Kevin A. Brown

Meta-Analysis of Antibiotics and the Risk of Community-Associated Clostridium difficile Infection

ABSTRACT The rising incidence of Clostridium difficile infection (CDI) could be reduced by lowering exposure to high-risk antibiotics. The objective of this study was to determine the association between antibiotic class and the risk of CDI in the community setting. The EMBASE and PubMed databases were queried without restriction to time period or language. Comparative observational studies and randomized controlled trials (RCTs) considering the impact of exposure to antibiotics on CDI risk among nonhospitalized populations were considered. We estimated pooled odds ratios (OR) for antibiotic classes using random-effect meta-analysis. Our search criteria identified 465 articles, of which 7 met inclusion criteria; all were observational studies. Five studies considered antibiotic risk relative to no antibiotic exposure: clindamycin (OR = 16.80; 95% confidence interval [95% CI], 7.48 to 37.76), fluoroquinolones (OR = 5.50; 95% CI, 4.26 to 7.11), and cephalosporins, monobactams, and carbapenems (CMCs) (OR = 5.68; 95% CI, 2.12 to 15.23) had the largest effects, while macrolides (OR = 2.65; 95% CI, 1.92 to 3.64), sulfonamides and trimethoprim (OR = 1.81; 95% CI, 1.34 to 2.43), and penicillins (OR = 2.71; 95% CI, 1.75 to 4.21) had lower associations with CDI. We noted no effect of tetracyclines on CDI risk (OR = 0.92; 95% CI, 0.61 to 1.40). In the community setting, there is substantial variation in the risk of CDI associated with different antimicrobial classes. Avoidance of high-risk antibiotics (such as clindamycin, CMCs, and fluoroquinolones) in favor of lower-risk antibiotics (such as penicillins, macrolides, and tetracyclines) may help reduce the incidence of CDI.

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 and Duration of Clostridium difficile Infection Risk Associated with Antibiotic Therapy: A Hospital Cohort Study

Antibiotic therapy is the principal risk factor for Clostridium difficile infection (CDI), but little is known about how risks cumulate over the course of therapy and abate after cessation. We prospectively identified CDI cases among adults hospitalized at a tertiary hospital between June 2010 and May 2012. Poisson regression models included covariates for time since admission, age, hospitalization history, disease pressure, and intensive care unit stay. Impacts of antibiotic use through time were modeled using 4 measures: current antibiotic receipt, time since most recent receipt, time since first receipt during a hospitalization, and duration of receipt. Over the 24-month study period, we identified 127 patients with new onset nosocomial CDI (incidence rate per 10,000 patient days [IR] = 5.86). Of the 4 measures, time since most recent receipt was the strongest independent predictor of CDI incidence. Relative to patients with no prior receipt of antibiotics in the last 30 days (IR = 2.95), the incidence rate of CDI was 2.41 times higher (95% confidence interval [CI] 1.41, 4.13) during antibiotic receipt and 2.16 times higher when patients had receipt in the prior 1–5 days (CI 1.17, 4.00). The incidence rates of CDI following 1–3, 4–6 and 7–11 days of antibiotic exposure were 1.60 (CI 0.85, 3.03), 2.27 (CI 1.24, 4.16) and 2.10 (CI 1.12, 3.94) times higher compared to no prior receipt. These findings are consistent with studies showing higher risk associated with longer antibiotic use in hospitalized patients, but suggest that the duration of increased risk is shorter than previously thought.

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.

