Karim Khader

Comparative Effectiveness of Vancomycin and Metronidazole for the Prevention of Recurrence and Death in Patients With Clostridium difficile Infection

Importance Metronidazole hydrochloride has historically been considered first-line therapy for patients with mild to moderate Clostridium difficile infection (CDI) but is inferior to vancomycin hydrochloride for clinical cure. The choice of therapy may likewise have substantial consequences on other downstream outcomes, such as recurrence and mortality, although these secondary outcomes have been less studied. Objective To evaluate the risk of recurrence and all-cause 30-day mortality among patients receiving metronidazole or vancomycin for the treatment of mild to moderate and severe CDI. Design, Setting, and Participants This retrospective, propensity-matched cohort study evaluated patients treated for CDI, defined as a positive laboratory test result for the presence of C difficile toxins or toxin genes in a stool sample, in the US Department of Veterans Affairs health care system from January 1, 2005, through December 31, 2012. Data analysis was performed from February 7, 2015, through November 22, 2016. Exposures Treatment with vancomycin or metronidazole. Main Outcomes and Measures The outcomes of interest in this study were CDI recurrence and all-cause 30-day mortality. Recurrence was defined as a second positive laboratory test result within 8 weeks of the initial CDI diagnosis. All-cause 30-day mortality was defined as death from any cause within 30 days of the initial CDI diagnosis. Results A total of 47 471 patients (mean [SD] age, 68.8 [13.3] years; 1947 women [4.1%] and 45 524 men [95.9%]) developed CDI, were treated with vancomycin or metronidazole, and met criteria for entry into the study. Of 47 147 eligible first treatment episodes, 2068 (4.4%) were with vancomycin. Those 2068 patients were matched to 8069 patients in the metronidazole group for a total of 10 137 included patients. Subcohorts were constructed that comprised 5452 patients with mild to moderate disease and 3130 patients with severe disease. There were no differences in the risk of recurrence between patients treated with vancomycin vs those treated with metronidazole in any of the disease severity cohorts. Among patients in the any severity cohort, those who were treated with vancomycin were less likely to die (adjusted relative risk, 0.86; 95% CI, 0.74 to 0.98; adjusted risk difference, –0.02; 95% CI, –0.03 to –0.01). No significant difference was found in the risk of mortality between treatment groups among patients with mild to moderate CDI, but vancomycin significantly reduced the risk of all-cause 30-day mortality among patients with severe CDI (adjusted relative risk, 0.79; 95% CI, 0.65 to 0.97; adjusted risk difference, –0.04; 95% CI, –0.07 to –0.01). Conclusions and Relevance Recurrence rates were similar among patients treated with vancomycin and metronidazole. However, the risk of 30-day mortality was significantly reduced among patients who received vancomycin. Our findings may further justify the use of vancomycin as initial therapy for severe CDI.

The Magnitude of Time-Dependent Bias in the Estimation of Excess Length of Stay Attributable to Healthcare-Associated Infections.

BACKGROUND Estimates of the excess length of stay (LOS) attributable to healthcare-associated infections (HAIs) in which total LOS of patients with and without HAIs are biased because of failure to account for the timing of infection. Alternate methods that appropriately treat HAI as a time-varying exposure are multistate models and cohort studies, which match regarding the time of infection. We examined the magnitude of this time-dependent bias in published studies that compared different methodological approaches. METHODS We conducted a systematic review of the published literature to identify studies that report attributable LOS estimates using both total LOS (time-fixed) methods and either multistate models or matching patients with and without HAIs using the timing of infection. RESULTS Of the 7 studies that compared time-fixed methods to multistate models, conventional methods resulted in estimates of the LOS to HAIs that were, on average, 9.4 days longer or 238% greater than those generated using multistate models. Of the 5 studies that compared time-fixed methods to matching on timing of infection, conventional methods resulted in estimates of the LOS to HAIs that were, on average, 12.6 days longer or 139% greater than those generated by matching on timing of infection. CONCLUSION Our results suggest that estimates of the attributable LOS due to HAIs depend heavily on the methods used to generate those estimates. Overestimation of this effect can lead to incorrect assumptions of the likely cost savings from HAI prevention measures.

