Clostridium difficile infection causes serious diarrheal disease. Although several drugs are available for treatment, including vancomycin, recurrences remain a problem. LFF571 is a semisynthetic thiopeptide with potency against C. difficile in vitro. In this phase 2 exploratory study, we compared the safety and efficacy (based on a noninferiority analysis) of LFF571 to those of vancomycin used in adults with primary episodes or first recurrences of moderate C. difficile infection. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The primary endpoint was the proportion of clinical cures at the end of therapy in the per-protocol population. Secondary endpoints included clinical cures at the end of therapy in the modified intent-to-treat (mITT) population, the time to diarrhea resolution, and the recurrence rate. Seventytwo patients were randomized, with 46 assigned to receive LFF571. Based on the protocol-specified definition, the rate of clinical cure for LFF571 (90.6%) was noninferior to that of vancomycin (78.3%). The 30-day sustained cure rates for LFF571 and vancomycin were 56.7% and 65.0%, respectively, in the per-protocol population and 58.7% and 60.0%, respectively, in the modified intent-to-treat population. Using toxin-confirmed cases only, the recurrence rates were lower for LFF571 (19% versus 25% for vancomycin in the per-protocol population). LFF571 was generally safe and well tolerated. The incidence of adverse events (AEs) was higher for LFF571 (76.1% versus 69.2% for vancomycin), although more AEs in the vancomycin group were suspected to be related to the study drug (38.5% versus 32.6% for LFF571). One patient receiving LFF571 discontinued the study due to an AE. (This study has been registered at ClinicalTrials.gov under registration no. NCT01232595.) C lostridium difficile infection is a potentially serious disease, with symptoms ranging from mild diarrhea to fatal complications, such as pseudomembranous colitis, toxic megacolon, bowel perforation, and sepsis, in approximately 5% of cases (1). Over the past decade, the severity of C. difficile infections has increased. This is due in part to the emergence of a more virulent C. difficile strain, NAP1/BI/027, which has caused outbreaks in the United States, Canada, and Europe since the early 2000s (2, 3). The current treatment regimens for C. difficile infection include therapy with oral vancomycin, metronidazole, or fidaxomicin. The initial response rates during and immediately after therapy are similar for all three agents in mild cases. Unfortunately, recurrent infection following successful initial treatment is a problem. Compared with oral vancomycin, the rate of recurrence can be lower for fidaxomicin and may be higher for metronidazole, although recently published data from two phase 3 studies revealed that the rates were similar for vancomycin-and metronidazole-treated patients (4-6). The recurrence rates associated with fidaxomicin appear to be reduced only in patients infected wi...

C lostridium difficile infection (CDI), the main cause of nosocomial infectious diarrhea, results from the growth of toxinproducing C. difficile in the colon following disruption of the normal enteric microbiota, usually as a consequence of antibiotic therapy (1). The frequency and severity of CDI have risen over the past decade, with associated increases in morbidity and mortality, especially among the elderly (2, 3). The increase in CDI has been attributed, at least in part, to the epidemic C. difficile BI/NAP1/027 strain, first reported in 2005 (1, 4). Current treatment of CDI includes metronidazole, vancomycin, or fidaxomicin, with cure rates of approximately 86 to 95% (5-7); however, 15 to 40% of patients experience recurrence following clinical cure (6-9). Reducing recurrence rates, together with improving outcomes for those severely affected by CDI, remains a substantial unmet medical need.Cadazolid is a novel, nonabsorbable antibiotic that acts by inhibiting bacterial protein synthesis. In vitro, cadazolid demonstrates potent activity against C. difficile, including the BI/NAP1/ 027 strain, with a low propensity for resistance development (10)(11)(12)(13). In cultures of toxigenic C. difficile, cadazolid strongly inhibits de novo formation of toxins A and B, the main virulence factors of C. difficile, and prevents in vitro C. difficile spore formation at sub-growth-inhibitory concentrations (11). In healthy male patients, single and twice-daily (BID) ascending oral doses of 30 to 3,000 mg cadazolid resulted in very low systemic exposure, with the majority of cadazolid being excreted unchanged in the feces (14). In a human gut model, cadazolid demonstrated narrowspectrum activity, eliminating CDI while having a very limited impact on the normal gut microbiota (15), which, together with preventing the formation of C. difficile spores, may indicate that cadazolid has the potential to reduce CDI recurrence.Here, we report the results of a phase 2 study investigating the efficacy and safety of three oral dosages of cadazolid, with vancomycin as an active reference, in patients with CDI.