Transfer of Patients With ST-Elevation Myocardial Infarction for Primary Percutaneous Coronary Intervention A Province-Wide Evaluation of “Door-in to Door-Out” Delays at the First Hospital

Background— Interhospital transfer of patients with ST-elevation myocardial infarction (STEMI) for primary percutaneous coronary intervention (PPCI) is associated with longer delays to reperfusion, related in part to turnaround (“door in” to “door out,” or DIDO) time at the initial hospital. As part of a systematic, province-wide evaluation of STEMI care, we examined DIDO times and associations with patient, hospital, and process-of-care factors. Methods and Results— We performed medical chart review for STEMI patients transferred for PPCI during a 6-month period (October 1, 2008, through March 31, 2009) and linked these data to ambulance service databases. Two core laboratory cardiologists reviewed presenting ECGs to identify left bundle-branch block and, in the absence of left bundle-branch block, definite STEMI (according to both cardiologists) or an ambiguous reading. Median DIDO time was 51 minutes (25th to 75th percentile: 35–82 minutes); 14.1% of the 988 patients had a timely DIDO interval (≤30 minutes as recommended by guidelines). The data-to-decision delay was the major contributor to DIDO time. Female sex, more comorbidities, longer symptom duration, arrival by means other than ambulance, arrival at a hospital not exclusively transferring for PPCI, arrival at a center with a low STEMI volume, and an ambiguous ECG were independently associated with longer DIDO time. When turnaround was timely, 70% of patients received timely PPCI (door-to-device time ≤90 minutes) versus 14% if turnaround was not timely ( P <0.0001). Conclusions— Benchmark DIDO times for STEMI patients transferred for PPCI were rarely achieved. Interventions aimed at facilitating the transfer decision, particularly in cases of ECGs that are difficult to interpret, are likely to have the best impact on reducing delay to reperfusion. # CLINICAL PERSPECTIVE {#article-title-17}Background— Interhospital transfer of patients with ST-elevation myocardial infarction (STEMI) for primary percutaneous coronary intervention (PPCI) is associated with longer delays to reperfusion, related in part to turnaround (“door in” to “door out,” or DIDO) time at the initial hospital. As part of a systematic, province-wide evaluation of STEMI care, we examined DIDO times and associations with patient, hospital, and process-of-care factors. Methods and Results— We performed medical chart review for STEMI patients transferred for PPCI during a 6-month period (October 1, 2008, through March 31, 2009) and linked these data to ambulance service databases. Two core laboratory cardiologists reviewed presenting ECGs to identify left bundle-branch block and, in the absence of left bundle-branch block, definite STEMI (according to both cardiologists) or an ambiguous reading. Median DIDO time was 51 minutes (25th to 75th percentile: 35–82 minutes); 14.1% of the 988 patients had a timely DIDO interval (⩽30 minutes as recommended by guidelines). The data-to-decision delay was the major contributor to DIDO time. Female sex, more comorbidities, longer symptom duration, arrival by means other than ambulance, arrival at a hospital not exclusively transferring for PPCI, arrival at a center with a low STEMI volume, and an ambiguous ECG were independently associated with longer DIDO time. When turnaround was timely, 70% of patients received timely PPCI (door-to-device time ⩽90 minutes) versus 14% if turnaround was not timely (P<0.0001). Conclusions— Benchmark DIDO times for STEMI patients transferred for PPCI were rarely achieved. Interventions aimed at facilitating the transfer decision, particularly in cases of ECGs that are difficult to interpret, are likely to have the best impact on reducing delay to reperfusion.

The Co-Seasonality of Pneumonia and Influenza With Clostridium difficile Infection in the United States, 1993–2008

Seasonal variations in the incidence of pneumonia and influenza are associated with nosocomial Clostridium difficile infection (CDI) incidence, but the reasons why remain unclear. Our objective was to consider the impact of pneumonia and influenza timing and severity on CDI incidence. We conducted a retrospective cohort study using the US National Hospital Discharge Survey sample. Hospitalized patients with a diagnosis of CDI or pneumonia and influenza between 1993 and 2008 were identified from the National Hospital Discharge Survey data set. Poisson regression models of monthly CDI incidence were used to measure 1) the time lag between the annual pneumonia and influenza prevalence peak and the annual CDI incidence peak and 2) the lagged effect of pneumonia and influenza prevalence on CDI incidence. CDI was identified in 18,465 discharges (8.52 per 1,000 discharges). Peak pneumonia prevalence preceded peak CDI incidence by 9.14 weeks (95% confidence interval: 4.61, 13.67). A 1% increase in pneumonia prevalence was associated with a cumulative effect of 11.3% over a 6-month lag period (relative risk = 1.113, 95% confidence interval: 1.073, 1.153). Future research could seek to understand which mediating pathways, including changes in broad-spectrum antibiotic prescribing and hospital crowding, are most responsible for the associated changes in incidence.

