By Carol A. Kemper, MD, FIDSA, FACP
Clostridioides difficile: Reduced Susceptibility to Vancomycin?
Source: Eubank TA, Dureja C, Garey KW, et al. Reduced vancomycin susceptibility in Clostridioides difficile is associated with lower rates of initial clinic cure and sustained clinic response. Clin Infect Dis. 2024;79(1):15-21.
Many sites have been reluctant to prescribe fidaxomicin as the first-line agent, despite fairly robust evidence indicating its efficacy relative to vancomycin in preventing recurrences. We still cannot predict who will do well with vancomycin and which patients are likely to relapse or to do more poorly. The gradual emergence of Clostridioides difficile (CD) with reduced vancomycin susceptibility may contribute to adverse outcomes when using this agent.
A Houston-based multicenter cohort study, performed from 2016 to 2021, examined CD susceptibility to vancomycin, ribotype identification, and sequence variation of the vanR gene, compared with clinical outcomes at 14 and 30 days. Reduced susceptibility was defined as a minimum inhibitory concentration (MIC) > 2 mcg/mL based on Clinical and Laboratory Standards Institute (CLSI) epidemiological cutoff values. The primary study outcome was 30-day sustained clinical response, and secondary outcomes were 14-day clinical response, 30-day recurrence, and 30-day mortality. Samples were prospectively collected, although the clinical portion of the study was based on retrospective database analysis. The study included adults (≥ 18 years of age) testing positive for CD (either nucleic acid amplification testing or toxin testing) who were treated with orally administered vancomycin monotherapy (metronidazole was not permitted beyond the first 48 hours of treatment). The average duration of vancomycin therapy was ~ 15 days.
Three hundred stool samples were analyzed, of which 102 (34%) demonstrated reduced vancomycin susceptibility (none demonstrated high-level resistance with MIC ≥ 32 mcg/mL). Fifty-three isolates were identified as the “hypervirulent” ribotype NAP1/B1/027 strain, 41 (77.4%) of which exhibited reduced vancomycin susceptibility. Sustained clinical response was observed at 30 days in 249 patients (83%), including 171/198 (86%) of patients with vancomycin-susceptible strains and 78/102 (76%) with reduced vancomycin susceptibility (P = 0.031). Clinical cure at 14 days also was significantly associated with vancomycin susceptibility vs. reduced susceptibility (96% vs. 89%, respectively) (P = 0.04). Of the 51 patients who did not achieve a sustained clinical response at 30 days, 20 (39%) had continued diarrhea at day 14, nine (18%) relapsed by 30 days, and 22 (43%) died within 30 days of their CD infection diagnosis.
In preliminary analysis, failing to achieve a 30-day sustained clinical response was significantly associated with ribotype 027 and a worse Charlson Comorbidity Index (CCI). However, in multivariate analysis, only reduced vancomycin susceptibility and a higher CCI score remained independent predictors of 30-day sustained clinical response.
Reduced vancomycin susceptibility was observed in 34% of clinical isolates and was associated with a reduced clinical response at 14 and 30 days. Despite evidence of reduced vancomycin susceptibility, 76% of such patients achieved a 30-day sustained clinical response with this agent. This is believed to be the result of extremely high concentrations of vancomycin within the gut lumen (ranging from 500 mcg/mL to 2,000 mcg/mL), which may “overcome” modest reductions in susceptibility. It also is possible that vancomycin may not be evenly distributed throughout the gut lumen.
Relapses in patients receiving vancomycin may occur in up to 20% to 25% of patients, and many are re-treated with the same agent, perhaps for longer durations or with an extended taper. This study provides several useful clues to clinical management. Firstly, while CD cultures are labor intensive, outcomes for patients with CD, especially hospitalized patients, are critical enough to justify the use of MIC as a therapeutic marker. Patients with continued diarrhea or who failed to achieve clinical cure at 14 days of treatment are unlikely to achieve a clinical response with vancomycin and experience higher rates of mortality, suggesting these patients should be switched to an alternate agent. A majority of ribotype 027 isolates (77.4%) exhibited reduced vancomycin susceptibility, and consideration could be given to pre-emptively treating patients with recognized 027 infection with an alternate agent. The Xpert gene test (Cepheid) detects both toxigenic genes and also presumptively identifies the 027 strain, providing a rapid diagnostic tool for differentiating these isolates.
