Constructing Ebola transmission chains from West Africa and estimating model parameters using internet sources.

During the recent Ebola crisis in West Africa, individual person-level details of disease onset, transmissions, and outcomes such as survival or death were reported in online news media. We set out to document disease transmission chains for Ebola, with the goal of generating a timely account that could be used for surveillance, mathematical modeling, and public health decision-making. By accessing public web pages only, such as locally produced newspapers and blogs, we created a transmission chain involving two Ebola clusters in West Africa that compared favorably with other published transmission chains, and derived parameters for a mathematical model of Ebola disease transmission that were not statistically different from those derived from published sources. We present a protocol for responsibly gleaning epidemiological facts, transmission model parameters, and useful details from affected communities using mostly indigenously produced sources. After comparing our transmission parameters to published parameters, we discuss additional benefits of our method, such as gaining practical information about the affected community, its infrastructure, politics, and culture. We also briefly compare our method to similar efforts that used mostly non-indigenous online sources to generate epidemiological information.

Interventions to control MRSA: high time for time-series analysis?

Time-series methods are useful in quasi-experimental study designs in which rates of antibiotic-resistant infections are ascertained before and after an intervention. However, uncertainties remain regarding the use of time-series analysis as an appropriate research methodology for analysing the effect of infection control interventions and antibiotic policies on the epidemiology of methicillin-resistant Staphylococcus aureus (MRSA). In particular, there is still a substantial gap in our understanding of what actually happens to MRSA incidence when a planned intervention is made on use of one or more antibiotic drug classes.

Susceptibilities of clinical Clostridium difficile isolates to antimicrobials: a systematic review and meta-analysis of studies since 1970.

OBJECTIVES: Although exposure to antibiotics can cause Clostridium difficile infection, certain antibiotics are used to treat C. difficile. Measurements of antimicrobial C. difficile activity could help to identify antibiotic risk and emergent resistance. Here, we describe publication patterns relating to C. difficile susceptibilities and estimate minimum inhibitory concentrations (MIC) for antibiotic classes in the published literature between January 1970 and June 2014. METHODS: We queried PUBMED and EMBASE for studies reporting antibiotic C. difficile MIC in English or French. We used mixed-effects models to obtain pooled estimates of antibiotic class median MIC (MIC50), 90th percentile of MIC (MIC90), and MIC90:MIC50 ratio. RESULTS: Our search identified 182 articles that met our inclusion criteria, of which 27 were retained for meta-analysis. Aminoglycosides (MIC50 120 mg/L, 95% CI 62-250), 3rd (MIC50 75 mg/L, 95% CI 39-130) and 2nd generation cephalosporins (MIC50 64 mg/L, 95% CI 27-140) had the least C. difficile activity. Rifamycins (MIC50 0.034 mg/L, 95% CI 0.012-0.099) and tetracyclines (MIC50 0.29 mg/L, 95% CI 0.054-1.7) had the highest level of activity. The activity of 3rd generation cephalosporins was more than three times lower than that of 1st generation agents (MIC50 19 mg/L, 95% CI 7.0-54). Time-trends in MIC50 were increasing for carbapenems (70% increase per 10 years) while decreasing for tetracyclines (51% decrease per 10 years). CONCLUSIONS: We found a 3500-fold variation in antibiotic C. difficile MIC50, with aminoglycosides as the least active agents and rifamycins as the most active. Further research is needed to determine how in vitro measures can help assess patient C. difficile risk and guide antimicrobial stewardship.

Development and Validation of a Natural Language Processing Tool to Identify Patients Treated for Pneumonia across VA Emergency Departments.

