Journal of Antimicrobial Chemotherapy

JAC Advance Access published online on January 23, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm492

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In vitro activity profile of ceftobiprole, an anti-MRSA cephalosporin, against recent Gram-positive and Gram-negative isolates of European origin

Chris M. Pillar, Mohana K. Aranza, Dineshchandra Shah and Daniel F. Sahm^*

Eurofins Medinet, Inc., Anti-Infective Services, 13665 Dulles Technology Drive, Herndon, VA 20171, USA

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^* Corresponding author. Tel: +1-703-480-2500; Fax: +1-703-480-2670; E-mail: dan.sahm{at}eurofinsmedinet.com

Received 17 July 2007; returned 23 September 2007; revised 21 November 2007; accepted 26 November 2007

	Abstract

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Objectives: To determine the in vitro activity profile of ceftobiprole, a pyrrolidinone cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA), for use as a contemporary baseline to help detect any changes in its activity profile throughout the course of clinical development and use.

Methods: MICs were determined by broth microdilution testing for ceftobiprole and comparators against 6680 isolates [1201 S. aureus, 460 coagulase-negative staphylococci (CoNS), 526 Streptococcus pneumoniae, 1213 Escherichia coli, 854 Klebsiella pneumoniae, 443 Proteus mirabilis, 406 Enterobacter cloacae, 387 Citrobacter spp., 291 Serratia marcescens, 621 Pseudomonas aeruginosa and 278 Acinetobacter spp.] from 31 sites in 12 countries.

Results: Ceftobiprole activity against MRSA (MIC₉₀ 2 mg/L) was 4-fold less than the activity against methicillin-susceptible S. aureus (MIC₉₀ 0.5 mg/L) and a similar trend was observed for methicillin-resistant CoNS (MIC₉₀ 2 mg/L) and methicillin-susceptible CoNS (MIC₉₀ 0.25 mg/L). Activity against S. pneumoniae (MIC₉₀s: penicillin-susceptible, 0.015 mg/L; -intermediate, 0.25 mg/L; -resistant, 0.5 mg/L) was comparable to that of ceftriaxone. Ceftobiprole activity against Enterobacteriaceae (MIC₉₀s: ceftazidime-susceptible, 0.12 mg/L; non-susceptible, >32 mg/L), P. aeruginosa (MIC₉₀s: ceftazidime-susceptible, 8 mg/L, non-susceptible, >32 mg/L) and Acinetobacter spp. (MIC₉₀: >32 mg/L for imipenem-susceptible and non-susceptible) was comparable to that of cefepime. As with cefepime, ceftobiprole activity was decreased among cephalosporin-resistant isolates of Gram-negative bacilli [extended-spectrum β-lactamase (ESBL) or non-ESBL mediated].

Conclusions: Ceftobiprole demonstrated potent in vitro activity against MRSA and showed activity against key Gram-negative bacilli comparable to that of cefepime. Given this broad spectrum of activity, ceftobiprole appears well suited for development and use in the treatment of a variety of healthcare-associated infections.

Key Words: susceptibility tests , MICs , microbiology

	Introduction

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The prevalence of antibiotic-resistant organisms within hospitals and the severity of the infections caused by these organisms have resulted in the need for more vigilant infection control practices to diminish transmission and the need for new antimicrobial agents for treatment of these infections. A novel, investigational cephalosporin, ceftobiprole, has documented activity against a variety of resistant bacteria commonly encountered in the healthcare settings of today and has shown to be an effective antibacterial agent in vivo.^1–3 Ceftobiprole, formerly designated BAL9141/Ro 63-9141, is a pyrrolidinone-3-ylidene-methyl cephalosporin with demonstrated in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA),^3–6 Enterobacteriaceae^3,6,7 and Pseudomonas aeruginosa.^6,7 Ceftobiprole was also found to be effective against ceftriaxone-resistant Streptococcus pneumoniae in a murine model of pneumonia,⁸ against MRSA in both rat and rabbit endocarditis^1,2 and against multiple Gram-negative and Gram-positive bacteria in a murine model of septicaemia.³ Due to these activities, ceftobiprole was selected for clinical development for the treatment of hospital-acquired pneumonia and complicated skin and skin structure infections.

