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Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, November 2006, p. 3959-3962, Vol. 50, No. 11
0066-4804/06/$08.00+0 doi:10.1128/AAC.00722-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
The R. M. Alden Research Laboratory, Santa Monica, California 90404,1 the UCLA School of Medicine, Los Angeles, California 900732
Received 11 June 2006/ Returned for modification 6 August 2006/ Accepted 8 September 2006
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20% of all hospitalizations for >18 million diabetics in the United States (1, 2). Early-stage DFIs are generally due to Staphylococcus aureus, and 20% of hospitalized DFI patients grow methicillin-resistant S. aureus (MRSA) (7); more-advanced DFIs involve aerobic gram-negative rods, and 45% also involve anaerobes (4.1 to 5.8 bacterial species isolated per specimen, composed of 2.9 to 3.5 aerobes and 1.2 to 2.6 anaerobes) (6). Recently, in 473 pretreatment DFIs, 48% grew S. aureus bacteria, of which approximately 25% were MRSA, and 42% grew anaerobes (D. M. Citron, E. J. C. Goldstein, B. A. Lipsky, A. Tice, D. E. Morgenstern, and M. A. Abramson, Abstr. 45th Intersci. Conf. Antimicrob. Agents Chemother., abstr. E-1440, 2005). Ceftobiprole (BAL 9141) is a new broad-spectrum pyrrolidinone cephem antimicrobial active against S. aureus bacteria, including MRSA and vancomycin-intermediate S. aureus, vancomycin-resistant Enterococcus faecalis (but not ampicillin-resistant enterococci), other gram-positive organisms, and many gram-negative rods except Proteus vulgaris or extended-spectrum beta-lactamase (ESBL)-producing strains of Enterobacteriaceae (3, 5, 8, 9, 15), but data on its activity against anaerobes are limited (14).
Consequently, we studied the activity of ceftobiprole against 443 aerobic and anaerobic strains isolated from pretreatment cultures (2001 to 2004) obtained after debridement from patients with symptomatic, complicated DFIs at 52 domestic clinical study sites and sent to our lab via overnight courier. All isolates (Table 1) were identified by standard criteria (10, 11). Standard antimicrobial laboratory powders were supplied by the manufacturers and reconstituted accordingly.
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Results are presented in Table 1. The ceftobiprole quality control strain MICs were as follows: S. aureus ATCC 29213, 0.25 µg/ml, seven times; 0.5 µg/ml, twice; Escherichia coli ATCC 25922, 0.03 µg/ml, once; 0.06 µg/ml, five times; Bacteroides fragilis ATCC 25285, 16 µg/ml, four times; Bacteroides thetaiotaomicron ATCC 29741, 16 µg/ml, twice; 32 µg/ml, twice; Clostridium difficile ATCC 700057, 2 µg/ml, once; 4 µg/ml, once; 8 µg/ml, once.
Ceftobiprole was the most consistently active of all the drugs tested against gram-positive organisms. Ceftobiprole inhibited all methicillin-susceptible S. aureus and Staphylococcus lugdunensis strains at 
0.5 µg/ml and had a MIC at which 90% of the isolates tested were inhibited (MIC90) of 1 µg/ml against MRSA and Staphylococcus epidermidis isolates, showing greater activity than linezolid (MIC90, 2 µg/ml). Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Streptococcus pyogenes isolates were all susceptible to 0.015 µg/ml of ceftobiprole. Ceftobiprole was active against corynebacteria at 0.125 µg/ml except all five Corynebacterium jeikeium strains, along with 1/10 Corynebacterium striatum strains, two/six Corynebacterium tuberculostearicum strains, and one Corynebacterium urealyticum strain, which had MICs of >32 µg/ml. Corynebacterium amycolatum strains showed a bimodal distribution with 11/15 isolates susceptible to 0.25 µg/ml and 4/15 isolates having MICs of >32 µg/ml.
