ABSTRACT
Ceftobiprole medocaril is a newly approved drug in Europe for the treatment of hospital-acquired pneumonia (HAP) (excluding patients with ventilator-associated pneumonia but including ventilated HAP patients) and community-acquired pneumonia in adults. The aim of this study was to evaluate the in vitro antimicrobial activity of ceftobiprole against prevalent Gram-positive and -negative pathogens isolated in Europe, Turkey, and Israel during 2005 through 2010. A total of 60,084 consecutive, nonduplicate isolates from a wide variety of infections were collected from 33 medical centers. Species identification was confirmed, and all isolates were susceptibility tested using reference broth microdilution methods. Ceftobiprole had high activity against methicillin-susceptible Staphylococcus aureus (MSSA) (100.0% susceptible), methicillin-susceptible coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci, and Streptococcus pneumoniae (99.3% susceptible), with MIC90 values of 0.25, 0.12, ≤0.06, and 0.5 μg/ml, respectively. Ceftobiprole was active against methicillin-resistant S. aureus (MRSA) (98.3% susceptible) and methicillin-resistant CoNS, having a MIC90 of 2 μg/ml. Ceftobiprole was active against Enterococcus faecalis (MIC50/90, 0.5/4 μg/ml) but not against most Enterococcus faecium isolates. Ceftobiprole was very potent against the majority of Enterobacteriaceae (87.3% susceptible), with >80% inhibited at ≤0.12 μg/ml. The potency of ceftobiprole against Pseudomonas aeruginosa (MIC50/90, 2/>8 μg/ml; 64.6% at MIC values of ≤4 μg/ml) was similar to that of ceftazidime (MIC50/90, 2/>16 μg/ml; 75.4% susceptible), but limited activity was observed against Acinetobacter spp. and Stenotrophomonas maltophilia. High activity was also observed against all Haemophilus influenzae (MIC90, ≤0.06 μg/ml) and Moraxella catarrhalis (MIC50/90, ≤0.06/0.25 μg/ml) isolates. Ceftobiprole demonstrated a wide spectrum of antimicrobial activity against this very large longitudinal sample of contemporary pathogens.
INTRODUCTION
Ceftobiprole medocaril (BAL5788, formerly Ro-65-5788) is the prodrug form of ceftobiprole (BAL9141, formerly Ro-63-9141), which is an extended-spectrum anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) parenteral cephalosporin with potent activity against Gram-positive and -negative bacterial pathogens. Ceftobiprole has been evaluated in several phase III clinical trials focusing on skin and skin structure infections (SSSI) (1, 2), community-acquired pneumonia (CAP) requiring hospitalization (3), and hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP) (4), and has recently obtained regulatory approval in Europe for the treatment of hospital-acquired pneumonia (excluding ventilator-associated pneumonia) and community-acquired pneumonia in adults. Ceftobiprole is relatively stable toward AmpC β-lactamases and has a strong affinity for penicillin binding proteins (PBPs), including PBP 2A, which mediates resistance to β-lactams in MRSA and methicillin (oxacillin)-resistant coagulase-negative staphylococci (CoNS) (5). PBP assay experiments have confirmed the remarkably high affinity of ceftobiprole to PBP 2A and showed that this β-lactam in low concentrations was also able to saturate PBPs 1, 3, and 4, a new property not shared by other β-lactams (6). Ceftobiprole also has high affinity against Streptococcus pneumoniae PBP 2x in penicillin-resistant and ceftriaxone-resistant strains and retains good in vitro activity against them (7, 8). In time-kill analysis, ceftobiprole was bactericidal against community-acquired and hospital-acquired MRSA strains (9).
Ceftobiprole also displays potent activity against Enterobacteriaceae and Pseudomonas aeruginosa isolates that is similar to those of advanced-generation cephalosporins such as cefepime (10–13). In addition, ceftobiprole has demonstrated activity against Haemophilus influenzae, Moraxella catarrhalis (7), and Enterococcus faecalis (8). These characteristics make ceftobiprole an attractive therapeutic candidate, given its broad spectrum (including MRSA and penicillin-resistant S. pneumoniae) and its potent bactericidal action.
The objective of the current study was to examine the susceptibility profiles and antibiograms of ceftobiprole and comparator agents tested by a standardized reference methodology against 60,084 clinical isolates collected during the years 2005 through 2010 from European region medical centers, Turkey, and Israel.
