The In vitro activity of BMY-28142 was compared with that of cefotaxime, ceftazidime, moxalactam, and imipenem against 639 clinical isolates and a number of in vitro-selected resistant mutants. BMY-28142 was the most potent compound against the members of the family Enterobacteriaceae with a MIC for 90% of the strains of 0.12 ,ug/ml. The activity against Pseudomonas aeruginosa was comparable to that of ceftazidime and imipenem. Strains of staphylococci were moderately susceptible to BMY-28142 (MIC required to inhibit 90% of strains, 4 ,ug/ml), but Streptococcus faecalis isolates were resistant. The activity of the five compounds was inoculum dependent for several gram-negative species. By a single-step selection procedure, resistant mutants were selected from strains of Citrobacter freundii, Enterobacter cloacae, and P. aeruginosa. The mutant frequencies with the cephalosporins, including BMY-28142, ranged between 10-6 and 10-8. BMY-28142 was the most active cephalosporin against these resistant organisms, most of them strong ,-lactamase producers. It inhibited all mutants of C. freundii and E. cloacae at 2 ,ug/ml and all mutants of P. aeruginosa at 32 ,ug/ml. Imipenem on the other hand was as active on all of these resistant organisms as on the parent strains. Fig. 1), is a new extended-spectrum cephalosporin for parenteral use. The compound is structurally similar to cefotaxime but has a 1-methylpyrrolidine instead of the acetoxy group at position 3 of the dihydrothiazine ring.The third-generation cephalosporins combine a highlactamase stability with a broad antibacterial spectrum and potent activities against gram-negative bacteria. However, their antibacterial activity against Pseudomonas aeruginosa is variable, and they are generally less active on gram-positive organisms than their first-generation counterparts. Moreover, several reports have shown the emergence in vitro and in vivo of resistant mutants at relatively high frequency (3,7,12). Most involved strains belong to Enterobacter, Citrobacter, and Pseudomonas spp., genera producing inducible cephalosporinases which can be derepressed to constitutive synthesis.The present study compares the in vitro activity of BMY-28142 with that of currently available third-generation cephalosporins and imipenem. Attention was paid to the rate of in vitro emergence of resistant mutants and the degree of cross-resistance of these mutants to the other compounds.MATERIALS lands. They were identified by standard criteria (4). In addition, a number of known resistant or P-lactamaseproducing strains from our culture collection were also included.Susceptibility studies. MICs were determined by an agar dilution technique. Serial dilutions (ranging from 0.008 to 128 ,ug/ml) of freshly prepared antibiotic were made in Mueller-Hinton agar. This medium was supplemented with 5% defibrinated horse blood for fastidious streptococci. The organisms were grown overnight in tryptic soy broth or Todd-Hewitt broth (streptococci) and diluted to an inoculum density of 107 cells per ml. Th...

A thorough validation of the bacterial adherence to hydrocarbons (BATH) test was performed by means of a bioluminescence assay. Ten different gram-negative strains were subjected to the BATH test. For the calculation of the adhesion index, several factors had to be taken into account: ATP leakage, the action of ATP-hydrolyzing enzymes, the change in the extraction efficiency of Nucleotide-Releasing Reagent for Microbial Cells (NRB; Lumac bv) after vortexing and the difference in light production after the addition of NRB. When the adhesion index values obtained by bioluminescence measurement were used as reference, the total plate count technique appeared to be unreliable in estimating the number of bacteria adhering to the hydrocarbon phase. A highly significant correlation was established, however, between those reference values and the adhesion index values obtained by the optical density reading for octane and especially for hexadecane. With xylene, no correlation was found between the optical density reading values and the total plate count or bioluminescence values.

The half-life of amikacin after a single intramuscular injection was determined in patients with severe renal failure who received 3.75 mg of drug/kg and in patients with various degrees of renal function who received 7.5 mg of drug/kg. The relation of the half-life of amikacin to levels of serum creatinine is practically identical to that of kanamycin. However, although concentrations of serum creatinine remained practically unchanged, rates of creatinine clearance may by considerably decreased in older subjects. This decrease may result in overestimation of the rate of glomerular filtration and subsequent overdosage. Therefore, the half-life of amikacin should be derived from values of rates of creatinine clearance or be predicted with use of a nomogram. The calculated half-life values may be used for development of appropriate dosage schedules for patients with various degrees of renal function. Such schedules would ensure therapeutic levels of drug and avoid potentially toxic accumulation of antibiotic.

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