Biomedical subjects
R Wise
Publications and source records attributed to R Wise.
Pharmacokinetics and tissue penetration of orally administered pefloxacin.
The pharmacokinetics of the quinolone pefloxacin were determined following a 400 mg oral dose given to each of six male volunteers. Concentrations were determined in serum and urine by high-performance liquid chromatography, and in cantharidin-induced inflammatory fluid by a microbiological assay. The mean peak serum level of 6.6 micrograms/ml was attained rapidly 0.8 h after administration. The mean serum elimination half-life was 11.6 h. Inflammatory fluid was penetrated quickly with a mean peak level of 3.9 micrograms/ml occurring at 2.4 h. Pefloxacin was excreted in the urine as the parent compound and its two metabolites, norfloxacin and pefloxacin N-oxide (24 h urinary recovery being 8.0%, 12.0% and 13.1% respectively of the dose). This study suggests that a twice or possibly once daily dosage may be sufficient to treat systemic infections caused by susceptible pathogens. Once daily dosing should be sufficient for urinary tract infections.
Commercially available fluorescein-conjugated monoclonal antibody for determining the in vitro activity of antimicrobial agents against Chlamydia trachomatis.
A simple, reproducible method for determining the antibiotic susceptibility of chlamydial isolates is described. Minimum inhibitory and lethal concentrations (MICs and MLCs) were determined for tetracycline and erythromycin titrated against a recent clinical isolate of Chlamydia trachomatis in McCoy cell cultures. A fluorescent antibody stain was found to be more sensitive than giemsa staining, generally giving two-fold higher values for both MICs and MLCs.
Cefoxitin resistance in Bacteroides species: evidence indicating two mechanisms causing decreased susceptibility.
Clinical isolates of Bacteroides species resistant to cefoxitin (not due to beta-lactamase) were obtained from two sources and examined for PBP affinity (to cefoxitin) and outer membrane proteins. Mutants of Bacteroides fragilis with decreased susceptibility to cefoxitin were obtained in the laboratory with the mutagen N-methyl-N'-nitro-N-nitrosoguanidine. No spontaneous mutants resistant to cefoxitin could be selected. Changes in the affinity of PBP 1 or PBP 2 were correlated with a decrease in susceptibility to cefoxitin. Two clinical isolates showing decreased affinity of PBPs for cefoxitin also showed outer membrane protein changes with a protein of 49-50,000 daltons apparently absent. Three strains did not have altered PBP affinity or altered outer membrane protein profile, one strain being a laboratory mutant.
In-vitro bacterial killing kinetics of ticarcillin/clavulanic acid.
An in-vitro model was developed to study the rates of killing by ticarcillin/clavulanic acid combinations of various beta-lactamase producing, ticarcillin resistant, logarithmic phase clinical isolates. Killing, defined as a 3 log reduction, was dependent on the organism, the concentration of clavulanic acid and the duration of exposure. For most isolates studied an optimum period of exposure to and concentration of clavulanic acid could be defined. Certain test strains showed optimum response to readily attainable in-vivo concentrations of clavulanic acid while other strains, although sensitive by MIC data showed a poor response. The clinical implications of this are discussed.
The pharmacokinetics of enoxacin in elderly patients.
Twenty-three patients of greater than 70 years of age, with proven urinary tract infections were treated with 200 mg of enoxacin twice daily. Serial blood samples were taken on day 1 and peak and trough levels on days 3 and 5. Enoxacin and oxo-enoxacin plasma levels were measured. The mean plasma half-lives of enoxacin and the oxo-metabolite were 6.1 h and 6.7 h respectively. The 2 h plasma level of enoxacin increased from a mean of 1.5 mg/l on day 1 to 2.65 mg/l on day 3 and 2.80 mg/l on day 5. No significant accumulation of the oxo-metabolite (as judged by the 2 h level) occurred. No alteration in enoxacin dosing in the elderly compared with that in younger patients is suggested. Eighty-five per cent of the patients were cured of their infection and no significant adverse advents were noted.
Intraperitoneal penetration of ticarcillin/clavulanic acid (Timentin).