MATERIALS AND METHODS
Bacterial strains tested.From the ceftobiprole SENTRY Antibiotic Surveillance Program in Europe (2005 to 2010), a total of 60,084 nonduplicate, consecutive clinical isolates were submitted from 33 medical centers in the following countries (number of sites): Belgium (1), France (5), Germany (4), Greece (2), Ireland (2), Israel (1), Italy (3), Poland (1), Portugal (1), Russia (2), Spain (3), Sweden (2), Switzerland (1), Turkey (2), the United Kingdom (2), and Ukraine (1). All organisms were isolated from documented infections, and only one strain per patient infection episode was included in the surveillance collection. The isolates were derived primarily from hospitalized patients with bloodstream infections, SSSI, pneumonias, urinary tract infections, and intra-abdominal infections, according to a common surveillance design (14). Species identification was performed at the participant medical center and confirmed at the monitoring laboratory (JMI Laboratories, North Liberty, IA, USA) using the Vitek 2 System (bioMérieux, Hazelwood, MO, USA), when necessary.
Susceptibility testing methods.All isolates were tested by the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method (M07-A9, 2012) (15) using validated commercially prepared panels (Thermo Fisher Scientific, Cleveland, OH, USA) in cation-adjusted Mueller-Hinton broth (with 5% lysed horse blood added for testing of fastidious streptococci or Haemophilus test medium [HTM] for testing of H. influenzae) against ceftobiprole and comparator antimicrobial agents. Susceptibility interpretations were based upon the CLSI M100-S23 and EUCAST breakpoints (16, 17) and the EUCAST breakpoints recently established for ceftobiprole for S. aureus (susceptible, ≤2 μg/ml; resistant, >2 μg/ml), S. pneumoniae (susceptible, ≤0.5 μg/ml; resistant, >0.5 μg/ml), and Enterobacteriaceae (susceptible, ≤0.25 μg/ml; resistant, >0.25 μg/ml) and non-species-specific breakpoints (susceptible, ≤4 μg/ml; resistant, >4 μg/ml) (18). Concurrent testing of ATCC quality control (QC) strains included S. aureus ATCC 29213, E. faecalis ATCC 29212, Escherichia coli ATCC 25922 and ATCC 35218, P. aeruginosa ATCC 27853, S. pneumoniae ATCC 49619, and H. influenzae ATCC 49247. All QC results were observed to be within published limits (16, 19).
RESULTS
Ceftobiprole activity against staphylococci.Ceftobiprole was very active against 15,426 S. aureus isolates (MIC50/90, 0.5/1 μg/ml; all MIC results at ≤4 μg/ml; 99.5% susceptible) (Tables 1 and 2). Ceftobiprole (MIC50/90, 0.25/0.5 μg/ml) was at least 16-fold more potent than ceftriaxone (MIC50/90, 4/>8 μg/ml) when tested against methicillin-susceptible S. aureus (MSSA) (Table 2). All S. aureus isolates were susceptible to vancomycin (MIC50/90, 1/1 μg/ml), and >99.9% of isolates were susceptible to linezolid (MIC50/90, 1/2 μg/ml), tigecycline (MIC50/90, 0.12/0.25 μg/ml), and daptomycin (MIC50/90, 0.25/0.5 μg/ml) (Table 2). Among 11,279 MSSA isolates, the ceftobiprole susceptibility rate was 100.0% (Table 2). Overall, 4,147 (26.9%) isolates were MRSA, and ceftobiprole was very active against most strains (MIC50/90, 1/2 μg/ml; 98.3% susceptible), with a potency most similar to those of vancomycin (MIC50/90, 1/1 μg/ml) and linezolid (MIC50/90, 1/2 μg/ml) (Table 2). High resistance rates among MRSA were observed for levofloxacin (88.6%), erythromycin (68.0%), and clindamycin (35.6/35.8%) (CLSI/EUCAST criteria), with lower rates observed for gentamicin (21.4/23.8%) and tetracycline (14.7/16.3%), while trimethoprim-sulfamethoxazole resistance was minimal (2.7%) (Table 2).
Frequency of occurrence and cumulative percent distribution of ceftobiprole MICs for all European organisms tested (2005 to 2010)
Antimicrobial activities of ceftobiprole and comparator agents when tested against bacterial isolates from European medical centers (2005 to 2010)
Ceftobiprole activity against 5,563 coagulase-negative staphylococci (CoNS) was similar to that found against MRSA and reflects the greater proportion of CoNS than of S. aureus isolates that were oxacillin resistant (76.3% versus 26.9%) (Table 1). One notable difference is the much higher overall rate of trimethoprim-sulfamethoxazole resistance observed for CoNS (39.1%) than for S. aureus (1.0%) (Table 2).