BACKGROUND: Identifying pneumonia using diagnosis codes alone may be insufficient for research on clinical decision making. Natural language processing (NLP) may enable the inclusion of cases missed by diagnosis codes. OBJECTIVES: This article (1) develops a NLP tool that identifies the clinical assertion of pneumonia from physician emergency department (ED) notes, and (2) compares classification methods using diagnosis codes versus NLP against a gold standard of manual chart review to identify patients initially treated for pneumonia. METHODS: Among a national population of ED visits occurring between 2006 and 2012 across the Veterans Affairs health system, we extracted 811 physician documents containing search terms for pneumonia for training, and 100 random documents for validation. Two reviewers annotated span- and document-level classifications of the clinical assertion of pneumonia. An NLP tool using a support vector machine was trained on the enriched documents. We extracted diagnosis codes assigned in the ED and upon hospital discharge and calculated performance characteristics for diagnosis codes, NLP, and NLP plus diagnosis codes against manual review in training and validation sets. RESULTS: Among the training documents, 51% contained clinical assertions of pneumonia; in the validation set, 9% were classified with pneumonia, of which 100% contained pneumonia search terms. After enriching with search terms, the NLP system alone demonstrated a recall/sensitivity of 0.72 (training) and 0.55 (validation), and a precision/positive predictive value (PPV) of 0.89 (training) and 0.71 (validation). ED-assigned diagnostic codes demonstrated lower recall/sensitivity (0.48 and 0.44) but higher precision/PPV (0.95 in training, 1.0 in validation); the NLP system identified more "possible-treated" cases than diagnostic coding. An approach combining NLP and ED-assigned diagnostic coding classification achieved the best performance (sensitivity 0.89 and PPV 0.80). CONCLUSION: System-wide application of NLP to clinical text can increase capture of initial diagnostic hypotheses, an important inclusion when studying diagnosis and clinical decision-making under uncertainty.

Prolonged antibiotic prophylaxis after cardiovascular surgery and its effect on surgical site infections and antimicrobial resistance.

BACKGROUND: Despite evidence supporting short antibiotic prophylaxis (ABP), it is still common practice to continue ABP for more than 48 hours after coronary artery bypass graft (CABG) surgery. METHODS AND RESULTS: To compare the effect of short (<48 hours) versus prolonged (>48 hours) ABP on surgical site infections (SSIs) and acquired antimicrobial resistance, we conducted an observational 4-year cohort study at a tertiary-care center. An experienced infection control nurse performed prospective surveillance of 2641 patients undergoing CABG surgery. The main exposure was the duration of ABP, and main outcomes were the adjusted rate of SSI and the isolation of cephalosporin-resistant enterobacteriaceae and vancomycin-resistant enterococci (acquired antibiotic resistance). Adjustment for confounding was performed by multivariable modeling. A total of 231 SSIs (8.7%) occurred after a median of 16 days, including 93 chest-wound infections (3.5%) and 13 deep-organ-space infections (0. 5%). After 1502 procedures using short ABP, 131 SSIs were recorded, compared with 100 SSIs after 1139 operations with prolonged ABP (crude OR, 1.0; CI, 0.8 to 1.3). After adjustment for possible confounding, prolonged ABP was not associated with a decreased risk of SSI (adjusted OR, 1.2; CI, 0.8 to 1.6) and was correlated with an increased risk of acquired antibiotic resistance (adjusted OR, 1.6; CI, 1.1 to 2.6). CONCLUSIONS: Our findings confirm that continuing ABP beyond 48 hours after CABG surgery is still widespread; however, this practice is ineffective in reducing SSI, increases antimicrobial resistance, and should therefore be avoided.

Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study.

BACKGROUND: Although human immunodeficiency virus (HIV)-related morbidity and mortality rates in patients with advanced HIV infection who are treated with combination antiretroviral drugs have declined, significant metabolic adverse effects associated with these regimens have been increasingly recognized. However, since data from patients studied before and after initiation of protease inhibitor (PI) therapy are scant, the true effect of PIs on these metabolic changes remains unknown. OBJECTIVES: To examine temporal trends in serum glucose and lipid levels after initiation of PI therapy, to assess whether changes are independent of virological response and improvement in disease severity, and to determine risk factors associated with the development of hyperglycemia, hyperlipidemia, and lipodystrophy. METHODS: A 5-year historical cohort analysis in a population of 221 HIV-infected patients observed in the Infectious Diseases Clinic of a tertiary care center from October 1, 1993, through July 31, 1998. Clinical and laboratory data were retrieved from medical records and a computerized database. The main outcome measure was the incidence of hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and lipodystrophy. Adjusted incidence rate ratios (IRRs) were estimated by means of Poisson regression. In addition, mixed regression analyses were performed to examine effects of PIs on serum lipid and glucose levels, modeled as continuous outcomes. RESULTS: The cumulative incidence of new-onset hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and lipodystrophy was 5%, 24%, 19%, and 13%, respectively. Most of these events occurred after initiation of PI therapy. Protease inhibitors were independently associated with hyperglycemia (adjusted IRR, 5.0; 95% confidence interval [CI], 1. 3-19.4), hypercholesterolemia (adjusted IRR, 2.8; 95% CI, 1.5-5.2), hypertriglyceridemia (adjusted IRR, 6.1; 95% CI, 3.1-11.7), and lipodystrophy (adjusted IRR, 5.1; 95% CI, 1.9-13.9). Anabolic steroids and psychotropic medications were also associated with lipodystrophy. Inclusion of potential intermediate variables (eg, virological suppression and increase in body weight) did not reduce the magnitude of the association with PIs. The association between hypertriglyceridemia and ritonavir was stronger than for other PIs (Wald test, P=.02). In contrast, the incidence of hyperglycemia, hypercholesterolemia, and lipodystrophy did not vary significantly across different PIs. Longitudinal mixed models confirmed that serum lipid levels were more substantially affected by antiretroviral therapy, particularly PIs, than serum glucose levels. Similarly, controlling for surrogate markers did not abolish the strong association between PIs and increase in serum lipid levels. CONCLUSION: We found an independent association between PI use and hyperglycemia, hyperlipidemia, and lipodystrophy that is not explained by the antiviral and therapeutic effect of PIs.