Ceftobiprole was active against E. coli and Enterobacter species (MIC90 for both, 0.125 µg/ml) and Klebsiella species (MIC90, 2 µg/ml). None of these isolates were ESBL producers. It was active against Proteus mirabilis at 0.125 µg/ml, but all four P. vulgaris strains had MICs of >32 µg/ml. Pseudomonas aeruginosa had MIC90s of 8, 4, and 4 µg/ml against ceftobiprole, cefepime, and ceftazidime, respectively.
Ceftobiprole was also active against gram-positive anaerobes. All Propionibacterium acnes strains were susceptible to 0.25 µg/ml. Peptostreptococci and clostridia were susceptible to 1 µg/ml except for Peptostreptooccus anaerobius (MIC90 of 4 µg/ml), one strain of Clostridium innocuum (MIC of 4 µg/ml), and one of three isolates of Clostridium clostridioforme (MIC of 8 µg/ml). Finegoldia magna isolates were highly susceptible to ceftobiprole (MIC, 0.5 µg/ml) and yet generally resistant to cefepime, ceftazidime, cefotaxime, and levofloxacin and had a cefoxitin MIC90 of 2 µg/ml.
All seven strains of Porphyromonas asaccharolytica, including a beta-lactamase-positive strain, and five of eight strains of Porphyromonas somerae were susceptible to 0.125 µg/ml of ceftobiprole. Bacteroides fragilis and B. fragilis group species, many of which were resistant to cefoxitin, and Prevotella bivia and Prevotella melaninogenica strains were less susceptible to ceftobiprole.
Recent data have shown that the in vitro activity of an antimicrobial agent against an anaerobic species may vary depending on the site of isolation, such as an intra-abdominal infection versus a DFI (Citron et al., 45th ICAAC). Consequently, it is important to test isolates from single clinical sources to determine a drug's potential.
In our study, ceftobiprole was generally active against MRSA, Staphylococcus haemolyticus, S. lugdunensis, and group B streptococci, in accord with other studies (3, 8). Hebeisen et al. (8) reported a MIC90 of 8 µg/ml against S. haemolyticus, while ours was 2 µg/ml. We found that ceftobiprole was active against most corynebacteria at 0.125 µg/ml but had species variability.
None of our E. coli or Klebsiella species isolates were ESBL producers. As reported previously (8), Proteus mirabilis strains were susceptible to ceftobiprole while P. vulgaris strains were resistant. Issa et al. (9) reported a ceftobiprole MIC90 of 8 µg/ml against 30 strains of P. aeruginosa, while Hebeisen et al. (8) reported a MIC90 of 16 µg/ml against 60 ceftazidime-susceptible strains but a MIC90 of >64 µg/ml against 17 ceftazidime-resistant strains. All of our P. aeruginosa isolates were susceptible to 8 µg/ml of ceftazidime and ceftobiprole, and their activities paralleled each other.
Like Wootton et al. (14), we also found B. fragilis and B. fragilis group species to be generally resistant to ceftobiprole, possibly due to chromosomal beta-lactamase activity of these strains. Unfortunately, they did not report on individual anaerobic species except B. fragilis and instead lumped them into broad groups; consequently, our data are not directly comparable. Propionibacterium acnes was susceptible to 0.25 µg/ml of ceftobiprole. In contrast to the work of Wootton et al. (14), who reported the ceftobiprole MIC90 of 59 grouped gram-positive anaerobic cocci as 32 µg/ml, our study noted that peptostreptococci were susceptible to 1 µg/ml except for Peptostreptococcus anaerobius, which had a MIC90 of 4 µg/ml. Similarly, Wootton et al. (14) studied 48 mixed species of clostridia and found a MIC90 of 64 µg/ml; however, in our study, most clostridia, such as Clostridium cadaveris, Clostridium perfringens, and Clostridium subterminale, were susceptible to 1 µg/ml except for some isolates of C. clostridioforme and C. innocuum.
Ceftobiprole had good activity against a wide range of gram-positive aerobes and anaerobes isolated from DFIs. Its activity against gram-negative aerobes and anaerobes was species dependent.
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ACKNOWLEDGMENTS |
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We thank Judee H. Knight and Alice E. Goldstein for various forms of assistance.
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FOOTNOTES |
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Published ahead of print on 18 September 2006.
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