Impact of Empirical-Therapy Selection on Outcomes of Intravenous Drug Users with Infective Endocarditis Caused by Methicillin-Susceptible Staphylococcus aureus

Albany College of Pharmacy, Albany, NY 12208-3492, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 11/2007; 51(10):3731-3. DOI: 10.1128/AAC.00101-07
Source: PubMed


This study compares beta-lactam and vancomycin among intravenous drug users with infective endocarditis caused by methicillin-susceptible Staphylococcus aureus. Patients who received vancomycin had higher infection-related mortality, even if they were switched to beta-lactam once culture results became available; this relationship persisted after logistic regression analysis controlling for clinical characteristics.

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    • "[16], [17], [18], [19], [20], [21] These combinations have been explored because, clinically, the use of an antistaphylococcal penicillin is desirable in the setting where beta lactams have activity. [22], [23] There are also reports showing an inverse relationship between vancomycin and beta lactam susceptibility, indicating that the use of beta lactam combinations may be particularly useful against organisms with reduced susceptibility to vancomycin, such as hVISA. [24], [25], [26] The objective of this investigation was to evaluate the potential for synergy between vancomycin and nafcillin against hVISA by time kill analysis and further evaluate the combination with an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model utilizing realistic drug concentrations and pharmacokinetics. "
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    ABSTRACT: Continued pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus including heterogeneously vancomycin-intermediate S. aureus (hVISA). Infections with hVISA are associated with poor patient outcomes, thus incentivizing novel treatments. Evidence suggests that vancomycin and anti-staphylococcal penicillin susceptibility are inversely related which indicates that the use of this combination may be particularly useful against methicillin-resistant S. aureus with reduced susceptibility to vancomycin, such as hVISA. The aim of this study was to evaluate the potential for synergy between vancomycin and nafcillin against hVISA. Twenty-five hVISA strains were evaluated for vancomycin and nafcillin minimum inhibitory concentration (MIC) by broth microdilution in duplicate. Potential for synergy was assessed by time-kill at 1/2x MIC in triplicate. Five strains were chosen, representing the range nafcillin MIC's available in the cohort -4, 16, 64, 128, and 256 µg/mL, and were run in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model in duplicate over 72 hours to evaluate the potential of the combination with simulated human pharmacokinetics. In addition, 4 fully glycopeptide susceptible strains of S. aureus including 2 methicillin-susceptible (MSSA) and 2 methicillin-resistant (MRSA) were run in the PK/PD model for comparison. In the time-kill, 92% of strains (23 of 25) displayed synergy with the combination of vancomycin and nafcillin. In the PK/PD model, all five strains of hVISA showed an improvement in overall activity (P≤0.004) and organism burden at 72 hours (P≤0.001) with the combination compared to either drug alone. The combination was also successful against both MRSA and MSSA in overall activity (P≤0.009) and organism burden at 72 hours (P≤0.016), though the magnitude of the effect was diminished against MSSA. The combination of vancomycin and nafcillin significantly improved antibacterial activity against hVISA, MRSA, and MSSA compared to either drug alone.
    PLoS ONE 07/2012; 7(7):e42103. DOI:10.1371/journal.pone.0042103 · 3.23 Impact Factor
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    • "The recent clinical practice guidelines by the Infectious Disease Society of America for the treatment of MRSA stated that vancomycin "is clearly inferior to beta-lactams for MSSA bacteremia and infective endocarditis" and cited five studies to support this statement [25]. Two of the cited studies assessed the use of vancomycin among intravenous drug users with endocarditis [26,27]. The three other cited studies compared outcomes among patients with S. aureus bacteremia who received vancomycin and those who received nafcillin or cefazolin [7-9]. "