Incidence and Outcomes Associated With Infections Caused by Vancomycin-Resistant Enterococci in the United States: Systematic Literature Review and Meta-Analysis.

BACKGROUND Information about the health and economic impact of infections caused by vancomycin-resistant enterococci (VRE) can inform investments in infection prevention and development of novel therapeutics. OBJECTIVE To systematically review the incidence of VRE infection in the United States and the clinical and economic outcomes. METHODS We searched various databases for US studies published from January 1, 2000, through June 8, 2015, that evaluated incidence, mortality, length of stay, discharge to a long-term care facility, readmission, recurrence, or costs attributable to VRE infections. We included multicenter studies that evaluated incidence and single-center and multicenter studies that evaluated outcomes. We kept studies that did not have a denominator or uninfected controls only if they assessed postinfection length of stay, costs, or recurrence. We performed meta-analysis to pool the mortality data. RESULTS Five studies provided incidence data and 13 studies evaluated outcomes or costs. The incidence of VRE infections increased in Atlanta and Detroit but did not increase in national samples. Compared with uninfected controls, VRE infection was associated with increased mortality (pooled odds ratio, 2.55), longer length of stay (3-4.6 days longer or 1.4 times longer), increased risk of discharge to a long-term care facility (2.8- to 6.5-fold) or readmission (2.9-fold), and higher costs (

Excess length of stay attributable to clostridium difficile infection (CDI) in the acute care setting: A multistate model

9,949 higher or 1.6-fold more). CONCLUSIONS VRE infection is associated with large attributable burdens, including excess mortality, prolonged in-hospital stay, and increased treatment costs. Multicenter studies that use suitable controls and adjust for time at risk or confounders are needed to estimate the burden of VRE infections. Infect Control Hosp Epidemiol. 2017;38:203-215.

Estimates of outbreak risk from new introductions of ebola with immediate and delayed transmission control

BACKGROUND Standard estimates of the impact of Clostridium difficile infections (CDI) on inpatient lengths of stay (LOS) may overstate inpatient care costs attributable to CDI. In this study, we used multistate modeling (MSM) of CDI timing to reduce bias in estimates of excess LOS. METHODS A retrospective cohort study of all hospitalizations at any of 120 acute care facilities within the US Department of Veterans Affairs (VA) between 2005 and 2012 was conducted. We estimated the excess LOS attributable to CDI using an MSM to address time-dependent bias. Bootstrapping was used to generate 95% confidence intervals (CI). These estimates were compared to unadjusted differences in mean LOS for hospitalizations with and without CDI. RESULTS During the study period, there were 3.96 million hospitalizations and 43,540 CDIs. A comparison of unadjusted means suggested an excess LOS of 14.0 days (19.4 vs 5.4 days). In contrast, the MSM estimated an attributable LOS of only 2.27 days (95% CI, 2.14-2.40). The excess LOS for mild-to-moderate CDI was 0.75 days (95% CI, 0.59-0.89), and for severe CDI, it was 4.11 days (95% CI, 3.90-4.32). Substantial variation across the Veteran Integrated Services Networks (VISN) was observed. CONCLUSIONS CDI significantly contributes to LOS, but the magnitude of its estimated impact is smaller when methods are used that account for the time-varying nature of infection. The greatest impact on LOS occurred among patients with severe CDI. Significant geographic variability was observed. MSM is a useful tool for obtaining more accurate estimates of the inpatient care costs of CDI.

Incidence of Extended-Spectrum β-Lactamase (ESBL)-Producing Escherichia coli and Klebsiella Infections in the United States: A Systematic Literature Review

Identifying incoming patients can have a larger risk-reduction effect than efforts to reduce transmissions from identified patients.