Importation, Antibiotics, and Clostridium difficile Infection in Veteran Long-Term Care: A Multilevel Case–Control Study

Context Variation in Clostridium difficile incidence among long-term care facilities is not well-understood. Contribution This study compared regional Veterans Health Administration long-term care facilities. There was wide variation in C difficile incidence that was largely explained by differences in overall use of antibiotics and the importation of C difficile from acute care settings, rather than individual patient factors, such as age, number of comorbidities, and antibiotic use. Implication Approaches that focus on infection control and institutional antibiotic stewardship may be most beneficial for reducing C difficile incidence in long-term care facilities. Clostridium difficile infection is a diarrheal disease that is associated with antibiotic and health care exposures. It has the highest prevalence, morbidity, and mortality of any health careassociated infection (1, 2). Risk factors have been extensively studied and include age, comorbidity burden, abdominal surgery, feeding tube use, and exposure to antibiotics and antacids (3). Almost all antibiotic classes are believed to increase risk; however, the risk is greatest for antibiotics with activity against gut flora but none against C difficile, including cephalosporins, fluoroquinolones, and clindamycin (4, 5). Antacids, especially proton-pump inhibitors, are believed to increase risk by reducing stomach acidity, thereby allowing increased numbers of viable C difficile to reach the gut. Although clinical risk factors have been extensively studied, the environmental and facility-level exposures that may drive C difficile transmission have not. What is known is that C difficile is transmitted by the fecaloral route, and patients with symptomatic disease or asymptomatic colonization have high bacterial loads in their stool and shed infectious spores into their environs for extended periods (6, 7). Exposure of patients to ward-level disease pressure, measured as the daily number of infectious patients with recent C difficile present in the same ward, predicts increased risk for infection (8). In addition to disease pressure, antibiotic use in wards has been shown to increase the risk for infection together with individual-level antibiotic exposure (9). This independent effect of ward antibiotic use may be due to the higher likelihood of asymptomatic C difficile colonization and shedding among patients with recent antibiotic exposure (7), which creates a greater environmental C difficile burden. Long-term care facilities provide services to residents requiring assistance with activities of daily living in a residential setting, skilled nursing, spinal cord injury care, and rehabilitation. In long-term care, antimicrobial use is generally high, with the point prevalence around 8%; of this, 25% to 75% may be inappropriate (10). To our knowledge, the effect of antimicrobial use on C difficile incidence in long-term care has never been explored. Further, long-term care residents have frequent contact with acute care facilities; therefore, importation of hospital-onset C difficile infection may be an important risk factor for infection in long-term care facilities (11). Models incorporating both individual- and facility-level risk factors can be used to distinguish risk factors that affect individual susceptibility to disease from those that that may be associated with the degree of environmental contamination and that may proxy spore ingestion (12). The objective of this study was to obtain a comprehensive picture of the individual and regional factors that drive C difficile infection risk across Veterans Health Administration (VHA) long-term care facilities, with an interest in the role of importation of persons with acute careonset C difficile infection and regional rates of antibiotic use. Methods Ethics Statement Study approval was obtained from the Research Ethics Board of the Veterans Affairs Salt Lake City Health Care System. The Board waived the need for consent because there was no contact with residents, and anonymity was assured. Study Design We conducted a retrospective study of VHA long-term care residents across 111 health care regions from 1 January 2006 through 31 December 2012. In the VHA, health care regions act as local health care systems and usually provide both acute and long-term care services. In most of these regions, long-term care services were delivered at a single facility (n= 89), although care was distributed across 2 or more locations (n= 22) in some regions. All long-term care facilities provide 24-hour nursing care, and some also provide psychiatric, spinal cord injury, or hospice care. This retrospective study used a multilevel, longitudinal, nested casecontrol design. To accurately estimate resident risk, a multilevel model that incorporated both resident-level risk factors (characteristics of specific at-risk persons) and regional risk factors (measures of