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JAC Advance Access originally published online on July 2, 2007
Journal of Antimicrobial Chemotherapy 2007 60(3):594-598; doi:10.1093/jac/dkm237
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Evaluation of ceftobiprole medocaril against Enterococcus faecalis in a mouse peritonitis model

Cesar A. Arias1–3, Kavindra V. Singh1,2, Diana Panesso3 and Barbara E. Murray1,2,4,*

1 Center for the Study of Emerging and Reemerging Pathogens, Division of Infectious Diseases, University of Texas Medical School at Houston, 6431 Fannin Street, MSB 2.112, Houston, TX 77030, USA 2 Department of Internal Medicine, University of Texas Medical School at Houston, 6431 Fannin Street, MSB 2.112, Houston, TX 77030, USA 3 Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Transv 9a No. 133-25, Bogota, Colombia 4 Department of Microbiology and Molecular Genetics, University of Texas Medical School at Houston, 6431 Fannin Street, MSB 2.112, Houston, TX 77030, USA

* Corresponding author. Tel: +1-713-500-6745; Fax: +1-713-500-6766; E-mail: bem.asst{at}uth.tmc.edu

Received 23 April 2007; returned 10 May 2007; revised 5 June 2007; accepted 6 June 2007


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Objectives: Ceftobiprole is a novel broad-spectrum cephalosporin with good in vitro activity against methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. The objective of this study was to assess the in vivo activity of ceftobiprole against four strains of E. faecalis, including ß-lactamase- producing (Bla+) and vancomycin-resistant strains.

Methods: Mice were infected intraperitoneally with strains of E. faecalis: (i) the Bla+ strain HH22; (ii) two vancomycin-resistant strains (TX2484 and V583); and (iii) OG1RF (a laboratory strain), using 10 x the LD50 for each strain. Ceftobiprole doses of 25, 12.5 and 6.25 mg/kg (single doses) and ampicillin 50, 25, 12.5 and 6.25 mg/kg (single and double doses) were administered subcutaneously immediately after bacterial challenge and mice were monitored for 96 h.

Results: All four E. faecalis had ceftobiprole MICs ≤0.5 mg/L. Despite being susceptible in vitro at the standard inoculum, ampicillin (single and double doses) did not protect mice against intraperitoneal challenge with Bla+ E. faecalis HH22, with a 50% protective dose (PD50) of >100 mg/kg, whereas ceftobiprole was protective (PD50 of 2 mg/kg). Ceftobiprole PD50s for vancomycin-resistant isolates TX2484 and V583 were 7.7 and 5.2 mg/kg, respectively, similar to those of single dose ampicillin (12.5 and 16.4 mg/kg, respectively). For OG1RF, both ampicillin and ceftobiprole protected all mice at doses of 25 and 12.5 mg/kg, respectively, with a PD50 of 4.2 and 8 mg/kg for ceftobiprole and ampicillin, respectively.

Conclusions: Ceftobiprole had comparable in vivo activity to that of ampicillin against vancomycin-resistant and ampicillin-susceptible strains of E. faecalis in the mouse peritonitis model. Ceftobiprole was superior in vivo to ampicillin against the Bla+ strain HH22. Our data support the further study of ceftobiprole as a therapeutic agent in humans infected with E. faecalis.

Keywords: enterococci , cephalosporins , animal model


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The current clinical challenges posed by enterococci include the increased incidence of nosocomial infections and the lack of enterococcal activity of several compounds due either to intrinsic resistance or the acquisition of resistance genes. Moreover, although still rare, resistance to recently approved antimicrobial agents with anti-enterococcal activity (e.g. daptomycin)1–4 has been documented in Enterococcus faecalis and other enterococcal species indicating that new therapeutic options for enterococcal infections might be needed in the future.