The association between antecedent vancomycin treatment and hospital-acquired vancomycin-resistant enterococci: a meta-analysis.

BACKGROUND: The association between vancomycin hydrochloride treatment and vancomycin-resistant enterococci (VRE) has been investigated in numerous studies with variable results. OBJECTIVES: To conduct a meta-analysis to estimate the magnitude of the association between vancomycin treatment and individual risk of VRE and to identify study characteristics that accounted for heterogeneity in study results. METHODS: Studies were identified using MEDLINE with index terms "Enterococcus," "Enterococcus faecalis," or "Enterococcus faecium" and "vancomycin," "drug resistance," "drug resistance, microbial," or "drug resistance, multiple or risk factors." Reports from conferences and reference lists of recent reviews were used. A total of 420 published reports and 98 conference reports were reviewed; 20 studies described in 15 published reports were included in the analysis. We recorded study period, hospital setting, case and control definitions, length of hospital stay, method of adjustment for differences in length of stay, and data on treatment with vancomycin. The odds ratio (OR) of vancomycin treatment provided the measure of association analyzed. A random-effects model was used to estimate the pooled OR. RESULTS: When results from all 20 studies were combined, the pooled OR was 4.5 (95% confidence interval, 3.0-6.9), but the test for heterogeneity was highly significant (P<.001). The 5 studies that used patients with vancomycin-susceptible enterococci as controls found a stronger association (pooled OR, 10.7; 95% confidence interval, 4.8-23.8) than the 15 studies that used controls who had no VRE isolated (pooled OR, 2.7; 95% confidence interval, 2.0-3.8). After restricting the analysis to the latter studies only, no heterogeneity was evident in the unadjusted study results. Patients with VRE had stayed in the hospital much longer than control patients. Studies that adjusted for this difference found only a small and nonsignificant association between vancomycin treatment and VRE (pooled OR, 1.4; 95% confidence interval, 0.74-2.60). We also detected publication bias, favoring report of studies that found a large measure of association. CONCLUSIONS: The reported strong association between vancomycin treatment and hospital-acquired VRE results from the selection of the reference group, confounding by duration of hospitalization, and publication bias. Studies that accounted for these factors found only a small and nonsignificant association.

Staphylococcus aureus catheter-associated bacteremia. Minimal effective therapy and unusual infectious complications associated with arterial sheath catheters.

OBJECTIVE: To determine factors that predict complications and examine outcomes of Staphylococcus aureus bacteremia according to the duration of antibiotic therapy. METHODS: Clinical data were extracted from charts of patients with positive blood cultures for S aureus at a single institution during a 2-year period. RESULTS: Of 102 patients with S aureus bacteremia, 55 were considered to have bacteremia attributable to an intravascular catheter, including five patients who were bacteremic after percutaneous transluminal coronary angioplasty. Among the other 50 patients with S aureus catheter-associated bacteremia, infection was community acquired in 18 and nosocomial in 32. Septic pulmonary emboli were more common in patients with community-acquired S aureus catheter-associated bacteremia, most of whom had Hickman catheters or venous access disks. Delayed removal of the infected catheter was associated with persistence of bacteremia (P = .01). With patients with early complications excluded, patients treated for 10 to 15 days had clinical characteristics similar to those of patients treated with longer courses of antibiotics and had similarly low rates of relapse (0% vs 4.7%). In contrast, treatment with parenteral antibiotics for less than 10 days appeared to be inadequate in that relapse occurred in two of three such patients. Staphylococcus aureus catheter-associated bacteremia associated with percutaneous transluminal coronary angioplasty was complicated by a femoral artery mycotic aneurysm in two of five patients. CONCLUSION: Approximately one third of S aureus catheter-related bacteremias were community acquired, reflecting increased usage of intravascular devices for home parenteral support. A 10- to 15-day course of parenteral antibiotics was equivalent to longer courses of therapy in patients without early complications.

