This pilot study evaluated the relationship between vancomycin exposure and emergence of hVISA by Etest® macromethod in patients with non-hVISA MRSA BSIs at baseline. Nearly all 7 cases of hVISA emerged during vancomycin treatment and 4 of 7 appeared within 15 days of the index MRSA blood culture (Table 1). One case of hVISA emerged after therapy discontinuation. Using a validated Bayesian technique to estimate each patient’s AUC0-24h and AUC24-48h values with limited PK sampling [10], we found that failure to achieve an AUC0-24h/MICBMD ratio of 521 and an AUC24-48h/MICBMD ratio of 650 was associated with an increased risk of hVISA emergence. Of the 7 patients for which hVISA emerged, 6 occurred in patients with AUC0-24h/MICBMD ratio less than 521 and AUC24-48h/MICBMD ratio less than 650. Interestingly, all 7 cases of hVISA emerged in patients who did not achieve AUC0-24h/MICBMD ratio of 521 or an AUC24-48h/MICBMD ratio of 650 (Table 1), suggesting the dual importance of both day 1 and day 2 vancomycin AUC exposures and cumulative vancomycin exposure over the first 2 days of therapy. Presence of infective endocarditis was also found to be associated with an increased risk of hVISA emergence in the multivariate analyses. This is consistent with a meta-analysis from van Hal and Paterson [13] which described an association between high-inoculum infections (e.g. infective endocarditis) and hVISA. Future studies should aim to better elucidate these findings, including the possibility that an alternative exposure threshold may exist for these patients. The observed associations between decreased baseline creatinine clearance and hVISA infection in the multivariate analyses are also not surprising given the number of reports of resistance emergence in this population throughout the literature [14].
Several things should be considered when interpreting these results. This study is subject to limitations inherent to the study design, namely confounding and selection bias. However, the comparable distribution of baseline characteristics between the CART-derived AUC24-48h/MICBMD groups and persistence of findings in the multivariate analysis suggest that confounding is unlikely to contribute to the exposure-response observed findings. Results may not be applicable to neutropenic and dialysis patients as these patients were excluded from this study; AMCH does not have an appreciable neutropenic population, and exposure variables are numerous and difficult to characterize for hemodialysis-dependent patients (e.g. sporadic dosing, inconsistent removal volumes due to variable durations and filters). Both of these excluded populations are frequently identified at risk for resistance emergence [14] and the incidence of hVISA emergence may be higher in these populations than that observed in our study population. Two study patients had emergence of hVISA within 2 days of vancomycin therapy. It is unclear if suboptimal exposure to vancomycin selected for these isolates or if they were present in a sufficient density for detection at baseline. Clear delineation between exposure accrual and subsequent resistance emergence should be an important consideration in future studies as well.
Our CART-derived AUCh/MICBMD ratio breakpoints for defining hVISA emergence can only be considered a rough estimation due to the small sample size. While vancomycin dose and concentration collections used to generate estimates of vancomycin PK parameters for each individual patient occurred within the first 5 days of therapy, most were obtained on days 1–3. Limiting collection to days 1 and 2 to estimate AUC0-24h and AUC24-48h would have been preferred, but this would have severely restricted our already small study sample. For this reason, we employed a vancomycin population PK model as the Bayesian prior that included creatinine clearance as a covariate to account for potential changes in renal function during the first few days of therapy. As previously described, use of a vancomycin population PK model including creatinine clearance ensured a good fit of the model to the observed vancomycin concentrations collected over the first few days of therapy relative to predicted concentrations in our study population [7]. Future studies should consider intensive PK collections on the day the exposure profile is estimated.
Lastly, hVISA phenotypes were not confirmed by population analysis profile (PAP)-area under the curve (AUC). However, the macrodilution Etest® used in the study has been shown to be a viable screening method with a specificity ranging from 89–98% with few false positives [6]. The presence of hVISA by macrodilution Etest® has also shown to be predictive of patient outcomes across of a number of studies, further highlighting the importance of findings from our pilot investigation and need for further study [13]. Finally, future hypothesis analyzing studies should include DNA fingerprinting of the first isolate and subsequent isolates to ensure that isolates are the same.