the prevalence of residents who were likely to shed C difficile spores) was used. To allow short-term pharmaceutical exposures to be measured in an appropriate retrospective window, the analysis data set was broken down into a longitudinal resident-day format. Because the resultant data set was extensive, a nested casecontrol design was used. Population Residents were considered at risk for onset of C difficile infection in a long-term care facility if they resided in an inpatient VHA long-term care facility for 3 or more of the previous 28 days and did not have a positive C difficile test result in the prior 8 weeks. Health care regions, and eligible residents within them, were included in the risk set if there were at least 6 years of data in which long-term and acute care censuses were greater than an average of 10 eligible, at-risk persons per day for each month of the given year. Regions without acute care facilities were excluded because imported cases of C difficile infection from non-VHA acute care facilities were not captured and would have led to an underestimate of C difficile importation in those regions. Definition of Cases and Controls Residents were considered cases on the date of a positive C difficile toxin test result 3 days or more after long-term care admission and at least 8 weeks from a previous positive result (13). Positive results were identified from VHA microbiology data using natural language processing (14). Eligible controls were resident-days that did not meet the case definition and could include resident-days from persons who later became cases. A 1%, unmatched, simple random sample of eligible controls was selected for analysis. Resident Risk Factors The 7 resident risk factors assessed were age, sex, number of days of acute care hospitalization within the previous 4 weeks, number of comorbid conditions, and 3 pharmaceutical exposures. The value of each time-varying parameter was assessed for each day. For comorbidities, acute and long-term care facility discharge diagnosis codes (International Classification of Diseases, Ninth Revision, Clinical Modification) were used to assess the presence of 14 comorbid conditions in the preceding year as per the Charlson comorbidity index (15, 16). For a given resident, the total number of comorbid conditions was summed. The following 3 pharmaceutical exposure variables were assessed, each in a 4-week retrospective window: proton-pump inhibitors; any antibiotic except C difficile treatment agents (metronidazole, oral vancomycin, and fidaxomicin); and an antibiotic risk index with 4 mutually exclusive risk levels consisting of high (receipt of cephalosporins, fluoroquinolones, or clindamycin), medium (receipt of penicillins, macrolides, or sulfonamides but no high-risk agents), low (receipt of tetracyclines), or no antibiotic receipt or receipt of C difficile treatment agents only. This antibiotic risk index was based on a similar index developed in an independent cohort study (17). Pharmaceutical exposure information was drawn from administration data of the VHA electronic medical record and included all courses given during inpatient care in VHA acute or long-term care facilities. Community exposures were not considered. In addition to the 7 resident risk factors, a control variable for the duration of follow-up time, defined as the total number of days a given resident stayed in a VHA acute or long-term care facility within the past 28 days, was measured and categorized into deciles. Health Care Regional Risk Factors The 5 regional risk factors measured were average resident age, average resident comorbidities, proton-pump inhibitor use, antibiotic use, and importation of cases of acute care C difficile infection. These factors were measured from the full resident population of the regions because residents who were not at risk (that is, those recently admitted with a recent positive C difficile test result) were just as likely if not more likely to transmit C difficile. Proton-pump inhibitor use and antibiotic use (excluding the C difficile treatment agents previously mentioned) were measured as days with therapy per 1000 resident-days. Exposure on a given day contributed 1 unit to the numerator, regardless of the number of specific agents, dosage, or number of doses administered on that day. Importation of cases of acute care C difficile infection was measured as the prevalence of residents in the region who were infected with C difficile at an acute care facility in the previous 8 weeks per 10000 resident-days. Acute careonset C difficile infection was defined as a patient with a positive C difficile toxin test result 3 or more days after admission to an acute care facility. Statistical Analysis The incidence of C difficile across the VHA, and within each region, was measured using the weighted mean. In all statistical analyses, sampling weights of 1 for cases and 100 for controls corresponded to the inverse of the probability of selection, allowing analyses to produce unbiased estimates of