This study has several limitations, including a lack of information on whether continued antibacterial therapy was used in some patients; the dose of vancomycin monotherapy was not specified; some patients were identified based on a positive nucleic acid amplification test result and may not have had active CD infection; and the duration of follow-up for clinical cure and relapse was only 30 days, although the usual definition of relapse is within eight weeks.
Antibiotics Reduce Culture Yield in Joint Infection
Source: Khodadadi RB, Damronglerd P, McHugh JW, et al. Effect of preoperative antibiotic therapy on operative culture yield for diagnosis of native joint septic arthritis. Clin Infect Dis. 2024;79:1062-1070.
These investigators assessed the degree to which the administration of pre-operative antibiotics in patients with native joint septic arthritis affects culture results. A presumptive diagnosis of native joint septic arthritis from joint aspirates often is based on the synovial cell count (> 30,000 cells/mcL), the proportion of neutrophils (> 90%), or a positive Gram stain, although a positive culture remains the gold standard, and greatly affects the choice of antibacterial therapy. For this reason, many experts advocate holding off on antibiotics until appropriate samples have been collected.
This retrospective cohort study included adults (≥ 18 years of age) with native joint septic arthritis who had both pre-operative synovial aspirates and intra-operative cultures performed. Any antibiotic therapy received following initial joint aspirate and within two weeks of surgery was recorded, including peri-operative antibiotics received prior to the collection of operative culture specimens, as well as the number of doses and duration of therapy.
A total of 299 patients with 311 affected joints were included in the study. Among these, 255 received pre-operative antibiotics and 46 patients did not. The median age was 62 years, most were male (63%), and 88.3% had mono-articular arthritis. The majority were believed to have hematogenous seeding of the joint (67.9%) based on positive blood cultures or evidence of infection elsewhere. Two-hundred sixty-six patients had blood cultures obtained and 123 (46.2%) were positive. A minority (4.3%) of patients had positive blood cultures in the presence of a red, hot joint when both joint aspirate and operative cultures were negative. The median number of antibiotic doses received was four (2-11) and the median number of days duration of antibacterial therapy was 1.0 (0.4-2.9 days). The median number of intra-operative cultures was three (1-3), although the median number of positive intra-operative cultures was one.
The overall yield from pre-operative aspirates was 67% and the overall yield from intra-operative cultures was 58.6%. The distribution of bacterial organisms was similar between those who did and did not receive pre-operative antibacterials. Methicillin-susceptible Staphylococcus aureus (MSSA)/methicillin-resistant S. aureus (MRSA) were the most common organisms identified, occurring in 58% of positive pre-operative cultures and 59.2% of intra-operative cultures, followed by Streptococcus species, coagulase-negative Staphylococcus, Pasteurella spp., and, lastly, gram negatives.
Among those who received pre-operative antibiotics, the yield from joint aspirates (68%) was modestly reduced to 57.1% at surgery (P < 0.001). In contrast, for those patients who received no antibiotics, the yield from joint aspirates (60.9%) modestly increased to 67.4% at the time of surgery (P = 0.24). The greater number of antibiotic doses and the longer duration of therapy prior to surgery was associated with lower culture yield. Streptococci appeared to be the most affected by antibiotic administration between joint aspiration and intra-operative culture. Interestingly, joint aspirates/synovial fluid cultures and intra-operative specimens were both positive in 52.3% of patients, whereas both were negative in 26.8%. From pre-operative to intra-operative, cultures changed from positive to negative in 14.6% of patients, whereas only a small number changed from negative to positive by the time of surgery (6.2%).
I found this study to be valuable with several salient points, and anything that can increase the chances of a positive culture is useful, including:
- Obtain blood cultures, even in the absence of fever or other clinical signs of infection; a majority of the patients (68%) in this study had hematogenous seeding; and a small number of patients (4.3%) with an apparent septic joint had positive blood cultures with both a culture-negative joint aspirate and operative specimens.
- Obtain both pre-operative synovial fluid culture and intra-operative cultures when possible.
- Obtain several intra-operative specimens for culture — in this study, only one of three intra-operative cultures was positive.
- Hold off on pre-operative treatment whenever reasonable; there is about a 19% higher culture yield in patients who do not receive antibiotics before the collection of operative specimens (including peri-operative antibiotics). This may be one of the few occasions when peri-operative antibiotics, prior to cut time, may not be indicated.
Carol A. Kemper, MD, FIDSA, is Medical Director, Infection Prevention, El Camino Hospital, Palo Alto Medical Foundation.