In Vitro Activities of BAL9141, a Novel Broad-Spectrum Pyrrolidinone Cephalosporin, against Gram-Negative Nonfermenters

Abstract

The activities of BAL9141 (formerly Ro 63-9141), a novel pyrrolidinone-3-ylidenemethyl cephalosporin, against 244 strains of gram-negative nonfermenters were evaluated. The overall MIC at which 50% of isolates are inhibited (MIC 50 ) and the overall MIC 90 were 2 and 64 g/ml, respectively, which are similar to those of imipenem, lower than those of the other cephalosporins tested, amoxicillin, and the ticarcillin-clavulanic acid combination, and much higher than those of ciprofloxacin. BAL9141 shows species-dependent activity in vitro against a variety of gram-negative nonfermentative pathogens.BAL9141 (formerly Ro 63-9141) is a novel pyrrolidinone-3-ylidenemethyl cephalosporin that consistently has activity against methicillin-resistant strains of Staphylococcus spp. but that exhibits promising in vitro and in vivo activities against a variety of gram-negative pathogens (1). The purpose of this study was to evaluate the activity of BAL9141 against a broad range of aerobic gram-negative glucose-nonfermentative rods.(Part of this work was presented at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, Calif., 1998 [R. Zbinden, V. Puenter, and A. von Graevenitz, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-19, 1998].).The MICs of BAL9141 and nine other antimicrobials were determined by the NCCLS agar dilution method on non-cation-adjusted Mueller-Hinton agar (Becton Dickinson Microbiology Systems, Cockeysville, Md.) for 244 gram-negative nonfermenters that were collected through 1995 in the Department of Medical Microbiology, University of Zurich, Zurich, Switzerland, and a reference strain, Pseudomonas aeruginosa ATCC 27853 (5). A 0.5 McFarland suspension in phosphatebuffered saline was diluted 1/10 to obtain the desired inoculum of 10 7 CFU/ml. A multipoint inoculator was used to deliver 10 4 CFU per spot to each test plate and to control plates without antibiotics. Cultures were incubated at 35°C for 20 h in an aerobic atmosphere in accordance with the NCCLS methodology (5). BAL9141 of known potency was supplied by F. Hoffmann-La Roche, Basel, Switzerland (courtesy of P. Hebeisen). The other compounds were obtained from commercial sources. Identification of the isolates studied was in accordance with recommended methods (4). The MICs of BAL9141 and the other antimicrobial agents are shown in Table 1. The modal MIC of BAL9141 for P. aeruginosa ATCC 27853 was 2 g/ml; the MICs of the other antimicrobial agents for P. aeruginosa fell within expected ranges (6). The MICs at which 50% of isolates are inhibited (MIC 50 s) and MIC 90 s for all 244 strains were 2 and 64 g/ml, respectively, for BAL9141; 8 and 64 g/ml, respectively, for cefepime; 64 and Ͼ64 g/ml, respectively, for cefotetan; 8 and Ͼ64 g/ml, respectively, for cefozopran; 8 and Ͼ64 g/ml, respectively, for ceftazidime; 8 and Ͼ64 g/ml, respectively, for ceftriaxone; 32 and Ͼ64 g/ml, respectively, for amoxicillinclavulanic acid; 32 and Ͼ64 g/ml, respectively, for ticarcillinclavulanic acid; 1 and 64 g/m...

Interactions of Ceftobiprole with β-Lactamases from Molecular Classes A to D

“…In several studies, the MICs for MRSA ranged from 0.12 g/ml to 4 g/ml, with MIC 90 values of 2 g/ml generally observed (3,15,19). In addition, ceftobiprole has activity against gram-negative bacteria, including Pseudomonas aeruginosa, similar to those of the extended-spectrum cephalosporins (17,18,40).…”

Probability of Target Attainment for Ceftobiprole as Derived from a Population Pharmacokinetic Analysis of 150 Subjects

“…Ceftobiprole, an investigational cephalosporin currently in phase III trials for complicated skin and skin structure infections (cSSSIs) and nosocomial pneumonia (NP), represents a major advance among the ␤-lactam antibiotics, in that its structure allows it to bind to PBP 2a and thus kill MRSA (4). Indeed, a considerable amount of preclinical data demonstrate that ceftobiprole acts in a bactericidal fashion in preclinical infection models, both in vitro and in vivo (3,6,9,10,12,15,16,19,33,34). The drug possesses excellent activity against MRSA and other resistant gram-positive pathogens, such as penicillin-resistant Streptococcus pneumoniae (3,6,9,12,16,19).…”

Activities of Ceftobiprole and Other β-Lactams against Streptococcus pneumoniae Clinical Isolates from the United States with Defined Substitutions in Penicillin-Binding Proteins PBP 1a, PBP 2b, and PBP 2x

“…Ceftobiprole, a new parenteral cephalosporin in phase 3 clinical trials, exhibits a broad spectrum of activities against many clinically important gram-negative and gram-positive pathogens, including the common CAP pathogens S. pneumoniae, H. influenzae, and S. aureus (12)(13)(14)24). Ceftobiprole is differentiated from other parenteral cephalosporins due to its low MICs for S. aureus, including methicillin-resistant strains, and for cefotaxime-or ceftriaxone-resistant S. pneumoniae (12)(13)(14).…”