Makoto Jones

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.

Comparative Effectiveness of Cefazolin Versus Nafcillin or Oxacillin for Treatment of Methicillin-Susceptible Staphylococcus aureus Infections Complicated by Bacteremia: A Nationwide Cohort Study

Background To treat patients with methicillin-susceptible Staphylococcus aureus (MSSA) infections, β-lactams are recommended for definitive therapy; however, the comparative effectiveness of individual β-lactams is unknown. This study compared definitive therapy with cefazolin vs nafcillin or oxacillin among patients with MSSA infections complicated by bacteremia. Methods This retrospective study included patients admitted to 119 Veterans Affairs hospitals from 2003 to 2010. Patients were included if they had a blood culture positive for MSSA and received definitive therapy with cefazolin, nafcillin, or oxacillin. Cox proportional hazards regression and ordinal logistic regression were used to identify associations between antibiotic therapy and mortality or recurrence. A recurrent infection was defined as a MSSA blood culture between 45 and 365 days after the first MSSA blood culture. Results Of 3167 patients, 1163 (37%) patients received definitive therapy with cefazolin. Patients who received cefazolin had a 37% reduction in 30-day mortality (hazard ratio [HR], 0.63; 95% confidence interval [CI], .51-.78) and a 23% reduction in 90-day mortality (HR, 0.77; 95% CI, .66-.90) compared with patients receiving nafcillin or oxacillin, after controlling for other factors. The odds of recurrence (odds ratio, 1.13; 95% CI, .94-1.36) were similar among patients who received cefazolin compared with patients who received nafcillin or oxacillin, after controlling for other factors. Conclusions In this large, multicenter study, patients who received cefazolin had a lower risk of mortality and similar odds of recurrent infections compared with nafcillin or oxacillin for MSSA infections complicated by bacteremia. Physicians might consider definitive therapy with cefazolin for these infections.

Trends in Antibiotic Use and Nosocomial Pathogens in Hospitalized Veterans With Pneumonia at 128 Medical Centers, 2006–2010

BACKGROUND In 2005, pneumonia practice guidelines recommended broad-spectrum antibiotics for patients with risk factors for nosocomial pathogens. The impact of these recommendations on the ability of providers to match treatment with nosocomial pathogens is unknown. METHODS Among hospitalizations with a principal diagnosis of pneumonia at 128 Department of Veterans Affairs medical centers from 2006 through 2010, we measured annual trends in antibiotic selection; initial blood or respiratory cultures positive for methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Acinetobacter species; and alignment between antibiotic coverage and culture results for MRSA and P. aeruginosa, calculating sensitivity, specificity, and diagnostic odds ratio using a 2 × 2 contingency table. RESULTS In 95 511 hospitalizations for pneumonia, initial use of vancomycin increased from 16% in 2006 to 31% in 2010, and piperacillin-tazobactam increased from 16% to 27%, and there was a decrease in both ceftriaxone (from 39% to 33%) and azithromycin (change from 39% to 36%) (P < .001 for all). The proportion of hospitalizations with cultures positive for MRSA decreased (from 2.5% to 2.0%; P < .001); no change was seen for P. aeruginosa (1.9% to 2.0%; P = .14) or Acinetobacter spp. (0.2% to 0.2%; P = .17). For both MRSA and P. aeruginosa, sensitivity increased (from 46% to 65% and 54% to 63%, respectively; P < .001) and specificity decreased (from 85% to 69% and 76% to 68%; P < .001), with no significant changes in diagnostic odds ratio (decreases from 4.6 to 4.1 [P = .57] and 3.7 to 3.2 [P = .95], respectively). CONCLUSIONS Between 2006 and 2010, we found a substantial increase in the use of broad-spectrum antibiotics for pneumonia despite no increase in nosocomial pathogens. The ability of providers to accurately match antibiotic coverage to nosocomial pathogens remains low.

Antibiotic prescription practices for pneumonia, skin and soft tissue infections and urinary tract infections throughout the US Veterans Affairs system