Ceftobiprole activity against enterococci.Ceftobiprole demonstrated good activity against 3,968 E. faecalis isolates (MIC50/90, 0.5/4 μg/ml) but was not active against 2,222 Enterococcus faecium isolates (MIC50, >8 μg/ml) (Table 1). This pattern correlated best to ampicillin susceptibility rates (Table 2). Vancomycin resistance was low for E. faecalis (1.2/1.3%) (CLSI/EUCAST criteria) but much higher for E. faecium (23.2/24.7%). Susceptibility rates of 99 to 100.0% were found for tigecycline, daptomycin, and linezolid tested against both E. faecalis and E. faecium.
Ceftobiprole activity against S. pneumoniae.Ceftobiprole was very active against S. pneumoniae, with MIC50 and MIC90 values of ≤0.06 and 0.5 μg/ml, respectively. All isolates were inhibited at a ceftobiprole MIC of 2 μg/ml or less, and 99.3% were susceptible to ceftobiprole (Tables 1 and 2). Overall, penicillin nonsusceptibility/resistance were 28.9/16.9% by CLSI criteria (16) (for oral penicillin V) and 28.9/5.0% by EUCAST criteria (17). Furthermore, ceftriaxone nonsusceptibility/resistance were 4.5/0.5% by CLSI criteria but 16.5/0.5% by EUCAST criteria; ceftobiprole susceptibility was 85.6% against the 202 ceftriaxone-nonsusceptible strains (Table 2). Erythromycin, clindamycin, tetracycline, and trimethoprim-sulfamethoxazole resistances were 30.6, 20.3, 24.4, and 18.8%, respectively. All isolates were susceptible to linezolid (MIC90, 1 μg/ml), and the majority of isolates were susceptible to levofloxacin (98.3%) (Table 2).
Ceftobiprole activity against other streptococci.Ceftobiprole was very active against all beta-hemolytic streptococci, including 1,170 isolates of S. pyogenes and 1,227 isolates of S. agalactiae, with a MIC50 and a MIC90 at ≤0.06 μg/ml. All isolates were inhibited at a ceftobiprole MIC of 0.25 μg/ml or less (Tables 1 and 2). Ceftobiprole (MIC50/90, ≤0.06/0.25 μg/ml) was at least 4-fold more active than penicillin (MIC50/90, 0.06/1 μg/ml; 22.5% nonsusceptible) and ceftriaxone (MIC90, 1 μg/ml) against 1,264 viridans group streptococci (Table 2).
Ceftobiprole activity against Enterobacteriaceae and nonfermentative Gram-negative bacilli.The activity of ceftobiprole against Enterobacteriaceae had a bimodal distribution, with 83.4% of isolates being inhibited at a MIC of ≤0.25 μg/ml (the EUCAST susceptibility breakpoint) and 12.7% having MIC values of ≥8 μg/ml (Table 1). Similar potencies and MIC distributions were observed for ceftazidime, cefepime, and ceftriaxone (data not shown). This pattern, shown for all cephalosporin agents tested, is a reflection of their limited activity against extended-spectrum β-lactamase (ESBL) phenotype strains of E. coli (11.3%) and Klebsiella spp. (26.8%). Ceftobiprole potency against P. aeruginosa (MIC50/90, 2/>8 μg/ml; 64.6% susceptible by the EUCAST non-species-specific susceptibility breakpoint of 4 μg/ml) was similar to those of cefepime (MIC50/90, 4/16 μg/ml; 78.6% susceptible) and ceftazidime (MIC50/90, 2/>16 μg/ml; 75.4% susceptible) (Table 2). Ceftobiprole had limited activity against Acinetobacter spp. (MIC50, >8 μg/ml) and Stenotrophomonas maltophilia (MIC50, >8 μg/ml) (Table 1).
Ceftobiprole activity against H. influenzae and M. catarrhalis.Ceftobiprole was the most potent (MIC90, ≤0.06 μg/ml) antimicrobial agent tested against H. influenzae, inhibiting all isolates at ≤0.5 μg/ml (Table 1). Ceftobiprole was also very active against M. catarrhalis, inhibiting with MIC50/90 values of ≤0.06/0.25 μg/ml, and all isolates were inhibited at MIC values of ≤0.5 μg/ml (Table 1).
