Comparative in vivo bioequivalence and in vitro dissolution of two cyclosporin A soft gelatin capsule formulations.

OBJECTIVE: A study was conducted to establish the bioequivalence between a newly developed cyclosporin A (CsA) oral formulation, Deximune soft-gelatin capsules (Dexcel Ltd.) and Sandimmune Neoral (Novartis Inc.). MATERIALS AND METHODS: The clinical investigation was designed as a randomized, open-labeled, two-period, two-treatment crossover study, in 24 healthy fasted male volunteers. The subjects were administered a single 200 mg CsA dose of either formulation. Serial venous blood samples were obtained over 24 hours after each administration to measure CsA in whole blood by a specific TDx-immunoassay. In addition, the comparative drug release rate was assessed using a dissolution apparatus test according to the USP-24 method. RESULTS: For both treatments, a mean maximum blood concentration (Cmax) of approximately 1,200 ng/ml was obtained at about 1.6 hours (tmax) after administration and the geometric mean of the area under the blood concentration-time curve (AUC) both for test and reference was approximately 4,900 ng x h/ml. Bioequivalence was conclusively demonstrated for both rate (Cmax and tmax) and extent (AUC) of CsA absorption, between the two treatments. Moreover, the CsA blood concentration measurement at 2 hours after administration (C2), demonstrated equivalent results between the two products. The point estimates and their 90% confidence intervals were within the respective equivalence ranges for the pharmacokinetic parameters and were included in the range for drugs with a narrow therapeutic index. The comparative dissolution test for both formulations showed an in vitro release rate of more than 90% within 15 minutes. CONCLUSIONS: Based on the results, the two oral CsA formulations compared are bioequivalent and can be interchanged without need for dosage adjustment.

Ciprofloxacin treatment of malignant external otitis.

The Ear, Nose, and Throat department of the Meir Hospital treated 91 patients with malignant external otitis during the past 16 years. The last 23 patients with malignant external otitis were treated with ciprofloxacin 750 mg twice daily, combined with local excision of the aural lesion. The records of 61 of our previous 68 patients who underwent surgery and were hospitalized and treated with an intravenous extended-spectrum penicillin and gentamicin for six to eight weeks, were analyzed. Twenty-one of 23 patients treated with ciprofloxacin were cured; therapy failed in two patients. Treatment averaged 16.8 days of hospitalization, and bacteriologic eradication was achieved after an average of 7.04 days, as compared with 49 and 15.3 days, respectively, in the group of patients with the intravenous treatment. The mean peak concentrations of ciprofloxacin in serum varied between 2.5 and 3.7 micrograms/ml, and the drug concentrations in different ear tissues were 0.2 to 13 micrograms/g. The treatment with ciprofloxacin was well tolerated with no significant side effects, whereas serious side effects were noted in 45.9 percent of the previous intravenously treated group. The concentrations of the drug in serum and ear tissues were higher than the average minimal inhibitory concentration for Pseudomonas aeruginosa. Use of ciprofloxacin treatment, combined with local excision of the aural lesion, will bring about healing of malignant external otitis in the majority of cases. Ciprofloxacin can be given on an ambulatory basis after a relatively short period of hospitalization.

The intravitreal penetration of orally administered ciprofloxacin in humans.

To evaluate the penetration of ciprofloxacin, a new wide-spectrum oral antibiotic, into the vitreous, ciprofloxacin was administered orally to 21 patients who were scheduled to undergo vitreal surgery. Seven patients received 750 mg ciprofloxacin 4 hr before surgery (group I), seven patients received this dose 8 hr before surgery (group II), and seven patients received two 750-mg doses of oral ciprofloxacin every 12 hr. The last dose was administered 12 hr before surgery (group III). Vitreous and blood samples were collected simultaneously and assayed for ciprofloxacin concentrations by bioassay and high-performance liquid chromatography.

Antibiotic prescribing for adults and children in Israeli emergency rooms.

The emergency room (ER) is an important focal point for the initiation of antimicrobial therapy but there are few data on antimicrobial prescribing in the ER. The objective of the study was to describe antimicrobial prescribing in Israeli ERs and to compare patterns of prescribing between four different ERs in Northern Israel. The medical records of all patients who attended the ERs during February 2001 were examined. Those patients who were discharged home with a prescription for an antibiotic formed the sample. Paediatric data were only available for two of the four ERs. A total of 970 adults and 470 children attended the four ERs during 1 month and were discharged home with an antibiotic prescription representing 14.6 and 19.9%, respectively, of the total number of patients who visited the ERs. The most common diagnosis leading to an antibiotic prescription was respiratory tract infections (64 in adults and 90% in children). In adults, cefuroxime-axetil and amoxycillin-clavulanate (both second-line antibiotics) were the most frequently prescribed antibiotics, together accounting for 50% of all antibiotic prescriptions, while in children amoxycillin-clavulanate was favoured (58.9%). 'Viral infections' accounted for 22.5% of all prescriptions in adults, but only 2.3% in children. Otitis media accounted for almost half of all prescriptions in children. For some diagnoses, such as pneumonia in adults and tonsillitis in children, there was uniformity of prescribing among the different ERs, while for other diagnoses, there were large discrepancies. The ER represents an important source of inappropriate antibiotic prescribing, and measures to curb inappropriate prescribing are urgently needed.

Patterns of systemic antibiotic use in a tertiary hospital in Israel in the years 1998-2000.

