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Background: Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2., Methods: We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day., Results: Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation., Conclusions: In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.)., (Copyright © 2020 Massachusetts Medical Society.)

Intravenous immunoglobulin (IVIG) is used to treat an increasing number of conditions. The anti-inflammatory and immunomodulatory effects of IVIG can be life-saving; however, recent administration may complicate evaluation for infection. To assess the impact of IVIG therapy on a variety of common viral, bacterial, fungal, and parasitic serologies we prospectively evaluated serologic changes pre- and post-IVIG infusion in 7 participants. The number of new antibody detections ranging from 2 to 5. New detections included positivity for Epstein-Barr virus early D antigen, herpes simplex virus, West Nile virus, cytomegalovirus, and the endemic mycoses Histoplasma and Coccidioides. The greatest number of newly positive serologies was observed in subjects receiving cumulative doses of IVIG in excess of 100 g. Our results illustrate the difficulty in serologic interpretation following IVIG therapy and suggest a dose-response to new positive results. These findings may be a helpful resource to clinicians facing similar circumstances., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test., Methods: In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review., Results: We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment., Conclusions: Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.)., (Copyright © 2019 Massachusetts Medical Society.)

Patients with coccidioidal meningitis require lifelong antifungal therapy. Cumulative toxicity and lack of antifungal efficacy require salvage therapy in the treatment of some patients. In a retrospective review of nine patients with coccidioidal meningitis treated with isavuconazole, successful therapy was seen in three patients and stable disease was confirmed in six patients. Isavuconazole may be a useful addition to the therapeutic choices currently available for coccidioidal meningitis., (Copyright © 2019 American Society for Microbiology.)

Urinary tract obstruction represents a common cause of kidney injury across the human life span, resulting in chronic kidney disease and end-stage renal disease. Yet, the extent of obstructive renal damage can be heterogeneous between individuals, implying the existence of unknown mechanisms that protect against or accelerate kidney injury. In this study, we investigated the role of urothelial remodeling in renal adaptation during congenital and acquired obstruction. In the Megabladder ( Mgb -/- ) model of congenital obstruction and unilateral ureteral ligation model of acute obstruction, progressive hydronephrosis is strongly associated with dynamic reorganization of the renal urothelium, which elaborates a continuous uroplakin (Upk) plaque. This led us to postulate that the Upk plaque prevents parenchymal injury during urinary tract obstruction. To test this hypothesis, we interbred Mgb -/- and Upk1b -/- mice, which lack the critical Upk1b subunit for Upk plaque formation. Upk1b -/- ; Mgb -/- mice experienced an accelerated onset of bilateral hydronephrosis with severe (>67%) parenchymal loss, leading to renal failure and mortality in adolescence. To investigate the function of the renal Upk plaque during acute obstruction, we destabilized the Upk plaque by Upk1b deletion or genetically depleted Upk + cells following unilateral ureteral obstruction. Both of these strategies accelerated renal parenchymal loss following ureteral ligation, attesting to a conserved, stabilizing role for Upk plaque deposition in the acutely obstructed kidney. In aggregate, these complementary experiments provide the first evidence that the Upk plaque confers an essential, protective adaptation to preserve renal parenchymal integrity during congenital and acquired urinary tract obstruction.

Coccidioidal meningitis remains a difficult clinical problem, and despite life-long therapy with triazole antifungals, relapses of disease and medication intolerance occur necessitating salvage treatment. We report two patients with recurrent coccidioidal meningitis who improved following a 2-week course of liposomal amphotericin B monotherapy and discuss potential advantages of this treatment option.

