Current guidelines suggest that disseminated Mycobacterium avium complex (MAC) infection be treated with a macrolide plus ethambutol or rifabutin or both. From 1993 to 1996, 198 AIDS patients with MAC bacteremia participated in a prospective, placebo-controlled trial of clarithromycin (500 mg b.i.d.) plus ethambutol (1,200 mg/d), with or without rifabutin (300 mg/d). At 16 weeks, 63% of patients in the rifabutin group and 61% in the placebo group (P = .81) had responded bacteriologically. Changes in clinical symptoms and time to survival were similar in both groups. Development of clarithromycin resistance during therapy was similar in the two groups; of patients who had a bacteriologic response, however, only 1 of 44 (2%) receiving rifabutin developed clarithromycin resistance, vs. 6 of 42 (14%) in the placebo group (P = .055). Thus, rifabutin had no impact on bacteriologic response or survival but may protect against development of clarithromycin resistance in those who respond to therapy.
An open-label, dose-response study of cefpodoxime proxetil (CPD), an expanded-spectrum cephalosporin, was conducted with 58 males with uncomplicated Neisseria gonorrhoeae infections with single doses of 600, 400, 200, 100, or Cefpodoxime proxetil (U-76,252) (CPD), an orally administered, expanded-spectrum cephalosporin with a broad spectrum of antimicrobial activity (2, 7, 9, 11), has been shown to be active against both penicillinase-producing and non-penicillinase-producing strains of Neisseria gonorrhoeae (2). Cefpodoxime is resistant to most ,-lactamases but is not itself a ,-lactamase inhibitor. In vitro studies of the activity of CPD against multiple strains of N. gonorrhoeae have shown excellent activity. The MICs of CPD for P-lactamase-negative strains were <0.008 ,ug/ml for 42 strains and <0.06 ,ug/ml for 33 strains. For P-lactamase-positive isolates, the MICs of CPD were <0.06 jig/ml for 25 strains and 0.015 ,ug/ml for 24 strains (9).The present study was an open-label, uncontrolled study in which males with uncomplicated N. gonorrhoeae infection were treated with single doses of 600, 400, 200, 100, or 50 mg of CPD administered orally in tablets (dose expressed in CPD equivalents).The protocol was approved by an institutional review board, and each participant gave written informed consent. Male patients with urethral discharge and Gram stains with gram-negative intracellular diplococci were enrolled. Exclusions included patients less than 18 or more than 60 years of age, patients with known allergy to ,-lactam antibiotics or probenecid, patients with coexisting syphilis (clinically or serologically diagnosed), patients who received antibiotic therapy c14 days prior to enrollment, patients with active symptoms of other serious illness, patients with complications of N. gonorrhoeae infection (e.g., epididymitis, septic arthritis, or disseminated N. gonorrhoeae), and patients who were previously enrolled in this study (reinfection or relapse) or who were receiving any other investigational drugs.
The clinical development programme for cefmetazole sodium included over 4000 patients treated by 78 investigators. Cefmetazole therapy was compared with that of cefoxitin sodium (cefoxitin) for the treatment of urinary tract, skin and soft tissue, lower respiratory, abdominal, and gynaecological infections (with cefoxitin-sensitive pathogens) and for the prevention of postoperative wound infection in patients undergoing surgical procedures. Both cefmetazole and cefoxitin were administered intravenously in all studies. Cefmetazole was as effective as cefoxitin in the treatment of the infections studied. In the surgical wound infection prophylaxis studies, multiple-dose cefmetazole therapy was more effective than multiple-dose cefoxitin therapy in patients undergoing lower gastrointestinal surgery; this difference approached statistical significance. Both multiple-dose and single-dose cefmetazole therapy were as effective as multiple-dose cefoxitin treatment in the other types of surgery studied. Clinical laboratory findings and adverse medical events reported among cefmetazole patients were similar to those observed in patients treated with cefoxitin.