Ceftobiprole is a novel broad-spectrum, ß-lactamase-stable, parenteral cephalosporin with high affinity for the penicillin binding proteins (PBPs) of Gram-positive cocci,5 including PBP2a of Staphylococcus aureus and PBP2x of pneumococci.6 The in vitro activity of ceftobiprole includes ß-lactamase-producing and vancomycin-resistant E. faecalis7 and ampicillin-susceptible Enterococcus faecium.5,8 Ceftobiprole medocaril (formerly BAL5788) is a water-soluble prodrug that has been used previously in several animal models including a mouse model of sepsis for Gram-positive and Gram-negative bacteria,5 a mouse abscess model of methicillin-resistant S. aureus (MRSA) and S. aureus with intermediate resistance to vancomycin (VISA)9 and a mouse pneumonia model with Haemophilus influenzae, Enterobacter cloacae and Klebsiella pneumoniae.10 Rat and rabbit models11,12 of MRSA and VISA endocarditis have also evaluated the activity of ceftobiprole medocaril in these infections. The tissue cage model (which is a foreign body infection model in which bacteria are injected into pre-implanted Teflon tissue cages)9 has also been established to assess the activity of ceftobiprole against MRSA. In general, ceftobiprole has comparable or superior activity versus the comparators (vancomycin, linezolid or other ß-lactams) in all models with a good correlation between in vitro susceptibility and in vivo activity. Clinical data on complicated skin and soft tissue infections indicated that ceftobiprole was as effective and safe as vancomycin in treating patients with these conditions.13 Phase III clinical trials of ceftobiprole medocaril in the treatment of hospital- and community-acquired pneumonia are currently underway.14

The mouse peritonitis model has been extensively used in the past to evaluate the in vivo antibiotic activity against enterococci but its use to assess the activity of ceftobiprole against E. faecalis isolates has not been reported. Although ceftobiprole has shown good in vitro activity against E. faecalis,7 in vivo data are lacking. Moreover, its in vitro spectrum indicates that it would be active against ß-lactamase producers and vancomycin-resistant isolates of E. faecalis.7 Therefore, our main goal was to evaluate the in vivo activity of ceftobiprole medocaril against isolates of E. faecalis, including ones exhibiting either vancomycin resistance or production of ß-lactamase, in the mouse peritonitis model. We also sought to determine if the presence of ß-lactamase in E. faecalis produced an in vivo effect in this model, despite the in vitro susceptibility at the standard inoculum for laboratory testing.


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Bacterial isolates

Four well characterized isolates of E. faecalis were included in this study (Table 1): (i) HH22 (TX0921), a Houston isolate from 1981, which was the first enterococcal isolate found to produce ß-lactamase;15 (ii) TX2484, also recovered in Houston in 1994 from the blood of a patient and harbouring the vanB gene cluster;16 (iii) V583, a vancomycin-resistant isolate (whose genome has been sequenced) recovered from the bloodstream of a patient;17,18 and (iv) OG1RF, a laboratory strain of E. faecalis that exhibits rifampicin and fusidic acid resistance19 used extensively for evaluation of E. faecalis.20,21


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  		Table 1. E. faecalis strains evaluated in the mouse peritonitis model

 
Antibiotics and in vitro susceptibility testing

For in vitro testing, ceftobiprole was diluted in 9.9% glacial acetic acid and 1% high quality dimethyl sulphoxide as recommended by the manufacturer (Johnson & Johnson, Raritan, NJ, USA). Vancomycin and ampicillin were obtained from Sigma, St Louis, MO, USA. The MICs of each antibiotic were determined by the agar dilution method using Mueller–Hinton (MH) agar-II (Becton–Dickinson and Company, Cockeysville, MD, USA) following the recommendations of the CLSI.22 E. faecalis ATCC 29212 and S. aureus ATCC 29213 strains were included as controls. High inoculum MICs in broth (using 107 cfu/mL) of ampicillin and ceftobiprole were determined for isolate E. faecalis HH22 in cation-adjusted MH broth (Becton–Dickinson and Company) following the recommendations of the CLSI.22