Antimicrobial stewardship programs are promoted as a strategy to reduce Clostridium difficile infections. We implemented an antimicrobial stewardship program comprised of formulary restriction plus prospective audit with feedback for high-cost and broad-spectrum antimicrobials. Subsequently, we reviewed all heath care facility-onset, health care facility-associated C difficile infections. We found that most of these infections were associated with the antecedent receipt of nonaudited, and often unnecessary, antimicrobials., (Copyright © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Meningitis and encephalitis are potentially life-threatening diseases with a wide array of infectious, postinfectious, and noninfectious causes. Diagnostic testing is central to determining the underlying etiology, treatment, and prognosis, but many patients remain undiagnosed due to suboptimal testing and lack of tests for all pathogens. In this article, we summarize the epidemiology, barriers to diagnosis, and current best tests for meningitis and encephalitis in developed countries. We end with a brief discussion of new test methods, such as multiplex panel-based tests and metagenomic sequencing, which are likely to alter diagnostic strategies for these conditions in the near future., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Importance: Clostridium difficile is a major cause of health care-associated infection, but disagreement between diagnostic tests is an ongoing barrier to clinical decision making and public health reporting. Molecular tests are increasingly used to diagnose C difficile infection (CDI), but many molecular test-positive patients lack toxins that historically defined disease, making it unclear if they need treatment., Objective: To determine the natural history and need for treatment of patients who are toxin immunoassay negative and polymerase chain reaction (PCR) positive (Tox-/PCR+) for CDI., Design, Setting, and Participants: Prospective observational cohort study at a single academic medical center among 1416 hospitalized adults tested for C difficile toxins 72 hours or longer after admission between December 1, 2010, and October 20, 2012. The analysis was conducted in stages with revisions from April 27, 2013, to January 13, 2015., Main Outcomes and Measures: Patients undergoing C difficile testing were grouped by US Food and Drug Administration-approved toxin and PCR tests as Tox+/PCR+, Tox-/PCR+, or Tox-/PCR-. Toxin results were reported clinically. Polymerase chain reaction results were not reported. The main study outcomes were duration of diarrhea during up to 14 days of treatment, rate of CDI-related complications (ie, colectomy, megacolon, or intensive care unit care) and CDI-related death within 30 days., Results: Twenty-one percent (293 of 1416) of hospitalized adults tested for C difficile were positive by PCR, but 44.7% (131 of 293) had toxins detected by the clinical toxin test. At baseline, Tox-/PCR+ patients had lower C difficile bacterial load and less antibiotic exposure, fecal inflammation, and diarrhea than Tox+/PCR+ patients (P < .001 for all). The median duration of diarrhea was shorter in Tox-/PCR+ patients (2 days; interquartile range, 1-4 days) than in Tox+/PCR+ patients (3 days; interquartile range, 1-6 days) (P = .003) and was similar to that in Tox-/PCR- patients (2 days; interquartile range, 1-3 days), despite minimal empirical treatment of Tox-/PCR+ patients. No CDI-related complications occurred in Tox-/PCR+ patients vs 10 complications in Tox+/PCR+ patients (0% vs 7.6%, P < .001). One Tox-/PCR+ patient had recurrent CDI as a contributing factor to death within 30 days vs 11 CDI-related deaths in Tox+/PCR+ patients (0.6% vs 8.4%, P = .001)., Conclusions and Relevance: Among hospitalized adults with suspected CDI, virtually all CDI-related complications and deaths occurred in patients with positive toxin immunoassay test results. Patients with a positive molecular test result and a negative toxin immunoassay test result had outcomes that were comparable to patients without C difficile by either method. Exclusive reliance on molecular tests for CDI diagnosis without tests for toxins or host response is likely to result in overdiagnosis, overtreatment, and increased health care costs.

Background: A major risk factor for the development of surgical site infections is Staphylococcus aureus carriage. Compared with non-carriers, S. aureus carriers have up to a 14-fold greater risk for post-surgical infections. Pre-operative screening for S. aureus carriage is controversial. Yet, targeted screening in high-risk patients or from clinically relevant sites may be beneficial. We aimed to determine whether S. aureus detection in high-risk surgical patients would be increased by culturing surgical sites, in addition to the nares, vs. nares-only culturing., Methods: Adults undergoing pre-operative evaluations in orthopedic and neurosurgical clinics were eligible for participation. For each subject, specimens were collected from the anterior nares and from the proposed surgical site. Samples were inoculated onto methicillin-resistant S. aureus-selective chromogenic agar plates and blood agar plates., Results: Of 150 subjects, 80 (53.3%) were women and 70 (46.7%) men. The mean age was 61 years and 77/150 (51.3%) had a BMI≥30. Culture results were available for 147/150 subjects. Of the 147 surgical site cultures, 54 (36.7%), 51 (34.7%), and 28 (19.0%) were collected from knee, hip, and lumbar sites, respectively; the remaining 14 (9.5%) were from cervical, thoracic, or infra-clavicular sites. Overall, 35/147 (23.8%) nasal cultures grew S. aureus; 29/147 (19.7%) grew methicillin-susceptible S. aureus (MSSA), and 6/147 (4.1%) grew methicillin-resistant S. aureus (MRSA). Only 2/147 (1.4%) surgical site cultures grew S. aureus; both grew MSSA and MSSA was cultured also from the nasal swabs of these subjects. Using nasal culture+surgical site culture as "true positive," the percentage of additional S. aureus carriers detected by the addition of surgical site screening was zero as compared to nasal screening alone., Conclusions: The detection of S. aureus carriage in high-risk surgical patients is not improved by swabbing surgical sites in addition to the nares.

