In vitro activity of ceftaroline, ceftobiprole and cethromycin against clinical isolates of Streptococcus pneumoniae collected from across Canada between 2003 and 2008

Sir, Streptococcus pneumoniae is an important cause of both invasive and non-invasive infections in all age groups throughout the world. While the introduction of pneumococcal conjugate vaccine led to a decrease in invasive pneumococcal disease, multidrug-resistant (MDR) strains not belonging to serotypes included in the vaccine are now increasing and may result in treatment failures, as predicted by pharmacokinetic and pharmacodynamic parameters.1,2 Ceftobiprole and ceftaroline are newly developed parenteral cephalosporins that exhibit broad-spectrum activity against Gram-positive, Gram-negative and anaerobic organisms, including S. pneumoniae and methicillin-resistant Staphylococcus aureus.3,4 Cethromycin is a new ketolide antimicrobial agent with in vitro activity against penicillin- and macrolide-resistant Gram-positive organisms, possibly due to a higher affinity for the target site on the ribosomal unit.5 The purpose of this study was to evaluate in vitro activities of ceftaroline, ceftobiprole, cethromycin and several other antimicrobial agents against clinical isolates of MDR S. pneumoniae strains submitted to the Canadian Bacterial Surveillance Network (CBSN) as part of an ongoing nationwide surveillance programme. We retrospectively selected 260 MDR isolates submitted to CBSN from 2003 to 2008. Isolates were defined as MDR if they were non-susceptible to amoxicillin and two other classes of drugs. In vitro susceptibility testing was performed by broth microdilution and breakpoint interpretations were as per CLSI guidleines.6 Of 260 selected isolates, 193 (74.2%) isolates were recovered from non-sterile specimens (113 sputum, 16 bronchial wash, 24 eye, 36 ear and 4 others) and 66 (25.4%) isolates were from sterile specimens (59 blood, 1 CSF and 6 others). The origin of one isolate was not known. Eighty-nine isolates (34.2%) were recovered from paediatric patients (0–15 years old), 98 (37.7%) from adults between 16 and 64 years of age, and 71 (27.3%) from adults aged ≥65 years. Age information for two isolates was not known. Overall, 85% (221/260) were non-susceptible to penicillin (non-meningitis parenteral breakpoint, MIC ≥ 4 mg/L), 100% were non-susceptible to amoxicillin (non-meningitis breakpoint, MIC ≥ 4 mg/L) and 73.5% (191/260) were non-susceptible to ceftriaxone (non-meningitis breakpoint, MIC ≥ 2 mg/L). In addition, 72.3% were resistant to clindamycin, 94.6% to erythromycin, 95.8% to trimethoprim/sulfamethoxazole and 75.4% to tetracycline. In this study, 90.4% (235/260) of isolates were serotype 19F (n = 145), 19A (n = 60) or 14 (n = 30). Of note, 90% (18 out of 20) of emergent MDR 19A isolates tested in this study belonged to ST320 (CC271), a single-locus variant of the Taiwan 19F-14 strain that spread globally in the 1990s. As shown in Table 1, ceftaroline, ceftobiprole and cethromycin were highly active against all MDR pneumococcal isolates. Overall, the MIC90s of ceftaroline (0.25 mg/L) and ceftobiprole (1 mg/L) were 8- and 2-fold lower, respectively, than the MIC90 of ceftriaxone (2 mg/L). Similarly, MIC90s of ceftaroline and ceftobiprole were 32- and 8-fold lower, respectively, than the MIC90 of amoxicillin (8 mg/L). Cethromycin, a new ketolide, also demonstrated increased potency compared with telithromycin, as the MIC90 of cethromycin was 0.12 mg/L (4-fold lower) compared with an MIC90 of telithromycin of 0.5 mg/L (Table 1). In vitro activities of new drugs against MDR pneumococcal isolates PEN, penicillin; ERY, erythromycin. In vitro activities of new drugs against MDR pneumococcal isolates PEN, penicillin; ERY, erythromycin. Among penicillin-non-susceptible (MIC ≥ 4 mg/L) isolates, the MIC90 of ceftaroline was 0.25 mg/L and the MIC90 of ceftobiprole was 1.0 mg/L, whereas that of ceftriaxone was 2 mg/L (Table 1). Similarly, the MIC90 of cethromycin was 0.12 mg/L, which was 4-fold lower than that of telithromycin. Among erythromycin-non-susceptible (MIC ≥ 0.5 mg/L) isolates, the MIC90 of cethromycin was 0.12 mg/L compared with an MIC90 of telithromycin of 0.5 mg/L (Table 1). Similarly, the results showed that ceftaroline, ceftobiprole and cethromycin were more active against emerging MDR serotype 19A than currently available drugs. In summary, among β-lactams tested, ceftaroline was the most potent against MDR S. pneumoniae isolates. Similarly, the ketolide cethromycin was more active than telithromycin. This work was supported in part by Advanced Life Sciences, Woodridge, IL, USA. D. E. L. has served on advisory boards for Advanced Life Sciences, Roche and OrthoMcNeil. He has also received research support from Roche. S. N. P., D. R. P., S. P.-P., A. M. and K. G.: none to declare. We are indebted to all of the hospitals and laboratories participating in the CBSN. We thank Remy Angela Pollock and Alla Buzina for their expert technical assistance with MLST, and acknowledge the use of the pneumococcal MLST database (Imperial College London), which is funded by the Wellcome Trust.

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