Mouse peritonitis model

Female, 4- to 6-week-old, outbred ICR mice (Harlan Sprague–Dawley, Houston) weighing between 19.1 and 25 g were used as described previously.23 Each dosing group was composed of six animals. Bacteria for inoculation were grown on brain heart infusion (BHI) agar (Difco Laboratories, Detroit, MI, USA) and subsequently inoculated in BHI broth at 37°C for 24 h. Mice were injected intraperitoneally with 1 mL of a solution containing the E. faecalis strain in 12.5% suspended sterile rat faecal extract23 with an inoculum of ≥10x the LD50 (LD50s of HH22, OG1RF and V583 were previously described;24 for isolate TX2484, LD50 was determined before the therapeutic assay). Antibiotics (ceftobiprole medocaril and ampicillin dissolved in water) were given subcutaneously as a single dose. Ampicillin doses of 100, 50, 25, 12.5 and 6.25 mg/kg were administered. For ceftobiprole, doses of 25, 12.5, 6.25, 3.12 and 1.56 mg/kg were used. To compensate for differences in half-life between ceftobiprole and ampicillin, an additional experiment was performed administering a second dose of ampicillin subcutaneously to animals infected with strain HH22 (TX0921), 2 h after bacterial inoculation. Based on previous observations,23 mice were monitored every 24 h for 96 h. The LD50 and 50% protective dose (PD50) were determined by the method described by Reed and Muench.25 All animal experiments followed the pre-approved guidelines of the Animal Welfare Committee of the University of Texas Health Science Center at Houston. Comparison of the survival curves of the ceftobiprole- and ampicillin-treated groups at similar doses was performed using a log-rank test with Prism for Windows® (version 4.00 GraphPad Software). A value of P < 0.05 was considered significant.


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In vitro activity of ceftobiprole

All four E. faecalis isolates had ceftobiprole MICs <0.5 mg/L, whereas vancomycin MICs were 0.5, 1, 128 and >512 mg/L for HH22, OG1RF, V583 and TX2484, respectively. Ampicillin MICs at standard inoculum were ≤1 mg/L for all four isolates. Use of a high inoculum increased the ampicillin MIC for isolate HH22 to 512 mg/L but produced only a minor rise in the ceftobiprole MIC (from 0.5 to 1 mg/L). These results confirmed the stability of ceftobiprole against ß-lactamase-producing enterococci and its good in vitro activity against the vancomycin-resistant E. faecalis isolates.

In vivo activity of ceftobiprole against ß-lactamase-producing E. faecalis

Figure 1 shows the dose–response curves for the ß-lactamase-producing E. faecalis HH22 (Figure 1a) and the laboratory strain OG1RF (Figure 1b). Ampicillin did not protect mice against intraperitoneal challenge with E. faecalis HH22 (inoculum of 1 x 109 cfu/mL, which was ~10x the calculated LD50 for the strain) at the administered doses (PD50 >100 mg/kg) (Table 1) with lethality similar to the control group (without antibiotic) (Figure 1a), demonstrating an in vivo effect of the ß-lactamase enzyme in the peritonitis model when a high bacterial inoculum is used. In contrast, ceftobiprole medocaril protected 100% and 83.3% of mice against intraperitoneal challenge with strain HH22 at a dose of 6.25 and 3.12 mg/kg, respectively (Figure 1a), with a PD50 of 2 mg/kg body weight (Table 1). In contrast, for OG1RF, both ceftobiprole and ampicillin were protective for all mice at doses of 12.5 and 25 mg/kg, respectively (Figure 1b) (P = 1.0, log-rank test). Similarly, no difference in mouse survival was found between ceftobiprole and ampicillin at lower doses (83.3% versus 66.6% survival at 96 h at doses of 12.5 mg/kg of ampicillin versus 6.25 mg/kg of ceftobiprole, respectively; P = 0.55) with a PD50 of 4.2 and 8 mg/kg for ceftobiprole and ampicillin (single dose), respectively (Table 1).