Fungal meningitis remains a severe and often lethal infection requiring aggressive antifungal therapy and in refractory cases the use of intrathecal amphotericin B (AmB). Administration of amphotericin B by this method may result in clinically apparent adverse reactions such as paresthesias, radiculitis, or myelopathy. Coadministration of hydrocortisone is therefore often given in an attempt to avoid these effects; however, the potential consequences of this approach on fungal growth or on drug synergy/antagonism had not previously been assessed. We used the checkerboard titration broth microdilution method to analyze interactions by fractional inhibitory concentration indices (FICIs). The combination of amphotericin B and hydrocortisone resulted in synergy or indifference against all isolates (Candida, Cryptococcus, and Coccidioides) during in vitro testing at low concentrations. Antagonism was observed using higher hydrocortisone concentrations (those not observed in vivo) suggesting possible steric hindrance or binding to AmB may occur at doses unlikely to be present during clinical care. Concurrent hydrocortisone and AmB administration should not be avoided due to in vitro antagonism concerns., (© The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Clostridium difficile is the most common cause of health care-associated infection in US hospitals. Recurrence occurs in 25% to 30% of patients., Objective: To determine the safety, fecal colonization, recurrence rate, and optimal dosing schedule of nontoxigenic C. difficile strain M3 (VP20621; NTCD-M3) for prevention of recurrent C. difficile infection (CDI)., Design, Setting, and Participants: Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from June 2011 to June 2013 among 173 patients aged 18 years or older who were diagnosed as having CDI (first episode or first recurrence) and had successfully completed treatment with metronidazole, oral vancomycin, or both at 44 study centers in the United States, Canada, and Europe., Interventions: Patients were randomly assigned to receive 1 of 4 treatments: oral liquid formulation of NTCD-M3, 10(4) spores/d for 7 days (n = 43), 10(7) spores/d for 7 days (n = 44), or 10(7) spores/d for 14 days (n = 42), or placebo for 14 days (n = 44)., Main Outcomes and Measures: The primary outcome was safety and tolerability of NTCD-M3 within 7 days of treatment. Exploratory secondary outcomes included fecal colonization with NTCD-M3 from end of study drug through week 6 and CDI recurrence from day 1 through week 6., Results: Among 168 patients who started treatment, 157 completed treatment. One or more treatment-emergent adverse events were reported in 78% of patients receiving NTCD-M3 and 86% of patients receiving placebo. Diarrhea and abdominal pain were reported in 46% and 17% of patients receiving NTCD-M3 and 60% and 33% of placebo patients, respectively. Serious treatment-emergent adverse events were reported in 7% of patients receiving placebo and 3% of all patients who received NTCD-M3. Headache was reported in 10% of patients receiving NTCD-M3 and 2% of placebo patients. Fecal colonization occurred in 69% of NTCD-M3 patients: 71% with 10(7) spores/d and 63% with 10(4) spores/d. Recurrence of CDI occurred in 13 (30%) of 43 placebo patients and 14 (11%) of 125 NTCD-M3 patients (odds ratio [OR], 0.28; 95% CI, 0.11-0.69; P = .006); the lowest recurrence was in 2 (5%) of 43 patients receiving 10(7) spores/d for 7 days (OR, 0.1; 95% CI, 0.0-0.6; P = .01 vs placebo]). Recurrence occurred in 2 (2%) of 86 patients who were colonized vs 12 (31%) of 39 patients who received NTCD-M3 and were not colonized (OR, 0.01; 95% CI, 0.00-0.05; P < .001)., Conclusions and Relevance: Among patients with CDI who clinically recovered following treatment with metronidazole or vancomycin, oral administration of spores of NTCD-M3 was well tolerated and appeared to be safe. Nontoxigenic C. difficile strain M3 colonized the gastrointestinal tract and significantly reduced CDI recurrence., Trial Registration: clinicaltrials.gov Identifier: NCT01259726.

Cytomegalovirus (CMV) retinitis is a potentially blinding infection that affects immunocompromised patients who are unable to generate a T-cell response against the organism. Infusion of CMV-specific leukocytes has been shown to be effective in patients with systemic CMV infection, especially those resistant to standard therapies. The authors report a case of a patient with CMV viremia with progressive retinitis in whom infusion of third-party donor-derived CMV pp65-specific T cells alone prompted resolution of CMV retinitis. This case suggests a potential role for CMV-specific leukocyte infusion in the treatment of CMV retinitis, especially in cases resistant or refractory to antiviral therapies., (Copyright 2015, SLACK Incorporated.)

Dermatologic problems are common in returning travelers who seek medical care. Some common illnesses such as cellulitis or abscesses occur in travelers but are not unique to this patient group. Additionally, dermatologic illnesses not due to infection such as drug eruptions or phototoxicity are seen. Skin manifestations occur in many tropical illnesses such as dengue, schistosomiasis, and leishmaniasis. This article reviews the common causes of cutaneous illnesses associated with travel including non-infectious causes, infections that are not limited to travelers, and infections that are almost exclusively seen in travelers.

The clinical manifestations of coccidioidomycosis vary depending upon the extent of exposure and immune status of the host. Recent studies have demonstrated an essential role for vitamin D in both innate and acquired immunity and serum levels strongly correlate with the development of upper respiratory tract infections, including tuberculosis. Despite similar pathophysiologic processes at play in the control of tuberculosis and invasive fungal infections, a possible association of low serum 25(OH) vitamin D levels had not previously been assessed in the latter patient group. Therefore, we performed a case-control study examining serum 25(OH) vitamin D levels in three distinct groups of patients with coccidioidomycosis as compared to healthy uninfected controls. Of the 89 patients included in this study, there were 26 negative controls, 23 who were immune, 22 with primary coccidioidal pneumonia, and 18 who had disseminated/meningeal infection. Serum 25(OH) vitamin D levels varied between groups with lowest levels seen in the group with disseminated/meningeal coccidioidomycosis (P= 0.14). In this evaluation of a diverse group of patients with varying forms of coccidioidomycosis we found no association of vitamin D with the acquisition or resolution of this infection. Vitamin D does not play a significant role in host susceptibility to coccidioidomycosis.

Background: In a patient with positive serum serology for coccidioidomycosis, the differential diagnosis of concurrent pleural effusions can be challenging. We, therefore, sought to clarify the performance characteristics of biochemical, serologic, and nucleic-acid-based testing in an attempt to avoid invasive procedures. The utility of adenosine deaminase (ADA), coccidioidal serology, and polymerase chain reaction (PCR) in the evaluation of pleuropulmonary coccidioidomycosis has not been previously reported., Methods: Forty consecutive patients evaluated for pleuropulmonary coccidioidomycosis were included. Demographic data, pleural fluid values, culture results, and clinical diagnoses were obtained from patient chart review. ADA testing was performed by ARUP Laboratories, coccidioidal serologic testing was performed by the University of California-Davis coccidioidomycosis serology laboratory, and PCR testing was performed by the Translational Genomics Research Institute using a previously published methodology., Results: Fifteen patients were diagnosed with pleuropulmonary coccidioidomycosis by European Organization for the Research and Treatment of Cancer/Mycoses Study Group criteria. Pleural fluid ADA concentrations were < 40 IU/L in all patients (range, < 1.0-28.6 IU/L; median, 4.7). The sensitivity and specificity of coccidioidal serologic testing was 100% in this study. The specificity of PCR testing was high (100%), although the overall sensitivity remained low, and was comparable to the experience of others in the clinical use of PCR for coccidioidal diagnostics., Conclusion: Contrary to prior speculation, ADA levels in pleuropulmonary coccidioidomycosis were not elevated in this study. The sensitivity and specificity of coccidioidal serologic testing in nonserum samples remained high, but the clinical usefulness of PCR testing in pleural fluid was disappointing and was comparable to pleural fluid culture.

