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Antimicrobial Agents and Chemotherapy, October 2004, p. 4037-4039, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.4037-4039.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Antistaphylococcal Activity of CB-181963 (CAB-175), an Experimental Parenteral Cephalosporin

Dianne B. Hoellman, Glenn A. Pankuch, and Peter C. Appelbaum*

Department of Pathology, Hershey Medical Center, Hershey, Pennsylvania

Received 23 April 2004/ Accepted 21 June 2004


   ABSTRACT
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Among 265 methicillin-susceptible and -resistant staphylococci, CB-181963 (CAB-175) had a 50% minimum inhibitory concentration of 2 µg/ml and a 90% minimum inhibitory concentration of 4 µg/ml. All strains except two vancomycin-resistant S. aureus and 5 vancomycin-intermediate S. aureus strains were also susceptible to vancomycin and teicoplanin, and all were susceptible to linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin. Most methicillin-resistant strains were levofloxacin resistant. CB-181963 was bactericidal against all six methicillin-resistant strains at four times the MIC after 24 h.


   TEXT
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Emergence of methicillin-, quinolone-, and, recently, vancomycin-intermediate and -resistant staphylococci, as well as the propensity of these organisms to cause serious systemic infections in immunocompromised hosts, necessitates other therapeutic modalities (1, 7, 8, 10, 13, 15, 18). During 2002, two clinical strains of vancomycin-resistant Staphylococcus aureus (VRSA) carrying the vanA gene, one from Detroit, Mich., and one from our hospital (Hershey, Pa.), have been isolated (2, 17). Most methicillin-resistant staphylococci are also resistant to available quinolones, such as ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin (1, 7, 10, 15). Thus, the latter compounds may not be safely used in empirical therapy of patients with methicillin-resistant staphylococcal infections.

CAB-175 (CB-181963) (Fig. 1) is a novel parenteral investigational cephalosporin belonging to the azomethine subclass that exhibits a broad antibacterial spectrum, including against gram-positive organisms. CB-181963 activity was tested by MIC against 265 strains of S. aureus, and its activity was compared to that of vancomycin, teicoplanin, linezolid, ranbezolid, tigecycline, quinupristin-dalfopristin, and levofloxacin. In addition, the activity of the above compounds was evaluated by time kill against six S. aureus strains.



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  		FIG. 1. CB-181963 chemical structure.

 
One-hundred ninety-nine methicillin-resistant and 66 methicillin-susceptible S. aureus strains were tested by agar dilution MIC. These strains included VRS-1 and VRS-2 (the Detroit and Hershey VRSA strains) and five vancomycin-intermediate S. aureus (VISA) strains. VRS-1 and the five VISA strains were obtained courtesy of Focus Technologies, Herndon, Va., via the National Institute for Allergy and Infectious Diseases and the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA). Six methicillin-resistant strains (including the Hershey Medical Center VRSA strain and one VISA strain) were tested by time-kill analysis. CB-181963 susceptibility powder was obtained from Cubist Pharmaceuticals, Lexington, Mass. Other antimicrobials were obtained from their respective manufacturers.

Agar dilution MICs were performed according to established recommendations in cation-adjusted Mueller-Hinton agar (BBL Microbiology Systems, Cockeysville, Md.). Vancomycin MICs were read after a full 24-h incubation (12).

Time-kill activities were measured, as described previously (9, 14), in cation-adjusted Mueller-Hinton broth with antibiotic concentrations of four, two, and one times the MIC. Growth controls were included in each experiment (9, 14). The initial inoculum for each strain was within the range of 5 x 105 to 5 x 106 CFU/ml. Viability counts of antibiotic-containing cultures were performed at 0, 3, 6, 12, and 24 h as described previously (9, 14). Colony counts were performed on plates yielding 30 to 300 bacterial colonies. The upper limit of sensitivity of colony counts was 300 CFU/ml (9, 14).

