Enteric microbiome profiles during a randomized Phase 2 clinical trial of surotomycin versus vancomycin for the treatment of Clostridium difficile infection.

OBJECTIVES: The effects of surotomycin (CB-183,315, MK-4261), a bactericidal cyclic lipopeptide, and vancomycin, the current standard-of-care for Clostridium difficile infection (CDI), on intestinal pathogens and microbiota were evaluated parallel to a Phase 2 randomized, double-blind clinical trial. METHODS: The single-centre cohort included 26 patients receiving surotomycin [125 or 250 mg twice daily (n = 9 each)] or oral vancomycin [125 mg four times daily (n = 8)] for 10 days. Faecal samples were collected at days 0-42 to quantify both C. difficile by conventional culture and the major components of the microbiome by quantitative PCR. RESULTS: Surotomycin 250 mg twice daily or vancomycin 125 mg four times daily reduced faecal C. difficile counts from ∼105-107 log10 cfu/g at baseline to ≤ 102 cfu/g by days 4-10 of treatment. Day 10 counts of C. difficile in 3/9 patients receiving surotomycin 125 mg twice daily remained detectable, including one patient who failed to achieve clinical cure. Bacteroidetes and Prevotella mean counts increased 0.7 log10 or remained unchanged with surotomycin 125 and 250 mg twice daily, respectively, whereas vancomycin reduced counts by 2.5-3.2 log10 (P < 0.02). Vancomycin reduced Firmicutes counts by 2.5-2.8 log10; surotomycin moderately suppressed these microbes in a dose-dependent manner. CONCLUSIONS: In this Phase 2 trial substudy, compared with vancomycin 125 mg four times daily, surotomycin 250 mg twice daily is as active in vivo against C. difficile, but was more sparing of microbiota. Surotomycin is no longer in development due to failed Phase 3 efficacy results.

Differences of the Fecal Microflora With Clostridium difficile Therapies.

BACKGROUND: During treatment of Clostridium difficile infection (CDI), patterns of pathogen reduction in relationship to changes in components of the normal microbiota are hypothesized to be predictive of response to treatment and subsequent sustained cure. METHODS: At a single center, subjects enrolled into phase 2 and 3 C. difficile treatment clinical trials (2003-2008) provided fecal samples to assess killing of C. difficile and changes to components of the microbiome. Quantitative bacterial cultures, measurement of C. difficile toxin titers, quantitative polymerase chain reaction of fecal samples for Bacteroidetes, Clostridium clusters XIVa and IV, and C. difficile were performed. RESULTS: Quantitative bacterial cultures showed a mean log10 C. difficile count (colony-forming units [CFU]) of 6.7 ± 2.0 at study entry; vancomycin treatment consistently reduced C. difficile counts to the limit of detection (2.0 log10 CFU/g), whereas metronidazole was associated with mean C. difficile counts 1.5-2 log10 higher at 10 days of treatment. In patients receiving tolevamer, C. difficile persisted in high counts during treatment; response to treatment was correlated with neutralization of toxin along with persistence of normal microbiota components. However, this was achieved in approximately half of subjects. Both vancomycin and metronidazole further suppressed microbiome components during treatment of CDI. Lactobacilli were observed to be a microbiome component that persisted during treatment of CDI. CONCLUSIONS: Differences of pathogen clearance and microbiome perturbation during treatment of CDI appear to explain treatment outcomes. The hypothesis that probiotic microbes could help prevent onset of CDI is supported by the observation of persistence of lactobacilli during and after treatment of CDI.

Microbiology of cardiac implantable electronic device infections in Calgary, Canada.

The microbiology of cardiac implantable electronic device (CIED) infections in Calgary, Alberta was described, identifying 50 infections from 2013 to 2019. The majority were Staphylococcus aureus (40.0%). There is significant economic burden, mostly related to inpatient costs, associated with CIED infections. However, there were no significant differences in costs stratified by organism.

The economic burden of cardiac implantable electronic device infections in Alberta, Canada: a population-based study using validated administrative data.

BACKGROUND: Cardiac implantable electronic devices (CIED) are being inserted with increasing frequency. Severe surgical site infections (SSI) that occur after device implantation substantially impact patient morbidity and mortality and can result in multiple hospital admissions and repeat surgeries. It is important to understand the costs associated with these infections as well as healthcare utilization. Therefore, we conducted a population-based study in the province of Alberta, Canada to understand the economic burden of these infections. METHODS: A cohort of adult patients in Alberta who had CIEDs inserted or generators replaced between January 1, 2011 and December 31, 2019 was used. A validated algorithm of International Classification of Diseases (ICD) codes to identify complex (deep/organ space) SSIs that occurred within the subsequent year was applied to the cohort. The overall mean 12-month inpatient and outpatient costs for the infection and non-infection groups were assessed. In order to control for variables that may influence costs, propensity score matching was completed and incremental costs between those with and without infection were calculated. As secondary outcomes, number of outpatient visits, hospitalizations and length of stay were assessed. RESULTS: There were 26,049 procedures performed during our study period, of which 320 (1.23%) resulted in SSIs. In both unadjusted costs and propensity score matched costs the infection group was associated with increased costs. Overall mean cost was $145,312 in the infection group versus $34,264 in the non-infection group. The incremental difference in those with infection versus those without in the propensity score match was $90,620 (Standard deviation $190,185). Approximately 70% of costs were driven by inpatient hospitalizations. Inpatients hospitalizations, length of stay and outpatient visits were all increased in the infection group. CONCLUSIONS: CIED infections are associated with increased costs and are a burden to the healthcare system. This highlights a need to recognize increasing SSI rates and implement measures to minimize infection risk. Further studies should endeavor to apply this work to full economic evaluations to better understand and identify cost-effective infection mitigation strategies.