In a large prospective comparison, the illumigene test detected Clostridium difficile in 98% of toxin-positive and 58% of toxin-negative samples confirmed positive by other methods. The Xpert was uniformly sensitive. Most samples with discrepant results had C. difficile concentrations below the illumigene limit of detection. The significance of low-level C. difficile detection needs investigation.

Direct tests for Clostridium difficile are 30-50 % more sensitive than tests for C. difficile toxins but the reasons for this discrepancy are incompletely understood. In addition to toxin degradation and strain differences, we hypothesized that C. difficile concentration could be important in determining whether toxins are detected in fecal samples. We performed standard curves on an FDA-approved real-time PCR test for the C. difficile tcdB gene (Xpert C. difficile/Epi, Cepheid) during a prospective comparison of a toxin immunoassay (Meridian Premier), PCR and toxigenic culture. Immunoassay-negative, PCR-positive samples were retested with a cell cytotoxin assay (TechLab). Among 107 PCR-positive samples, 46 (43.0 %) had toxins detected by immunoassay and an additional 18 (16.8 %) had toxin detected by the cytotoxin assay yielding 64 (59.8 %) toxin-positive and 43 (40.2 %) toxin-negative samples. Overall, toxin-negative samples with C. difficile had 10(1)-10(4) fewer DNA copies than toxin-positive samples and most discrepancies between toxin tests and PCR were associated with a significant difference in C. difficile quantity. Of the toxin-positive samples, 95 % had ≥ 4.1 log(10) C. difficile tcdB DNA copies/mL; 52 % of immunoassay-negative samples and 70 % of immunoassay and cytotoxin negative samples had <4.1 log(10) C. difficile tcdB DNA copies/mL. These findings suggest that fecal C. difficile concentration is a major determinant of toxin detection and C. difficile quantitation may add to the diagnostic value of existing test methods. Future studies are needed to validate the utility of quantitation and determine the significance of low concentrations of C. difficile in the absence of detectable toxin.

Clostridium difficile testing is shifting from toxin detection to C. difficile detection. Yet, up to 60% of patients with C. difficile by culture test negative for toxins and it is unclear whether they are infected or carriers. We reviewed medical records for 7046 inpatients with a C. difficile toxin test from 2005 to 2009 to determine the duration of diarrhea and rate of complications and mortality among toxin-positive (toxin+) and toxin- patients. Overall, toxin- patients had less severe diarrhea, fewer diarrhea days, and lower mortality (P < 0.001, all comparisons) than toxin+ patients. One toxin- patient (n = 1/6121; 0.02%) was diagnosed with pseudomembranous colitis, but there were no complications such as megacolon or colectomy for fulminant CDI among toxin- patients. These data suggest that C. difficile-attributable complications are rare among patients testing negative for C. difficile toxins. More studies are needed to evaluate the clinical significance of C. difficile detection in toxin- patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Diarrhea is common among hospitalized patients but the causes are distinct from those of diarrhea in the community. We review existing data about the epidemiology of nosocomial diarrhea and summarize recent progress in understanding the mechanisms of diarrhea. Clinicians should recognize that most cases of nosocomial diarrhea have a noninfectious etiology, including medications, underlying illness, and enteral feeding. Apart from Clostridium difficile, the frequency of infectious causes such as norovirus and toxigenic strains of Clostridium perfringens, Klebsiella oxytoca, Staphylococcus aureus, and Bacteroides fragilis remains largely undefined and test availability is limited. Here we provide a practical approach to the evaluation and management of nosocomial diarrhea when tests for C. difficile are negative.

The serum (1→3)-β-d-glucan assay has emerged as an important diagnostic test for invasive fungal disease. The utility of this assay in coccidioidomycosis has not been previously studied. Using a cutoff value of ≥80 pg/ml, we found the sensitivity (43.9%), specificity (91.1%), positive predictive value (81.8%), and negative predictive value (64.1%) to be similar to those of the assay in diagnosing other invasive mycoses.

We describe a case of hepatic mucormycosis with abscess, an uncommon presentation of mucormycetes infection. Our patient was initially treated with transcutaneous pigtail catheter placement, liposomal amphotericin B, and micafungin without improvement. The patient subsequently improved after hepatic segmentectomy and hemidiaphragm resection., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Patients with anti-IFN-γ autoantibodies have impaired IFN-γ signaling, leading to severe disseminated infections with intracellular pathogens, especially nontuberculous mycobacteria. Disease may be severe and progressive, despite aggressive treatment. To address the underlying pathogenic IFN-γ autoantibodies we used the therapeutic monoclonal rituximab (anti-CD20) to target patient B cells. All subjects received between 8 and 12 doses of rituximab within the first year to maintain disease remission. Subsequent doses were given for relapsed infection. We report 4 patients with refractory disease treated with rituximab who had clinical and laboratory evidence of therapeutic response as determined by clearance of infection, resolution of inflammation, reduction of anti-IFN-γ autoantibody levels, and improved IFN-γ signaling.