Thirty-eight patients undergoing elective abdominal surgery were given 3.0 g ticarcillin plus 0.2 g clavulanic acid as a single intravenous injection at varying times prior to the operation. Sterile assay discs were placed on the peritoneal surface in order to measure peritoneal fluid levels of each agent. Simultaneous serum levels were also measured. A total of 38 serum and peritoneal samples were analysed. There was rapid penetration of both agents into peritoneal fluid. The mean peritoneal fluid levels of ticarcillin were 70% (S.D. 13) of the serum level and 67% (S.D. 4) for clavulanic acid. The peritoneal levels of both agents declined in parallel to the serum levels (the half-lives being about 1 h) and the ratio of ticarcillin-clavulanic acid in serum and peritoneal fluid did not vary significantly with time.
The effect of imipenem on strains of Enterobacteriaceae expressing Richmond & Sykes class I beta-lactamases.
Fourteen strains of Enterobacteriaceae producing Richmond & Sykes Class I beta-lactamase were studied. The ability of cefoxitin and imipenem to induce beta-lactamase production (reversible derepression) and to select stably derepressed mutants in these strains was assessed. beta-Lactamase induction by cefoxitin and imipenem was demonstrated by the disc diffusion technique in all strains. Cefoxitin selected stably derepressed mutants for all strains in broth cultures, but in an identical experiment imipenem did not. The susceptibility of each strain and its stably derepressed mutant (selected with cefoxitin) to a range of beta-lactam antibiotics was then ascertained. The stably derepressed mutants exhibited decreased susceptibility to all antibiotics tested except imipenem. The decrease in susceptibility varied between strains and between antibiotics but reached a maximum of a 256-fold decrease. The beta-lactamase activity of selected stably derepressed mutant strains showed at least a 600-fold increase in activity. Imipenem would therefore seem an appropriate choice for therapy of infections caused by this group of organisms, as it is active against derepressed mutants and unlikely to select any such strains during therapy.
Induction of beta-lactamases in gram-negative bacilli.
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Factors affecting the in-vitro activity of roxithromycin.
The effect of human serum and CO2 on the activity of roxithromycin and erythromycin was assessed. Protein binding of roxithromycin in serum from various animal sources, acid alpha 1-glycoprotein and human albumin V was determined. There was a four- to eight-fold increase in MIC and MBC of roxithromycin in the presence of 70 and 100% human serum (minimum effect seen with erythromycin) and for both compounds there was a four- to eight-fold increase in MIC for fastidious organisms in the presence of CO2. Roxithromycin appears to be selectively bound to acid alpha 1-glycoprotein, binding decreases with an increase in roxithromycin concentration (saturable at 10 mg/l) and protein binding is variable depending on animal source (86% human, 10% guinea pig) and this must be considered when data on activity from animal studies are evaluated.
Pharmacokinetics and tissue penetration of Ro 23-6240, a new trifluoroquinolone.
A 400-mg dose of the trifluorinated quinolone Ro 23-6240 was administered orally to each of six healthy male volunteers, after which the concentrations of this agent in serum and cantharidin-induced inflammatory fluid were measured. Absorption was rapid, with a mean peak level in serum of 6.1 micrograms/ml, which was attained 0.71 h after administration. The elimination half-life in serum was 11.95 h. The agent penetrated the inflammatory fluid rapidly; the percent penetration was 89.7%. Urinary recovery of Ro 23-6240 was 58.6% by 72 h.
In vitro activity of CGP 31608, a new penem.