Figure 1
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  		Figure 1. Survival and dose–response curves for mice infected intraperitoneally with (a) E. faecalis HH22 (a ß-lactamase producer) and (b) OG1RF. Ceftobiprole (BPR) (dotted lines) and ampicillin (AMP) (continuous lines) were given subcutaneously. All animal groups received the same dose range of antibiotics (see the Materials and methods section) and only the lowest doses of ceftobiprole or ampicillin that protected 100% of mice at 96 h are depicted (doses above the one shown had the same effect). For HH22, ampicillin was administered as a single dose (x1) or in two doses given 2 h apart (x2). Only single dose ampicillin is shown for OG1RF.

 
We also evaluated survival of mice after peritoneal challenge with strain HH22 (ß-lactamase-producing) after administering two doses of ampicillin (given subcutaneously, 2 h apart) and compared survival with that of the ceftobiprole group. We found no difference in mortality between administering one or two doses of ampicillin (PD50 > 100 mg/kg for both groups) (Figure 1a). These findings confirm the in vivo effect of the enterococcal ß-lactamase in the peritonitis model and demonstrate the good in vivo activity of ceftobiprole against this ß-lactamase-producing strain.

The enterococcal ß-lactamase enzyme is identical to the class A staphylococcal enzyme15 and ceftobiprole is a poor substrate for class A enzymes (particularly the staphylococcal penicillinase PC1).5 In a previous study, the rate of ceftobiprole hydrolysis of the class A staphylococcal PC1 enzyme was only 0.93 mol of substrate hydrolysed/mol of enzyme/min, whereas for penicillin it was 10 000 mol of substrate hydrolysed/mol of enzyme/min.5 Therefore, it is likely that the activity of ceftobiprole against ß-lactamase-producing E. faecalis is due to its inherent stability to hydrolysis by this enzyme.

In vivo activity of ceftobiprole against vancomycin-resistant enterococci

Figure 2 shows the dose–response curves for strains TX2484 (Figure 2a) and V583 (Figure 2b) (VanB vancomycin-resistant isolates) after intraperitoneal challenge with 1.7 x 108 and 2.1 x 109 cfu/mL, respectively (~10 x the calculated PD50 for the strain). Both ampicillin (25 mg/kg x 1) and ceftobiprole (12.5 mg/kg x 1) protected 100% of mice (P = 1.0, log-rank test). The PD50s of ceftobiprole and ampicillin were 7.7 mg/kg and 12.5 mg/kg, respectively, for TX2484 (Table 1), and 5.2 and 16.4 mg/kg, respectively, for V583 (Table 1). The results indicate that the efficacy of ceftobiprole in the mouse peritonitis model is independent of vancomycin resistance. Also, our findings support the fact that the activity of ceftobiprole is comparable to that of ampicillin in the mouse peritonitis model for non-ß-lactamase-producing ampicillin-susceptible strains of E. faecalis, a unique characteristic of ceftobiprole amongst the cephalosporins.


Figure 2
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  		Figure 2. Survival and dose–response curves for mice infected intraperitoneally with the vancomycin-resistant strains (a) E. faecalis TX2484 and (b) E. faecalis V583. Ceftobiprole (BPR) (dotted lines) and ampicillin (AMP) (continuous lines) were given subcutaneously as a single dose. All animal groups received the same dose range of antibiotics (see the Materials and methods section) and only the lowest doses of ceftobiprole or ampicillin that protected 100% of mice at 96 h are depicted (doses above the ones shown had the same effect).

