Research ArticleClinical Studies
Open Access

Effect of the Minimum Inhibitory Concentration of Vancomycin on the Clinical Outcome of Enterococcus faecium Bacteremia

TAKANOBU HOSHI, KEI WATANABE, YUTA FUKUMURA, KOJI MIYAZAKI, MADOKA TAKAHASHI, SAKAE TANIGUCHI, NAOKI WADA, MIKA MIURA, SHOYA KATO, KAZUNORI YAMADA, SATOSHI FUJII and HIDEKI SATO
In Vivo September 2023, 37 (5) 2197-2202; DOI: https://doi.org/10.21873/invivo.13319

Abstract

Background/Aim: Vancomycin (VCM) is an antibiotic widely used in the treatment of resistant bacteria. In patients with methicillin-resistant Staphylococcus aureus (MRSA) infection, the clinical outcome differs according to the VCM minimum inhibitory concentration (MIC) of isolates. However, the effect of VCM MIC on the clinical outcome is unclear for bacterial species other than MRSA. This study evaluated the relationship between the VCM MIC and clinical outcomes in patients with Enterococcus faecium bacteremia. Patients and Methods: This study included patients who had E. faecium detected in at least one set of blood cultures between April 2011 and March 2022. The study assessed the outcome according to the VCM MIC. The primary outcome was the 30-day mortality rate. Measures of interest included the initial serum concentration of VCM, MIC, the area under the curve (AUC), and the AUC over 24-48 hours (AUC24-48 h). Results: A total of 26 patients were included in the study, of whom 5 died and 21 survived. The 30-day mortality was higher in patients with higher MICs and lower serum albumin levels. Patients with a serum albumin level <2.0 mg/dl and a MIC ≥1 μg/ml had significantly shorter survival than those who did not (p=0.013, log-rank test). Conclusion: The 30-day mortality rate of patients with E. faecium bacteremia is associated with the VCM MIC of E. faecium isolates and the patient’s nutritional status. Patients with albumin <2 mg/dl and MIC ≥1 μg/ml may have a poor outcome and require careful clinical monitoring.

Key Words:

Vancomycin (VCM) is an antibiotic widely used against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci, Enterococcus faecium, and infections caused by other resistant bacteria. In recent years, VCM-resistant Staphylococcus aureus (VRSA) and VCM-resistant enterococci (VRE) have become clinical problems. These resistant organisms not only limit therapeutic options but may also affect treatment outcomes of infectious diseases. VCM resistance in enterococcal bacteremia has been reported to increase the risk of mortality compared to VCM-susceptible enterococci (1). A history of VCM, meropenem, and tazobactam/piperacillin use has been reported as one of the risk factors for selection for VRE (2). Proper use of VCM in appropriate patients is recommended to avoid selection for VRE and VRSA. When using VCM, active therapeutic drug monitoring (TDM) support is recommended in order to maximize the therapeutic effectiveness and prevent adverse effects (3). For TDM of VCM in Japan, an area under the curve (AUC)-guided dosing design using the ratio of AUC to minimum inhibitory concentration (AUC/MIC) of 400-600 as an index is recommended (3-5) because compared with the alternative trough value guide, it is associated with a lower risk of renal injury. Achieving an AUC/MIC ≥400 is the target value for successful treatment, especially in MRSA infections, and active TDM support is required from the early stage of treatment to achieve the target value. In MRSA infections with a MIC ≥2 μg/ml, it is difficult to achieve an AUC/MIC ≥400, and failure to achieve this target can result in treatment failure (6). The effect of the MIC of the bacterial isolate on the therapeutic outcome of infections is a concern, but there is no established evidence for the therapeutic effect of VCM based on AUC/MIC or MIC differences for bacterial species other than MRSA (3). E. faecium bacteremia is a frequent infection in clinical settings, and like MRSA and methicillin-resistant coagulase-negative staphylococci, VCM is considered the first-line treatment. Therefore, it is important to understand the effect of the E. faecium VCM MIC on treatment effectiveness. In this study, we evaluated the effects of VCM AUC/MIC and MIC on the effectiveness of treatment of E. faecium bacteremia, in order to develop new management strategies for using VCM to treat E. faecium bacteremia.

Patients and Methods

Facility overview. The retrospective study was conducted at Sapporo Tokushukai Hospital, a 301-bed secondary emergency medical hospital in Sapporo, Hokkaido, Japan. The hospital has a bacteriological laboratory. TDM support for VCM administration is provided by the ward pharmacist in real time for all patients.