Attributable mortality of healthcare-associated infections due to multidrug-resistant gram-negative bacteria and methicillin-resistant staphylococcus aureus

BACKGROUND Despite a reported worldwide increase, the incidence of extended-spectrum β-lactamase (ESBL) Escherichia coli and Klebsiella infections in the United States is unknown. Understanding the incidence and trends of ESBL infections will aid in directing research and prevention efforts. OBJECTIVE To perform a literature review to identify the incidence of ESBL-producing E. coli and Klebsiella infections in the United States. DESIGN Systematic literature review. METHODS MEDLINE via Ovid, CINAHL, Cochrane library, NHS Economic Evaluation Database, Web of Science, and Scopus were searched for multicenter (≥2 sites), US studies published between 2000 and 2015 that evaluated the incidence of ESBL-E. coli or ESBL-Klebsiella infections. We excluded studies that examined resistance rates alone or did not have a denominator that included uninfected patients such as patient days, device days, number of admissions, or number of discharges. Additionally, articles that were not written in English, contained duplicated data, or pertained to ESBL organisms from food, animals, or the environment were excluded. RESULTS Among 51,419 studies examined, 9 were included for review. Incidence rates differed by patient population, time, and ESBL definition and ranged from 0 infections per 100,000 patient days to 16.64 infections per 10,000 discharges and incidence rates increased over time from 1997 to 2011. Rates were slightly higher for ESBL-Klebsiella infections than for ESBL-E. coli infections. CONCLUSION The incidence of ESBL-E. coli and ESBL-Klebsiella infections in the United States has increased, with slightly higher rates of ESBL-Klebsiella infections. Appropriate estimates of ESBL infections when coupled with other mechanisms of resistance will allow for the appropriate targeting of resources toward research, drug discovery, antimicrobial stewardship, and infection prevention. Infect Control Hosp Epidemiol 2017;38:1209-1215.

Costs and Mortality Associated With Multidrug-Resistant Healthcare-Associated Acinetobacter Infections.

OBJECTIVE The purpose of this study was to quantify the effect of multidrug-resistant (MDR) gram-negative bacteria and methicillin-resistant Staphylococcus aureus (MRSA) healthcare-associated infections (HAIs) on mortality following infection, regardless of patient location. METHODS We conducted a retrospective cohort study of patients with an inpatient admission in the US Department of Veterans Affairs (VA) system between October 1, 2007, and November 30, 2010. We constructed multivariate log-binomial regressions to assess the impact of a positive culture on mortality in the 30- and 90-day periods following the first positive culture, using a propensity-score-matched subsample. RESULTS Patients identified with positive cultures due to MDR Acinetobacter (n=218), MDR Pseudomonas aeruginosa (n=1,026), and MDR Enterobacteriaceae (n=3,498) were propensity-score matched to 14,591 patients without positive cultures due to these organisms. In addition, 3,471 patients with positive cultures due to MRSA were propensity-score matched to 12,499 patients without positive MRSA cultures. Multidrug-resistant gram-negative bacteria were associated with a significantly elevated risk of mortality both for invasive (RR, 2.32; 95% CI, 1.85-2.92) and noninvasive cultures (RR, 1.33; 95% CI, 1.22-1.44) during the 30-day period. Similarly, patients with MRSA HAIs (RR, 2.77; 95% CI, 2.39-3.21) and colonizations (RR, 1.32; 95% CI, 1.22-1.50) had an increased risk of death at 30 days. CONCLUSIONS We found that HAIs due to gram-negative bacteria and MRSA conferred significantly elevated 30- and 90-day risks of mortality. This finding held true both for invasive cultures, which are likely to be true infections, and noninvasive infections, which are possibly colonizations. Infect Control Hosp Epidemiol 2017;38:848-856.

The Potential for Interventions in a Long-term Acute Care Hospital to Reduce Transmission of Carbapenem-Resistant Enterobacteriaceae in Affiliated Healthcare Facilities

BACKGROUND Our objective was to estimate the per-infection and cumulative mortality and cost burden of multidrug-resistant (MDR) Acinetobacter healthcare-associated infections (HAIs) in the United States using data from published studies. METHODS We identified studies that estimated the excess cost, length of stay (LOS), or mortality attributable to MDR Acinetobacter HAIs. We generated estimates of the cost per HAI using 3 methods: (1) overall cost estimates, (2) multiplying LOS estimates by a cost per inpatient-day (

Efficient parameter estimation for models of healthcare-associated pathogen transmission in discrete and continuous time

4,350) from the payer perspective, and (3) multiplying LOS estimates by a cost per inpatient-day from the hospital (