 
The affinity of ceftobiprole for PBP2a of staphylococci is notable (IC50 for competition with fluorescein-labelled ampicillin was reported to be 0.87 µM for ceftobiprole, as compared with 115 µM and >500 µM for ceftriaxone and methicillin, respectively).5 It is plausible that members of the pyrrolidinone-3-ylidenemethyl cephems (to which ceftobiprole belongs) also exhibit high affinities for the E. faecalis PBPs and this feature may explain its in vivo and in vitro activity. As a caveat, ceftobiprole lacks affinity for PBP5 of E. faecium5 (IC50 > 500 µM) which is commonly overexpressed and/or mutated26 in multiresistant isolates of E. faecium, indicating that this compound will not be useful in the treatment of resistant E. faecium infections.

In conclusion, we found an in vivo effect of the E. faecalis ß-lactamase when ampicillin was used as therapy in the mouse peritonitis model that is probably related to the high inoculum used, similar in some aspects to the high density of organisms found in cardiac vegetations where the presence of this enzyme in E. faecalis also showed a biological effect when ampicillin was used, despite in vitro susceptibility at standard inoculum.27 However, the dose–response curves and PD50s of ceftobiprole for HH22 and non-ß-lactamase-producing isolates showed no evidence of an in vivo effect of the enterococcal ß-lactamase against ceftobiprole. The in vivo data presented here support the activity of ceftobiprole against isolates of E. faecalis including vancomycin-resistant and ß-lactamase-producing strains. Our findings indicate that ceftobiprole is a promising novel alternative for multidrug-resistant E. faecalis infections and support its further exploration as a therapeutic agent in humans.


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This study was supported by a grant from Johnson & Johnson Pharmaceutical Research and Development, L.L.C. D. P. was partially funded by a graduate scholarship from The Instituto Colombiano para el Desarrollo de la Ciencia y Tecnología, ‘Francisco José de Caldas’, COLCIENCIAS.


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B. E. M. has served as a consultant to Johnson and Johnson, the funding source of this project.


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1 Munoz-Price LS, Lolans K, Quinn JP. Emergence of resistance to daptomycin during treatment of vancomycin-resistant Enterococcus faecalis infection. Clin Infect Dis (2005) 41:565–6.[CrossRef][Web of Science][Medline]

2 Kanafani ZA, Federspiel JJ, Fowler VG Jr. Infective endocarditis caused by daptomycin-resistant Enterococcus faecalis: a case report. Scand J Infect Dis (2007) 39:75–7.[CrossRef][Web of Science][Medline]

3 Long JK, Choueiri TK, Hall GS, et al. Daptomycin-resistant Enterococcus faecium in a patient with acute myeloid leukemia. Mayo Clin Proc (2005) 80:1215–6.[Abstract/Free Full Text]

4 Green MR, Anasetti C, Sandin RL, et al. Development of daptomycin resistance in a bone marrow transplant patient with vancomycin-resistant Enterococcus durans. J Oncol Pharm Pract (2006) 12:179–81.[Abstract/Free Full Text]

5 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]

6 Chambers HF. Ceftobiprole: in-vivo profile of a bactericidal cephalosporin. Clin Microbiol Infect (2006) 12(Suppl_2):17–22.[Medline]

7 Arias CA, Singh KV, Panesso D, et al. Time-kill and synergism studies of ceftobiprole against Enterococcus faecalis including ß-lactamase-producing and vancomycin-resistant isolates. Antimicrob Agents Chemother (2007) 51:2043–7.[Abstract/Free Full Text]

8 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]

9 Vaudaux P, Gjinovci A, Bento M, et al. Intensive therapy with ceftobiprole medocaril of experimental foreign-body infection by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother (2005) 49:3789–93.[Abstract/Free Full Text]

10 Rouse MS, Hein MM, Anguita-Alonso P, et al. Ceftobiprole medocaril (BAL5788) treatment of experimental Haemophilus influenzae, Enterobacter cloacae, and Klebsiella pneumoniae murine pneumonia. Diagn Microbiol Infect Dis (2006) 55:333–6.[CrossRef][Web of Science][Medline]

11 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]

12 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]

13 Noel GJ, Strauss RS, Pypstra R, et al. Successful treatment of complicated skin infection (cSSSI) due to staphylococci, including methicillin-resistant Staphylococcus aureus (MRSA) with ceftobiprole. In: Abstracts of the Forty-sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, 2006. Washington, DC, USA: American Society for Microbiology. Abstract L-1212, p. 374.

