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. 2006 Sep 18;50(11):3959–3962. doi: 10.1128/AAC.00722-06

In Vitro Activity of Ceftobiprole against Aerobic and Anaerobic Strains Isolated from Diabetic Foot Infections▿

Ellie J C Goldstein 1,2,*, Diane M Citron 1, C Vreni Merriam 1, Yumi A Warren 1, Kerin L Tyrrell 1, Helen T Fernandez 1
PMCID: PMC1635191  PMID: 16982780

Abstract

Against 443 aerobic and anaerobic bacteria isolated from diabetic foot infections, ceftobiprole MICs (μg/ml) at which 90% of the isolates tested were inhibited were as follows: methicillin-resistant Staphylococcus aureus, 1; methicillin-susceptible S. aureus and Staphylococcus lugdunensis, 0.5; Anaerococcus prevotii, 0.125; Finegoldia magna, 0.5; Peptoniphilus asaccharolyticus, 1; Peptostreptococcus anaerobius, 4; Escherichia coli and Enterobacter species, 0.125; Klebsiella species, 2; and Pseudomonas aeruginosa, 8.

Diabetic foot infections (DFIs) are common complications and account for ∼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.

TABLE 1.

Comparative in vitro activity of ceftobiprole against 251 aerobic and 192 anaerobic strains isolated from pretreatment cultures of patients with diabetic foot infections