Participants. Hospitalized patients with E. faecium detected in at least one set of blood cultures between April 2011 and March 2022 were included in the analysis.

Exclusion criteria. Patients who were transferred to other hospitals, received antibiotics other than VCM, patients on dialysis (hemodialysis, continuous renal replacement therapy), patients whose serum VCM concentrations were not measured, and patients with recurrent E. faecium bacteremia were excluded.

Survey items. The primary outcome was the difference in 30-day mortality due to differences in VCM MIC (μg/ml) of E. faecium. Other variables considered included patient background (age, sex, comorbidities, primary infection, quick SOFA score), laboratory data (C-reactive protein, white blood cell count, albumin level, total bilirubin level), Geriatric Nutritional Risk Index, AUC24-48 h (mg/l-h), AUC24-48 h/MIC, duration of VCM treatment (days), time to negative blood culture (days), time to starting VCM administration (days), initial blood concentration of VCM (μg/ml), number of VCM administrations before the initial blood concentration measurement, initial VCM administration method change after TDM (%), first loading-dose rate (%), first VCM dose (mg/kg), steady-state VCM maintenance dose (mg/kg), and survival (days).

Definitions of terms. The 30-day mortality rate (%) was the mortality rate within 30 days from the date of the positive blood culture report. The duration of treatment (days) was the period from the date of initiation of antimicrobial therapy to the date of termination. The time to negative blood culture (days) was the period from the date of the first positive blood culture submission to the date of negative blood culture submission. A positive blood culture was defined when one or more sets of blood cultures were positive for E. faecium (including multiple positive cultures). Relapse was defined as a case of E. faecium bacteremia within 1 month after completion of antimicrobial therapy after confirmation of a negative blood culture. Time to VCM therapy (days) was the period from the date of positive blood culture submission to the date of VCM initiation. The maintenance dose (mg/kg) was the dose at the fourth administration of VCM.

Patients were grouped into two groups according to a combination of their initial serum albumin level and VCM. Patients with a serum albumin <2.0 mg/dl and VCM MIC ≥1 μg/ml were assigned to Group A, and the rest of the patients, including patients who fulfilled only one of the two conditions for inclusion in Group A, were included in Group B.

AUC and MIC measurement methods. The AUC24-48 h/MIC at the time of the initial blood concentration measurement was calculated. The AUC was calculated using Practical AUC-Guided TDM for Vancomycin ver. 2.1, and the MIC was measured using the micro-liquid dilution method. Practical AUC-Guided TDM for Vancomycin uses Yasuhara’s equation (7) in the population pharmacokinetic model equation (adults) to calculate the AUC.

Statistical analysis. Continuous variables were compared using Student’s t-test or the Mann-Whitney U-test, as appropriate considering normality and variance, and data are shown as the mean or the median (interquartile range), respectively. Categorical variables were compared using Fisher’s exact test. The log-rank test was used to compare survival between groups. p-Values <0.05 were regarded as statistically significant. Statistical analysis was performed using EZR version 1.54 (Jichi Medical University Saitama Medical Center, Saitama, Japan) (8).

Ethical considerations. The study was approved by the research ethics committee of Mirai Medical Research Center (ethical review number: 1413). The requirement for informed consent was waived because of the retrospective study design.

Results

Participants. A total of 48 patients had E. faecium detected in at least one set of blood cultures from April 2011 to March 2022. Of the 48 patients, 22 were excluded (no VCM use: n=16; no VCM blood level measurement: n=2; on dialysis: n=1; death before blood culture report: n=2; and transfer: n=1), leaving 26 eligible patients, of whom five died (non-survivor group), and 21 survived (survivor group) (Table I).

View this table:
Table I.

Comparison of patient characteristics in the 30-day survival and 30-day mortality groups.

Participant characteristics and outcomes. The participant characteristics according to survival status are shown in Table I. The prevalence of E. faecium isolates with a VCM MIC <1 μg/ml differed significantly between the non-survivor (0%) and survivor (57.1%) groups (Table I). There were also significant differences in survival according to the mean serum albumin level (non-survivor group: 1.9 mg/dl, survivor group: 2.5 mg/dl) and low albumin/high MIC status (non-survivor group: 80.0%, survivor group: 9.5%) (Table I). There were no significant differences in the other variables, including comorbidities (Table I).

