Different linezolid antimicrobial susceptibility testing (AST) methodologies yield various results. In 2018, we transitioned our linezolid AST methodology from the Etest to Vitek 2. We sought to evaluate the impact of this change on antibiotic use among 181 inpatients with vancomycin-resistant enterococcal (VRE) infections. The transition from Etest to Vitek 2 resulted in an increase in linezolid susceptibility (38% versus 96%; P < 0.001) and a reduction in time to active antibiotic therapy (3 versus 2.
KEYWORDS: linezolid, microbial sensitivity tests, vancomycin-resistant enterococci
ABSTRACT
Different linezolid antimicrobial susceptibility testing (AST) methodologies yield various results. In 2018, we transitioned our linezolid AST methodology from the Etest to Vitek 2. We sought to evaluate the impact of this change on antibiotic use among 181 inpatients with vancomycin-resistant enterococcal (VRE) infections. The transition from Etest to Vitek 2 resulted in an increase in linezolid susceptibility (38% versus 96%; P < 0.001) and a reduction in time to active antibiotic therapy (3 versus 2.6 days; P = 0.007).
INTRODUCTION
Limited therapeutic options are available for the treatment of severe vancomycin-resistant enterococcal (VRE) infections. Daptomycin and linezolid are first-line agents, and similar clinical outcomes have been observed for VRE bacteremia when utilizing daptomycin or linezolid, if both were susceptible (1–3). Different linezolid antimicrobial susceptibility testing (AST) methodologies may yield various results (4, 5), but linezolid nonsusceptibility is uncommon (6).
On annual review of our institution’s antibiogram, the VRE linezolid nonsusceptibility rate was noted to be high compared with that in published literature. We were using the Etest (bioMérieux, Inc., Durham, NC) for linezolid AST. Subsequently, we assessed the possibility that the difference was due to inadequate staff training, because Etest interpretation is complicated by the hazy and trailing growth of enterococci. After several educational sessions, we determined that Etest reading was likely not the sole contributor to the observed differences.
Subsequently, confirmation testing with MicroScan and Vitek 2 (bioMérieux, Inc., Durham, NC) revealed that the Etest yielded MICs that were 1 to 2 fold dilutions higher than those with Vitek 2 and MicroScan. Given our use of the lower CLSI MIC susceptibility breakpoint (2 μg/ml versus EUCAST 4 μg/ml), this resulted in a high number of linezolid-nonsusceptible enterococcal isolates. In 2018, we transitioned our linezolid AST methodology from the manual Etest to reporting the linezolid susceptibility off the automated Vitek 2. The purpose of this study was to evaluate the impact of this change on linezolid susceptibility rates and antibiotic use among patients with VRE infections.
This was a single-center retrospective, quasi-experimental study of adult inpatients with ampicillin- and vancomycin-resistant Enterococcus faecium infections requiring antibiotic therapy. Patients were excluded if they had VRE isolates in a urine culture and no other site. The primary outcome was time to active antibiotic therapy, calculated using the time of culture collection and the time of administration of a susceptible antibiotic. The definitive antibiotic was defined as the final antibiotic used for treatment in the inpatient setting. Susceptibility was defined using CLSI breakpoints for E. faecium (7). Linezolid MIC of ≤2 μg/ml was considered susceptible, and daptomycin MIC of ≤4 μg/ml was considered susceptible dose dependent.
In the preintervention group, ampicillin, vancomycin, linezolid, and quinupristin-dalfopristin enterococcal ASTs were performed using Vitek 2. Only ampicillin, vancomycin, and quinupristin-dalfopristin results were reported in the electronic medical record (EMR), and the linezolid AST result from Vitek 2 was suppressed. If an enterococcal isolate from a nonurinary site tested resistant to vancomycin, linezolid, and daptomycin, then Etests were performed and reported. In the postintervention group, ampicillin, vancomycin, linezolid, and quinupristin-dalfopristin enterococcal ASTs were performed using Vitek 2. Ampicillin, vancomycin, and quinupristin-dalfopristin results were reported in the EMR. The linezolid AST result was reported in the EMR only for vancomycin-resistant enterococcal isolates from nonurinary sites (cascade reporting). Similar to the preintervention group, daptomycin Etests were performed and reported on nonurinary VRE isolates.
A total of 116 patients with VRE infections were included. Tissue and intra-abdominal were the most common culture types, and the rate of bacteremia was similar in both groups (Table 1). A reduction in time to the linezolid AST report in the EMR was observed (4.0 versus 2.6 days; P < 0.001), whereas the time to the daptomycin AST report remained the same. Reduced linezolid MICs resulted in an increase in linezolid-susceptible isolates (38% versus 98%, P < 0.001). The majority of enterococci (94%) in the postintervention group had an MIC of 2 μg/ml. Among the patients with VRE infection who were treated with a susceptible antibiotic, time to active antibiotic therapy was reduced in the postintervention group (3.1 versus 2.6 days; P = 0.002) (Table 2). The time between identification of enterococci and active antibiotic administration was also reduced in the postintervention group (1.1 versus 0.8 days; P = 0.007).
TABLE 1.
