In vitro activity of ceftobiprole against clinical isolates of Pseudomonas aeruginosa obtained from Canadian intensive care unit (ICU) patients as part of the CAN-ICU Study

Abstract

Sir, In recent years, Pseudomonas aeruginosa isolates resistant to multiple classes of antimicrobial agents have become increasingly common. Several mechanisms may contribute to antimicrobial resistance among P. aeruginosa, including the production of a chromosomally encoded AmpC b-lactamase. Ceftobiprole (BAL9141), an investigational pyrrolidinone cephalosporin, is reported to have activity against a broad spectrum of clinically important Gram-negative bacteria including P. aeruginosa. Additionally, in vitro studies have demonstrated that ceftobiprole is hydrolysed very slowly by AmpC cephalosporinases. The purpose of this report was to describe the in vitro activity of ceftobiprole versus 419 clinical isolates of P. aeruginosa obtained from patients in an intensive care unit (ICU) setting. Cefepime was used as a comparator antimicrobial agent. From September 2005 to June 2006, inclusive, P. aeruginosa isolates were collected as part of the Canadian National Intensive Care Unit (CAN-ICU) Study. The CAN-ICU Study included 19 medical centres from all regions of Canada with active ICUs. Each centre submitted a maximum of 300 consecutive pathogens isolated from blood, urine, tissue/wound and respiratory specimens (one pathogen per cultured site per patient) of ICU patients. Centres were requested to only obtain ‘clinically important’ specimens from patients with a presumed infectious disease. Surveillance swabs, eye, ear, nose and throat swabs were excluded, as were anaerobic bacteria and fungi. Isolates were shipped to the reference laboratory (Health Sciences Centre, Winnipeg, MB, Canada) on Amies charcoal swabs, subcultured onto appropriate media and stocked in skimmed milk at 2808C until MIC testing was performed. The in vitro activities of ceftobiprole and cefepime were determined by microbroth dilution in accordance with the CLSI guidelines. MIC interpretive standards for cefepime were defined according to CLSI breakpoints. At present, susceptibility breakpoints for ceftobiprole do not exist. In total, 419 isolates of P. aeruginosa were collected as part of the CAN-ICU Study. The breakdown of these 419 isolates by specimen source was as follows: respiratory (69.0%), wound (12.4%), urine (10.7%) and blood (7.9%). The MIC distributions of ceftobiprole and cefepime for the isolates were very similar (Table 1). At an antimicrobial concentration of 8 mg/L, 74.7% and 78.7% of our isolates would be inhibited by ceftobiprole and cefepime, respectively. The MIC50 and MIC90 values of ceftobiprole were 4 and 16 mg/L. The corresponding MIC50 and MIC90 values of cefepime were 4 and 32 mg/L. The MIC50/ MIC90 values of ceftobiprole and cefepime were comparable, regardless of specimen source. Cross-resistance between ceftobiprole and cefepime was observed. Of 43 cefepime-resistant isolates (MIC 32 mg/L), only 3 (7.0%) had an MIC of ceftobiprole of 8 mg/L. Similarly, only 6 of 40 isolates (15%) with a ceftobiprole MIC of 32 mg/L were susceptible to cefepime. In agreement with our results, previous studies have reported similar in vitro activity between ceftobiprole and cefepime when evaluated against P. aeruginosa. A recent study by Pillar et al. documented a lower modal MIC of cefepime in comparison with ceftobiprole against P. aeruginosa isolates (1 mg/L versus 2 mg/L). However, the MIC50 and MIC90 values were identical (4 and 16 mg/L respectively) for both antimicrobials. Our data demonstrate a high degree of cross-resistance between ceftobiprole and cefepime. Hebeisen et al. have previously described the finding of cross-resistance between ceftazidime, cefepime and ceftobiprole. These investigators reported the activity of ceftobiprole against 17 ceftazidime-non-susceptible P. aeruginosa isolates (MIC50 of 16 mg/L and MIC90 of .64 mg/L for ceftazidime). The MIC50 and MIC90 values of ceftobiprole against these isolates were 16 and .64 mg/L, respectively. The corresponding MIC50 and MIC90 values of cefepime versus the ceftazidime-non-susceptible isolates were 32 and 32 mg/L. Cross-resistance has also been described in a study by Pillar et al., where the MIC50/MIC90 values of ceftobiprole against 491 ceftazidime-susceptible and 130 ceftazidime-non-susceptible P. aeruginosa isolates were 2/8 and 16/.32 mg/L, respectively. In summary, ceftobiprole and cefepime demonstrated comparable in vitro activity against P. aeruginosa clinical isolates from Canadian ICUs and cross-resistance between these agents was common. Whether ceftobiprole will be clinically useful in the treatment of serious infections caused by P. aeruginosa remains to be determined.