Health and economic outcomes of antibiotic resistance in Pseudomonas aeruginosa.

BACKGROUND: Antimicrobial resistance is an increasing problem. OBJECTIVE: To examine the clinical and economic impact of antibiotic resistance in Pseudomonas aeruginosa. METHODS: In-hospital mortality, secondary bacteremia, length of stay, and hospital charges were examined in a cohort of 489 inpatients with positive clinical cultures for P aeruginosa. One hundred forty-four had a resistant baseline P aeruginosa isolate and 30 had resistance emerge during follow-up. Multivariable and survival analytic methods were used to adjust for confounding and effects of time. RESULTS: The overall in-hospital mortality rate was 7.6%, 7.7% in patients with a resistant isolate at baseline (relative risk [RR], 1.3; 95% confidence interval [CI], 0.6-2.8) and 27% in patients in whom resistance emerged (RR, 3.0; 95% CI, 1.2-7.8). Secondary bacteremia developed in 1.4% of patients in whom resistance did not emerge and in 14% of those in whom resistance emerged (RR, 9.0; 95% CI, 2.7-30). The median duration of hospital stay following the initial P aeruginosa isolate was 7 days. Emergence of resistance, but not baseline resistance, was significantly associated with a longer hospital stay (P<.001 and P=.71, respectively). The average daily hospital charge was $2059. Neither baseline resistance nor emergence of resistance had a significant effect on the daily hospital charge. In a matched cohort analysis, a trend was seen toward increased total charges in patients demonstrating emergence of resistance (difference, $7340; P=.14). CONCLUSIONS: Emergence of antibiotic resistance in P aeruginosa results in severe adverse outcomes. Efforts should be directed toward early detection and prevention of emergence of antibiotic resistance.

Clinical correlates of secondary meningitis in HIV-infected adults.

BACKGROUND: Neurologic complaints are common in adults infected with the human immunodeficiency virus, but little is known about which clinical features are associated with secondary causes of meningitis. METHODS: A retrospective cross-sectional study of adults infected with the human immunodeficiency virus who received a diagnostic lumbar puncture (LP) in the infectious disease clinic, emergency department, and inpatient wards of the Deaconess Hospital, Boston, Mass, from 1989 through 1992 to determine which clinical features available at the time of LP are correlated with definite or probable secondary meningitis. RESULTS: Of the 491 LPs, 90% were performed in whites, 93% in men, and 11% in injection drug users. Cerebrospinal fluid test results revealed secondary meningitis in 39 (7.9%) of 491 LPs performed on 322 individuals. Cryptococcal meningitis was the predominant type (27 cases); no bacterial or tuberculous meningitis was found. In multivariate analyses, a history of non-Hodgkin's lymphoma (adjusted odds ratio [OR], 4.3; 95% confidence interval [CI], 1.5 to 12.5), a history of herpes simplex virus infection (OR, 2.5; 95% CI, 1.2 to 5.0), nausea and/or vomiting (OR, 2.0; 95% CI, 1.03 to 4.0), headache in a person with the acquired immunodeficiency syndrome (OR, 2.1; 95% CI, 1.03 to 4.4), and cranial nerve abnormalities (OR, 5.1; 95% CI, 1.8 to 14.1) were positive correlates of opportunistic meningitis; current fluconazole use (OR, 0.3; 95% CI, 0.1 to 0.8) conferred a lower risk. CONCLUSION: In similar clinical settings, physicians and their human immunodeficiency virus-infected patients should consider these features when assessing the risk of secondary meningitis and the necessity for immediate LP.

