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Antimicrobial Agents and Chemotherapy, September 2008, p. 3418-3423, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00336-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vitro Activity of Ceftobiprole against Pathogens from Two Phase 3 Clinical Trials of Complicated Skin and Skin Structure Infections{triangledown}

Karen M. Amsler,1* Todd A. Davies,1 Wenchi Shang,1 Michael R. Jacobs,2 and Karen Bush1

Johnson & Johnson Pharmaceutical Research & Development L.L.C., Raritan, New Jersey,1 Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio2

Received 11 March 2008/ Returned for modification 10 April 2008/ Accepted 21 June 2008


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ABSTRACT
 
In phase 3 clinical trials for ceftobiprole treatment of complicated skin and skin structure infections, 1,219 gram-positive and 276 gram-negative aerobic baseline pathogens were identified. Ceftobiprole inhibited all staphylococcal isolates, including methicillin-resistant strains, at MICs of ≤4 µg/ml. Against Enterobacteriaceae and Pseudomonas aeruginosa isolates, the potency of ceftobiprole was similar to that of cefepime.


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TEXT
 
Gram-positive organisms, predominantly Staphylococcus aureus, are among the most common pathogens in skin infections, with an increasing prevalence of methicillin-resistant S. aureus (MRSA) observed in localized areas from 1998 to 2004 (13). Gram-negative bacilli, particularly Pseudomonas aeruginosa and Escherichia coli, as well as anaerobic bacteria, can be recovered from more complicated infections, including diabetic foot infections (DFIs), with as many as 83.8% of serious DFIs reported as being polymicrobial (4, 6, 10, 13). This presents a major therapeutic challenge, as many recent anti-MRSA agents with clinical indications for the treatment of skin infections have activity only against gram-positive pathogens (8, 18, 20).

Ceftobiprole is a broad-spectrum, investigational cephalosporin with demonstrated activity against methicillin-susceptible and methicillin-resistant staphylococci, in addition to many Enterobacteriaceae and P. aeruginosa isolates (1, 3, 7, 9). Two phase 3 clinical trials of ceftobiprole and comparator agents for the treatment of complicated skin and skin structure infections (cSSSIs) were recently completed (15, 16). The first trial focused on skin infections caused by aerobic gram-positive pathogens (16); the second trial included isolates from infections caused by both aerobic and anaerobic gram-positive and gram-negative pathogens as well as DFIs (15). We now report on the in vitro activities of ceftobiprole against the baseline pathogens isolated from these two phase 3 clinical trials for treatments of cSSSIs.

Valid baseline pathogens (n = 1,506) were obtained from 1,271 subjects from the modified intent-to-treat (mITT) patient population enrolled in two international, multicenter, randomized, double-blind phase 3 clinical trials for treatments of cSSSIs conducted from 2004 to 2006. The study population and the microbiological evaluations have been described previously (15, 16). Valid baseline isolates from both treatment arms of the mITT patient population were used in this analysis.

The central laboratory confirmed the isolate identifications, performed susceptibility testing, and tested the isolates for the presence of mecA, as described previously (15, 16). Anaerobic cultures were also performed if anaerobic pathogens were suspected; the isolates were identified with RapID ANAII system kits (Remel, Lenexa, KS), and the MICs were determined by the Clinical and Laboratory Standards Institute (CLSI; formerly NCCLS) reference agar dilution method (14).

All staphylococcal isolates were screened for reduced susceptibility to vancomycin by the CLSI method (5). S. aureus isolates with vancomycin MICs of 2 µg/ml were also tested for their vancomycin susceptibilities by the recommended 24-h Etest method (AB Biodisk, Solna, Sweden) and screened for the heterogeneous vancomycin-intermediate phenotype by the macro-Etest method with 48 h of incubation (19). None of the isolates tested positive for the heterogeneous vancomycin-intermediate phenotype or had elevated vancomycin MICs.

