Introduction: Determining the cause of community-acquired pneumonia (CAP) remains problematic. In this observational study, we systematically applied currently approved diagnostic techniques in patients hospitalized for CAP in order to determine the proportion in which an etiological agent could be identified.Methods: All patients admitted with findings consistent with CAP were included. Sputum and blood cultures, urine tests for pneumococcal and Legionella antigens, nasopharyngeal swab for viral PCR, and serum procalcitonin were obtained in nearly every case. Admission-related electronic medical records were reviewed in entirety.Results: By final clinical diagnosis, 44 patients (17.0%) were uninfected. A causative bacterium was identified in only 60 (23.2%) cases. PCR identified a respiratory virus in 42 (16.2%), 12 with documented bacterial coinfection. In 119 (45.9%), no cause for CAP was found; 69 (26.6%) of these had a syndrome indistinguishable from bacterial pneumonia. Procalcitonin was elevated in patients with bacterial infection and low in uninfected patients or those with viral infection, but with substantial overlap.Conclusions: Only 23.2% of 259 patients admitted with a CAP syndrome had documented bacterial infection; another 26.6% had no identified bacterial etiology, but findings closely resembled those of bacterial infection. Nevertheless, all 259 received antibacterial therapy. Careful attention to the clinical picture may identify uninfected patients or those with viral infection, perhaps with reassurance by a non-elevated procalcitonin. Determining an etiologic diagnosis remains elusive. Better discriminators of bacterial infection are sorely needed. Published by Elsevier Ltd on behalf of The British Infection Association.

BACKGROUND:The purpose of this investigation was to determine if disruption of the colonic epithelium during Clostridium difficile infection (CDI) is associated with bacteraemia due to secondary bacterial invasion by enteric organisms.METHODS:We reviewed the medical records of 505 randomly selected individuals from a database of patients who tested positive for C. difficile toxin and identified bacteraemias that occurred in 2 periods-the pre-CDI and post-CDI periods. Medical records were reviewed to determine a source for each case of bacteraemia. Staphylococcal bacteraemias were excluded from the analysis.RESULTS:In the pre-CDI period, 28 of 505 (5.5%) patients had non-staphylococcal bacteraemia. A focus of infection was found in 24 of 28 (85.7%) cases. During CDI, 30 of 505 (5.9%) patients had non-staphylococcal bacteraemia; in the majority (19 cases, 63.3%) a focus of infection was not identified (p < 0.001). In the pre-CDI period, 16 of 28 (57.1%) blood cultures yielded Gram-negative pathogens compared to 9 of 30 (30%) in the CDI period (p = 0.04). Seven of 28 (25%) blood cultures in the pre-CDI period yielded enterococci compared to 15 of 30 (50%) in the CDI period (p = 0.05).CONCLUSIONS:The incidence of non-staphylococcal bacteraemias in the pre- and post-CDI periods was nearly the same. Cases of bacteraemias in the CDI period more frequently involved organisms of unknown source and uncertain pathogenicity, and were usually not found to require antimicrobial therapy. The data favour the assumption that CDI-associated bacteraemia may be associated with bacterial invasion of the damaged colonic epithelium.

BACKGROUNDVancomycin is the only US Food and Drug Administration-approved drug for treatment of Clostridium difficile infection (CDI). Metronidazole has been widely used for this purpose but may be inferior to vancomycin, especially for hospitalized patients with severe disease. We report a prospective, double-blind, randomized controlled trial comparing nitazoxanide with vancomycin for treatment of CDI.METHODSFifty patients with CDI were randomized to receive vancomycin or nitazoxanide for 10 days. An initial response was considered to be the absence of all CDI symptoms between days 11 and 13, and a final response was considered to be lack of symptom recurrence by day 31.RESULTSOne patient fulfilled an exclusion criterion and was removed from the study. Twenty-seven patients received vancomycin, and 23 received nitazoxanide; 23 and 18 patients, respectively, completed the full course of treatment. Initial responses occurred in 20 (74%) of 27 patients treated with vancomycin and in 17 (77%) of 22 patients treated with nitazoxanide (95% confidence interval, -24% to +28%). In those who completed therapy, response rates were 87% (20 of 23 patients) in the vancomycin group and 94% (17 of 18 patients) in the nitazoxanide group (95% confidence interval, -18% to +30%). Times to complete resolution of symptoms were similar in the 2 groups (P = .55). Two patients in the vancomycin group and 1 patient in the nitazoxanide group experienced relapse within 31 days after beginning treatment. Sustained response rates were 78% (18 of 23 patients) for the vancomycin group, and 89% (16 of 18 patients) for the nitazoxanide group (95% confidence interval, -18% to +35%).CONCLUSIONSThe small sample precludes conclusions about noninferiority of nitazoxanide to vancomycin. Nevertheless, this is the first recent randomized controlled trial to compare any antimicrobial agent other than metronidazole with vancomycin. Results suggest that nitazoxanide may be as effective as vancomycin in treating CDI.TRIAL REGISTRATIONClinicalTrials.gov identifier: NCT00384527.