Vancomycin-resistant enterococci in intensive care units: high frequency of stool carriage during a non-outbreak period.

BACKGROUND: We aimed to define the epidemiological associations of vancomycin-resistant enterococci (VRE) in intensive care units (ICUs) during a non-outbreak period by examining prevalence, risk factors for colonization, frequency of acquisition, and molecular strain types. DESIGN: A prospective cohort design was followed. Consecutive patient admissions to 2 surgical ICUs at a tertiary care hospital were enrolled. The main outcome measures were results of serial surveillance cultures screened for VRE. RESULTS: Of 290 patients enrolled, 35 (12%) had colonization with VRE on admission. The VRE colonization or infection had been previously detected by clinical cultures in only 4 of these patients. Using logistic regression, VRE colonization at the time of ICU admission was associated with second- and third-generation cephalosporins (odds ratio [OR] = 6.0, P<.0001), length of stay prior to surgical ICU admission (OR = 1.06, P = .001) greater than 1 prior ICU stay (OR = 9.6, P = .002), and a history of solid-organ transplantation (OR = 3.8, P = .021). Eleven (12.8%) of 78 patients with follow-up cultures acquired VRE. By pulsed-field gel electrophoresis, 2 strains predominated, one of which was associated with an overt outbreak on a non-ICU ward near the end of the study period. CONCLUSIONS: Colonization was common and usually not recognized by clinical culture. Most patients who had colonization with VRE and were on the surgical ICU acquired VRE prior to surgical ICU entry. Exposure to second- and third-generation cephalosporins, but not vancomycin, was an independent risk factor for colonization. Prospective surveillance of hospitalized patients may yield useful insights about the dissemination of nosocomial VRE beyond what is appreciated by clinical cultures alone.

Scaling-up NLP Pipelines to Process Large Corpora of Clinical Notes.

INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Big Data and Analytics in Healthcare". OBJECTIVES: This paper describes the scale-up efforts at the VA Salt Lake City Health Care System to address processing large corpora of clinical notes through a natural language processing (NLP) pipeline. The use case described is a current project focused on detecting the presence of an indwelling urinary catheter in hospitalized patients and subsequent catheter-associated urinary tract infections. METHODS: An NLP algorithm using v3NLP was developed to detect the presence of an indwelling urinary catheter in hospitalized patients. The algorithm was tested on a small corpus of notes on patients for whom the presence or absence of a catheter was already known (reference standard). In planning for a scale-up, we estimated that the original algorithm would have taken 2.4 days to run on a larger corpus of notes for this project (550,000 notes), and 27 days for a corpus of 6 million records representative of a national sample of notes. We approached scaling-up NLP pipelines through three techniques: pipeline replication via multi-threading, intra-annotator threading for tasks that can be further decomposed, and remote annotator services which enable annotator scale-out. RESULTS: The scale-up resulted in reducing the average time to process a record from 206 milliseconds to 17 milliseconds or a 12- fold increase in performance when applied to a corpus of 550,000 notes. CONCLUSIONS: Purposely simplistic in nature, these scale-up efforts are the straight forward evolution from small scale NLP processing to larger scale extraction without incurring associated complexities that are inherited by the use of the underlying UIMA framework. These efforts represent generalizable and widely applicable techniques that will aid other computationally complex NLP pipelines that are of need to be scaled out for processing and analyzing big data.

The values of quantitative serum HIV-1 RNA levels and CD4 cell counts for predicting survival time among HIV-positive individuals with CD4 counts of < or = 50 x 10(6) cells/l.

OBJECTIVE: To evaluate the HIV-1 RNA level as a predictor of survival time among individuals with advanced AIDS. METHODS: The serum HIV-1 RNA level, the CD4 cell count, and other clinical variables were evaluated at baseline, as predictors of survival time, among 56 retrospectively identified HIV-1 positive individuals with < or = 50 x 10(6) CD4 cells/l who attended the Beth Israel Deaconess Medical Center, Division of Infectious Diseases, between 1 July 1989 and 30 September 1993. RESULTS: During follow-up, 55 of these 56 patients died. The median survival time was 20.5 months. In univariate Cox proportional hazard modeling neither the baseline HIV-1 RNA level nor the CD4 cell count were predictive of survival time. However, in multivariate models longer survival time was associated with the use of trimethoprim-sulphamethoxazole at entry [hazard ratio (HR), 0.42; P = 0.007], whereas shorter survival time was associated with a history of an AIDS-defining illness other than Pneumocystis carinii pneumonia (HR, 2.87; P = 0.007). Correlative analysis revealed a modest correlation of the baseline CD4 cell count with survival time (Spearman p = 0.41; P = 0.002). However, no correlation was found between HIV RNA levels and survival time (P = 0.5). CONCLUSIONS: In this population with very advanced disease, the HIV-1 RNA level was a poor discriminator of survival time, being inferior to the CD4 cell count and to specific clinical variables such as the nature of the prior AIDS-defining illness and the type of Pneumocystis carinii pneumonia prophylaxis employed. Among individuals with advanced AIDS, these data emphasize the relative importance of the CD4 cell count and of specific clinical factors, over the HIV-1 RNA level in predicting survival time.