Organism(s) (no. of strains) and antibiotic MIC (μg/ml)
Organism(s) (no. of strains) and antibiotic MIC (μg/ml)
Range MIC50 MIC90 Range MIC50 MIC90
Corynebacterium amycolatum (15)     Cefoxitin 0.5-16 4 4
    Ceftobiprole 0.015->32 0.125 >32     Levofloxacin ≤0.125-1 0.25 1
    Cefepime 0.25->32 0.5 2     Linezolid 1-1 1 1
    Ceftazidime 16->64 64 >64     Daptomycin 0.25-1 0.5 0.5
    Cefotaxime 0.125->32 0.5 1     Vancomycin 0.125-1 0.5 0.5
    Cefoxitin 1->128 8 32
    Levofloxacin ≤0.125->16 8 >16 Streptococcus agalactiae (15)
    Linezolid ≤0.25-0.5 0.5 0.5     Ceftobiprole 0.015-0.03 0.015 0.015
    Daptomycin ≤0.06->8 0.25 0.5     Cefepime 0.06-0.125 0.125 0.125
    Vancomycin 0.25-0.5 0.5 0.5     Ceftazidime 0.5-1 0.5 0.5
    Cefotaxime ≤0.015-0.03 0.03 0.03
Corynebacterium spp.a (26)     Cefoxitin 4-4 4 4
    Ceftobiprole 0.015->32 0.06 >32     Levofloxacin 0.5-2 0.5 2
    Cefepime 0.06->32 1 >32     Linezolid 1-2 1 2
    Ceftazidime 0.5->64 32 >64     Daptomycin 0.25-1 1 1
    Cefotaxime 0.03->32 1 >32     Vancomycin 0.25-0.5 0.5 0.5
    Cefoxitin 0.125->128 8 64
    Levofloxacin ≤0.125->16 0.25 >16 Streptococcus spp., otherb (15)
    Linezolid ≤0.25-2 0.5 1     Ceftobiprole ≤0.002-0.008 0.008 0.008
    Daptomycin ≤0.06-2 0.5 2     Cefepime ≤0.015-0.03 ≤0.015 0.03
    Vancomycin 0.125-1 0.5 0.5     Ceftazidime 0.125-0.25 0.25 0.25
    Cefotaxime ≤0.015 ≤0.015 ≤0.015
Staphylococcus aureus, oxacillin     Cefoxitin 0.5-1 1 1
        resistant (40)     Levofloxacin 0.25-16 0.5 1
    Ceftobiprole 0.5-2 1 1     Linezolid 0.5-2 1 2
    Cefepime 4->32 >32 >32     Daptomycin 0.125-0.25 0.25 0.25
    Ceftazidime 16->64 >64 >64     Vancomycin 0.25-0.5 0.5 0.5
    Cefotaxime 4->32 32 >32
    Cefoxitin 32->128 64 >128 Escherichia coli (15)
    Levofloxacin 0.25->16 16 >16     Ceftobiprole 0.015-2 0.03 0.125
    Linezolid ≤0.25-4 2 4     Cefepime ≤0.015-1 0.06 0.25
    Daptomycin 0.5-2 1 2     Ceftazidime 0.06-64 0.25 2
    Vancomycin 0.5-1 1 1     Cefotaxime ≤0.015-32 0.03 0.5
    Cefoxitin 2->128 8 32
Staphylococcus aureus, oxacillin     Levofloxacin ≤0.125->16 ≤0.125 16
        susceptible (20)
    Ceftobiprole 0.25-0.5 0.25 0.5 Enterobacter spp.c (15)
    Cefepime 1-4 2 4     Ceftobiprole 0.03-1 0.06 0.125
    Ceftazidime 8-16 8 8     Cefepime 0.03-16 0.06 0.25
    Cefotaxime 0.5-2 1 2     Ceftazidime 0.25-8 0.5 1
    Cefoxitin 4-8 4 8     Cefotaxime 0.06-8 0.25 0.5
    Levofloxacin ≤0.125-1 0.25 0.25     Cefoxitin 4->128 >128 >128
    Linezolid 1-4 2 4     Levofloxacin ≤0.125-8 ≤0.125 1
    Daptomycin 0.5-2 1 1
    Vancomycin 0.5-1 0.5 1 Klebsiella spp.d (15)
    Ceftobiprole 0.03-2 0.125 2
Staphylococcus epidermidis (15)     Cefepime 0.03-0.06 0.03 0.06
    Ceftobiprole 0.125-1 0.5 1     Ceftazidime 0.06-0.25 0.125 0.25
    Cefepime 0.5-8 4 8     Cefotaxime ≤0.015-0.06 ≤0.015 0.03
    Ceftazidime 4-32 16 32     Cefoxitin 2-8 4 4
    Cefotaxime 0.5-8 4 8     Levofloxacin ≤0.125 ≤0.125 ≤0.125
    Cefoxitin 2-32 16 32
    Levofloxacin ≤0.125->16 0.25 8 Proteus-Providencia groupe (15)
    Linezolid 1-2 1 2     Ceftobiprole 0.004->32 0.06 >32
    Daptomycin 0.5-2 1 1     Cefepime ≤0.015-0.5 0.06 0.25
    Vancomycin 1-2 1 2     Ceftazidime ≤0.03-2 0.06 4
    Cefotaxime ≤0.015->32 ≤0.015 16
Staphylococcus haemolyticus (15)     Cefoxitin 2-16 4 16
    Ceftobiprole 0.25-2 1 2     Levofloxacin ≤0.125-1 ≤0.125 0.25
    Cefepime 2->32 8 >32
    Ceftazidime 16->64 64 >64 Pseudomonas aeruginosa (15)
    Cefotaxime 2->32 8 >32     Ceftobiprole 0.5-8 2 8
    Cefoxitin 2->128 32 >128     Cefepime 0.5-8 2 4