OBJECTIVES Currently used metrics for antibiotic utilization are not linked to a diagnosis and may be difficult to interpret. We aimed to describe patterns and variation in antibiotic management of three common infectious disease diagnoses in Veterans Affairs Medical Centers (VAMCs). METHODS This descriptive retrospective cohort study included all veterans discharged between 2007 and 2009 after an acute care admission to a VAMC and a principal ICD-9-CM code for pneumonia (PNEU), skin and soft-tissue infections (SSTI), urinary tract infections (UTI) or non-infectious disease-related diagnoses (NON_INF). Systemic antibiotic use was assessed based on barcode medication administration data. A treatment period was defined as a time of uninterrupted inpatient antibiotic therapy with no gaps of >1 calendar day. RESULTS Over the study period there were 1.44 million discharges with an acute care admission to 128 VAMCs included in the study. Of the discharges, 58 118 had a primary ICD-9-CM diagnosis classifiable as PNEU, 36 797 as SSTI, 30 223 as UTI and 1 243 098 as NON_INF. Empirical antibiotic use during the first 2 hospital days was frequent for all infectious disease diagnoses. Type of empirical coverage varied among facilities for all conditions, as did treatment durations. Roughly half of all empirical courses of therapy where the patient was still hospitalized on day 4 did not exhibit any change to the antibiotic regimen. CONCLUSIONS There is substantial variation in the management of common infectious diseases with regard to choice of empirical agents and duration of therapy. Diagnosis-specific antibiotic use metrics may prove useful for antibiotic stewardship programmes.

Drugs of Last Resort? The Use of Polymyxins and Tigecycline at US Veterans Affairs Medical Centers, 2005–2010

Multidrug-resistant (MDR) and carbapenem-resistant (CR) Gram-negative pathogens are becoming increasingly prevalent around the globe. Polymyxins and tigecycline are among the few antibiotics available to treat infections with these bacteria but little is known about the frequency of their use. We therefore aimed to estimate the parenteral use of these two drugs in Veterans Affairs medical centers (VAMCs) and to describe the pathogens associated with their administration. For this purpose we retrospectively analyzed barcode medication administration data of parenteral administrations of polymyxins and tigecycline in 127 acute-care VAMCs between October 2005 and September 2010. Overall, polymyxin and tigecycline use were relatively low at 0.8 days of therapy (DOT)/1000 patient days (PD) and 1.6 DOT/1000PD, respectively. Use varied widely across facilities, but increased overall during the study period. Eight facilities accounted for three-quarters of all polymyxin use. The same statistic for tigecycline use was twenty-six VAMCs. There were 1,081 MDR or CR isolates during 747 hospitalizations associated with polymyxin use (1.4/hospitalization). For tigecycline these number were slightly lower: 671 MDR or CR isolates during 500 hospitalizations (1.3/hospitalization) (p = 0.06). An ecological correlation between the two antibiotics and combined CR and MDR Gram-negative isolates per 1000PD during the study period was also observed (Pearson’s correlation coefficient r = 0.55 polymyxin, r = 0.19 tigecycline). In summary, while polymyxin and tigecycline use is low in most VAMCs, there has been an increase over the study period. Polymyxin use in particular is associated with the presence of MDR Gram-negative pathogens and may be useful as a surveillance measure in the future.

Double trouble: how big a problem is redundant anaerobic antibiotic coverage in Veterans Affairs medical centres?

OBJECTIVES To assess the prevalence of, and the variation in, avoidable use of metronidazole in the Veterans Affairs (VA) healthcare system METHODS Barcode Medication Administration (BCMA) data were retrospectively assessed for all patients hospitalized between January 2006 and December 2010 in acute-care wards of all VA medical centres (VAMCs) with complete BCMA data and at least 10 acute-care non-intensive care unit (ICU) beds. Potentially avoidable metronidazole days of therapy (DOT) were defined as the administration of metronidazole with another anti-anaerobic antibiotic on the same day for at least two consecutive days during the same hospitalization. Metronidazole was not considered redundant in combination with another anti-anaerobic agent within 28 days after a positive test for Clostridium difficile and during hospitalizations associated with discharge diagnosis codes for cholecystitis or cholangitis. RESULTS A total of 128 VAMCs satisfied the inclusion criteria. Over the study period there were a total of 782,821 DOT of metronidazole (57.4 DOT per 1000 patient-days), of which 183,267 (23.4%) fulfilled the criteria for avoidable metronidazole DOT. The percentage of avoidable metronidazole DOT remained stable over the study period (22.8% in 2006 and 22.9% in 2010) despite a decrease in overall metronidazole use. There was wide variation in the percentage of avoidable metronidazole DOT among facilities (2010: median 20.3%, IQR 15.3%-29.4%). Piperacillin/tazobactam was the most commonly administered drug on avoidable metronidazole DOT (56.8%). CONCLUSIONS Potentially avoidable use of metronidazole affected about a quarter of all days when metronidazole was given. The combination of metronidazole with piperacillin/tazobactam was particularly common and represents a possible target for antibiotic stewardship interventions.