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    ABSTRACT: The high prevalence of methicillin-resistant S. aureus (MRSA) has led clinicians to select antibiotics that have coverage against MRSA, usually vancomycin, for empiric therapy for suspected staphylococcal infections. Clinicians often continue vancomycin started empirically even when methicillin-susceptible S. aureus (MSSA) strains are identified by culture. However, vancomycin has been associated with poor outcomes such as nephrotoxicity, persistent bacteremia and treatment failure. The objective of this study was to compare the effectiveness of vancomycin versus the beta-lactam antibiotics nafcillin and cefazolin among patients with MSSA bacteremia. The outcome of interest for this study was 30-day in-hospital mortality. This retrospective cohort study included all adult in-patients admitted to a tertiary-care facility between January 1, 2003 and June 30, 2007 who had a positive blood culture for MSSA and received nafcillin, cefazolin or vancomycin. Cox proportional hazard models were used to assess independent mortality hazards comparing nafcillin or cefazolin versus vancomycin. Similar methods were used to estimate the survival benefits of switching from vancomycin to nafcillin or cefazolin versus leaving patients on vancomycin. Each model included statistical adjustment using propensity scores which contained variables associated with an increased propensity to receive vancomycin. 267 patients were included; 14% (38/267) received nafcillin or cefazolin, 51% (135/267) received both vancomycin and either nafcillin or cefazolin, and 35% (94/267) received vancomycin. Thirty (11%) died within 30 days. Those receiving nafcillin or cefazolin had 79% lower mortality hazards compared with those who received vancomycin alone (adjusted hazard ratio (HR): 0.21; 95% confidence interval (CI): 0.09, 0.47). Among the 122 patients who initially received vancomycin empirically, those who were switched to nafcillin or cefazolin (66/122) had 69% lower mortality hazards (adjusted HR: 0.31; 95% CI: 0.10, 0.95) compared to those who remained on vancomycin. Receipt of nafcillin or cefazolin was protective against mortality compared to vancomycin even when therapy was altered after culture results identified MSSA. Convenience of vancomycin dosing may not outweigh the potential benefits of nafcillin or cefazolin in the treatment of MSSA bacteremia.
    BMC Infectious Diseases 10/2011; 11(1):279. DOI:10.1186/1471-2334-11-279 · 2.61 Impact Factor
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    • "In one study, vancomycin was an independent factor associated with failure of treatment in MSSA bacteraemia [8]. Use of empirical vancomycin for MSSA endocarditis in IVDUs has been associated with higher mortality in comparison with those treated with ␤-lactams [9]. In addition, during recent years vancomycin minimum inhibitory concentration (MIC) creep both for MSSA and MRSA strains has been progressing, and almost 80% of both strains now have a vancomycin MIC of 1 ␮g/mL [10]. "
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    ABSTRACT: Gram-positive bacteria account for >80% of all cases of endocarditis. Currently, staphylococci are the leading cause of endocarditis worldwide. Daptomycin is the drug of choice for empirical antibiotic therapy of staphylococcal endocarditis due to its optimal activity both against meticillin-susceptible Staphylococcus aureus and meticillin-resistant S. aureus (MRSA) strains. Daptomycin has not been proven to be superior to vancomycin in the treatment of MRSA endocarditis. However, daptomycin should be considered the drug of choice for the treatment of MRSA endocarditis caused by strains with a vancomycin minimum inhibitory concentration (MIC) of 2μg/mL, for heterogeneous vancomycin-intermediate S. aureus (hVISA) phenotypes and for glycopeptide-intermediate S. aureus (GISA) strains. Daptomycin is the drug of choice for rescue therapy in cases of MRSA endocarditis in which vancomycin has failed. The appropriate dose of daptomycin has not yet been established; however, for treatment of left-sided endocarditis the dose of daptomycin should be higher than the recommended dose of 6mg/kg/day. Combination antibiotic therapy with daptomycin (e.g. combined with fosfomycin) is a promising treatment for MRSA endocarditis and warrants further investigation. In vivo studies show that daptomycin is superior to vancomycin in the treatment of meticillin-resistant coagulase-negative staphylococci experimental endocarditis, although clinical data are required. Daptomycin could represent an efficacious treatment for vancomycin-resistant Enterococcus faecium endocarditis. Finally, the pharmacokinetic profile of daptomycin makes it an excellent drug for outpatient parenteral antimicrobial therapy.
    International journal of antimicrobial agents 03/2011; 38(5):365-70. DOI:10.1016/j.ijantimicag.2010.11.038 · 4.30 Impact Factor
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