The use of voriconazole, a trifluorinated antifungal, has been associated with the development of fluoride excess and periostitis/exostoses. We evaluated a cohort of patients on long-term triazole therapy and found that other fluorinated triazoles (fluconazole and posaconazole) conferred no risk for the development of hyperfluorosis and its complications in our cohort.

Background: We have observed a number of patients who fail to develop coccidioidal complement fixing (CF) antibody (immunoglobulin [IgG]) after the initiation of early antifungal therapy. Although this is the first description of this phenomenon in mycology, a precedent for the abrogation of the immune response has been observed in other conditions, including primary syphilis and primary Lyme disease., Methods: We conducted a retrospective case-control study to determine any patient-specific risk factors associated with this observation. Additionally, in vitro analysis of the coccidioidal CF (IgG) antigen (Cts1) was performed after Coccidioides was grown under escalating fluconazole concentrations., Results: Seventeen patients persistently positive for coccidioidal IgM antibodies without developing an IgG response (cases) were compared with 64 consecutive patients who did develop coccidioidal CF (IgG) antibodies (controls). Early treatment with antifungals (within 2 weeks of symptom onset) was associated with an abrogation of IgG antibody production (P < .001). With immunodiffusion testing, control serum demonstrated a lack of IgG seroreactivity when Coccidioides posadasii grown in the presence of escalating fluconazole doses (0.5-128 μg/mL) was used as the antigen; however, control serum remained seroreactive for the presence of IgM. The coccidioidal IgG antigen (Cts1) was shown to be diminished when cultures were grown in the presence of fluconazole, lending further in vitro plausibility to our findings., Conclusions: The abrogation of an IgG response in patients treated early in the course of coccidioidal infection may complicate serodiagnosis and epidemiologic studies, and further study to determine the potential clinical implications should be performed.

Since publication of the Society for Healthcare Epidemiology of America position paper on Clostridium difficile infection in 1995, significant changes have occurred in the epidemiology and treatment of this infection. C. difficile remains the most important cause of healthcare-associated diarrhea and is increasingly important as a community pathogen. A more virulent strain of C. difficile has been identified and has been responsible for more-severe cases of disease worldwide. Data reporting the decreased effectiveness of metronidazole in the treatment of severe disease have been published. Despite the increasing quantity of data available, areas of controversy still exist. This guideline updates recommendations regarding epidemiology, diagnosis, treatment, and infection control and environmental management.

Background: The use of a clinical prediction score to improve the practice of instituting airborne-transmission precautions in patients with suspected tuberculosis holds promise for increasing appropriate isolation and decreasing unnecessary isolation. The objective of this study was to derive and validate a clinical prediction score for patients with suspected tuberculosis., Methods: We used a case-control study design to evaluate differences between patients with a diagnosis of tuberculosis and those placed under airborne precautions who had negative culture results. We developed risk scores based on a multivariable analysis of independently significant factors associated with tuberculosis. Subsequently, we evaluated the sensitivity and specificity of the score in a separate (validation) cohort of patients., Results: Within our population, we found 4 clinical factors associated with tuberculosis: chronic symptoms (odds ratio [OR], 10.2 [95% confidence interval {CI}, 2.95-35.4]), upper lobe disease on chest radiograph (OR, 5.27 [95% CI, 1.6-17.23]), foreign-born status (OR, 7.01 [95% CI, 2.1-23.8]), and immunocompromised state other than human immunodeficiency virus infection (OR, 8.14 [95% CI, 2.08-31.8]). Shortness of breath (OR, 0.13 [95% CI, 0.04-0.45]) was found to be associated with non-tuberculosis diagnoses and considered a negative predictor in the model. Using a cut-off point to maximize sensitivity, we applied the prediction rule to the validation cohort, resulting in a sensitivity of 97% and a specificity of 42%., Conclusion: The tuberculosis prediction rule derived from our patient population could improve utilization of airborne precautions. Clinical prediction rules continue to show their utility for improvement in isolation practices in different demographic areas.

To demonstrate that injecting drug use is a major risk factor of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infection and injecting drug users may be a reservoir of CA-MRSA infection in our community, we conducted a matched case-control study. Cases were CA-MRSA-infected patients at University of California, Davis, Medical Center, Sacramento, CA, from December 1, 2003, to May 31, 2004. Two control groups were community-associated methicillin-susceptible S. aureus (CA-MSSA)-infected patients and a randomly selected uninfected patient group in the same hospital. Controls were matched to cases by age and isolate culture date. One hundred twenty-seven CA-MSSA patients and 381 randomly selected uninfected controls were selected to match the 127 CA-MRSA cases. The adjusted odds ratio of injecting drug use compared with the CA-MSSA group was 2.11 (95% confidence interval [CI], 1.1-4.3) and 4.09 (95% CI, 2.2-7.5) compared with the uninfected group. We suggest that injecting drug use is a significant risk factor for CA-MRSA infection, which could contribute to the increasing prevalence of CA-MRSA in an urban community.