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10 11 12 Daniel M. Musher,* Atisha Manhas, Pranav Jain, Franziska Nuila, 13 14 Amna Waqar, Nancy Logan, Bernard Marino, Edward A. Graviss, 15 16 17 From the Medical Service (Infectious Disease Section), Michael E. DeBakey 18 Veterans Affairs Medical Center, Houston, Texas, the Departments of Medicine 19 and Molecular Virology and Microbiology, Baylor College of Medicine, and the 20 Department of Pathology, Baylor College of Medicine, Houston, Texas 21 22 These data were presented in preliminary form at the 44th annual meeting of the 23 Infectious Disease Society of America, October, 2006 24 25 Running title: Detection of C. difficile toxin 26 27

Purpose. The role of concurrent use of proton-pump inhibitors (PPIs) in the outcomes of treatment for Clostridium difficile colitis was studied.Methods. The records of inpatients at a large Veterans Affairs medical center in whom C. difficile colitis was diagnosed between June 2004 and July 2005 were retrospectively reviewed. Data collected included patient characteristics at baseline, antibiotic therapy prescribed before and during therapy for C. difficile colitis, concurrent treatment with a PPI, response to therapy for C. difficile colitis, and recurrence of the disease in the 90 days after symptoms resolved. Outcomes of therapy were classified as cures, treatment failures, or disease recurrences.Results. A total of 140 patients (138 men and 2 women) were included in the study. Ninety-seven (69%) of patients received a PPI and 43 (31%) did not. Of patients receiving a PPI, 37 (38%) were cured of C. difficile colitis, 20 (21%) did not respond to therapy, and 40 (41%) had disease recurrence. Among the non-PPI patients, 27 (63%) were cured, 9 (21%) did not respond, and 7 (16%) had recurrence. Patients receiving PPIs were 4.17 times as likely to have recurrence as their counterparts who did not.Conclusion. PPI therapy was associated with an increased risk of recurrent C. difficile colitis.

ABSTRACT Several kinds of laboratory techniques are available to detect Clostridium difficile toxin in fecal samples. Because questions have been raised about the reliability of immunoassays compared to the accepted standard, cytotoxicity assay, we studied three enzyme immunoassays (EIAs) and one rapid EIA, which demonstrated relatively good sensitivities and specificities compared to cytotoxicity assay.

OBJECTIVES:Clostridium difficile-associated disease has increased in incidence and severity. Recommended treatments include metronidazole and vancomycin. Recent investigations, however, document the failure of metronidazole to cure a substantial proportion of patients with Clostridium difficile colitis, but oral administration of vancomycin raises concerns over selection of antibiotic-resistant organisms in the hospital environment. We have recently shown that nitazoxanide is as effective as metronidazole in initial therapy for C. difficile colitis. We hypothesized that this drug might be effective in treating patients who fail therapy with metronidazole.METHODS:In the present study, we identified 35 patients who failed treatment with metronidazole for C. difficile colitis; failure was defined as either no improvement in symptoms or signs of disease (28 patients) after >or= 14 days of treatment with metronidazole or prompt recurrence on at least two occasions after initially responding to such treatment (seven patients). These patients were ill with numerous co-morbidities. Nitazoxanide, 500 mg twice daily, was given for 10 days; results from all patients are included.RESULTS:Twenty-six (74%) of 35 patients responded to nitazoxanide, of whom seven later had recurrent disease, yielding a cure rate of 19 of 35 (54%) from initial therapy. Three who initially failed and one who had recurrent disease were re-treated with, and responded to, nitazoxanide. Thus, the aggregate cure with nitazoxanide in this difficult-to-treat population was 23 of 35 (66%).CONCLUSIONS:Nitazoxanide appears to provide effective therapy for patients with C. difficile colitis who fail treatment with metronidazole.

BACKGROUND:Clostridium difficile colitis has increased in incidence and severity, and treatment failure with metronidazole therapy has increasingly been documented. It is uncertain whether treatment with vancomycin is more effective than treatment with metronidazole, but concern over the emergence of vancomycin resistance has motivated the search for alternative therapy. Nitazoxanide, a nitrothiazolide, blocks anaerobic metabolism of eukaryocyes and effectively treats intestinal infestation due to Cryptosporidium or Giardia species. At low concentrations, this compound inhibits C. difficile in vitro.METHODS:We designed a prospective, randomized, double-blind study to compare nitazoxanide to metronidazole in treating hospitalized patients with C. difficile colitis.RESULTS:Thirty-four patients received metronidazole at a dosage of 250 mg 4 times per day for 10 days, 40 patients received nitazoxanide at a dosage of 500 mg 2 times per day for 7 days, and 36 patients received nitazoxanide at a dosage of 500 mg 2 times per day for 10 days. After 7 days of treatment, 28 (82.4%) of 34 patients had responded to metronidazole therapy, compared with 68 (89.5%) of 76 who had received nitazoxanide therapy (difference, 7.1%; 95% confidence interval, -7.1% to 25.5%). Thirty-one days after beginning treatment, sustained responses were observed in 19 (57.6%) of 33 patients who had received metronidazole therapy for 10 days, compared with 25 (65.8%) of 38 who had received nitazoxanide for 7 days and 26 (74.3%) of 35 who had received nitazoxanide for 10 days (P = .34).CONCLUSION:Nitazoxanide is at least as effective as metronidazole in treating C. difficile colitis.

BACKGROUND:Clostridium difficile is a frequent cause of serious nosocomial infection. Earlier reports have suggested that treatment with metronidazole cured nearly 90% of patients, with only a modest rate of recurrence of infection. In recent years, the rate of response to treatment with this drug has appeared to be much lower.METHODS:We undertook a prospective, observational study of 207 patients who were treated with metronidazole for C. difficile colitis.RESULTS:A total of 103 patients (50%) were cured by the initial course of therapy and had no recurrence of disease. Forty-six patients (22%) continued to have symptoms of colitis for > or = 10 days despite treatment, and 58 (28%) responded initially but had a recurrence within the ensuing 90 days. The mortality rate among patients who developed C. difficile colitis was 27%, and it was higher among patients who did not respond fully to an initial course of therapy, compared with those who did (33% vs. 21%; P < .05).CONCLUSIONS:Because of the relatively poor response to therapy, additional approaches to prevention and/or treatment of C. difficile colitis appear to be warranted.