Novel antibacterial drugs that are effective against infections caused by multidrug resistant pathogens are urgently needed. In a previous report, we have shown that tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. During the course of our optimization program, lead compound 5 was deprioritized due to adverse findings in cardiovascular safety studies. In the effort of mitigating these findings and optimizing further the pharmacological profile of this class of compounds, we have identified a subseries of tetrahydropyran-based molecules that are potent DNA gyrase and topoisomerase IV inhibitors and display excellent antibacterial activity against Gram positive pathogens, including clinically relevant resistant isolates. One representative of this class, compound 32d, elicited only weak inhibition of hERG K(+) channels and hNaV1.5 Na(+) channels, and no effects were observed on cardiovascular parameters in anesthetized guinea pigs. In vivo efficacy in animal infection models has been demonstrated against Staphylococcus aureus and Streptococcus pneumoniae strains.

The promotion of colonization with vancomycin-resistant enterococci (VRE) is one potential side effect during treatment of Clostridium difficile-associated diarrhea (CDAD), resulting from disturbances in gut microbiota. Cadazolid (CDZ) is an investigational antibiotic with potent in vitro activity against C. difficile and against VRE and is currently in clinical development for the treatment of CDAD. We report that CDZ treatment did not lead to intestinal VRE overgrowth in mice.C urrent antibiotic treatment of Clostridium difficile-associated diarrhea (CDAD) is mostly done with oral metronidazole (MDZ) and vancomycin (VAN), while only VAN is approved by the FDA. Both drugs promote overgrowth of vancomycin-resistant enterococci (VRE) in the gut and long-term colonization on treatment (1). Recently, the antibiotic fidaxomicin (FDX) was approved by the FDA as a new treatment option for CDAD. Its clinical impact on VRE overgrowth is still unclear. Colonization with VRE represents a major source for VRE bloodstream infections, endocarditis, and urinary tract infections, a particular problem in intensive care units (ICUs) (2-5). Infections caused by VRE are more serious and are associated with a higher mortality rate than those caused by vancomycin-sensitive enterococci (6-9). VRE control appears to be highly challenging. Therefore, preventing VRE colonization represents an important health care goal, particularly in the ICU. FIG 1Mice were pretreated with cadazolid, vancomycin, fidaxomicin, or metronidazole once daily at the indicated doses per kilogram body weight per day (vehicle-treated group, 0 mg/kg) from day Ϫ2 to day ϩ2 and infected with VRE on day 0. Results are expressed as change in log CFU per cecum (versus vehicle group) at 3 days postinfection. Shown are 25% to 75% interquartile range (box), median (intersection), and minimum-maximum (t bar) values for each group. Data were pooled from two similar, independent experiments. API, active pharmacological ingredient. *, P Ͻ 0.05; ***, P Ͻ 0.001. (10), exhibited efficacy and potency in prevention of CDAD similar or superior to VAN, MDZ, and FDX in the mouse model for CDAD (10, 11). CDZ exhibited potent in vitro activity not only against C. difficile clinical isolates but also against VRE (MIC 90 , 2 g/ml) (12, 13), while having a limited impact on bacteria of the normal gut microflora in the in vitro human gut model (14). Recently, a phase 2 trial in CDAD showed clinical cure rates with CDZ treatment similar to those with VAN treatment, while having lower recurrence rates, resulting in higher sustained cure rates (15).In order to investigate the impact of CDZ on intestinal VRE expansion, a mouse model for VRE colonization was employed (1; see Supplementary Material and Methods in the supplemental material). All animal housing and experiments were conducted in agreement with the Swiss Federal Ordinance for animal protection, the animal welfare guidelines from the Cantonal Veterinary Office Basellandschaft, and the Actelion Pharmaceuticals, Ltd., internal anim...

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SLAP lesions disrupt the perilabral architecture, but so far there have been no reports about posterior instability due to SLAP lesions. In a prospective study of 30 patients with recurrent posterior instability, we found SLAP lesions as a reason for instability in three cases. The purpose of this study is to point out that SLAP lesions can be a cause of posterior instability. Thirty patients with clinical posterior shoulder instability underwent diagnostic arthroscopy before operative stabilization procedures, three of whom (three males, aged 29-51 years) showed a SLAP lesion (once case each of types II, III, and IV) as a cause of posterior instability. All three patients had a history of a fall on the outstretched arm. All patients underwent arthroscopic refixation of the labrum. After arthroscopic refixation of the SLAP lesions, two patients were completely stable (SLAP II and III), whereas one patient (SLAP IV) reported microinstability during overhead activity but complete stability during activity of daily living. The same patient complained about moderate pain in extreme external-flexion rotation with slightly reduced range of motion in external-flexion position. All other patients were free of pain and showed free range of motion. Our results demonstrate that SLAP lesions can be a cause for posterior shoulder instability. In our cases, posterior shoulder instability caused by SLAP lesions was successfully treated by arthroscopic refixation of the torn biceps anchor. When treating posterior shoulder instability, SLAP lesions should be taken into account.

Histometric studies in 34 boys with retractile testes and 21 controls with normal descent showed no significant statistic differences with regard to tubulus diameter and spermatogonia count. Operative treatment of retractile testes, therefore, is not indicated.