Characteristics of Antimicrobial Stewardship Programs at Veterans Affairs Hospitals: Results of a Nationwide Survey

BACKGROUND Antimicrobial stewardship programs (ASPs) are variably implemented. OBJECTIVE To characterize variations of antimicrobial stewardship structure and practices across all inpatient Veterans Affairs facilities in 2012 and correlate key characteristics with antimicrobial usage. DESIGN A web-based survey regarding stewardship activities was administered to each facilitys designated contact. Bivariate associations between facility characteristics and inpatient antimicrobial use during 2012 were determined. SETTING Total of 130 Veterans Affairs facilities with inpatient services. RESULTS Of 130 responding facilities, 29 (22%) had a formal policy establishing an ASP, and 12 (9%) had an approved ASP business plan. Antimicrobial stewardship teams were present in 49 facilities (38%); 34 teams included a clinical pharmacist with formal infectious diseases (ID) training. Stewardship activities varied across facilities, including development of yearly antibiograms (122 [94%]), formulary restrictions (120 [92%]), stop orders for antimicrobial duration (98 [75%]), and written clinical pathways for specific conditions (96 [74%]). Decreased antimicrobial usage was associated with having at least 1 full-time ID physician (P=.03), an ID fellowship program (P=.003), and a clinical pharmacist with formal ID training (P=.006) as well as frequency of systematic patient-level reviews of antimicrobial use (P=.01) and having a policy to address antimicrobial use in the context of Clostridium difficile infection (P=.01). Stop orders for antimicrobial duration were associated with increased use (P=.03). CONCLUSIONS ASP-related activities varied considerably. Decreased antibiotic use appeared related to ID presence and certain select practices. Further statistical assessments may help optimize antimicrobial practices. Infect Control Hosp Epidemiol 2016;37:647-654.

Relationships Between the Importation, Transmission, and Nosocomial Infections of Methicillin-Resistant Staphylococcus aureus: An Observational Study of 112 Veterans Affairs Medical Centers

BACKGROUND The study of hospital methicillin-resistant Staphylococcus aureus (MRSA) epidemiology is complicated by its transmissibility. Our objective was to understand how MRSA importation and transmission influence MRSA nosocomial infections in Veterans Affairs Medical Centers (VAMCs). METHODS We performed hospital-level analyses of acute-care MRSA admission prevalence, acquisition rates, and incident nosocomial clinical culture (INCC) rates, each a surrogate measure of importation, transmission, and nosocomial infection, respectively. We studied 112 VAMCs from October 2007 through September 2010, after the start of a bundled intervention including active surveillance for MRSA. We analyzed data using generalized linear mixed models. RESULTS A total of 2.9 million surveillance tests were collected from 1.4 million patient admissions. Overall MRSA admission prevalence was 11.4%, acquisition was 5.2 per 1000 patient-days at risk, and INCC was 1.8 per 1000 patient-days at risk. A 10% increase in a hospitals average admission prevalence was associated with a 9.7% increase in its weekly acquisition rates (P < .001) and a 9.8% increase in its weekly INCC rates (P < .001). Significant decreases were observed in all 3 measures during the study period (P < .001). When INCC rates were stratified by nasal MRSA carriage at admission, a significant downward trend was observed only among those initially negative. CONCLUSIONS Measured associations between MRSA admission prevalence, acquisition rate, and INCC rate were consistent with the hypothesis that decreased acquisition led to decreased importation, which in turn further abated acquisition. The downward trend in INCC rate specifically among individuals with negative admission surveillance tests suggests that decreasing transmission contributed to lower rates of nosocomial MRSA infection.

The Impact of Healthcare-Associated Methicillin-Resistant Staphylococcus Aureus Infections on Post-Discharge Healthcare Costs and Utilization

OBJECTIVE Healthcare-associated methicillin-resistant Staphylococcus aureus (MRSA) infections are a major cause of morbidity, mortality, and cost among hospitalized patients. Little is known about their impact on post-discharge resource utilization. The purpose of this study was to estimate post-discharge healthcare costs and utilization attributable to positive MRSA cultures during a hospitalization. METHODS Our study cohort consisted of patients with an inpatient admission lasting longer than 48 hours within the US Department of Veterans Affairs (VA) system between October 1, 2007, and November 30, 2010. Of these patients, we identified those with a positive MRSA culture from microbiology reports in the VA electronic medical record. We used propensity score matching and multivariable regression models to assess the impact of positive culture on post-discharge outpatient, inpatient, and pharmacy costs and utilization in the 365 days following discharge. RESULTS Our full cohort included 369,743 inpatients, of whom, 3,599 (1.0%) had positive MRSA cultures. Our final analysis sample included 3,592 matched patients with and without positive cultures. We found that, in the 12 months following hospital discharge, having a positive culture resulted in increases in post-discharge pharmacy costs (

The Effect of a Nationwide Infection Control Program Expansion on Hospital-Onset Gram-Negative Rod Bacteremia in 130 Veterans Health Administration Medical Centers: An Interrupted Time-Series Analysis

776, P<.0001) and inpatient costs (