OBJECTIVES: To investigate the pattern of antibiotic use in the hospital over a 3-year period according to individual drugs and hospital departments. SETTING: 335 adult beds of a tertiary hospital in Northern Israel during the years 1998-2000. An antibiotic control policy restricts the use of the most expensive antibiotics and those with broad spectrum of activity and a major impact on bacterial resistance. METHODS: The ATC/DDD and DU 90% methodologies were used. The use of antibiotics was expressed as the number of defined daily doses (DDD) per 100 bed-days. RESULTS: The total antibiotic use varied during the study period from 93.7-101.0 DDD/100 bed-days (p < 0.1). Thirteen drugs accounted for 90% of the total volume. The use of broad spectrum penicillins was the highest of all drugs followed by cephalosporins and oral quinolones. The highest rates of antibiotic use were found in the departments of ENT, urology, gynecology and orthopedics and in the intensive care unit (ICU). The total restricted antibiotics use was 7.2 DDD/100 bed-days and was the highest in the ICU. CONCLUSIONS: The ATC/DDD methodology provided delineation and interpretation of antibiotic usage patterns in the hospital. Although the overall use is higher then that found in several reports from European hospitals, stratification by individual drugs and by hospital department yielded similar trends.

A modified HPLC method for the determination of vancomycin in plasma and tissues and comparison to FPIA (TDX).

A modified high performance liquid chromatography (HPLC) method for the quantification of vancomycin levels in plasma and tissues is described. The method uses solid phase extraction (SPE) of vancomycin from the samples and reversed phase HPLC with UV detection. The method was fully validated in terms of recovery, linearity, selectivity and various stability conditions. Vancomycin was determined in plasma samples obtained from 15 patients undergoing cardiopulmonary bypass, before and repeatedly during 12 h after drug administration. The vancomycin levels in plasma were measured by HPLC and by fluorescence polarization immunoassay (FPIA) (TDX). The following correlation was found: TDX = 0.84 HPLC + 1.04. The mean vancomycin levels in skin, fat, atrium, pericardium and sternum, before and after bypass, are reported.

Herpes zoster oticus: treatment with acyclovir.

Herpes zoster oticus produces facial paralysis with a low recovery rate. Acyclovir, a specific virostatic drug, was given intravenously in five herpes zoster oticus patients, and in three of them was followed by oral therapy. In follow-ups of 1 to 24 months, one patient had grade I recovery, three patients grade II, and one grade III. These good results encourage the use of acyclovir in herpes zoster oticus patients.

Successful treatment of malignant external otitis with oral ciprofloxacin: report of experience with 23 patients.

Twenty-three consecutive patients with malignant external otitis (MEO) were treated with oral ciprofloxacin, 1.5-2.25 g/day for 6 weeks. Treatment was combined with local surgical debridement. Patients were discharged early for ambulatory follow-up. Few minor side effects were reported, and full compliance with the study drug was observed. In 21 patients cure was achieved; in 2 the response was not adequate. Oral ciprofloxacin is an effective, convenient, nontoxic, economically justified alternative to the combination intravenous therapy previously advocated.

Endocarditis caused by Blastoschizomyces capitatus and taxonomic review of the genus.

Blastoschizomyces capitatus Salkin, Gordon, Samsonoff et Rieder was found to be the etiologic agent of endocarditis in a patient with a prosthetic mitral valve. Cultures inoculated with peripheral blood and portions of the valve yielded B. capitatus. Examination of stained tissue sections revealed the presence of fungal filaments morphologically consistent with this organism. The salient characteristics of B. capitatus and the factors contributing to its recognition as a distinct taxon are described.

Epidemiology of candidemia--a nationwide survey in Israel.

Bloodstream infections with Candida are often lethal and have been reported to be increasing in frequency. The current retrospective study describes the magnitude and epidemiological characteristics of candidemia in all western-type hospital facilities in Israel in 1994. Comprehensiveness of the data from the reporting hospitals was checked by cross-study of the data from the infectious diseases records and from the hospitalization records. Vital status of all reported cases was evaluated 1 year after the diagnosis. Data on 298 newly diagnosed cases of candidemia were received from 14 of the 18 general hospitals in Israel. The proportion of candidemia in the Israeli hospitals ranged from 0.1 to 0.01% of all admissions, with a mean of 0.05%. The incidence of candidemia differed significantly between the wards from 4-5/10,000 in general surgery and internal medicine wards to about 60/10,000 and 80/10,000 in intensive care and preterm units, respectively. Of all detected cases 53.6% were Candida albicans. Another nine specific species of Candida (mainly Candida parapsilosis, Candida tropicalis and Candida glabrata) were detected, with major differences between the various hospitals. The species of Candida differed significantly by sex and age. Of the cases of candidemia 21.5% died within 30 days of the isolation of the pathogen. The one-year mortality rate was 31.9%. Species-specific 30-day mortality rate was highest for C. glabrata. Throughout the analysis, C. glabrata emerged as a unique cause of candidemia, producing higher mortality, appearing at a younger age and predominating among females.

Pharmacokinetics of vancomycin administered as prophylaxis before cardiac surgery.

Vancomycin concentrations in serum, tissues, and sternum, administered as prophylaxis to patients during coronary artery bypass surgery, were measured. Vancomycin (15 mg/kg) was administered to 15 patients 1 hour before skin incision. Blood, tissue, and sternum samples were collected before, during, and after bypass. The concentration in serum at the end of infusion was 55.1 +/- 22.8 microg/mL, the mean elimination half-life was 9 +/- 4 hours, the areas under the concentration-time curve (AUC) from 0 to 12 hours and from 0 to infinity were 90.6 +/- 25.1 and 289.7 +/- 86.5 microg/h per mL, respectively, the mean residence time (MRT) was 11.9 +/- 5.0 hours, the mean volume of distribution was 51.1 +/- 12.2 L, and the total clearance was 78.3 +/- 32.6 mL/min. Vancomycin concentrations in serum, tissues, and sternum during the operation were greater than the MIC90 for most staphylococci and ranged from 16 to 55 microg/mL in serum and from 4 to 39 microg/g in sternum and tissues.