Baseline patient and culture characteristics
| Characteristica | Results |
P value | |
|---|---|---|---|
| Preintervention (n = 67) | Postintervention (n = 49) | ||
| Male (n [%]) | 31 (46) | 23 (47) | 0.943 |
| Age (yr, median [IQR]) | 61 (52–70) | 60 (40–75) | 0.245 |
| VRE culture typeb (n [%]) | |||
| Tissue | 32 (48) | 19 (39) | 0.335 |
| Intra-abdominal fluid | 21 (31) | 16 (33) | 0.881 |
| Blood | 16 (24) | 17 (35) | 0.202 |
| Urine | 7 (10) | 5 (10) | 0.966 |
| Wound drainage | 4 (6) | 3 (6) | 0.973 |
| Other | 2 (3) | 1 (2) | 0.742 |
| Time between culture collection and AST report in EMR (days, median [IQR]) | |||
| Daptomycinc | 4.1 (3.7–5.1) | 4.1 (3.7–4.8) | 0.589 |
| Linezolidd | 4.0 (3.8–5.1) | 2.6 (2.3–3.3) | <0.001 |
| MIC (μg/ml) | |||
| Linezolidd (n [%]) | <0.001 | ||
| <2 | 7 (12) | 2 (4) | |
| 2 | 16 (27) | 46 (94) | |
| 3 | 22 (37) | 0 (0) | |
| 4 | 14 (24) | 0 (0) | |
| >4 | 0 (0) | 1 (1) | |
| Daptomycinc (n [%]) | 0.172 | ||
| <2 | 0 (0) | 3 (7) | |
| 2 | 5 (10) | 5 (11) | |
| 3–4 | 40 (77) | 33 (75) | |
| 6–8 | 4 (8) | 2 (5) | |
| >8 | 3 (6) | 1 (2) | |
VRE, vancomycin-resistant enterococci; AST, antimicrobial susceptibility testing; EMR, electronic medical record.
Not mutually exclusive.
n = 52 and 44 for pre- and postintervention, respectively.
n = 59 and 49 for pre- and postintervention, respectively.
TABLE 2.
Treatment characteristics and outcomes
| Characteristic/outcome | Result |
P value | |
|---|---|---|---|
| Preintervention (n = 67) | Postintervention (n = 49) | ||
| Time to active antibiotic therapya (days, median [IQR]) | 3.1 (2.3–4.2) | 2.6 (1.2–3.1) | 0.002 |
| Definitive therapy (n [%]) | 0.146 | ||
| Daptomycin | 49 (73) | 33 (67) | |
| Linezolid | 13 (19) | 16 (33) | |
| Quinupristin-dalfopristin | 3 (4) | 0 (0) | |
| Tigecycline | 2 (3) | 0 (0) | |
| Inpatient duration of therapy (days, median [IQR]) | |||
| Daptomycinb | 5 (3–10) | 7 (2.8–10.2) | 0.695 |
| Linezolidc | 2 (1–7.1) | 7.3 (3.1–15.2) | 0.007 |
| Discharged on intravenous antibiotic (n [%]) | 27 (40) | 19 (39) | 0.868 |
| Length of stay (days, median [IQR]) | 16 (12–39) | 19 (10–32.5) | 0.801 |
| Readmission (90 days, all cause) (n [%]) | 23 (34) | 9 (18) | 0.057 |
| Mortality (90 days, all cause) (n [%]) | 15 (22) | 8 (16) | 0.419 |
Time between culture collection and initiation of first active antibiotic administration. Three patients did not receive therapy with a susceptible antibiotic during the admission. n = 64 and 49 for pre- and postintervention, respectively.
n = 64 and 42 for pre- and postintervention, respectively.
n = 16 and 20 for pre- and postintervention, respectively.
In summary, after a change in linezolid AST methodology, we observed an increase in linezolid susceptibility rates and a decrease in time to active therapy. The reduction in time to active therapy may be attributed to the reduced time to linezolid AST reporting in the EMR. No other changes in microbiology workflow surrounding this area occurred during the study period, supported by no differences in time to daptomycin AST reporting and susceptibility rates (control variables).
Improved linezolid susceptibility rates and faster AST reporting may contribute to quicker and safer effective antimicrobial management. For example, no patients in the postintervention group received toxic antibiotics, such as quinupristin-dalfopristin, compared to three patients in the preintervention group (Table 2). Daptomycin susceptibility was high and was likely an option. However, delayed daptomycin AST reporting may have prevented prescribers from recognizing daptomycin as an option. Prompt initiation of active antibiotics for the treatment of VRE bloodstream infections has been associated with improved clinical outcomes (8). Despite a statistically significant reduction in the time to active antibiotic therapy, only 20% of patients had bacteremia, and no difference in mortality was observed.
The study had several limitations. First, given the single-center retrospective study design, the data are limited by the availability and accuracy of documentation and are subject to selection bias. The results may not be reproducible at other sites, particularly in the setting of differences in technologist skill, breakpoints (CLSI versus EUCAST), and prescribing patterns. Prescribers may prefer daptomycin for VRE infections, and drug-drug interactions with linezolid often preclude its use. These factors may have contributed to the lack of difference in definitive antibiotic selection, despite linezolid’s lower cost and availability as an oral agent. Second, this study was not designed to evaluate clinical outcomes. Baseline comorbidities and clinical data pertinent to making conclusions regarding clinical outcomes were not captured. We also did not evaluate safety outcomes, such as medication-related side effects. Finally, we did not measure the impact of this change on microbiological labor and cost. However, we anticipate a reduction in both, given the additional cost of Etest strips and the automated Vitek 2 platform, which was already in use in the preintervention group.
This study demonstrates improvements in linezolid susceptibility rates and time to active antibiotic therapy among patients with VRE infections after transitioning linezolid AST methodology from the manual Etest to the automated Vitek 2. The findings provide support for investigating outliers in susceptibility rates in order to identify opportunities to optimize AST.
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