Based on the clinical indications, ceftobiprole is intended for use in the hospital for the treatment of infections that frequently involve β-lactam-resistant Gram-negative and Gram-positive organisms, including MRSA. Because of its use in an environment where antibiotic resistance is already prevalent and the spread or emergence of resistance is of concern, continued surveillance throughout the development of ceftobiprole and beyond is warranted. This study was undertaken to establish the in vitro activity of ceftobiprole against recent European clinical isolates representative of the bacterial species and resistant-phenotypes for which ceftobiprole is intended, and to determine its activity relative to other currently utilized cephalosporins. These data will provide a baseline reference of the activity of ceftobiprole against contemporary European clinical isolates and will facilitate the detection of changes in its spectrum of activity should they occur during its clinical development or use.

	Materials and methods

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Organism collection and identification

Over a period of 10 months (November 2005–August 2006), a total of 6680 non-consecutive single-patient isolates were collected from 31 hospitals across the following 12 European countries: Belgium (2 hospitals; 6.8% of total isolates), the Czech Republic (2 hospitals; 6.3% of total isolates), France (5 hospitals; 17.3% of total isolates), Germany (4 hospitals; 14.2% of total isolates), Hungary (2 hospitals; 6.6% of total isolates), Italy (4 hospitals; 12.3% of total isolates), The Netherlands (1 hospital; 2.9% of total isolates), Poland (1 hospital; 3.3% of total isolates), Slovakia (1 hospital; 3.0% of total isolates), Spain (4 hospitals; 13.0% of total isolates), Sweden (1 hospitals; 2.5% of total isolates) and the UK (4 hospitals; 11.8% of total isolates). Isolates were limited to one per patient, and Amies transport swabs (Copan Diagnostics Inc., Corona, CA, USA) from overnight cultures of the bacterial isolates were shipped to a central laboratory (Eurofins Medinet, Inc., Herndon, VA, USA) for testing. Upon receipt, isolates were plated and subcultured onto appropriate media,⁹ after which the reported identification of isolates were confirmed by standard clinical methods.⁹ Pure cultures of the isolates were frozen and stored at –70°C. Isolates received included: 1201 S. aureus, 460 coagulase-negative staphylococci (CoNS), 526 S. pneumoniae, 1213 Escherichia coli, 854 Klebsiella pneumoniae, 443 Proteus mirabilis, 406 Enterobacter cloacae, 387 Citrobacter spp., 291 Serratia marcescens, 621 P. aeruginosa and 278 Acinetobacter spp. These included 22.6% urinary tract isolates, 23.5% respiratory tract isolates, 23.2% bloodstream isolates, 13.1% wound isolates, 6.0% skin isolates with the remainder (11.7%) of either other or unknown origin. A designated number of each species was requested from each of the institutions enrolled in the study regardless of antibiotic resistance phenotype, with the exception of S. aureus where it was requested that 75% of the total isolates be MRSA.

Antimicrobial testing

All isolates were tested by broth microdilution according to the guidelines set forth in standard M7-A7 by the CLSI (formerly NCCLS).¹⁰ In short, isolates were revived from freezer stocks by streaking onto rich media and subsequent incubation overnight as appropriate. Overnight cultures grown from isolated colonies on the aforementioned plates were adjusted to the appropriate OD¹¹ and were used to inoculate Sensititre microdilution panels (TREK Diagnostics, Westlake, OH, USA) for susceptibility testing. The antimicrobial agents tested varied by species; each comparator tested by species is listed in Tables 1–3. MICs were interpreted as susceptible, intermediate or resistant according to CLSI M100-S17 criteria,¹¹ where applicable. Putative extended-spectrum β-lactamase (ESBL) isolates of E. coli, K. pneumoniae and P. mirabilis were identified based on the interpretive criteria set forth in CLSI M100-S17.¹¹ Putative derepressed AmpC isolates of E. cloacae and Citrobacter spp. were based on the screening guidelines set forth by Livermore and Brown¹² (isolates were resistant to ceftazidime, ceftriaxone and cefotaxime; the activity of ceftazidime and cefotaxime are unaffected in combination with clavulanic acid; and the isolates are susceptible to imipenem and meropenem). Results were examined to ensure that reported MICs were within acceptable standards set by the CLSI¹¹ based on the comparator agent used and the following ATCC quality control strains: ATCC 25922 (E. coli), ATCC 27853 (P. aeruginosa), ATCC 29212 (Enterococcus faecalis), ATCC 29213 (S. aureus), ATCC 35218 (E. coli), ATCC 49619 (S. pneumoniae) and ATCC 700603 (K. pneumoniae).