Background: Adoption rates for electronic health records (EHRs) have been slow, despite growing enthusiasm. Cost is a frequently cited obstacle to implementing an EHR. The body of literature citing a positive return on investment is largely anecdotal and infrequently published in peer-reviewed journals., Study Design: Five ambulatory offices, with a total of 28 providers, within the University of Rochester Medical Center, participated in a pilot project using an EHR to document the return on investment. A staged implementation of the Touchworks EHR (Allscripts) was undertaken from November 2003 to March 2004. Measurements of key financial indicators were made in the third calendar quarters of 2003 and 2005. These indicators included chart pulls, new chart creation, filing time, support staff salary, and transcription costs. In addition, patient cycle time, evaluation and management codes billed, and days in accounts receivable were evaluated to assess impact on office efficiency and billing. The savings realized were compared with the costs of the first 2 years of EHR use to determine return on investment., Results: Total annual savings were $393,662 ($14,055 per provider). Total capital cost was $484,577. First-year operating expenses were $24,539. Total expenses for the first year were $509,539 ($18,182 per provider). Ongoing annual cost for subsequent years is $114,016 ($4,072 per provider). So, initial costs were recaptured within 16 months, with ongoing annual savings of $9,983 per provider., Conclusions: An EHR can rapidly demonstrate a positive return on investment when implemented in ambulatory offices associated with a university medical center, with a neutral impact on efficiency and billing.

To describe the epidemiology of Clostridium difficile in children, we cultured stool specimens from patients at the Children's Hospital Central California, Madera, CA (CHCC, n = 676) and at the University of California Davis Medical Center Pediatric Hospital, Sacramento, CA (UCDMC-PH, n = 301) for C. difficile, and toxins A and B genes and strain identity of the isolates were determined by polymerase chain reaction assays. A higher percentage of patients from UCDMC-PH were culture positive (148/301, 49%) and colonized with toxigenic strains (45/301, 15%) compared with CHCC (colonized = 178/676, 26%; toxigenic = 96/676, 14%, P < or = .001). Multiple logistic regression analysis showed decreased colonization with inpatient status (odds ratio [OR] = 0.64; 95% confidence interval [CI] = 0.46, 0.89; P = .007) and use of H-2 antagonists (OR = 0.55; 95% CI = 0.36, 0.84; P = .006), whereas underlying conditions (colonization: OR = 1.42; 95% CI = 1.02, 1.96; P = .04; toxin positive: OR = 1.60; 95% CI = 1.04, 2.44; P = .03) and exposure to > or =2 antiinfectives (colonization: OR = 1.56; 95% CI = 1.10, 2.20; P = .01; toxin positive: OR = 1.71; 95% CI = 1.10, 2.66; P = .02) increased colonization. Most isolates appear to be community acquired, although molecular analysis suggests some nosocomial transmission at UCDMC-PH. These data suggest that the epidemiology of colonization with C. difficile in children is different than previously reported.

Stool specimens from 152 hospitalized patients with diarrhea were analyzed for the presence of enterotoxigenic Bacteroides fragilis (ETBF) by a nested polymerase chain reaction (PCR) assay. ETBF gene sequences were directly detected in 14/152 (9.21%) stools of patients. The prevalence of ETBF in hospital-acquired diarrhea was statistically significant when compared to a prevalence of 2.3% in control subjects (P = 0.04). B. fragilis was cultured from 19.7% (30/152) patients with diarrhea; 4 of these isolates were enterotoxigenic. To determine whether colonization with B. fragilis is heterogeneous in nature, multiple colonies from 17 individual patients were analyzed for enterotoxin gene sequences and genotyped by arbitrarily primed PCR. Of these 17 patients, 13 harbored multiple strain types suggesting heterogeneity of colonization with both enterotoxigenic and non-enterotoxigenic strains. Identification of ETBF in the stools of 10 patients in the absence of a positive culture is likely due to the noted heterogeneity and suggests that detection of enterotoxin by PCR should be performed directly in the stool. These preliminary data indicate that ETBF may play a role in hospital-acquired diarrhea of unknown origin and suggest the need for further studies.

Methicillin-resistant Staphylococcus aureus (MRSA) has long been a common pathogen in healthcare facilities, but in the past decade, it has emerged as a problematic pathogen in the community setting as well. A retrospective case series study of patients from whom MRSA was isolated from December 1, 2003, through May 31, 2004, was conducted at the University of California, Davis, Medical Center. Patient data were collected from electronic medical records and traditional chart reviews to determine whether MRSA acquisition was likely to have been in the community or in the hospital. Antimicrobial susceptibility testing and pulsed-field gel electrophoresis (PFGE) were performed for all confirmed isolates. Skin and soft tissue were the most common infection sites for all MRSA patients. Among the 283 MRSA infections, 127 (44.9%) were defined as community-associated (CA)-MRSA. Ninety-six percent of the CA-MRSA isolates were susceptible to clindamycin. Double-disk diffusion tests were performed to examine inducible clindamycin resistance by erythromycin induction on both CA and hospital-associated (HA) clindamycin-susceptible and erythromycin-resistant isolates. Ten percent (17 of 183) were positive. Most CA-MRSA isolates were identified by PFGE as a unique strain, genotype USA300, which was not genetically related to the predominant genotype, USA100, in the HA-MRSA isolates. Injecting drug users accounted for 49% of CA-MRSA infections but only 19% of the HA-MRSA infections (odds ratio, 4.2; 95% confidence interval, 2.4 to 7.4). Our study shows that a single clone of CA-MRSA accounts for the majority of infections. This strain originated in the community and is not related to MRSA strains from healthcare settings. Injecting drug users could be a major reservoir for CA-MRSA transmission.