Calculation of cutoff values using receiver-operating characteristic curves. The cutoff values of the VCM MIC, AUC24-48 h/MIC and serum albumin level were measured using receiver-operating characteristic (ROC) curves. A serum albumin level of 2.0 mg/dl [AUC=0.8, 95% confidence interval (CI)=0.63-1.00], an AUC24-48 h/MIC of 323.1 (AUC=0.7, 95%CI=0.45-0.99), and a MIC of 1 μg/ml (AUC=0.8, 95%CI=0.67-0.94) were calculated as the values with the maximum sensitivity and specificity in the ROC curve analysis. Based on these results, we set cutoff values of 2.0 mg/dl for serum albumin, and 1 μg/ml for the VCM MIC.

Log-rank test for survival. A log-rank test was performed the assess the significance of the difference in survival between the two groups (Group A: albumin <2.0 mg/dl and MIC ≥1 μg/ml, Group B: other) (Figure 1). The survival between the two groups differed significantly (p=0.013).

Figure 1.
Figure 1.

A log-rank test was performed the assess the significance of the difference in survival between the two groups (Group A: albumin <2.0 mg/dl and MIC ≥1 μg/ml, Group B: other). The survival between the two groups differed significantly (p=0.013).

Discussion

The aim of this study was to clarify the effect of the VCM MIC on therapeutic effectiveness in patients with E. faecium bacteremia. Jumah et al. (9) reported that the MICEtest value was significantly higher in patients with fatal E. faecium bacteremia than in those who survived, with a VCM therapeutic index (AUC0-24 h/MIC) of 389. In this study, we evaluated the effect of MIC on the therapeutic effectiveness and the AUC24-48 h/MIC on the second day of treatment based on AUC24-48 h calculated using PAT. Previous studies (9-11) have included two strains of Enterococcus, E. faecium and E. faecalis, as the target infecting organisms, and there are few reports limited to E. faecium. Therefore, limiting this study to patients with E. faecium bacteremia yields novel findings.

Regarding the primary outcome, the association between different MICs of E. faecium and 30-day mortality, the proportion of patients with a VCM MIC <1 μg/ml was 57.1% (12/21) in the survivor group and 0% (0/5) in the non-survivor group, and the MIC in the non-survivor group was significantly higher than that in the survivor group. These results are consistent with previous studies (9) and, suggest that differences in isolated MICs may affect clinical outcomes. This study and previous studies (9) have used different methods of measuring MICs, namely, the micro-liquid dilution method and Etest. The similarities in the results of the effect of VCM MIC on clinical outcomes suggest that both methods of measuring the MIC are useful. No significant differences were found in the AUC24-48 h for the two groups (survivors and non-survivors). This result is also consistent with the results of a previous study (9). Possible reasons for the lack of difference in the AUC in this study or the previous study are that the AUCs were calculated from a single point blood draw, and augmented renal clearance or acute kidney injury in some patients may have affected the clearance of VCM. Therefore, the effect of renal VCM clearance should be considered when studying the relationship between the achievement of AUC or AUC/MIC targets and clinical outcomes. MIC measurement error is also a concern. However, the similarity in relationship between MIC and clinical response using the micro-liquid dilution method and the different Etest assay methods suggests that the VCM MIC may be a more useful indicator than the AUC or AUC/MIC for predicting the outcome in patients with E. faecium bacteremia. Based on these findings, we believe that in the early stages of treatment of E. faecium bacteremia, it is necessary to consider the impact of the VCM MIC on the clinical E. faecium isolate and the clinical outcome and to monitor treatment according to the MIC.

Regarding the MIC distribution of Enterococcus species, susceptibility pattern surveillance of urine samples of patients with urinary tract infections in Japan (12) found that the VCM MIC range for Enterococcus faecalis was 0.5-2.0 μg/ml. In this study, the VCM MIC range for E. faecium was 0.25-2.0 μg/ml. Although the results for E. faecalis and E. faecium are not directly comparable, their susceptibility patterns are similar, and the baseline MIC distribution in this study is consistent with expectations from an epidemiological perspective. Patients in the non-survivor group were significantly more likely to have a VCM MIC ≥1 μg/ml. Based on these results, it is necessary to carefully monitor the clinical course of patients with a VCM MIC ≥1 μg/ml because of the possibility of a poor clinical response. If a clinical response is not achieved, it may be necessary to consider switching to another anti-MRSA agent, such as linezolid. Regarding specific treatment strategies for each MIC in patients with E. faecium bacteremia, we believe that in those with a VCM MIC ≥2 μg/ml it should be switched to another anti-MRSA agent, whereas in those with a MIC 1 μg/ml it should be carefully clinically monitored.