The most prevalent of the 1,219 gram-positive aerobic baseline pathogens included S. aureus (341 [36.6%] MRSA isolates; 591 [63.4%] methicillin-susceptible S. aureus [MSSA] isolates), coagulase-negative staphylococci (43 of 87 [49.4%] of which were methicillin resistant), and Streptococcus pyogenes. Among the microbiologically evaluable subjects with DFIs, the predominant pathogens were MSSA (38%), MRSA (13%), E. coli (10%), Streptococcus agalactiae (9%), Enterobacter cloacae (9%), P. aeruginosa (8%), Proteus mirabilis (7%), and Klebsiella pneumoniae (6%) (15).

Ceftobiprole MICs were ≤4 µg/ml against all staphylococci, with MICs two- to fourfold lower for the methicillin-susceptible strains than for the methicillin-resistant strains (Table 1; Fig. 1). The ceftobiprole MICs against the staphylococci were comparable to or slightly less than the vancomycin MICs and were frequently less than the linezolid MICs (Table 1). Six mecA-positive S. aureus isolates were oxacillin susceptible. Against the 152 beta-hemolytic streptococci, the ceftobiprole MICs were ≤0.25 µg/ml (Table 1). Unlike ceftazidime (MIC90 of >128 µg/ml), the ceftobiprole MIC90 (0.5 µg/ml) was less than the linezolid and vancomycin MIC90s against 17 Enterococcus faecalis isolates (Table 1).


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  		TABLE 1. In vitro activity of ceftobiprole and other antibacterial agents against gram-positive baseline isolates from two phase 3 clinical trials of the treatments for cSSSIs


Figure 1
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  		FIG. 1. Ceftobiprole MIC distributions for MSSA (solid bars; n = 591) and MRSA (open bars; n = 341) baseline isolates from two phase 3 clinical trials of cSSSIs.

The ceftobiprole MIC50 and modal MICs against the Enterobacteriaceae were comparable to those of cefepime and were often less than those of ceftazidime (Table 2). Among the Enterobacteriaceae, the proportions of isolates for which the MICs were ≤4 µg/ml were 85% for ceftobiprole, 91% for cefepime, and 87% for ceftazidime. High cephalosporin MICs (>16 µg/ml) were associated with extended-spectrum β-lactamase production in 11/203 Enterobacteriaceae isolates (7 Klebsiella sp., 3 P. mirabilis, and 1 E. coli), whereas high cephalosporin MICs for Enterobacter spp., Serratia marcescens, and Citrobacter spp. were more likely to be associated with elevated levels of production of AmpC cephalosporinases (data not shown).


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  		TABLE 2. In vitro activity of ceftobiprole and other antibacterial agents against predominant gram-negative baseline pathogens from phase 3 cSSSI clinical trials

Ceftobiprole MICs were ≤4 µg/ml against 52% of the P. aeruginosa isolates, whereas the cefepime and ceftazidime MICs were ≤4 µg/ml against 63.5% and 57% of the isolates, respectively. The ceftobiprole MICs tended to follow those of cefepime, with 88% of the pseudomonal isolates having MICs for these two agents within 1 doubling dilution. Pseudomonal isolates with either ceftazidime or ceftobiprole MICs >16 µg/ml had high levels of β-lactamase activity, presumably due to AmpC hyperproduction (17).

Among the anaerobic pathogens, five of eight Bacteroides fragilis group and Prevotella sp. isolates were β-lactamase positive and had ceftobiprole MICs of 4 to >64 µg/ml (Table 2). The three β-lactamase-negative isolates had ceftobiprole MICs of ≤0.12 µg/ml, similar to those for the gram-positive anaerobic isolates Eubacterium aerofaciens and Peptostreptococcus tetradius (ceftobiprole MICs, 0.06 and 0.25 µg/ml, respectively).

