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Antimicrobial Agents and Chemotherapy, November 2006, p. 3956-3958, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00724-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Postantibiotic Effect of Ceftobiprole against 12 Gram-Positive Organisms

Department of Pathology, Hershey Medical Center, Hershey, Pennsylvania 17033

Received 12 June 2006/ Returned for modification 1 July 2006/ Accepted 8 July 2006

	ABSTRACT

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The in vitro postantibiotic effects (PAEs), postantibiotic sub-MIC effects (PA-SMEs), and sub-MIC effects of ceftobiprole were determined for 12 gram-positive organisms. Pneumococcal, staphylococcal, and enterococcal PAEs were 1.4 to 3.1 h, 0 to 1.8 h, and 0 to 0.9 h, respectively. The PA-SMEs (0.4 times the MIC) for pneumococci, staphylococci, and enterococci were 4.8 to >10.3 h, 1.5 to 9.6 h, and 3.8 to >10.7 h, respectively.

	TEXT

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The postantibiotic effect (PAE) is a pharmacodynamic parameter that may be considered in choosing antibiotic dosing regimens. It is defined as the length of time that bacterial growth is suppressed following brief exposure to an antibiotic (2-4). Odenholt-Tornqvist and colleagues (11, 12) have suggested that during intermittent dosage regimens, suprainhibitory levels of antibiotic are followed by subinhibitory levels that persist between doses, and they have hypothesized that persistent subinhibitory levels could extend the PAE. The effect of sub-MIC concentrations on growth during the PAE period has been defined as the postantibiotic sub-MIC effect (PA-SME), representing the time interval that includes the PAE plus the additional time during which growth is suppressed by sub-MIC concentrations. In contrast to the PA-SME, the sub-MIC effect (SME) measures the direct effect of subinhibitory levels on cultures which have not been previously exposed to antibiotics (11, 12).

We examined the in vitro PAE, PA-SME, and SME of ceftobiprole, a new intravenous cephalosporin with expanded activity, against 12 gram-positive bacteria including methicillin-resistant staphylococci (1, 5, 6). We studied one strain each of penicillin-susceptible, -intermediate, and -resistant Streptococcus pneumoniae; two methicillin-susceptible Staphylococcus aureus strains; four strains of methicillin-resistant S. aureus (MRSA) (one vancomycin susceptible, two vancomycin intermediate, and one vancomycin resistant); and three strains of Enterococcus faecalis. Organisms were identified by standard methods (9).

Ceftobiprole MICs were determined by macrodilution procedures (10). The PAE was determined by the viable plate count method (4), using Mueller-Hinton broth (Difco Laboratories, Detroit, Mich.) supplemented with 5% lysed horse blood when testing pneumococci. The PAE was induced by exposure to 10 times the MIC of ceftobiprole for 1 h.

For PAE testing, tubes containing 5 ml broth with antibiotic were inoculated with approximately 5 x 10⁶ CFU/ml. Inocula were prepared by suspending growth from an overnight blood agar plate in broth. Growth controls with inoculum but no antibiotic were included with each experiment. Inoculated test tubes were placed in a shaking water bath at 35°C for an exposure period of 1 h. At the end of the exposure period, cultures were diluted 1:1,000 in prewarmed broth to remove the antibiotic by dilution. Antibiotic removal was confirmed by comparing growth curves of a control culture containing no antibiotic to another containing ceftobiprole at 0.001 times the exposure (10 times MIC) concentration.

Viability counts were determined before exposure and immediately after dilution (0 h) and then every 2 h until turbidity of the tube reached a no. 1 McFarland standard. The PAE was defined as T – C; T = time required for viability counts of an antibiotic-exposed culture to increase by 1 log₁₀ above counts immediately after dilution; C = corresponding time for growth control (4).

In cultures designated for PA-SME testing, the PAE was induced as described above, after exposure to 10 times the MIC (see above). Following a 1:1,000 dilution, cultures were divided into four tubes. To three tubes, ceftobiprole was added to produce final subinhibitory concentrations of 0.2, 0.3, and 0.4 times the MIC. The fourth tube did not receive antibiotic. Viability counts were determined before exposure, immediately after dilution, and then every 2 h until their culture turbidity reached a no. 1 McFarland standard. Cultures designated for SME testing were treated the same as for PA-SME testing except that the PAE was not induced.