Time-kill assays were analyzed by determining the number of strains which yielded 1, 2, and 3 log10 CFU/ml decrease at 0, 3, 6, 12, and 24 h compared to counts at time 0 h. Antimicrobials were considered bactericidal at the lowest concentration that reduced the original inoculum by greater than 3 log10 CFU/ml (99.9%) at each of the time periods and was considered bacteriostatic if the inoculum was reduced by less than 3 log10 CFU/ml. The problem of bacterial carryover was addressed by dilution as described previously (9, 14).

Staphylococcal MICs are listed in Table 1. As can be seen, CB-18963 had MICs of ≤4 µg/ml against all staphylococci tested, with slightly higher MICs (0.5 to 4 µg/ml) in methicillin-resistant compared to methicillin-susceptible strains (≤0.12 to 1 µg/ml). CAB-18963 was equally active against VRSA and VISA strains. Vancomycin and teicoplanin were active against all strains except those with raised glycopeptide MICs, while linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin were potent (MICs of ≤0.06 to 8 µg/ml) against all organisms irrespective of their ß-lactam or glycopeptide susceptibility. Levofloxacin resistance occurred frequently among methicillin-resistant S. aureus strains. NARSA repository identifiers as well as relevant MICs of active compounds against the two VRSA and five VISA strains are listed in Table 2.


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  		TABLE 1. MICs (in micrograms per milliliter) for 265 S. aureus strains

 

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  		TABLE 2. MICs of available compounds active against VISA and VRSA strains

 
MICs of strains tested by time kill are listed in Table 3, and kill kinetic results are listed in Table 4. CAB-18963 gave the best kill kinetics of the tested compounds, with bactericidal activity against five of the six strains tested at two times the MIC and against all six strains at four times the MIC after 24 h. Bactericidal activity against the Hershey VRSA strain occurred at two times the MIC after 24 h. By comparison, vancomycin and levofloxacin were bactericidal against three strains and teicoplanin was bactericidal against one strain at two times the MIC after 24 h. Both ozaxolidinones, tigecycline and quinupristin/dalfopristin, were bacteriostatic.


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  		TABLE 3. MICs for six S. aureus strains tested by time kill

 

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  		TABLE 4. Time-kill results of six S. aureus strains

 
CB-181963 (CAB-175) is a novel parenteral investigational cephalosporin belonging to the azomethines that exhibits a broad antibacterial spectrum against both gram-positive and gram-negative bacteria (D. C. Draghi, C. Thornsberry, D. F. Sahm, and J. A. Karlowsky, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-544, 2003; R. Cha, Abstr. 43rd ICAAC, abstr. E-2011; V. Huang, W. J. Brown, and M. J. Rybak, Abstr. 43rd ICAAC, abstr. E-2012; J. A. Silverman, N. Cotreono, V. Laganas, G. Thorne, and J. Alder, Abstr. 13th Eur. Congr. Clin. Microbiol. Infect. Dis., abstr. P-793, 2003; V. Huang, and M. J. Rybak, Abstr. 13th Eur. Congr. Clin. Microbiol. Infect. Dis., abstr. P-791, 2003). The above workers obtained MICs similar to ours in a study of the Michigan VRSA and VISA as well as for other methicillin-susceptible and -resistant S. aureus strains. Our findings of CB-18963 activity against the Hershey VRSA as well as five other VISA strains were similar to those obtained by the Michigan group (Abstr. 44th ICAAC, abstr. P-791, 2004). CB-18963 was also bactericidal against all six strains tested (including the Hershey VRSA and one VISA strain) at four times the MIC after 24 h.

Activity of other compounds tested were similar to those described previously by various workers (3-6, 9, 11, 16).

Results of these studies indicate a potential place for CB-18963 in therapy of staphylococcal infections, including those caused by methicillin- and vancomycin-resistant strains. Toxicity and pharmacokinetic/pharmacodynamic studies (which are not available at this time) are necessary before results of in vitro tests can be tested in humans.


   ACKNOWLEDGMENTS
 
This study was supported by a grant from Cubist Pharmaceuticals.

We thank NARSA via Focus Technologies, Inc., for provision of the Michigan VRSA as well as the five VISA strains.


   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. Back


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Antimicrobial Agents and Chemotherapy, October 2004, p. 4037-4039, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.4037-4039.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.




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