View this table: [in this window] [in a new window]   Table 1. In vitro activity of ceftobiprole and comparators against Gram-positive organisms

 

View this table: [in this window] [in a new window]   Table 2. In vitro activity of ceftobiprole and comparators against Enterobacteriaceae

 

View this table: [in this window] [in a new window]   Table 3. In vitro activity of ceftobiprole and comparators against P. aeruginosa and Acinetobacter spp.

 

	Results

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Gram-positive pathogens

The in vitro activity of ceftobiprole was examined against 1201 S. aureus, the majority of which (66%) were MRSA. Ceftobiprole MICs ranged between 0.12–1 mg/L for methicillin-susceptible S. aureus (MSSA) and 0.25–4 mg/L for MRSA (Table 1). Against MSSA, ceftobiprole had an MIC₅₀ of 0.25 mg/L and an MIC₉₀ of 0.5 mg/L. Ceftobiprole MICs against MRSA (an MIC₅₀ of 1 mg/L and an MIC₉₀ of 2 mg/L) were elevated relative to MSSA (Table 1). Of the MRSA isolates tested, 42 isolates (5.3%) had an MIC of 4 mg/L. Based on MIC₅₀/MIC₉₀ values, the activity of ceftobiprole (0.5/2 mg/L) against the tested S. aureus overall was comparable to that of vancomycin (1/1 mg/L), teicoplanin (0.5/1 mg/L) and linezolid (2/2 mg/L).

Ceftobiprole was also active against both methicillin-susceptible CoNS (MIC₅₀ 0.12 mg/L, MIC₉₀ = 0.25 mg/L) and methicillin-resistant CoNS (MIC₅₀ = 1 mg/L, MIC₉₀ = 2 mg/L) (Table 1). As was observed with S. aureus, ceftobiprole MICs against methicillin-resistant CoNS were higher than against methicillin-susceptible CoNS. However, the majority of methicillin-resistant CoNS (81.6%) had ceftobiprole MICs 1 mg/L. Among the subset of isolates (5.4%) that had MICs 4 mg/L, only one (S. saprophyticus with a ceftobiprole MIC of 8 mg/L) had an MIC > 4 mg/L and is currently undergoing further characterization.

Ceftobiprole MICs against S. pneumoniae (MIC₅₀ = 0.015 mg/L, MIC₉₀ = 0.25 mg/L) were lower than those of ceftriaxone (MIC₅₀ = 0.03 mg/L, MIC₉₀ = 1 mg/L) and cefuroxime (MIC₅₀ = 0.03 mg/L, MIC₉₀ = 4 mg/L) (Table 1). As with ceftriaxone and cefuroxime, ceftobiprole MICs increased with increasing resistance to penicillin(MIC₉₀s of 0.015, 0.25 and 0.5 mg/L for penicillin-susceptible, -intermediate and -resistant isolates, respectively), but even among penicillin-resistant isolates, ceftobiprole MICs did not exceed 1 mg/L.

Enterobacteriaceae

The in vitro activity of ceftobiprole and other cephalosporin comparators against ceftazidime-susceptible and non-susceptible Enterobacteriaceae is presented in Table 2. Among ceftazidime-susceptible Enterobacteriaceae, the ceftobiprole MIC₉₀ was 0.12 mg/L, which was the same as the MIC₉₀ for cefepime, and two doubling dilutions lower than the MIC₉₀s obtained with either ceftazidime or ceftriaxone. This hierarchy of activity was generally consistent across populations of Enterobacteriaceae largely susceptible to ceftazidime, including non-ESBL E. coli and K. pneumoniae and non-derepressed AmpC E. cloacae and Citrobacter spp.