Hazard identification and risk assessment paradigms depend on the presumption of the similarity of rodents to humans, yet species specific responses, and the extrapolation of high-dose effects to low-dose exposures can affect the estimation of human risk from rodent data. As a consequence, a human relevance framework concept was developed by the International Programme on Chemical Safety (IPCS) and International Life Sciences Institute (ILSI) Risk Science Institute (RSI) with the central tenet being the identification of a mode of action (MOA). To perform a MOA analysis, the key biochemical, cellular, and molecular events need to first be established, and the temporal and dose-dependent concordance of each of the key events in the MOA can then be determined. The key events can be used to bridge species and dose for a given MOA. The next step in the MOA analysis is the assessment of biological plausibility for determining the relevance of the specified MOA in an animal model for human cancer risk based on kinetic and dynamic parameters. Using the framework approach, a MOA in animals could not be defined for metal overload. The MOA for phenobarbital (PB)-like P450 inducers was determined to be unlikely in humans after kinetic and dynamic factors were considered. In contrast, after these factors were considered with reference to estrogen, the conclusion was drawn that estrogen-induced tumors were plausible in humans. Finally, it was concluded that the induction of rodent liver tumors by porphyrogenic compounds followed a cytotoxic MOA, and that liver tumors formed as a result of sustained cytotoxicity and regenerative proliferation are considered relevant for evaluating human cancer risk if appropriate metabolism occurs in the animal models and in humans.

Objective: To examine the usefulness of temporal and spatial analysis in identifying nosocomial transmission of Clostridium difficile among pediatric patients hospitalized on four wards at The Children's Hospital of Central California from September 8, 1998, to January 16, 1999., Design: Stool specimens obtained from the clinical microbiology laboratory during the study period were tested by culture and latex agglutination for C. difficile. Polymerase chain reaction was used to identify toxin genes. Isolates obtained were mapped to a grid for each ward and were analyzed using the Knox test. Results were compared with DNA fingerprints generated by arbitrarily primed polymerase chain reaction., Results: Total occupancy of these 4 wards was 438 during the study period. Stool specimens were available for 256 (58%) of these patients, yielding 67 C. difficile isolates and generating 2,211 case pairs for analysis by the Knox test. After stratification by toxin status, 5 clustered pairs of toxigenic isolates were identified on 1 of the wards by this method. Fingerprint analysis identified 4 clusters with indistinguishable banding patterns on 2 of the 4 wards. Two of the identified clusters were toxigenic and 2 were nontoxigenic. None of these clusters corresponded to clusters identified by the Knox test., Conclusions: The Knox test is an ineffective method for identifying cases resulting from nosocomial transmission of C. difficile in a pediatric setting due to the persistence of C. difficile spores and the unique environment of a pediatric hospital. Molecular analysis remains the most effective method.

The frequency of Clostridium difficile strains in stool samples of patients with diarrhea hospitalized in the hematology/oncology, surgery, orthopedics, transplantology ward, and emergency room of Davis Medical Center was analyzed. A total of 786 stool samples collected from patients with diarrhea and 180 samples taken from the hospital environment were cultured for C. difficile by routine methods. There were 119 strains of C. difficile isolated: 97 (12.3%) strains from patients' stools (no enteropathogen other than C. difficile was detected in these stool samples) and 22 (12.2%) strains from the hospital environment. It was confirmed that hospital environment plays an important role in transmission of C. difficile by AP-PCR and PCR ribotyping. Among 97 C. difficile strains isolated from patient' stools 25 were nontoxigenic (A-/B-), 67 were toxigenic (A+/B+), and 5 strains were toxin B-positive/toxin A-negative. Analysis of concomitant symptoms among hospitalized patients with diarrhea demonstrated significantly longer duration of diarrhea caused by nontoxigenic strains than in cases of diarrhea caused by toxigenic strains. On the other hand, among patients infected by toxigenic strains, significantly higher leukocytosis and longer duration of fever were observed. The resistance of isolated C. difficile strains to erythromycin and clindamycin indicated the possibility of transmission in the hospital strains with macrolide-lincosamide-streptogramin B resistance type.

We analyzed 226 strains of Clostridium difficile for the presence of erythromycin ribosomal methylase B (ermB) genes. Forty-four strains (19.4%) carried ermB genes and were resistant to erythromycin. Toxin A and toxin B gene sequences were identified in 81.9% of these 44 strains. Strains of C. difficile that carry ermB genes are common etiologic agents of C. difficile-associated diarrhea.

New optimism surrounds treatments for chronic hepatitis B (CHB). Interferon- alpha , lamivudine, and adefovir dipivoxil are currently approved by the United States Food and Drug Administration for the treatment of CHB. All 3 treatments possess unique characteristics with respect to their side effect profiles, potencies, and treatment niches within the spectrum of CHB. New agents, which are in various stages of clinical development, represent potential improvements within existing, as well as novel, classes of antiviral therapy, and they offer significant promise of a cure for the many patients with chronic and progressive hepatitis B. However, there remain many challenges in understanding the implications of drug resistance, the role of combination therapy, and how to define the response to therapy within subsets of patients with hepatitis B.

