George Beskid

Enteral, Oral, and Rectal Absorption of Ceftriaxone Using Glyceride Enhancers

In vivo models in rodents and primates were used to investigate ways of overcoming the poor oral and rectal absorption of ceftriaxone. The sodium salt of ceftriaxone at 20 mg/kg was formulated in C8-C10 chain length, mono- and diglyceride extracts of coconut oil (Capmul) and administered intraduodenally to adult rats. Peak plasma levels of 17-52 micrograms/ml and bioavailability averaging 38% were attained. Significant plasma levels (42-45 micrograms/ml) were also demonstrated in squirrel monkeys with doses of 20 mg/kg ceftriaxone formulated in Capmul and given by the enteral route. Enteric-coated capsules containing this formulation were also orally administered to squirrel monkeys and gave high plasma levels (10-31 micrograms/ml) between 1 and 6 h following dosing. In rectal absorption studies, ceftriaxone formulated in Capmul as a suspension gave peak blood levels of 62-84 micrograms/ml (average bioavailability 42%) in the rabbit. In the baboon, rectal administration of ceftriaxone formulated with Capmul in a Witepsol H15 suppository gave Cmax levels ranging from 9 to 48 micrograms/ml, depending on the dose of the antibiotic and the drug/enhancer ratio.

Multicenter in vitro comparative study of fluoroquinolones against 25,129 Gram-positive and Gram-negative clinical isolates☆

In vitro activities of fleroxacin, ciprofloxacin, ofloxacin, and lomefloxacin were evaluated against 25,129 fresh bacterial isolates from 51 US hospital or medical center laboratories, beginning in October of 1990. Susceptibility rates were > or = 85% against most species of Gram-negative bacteria. Notable exceptions were Pseudomonas, Acinetobacter, Xanthomonas, and Providencia. The study drugs displayed similar activity against most Gram-negative species. At least 90% of oxacillin-susceptible staphylococci were susceptible but, of oxacillin-resistant strains, only approximately 60% of Staphylococcus epidermidis and 25% of Staphylococcus aureus were susceptible to the quinolones tested. Staphylococcus saprophyticus strains were less susceptible to fleroxacin (42%) than to the other compounds (79%-97%). Ofloxacin and ciprofloxacin were more active against streptococci, and none of the compounds demonstrated appreciable activity against enterococci. Thus, the spectra of activity of fluoroquinolones illustrate that they remain effective agents for the treatment of many types of infections caused by Gram-negative pathogens.

Correlation of the Results of Antibiotic Synergy and Susceptibility Testing in Vitro with Results in Experimental Mouse Infections

Recent clinical isolates (approximately 150 strains) of the family Enterobacteriaceae were examined by agar diffusion, microdilution, and the Autobac automated system for their responses to beta-lactam antibiotics singly and in combination with amdinocillin (formerly called mecillinam). The ratio of ampicillin, carbenicillin, and cephalothin to amdinocillin was maintained at a 10:1 ratio in most of the evaluations. The same isolates were studied in mice challenged with 100 to 1000 LD50s and treated with graded doses of the antibiotics singly and in combination. Efficacy in vivo was based on the concentration of antibiotic in milligrams per kilograms (mg/kg) required to protect 50% of the animals (PD50). After a single administration of the antibiotics, plasma levels were determined in the critical time period (30 min to 4 hr) during which the acute, overwhelming systemic infections could be controlled by appropriate therapy. Regression curves comparing in vivo and in vitro results were used to establish cut-off points for categorizing bacterial susceptibility in each of the laboratory tests for the single agents and combinations. A high degree of synergism between amdinocillin and the beta-lactam agents was demonstrated in animals (54 to 78% of the strains examined) and to a lesser extent by laboratory methodologies. There was an excellent correlation of in vivo and in vitro responses to ampicillin, carbenicillin, and cephalothin alone and in combination with amdinocillin for those species for which the single antibiotics are generally indicated. The correlations validated the chosen cut-off points. The correlation of in vivo and in vitro responses to the single or combined antibiotics was generally poorer for those species not usually responsive to the single antibiotics. The greatest difficulty in predicting proper in vivo responses, based on the results of in vitro tests, was observed with amdinocillin.

Effect of Medium Chain Glycerides on Enteral and Rectal Absorption of β-Lactam and Aminoglycoside Antibiotics

The rat enteral and rabbit rectal models were utilized to study the effect of Capmul (medium chain glycerides) on the absorption of a selection of beta-lactam and aminoglycoside antibiotics. All tested non-orally available beta-lactam antibiotics (cefamandole, cefotaxime, moxalactam, cefoxitin, mezlocillin, carumonam, penicillin G and amdinocillin) showed increased absorption enterally in rats and rectally in rabbits when formulated with Capmul. The orally available beta-lactam antibiotics, cephalexin and cephradine, were not enhanced in their enteral or rectal absorption by Capmul in the two model systems. Ampicillin absorption was enhanced rectally and enterally by Capmul. Rectal absorption of the aminoglycoside antibiotics, tobramycin and gentamycin, was enhanced by Capmul while enteral absorption was not.

In vivo Evaluation of a Dual-Action Antibacterial, Ro 23-9424, Compared to Cefotaxime and Fleroxacin

The dual-action antibacterial R 23-9424 (desacetylcefotaxime linked to the quinolone fleroxacin) is a new antibacterial agent with excellent in vitro activity. It was evaluated for in vivo efficacy in comparison with the cephalosporin cefotaxime and the quinolone component, fleroxacin. Ro 23-9424 demonstrated significant activity against all strains tested in systemic infections, including those strains resistant in vivo to cefotaxime (Staphylococcus aureus 753, Serratia marcescens SM and Pseudomonas aeruginosa 8780) and fleroxacin (Streptococcus pneumoniae 6301 and Streptococcus pyogenes. In prophylactic studies, Ro 23-9424 compared favorably with fleroxacin against Escherichia coli and with cefotaxime against S. pyogenes, but Ro 23-9424 was considerably more active than cefotaxime against E. coli and more active than fleroxacin against S. pyogenes. In a murine pneumonia model, Ro 23-9424 was equivalent in activity to cefotaxime against S. pneumoniae and more active than cefotaxime against Klebsiella pneumoniae. Fleroxacin was inactive against S. pneumoniae and about 20-fold more active than Ro 23-9424 against K. pneumoniae. In a murine meningitis infection caused by S. pneumoniae, Ro 23-9424 was 3 times as active as cefotaxime, while fleroxacin was inactive. When meningitis was induced by K. pneumoniae, Ro 23-9424 was as active as the quinolone, while cefotaxime was inactive. In a neutropenic (immunocompromised) model, Ro 23-9424 was more active than cefotaxime against P. aeruginosa and 5-fold less active than fleroxacin. In the control normal (immunocompetent) mouse infection, Ro 23-9424 was 3-fold more active than cefotaxime, but 10-fold less active than fleroxacin.

Studies on the in vitro development of drug resistance of Proteeae to sulfonamides, trimethoprim and combinations of a sulfonamide and trimethoprim.

A strain of Proteus mirabilis repeatedly subcultured in the presence of a combination of sulfisoxazole and 0.4 microgram/ml of trimethoprim and a strain of P. vulgaris subcultured in the presence of sulfamethoxazole and trimethoprim combined in a 5:1 ratio gradually developed resistance to the combinations. However, the level of resistance developed by the organisms exposed to the combination was always appreciably lower than the level of resistance developed by the same strains exposed to either the sulfonamide or trimethoprim alone.