    Levofloxacin ≤0.125->16 8 >16     Ceftazidime 1-8 2 4
    Linezolid 0.5-2 1 2     Cefotaxime 4->32 8 32
    Daptomycin 0.25-0.5 0.5 0.5     Levofloxacin 0.25-4 0.5 2
    Vancomycin 0.5-2 1 2
Bacteroides fragilis (10)
Staphylococcus lugdunensis (15)     Ceftobiprole 4->128 8 >128
    Ceftobiprole 0.125-0.5 0.5 0.5     Cefepime 8->128 64 >128
    Cefepime 0.25-2 2 2     Ceftazidime 8->128 32 >128
    Ceftazidime 8-32 16 16     Cefotaxime 16->128 64 >128
    Cefotaxime 0.5-1 1 1     Cefoxitin 8-128 8 64
    Levofloxacin 2->32 2 >32     Daptomycin 0.5-1 0.5 1
    Linezolid 2-8 8 8     Vancomycin 0.5-0.5 0.5 0.5
Bacteroides fragilis groupf (16) Anaerococcus prevotii (13)
    Ceftobiprole 0.06->128 16 >128     Ceftobiprole ≤0.03-0.25 0.03 0.125
    Cefepime 16->128 >128 >128     Cefepime ≤0.06-2 0.5 1
    Ceftazidime 8->128 >128 >128     Ceftazidime 0.5-8 1 8
    Cefotaxime 0.5->128 64 >128     Cefotaxime ≤0.06-0.25 0.125 0.25
    Cefoxitin 2-64 32 64     Cefoxitin ≤0.06-0.5 0.125 0.5
    Linezolid 2-8 4 8     Levofloxacin 2->32 16 >32
    Linezolid 0.25-1 1 1
Porphyromonas spp.g (15)     Daptomycin ≤0.06-0.25 ≤0.06 0.125
    Ceftobiprole ≤0.03-32 ≤0.03 16     Vancomycin 0.125-0.5 0.25 0.5
    Cefepime 0.25-16 1 16
    Ceftazidime ≤0.06-16 0.5 2 Finegoldia magna (30)
    Cefotaxime ≤0.06-4 ≤0.06 2     Ceftobiprole ≤0.03-0.5 0.25 0.5
    Cefoxitin ≤0.06-1 0.25 0.5     Cefepime 1->32 32 >32
    Levofloxacin 0.25-16 1 2     Ceftazidime 1->32 16 >32
    Linezolid 0.5-2 1 2     Cefotaxime 0.25-32 8 32
    Vancomycin 2-8 4 8     Cefoxitin 0.25-4 2 2
    Levofloxacin 0.25->32 2 >32
Prevotella bivia (17)     Linezolid 0.5-4 2 2
    Ceftobiprole ≤0.03-128 16 64     Daptomycin 0.125-2 1 2
    Cefepime 1->128 128 >128     Vancomycin 0.125-0.5 0.25 0.5
    Ceftazidime 0.5-128 64 128
    Cefotaxime ≤0.06-32 16 32 Peptoniphilus asaccharolyticus (20)
    Cefoxitin 0.25-4 1 4     Ceftobiprole ≤0.03-1 0.03 1
    Levofloxacin 2->32 4 >32     Cefepime 0.25-32 1 2
    Linezolid 1-4 2 4     Ceftazidime 0.125->32 0.5 32
    Cefotaxime ≤0.06-16 0.125 2
Prevotella melaninogenica (10)     Cefoxitin ≤0.06-1 0.25 1
    Ceftobiprole 0.5-32 4 16     Levofloxacin 4->32 8 >32
    Cefepime 1-32 16 32     Linezolid 0.5-2 1 2
    Ceftazidime 0.5-32 4 16     Daptomycin ≤0.06-1 ≤0.06 0.25
    Cefotaxime 0.5-8 2 8     Vancomycin 0.125-0.5 0.125 0.25
    Cefoxitin 1-2 1 2
    Levofloxacin 0.5-32 1 16 Peptostreptococcus anaerobius (10)
    Linezolid 1-4 2 2     Ceftobiprole 0.25-4 1 4
    Cefepime 0.5-8 0.5 8
Clostridium spp.h (19)     Ceftazidime 0.5-8 1 8
    Ceftobiprole ≤0.03-8 0.125 4     Cefotaxime 0.125-1 0.25 1
    Cefepime ≤0.03-128 2 64     Cefoxitin 0.5-1 0.5 1
    Ceftazidime 0.06->128 4 >128     Levofloxacin 0.5->32 0.5 >32
    Cefotaxime ≤0.06->128 4 32     Linezolid 0.5-1 1 1
    Cefoxitin 0.06-32 2 16     Daptomycin 0.25-0.25 0.25 0.25
    Levofloxacin 0.125-16 0.5 16     Vancomycin 0.25-0.5 0.25 0.5
    Linezolid 2-8 2 8
    Daptomycin ≤0.06-8 1 4 Anaerobic gram-positive cocci,
    Vancomycin 0.25-16 1 4         otheri (17)
    Ceftobiprole ≤0.03-1 0.06 0.5
Propionibacterium acnes (15)     Cefepime 0.25-8 0.5 4
    Ceftobiprole ≤0.03-0.25 0.06 0.125     Ceftazidime 0.25-32 4 16
    Cefepime 1-8 2 4     Cefotaxime ≤0.06-2 0.25 2
    Ceftazidime 2-8 4 8     Cefoxitin ≤0.06-8 0.25 1
    Cefotaxime ≤0.06-0.5 0.125 0.25     Levofloxacin 0.125->32 4 >32
    Cefoxitin ≤0.06-1 0.5 1     Linezolid 0.5-2 1 2
    Levofloxacin 0.25-16 0.5 1     Daptomycin ≤0.06-1 0.125 1
    Linezolid 0.5-0.5 0.5 0.5     Vancomycin 0.125-1 0.5 1
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a