Against ceftazidime non-susceptible Enterobacteriaceae overall, MICs of ceftobiprole and comparator cephalosporins were notably increased, as the MIC₉₀ of each agent was >32 mg/L against this resistant population of organisms (Table 2). By MIC₅₀ and MIC₉₀, this pattern was generally maintained across all populations of enteric species studied where high levels of ceftazidime resistance are expected (ESBL screen-positive populations of E. coli, K. pneumoniae and P mirabilis; derepressed AmpC screen-positive populations of E. cloacae and Citrobacter spp.). Although the MIC₉₀ remained at >32 mg/L for the tested cephalosporins against putative derepressed AmpC isolates of E. cloacae and Citrobacter spp., the MIC₅₀ of ceftobiprole (8 mg/L for E. cloacae, 2 mg/L for Citrobacter spp.) and cefepime (4 mg/L for E. cloacae, 2 mg/L for Citrobacter spp.) against these isolates were lower than the other tested cephalosporins. Although the MIC₉₀s of each cephalosporin were >32 mg/L against ESBL screen-positive isolates, MIC distribution analysis for the tested cephalosporins against ESBL screen-positive isolates overall showed an 4-fold advantage in the in vitro activity of both cefepime and ceftazidime over the lower range of concentrations relative to ceftobiprole (at 2 mg/L, 18.6% and 12.4% of these isolates were inhibited by cefepime and ceftazidime, respectively; at 8 mg/L, 30.9% of isolates were inhibited by both cefepime and ceftazidime).

P. aeruginosa and Acinetobacter spp.

Both ceftobiprole and cefepime were indistinguishable by MIC₅₀ (4 mg/L) and MIC₉₀ (16 mg/L) against P. aeruginosa overall, and were at least 4-fold more potent than ceftazidime (>32 mg/L) by MIC₉₀ (Table 3). Against ceftazidime-susceptible P. aeruginosa isolates, ceftobiprole MICs ranged between 0.03 and >32 mg/L with an MIC₅₀ of 2 mg/L and an MIC₉₀ of 8 mg/L (Table 3). Against these isolates, the activity of ceftobiprole was similar to that of cefepime, where 59.3% and 60.3% of isolates were inhibited by 2 mg/L of ceftobiprole and cefepime, respectively. At 8 mg/L, 90.2% of isolates were inhibited by ceftobiprole relative to 95.1% of isolates inhibited by cefepime. Both cefepime and ceftobiprole inhibited fewer of these isolates at their respective MIC₅₀s and MIC₉₀s than ceftazidime (76.6% isolates inhibited at 2 mg/L and 100% isolates inhibited at 8 mg/L).

Against ceftazidime non-susceptible (MIC 16 mg/L) P. aeruginosa, ceftobiprole MICs were higher than against ceftazidime-susceptible isolates (MIC₅₀ = 16 mg/L, MIC₉₀ > 32 mg/L) (Table 3). Among ceftazidime-susceptible isolates, 2.2% of isolates had ceftobiprole MICs 32 mg/L, whereas among ceftazidime non-susceptible isolates, 38.5% had ceftobiprole MICs 32 mg/L. At concentrations 4 and 8 mg/L, ceftobiprole inhibited 26.9% and 44.6% of isolates, respectively. In contrast, cefepime inhibited 8.5% of isolates at 4 mg/L and 24.6% of isolates at 8 mg/L. At 16 mg/L, cefepime and ceftobiprole inhibited a similar number of isolates (63.1% and 61.5%, respectively), while only 17.7% of these isolates were inhibited by ceftazidime at the same concentration.

