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bClostridium difficile is a leading cause of health care-associated diarrhea with significant morbidity and mortality, and new options for the treatment of C. difficile-associated diarrhea (CDAD) are needed. Cadazolid is a new oxazolidinone-type antibiotic that is currently in clinical development for treatment of CDAD. Here, we report the in vitro and in vivo antibacterial evaluation of cadazolid against C. difficile. Cadazolid showed potent in vitro activity against C. difficile with a MIC range of 0.125 to 0.5 g/ml, including strains resistant to linezolid and fluoroquinolones. In time-kill kinetics experiments, cadazolid showed a bactericidal effect against C. difficile isolates, with >99.9% killing in 24 h, and was more bactericidal than vancomycin. In contrast to metronidazole and vancomycin, cadazolid strongly inhibited de novo toxin A and B formation in stationary-phase cultures of toxigenic C. difficile. Cadazolid also inhibited C. difficile spore formation substantially at growth-inhibitory concentrations. In the hamster and mouse models for CDAD, cadazolid was active, conferring full protection from diarrhea and death with a potency similar to that of vancomycin. These findings support further investigations of cadazolid for the treatment of CDAD.C lostridium difficile infection (CDI), or CDAD for C. difficileassociated diarrhea, is a major health care problem and a leading cause of morbidity and mortality in elderly hospitalized patients (1, 2). During the past decade, there has been a renewed interest in CDAD triggered by an increase in both frequency and severity of the disease in the Western world and the discovery of new hypervirulent strains (3-6), as well as an increased incidence of CDAD in the community (7). CDAD results from overgrowth of toxin-producing strains in the colon, typically following disturbances of the normal protective enteric flora. Clinical symptoms range from asymptomatic colonization to diarrhea, severe pseudomembranous colitis, sepsis, and death. The main virulence factors of C. difficile are two high-molecular-weight toxins, the enterotoxin toxin A (TcdA) and the cytotoxin toxin B (TcdB), while the contribution of the binary toxin remains unclear (8). Toxin A and toxin B cause damage to the intestinal epithelial barrier and promote mucosal inflammation. In fact, the main clinical symptoms of CDAD (secretory diarrhea and inflammation of the colonic mucosa) can be explained by the action of toxins A and B (8). Moreover, C. difficile produces endospores that are resistant to antibiotic treatment and routine disinfection (9). Spores surviving in the gut of patients and in the hospital environment may play a major role in reinfection and relapse of CDAD. Current antibiotic therapy for CDAD includes vancomycin and metronidazole, which have limited treatment success in severe disease, and high recurrence rates of up to 30% have been observed with these treatments (10). Only one new antibiotic, fidaxomicin (11, 12), has been approved in the last 30 years for this indication. In c...

The pathogenesis of aspirin-sensitive asthma remains unknown. Using a new model of platelet activation, initially described as a response of platelets to IgE antibody-dependent stimuli, this study was designed to test the hypothesis of a possible involvement of platelets in aspirin-sensitive asthma. Washed platelets from 35 aspirin-sensitive asthmatics showed an abnormal in vitro response to cyclooxygenase inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs) – aspirin, indomethacin or flurbiprofen – characterized by the generation of a cytocidal supernatant and (14 patients explored) a burst of chemiluminescence; these drugs had no similar effect on platelets from 31 controls (p <0.0001). It was shown that the abnormal platelet response to NSAIDs was not mediated by IgE. In contrast to platelets, aspirin-sensitive asthmatic leukocytes generated neither cytocidal factors nor chemiluminescence in the presence of NSAIDs. Sodium salicylate and salicylamide, which, though structurally similar to aspirin, do not inhibit cyclooxygenase and are well tolerated by aspirin-sensitive asthmatics, did not activate their platelets to release cytocidal factors. Moreover, preincubation of platelets with sodium salicylate, salicylamide or prostaglandin endoperoxide PGH₂, highly prevented their abnormal response to NSAIDs (>80%; p <0.0001). Since several lipoxygenase inhibitors (NDGA, esculetin), including inhibitors of both cyclooxygenase and lipoxygenase (ETYA, BW_755C), did not activate patient platelets and prevented the subsequent abnormal response to NSAIDs, it is suggested that the abnormal platelet activation by NSAIDs is not only the consequence of an inhibition of cyclooxygenase, but also involves generation of lipoxygenase metabolites of arachidonate. Besides, platelets from 4 aspirin-sensitive asthmatics undergoing aspirin desensitization were found to have completely lost their abnormal responsiveness to NSAIDs. These findings represent the first identification in aspirin-intolerant asthmatics of a specific abnormal cellular response to drugs inducing asthmatic attacks and open new perspectives into the pathogenesis, prevention and diagnosis of this disease. They also provide support to the concept of a role for platelets in asthma.