The PA-SME was defined as T_pa – C; T_pa = time required for cultures previously exposed to antibiotic and then reexposed to different sub-MIC concentrations to increase by 1 log₁₀ above counts immediately after dilution; C is the corresponding time for the unexposed control (11, 12). The SME was defined as T_s – C; T_s is the time required for the cultures exposed only to sub-MIC concentrations to increase 1 log₁₀ above counts immediately after dilution; C is the corresponding time for the unexposed control. The PA-SME and SME (11, 12) were measured in two separate experiments. For each experiment, viability counts (log₁₀ CFU/ml) were plotted against time, and results were expressed as two separate values (Table 1) with assays done twice, each time starting with a new inoculum.

The length of the PAEs for all strains varied from 0 h to3.1 h. PA-SMEs were longer than PAEs for all strains tested and increased with the subinhibitory concentration of ceftobiprole.

For the three pneumococci, the mean PAE was 1.8 h, ranging between 1.4 and 3.1 h. The PAEs for pneumococci did not differ based upon penicillin sensitivity. However, at subinhibitory concentrations of 0.3 and 0.4 times the MIC, the PA-SMEs of the penicillin-resistant strain were lower (4.1 to 5.3 h) than values for penicillin-susceptible and intermediate strains (6.7 to >10.3 h) (Table 1).

Staphylococcal PAEs were slightly lower for methicillin-susceptible strains (mean, 0.4 h; range, 0 to 0.8 h) than for methicillin-resistant strains (mean, 1.0 h; range, 0 to 1.8 h). The PAEs for the vancomycin-sensitive strains (mean, 0.6 h; range, 0 to 1.1 h) did not differ from those for vancomycin-intermediate and -resistant strains (mean, 1.0 h; range, 0 to 1.8 h). PA-SMEs at 0.4 times the MIC were longer than PAEs plus SMEs for one methicillin-sensitive and two methicillin-resistant strains.

The three E. faecalis strains had a mean PAE of 0.4 h (0 to 0.9 h). At 0.4 times the MIC, PA-SMEs (3.8 to >10.7 h) were longer than PAEs plus SMEs for all three strains.

The ceftobiprole PAEs found in this study are similar to those from other in vitro studies of ß-lactams tested against gram-positive cocci (4). In a neutropenic murine model, ceftobiprole produced long PAEs of 3.8 to 4.8 h with MRSA but only 0 to 0.8 h with penicillin-resistant pneumococci. (D. Andes and W. A. Craig, Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 1079, 2000). Different results compared with those obtained by Craig and Andes (40th ICAAC) may at least partially be explained by different techniques, different strains, and other factors, such as drug half-life, which may play a role in vivo but not in vitro. In this study, the PA-SMEs were usually longer than PAEs for all strains tested. The long PA-SMEs suggest that continued exposure to sub-MIC levels of ceftobiprole following a suprainhibitory level may allow for greater suppression of growth in vivo. These PA-SMEs may be more clinically relevant than the PAEs during intermittent dosage regimens, since suprainhibitory concentrations will be followed by exposure to subinhibitory concentrations in vivo. Longer intervals between doses may be possible when an antibiotic has a prolonged PAE and PA-SME, because regrowth continues to be prevented when serum and tissue levels fall below MICs (2, 4, 7). The PAE and PA-SME would be important only for organisms with high MICs where levels in serum (at least of free drug) would fall below the MIC.

For ceftobiprole and other ß-lactam antibiotics, the length of time that the serum concentration exceeds the MIC (T>MIC) is considered to be the best index of antibacterial efficacy (8; Andes and Craig, 40th ICAAC). Ceftobiprole (BAL 9141) is administered as a prodrug (BAL 5788; ceftobiprole medocaril), which is rapidly converted to BAL 9141 in the plasma (13).

Schmitt-Hoffmann and colleagues have found that infusions of BAL 5788 at 500 to 1,000 mg yield total ceftobiprole concentrations that exceed the MIC at which 100% of MRSA isolates are inhibited (4 µg/ml) for 5 to 7 h or 42 to 58% of a 12-h dosing interval (13). At these doses, concentrations in serum would exceed the MICs for the strains used in this study over the entire dosing interval. The pharmacokinetic profile of ceftobiprole together with the PAE and PA-SME found in this study support the twice-daily dosing of ceftobiprole for infections caused by gram-positive cocci.

	ACKNOWLEDGMENTS

 
This study was supported by a grant from Ortho McNeil Pharmaceutical Research Institute, Raritan, N.J.

	FOOTNOTES

 
* Corresponding author. Mailing address: Department of Pathology, Hershey Medical Center, P.O. Box 850, Hershey, PA 17033. Phone: (717) 531-5113. Fax: (717) 531-7953. E-mail: pappelbaum{at}psu.edu.

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