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Antimicrobial Agents and Chemotherapy, June 2009, p. 2360-2366, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01452-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

In Vitro Activity of Ceftaroline Alone and in Combination against Clinical Isolates of Resistant Gram-Negative Pathogens, Including β-Lactamase-Producing Enterobacteriaceae and Pseudomonas aeruginosa{triangledown}

Céline Vidaillac,1 Steve N. Leonard,1,3,{dagger} Helio S. Sader,4 Ronald N. Jones,4,5 and Michael J. Rybak1,2,3*

Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences,1 School of Medicine, Wayne State University, Detroit, Michigan 48201,2 Detroit Receiving Hospital, Detroit, Michigan 48201,3 JMI Laboratories, Inc., 345 Beaver Kreek Center, Suite A, North Liberty, Iowa 52317,4 Tufts University School of Medicine, Boston, Massachusetts5

Received 30 October 2008/ Returned for modification 10 December 2008/ Accepted 27 March 2009

Ceftaroline is a novel broad-spectrum cephalosporin that exhibits bactericidal activity against many gram-positive and -negative pathogens. However, the activity of ceftaroline cannot be solely relied upon for eradication of multidrug-resistant gram-negative isolates, such as Pseudomonas aeruginosa and extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, which represent a current clinical concern. As drug combinations might be beneficial by potential synergy, we evaluated the in vitro activity of ceftaroline combined with meropenem, aztreonam, cefepime, tazobactam, amikacin, levofloxacin, and tigecycline. Susceptibility testing was performed for 20 clinical P. aeruginosa isolates, 10 ESBL-producing Escherichia coli isolates, 10 ESBL-producing Klebsiella pneumoniae isolates, and 10 AmpC-derepressed Enterobacter cloacae isolates. Time-kill experiments were performed for 10 isolates using antimicrobials at one-fourth the MIC. Ceftaroline exhibited a MIC range of 0.125 to 1,024 µg/ml and was reduced 2- to 512-fold by combination with tazobactam (4 µg/ml) for ESBL-producing strains. In time-kill experiments, ceftaroline plus amikacin was synergistic against 90% of the isolates (and indifferent for one P. aeruginosa isolate). Ceftaroline plus tazobactam was indifferent for E. cloacae and P. aeruginosa strains but synergistic against 100% of E. coli and K. pneumoniae isolates. Combinations of ceftaroline plus meropenem or aztreonam were also synergistic for all E. coli and E. cloacae isolates, respectively, but indifferent against 90% of the other isolates. Finally, combinations of ceftaroline plus either tigecycline, levofloxacin, or cefepime were indifferent for 100% of the isolates. No antagonism was observed with any combination. Ceftaroline plus amikacin appeared as the most likely synergistic combination. This represents a promising therapeutic option, and further studies are warranted to elucidate the clinical value of ceftaroline combinations against resistant gram-negative pathogens.

* Corresponding author. Mailing address: Anti-Infective Research Laboratory, Pharmacy Practice 4148, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201. Phone: (313) 577-4376. Fax: (313) 577-8915. E-mail: m.rybak{at}wayne.edu

{triangledown} Published ahead of print on 6 April 2009.

{dagger} Present address: Northeastern University, School of Pharmacy, Boston, MA.

Antimicrobial Agents and Chemotherapy, June 2009, p. 2360-2366, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01452-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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