Vancomycin In Vitro Bactericidal Activity and Its Relationship to Efficacy in Clearance of Methicillin-Resistant Staphylococcus aureus Bacteremia

University of the Pacific School of Pharmacy and San Diego VA Medical Center, San Diego, California 92161, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 07/2007; 51(7):2582-6. DOI: 10.1128/AAC.00939-06
Source: PubMed


We examined the relationship between the time to clearance of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia while patients were receiving vancomycin therapy and the in vitro bactericidal activity of vancomycin. Vancomycin killing assays were performed with 34 MRSA bloodstream isolates (17 accessory gene regulator group II [agr-II] and 17 non-agr-II isolates) from 34 different patients with MRSA bacteremia for whom clinical and microbiological outcomes data were available. Vancomycin doses were prospectively adjusted to achieve peak plasma concentrations of 28 to 32 mug/ml and trough concentrations of 8 to 12 microg/ml. Bactericidal assays were performed over 24 h with approximately 10(7) to 10(8) CFU/ml in broth containing 16 microg/ml vancomycin. The median time to clearance of bacteremia was 6.5 days for patients with MRSA isolates demonstrating > or =2.5 reductions in log(10) CFU/ml at 24 h and >10.5 days for patients with MRSA isolates demonstrating <2.5 log(10) CFU/ml by 24 h (P = 0.025). The median time to clearance was significantly longer with MRSA isolates with vancomycin MICs of 2.0 microg/ml compared to that with MRSA isolates with MICs of < or =1.0 microg/ml (P = 0.019). The bacteremia caused by MRSA isolates with absent or severely reduced delta-hemolysin expression was of a longer duration of bacteremia (10 days and 6.5 days, respectively; P = 0.27) and had a decreased probability of eradication (44% and 78%, respectively; P = 0.086). We conclude that strain-specific microbiological features of MRSA, such as increased vancomycin MICs and decreased killing by vancomycin, appear to be predictive of prolonged MRSA bacteremia while patients are receiving vancomycin therapy. Prolonged bacteremia and decreased delta-hemolysin expression may also be related. Evaluation of these properties may be useful in the consideration of antimicrobial therapies that can be used as alternatives to vancomycin for the treatment of MRSA bacteremia.