Complex cardiac implantable electronic device infections in Alberta, Canada: An epidemiologic cohort study of validated administrative data.

OBJECTIVE: To establish the epidemiology of cardiac implantable electronic device (CIED) infections in Alberta, Canada, using validated administrative data. DESIGN: Retrospective, population-based cohort study. SETTING: Alberta Health Services is a province-wide health system that services all of Alberta, Canada. PARTICIPANTS: Adult patients who underwent first-time CIED implantation or generator replacement in Alberta, Canada, between January 1, 2011, and December 31, 2019. METHODS: CIED implant patients were identified from the Paceart database. Patients who developed an infection within 1 year of the index procedure were identified through validated administrative data (International Classification of Diseases, Tenth Revision in Canada). Demographic characteristics of patients were summarized. Logistic regression models were used to analyze device type, comorbidities, and demographics associated with infection rates and mortality. RESULTS: Among 27,830 CIED implants, there were 205 infections (0.74%). Having 2 or more comorbidities was associated with higher infection risk. Generator replacement procedures (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.34-0.84; P = .008), age increase of every 10 years (OR, 0.73; 95% CI, 0.66-0.82; P ≤ .001), and index procedure after 2014 were associated with decreased risk. Comparing the infected to uninfected groups, the hospitalization rates were 2.63 compared to 0.69, and the mortality rates were 10.73% compared to 3.49%, respectively (P < .001). CONCLUSIONS: There is a slightly lower overall rate of CIED infections Alberta, Canada compared to previously described epidemiology. Implants after 2014, and generator replacements showed a decreased burden of infection. Patients with younger age, and 2 or more comorbidities are at greatest risk of CIED infection. The burden of hospitalization and mortality is substantially higher in infected patients.

Validating administrative data to identify complex surgical site infections following cardiac implantable electronic device implantation: a comparison of traditional methods and machine learning.

BACKGROUND: Cardiac implantable electronic device (CIED) surgical site infections (SSIs) have been outpacing the increases in implantation of these devices. While traditional surveillance of these SSIs by infection prevention and control would likely be the most accurate, this is not practical in many centers where resources are constrained. Therefore, we explored the validity of administrative data at identifying these SSIs. METHODS: We used a cohort of all patients with CIED implantation in Calgary, Alberta where traditional surveillance was done for infections from Jan 1, 2013 to December 31, 2019. We used this infection subgroup as our "gold standard" and then utilized various combinations of administrative data to determine which best optimized the sensitivity and specificity at identifying infection. We evaluated six approaches to identifying CIED infection using administrative data, which included four algorithms using International Classification of Diseases codes and/or Canadian Classification of Health Intervention codes, and two machine learning models. A secondary objective of our study was to assess if machine learning techniques with training of logistic regression models would outperform our pre-selected codes. RESULTS: We determined that all of the pre-selected algorithms performed well at identifying CIED infections but the machine learning model was able to produce the optimal method of identification with an area under the receiver operating characteristic curve (AUC) of 96.8%. The best performing pre-selected algorithm yielded an AUC of 94.6%. CONCLUSIONS: Our findings suggest that administrative data can be used to effectively identify CIED infections. While machine learning performed the most optimally, in centers with limited analytic capabilities a simpler algorithm of pre-selected codes also has excellent yield. This can be valuable for centers without traditional surveillance to follow trends in SSIs over time and identify when rates of infection are increasing. This can lead to enhanced interventions for prevention of SSIs.

Subacute sclerosing panencephalitis in pregnancy.

We present a case of subacute sclerosing panencephalitis that developed in a previously healthy 29-year-old pregnant woman who had returned from a trip to rural India shortly before the onset of symptoms. She was admitted to hospital at 27 weeks' gestation with a history of cognitive decline and difficulty completing simple tasks. She had no clinical signs of infection. The working diagnosis was autoimmune encephalitis, although extensive investigations did not lead to a final classifying diagnosis. The patient became comatose and developed hypertension, and an emergency caesarean section was done at 31 weeks to deliver the child, who seemed healthy. The patient died about 6 weeks after the onset of symptoms. The patient was found to have had subacute sclerosing panencephalitis at autopsy. In this Grand Round, we review the clinical features and treatment of subacute sclerosing panencephalitis, and the epidemiological and public health aspects of the case.