Ceftobiprole and the tested comparator cephalosporin MIC₉₀s against Acinetobacter spp. overall were above the highest concentration tested (>32 mg/L) (Table 3). Against imipenem-susceptible strains, ceftobiprole had an MIC₅₀ of 0.5 mg/L, but that increased to >32 mg/L among imipenem non-susceptible strains. Interestingly, among the tested Acinetobacter spp. overall, the ceftobiprole MIC₅₀ (1 mg/L) was lower than that of either cefepime (4 mg/L) or ceftazidime (4 mg/L).

	Discussion

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Ceftobiprole was active in vitro against methicillin-resistant staphylococci isolated throughout Europe. Against both MRSA and methicillin-resistant CoNS, ceftobiprole had an MIC₉₀ of 2 mg/L, which was in agreement with previous studies where MIC₉₀s between 1 and 4 mg/L were observed against MRSA, and an MIC₉₀ of 2 mg/L was observed against methicillin-resistant CoNS.^3,4,6,13 Other studies have also shown that against staphylococci, ceftobiprole was bactericidal and was active in vitro against glycopeptide-non-susceptible staphylococci.^3,5,14 Based on the findings of this current study and those of others, the activity of ceftobiprole against MRSA has been clearly established. The ability of ceftobiprole to be active against methicillin-resistant staphylococci is accomplished by its ability to bind and inhibit the transpeptidase activity of PBP2a.^2,15 No clinically available cephalosporins successfully target PBP2a, although, aside from ceftobiprole, there are other β-lactams currently in development that display activity against MRSA.^16–18

As an agent to combat MRSA, ceftobiprole is intended for use in hospitals, an environment where antibiotic resistance is well established. Usage in such an environment highlights the importance of studies regarding the development of resistance to ceftobiprole. Previous reports where both S. aureus and CoNS, including methicillin-resistant isolates, were serially passaged in the presence of ceftobiprole showed that resistance to ceftobiprole was slow to develop under these conditions. After passaging, the highest ceftobiprole MIC observed was 8 mg/L which represented a 4-fold increase in the initial MIC.⁴ A separate study noted that after serial passage against three strains of MRSA and one strain of MSSA, ceftobiprole MICs never rose more than one doubling dilution after passage and ceftobiprole MICs remained below 4 mg/L.³ In the same study, against one MRSA in particular, ceftobiprole MICs did not increase during serial passage, remaining between 0.5 and 1 mg/L, in contrast to imipenem where MICs increased at least 8-fold (from 4 to >32 mg/L) by the third passage.³ Although it is impossible to know how quickly resistance will emerge to ceftobiprole in a clinical setting, the emergence of ceftobiprole resistance via chromosomal mutation was not readily observable in the laboratory. To this point, it is important to note that resistant mutants were obtained among MRSA serially passaged in the presence of an investigational anti-MRSA carbapenem and resistance was determined to arise as a result of multiple mutations within mecA.¹⁹ What effect these mutations may have on the anti-MRSA activity of ceftobiprole has yet to be determined.

Regardless of penicillin-susceptibility status, ceftobiprole was highly active against S. pneumoniae, even though ceftobiprole's MIC₉₀s increased with growing resistance to penicillin. This level of activity was comparable to or slightly greater than that of ceftriaxone and, overall, these results are in agreement with those observed in previous studies.^3,6 In summary, these data demonstrate that ceftobiprole has a potency against S. pneumoniae that is at least comparable to that of ceftriaxone.