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Available from: Jerome J Schentag, Feb 13, 2015
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    • "The susceptibility breakpoint for vancomycin has been set at ≤2 ␮g/mL and on this basis the frequency of in vitro resistance to vancomycin remains low in most institutions. However, multiple reports have been published on the occurrence of elevated minimum inhibitory concentrations (MICs) among MRSA strains and the associated detrimental effect on the efficacy of vancomycin [2] [3]. Indeed, a recent meta-analysis reported a vancomycin MIC ≥ 1 ␮g/mL as a factor independently predictive of treatment failure [odds ratio (OR) = 2.69, 95% confidence interval (CI), 1.60–4.51] "
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    ABSTRACT: Elevated minimum inhibitory concentrations (MICs) of vancomycin against meticillin-resistant Staphylococcus aureus (MRSA) and the emergence of heteroresistant S. aureus strains have led to increased use of anti-MRSA antibiotics other than vancomycin. Ceftaroline fosamil is a novel cephalosporin with activity against MRSA, but there are limited clinical data on its use for MRSA bacteraemia (MRSAB) and against strains exhibiting high vancomycin MICs (2–4 μg/mL). This multicentre, retrospective, case–control study compared the microbiological and clinical effectiveness of ceftaroline used after vancomycin failure with that of vancomycin-treated controls for the treatment of MRSA with vancomycin MICs ≥ 2 μg/mL. In total, 32 patients were matched 1:1 with respect to vancomycin MIC, age and origin of bacteraemia. In the ceftaroline group, patients received prior MRSA therapy for a median of 5 days [interquartile range (IQR), 3–15.8 days] prior to switching to ceftaroline. Median time to eradication of MRSA was significantly less after treatment with ceftaroline compared with vancomycin [4 days (IQR, 3–7.5 days) vs. 8 days (IQR, 5.8–19.5 days); P = 0.02]. Both clinical success at the end of treatment and recurrence of MRSA at Day 7 were trending towards being inferior in the vancomycin group, although the results did not attain statistical significance [81% vs. 44% (P = 0.06) and 6% vs. 38% (P = 0.08), respectively]. Ceftaroline added at the point of vancomycin failure resolves MRSAB more rapidly and with a higher rate of clinical success, therefore ceftaroline should be considered as an alternative for these difficult-to-treat infections.
    International Journal of Antimicrobial Agents 09/2014; 44(6). DOI:10.1016/j.ijantimicag.2014.07.024 · 4.30 Impact Factor
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    • "A recent report identified the retention of implicated medical devices, MRSA infection in at least two sites, and a vancomycin minimal inhibitory concentration (MIC) of 2 µg/mL as independent risk factors for persistent MRSA bacteremia [7]. Endocarditis, septic shock, complicated bacteremia, decreased vancomycin susceptibility, heteroresistance, agr dysfunction, and low-level in vitro resistance to thrombin-induced platelet microbicidal protein were also implicated as independent risk factors for persistent MRSA bacteremia in other studies [8-10]. Additionally, one study showed that metastatic infection, congestive heart failure, and elevated vancomycin MICs for subsequent MRSA isolates were independent predictors of 30-day mortality in persistent MRSA bacteremia [11]. "
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    ABSTRACT: The high mortality attributable to persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in spite of glycopeptide treatment has heightened the need for early detection and intervention with alternative agents. The purpose of this study was to determine the clinical characteristics of and risk factors for persistent MRSA bacteremia. All first episodes of significant MRSA bacteremia at a 710-bed academic medical center from November 2009 through August 2010 were recorded. Blood cultures were conducted at 3 days and every 2 to 3 days thereafter until clearance. Clinical characteristics and outcomes were compared between persistent MRSA bacteremia (≥ 7 days) and nonpersistent MRSA bacteremia (≤ 3 days). Of 79 patients with MRSA bacteremia during the study period, 31 (39.2%) had persistent MRSA bacteremia. The persistent MRSA bacteremia group had significantly higher 30-day mortality than the nonpersistent MRSA bacteremia group (58.1% vs. 16.7%, p < 0.001). Multivariate analysis indicated that metastatic infection at presentation (odds ratio [OR], 14.57; 95% confidence interval [CI], 3.52 to 60.34; p < 0.001) and delayed catheter removal in catheter-related infection (OR, 3.80; 95% CI, 1.04 to 13.88; p = 0.004) were independent predictors of persistent MRSA bacteremia. Patients with a time to blood culture positivity (TTP) of < 11.8 hours were at increased risk of persistent MRSA bacteremia (29.0% vs. 8.3%, p = 0.029). High mortality in patients with persistent MRSA bacteremia was noted. Early detection of metastatic infection and early removal of infected intravascular catheters should be considered to reduce the risk of persistent MRSA bacteremia. Further studies are needed to evaluate the role of TTP for predicting persistent MRSA bacteremia.
    The Korean Journal of Internal Medicine 11/2013; 28(6):678-86. DOI:10.3904/kjim.2013.28.6.678 · 1.43 Impact Factor
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    • "Vancomycin has been the mainstay for treating MRSA infections, including MRSA BSI, and continued to be widely used in many countries. Although most clinical MRSA isolates are susceptible to vancomycin, several studies have demonstrated that higher vancomycin minimum inhibitory concentration (MIC) levels (≥ 1.5 mg/L) of the causative MRSA isolates predict higher vancomycin treatment failure rates, despite of being susceptible to vancomycin [5,6,8,9]. A possible basis for this observation is that an AUC/MIC ratio ≥ 400 is required to achieve clinical effectiveness when using vancomycin to treat S. aureus infections [10]; however, this target is difficult to achieve if the causative MRSA isolates have a vancomycin MIC > 1 mg/L [10]. "
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    ABSTRACT: Background The present study was designed to investigate whether teicoplanin minimum inhibitory concentrations (MICs) of methicillin-resistant Staphylococcus aureus (MRSA) isolates play a role in the prognosis of patient with teicoplanin-treated MRSA bloodstream infection (BSI). Methods Between 1 January 2006 and 31 December 2009, adult patients with teicoplanin-treated MRSA BSI in two Taiwan medical centers were retrospectively enrolled. Their blood MRSA isolates were submitted for determination of MICs to various antibiotics and multi-locus sequence types. All-cause mortalities on Days 14 and 30, as well as clinical response at the end of teicoplanin therapy were treated as endpoints. Results Two hundred seventy adult patients were enrolled and 210 blood MRSA isolates were available. Independent risk factors for un-favorable outcome at the end of teicoplanin therapy included septic shock (p < 0.0001) and an elevated C-reactive protein level (p = 0.0064). The independent risk factors for all-cause Day 14 mortality (13.0%) included the presence of auto-immune diseases (p = 0.0235), septic shock (p = 0.0253) and thrombocytopenia (p = 0.0018). The independent risk factors for all-cause Day 30 mortality (26.3%) included age (p = 0.0102), septic shock (p < 0.0001) and thrombocytopenia (p = 0.0059). Conclusions The current study didn’t find a significant role for teicoplanin MICs in the prognosis of adult patients with teicoplanin-treated MRSA BSI.
    BMC Infectious Diseases 04/2013; 13(1):182. DOI:10.1186/1471-2334-13-182 · 2.61 Impact Factor
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