We found that both vancomycin AUC24/MIC and Ctrough during the initial 72 h of treatment had fair performance in predicting 30-day mortality. However, when AUC24/MIC and Ctrough were transformed into binary variables with each cutoff value and analyzed in the regression model, only Ctrough ≥ 13.94 μg/mL was an independent risk factor for 30-day mortality in patients with enterococcal bacteremia.
The literature suggests that the risk of nephrotoxicity increases as a function of Ctrough or AUC [22,23,24], which is in accordance with our results. In our study, a higher Ctrough was significantly associated with both 30-day mortality and nephrotoxicity, but not with clinical failure. This may be explained by a higher burden of comorbidity and a higher incidence of both AKI at the onset of bacteremia and nephrotoxicity in those who died within 30 days. Although these variables turned out to be statistically insignificant after multivariable analysis, it is possible that we did not find a significant association due to the small population size.
Three studies demonstrated the benefit of higher vancomycin exposure in the treatment of enterococcal infections, all of which were notably different from our study [5, 7, 8]. In studies by Jumah et al. [5] and Sohn et al. [7], the severity of infection measured by the proportion of ICU patients at baseline, who might benefit from higher drug exposure, was higher than that of our population (14% and 37.8%, respectively, compared to 3.1% in our study). Moreover, those studies included larger proportions of infection with Enterococcus faecalis (36.8% and 29.7%, respectively, compared to 4.5% in our study), the majority of which are susceptible to penicillin. Although the proportion of concurrent antibiotic use did not differ between the survivor and non-survivor groups in those studies, there might have been an unadjusted difference in the use of antibiotics that are active against enterococci. Considering the low Pitt bacteremia score and low percentage of ICU admissions in our study, avoiding an unnecessarily high Ctrough might be justifiable when treating infections in non-severe conditions. Katip et al. restricted their study population to ampicillin-resistant enterococcal infections and reported that vancomycin AUC24/MIC ≥ 400 during the initial 72 h of treatment was associated with a higher likelihood of a better clinical outcome, which was a composite of the resolution of signs and symptoms related to enterococcal infection [8]. However, the adjusted hazard ratio for nephrotoxicity was 3.95 (95% CI 1.09–14.47). This might be quite high considering that the study population largely comprised patients with non-severe infections (non-bacteremic urinary tract infections, 70.2%; non-bacteremic wound infections, 12.5%).
Ctrough has been used as a surrogate marker for AUC/MIC because it is difficult to estimate the AUC using conventional methods. The new ASHP guidelines updated in 2020 no longer recommend Ctrough-based monitoring for serious MRSA infections [4]. However, they acknowledged that there is insufficient evidence to apply the same recommendation to non-MRSA infections. In addition to our study, Nakakura et al. [6] and Sohn et al. [7] found a significant association between Ctrough and mortality. Considering this, clinicians who practice in settings where AUC24/MIC are not routinely obtained may benefit from monitoring Ctrough when treating enterococcal bacteremia.
Our study has several strengths. First, by measuring MICs with BMD, the reliability of AUC24/MIC was higher than in previous studies, all of which did not confirm MIC by BMD or the E-test except Jumah et al. [5]. Second, we excluded cases in which antibiotics other than vancomycin with in vitro activity against enterococci were used.
However, this study also has important limitations. First, there are inherent limitations from the retrospective nature of the study. We used logistic regression to mitigate confounding; however, the possibility of unobserved bias could not be excluded. Furthermore, there might have been variability in how vancomycin dosage was adjusted after the measurement of Ctrough, which is difficult to control in a retrospective study and could have affected treatment outcomes. Second, the composition of the patients included in our study may limit the generalizability of the results. Patients with chronic kidney disease were unintentionally excluded due to the exclusion criteria unrelated to renal function. Also, most of the patients had either solid or hematological malignancies. Third, intraabdominal infection was the focus of bacteremia in about half of the study population. Considering the often polymicrobial nature of intraabdominal infections, antimicrobial treatment other than vancomycin might have affected the clinical outcomes. However, we excluded the patients with polymicrobial bacteremia to minimize such impact. Fourth, we calculated AUC24/MIC with a single concentration (Ctrough) since peak concentrations had not been measured. However, while larger studies should verify it, Neely et al. reported that trough-only data could generate reliable AUC estimates [25]. Fifth, there are limitations in the outcome measures. Although mortality is generally the most objective indicator, it may not fully reflect the clinical outcome when infection-attributable mortality is low. Clinical failure, one of the secondary outcomes, included some subjective variables. However, higher Ctrough was consistently not associated with better clinical outcomes in various measures. Last, there is a risk of overfitting. The study dataset was used both for derivation and application of the ROC curves. Furthermore, there is a sampling error in the selection of thresholds. The result from this study needs external validation in future studies. Our results call for a prospective study with a larger population to determine PK parameters to optimize outcomes in enterococcal bacteremia.
In conclusion, monitoring Ctrough during the initial 72 h may be useful as a pharmacokinetic target for the treatment of enterococcal bacteremia. Avoiding high Ctrough in this setting may prove beneficial for the prevention of nephrotoxicity without compromising treatment efficacy.