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Objectives: The 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.Methods: Ribotyping 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.Results: Seventy-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.Conclusions: For 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. [ABSTRACT FROM AUTHOR]

A study on the importance of the route of antibiotic administration on achievable extravascular fluid drug concentration was performed in a rabbit model. Cefazolin was given either by repeated intramuscular injection or by constant intravenous infusion for 12 to 26 h. Cefazolin penetration into a high and low protein extravascular space was measured by sampling subcutaneous Visking chambers filled with serum or saline. Application of pharmacokinetic principles to equilibrium conditions allowed accurate prediction of the extravascular fluid concentrations. [ABSTRACT FROM PUBLISHER]

Peak serum concentrations of four penicillin and two cephalosporin antibiotics were predicted from quantitative antibiotic binding to serum and tissue proteins in dogs. Predicted total peak serum antibiotic levels varied from 5.1 mg/l00 ml for the 17.0% canine serum-bound methicillin to 16.5 mg/100 ml for the 83.6% serum-bound nafcillin. Actual peak antibiotic concentrations measured following rapid intravenous injection into dogs were in agreement with predicted concentrations for all drugs except nafcillin. [ABSTRACT FROM PUBLISHER]

The clearance of Staphylococcus aureus from perforated peritoneal capsules which are accessible to phagocytic cells, and subcutaneous Visking chambers which exclude phagocytes, was studied simultaneously in eight rabbits implanted with both devices. Animals were treated with cephalothin, 100 mg/kg im every 8 h for sixteen doses, beginning 24 h after inoculation of the infection sites with S. aureus (cephalothin MIC 0.125 mg/l, MBC 0.5 mg/l). At the start of cephalothin, subcutaneous chambers contained a higher concentration of S. aureus (8.4 log10 cfu/ml) than peritoneal capsules (6.8 log10 cfu/ml, P less than 0.001). There was a significant bactericidal effect in subcutaneous chambers on both the third and sixth day of treatment (P less than 0.002), whereas in peritoneal capsules this did not occur until day six. The total reduction in bacterial count in subcutaneous chambers (7.0 log10 cfu/ml) was significantly greater than in capsules (4.4 log10 cfu/ml, P less than 0.002). The mean concentration of cephalothin in subcutaneous chambers (10.7 mg/l) was significantly higher than in peritoneal capsules (6.1 mg/l, P less than 0.02), but no difference in in-vitro killing of S. aureus was detected at these concentrations. We conclude that cephalothin clearance of S. aureus from a site accessible to phagocytes was delayed when compared to a phagocyte-inaccessible site. [ABSTRACT FROM AUTHOR]

Ketoconazole and flucytosine were administered alone and in combination for ten days to rabbits with four candida isolates growing in subcutaneously implanted semipermeable chambers. The peak concentrations of ketoconazole in serum and in the chamber were 20.3 and 3.8 mg/l, respectively, and the concentrations of flucytosine 47.7 and 37.3 mg/l, respectively. The two drugs combined resulted in better fungistatic activity than either drug alone against all four isolates. Correlation of efficacy in the rabbit model with in-vitro MICs was good for flucytosine, but poor for ketoconazole. [ABSTRACT FROM AUTHOR]

Ciprofloxacin, azlocillin, ceftizoxime, and amikacin were studied alone and in combination against six Enterobacteriaceae and six strains of Pseudomonas aeruginosa in an infected chamber model in rabbits simulating a closed space infection. In-vivo results were compared with in-vitro tests of inhibition, killing and synergy. Ciprofloxacin was the most effective single agent, with efficacy against five of the six Enterobacteriaceae when used in low doses, and two of the six pseudomonads when used in high doses. The development of in-vitro resistance to ciprofloxacin was observed during therapy in strains which failed to be eradicated. Ciprofloxacin and azlocillin together was the most effective regimen, with efficacy against eleven of the twelve strains. Synergy, as determined by chequerboard testing, did not correlate with in-vivo outcome. Unlike mezlocillin, azlocillin, ceftizoxime or amikacin, MIC testing of ciprofloxacin was predictive of in-vivo success. [ABSTRACT FROM AUTHOR]

The penetration of the new third-generation cephalosporin, ceftizoxime, into extravascular fluid was determined in a rabbit model using four subcutaneous Visking chambers per rabbit. Ceftizoxime was given im at a dosage of 50 mg/kg every 3 h for 8 doses. Serum peak level was 52.4 mg/l and Visking chamber peak was 20.7 mg/l after the first dose and 28.2 mg/l after the eighth dose. Chamber area under the curve (AUC) was 44% of serum AUC after the first dose and 79.4% of serum AUC after the eighth dose. Ceftizoxime data from tissue and body fluid penetration studies in humans were reviewed and compared with similar studies of other third-generation β-lactams and cefazolin. Ceftizoxime concentrations in fluid-filled spaces (pleural fluid, ascites, amniotic fluid), secretory fluids (bile, sputum), and body tissues (prostate, uterus, gallbladder, cardiac atrium, bone) were usually well above the minimum inhibitory concentration (MIC) of susceptible pathogens. Mean levels in prostatic fluid and aqueous humour were between 1 and 2 mg/l after a single 1 g dose, which is likely to be adequate for some but not all potential pathogens. Mean levels in breast milk and uninflamed cerebrospinal fluid (CSF) were below 0.5 mg/l after single doses of 1 and 2 g respectively, whereas inflamed CSF contained a mean concentration above 3.5 mg/l after multiple doses of 30 mg/kg. In comparison with cefotaxime, the only other third-generation cephalosporin comparably studied to date, ceftizoxime generally achieved higher extravascular levels when the same dosage was given. [ABSTRACT FROM PUBLISHER]