The activity of ceftobiprole against Enterobacteriaceae depended largely on the β-lactam resistance phenotypes of the tested isolates. Ceftobiprole was highly active against ceftazidime-susceptible (ceftobiprole MIC₅₀/MIC₉₀: 0.06/0.12 mg/L) and non-ESBL isolates of K. pneumoniae, E. coli and P. mirabilis (ceftobiprole MIC₅₀s/MIC₉₀s: 0.03/0.06–0.12 mg/L), which was similar to the activities exhibited by cefepime and ceftriaxone, though ceftriaxone was the most active agent tested against non-ESBL P. mirabilis (MIC₅₀ and MIC₉₀ 0.015 mg/L). Against non-derepressed AmpC isolates of E. cloacae and Citrobacter spp., slightly higher ceftobiprole MIC₉₀s (4 mg/L for E. cloacae, 1 mg/L for Citrobacter spp.) were observed relative to cefepime (0.5 mg/L for both E. cloacae and Citrobacter spp.), though by MIC₅₀ these agents were of comparable activity against these isolates. These findings were in agreement with previous reports in which ceftobiprole was similar in activity to cefepime against enteric species.^3,6,7 Ceftobiprole and cefepime MICs were notably higher among both ceftazidime non-susceptible isolates, ESBL screen-positive and derepressed AmpC screen-positive isolates. Although the activities of both agents were diminished against these phenotypes, cefepime tended to be slightly more potent than ceftobiprole over the dilution range tested by MIC distribution, MIC₅₀ and MIC₉₀.

The decreased level of activity of both cefepime and ceftobiprole against ceftazidime non-susceptible and derepressed AmpC screen-positive isolates of E. cloacae and Citrobacter spp. is likely a reflection of their relative stability to class C β-lactamases.³ Consistent with a previous study,³ cefepime maintained slightly greater activity than ceftobiprole against ceftazidime non-susceptible isolates and derepressed AmpC screen-positive isolates. However, both ceftobiprole and cefepime were more active against these isolates than were other cephalosporins.³ Clearly, the activity of ceftobiprole and cefepime against collections of these enteric species depends on the incidence and proportion of derepressed AmpC strains in a given population. In addition to these findings, it is of importance to note that along with the moderate stability of ceftobiprole and cefepime against AmpC enzymes,^3,20,21 both also have a lower potential for inducing chromosomal AmpC production than other β-lactams (e.g. imipenem and cefoxitin) do.²⁰

As with other cephalosporins, the in vitro activity of ceftobiprole against ESBL screen-positive strains of E. coli, K. pneumoniae and P. mirabilis was notably diminished. This finding is consistent with other studies^3,6,7 and likely reflects the increased susceptibility of ceftobiprole and other cephalosporins to hydrolysis by mutated class A β-lactamases (TEM- and SHV-type enzymes) associated with the majority of ESBLs that exist among these species. Interestingly, according to the cumulative MICs obtained against the ESBL isolates, ceftazidime was found to have activity comparable to that of cefepime and superior to that of ceftobiprole and ceftriaxone. Although limited in vitro activity had been observed with cefepime against these isolates in previous studies,^3,6,21,22 the level of activity observed with ceftazidime was somewhat unexpected.

No molecular analysis was done to definitively identify the specific ESBLs; however, the increased activity of ceftazidime relative to ceftobiprole against ESBLs as noted in this study could be explained best by the relative prevalence of CTX-M β-lactamases among the population studied. CTX-M ESBLs are commonly encountered in Europe and Asia,^21,23–25 and most CTX-M enzymes efficiently hydrolyse ceftriaxone and cefotaxime but not ceftazidime, although a point mutation can confer activity against ceftazidime as well.²⁴ Therefore, the relatively high prevalence of isolates with the putative CTX-M profile (i.e. susceptible to ceftazidime, resistant to ceftriaxone and cefotaxime) within the ESBLs of European origin in this study (E. coli, 29%; K. pneumoniae, 22%; P. mirabilis, 44%) is the most likely explanation for the ceftazidime activity observed at concentrations below its susceptibility breakpoint of 8 mg/L against a proportion (30%) of the ESBL isolates overall. Furthermore, high ceftobiprole MICs (>32 mg/L) were observed among the putative CTX-M isolates (data not shown), suggesting that ceftobiprole's diminished activity against ESBL isolates relative to ceftazidime is due to ceftobiprole's instability to CTX-M β-lactamases. Therefore, this suggests that the activity of ceftobiprole relative to other advanced generation cephalosporins is affected by both the prevalence and types of ESBLs that are encountered in a specific environment.