The predominant clinical isolates detected in these studies, including anaerobes, were consistent with those detected in other recent clinical studies of cSSSIs, including studies of DFIs (2, 4, 8, 11). The prevalence of MRSA was 37% among the S. aureus isolates collected from 2004 to 2006 for this study, which was higher than that seen for the MRSA isolates from tigecycline cSSSI studies (25%) collected from 2002 to 2004 (2) or for the MRSA isolates from patients with DFIs (24%) collected from 2001 to 2004 in the ertapenem cSSSI studies (4). Other recent studies of cSSSIs have reported a higher prevalence of MRSA isolates than MSSA isolates. In a study that was conducted in 2003 and 2004 and that compared dalbavancin and linezolid, 57% of the S. aureus isolates were MRSA (8), and in a study that was conducted in 2002 and 2003 and that examined the efficacies of linezolid and vancomycin, MRSA occurred as a baseline pathogen 50% more frequently than MSSA (20). The somewhat lower rates of detection of MRSA isolates in the studies of ceftobiprole are possibly related to the distribution of the geographical sites in which these multinational studies were conducted. As was observed from surveillance studies (13), the prevalence of MRSA in the United States (47%) and Latin America (38%) was almost double that in Europe (22%), where many of the ceftobiprole clinical study sites were located.

The predominant gram-negative pathogens in the studies of ceftobiprole were E. coli, P. aeruginosa, P. mirabilis, E. cloacae, and K. pneumoniae. With the exception of P. aeruginosa, these pathogens were also reported to be among the most prevalent in other studies (2, 4, 8, 11), generally consistent with multinational surveillance data from the SENTRY program covering the years from 1998 to 2004 (13).

Among the pathogens identified from subjects with DFIs, the predominant aerobic isolates were MSSA, MRSA, S. agalactiae, E. cloacae, E. coli, P. mirabilis, P. aeruginosa, and K. pneumoniae, similar to those in other studies of DFIs (4). The anaerobic isolates recovered in this study were consistent with the anaerobic pathogens detected during other studies of DFIs (4, 11), in which the major anaerobes included B. fragilis group and Prevotella sp. isolates.

The data presented here confirm the broad-spectrum in vitro activity of ceftobiprole against the major pathogens that cause cSSSIs. On the basis of the MIC distributions, with most MICs less than 4 µg/ml, the probability of pharmacodynamic target attainment (12) was >90% for the dosing regimen used to treat infections caused by gram-positive or gram-negative pathogens (500 mg given intravenously every 8 h). These results, together with clinical cure rates exceeding 90% (15, 16), suggest that ceftobiprole should be considered a potential agent for the treatment of complicated skin infections, including those caused by mixed populations of gram-negative and gram-positive pathogens.


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ACKNOWLEDGMENTS
 
We thank Saralee Bajaksouzian and Anne Windau from Case Western Reserve University and University Hospitals Case Medical Center for their technical contributions to the susceptibility and multiplex PCR data, Barbara Foleno from Johnson & Johnson Pharmaceutical Research & Development, L.L.C., for testing of the isolates for the heterogeneous vancomycin-intermediate phenotype; and Markus Heep from Basilea Pharmaceutica for his initial contributions to the susceptibility testing paradigm and review of the manuscript.


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FOOTNOTES
 
* Corresponding author. Mailing address: Johnson & Johnson Pharmaceutical Research & Development LLC, 1000 Route 202 South, OMP B225, Raritan, NJ 08869. Phone: (908) 704-5425. Fax: (908) 707-3501. E-mail: kamsler{at}prdus.jnj.com Back

{triangledown} Published ahead of print on 30 June 2008. Back


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Antimicrobial Agents and Chemotherapy, September 2008, p. 3418-3423, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00336-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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  • Kimko, H., Murthy, B., Xu, X., Nandy, P., Strauss, R., Noel, G. J. (2009). Population Pharmacokinetic Analysis of Ceftobiprole for Treatment of Complicated Skin and Skin Structure Infections. Antimicrob. Agents Chemother. 53: 1228-1230 [Abstract] [Full Text]  

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