The in vitro activity of CGP 31608, a semisynthetic penem derivative, was compared with that of Sch 34343, imipenem, cefoxitin, cefuroxime, and ceftazidime and other beta-lactams, when appropriate, against 628 recent isolates and other beta-lactam-resistant strains. The MICs of CGP 31608 against 90% of the members of the family Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Neisseria spp., Bacteroides spp., Clostridium spp., staphylococci, and Streptococcus pneumoniae were between 0.25 and 8 micrograms/ml. The susceptibility of beta-lactamase-producing strains and known porin mutants of the Enterobacteriaceae suggests that CGP 31608 is resistant to many important beta-lactamases (including the mutationally derepressed chromosomal enzymes) and is not excluded from the bacterial cell in strains expressing these known porin mutations. Generally, CGP 31608 was less active than imipenem, Sch 34343, and the cephalosporins, except against Pseudomonas aeruginosa. The activity of CGP 31608 against Staphylococcus aureus (including methicillin-resistant strains) was greater than that of the cephalosporins. The major target site in Escherichia coli K-12 for CGP 31608 was penicillin-binding protein 2. The serum protein binding of 5 micrograms of CGP 31608 per ml was 14%, and serum had little effect on activity.
Pharmacokinetics and tissue penetration of roxithromycin after multiple dosing.
The pharmacokinetics of the macrolide roxithromycin (RU 28965) were studied during and after administration of 150 mg every 12 h for 3 days (five doses) in six volunteers. The concentrations in serum, blister fluid, and urine were measured. Mean levels in serum taken at 1.5 h after the morning dose increased from 4.4 micrograms/ml on day 1 to 5.9 micrograms/ml on day 2 and 7.4 micrograms/ml on day 3. The mean serum and blister fluid elimination half-lives on day 3 were 13.2 and 12.5 h, respectively. Roxithromycin penetrated blister fluid well; the mean percent penetration (as measured by the ratio of areas under the curve) was 85%. After the final dose, a mean of 10.5% of that dose was recovered in 12 h as microbiologically active compound.
Cardiorespiratory arrests temporally associated with injection of intravenous ampicillin in infants: investigation of a suspected cluster.
In August 1985, the FDA received reports of infants who had cardiorespiratory arrests associated with a widely used IV ampicillin product. The events occurred during July and August 1985 in three hospitals located in different parts of the United States. To assess the possibility of a product defect, an epidemiologic investigation was undertaken to determine whether the suspect ampicillin product was associated with an excess number of serious adverse events among infants in 1985. Because complete ampicillin brand information was unavailable for two of the three hospitals, a nonconcurrent cohort study was conducted to test whether the proportion of serious adverse events among infants who were hospitalized between July 1 and Aug 23, 1985, and exposed to any brand of IV ampicillin was different from the proportion of serious adverse events among infants who were hospitalized during the same time in 1984 and exposed to IV ampicillin. No statistically significant difference was found. A follow-up incidence density study at the hospital for which complete ampicillin brand information was known determined that the suspect ampicillin product was not associated with an increased number of serious adverse events in 1985. No common lots of the suspect ampicillin product were identified at the three hospitals. It was concluded that the suspect ampicillin product was not the cause of the cluster of serious adverse events observed among infants in July and August 1985 based on epidemiologic findings.
Campylobacter pyloridis and associated gastritis: investigator blind, placebo controlled trial of bismuth salicylate and erythromycin ethylsuccinate.
An investigator blind trial was performed comparing bismuth salicylate, erythromycin ethylsuccinate, and placebo in the treatment of Campylobacter pyloridis associated gastritis in patients without peptic ulceration. Fifty patients fulfilled the study criteria. There was a strong correlation between the presence of C pyloridis and histologically confirmed gastritis. Clearance of organisms led to improvement of the gastritis. C pyloridis was cleared from 15 patients; of these, 13 had gastritis initially, which resolved in 12. Conversely, gastritis resolved in only four of 32 patients not cleared of organisms (p less than 0.0001). There was significantly greater improvement in endoscopic appearances in the patients cleared of C pyloridis compared with those whose infection persisted (p less than 0.001). In the three treatment groups organisms were cleared from 14 of 18 patients receiving the locally active bismuth salicylate, only one of 15 patients receiving erythromycin ethylsuccinate, and none of 17 patients taking placebo. These findings suggest that the ideal antimicrobial for the successful eradication of C pyloridis associated gastritis should be locally active, stable at low pH, and should penetrate gastric mucus. The resolution of gastritis and improvement in endoscopic appearances associated with clearance of C pyloridis support the view that these organisms may play a part in this condition.
Beta-lactams and imipenem.
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Bedside and rapid bacteriology.
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