As was observed with Enterobacteriaceae, the activity of ceftobiprole and cefepime against P. aeruginosa and Acinetobacter spp. was also dependent on the expression of β-lactam resistance. The level of activity of ceftobiprole against P. aeruginosa overall (MIC₅₀/MIC₉₀ = 4/16 mg/L) was comparable to cefepime (MIC₅₀/MIC₉₀ = 4/16 mg/L), which was consistent with the findings of another study.^3,7 MICs of both ceftobiprole and cefepime increased significantly among ceftazidime non-susceptible P. aeruginosa by both MIC₉₀ and MIC distribution as observed in a previous study.³

Against Acinetobacter spp., ceftobiprole displayed only moderate activity which was comparable to that of both cefepime and ceftazidime. These findings were similar to those reported in a previous study.⁶ Interestingly, as evidenced by ceftobiprole's MIC₅₀ of 1 mg/L compared with that of cefepime (4 mg/L) and ceftazidime (4 mg/L), at the lower concentrations tested, ceftobiprole inhibited a greater percentage of the Acinetobacter spp. isolates in this study.

In conclusion, ceftobiprole was active against clinically relevant Gram-positive and Gram-negative pathogens of European origin. Notably, ceftobiprole displayed potent activity against MRSA and was comparable to cefepime against Enterobacteriaceae, P. aeruginosa and Acinetobacter spp. The impact that the most prevalent ‘local’ resistance mechanisms may have on the in vitro profiles of agents such as ceftobiprole and other β-lactams, as observed among the Gram-negative organisms in this study, illustrates the necessity for widespread geographical surveillance. Concomitant with the intended use of ceftobiprole in hospitals against these challenging pathogens, continued surveillance of its activity is warranted to monitor for the emergence of resistance both during its development and after its approval for clinical use.

	Funding

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This study was funded by Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Raritan, NJ, USA.

	Transparency declarations

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None to declare.

	References

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1 . Chambers HF. Evaluation of ceftobiprole in a rabbit model of aortic valve endocarditis due to methicillin-resistant and vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother (2005) 49:884–8.[Abstract/Free Full Text]

2 . Entenza JM, Hohl P, Heinze-Krauss I, et al. BAL9141, a novel extended-spectrum cephalosporin active against methicillin-resistant Staphylococcus aureus in treatment of experimental endocarditis. Antimicrob Agents Chemother (2002) 46:171–7.[Abstract/Free Full Text]

3 . Hebeisen P, Heinze-Krauss I, Angehrn P, et al. In vitro and in vivo properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci. Antimicrob Agents Chemother (2001) 45:825–36.[Abstract/Free Full Text]

4 . Bogdanovich T, Ednie LM, Shapiro S, et al. Antistaphylococcal activity of ceftobiprole, a new broad-spectrum cephalosporin. Antimicrob Agents Chemother (2005) 49:4210–9.[Abstract/Free Full Text]

5 . Deshpande L, Rhomberg PR, Fritsche TR, et al. Bactericidal activity of BAL9141, a novel parenteral cephalosporin against contemporary Gram-positive and Gram-negative isolates. Diagn Microbiol Infect Dis (2004) 50:73–5.[Medline]

6 . Jones RN, Deshpande LM, Mutnick AH, et al. In vitro evaluation of BAL9141, a novel parenteral cephalosporin active against oxacillin-resistant staphylococci. J Antimicrob Chemother (2002) 50:915–32.[Abstract/Free Full Text]

7 . Issa NC, Rouse MS, Piper KE, et al. In vitro activity of BAL9141 against clinical isolates of gram-negative bacteria. Diagn Microbiol Infect Dis (2004) 48:73–5.[CrossRef][Web of Science][Medline]

8 . Azoulay-Dupuis E, Bedos JP, Mohler J, et al. Efficacy of BAL5788, a prodrug of cephalosporin BAL9141, in a mouse model of acute pneumococcal pneumonia. Antimicrob Agents Chemother (2004) 48:1105–11.[Abstract/Free Full Text]

9 . Murray PR, Baron EJ, Jorgensen JH, et al. Manual of Clinical Microbiology (2007) Washington, DC: ASM Press.

10 . Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Test for Bacteria That Grow Aerobically—Seventh Edition: Approved Standard M7-A7 (2006) Wayne, PA, USA: CLSI.