The reasons for the poor clinical outcome of E. faecium bacteremia in patients with high VCM MICs in this study are unclear. In addition to the difference in MIC of VCM, other properties of Staphylococcus aureus, such as biofilm formation (13) and Panton-Valentine leucocidin production (14, 15), are among the factors that make MRSA infections refractory to VCM. However, E. faecium does not have the same properties as MRSA, and it is possible that the VCM MIC in clinical isolates may directly affect the clinical outcome. It is notable that a 4 out of 5 of E. faecium isolates in the non-survivor group had an MIC=1 μg/ml. The specific treatment strategies for VCM against strains with MIC=1 μg/ml warrant further study. However, VCM may have a lower therapeutic threshold against E. faecium than against MRSA, and a lower AUC/MIC target may be possible, as the cutoff value (AUC/MIC24-48 h) based on the ROC curve was calculated to be 323.1.

The serum albumin level was significantly lower in the non-survivor group than in the survivor group. However, there was no significant difference in the GNRI between groups. As the prognosis of E. faecium bacteremia in patients with hypoalbuminemia has been reported to be poor (16-18), baseline nutritional status may have affected the 30-day mortality. However, we used the albumin level at the start of treatment in the evaluation and did not consider nutritional management or changes in the albumin level thereafter. To conclude that hypoalbuminemia is a risk factor for increased 30-day mortality in E. faecium bacteremia, it is necessary to re-evaluate the results taking subsequent serum albumin measurements into consideration. There were no other baseline differences between the groups, and no other patient characteristics other than the baseline albumin level were associated with the 30-day mortality.

Based on the results of the analysis, we hypothesized that hypoalbuminemia (<2.0 mg/dl) and MIC ≥1 μg/ml may affect the 30-day mortality in patients with E. faecium bacteremia and performed a log-rank test for survival time. Patients in Group A (albumin <2.0 mg/dl and MIC ≥1 μg/ml) had a significantly shorter survival time than those in Group B (the rest). From previous studies (9-11), AUC24/MIC, age, and trough VCM levels, have been identified as factors affecting 30-day mortality, but to our knowledge, there have been no previous reports evaluating the impact of nutritional indicators such as albumin on 30-day mortality. These results suggest that in patients with E. faecium bacteremia with MIC ≥1 μg/ml and hypoalbuminemia (albumin <2.0 mg/dl), it is important to provide more focused support, including TDM.

There are several limitations to this study. First, because it was a single-center study, there was a limited number of cases, and it was not possible to perform a multivariable analysis of risk factors for 30-day mortality. Second, due to the 10-year study period, compliance with a uniform VCM dosing regimen was not possible because of the changes in human and environmental resources. Third, the AUC24-48 h/MIC was calculated based on a single blood sample for trough values. Therefore, in order to construct a more accurate AUC24-48 h/MIC index, analysis using data obtained from two blood samples is required. Multicenter studies should be conducted to address these issues, to shorten the study period and increase the number of cases.

Conclusion

The VCM MIC of E. faecium isolates and the nutritional status of the patient may affect the 30-day mortality rate of patients with E. faecium bacteremia. Patients with albumin <2 mg/dl and MIC ≥1 μg/ml may have a poor outcome and require careful clinical monitoring.

Footnotes

  • Authors’ Contributions

    TH designed the study and acquired the data. TH, KY, SF and HS prepared and edited the article. KW, YF, KM, MT, ST, NW, MM and SK were involved in patient care and reviewed the electronic records. All the Authors have read and approved the article.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare in relation to this study.

  • Received May 18, 2023.
  • Revision received June 8, 2023.
  • Accepted June 9, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Effect of the Minimum Inhibitory Concentration of Vancomycin on the Clinical Outcome of Enterococcus faecium Bacteremia
TAKANOBU HOSHI, KEI WATANABE, YUTA FUKUMURA, KOJI MIYAZAKI, MADOKA TAKAHASHI, SAKAE TANIGUCHI, NAOKI WADA, MIKA MIURA, SHOYA KATO, KAZUNORI YAMADA, SATOSHI FUJII, HIDEKI SATO
In Vivo Sep 2023, 37 (5) 2197-2202; DOI: 10.21873/invivo.13319
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