Toxigenic Clostridium difficile isolates harbor a 19 kb pathogenicity locus that encodes the genes for toxins A and B. Toxins A and B are among the largest known bacterial toxins expressing potent cytotoxicity and enterotoxicity, and thus the major virulence factors in C. difficile associated diarrhea. Cloning and sequencing of toxin genes is of interest for studies of molecular pathogenesis. We report the amplification and cloning of the complete toxin A gene into an Escherichia coli expression vector. Ten clones analyzed contained the complete toxin A gene. Four of these clones showed cytotoxic activity in cell culture, and were positive for toxin A as determined by ELISA. Toxin A expression was confirmed by Western immunoblot analysis. The presence of cytotoxic activity in cell culture suggests that toxin A activity is independent of other genes in the pathogenicity locus.

Clostridium difficile has become the most common cause of hospital acquired diarrhea after antibiotic treatment. The aim of this study was to determine the frequency of C. difficile associated diarrhea among hematology/oncology ward patients and to characterize isolated strains. Twenty three toxigenic and thirteen non-toxigenic strains were detected among fecal isolates. Antibiotic susceptibility testing to erythromycin and clindamycin demonstrated a high degree of resistance (MIC > 256 ug/ml) to both antibiotics in 9 out of 13 nontoxigenic C. difficle strains. Out of 7 patients with maximal frequency of diarrhea (10 empties/day) in 4 cases non-toxigenic strains of C. difficile were isolated. In these cases duration of diarrhea was longer in time than in cases of diarrhea caused by toxigenic strains. Further investigation with a larger patient population is necessary to better understand the role that non-toxigenic C. difficile strains play in disease development.

When introduced in 1959, amphotericin B deoxycholate (AmBD) was clearly a life-saving drug. Randomized studies demonstrating its efficacy were not thought to be necessary, and it was granted indications for many invasive fungal infections. Despite its formidable toxicities, AmBD is thus often used as the primary comparator in studies of invasive fungal infections. Safer lipid-based versions of amphotericin B (AmB) have been introduced, but difficulties with studying these agents generally led to licensure for salvage therapy, not primary therapy. However, the cumulative clinical experience to date with the lipid-based preparations is now adequate to demonstrate that these agents are no less active than AmBD, and, for some infections, it can now be stated that specific lipid-based preparations of AmB are superior to AmBD. Given their superior safety profiles, these preparations can now be considered suitable replacements for AmBD for primary therapy for many invasive fungal infections in clinical practice and research.

Recurrence of Clostridium difficile-associated diarrhea (CDAD) occurs in 15 to 20% of patients after discontinuation of treatment. Arbitrarily primed PCR was used to investigate the epidemiology of recurrent CDAD in 18 patients. Reinfection with a new strain occurred in 6 of 18 patients (33.3%), while 12 patients relapsed with the original strain shortly after discontinuation of treatment. These data suggest that reinfection with exogenous C. difficile is a common problem and that not all recurrences are due to relapse.

Objective: Moxifloxacin is characterized by high activity against Gram-positive cocci and some Gram-positive and -negative anaerobes, including Clostridium difficile. This study investigates the role of prior quinolone use in relation to patterns of susceptibility of C. difficile to moxifloxacin., Methods: Sixty-three clinical isolates of C. difficile were investigated for toxigenicity, susceptibility to moxifloxacin, and mutations in the DNA gyrase gene. The medical histories for 50 of these patients were available and used to identify previous fluoroquinolone use., Results: Thirty-three (52.4%) strains showed resistance to moxifloxacin (MICs > or = 16 mg/L). All moxifloxacin-resistant strains harbored a mutation at amino acid codon Ser-83 of gyrA. Forty-five isolates (71.4%) were toxigenic; all moxifloxacin-resistant strains were in this group. Resistance to moxifloxacin was associated with prior use of fluoroquinolones (P-value 0.009, chi-square)., Conclusions: Although the use of moxifloxacin to treat C. difficile-associated diarrhea is not likely to be common, these data show a relationship between antecedent fluoroquinolone use and resistance to moxifloxacin in C. difficile isolates, and raise questions regarding selection pressure for resistance placed on colonizing bacteria exposed to fluoroquinolones. Mutations in gyrA are involved in moxifloxacin resistance.

Clostridium difficile remains the leading cause of nosocomially acquired diarrhoea. C. difficile usually exhibits resistance against beta-lactam antibiotics, whereas susceptibility to other drugs may vary. This study investigated the antimicrobial susceptibility of C. difficile to different antibiotics over a period of time and characterizes molecular mechanisms for resistance. One hundred and seventy-three toxigenic and 19 non-toxigenic C. difficile strains, recovered from patients in two university hospitals in Germany between 1986 and 2001, were investigated for their susceptibility to erythromycin, clindamycin, moxifloxacin, vancomycin and metronidazole employing the Etest. The genetic background for resistance was analysed using PCR and DNA sequencing. All strains were susceptible to vancomycin and metronidazole. Resistance to erythromycin, clindamycin and moxifloxacin was found in 27%, 36% and 12% of the tested strains, respectively. High-level resistance (MIC > 128 mg/L) against erythromycin and clindamycin was detected in 25% of the strains tested. Thirty-four of the macrolide-lincosamide-streptogramin B (MLS(B))-resistant strains carried the erythromycin resistance methylase gene. The results indicate an increase in the prevalence of resistance to MLS(B) and fluoroquinolone antibiotics in C. difficile. Fluoroquinolone resistance is associated with resistance to MLS(B) antimicrobials.