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Antimicrobial Agents and Chemotherapy, August 2009, p. 3437-3441, Vol. 53, No. 8
0066-4804/09/$08.00+0 doi:10.1128/AAC.00317-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Inoculum Effect with Cefazolin among Clinical Isolates of Methicillin-Susceptible Staphylococcus aureus: Frequency and Possible Cause of Cefazolin Treatment Failure
Esteban C. Nannini,1
Martin E. Stryjewski,2,3
Kavindra V. Singh,5
Agathe Bourgogne,5
Tom H. Rude,4
G. Ralph Corey,4
Vance G. Fowler Jr.,4 and
Barbara E. Murray5,6*
Division of Infectious Diseases, School of Medicine, Universidad Nacional de Rosario, Rosario, Argentina,1 Duke Clinical Research Institute, Durham, North Carolina,2 Department of Medicine and Division of Infectious Diseases, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno (CEMIC), Buenos Aires, Argentina,3 Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina,4 Center for the Study of Emerging and Re-Emerging Pathogens, Division of Infectious Diseases, Department of Internal Medicine,5 Department of Microbiology and Molecular Genetics, The University of Texas Medical School, Houston, Texas6
Received 9 March 2009/ Returned for modification 13 April 2009/ Accepted 21 May 2009
Methicillin (meticillin)-susceptible Staphylococcus aureus (MSSA) strains producing large amounts of type A β-lactamase (Bla) have been associated with cefazolin failures, but the frequency and impact of these strains have not been well studied. Here we examined 98 MSSA clinical isolates and found that 26% produced type A Bla, 15% type B, 46% type C, and none type D and that 13% lacked blaZ. The cefazolin MIC90 was 2 µg/ml for a standard inoculum and 32 µg/ml for a high inoculum, with 19% of isolates displaying a pronounced inoculum effect (MICs of 
16 µg/ml with 107 CFU/ml) (9 type A and 10 type C Bla producers). At the high inoculum, type A producers displayed higher cefazolin MICs than type B or C producers, while type B and C producers displayed higher cefamandole MICs. Among isolates from hemodialysis patients with MSSA bacteremia, three from the six patients who experienced cefazolin failure showed a cefazolin inoculum effect, while none from the six patients successfully treated with cefazolin showed an inoculum effect, suggesting an association between these strains and cefazolin failure (P = 0.09 by Fisher's exact test). In summary, 19% of MSSA clinical isolates showed a pronounced inoculum effect with cefazolin, a phenomenon that could explain the cases of cefazolin failure previously reported for hemodialysis patients with MSSA bacteremia. These results suggest that for serious MSSA infections, the presence of a significant inoculum effect with cefazolin could be associated with clinical failure in patients treated with this cephalosporin, particularly when it is used at low doses.
* Corresponding author. Mailing address: Department of Internal Medicine, Division of Infectious Diseases, Center for the Study of Emerging and Re-Emerging Pathogens, 2.112 MSB, University of Texas Medical School, 6431 Fannin St., Houston, TX 77030. Phone: (713) 500-6745. Fax: (713) 500-6766. E-mail: bem.asst{at}uth.tmc.edu
Published ahead of print on 1 June 2009.
Antimicrobial Agents and Chemotherapy, August 2009, p. 3437-3441, Vol. 53, No. 8
0066-4804/09/$08.00+0 doi:10.1128/AAC.00317-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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