Pharmacokinetics of F105, a human monoclonal antibody, in persons infected with human immunodeficiency virus type 1.

F105 is a human monoclonal antibody that binds to the CD4 binding site of human immunodeficiency virus type 1 gp120 and neutralizes clinical and laboratory isolates of the human immunodeficiency virus. This phase I study investigated the disposition of the antibody in humans. F105 was administered over a 60-minute period at two dose levels, 100 and 500 mg/m2. Blood samples were obtained for up to 56 days. The clearance of the antibody was 0.33 ml/min with a corresponding half-life of approximately 13 days. Peak concentrations achieved at the higher dose level were 216.19 +/- 9.62 micrograms/ml. The disposition of the drug was linear for the doses studied. Simulations were performed to design future studies aimed at investigating the efficacy of the antibody. This study concluded that F105 can be administered as a bolus dose every 21 days.

Molecular typing of coagulase-negative staphylococci from blood cultures does not correlate with clinical criteria for true bacteremia.

PURPOSE: Determining whether a blood culture that contains coagulase-negative staphylococci represents bacteremia or contamination is a clinical dilemma. We compared molecular-typing results of coagulase-negative staphylococcal blood culture isolates with clinical criteria for true bacteremia. SUBJECTS AND METHODS: Pulsed-field gel electrophoresis and arbitrary primed polymerase chain reaction (PCR) were used to determine whether patients with two or more blood cultures with coagulase-negative staphylococcal isolates had the same strain of organism in each culture (same strain bacteremia). We evaluated three different clinical criteria for bacteremia: whether the patient received more than 4 days of antibiotics, whether there was an explicit note in the medical chart in which the physician diagnosed a true bacteremia, and the Centers for Disease Control surveillance criteria for primary bloodstream infection. Agreement between same-strain bacteremia and each definition was examined, based on the assumption that most true infections should be the result of a single strain. RESULTS: The study sample consisted of 42 patients and 106 isolates. Nineteen of the 42 bacteremias (45%) were the same strain. Classification of bacteremias as same-strain correlated poorly with all three clinical assessments (range of percent agreement, 50% to 57%; range of kappa statistic, 0.01 to 0.15). There were both false-positive and false-negative errors. Patients with three or more positive blood cultures were more likely to have same-strain bacteremia than those with only two positive cultures [11 of 15 (73%) vs 8 of 27 (30%), P = 0.006]. Pulsed-field gel electrophoresis was more discriminating than arbitrary primed PCR (percent agreement, 83%; kappa, 0.67). CONCLUSION: Molecular typing correlated poorly with clinical criteria for true bacteremia, suggesting either that true bacteremias are frequently the result of multiple strains or that the commonly used clinical criteria are not accurate for distinguishing contamination from true bacteremia. Vancomycin treatment of clinically defined coagulase-negative staphylococcal bacteremia may frequently be unnecessary.

Clinical and molecular epidemiology of sporadic and clustered cases of nosocomial Clostridium difficile diarrhea.