Cefpimizole sodium (AC-1370, U-63196E) was administered intramuscularly in doses from 100 mg (0.5 ml) to 2,000 mg (two 3.5-ml doses) to healthy human volunteers in three double-blind placebo and positivecontrolled (cefotaxime, cephalothin) single-dose studies and in two multiple-dose studies. Mild transient pain was observed at the injection site, but no erythema, petechia, necrosis, or atrophy was noted. Creatinine phosphokinase values were increased during the study in the cefpimizole-and placebo-treated groups but began to return to normal toward the end of the study period (day 5). They were not paralleled by a similar magnitude of elevation in serum glutamic oxalacetic transaminase and lactate dehydrogenase or by pain and tenderness. There were no clinically meaningful or statistically significant changes (P > 0.5) or trends in vital signs and no other patterns of drug-related clinical abnormalities noted in any of the laboratory measurements evaluated (hematology, chemistry, urinalysis). No serious side effects occurred during or after the study. Cefpimizole was well tolerated locally and systemically by all the subjects at all administered dosage levels. Cefpimizole concentrations in serum (microbiological assay) remained above 1 ,ug/ml at 12 h after drug administration for all dose levels. The median peak concentrations in plasma for the 500-and 1,000-mg twice-daily dosages of cefpimizole were, respectively, 21.6 and 45.5 ,Ig/ml on day 1, 16.2 and 43.7 ,ug/ml on day 3, and 20.1 and 41.4,ug/ml on day 6 of the study. The apparent terminal disposition half-life throughout the study was about 2.0 h. The median amounts of cefpimizole excreted in the urine for the first 12 h of each day evaluated were 370 and 1,071 mg on day 1, 416 and 972 mg on day 3, and 370 and 975 mg on day 6 for the 500-and 1,000-mg twice-daily dosages, respectively. Dose proportionality of cefpimizole was obtained for the 500-and 1,000-mg and the 2,000-mg groups. The absorption, distribution, and elimination of cefpimizole after multiple-dose intramuscular administration were uniform, were linear in relation to dose, and did not result in drug accumulation.Cefpimizole sodium (U-63196E, AC-1370), 7-P-(D-(-)-x-(4(5)-carboxyimidazole-5(4)-carboxamido)phenylacetamido)-3-(4-,-sulfoethylpyridinium)-methyl-3-cephem-4-carboxylic acid, sodium salt, is a new cephalosporin with activity against a broad spectrum of gram-negative bacteria, including Pseudomonas aeruginosa. The drug was developed and is marketed by the Ajinomoto Company in Japan and has the chemical structure shown in Fig. 1 statistically cited variables were considered to be pertinent to the results of the study.Cefpimizole has been reported to have greater activity in vivo than in vitro (6), to inhibit many ampicillin-resistant bacteria and have stability against hydrolysis by chromosomal ,B-lactamases (3), and to augment phagocyte function by human macrophages and neutrophils (4, 5).The pharmacokinetics of cefpimizole (1) in humans receiving single-and multiple-dose intravenous inf...
In this study, local and systemic tolerance and pharmacokinetics of trospectomycin sulfate in human beings were evaluated for the first time. Trospectomycin sulfate (U-63,366F; trospectomycin) or sterile saline was administered to 96 healthy male volunteers in doses ranging from 0.25 ml (75 mg) to 3.3 ml (1,000 mg) in a single intramuscular iujection in a double-blind, randomized design. Volunteers were screened to establish baseline vital signs and laboratory test values. Pain and tenderness at the injection site, which occurred at doses of 450 mg and above, were the most common side effects; they were mild in severity and transient. Adverse drug experiences reported by subjects included nausea, dizziness, light-headedness, diaphoresis, costal pain, and perioral numbness. The perioral numbness (paresthesia) experienced at doses of 750, 900, and 1,000 mg was probably drug related. No Clostridium difficile toxin was detected in fecal samples. Pharmacokinetic calculations based on data obtained by high-performance liquid chromatography showed that after a 1,000-mg intramuscular dose of trospectomycin (3.3 ml), the serum mean half-life was 1.85 h (1.70 to 2.02 h), mean area under the serum concentration-time curve was 140.2 ,ug h/ml and was linear with dose, mean peak concentration was 28.3 ,g/ml (20.4 to 34.7 pg/ml), mean time to maximum concentration was 71 min (30 to 120 min), and the elimination rate constant was 0.307 h-1. The elimination rate constant and half-life did not vary with dose. Little trospectomycin was detected in 2-day fecal collections. A few randomly occurring abnormal clinical laboratory test values and vital signs were observed. For the trospectomycin-treated group, creatinine phosphokinase increased substantially for 24 h after injection and then decreased through day 5, while serum glutamic oxalacetic transaminase and lactate dehydrogenase increased slightly.
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