Corynebacterium aurimucosum (2), Corynebacterium jeikeium (5), Corynebacterium striatum (10), Corynebacterium tuberculostearicum (6), Corynebacterium urealyticum (1), and Corynebacterium xerosis (2).

b

S. dysgalactiae subsp. equisimilis (12) and S. pyogenes (3).

c

Enterobacter aerogenes (4) and Enterobacter cloacae (11).

d

Klebsiella oxytoca (9) and Klebsiella pneumoniae (6).

e

Proteus mirabilis (8), P. vulgaris (4), and Providencia rettgeri (3).

f

Bacteroides caccae (1), Bacteroides distasonis (1), Bacteroides ovatus (3), Bacteroides stercoris (2), Bacteroides theta (4), Bacteroides uniformis (3), and Bacteroides vulgatus (2).

g

Porphyromonas asaccharolytica (7) and Porphyromonas somerae (formerly Porphyromonas levii) (8).

h

Clostridium aminovalericum (1), Clostridium cadaveris (4), Clostridium clostridioforme (3), Clostridium innocuum (1), Clostridium malenomenatum (1), Clostridium perfringens (6), Clostridium sphenoides (1), and Clostridium subterminale (2).

i

Anaerococcus tetradius (7), Anaerococcus vaginalis (2), Peptostreptococcus micros (6), and Peptoniphilus harei (2).

Anaerobic susceptibility testing was performed by the agar dilution method according to CLSI standard M11-A6 (12) with a final inoculum of 105 CFU/spot. Plates were incubated at 37°C for 44 to 48 h in an anaerobic chamber (Anaerobe Systems, California). Aerobic isolates were subcultured onto Trypticase soy blood agar and tested by the broth microdilution method using cation-adjusted Mueller-Hinton broth, with lysed horse blood supplementation for streptococci and corynebacteria (4, 13). The trays were prepared in-house with serial twofold dilutions of the drugs by using the Quick-Spense apparatus (Sally Spring Instrument Co. Inc., Germantown, MD) and stored at −70°C until use. Colonies were suspended from overnight growth and added to the trays for a final inoculum of approximately 5 × 105 CFU/ml. The trays were incubated for 18 to 24 h and examined.

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.

Acknowledgments

This study was funded in part by a grant from Johnson & Johnson Pharmaceutical Research & Development.

We thank Judee H. Knight and Alice E. Goldstein for various forms of assistance.

Footnotes

▿

Published ahead of print on 18 September 2006.

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