PURPOSE: A prospective clinical and molecular epidemiologic study was conducted to define the frequency of nosocomial Clostridium difficile patient-to-patient transmission in an urban tertiary referral hospital. PATIENTS AND METHODS: Over a 6-month period, environmental cultures for C difficile were obtained from patients with new positive stool cytotoxin assay (index cases); stool samples were obtained from selected patient contacts (the roommate, occupants of adjacent rooms, and the patient occupying the index room after discharge of the index case); and hand cultures were obtained from personnel contacts. C difficile isolates were analyzed by pulse-field gel electrophoresis (PFGE) or, for isolates that were nontypeable by PFGE, by restriction enzyme analysis. RESULTS: During the study period, we identified 98 index cases of C difficile toxin-associated diarrhea, including focal outbreaks on two wards totaling 26 cases within a 2-month interval. Environmental contamination was detected at > or = 1 sites in 58% of rooms and often involved wide dispersed areas. Among 99 prospectively identified patient contacts, C difficile was cultured from the stool of 31 (31%), including 12 with diarrhea and 19 who were asymptomatic. C difficile was cultured from the hands of 10 (14%) of 73 personnel. Molecular analysis resolved 31 typing profiles among the index isolates; the most common profile (designated strain D1) was represented by 30 isolates. Among the isolates from patient contacts, 5 of 12 from symptomatic contacts matched the corresponding index isolate, and only 1 of 19 from asymptomatically colonized contacts matched. Transmission to personnel or patient contacts of the strain cultured from the corresponding index case was correlated strongly with the intensity of environmental contamination. Strain D1 was frequently represented among isolates associated with heavy environmental contamination, with personnel carriage, and with development of symptomatic illness among prospectively identified contacts. CONCLUSIONS: Intense environmental contamination and transmission to close personnel and patient contacts represented coordinated properties of an individual epidemic strain. For most epidemiologically linked contacts, positive cultures for C difficile did not result from transmission from the presumed index case.

The epidemiology of nephrotoxicity associated with conventional amphotericin B therapy.

PURPOSE: We sought to quantify the incidence of, define risk factors for, and examine the relation between renal functional impairment and treatment with conventional amphotericin B. SUBJECTS AND METHODS: We performed a 9-year retrospective analysis of amphotericin B-associated nephrotoxicity in 494 adult inpatients who received > or = 2 doses of amphotericin B. Nephrotoxicity was classified according to two nonmutually exclusive severity categories (50% increase or doubling in the baseline creatinine level). RESULTS: The median cumulative dosage of amphotericin B was 240 mg (interquartile range, 113 to 500 mg), with the majority of patients (n = 361) receiving it for empiric treatment. Overall, 139 (28%) patients experienced renal toxicity, including 58 (12%) with moderate-to-severe nephrotoxicity. The rate of nephrotoxicity was relatively constant during amphotericin B treatment. For each 10-mg increase in the mean daily amphotericin B dose, the adjusted rate of renal toxicity increased by a factor of 1.13 (95% confidence interval: 1.02 to 1.25). We defined 5 categorical risk factors: mean daily amphotericin B dose > or = 35 mg, male sex, weight > or = 90 kg, chronic renal disease, and use of amikacin or cyclosporine. The incidence of moderate-to-severe nephrotoxicity was 4% (6 of 137) in patients with none of these risk factors, 8% (14 of 181) in those with 1 risk factor, 18% (21 of 117) in those with 2 risk factors, and 29% (17 of 59) in patients with > or = 3 risk factors. Nephrotoxicity rarely led to hemodialysis (n = 3); however, at the time of discharge or death, 70% of patients with moderate-to-severe nephrotoxicity had a serum creatinine level that was > or = 0.5 mg/dL above baseline. CONCLUSION: Amphotericin B-related nephrotoxicity is an important dose-dependent and duration-dependent toxicity that is accentuated by certain nephrotoxic drugs and patient characteristics. Patients with more than two risk factors for nephrotoxicity are potential candidates for alternative antifungal therapy.

Major infectious complications after orthotopic liver transplantation and comparison of outcomes in patients receiving cyclosporine or FK506 as primary immunosuppression.