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Immunoglobulin administered to adults with neuroinvasive disease appeared to be safe but was not demonstrated to improve clinical outcomes.

This is a repository copy of Cadazolid for the treatment of Clostridium difficile infection: results of two double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials.

Infective endocarditis is an uncommon manifestation of infection with Histoplasma capsulatum. The diagnosis is frequently missed, and outcomes historically have been poor. We present 14 cases of Histoplasma endocarditis seen in the last decade at medical centers throughout the United States. All patients were men, and 10 of the 14 had an infected prosthetic aortic valve. One patient had an infected left atrial myxoma. Symptoms were present a median of 7 weeks before the diagnosis was established. Blood cultures yielded H. capsulatum in only 6 (43%) patients. Histoplasma antigen was present in urine and/or serum in all but 3 of the patients and provided the first clue to the diagnosis of histoplasmosis for several patients. Antibody testing was positive for H. capsulatum in 6 of 8 patients in whom the test was performed.Eleven patients underwent surgery for valve replacement or myxoma removal. Large, friable vegetations were noted at surgery in most patients, confirming the preoperative transesophageal echocardiography findings. Histopathologic examination of valve tissue and the myxoma revealed granulomatous inflammation and large numbers of organisms in most specimens. Four of the excised valves and the atrial myxoma showed a mixture of both yeast and hyphal forms on histopathology.A lipid formulation of amphotericin B, administered for a median of 29 days, was the initial therapy in 11 of the 14 patients. This was followed by oral itraconazole therapy, in all but 2 patients. The length of itraconazole suppressive therapy ranged from 11 months to lifelong administration. Three patients (21%) died within 3 months of the date of diagnosis. All 3 deaths were in patients who had received either no or minimal (1 day and 1 week) amphotericin B.

ObjectivesThe aim of this study was to evaluate the susceptibilities of Clostridium difficile isolates to cadazolid, a novel antibiotic for the treatment of C. difficile infection.MethodsRibotyping and susceptibilities were determined for C. difficile isolates from a multicentre, double-blind, Phase 2 study of oral cadazolid in patients with C. difficile infection (NCT01222702, ClinicalTrials.gov; EudraCT 2010-020941-29, European Clinical Trials Database). Patients were randomized to receive 250, 500 or 1000 mg of cadazolid twice daily or 125 mg of vancomycin four times daily, for 10 days. MICs of cadazolid, vancomycin, fidaxomicin, linezolid and moxifloxacin were determined at baseline for all patients and post-baseline for patients with clinical failure or recurrence, using the agar dilution method.ResultsSeventy-eight of 84 patients had an evaluable toxigenic C. difficile isolate at baseline. The most frequent PCR ribotype was 027 (15.4%). Cadazolid MICs for baseline isolates (including epidemic strain 027) ranged from 0.06 to 0.25 mg/L. Baseline cadazolid MICs were similar to those of fidaxomicin and lower than those of vancomycin, linezolid and moxifloxacin. For each clinical outcome group (clinical cure, clinical failure, sustained clinical response and clinical failure or recurrence), the baseline cadazolid MIC range was 0.06–0.25 mg/L. Mean (min–max) cadazolid faecal concentration (μg/g) on day 5 was 884 (101–2710), 1706 (204–4230) and 3226 (1481–12 600) for the doses 250, 500 and 1000 mg, respectively.ConclusionsFor all cadazolid doses, the faecal concentration was in excess of several thousand-fold the MIC90 for C. difficile. The MIC of cadazolid for all C. difficile isolates, including epidemic strains, was low and in the same narrow range regardless of treatment outcome.

Antibiotic treatment for pelvic inflammatory disease (PID) is often broad spectrum and targets a diverse range of vaginal flora. Treatment of PID in nursing mothers presents a particular clinical challenge because use of antimicrobials during breastfeeding poses several potential risks to infants. Excretion of drugs into breast milk can occur through different mechanisms and depends on the characteristics of both the drug and the mother. Whether daptomycin is excreted into breast milk is unknown, as is its subsequent exposure to breastfeeding infants and the associated risks. We describe a case of PID caused by methicillin-resistant Staphylococcus aureus, an uncommon pathogen in PID, in a breastfeeding mother who was successfully treated with daptomycin. Daptomycin concentrations in her breast milk were measured to determine potential exposure to her infant. These concentrations were extremely low, with an estimated milk:plasma ratio of 0.0012. Although additional confirmatory studies are needed, daptomycin may be a reasonable option in the treatment of PID caused by gram-positive organisms that are resistant to other antibiotics.