14 ClinicalTrials.gov. 25 May 2007. http://www.clinicaltrials.gov/ct/show/NCT00210964?order=1.

15 Murray BE, Mederski-Samaroj B. Transferable ß-lactamase. A new mechanism for in vitro penicillin resistance in Streptococcus faecalis. J Clin Invest (1983) 72:1168–71.[Web of Science][Medline]

16 Coque TM, Murray BE. Identification of Enterococcus faecalis strains by DNA hybridization and pulsed-field gel electrophoresis. J Clin Microbiol (1995) 33:3368–9.[Free Full Text]

17 Sahm DF, Kissinger J, Gilmore MS, et al. In vitro susceptibility studies of vancomycin-resistant Enterococcus faecalis. Antimicrob Agents Chemother (1989) 33:1588–91.[Abstract/Free Full Text]

18 Evers S, Sahm DF, Courvalin P. The vanB gene of vancomycin-resistant Enterococcus faecalis V583 is structurally related to genes encoding D-Ala:D-Ala ligases and glycopeptide-resistance proteins VanA and VanC. Gene (1993) 124:143–4.[CrossRef][Web of Science][Medline]

19 Murray BE, Singh KV, Ross RP, et al. Generation of restriction map of Enterococcus faecalis OG1 and investigation of growth requirements and regions encoding biosynthetic function. J Bacteriol (1993) 175:5216–23.[Abstract/Free Full Text]

20 Qin X, Singh KV, Weinstock GM, et al. Effects of Enterococcus faecalis fsr genes on production of gelatinase and a serine protease and virulence. Infect Immun (2000) 68:2579–86.[Abstract/Free Full Text]

21 Teng F, Nannini EC, Murray BE. Importance of gls24 in virulence and stress response of Enterococcus faecalis and use of the Gls24 protein as a possible immunotherapy target. J Infect Dis (2005) 191:472–80.[CrossRef][Web of Science][Medline]

22 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Fifteenth Informational Supplement M100-S15 (2005) PA, USA: Wayne.

23 Singh KV, Qin X, Weinstock GM, et al. Generation and testing of mutants of Enterococcus faecalis in a mouse peritonitis model. J Infect Dis (1998) 178:1416–20.[CrossRef][Web of Science][Medline]

24 Pai SR, Singh KV, Murray BE. In vivo efficacy of the ketolide ABT-773 (cethromycin) against enterococci in a mouse peritonitis model. Antimicrob Agents Chemother (2003) 47:2706–9.[Abstract/Free Full Text]

25 Reed L, Muench H. A simple method for estimating fifty percent end points. Am J Hyg (1938) 27:493–7.

26 Ligozzi M, Pittaluga F, Fontana R. Modification of penicillin-binding protein 5 associated with high-level ampicillin resistance in Enterococcus faecium. Antimicrob Agents Chemother (1996) 40:354–7.[Abstract/Free Full Text]

27 Hindes RG, Willey SH, Eliopoulos GM, et al. Treatment of experimental endocarditis caused by a ß-lactamase-producing strain of Enterococcus faecalis with high-level resistance to gentamicin. Antimicrob Agents Chemother (1989) 33:1019–22.[Abstract/Free Full Text]


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S. D Anderson and J. G Gums
Ceftobiprole: An Extended-Spectrum Anti-Methicillin-Resistant Staphylococcus aureus Cephalosporin
Ann. Pharmacother., June 1, 2008; 42(6): 806 - 816.
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