170 Chapter 8 evidence that tolerance may be an unappreciated pathway to treatment failure [91]. Glycopeptide tolerance has been frequently observed in S. aureus, with a prevalence of up to 43% in MRSA isolates [87,92]. While it is suspected that antibiotic tolerance is a contributor to refractory and relapsing infections, there are few studies that have directly addressed this question. Given the definition of decreased antibiotic killing in antibiotic tolerance, one could hypothesize that antibiotic tolerance may play a role in persistent bacteremia. Britt et al. performed a retrospective cohort study of 225 patients with SAB comparing frequency of clinical failure (30 day allcause mortality, persistent signs and symptoms of bacteremia, recurrent bacteremia within 30 days, and blood culture positive >5 days) between isolates with and without vancomycin tolerance [88]. In their study, 26.7% of the isolates exhibited vancomycin tolerance, which was associated with clinical failure in unadjusted (68.3% vs. 40.6%) and multivariable analysis (adjusted risk ratio, 1.74; 95% CI, 1.35–2.24; p < 0.001). The average bacteremia duration did not significantly vary between the two groups, nor did the proportion with blood cultures positive for >3 days (48.2% in vancomycintolerant (VT) vs. 38.4% in non-VT). Another smaller study of 163 patients with MRSAB from St. Louis, USA, noted just 4.3% of isolates were vancomycin-tolerant with no statistically significant effect on clinical outcomes. Finally, a study by Moise et al. noted increased duration of bacteremia (median time to clearance 6.5 days vs. >10.5 days, p = 0.025) when MRSA isolates were stratified by tolerance (≤2.5 log10 decrease in colony-forming units/mL over 24 h of vancomycin treatment) [93]. Larger studies are needed to determine the clinical impact of antibiotic tolerance in persistent MRSAB. The mechanisms of antibiotic tolerance are incompletely understood, especially in S. aureus. To identify if antibiotic tolerance evolves within patients, Elgrail et al. performed WGS on 206 MRSA isolates from 20 patients with persistent MRSAB [94]. Their results showed that MRSA can evolve antibiotic tolerance within the host due to mutations in the TCA cycle (odhA and citZ) and stringent response (relA). Interestingly, these mutants were transient and were not present in subsequent positive blood cultures, suggesting there is phenotypic heterogeneity and a fitness cost to tolerance, which has been described in other pathogens [95]. Reduced vancomycin susceptibility and heterogenous vancomycinintermediate S. aureus Vancomycin is the oldest and most frequently used drug in our arsenal against MRSA [96]. Despite being used for almost 65 years, vancomycin resistance (MIC ≥ 16 µg/ mL) is extraordinarily uncommon, with just 52 incidents of vancomycin-resistant S. aureus (VRSA) reported worldwide in the past two decades [97]. Vancomycinintermediate S. aureus (VISA) is defined by a vancomycin MIC between 4 and 8 µg/mL
RkJQdWJsaXNoZXIy MTk4NDMw