Sensory integration during foraging: the importance of fruit hardness, colour, and odour to brown lemurs

Animal reliance on fruit signals, such as hardness, colour, and odour, during foraging is poorly understood. Here, we present data on fruit foraging behaviour and efficiency (rate of fruit ingestion) of three groups of wild, frugivorous brown lemurs (Eulemur fulvus, N = 29 individuals) in Ankarafantsika National Park, Madagascar. We quantify fruit hardness using a modified force gauge, fruit colour using spectroscopy, and fruit odour using volatile organic compound (VOC) sampling with gas chromatography-mass spectrometry. We relate lemur foraging behaviour to fruit traits by calculating touching, visual inspection, and sniffing indices and relate lemur foraging efficiency to fruit traits by calculating acceptance indices. The use of different sensory modalities by lemurs is marginally predicted in one case by fruit traits—fruits with higher overall smell signals are sniffed less than fruits with lower overall smell signals. When controlling for all fruit traits, fruit size is the only significant predictor of fruit foraging efficiency—lemurs forage more rapidly on smaller fruits relative to larger fruits.

Impact of El Niño Southern Oscillation on infectious disease hospitalization risk in the United States

Although the global climate is changing at an unprecedented rate, links between weather and infectious disease have received little attention in high income countries. The “El Niño Southern Oscillation” (ENSO) occurs irregularly and is associated with changing temperature and precipitation patterns. We studied the impact of ENSO on infectious diseases in four census regions in the United States. We evaluated infectious diseases requiring hospitalization using the US National Hospital Discharge Survey (1970–2010) and five disease groupings that may undergo epidemiological shifts with changing climate: (i) vector-borne diseases, (ii) pneumonia and influenza, (iii) enteric disease, (iv) zoonotic bacterial disease, and (v) fungal disease. ENSO exposure was based on the Multivariate ENSO Index. Distributed lag models, with adjustment for seasonal oscillation and long-term trends, were used to evaluate the impact of ENSO on disease incidence over lags of up to 12 mo. ENSO was associated more with vector-borne disease [relative risk (RR) 2.96, 95% confidence interval (CI) 1.03–8.48] and less with enteric disease (0.73, 95% CI 0.62–0.87) in the Western region; the increase in vector-borne disease was attributable to increased risk of rickettsioses and tick-borne infectious diseases. By contrast, ENSO was associated with more enteric disease in non-Western regions (RR 1.12, 95% CI 1.02–1.15). The periodic nature of ENSO may make it a useful natural experiment for evaluation of the impact of climatic shifts on infectious disease risk. The impact of ENSO suggests that warmer temperatures and extreme variation in precipitation events influence risks of vector-borne and enteric disease in the United States.

It’s Not Easy Being Blue: Are There Olfactory and Visual Trade-Offs in Plant Signalling?

Understanding the signals used by plants to attract seed disperses is a pervasive quest in evolutionary and sensory biology. Fruit size, colour, and odour variation have long been discussed in the controversial context of dispersal syndromes targeting olfactory-oriented versus visually-oriented foragers. Trade-offs in signal investment could impose important physiological constraints on plants, yet have been largely ignored. Here, we measure the reflectance and volatile organic compounds of a community of Malagasy plants and our results indicate that extant plant signals may represent a trade-off between olfactory and chromatic signals. Blue pigments are the most visually-effective – blue is a colour that is visually salient to all known seed dispersing animals within the study system. Additionally, plants with blue-reflecting fruits are less odiferous than plants that reflect primarily in other regions of the colour spectrum.