In vitro antibacterial activity of BMY-28142, a new extended-spectrum cephalosporin

Abstract

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...

High-pressure liquid chromatographic analysis of BMY-28142 in plasma and urine

“…1). It is very active against Staphylococcus aureus and Pseudomonas aeruginosa and more potent than other new broadspectrum ,B-lactam antibiotics against some members of the Enterobacteriaceae family (3,6,11). BMY-28142 is also very effective against many P-lactamase-producing strains.…”

SHV-Type Extended-Spectrum Beta-Lactamase Production Is Associated with Reduced Cefepime Susceptibility in Enterobacter cloacae

“…In vitro studies performed prior to the commercial availability of cefepime showed that the MIC 90 ranged from 0.06 to 0.5 g/ml (12,25,26). In contrast, an assessment of isolates from North American intensive care units in 2003 showed that the MIC 90 was 2 g/ml, with MICs of some isolates as high as Ͼ16 g/ml (20).…”

Pharmacokinetics of cefepime in patients with respiratory tract infections

“…Against members of the family Enterobacteriaceae, MICs for 90% of strains are generally <0.5 mg/liter, against Pseudomonas aeruginosa they are <8 mg/liter, and against Staphylococcus aureus they are <4 mg/liter (6,15,16). In healthy adult volunteers, cefepime exhibited a multicompartmental serum concentration-versus-time profile with an elimination half-life (t12,3) of approximately 2 h (14).…”

“…Against members of the family Enterobacteriaceae, MICs for 90% of strains are generally <0.5 mg/liter, against Pseudomonas aeruginosa they are <8 mg/liter, and against Staphylococcus aureus they are <4 mg/liter (6,15,16 While those investigations involved noninfected volunteers who were evaluated following single-dose administra-tion, the ultimate recipients of an intravenous antibiotic are hospitalized patients who receive maintenance-dose therapy for the treatment of infections. Pharmacokinetic parameters derived from single-dose studies, however, do not always accurately predict multiple-dose disposition (8).…”