteremia (OR = 0.83; 95% CI, 0.53, 1.30, I2 = 2%) (Table 3). Similar findings were observed in the sub-analyses based on vancomycin MIC and the use of additional anti-MRSA agents as shown in Table 3 and S3 Fig 2S in S1 File. The remaining sub-analyses are available in the S3 Figs 3S–6S in S1 File.

Sensitivity analyses.

A sensitivity analysis by the leave-one-out approach did not change the results of the overall pooled odds of all-cause mortality among MRSA BSI patients, except for removing the Arshad et al., study where the protective effect of daptomycin over vancomycin became statistically significant (OR = 0.78; 95% CI, 0.62, 0.99, I2 = 9%) (S2 Table in S2 File) [39]. This was similar for the clinical failure and persistent bacteremia outcome (S2 Table in S2 File).

Publication bias.

There was no evidence of publication bias for the outcome mortality using Egger’s regression test (p = 0.970) and Rank correlation tests (p = 0.631). Similarly, the Egger’s and Rank correlation tests for publication bias were not statistically significant for clinical failure (p = 0.640 and p = 0.667) and persistent bacteremia (p = 0.546 and p = 0.205).

Discussion

This meta-analysis compared the effectiveness of daptomycin versus vancomycin in preventing poor outcomes among patients with MRSA BSIs. MRSA BSIs remain difficult to treat and are associated with high mortality. The existing treatment options for MRSA BSI require more investigation to balance the therapeutic effectiveness with potential toxicities. Switching to daptomycin within the first 5 days of antibiotic therapy was associated with a significant reduction in the odds of mortality compared to remaining on vancomycin. Further, earlier switching may be better: switching within three days conferred lower odds of mortality than switching within five days. Yet, a late switch to daptomycin after five days or any time during treatment was not associated with reduced mortality. Comparable results were observed between early daptomycin switching time and reduced clinical failure and persistent bacteremia.

It was somewhat surprising that daptomycin use was not significantly associated with mortality among initial users compared to starting on vancomycin. However, there was a trend in which most included studies favored daptomycin versus vancomycin for the prevention of mortality. Indeed, the overall pooled results from this study closely aligned with a recently published meta-analysis by Maraolo et al. demonstrating comparable efficacy between daptomycin and vancomycin in preventing mortality associated with MRSA bloodstream infections [48]. This meta-analysis is unique in that it is the first to include the concept of switching time. The study results indicate that patients may benefit upon switching from vancomycin to daptomycin, regardless of the vancomycin MIC levels. The current IDSA (Infectious Disease Society of America) guidelines recommend switching from vancomycin to daptomycin when there is vancomycin treatment failure, especially if the vancomycin MIC is > 2 mg/L [8]. However, findings from this study suggest this switch should occur early during infection (i.e., within 3 to 5 days), which may be around the time the laboratory confirms the isolation of MRSA but potentially before vancomycin MIC is known. Further, daptomycin use was significantly associated with reduced odds of mortality, clinical failure, and persistent bacteremia for studies that included patients infected with MRSA strains with a vancomycin MIC ranging from 1 to 2 mg/L, which is considered susceptible. Therefore, physicians should prioritize switching to daptomycin within 3–5 days of treatment while still factoring in the vancomycin MIC in making the decision to switch. These results fully agree with a prior meta-analysis by Samura et al that focused exclusively on seven studies that included bacteremia patients with MRSA vancomycin MIC > 1 mg/L [49]. In all, this meta-analysis supports other research that found that clinical decisions to switch patients to daptomycin should not solely rely on the vancomycin MIC because other factors may play a role on patient outcomes [50–52].

Persistence of bacteremia and clinical failure are direct outcomes associated with antibiotic treatment and are on the causal pathway between antibiotic treatment and mortality. Persistent bacteremia is an important outcome to assess when comparing antibiotic effectiveness because it is associated with increased risk of metastatic spread of the infection and mortality. The IDSA recommends reevaluating treatment after persistent bacteremia for 7 days [8]. Clinical failure definitions include persistence, but also encompass lack of response to the antibiotic as measured by new or worsening signs and symptoms of infection. The goals of antibiotic treatment are to prevent persistent infection, clinical failure, and mortality. However, the significant findings of improved efficacy against clinical failure in the daptomycin-treated group were relatively counterbalanced by higher rates heterogeneity.

Use of daptomycin may overcome the limitations of vancomycin. These limitations include difficulty in dosing vancomycin, nephrotoxicity, and the prevalence of strains of MRSA that have reduced susceptibility to vancomycin (e.g., high vancomycin MIC) [7, 16, 53].

The beneficial effect of combination antibiotic therapy with daptomycin in this study supports previous studies that found that adding other anti-MRSA antibiotics to daptomycin results in clearance of persistent MRSA BSIs and no clinical benefits if the decision to include additional agent occurs late in the treatment course [54, 55]. This advantage could be associated with the synergistic effects of daptomycin with other antibiotics such as ceftaroline [41, 44, 56]. However, the roles of combination therapy from this study remain unclear and warrants further study.

This meta-analysis has limitations. First, the study’s findings may be influenced by the inability to obtain the detailed reasons behind switching from vancomycin to daptomycin. Only six studies reported switching because of vancomycin MIC values or treatment failure [27, 29, 30, 32, 38, 42]. Second, the majority of the selected studies included patients with MRSA strains with vancomycin MICs ≥1 mg /L. Thus, the external validity of this meta-analysis may be limited, because findings from this study may not be generalizable to populations with vancomycin MIC < 1. Also, the results may not be generalizable to patients with complex infections. Fewer than 30% of the patients included in this meta-analysis had endocarditis. Also, comprehensive data on treatment outcomes for individual patients with endocarditis could not be acquired from all patients in all included studies. Third, most included studies recommended daptomycin at an initial dose of 6 mg/kg/day and thus this meta-analysis cannot assess the impact of high doses of daptomycin (i.e., 8–10 mg/kg IV once daily). Lastly, the link between switching from vancomycin to daptomycin and mortality may be confounded by immortal treatment bias because patients who die early do not switch antibiotics. However, this would impact both early and later switching, yet the beneficial effect was seen solely among those who switched to daptomycin early during treatment.

In conclusion, this study’s findings show that an early switch from vancomycin to daptomycin within the first 5 days of treatment initiation was associated with lower odds of mortality, persistent bacteremia, and clinical failure. This clinical benefit was not seen when the switch occurred later. These results, coupled with adverse events associated with vancomycin use, such as nephrotoxicity, may further support early daptomycin switch over remaining on vancomycin for MRSA BSI; even for susceptible vancomycin strains (MIC range 1–2 mg/L). However, more RCTs and prospective studies are needed to investigate the causal association between switching to daptomycin and improved outcomes among MRSA BSIs patients.

Supporting information

S1 File. Supporting figures.

https://doi.org/10.1371/journal.pone.0293423.s001

(DOCX)

S2 File. Supporting tables.

https://doi.org/10.1371/journal.pone.0293423.s002

(DOCX)

S3 File. Search terms.

https://doi.org/10.1371/journal.pone.0293423.s003

(DOCX)

S4 File. Meta-analysis of observational studies in epidemiology checklist.

https://doi.org/10.1371/journal.pone.0293423.s004

(DOC)

Acknowledgments

The authors would like to acknowledge contributions made by Riley J Samuelson, an Education and Outreach Librarian, Hardin Library, University of Iowa, who helped us with the literature search strategy. Authors also thank the class members of the EPID:5214: Spr21 Meta-Analysis of Epidemiologic Studies for their in-class feedback.

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