A retrospective cohort study was conducted to determine the incidence of major infectious complications after orthotopic liver transplantation and to compare outcomes in patients receiving either cyclosporine (CsA) or FK506 (tacrolimus) as primary immunosuppression. Of 133 transplants performed in 118 patients, 124 transplant episodes were evaluated. Cytomegalovirus (CMV) infection (INF) and disease (DIS), deep fungal infection (DFI), and intraabdominal bacterial infections (IAI) were catalogued. The overall incidences of major infectious outcomes were: CMV INF = 33%; CMV DIS = 19%; DFI = 15%; and IAI = 25%. Cox proportional hazard analysis identified donor seropositivity, OKT3 as secondary immunosuppression and initial intensive care unit (ICU) duration as risk factors for CMV INF and DIS in the overall population. Fungal colonization was the dominant risk factor associated with deep fungal infection. A choledochojejunostomy anastomosis, the number of cellular blood products transfused at the time of transplantation surgery, and prior CMV INF were independent risk factors for both fungal colonization and deep infection. The single risk factor identified for intraabdominal bacterial infections was the number of cellular blood products transfused at the time of surgery. In the Cox proportional hazards model the relative risk (RR) for each category of infection was lower in the FK506 group (CMV: RR = .87, 95% confidence interval [C.I.] = [.32-2.4]; DFI: .58 [.13-2.6]; IAI: .51 [.15-1.7]), but the effect was not statistically significant. Survival was similar in patients receiving FK506 or CsA. CMV INF and DFI were independent predictors of death for all patients. Risk factors identified for CMV INF and DIS support the findings of others. Higher intraoperative blood product requirements and complicated intraoperative or postoperative courses increase the risk for IAI or DFI. The development of effective strategies to prevent CMV and fungal infections in liver transplant recipients remains a priority for future endeavors.

Frequency, risk factors, and outcome for bacteremia after percutaneous transluminal coronary angioplasty.

The objectives of this study were to examine bacteremias after percutaneous transluminal coronary angioplasty (PTCA) with respect to incidence, outcome, and risk factors. Patients undergoing PTCA from January 1990 through April 1994 were studied; during this period a total of 4,217 PTCAs were performed in 3,473 patients. With use of predefined clinical and microbiologic criteria, bacteremias were divided into 3 categories according to the relation to the PTCA procedure: PTCA-related, unrelated, and indeterminate. Ninety-one patients with at least 1 positive blood culture during a 7-week period after PTCA were identified. The bacteremia was classified as unrelated to the PTCA procedure in 32 patients, PTCA-related in 27, and indeterminant in the remaining 32 patients. The attack rate of PTCA-related bacteremia during the 52-month period was 0.64%. The most common organisms causing PTCA-related bacteremia were Staphylococcus aureus (14 patients), coagulase-negative staphylococci (9 patients) and group B streptococci (6 patients). Septic complications, which included femoral artery mycotic aneurysm, septic arthritis, and septic thrombosis, occurred in 10 patients (0.24%). Independent risk factors for PTCA-related bacteremia included duration of procedure (odds ratio [OR] 2.9; p = 0.04), number of catheterizations at the same site (OR 4.0; p = 0.015), difficult vascular access (OR 14.9; p = 0.007), arterial sheath in place > 1 day (OR 6.8; p = 0.025), congestive heart failure (OR 43.3; p = 0.002). Thus, PTCA-related bacteremia is an infrequent complication of PTCA but can be associated with significant morbidity, particularly when the infecting organism is S. aureus. Four of the 5 risk factors for PTCA-related bacteremia appear to correlate directly with increased vascular injury or maintenance of the arterial entry for the procedure.

Phase I study of a human monoclonal antibody directed against the CD4-binding site of HIV type 1 glycoprotein 120.

A phase I dose escalation study was conducted with the human monoclonal anti-gp120 antibody F105, to evaluate the safety, pharmacokinetics, and functional activity of F105 in HIV-1-infected individuals. F105 is an IgG1(kappa) antibody reactive with a discontinuous epitope that overlaps the CD4-binding site of gp120. F105 neutralizes laboratory strains of HIV-1 and some primary isolates, and synergizes with other antibodies in neutralizing an expanded spectrum of isolates. Four patients each with CD4 counts between 200 and 500/mm3 received a single dose of F105 at 100 or 500 mg/m2, intravenously. Sustained levels of F105 were obtained in plasma, and there was no evidence of an immune response to F105 as determined by a double-antigen immunoassay. No patient experienced any toxicity. Infused antibody retained full functional activity as detected by the ability of sera to block the binding of labeled F105 to HIV-1-infected cells. Of note, all patients had preexisting antibody to the gp120 CD4-binding site. The ability to culture virus by quantitative microculture remained unchanged by this single dose of antibody. Thus, it can be concluded that F105 is safe and nontoxic as a single injection at the doses tested. Furthermore, the antibody retains full gp120-binding activity. In these patients, with preexisting CD4-binding site antibody, there is no evidence of anti-HIV-1 activity following a single antibody infusion.