11 . Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Seventeenth Informational Supplement M100-S17 (2007) Wayne, PA, USA: CLSI.

12 . Livermore DM, Brown DF. Detection of β-lactamase-mediated resistance. J Antimicrob Chemother (2001) 48(Suppl_1):59–64.[Abstract]

13 . Goldstein EJ, Citron DM, Merriam CV, et al. In vitro activity of ceftobiprole against aerobic and anaerobic strains isolated from diabetic foot infections. Antimicrob Agents Chemother (2006) 50:3959–62.[Abstract/Free Full Text]

14 . Deshpande LM, Jones RN. Bactericidal activity and synergy studies of BAL9141, a novel pyrrolidinone-3-ylidenemethyl cephem, tested against streptococci, enterococci and methicillin-resistant staphylococci. Clin Microbiol Infect (2003) 9:1120–4.[CrossRef][Web of Science][Medline]

15 . Heinze-Krauss I, Angehrn P, Guerry P, et al. Synthesis and structure–activity relationship of (lactamylvinyl)cephalosporins exhibiting activity against staphylococci, pneumococci, and enterococci. J Med Chem (1996) 39:1864–71.[CrossRef][Web of Science][Medline]

16 . Koga T, Abe T, Inoue H, et al. In vitro and in vivo antibacterial activities of CS-023 (RO4908463), a novel parenteral carbapenem. Antimicrob Agents Chemother (2005) 49:3239–50.[Abstract/Free Full Text]

17 . Sader HS, Fritsche TR, Kaniga K, et al. Antimicrobial activity and spectrum of PPI-0903M (T-91825), a novel cephalosporin, tested against a worldwide collection of clinical strains. Antimicrob Agents Chemother (2005) 49:3501–12.[Abstract/Free Full Text]

18 . Ueda Y, Kanazawa K, Eguchi K, et al. In vitro and in vivo antibacterial activities of SM-216601, a new broad-spectrum parenteral carbapenem. Antimicrob Agents Chemother (2005) 49:4185–96.[Abstract/Free Full Text]

19 . Katayama Y, Zhang HZ, Chambers HF. PBP 2a mutations producing very-high-level resistance to β-lactams. Antimicrob Agents Chemother (2004) 48:453–9.[Abstract/Free Full Text]

20 . Queenan AM, Bush K. Ceftobiprole: effect on AmpC β-lactamase induction and resistance frequency in Gram-negative bacteria. In: Abstracts of the Forty-fifth Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2005. Washington, DC, USA: American Society for Microbiology. Poster C1–55.

21 . Sader HS, Hsiung A, Fritsche TR, et al. Comparative activities of cefepime and piperacillin/tazobactam tested against a global collection of Escherichia coli and Klebsiella spp. with an ESBL phenotype. Diagn Microbiol Infect Dis (2007) 57:341–4.[CrossRef][Web of Science][Medline]

22 . Puerto AS, Fernandez JG, del Castillo Jde D, et al. In vitro activity of β-lactam and non-β-lactam antibiotics in extended-spectrum β-lactamase-producing clinical isolates of Escherichia coli. Diagn Microbiol Infect Dis (2006) 54:135–9.[CrossRef][Web of Science][Medline]

23 . Chanawong A, M'Zali FH, Heritage J, et al. Three cefotaximases, CTX-M-9, CTX-M-13, and CTX-M-14, among Enterobacteriaceae in the People's Republic of China. Antimicrob Agents Chemother (2002) 46:630–7.[Abstract/Free Full Text]

24 . Livermore DM, Canton R, Gniadkowski M, et al. CTX-M: changing the face of ESBLs in Europe. J Antimicrob Chemother (2007) 59:165–74.[Abstract/Free Full Text]

25 . Munday CJ, Xiong J, Li C, et al. Dissemination of CTX-M type β-lactamases in Enterobacteriaceae isolates in the People's Republic of China. Int J Antimicrob Agents (2004) 23:175–80.[CrossRef][Web of Science][Medline]

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