171 Persistent MRSA bacteremia 8 and is more frequent with an estimated prevalence of between 0.3 and 18% depending on the geographic area [98]. In theory, vancomycin is an appropriate treatment for MRSAB isolates with vancomycin MIC between 1 and 2 µg/mL. There has been a longstanding debate questioning whether MRSA with elevated vancomycin MIC (>1.5 µg/ mL) is associated with worse clinical outcomes or not. The majority of data, including two systematic reviews and meta-analyses, indicates that MRSAB due to isolates with high vancomycin MIC (>1.5 µg/mL) is associated with increased mortality compared to MRSAB due to isolates with low-vancomycin MIC (<1.5 µg/mL) [93,99,100]. This finding is not necessarily related to failure of vancomycin, as an elegant study by Holmes et al. also found worse clinical outcomes in MSSA bacteremia isolates with elevated vancomycin MIC, despite treatment with flucloxacillin and not vancomycin [101]. This finding is consistent with the Infectious Disease Society of America (IDSA) recommendations to base treatment decisions in patients infected with MRSA isolates with vancomycin MIC of 2 µg/mL upon clinical conditions [91]. The majority of studies examining the risk of elevated vancomycin MIC with clinical outcomes used composite outcomes for treatment failure, often including (but not always specifying) persistent bacteremia [100]. When the systematic review and meta-analysis by van Hal et al. limited their analysis exclusively to studies that examined persistent MRSAB, the OR was 2.44 but was not significant (95% CI, 0.72–8.24) [100]. Some individual studies did show an association, such as a retrospective cohort of 222 MRSAB patients by Neuner et al. that identified a significantly higher rate of persistent MRSAB when vancomycin MIC was 2 µg/mL compared to <2 µg/mL (16% vs. 5 %, p = 0.012) [102]. Another smaller study by Yoon et al. also found vancomycin MIC of 2 µg/mL is an independent predictor of persistent MRSAB (OR 6.34; 95% CI, 1.21–33.09) [65]. Another newer study by Adani et al. of 166 patients from an institution with blinded vancomycin MIC showed no significant difference in persistent bacteremia rates between isolates with MIC < 2 µg/mL vs. 2 µg/mL (16.5% vs. 17.3%, p = 0.884) [103]. Heterogenous VISA (hVISA) is another microbiologic phenomenon that could contribute to decreased vancomycin efficacy [104]. The first reported case of hVISA was in 1996 from a patient in Japan with MRSA pneumonia that did not respond to vancomycin [105]. Despite susceptibility testing showing vancomycin MIC of 4 µg/ mL, a subpopulation was discovered with MICs ranging from 5 to 9 µg/mL. An isolate with vancomycin MIC in the susceptible range (≤2 µg/mL) with a subpopulation with vancomycin MIC in the intermediate range (4–8 µg/mL) has become diagnostic of hVISA [106]. Similar to the challenges of identifying antibiotic tolerance, the detection of hVISA is laborious and utilizes the population analysis profile (PAP) area under the curve (AUC) technique, which is not feasible in the clinical microbiology lab on a routine basis [104]. It was previously thought that hVISA is a precursor to VISA as selection pressure during treatment with vancomycin generates outgrowth of the VISA subpopulation [107,108], although more recent data from in vitro evolutionary
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