DISCUSSION
HAP is associated with significant mortality and has been reported to account for ∼25% of all infections in intensive care units (20, 21). Increasing multidrug resistance (MDR) has complicated empirical therapy for patients with HAP and VAP, especially in patients with risk factors for MDR pathogens, often necessitating a combination therapy approach (22). It has been recommended that monotherapy should be used whenever possible to reduce the risk of MDR development and adverse outcomes (22). CAP is a significant cause of morbidity and mortality in developed countries, especially in the elderly, with up to 60% of patients requiring hospitalization (23, 24). Resistance among the CAP pathogens is increasing and of major concern; an analysis of pneumococcal resistance rates in the United States spanning the years 1998 to 2009 demonstrated remarkable increases in nonsusceptibility to commonly used β-lactam agents (25).
In this very large (60,084 isolates) and longitudinal (2005 to 2010) European antimicrobial resistance surveillance study, ceftobiprole showed broad-spectrum activity against Gram-positive and Gram-negative pathogens causative of HAP and CAP. Ceftobiprole demonstrated high potency against staphylococci, including MRSA and methicillin-resistant CoNS. Ceftobiprole was also very potent against all beta-hemolytic and viridans streptococci and demonstrated activity against nearly all E. faecalis isolates but not E. faecium. The majority of Enterobacteriaceae (non-ESBL producing) were also inhibited by ceftobiprole, an activity most like those of cefepime, ceftriaxone, and ceftazidime. Activity against P. aeruginosa (64.6% susceptible by the EUCAST non-species-specific susceptibility breakpoint of 4 μg/ml) was lower than but similar to those of cefepime (78.6% susceptible) and ceftazidime (75.4% susceptible). Ceftobiprole had more limited activity against Acinetobacter spp., S. maltophilia, and ESBL phenotypes of Enterobacteriaceae, as noted with other marketed broad-spectrum cephalosporins.
Ceftobiprole continues to demonstrate high potency against the causative agents of CAP, with 99.3% of 4,443 S. pneumoniae isolates testing susceptible, as well as 2,052 strains of H. influenzae inhibited at MIC values of ≤0.5 μg/ml and 200 strains of M. catarrhalis inhibited at MIC values of ≤0.5 μg/ml. Ceftobiprole was especially potent against penicillin-susceptible (MIC, ≤2 μg/ml) strains of S. pneumoniae, which represented 95.0% of all isolates, and potencies (although lower) were retained against penicillin-resistant and ceftriaxone-resistant strains.
In summary, ceftobiprole exhibited excellent coverage of Gram-positive pathogens, including MRSA, and has a spectrum of activity against Gram-negative bacilli similar to those of third-generation and fourth-generation cephalosporins consistently over a period of 6 years. These in vitro results from an extensive European surveillance study evaluating 60,084 organisms confirm a large volume of earlier reports on the broad spectrum of activity of ceftobiprole and hence demonstrate its potential to be utilized as a single agent for the empirical therapy of pneumonia. Clinical data from patients with pneumonia enrolled in large phase III studies have demonstrated that ceftobiprole medocaril is noninferior to the combination of high-dose ceftazidime and linezolid for the treatment of HAP (excluding VAP) (4) and noninferior to high-dose ceftriaxone with or without linezolid for the treatment of CAP requiring hospitalization (3). Ceftobiprole offers a number of advantages in potency, spectrum, and β-lactamase stability compared to currently marketed third-generation cephems and other β-lactams, especially with its enhanced coverage of MDR S. aureus and CoNS, including methicillin-resistant strains.
ACKNOWLEDGMENTS
We express our appreciation to S. Benning, M. Stilwell, and M. Janecheck for help in the preparation of the manuscript and to the JMI staff members for scientific assistance in performing this study.
This study was funded under a service agreement with Basilea Pharmaceutica International AG (Basel, Switzerland).
JMI Laboratories, Inc., received research and educational grants in 2009 to 2013 from Achaogen, Aires, American Proficiency Institute (API), Anacor, Astellas, AstraZeneca, Bayer, bioMérieux, Cempra, Cerexa, Contrafect, Cubist Pharmaceuticals, Daiichi, Dipexium, Enanta, Furiex, GlaxoSmithKline, Johnson & Johnson, LegoChem Biosciences Inc., Meiji Seika Kaisha, Merck, Nabriva, Novartis, Paratek, Pfizer, PPD Therapeutics, Premier Research Group, Rempex, Rib-X Pharmaceuticals, Seachaid, Shionogi, The Medicines Co., Theravance, Thermo Fisher, and some other corporations. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest, J&J, and Theravance. In regard to speakers bureaus and stock options, we have nothing to declare.
FOOTNOTES
- Received 7 February 2014.
- Returned for modification 24 March 2014.
- Accepted 19 April 2014.
- Accepted manuscript posted online 28 April 2014.
- Copyright © 2014, American Society for Microbiology. All Rights Reserved.
