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Antimicrobial Agents and Chemotherapy, November 2008, p. 4209-4210, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00712-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

In Vitro Activity of Ceftaroline against Streptococcus pneumoniae Isolates Exhibiting Resistance to Penicillin, Amoxicillin, and Cefotaxime

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Ten to forty percent of bacteremic pneumococcal infections occur in hospitalized patients, with the respiratory tract being the main portal of entry (2, 3). Empirical therapy of hospital-acquired pneumonia should cover Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) as "core pathogens" (1).

This study explored the in vitro activity of ceftaroline, a parenteral anti-MRSA cephalosporin in phase 3 development, against S. pneumoniae isolates not susceptible to previous parenteral antimicrobials.

Among the S. pneumoniae isolates received in the Spanish Pneumococcal Reference Laboratory (January 2005 to September 2007), 655 strains were selected. 60 were nonsusceptible to penicillin, 250 to amoxicillin, and 170 to cefotaxime; 339 were resistant to erythromycin, and 152 were resistant to levofloxacin, according to current CLSI breakpoints (parenteral drugs/nonmeningitis) (5). Of these isolates, 337 (51.5%) were invasive (84.3% from bacteremia).

Antimicrobial susceptibility was determined by agar dilution (4) in Mueller-Hinton agar (Difco Laboratories, Detroit, MI) supplemented with 5% sheep blood (Biomedics, Madrid, Spain), with 10⁵ CFU/ml final inocula, incubating under 5% CO₂ (6, 7). S. pneumoniae ATCC 6303, S. pneumoniae ATCC 49619, and five clinical isolates were used as controls (6, 7). CLSI breakpoints (susceptibility/resistance [µg/ml]) for parenteral drugs/nonmeningitis (5) considered were as follows: penicillin (2/8); amoxicillin (2/8); cefuroxime-sodium (0.5/2); cefotaxime, ceftriaxone, and cefepime (1/4); erythromycin (0.25/1); and levofloxacin (2/8). No CLSI breakpoints are defined for ampicillin and ceftaroline.

Among the 595 penicillin-susceptible (MIC 2 µg/ml) strains, MIC₅₀/MIC₉₀ (µg/ml) and percent susceptibility were as follows: 4/8 and 31.6% for cefuroxime, 2/8 and no breakpoint for ampicillin, 2/8 and 66.7% for amoxicillin, 1/2 and 66.4% for cefepime, 1/2 and 80.7% for cefotaxime, 1/2 and 100% for penicillin, and 0.5/1 and 98.8% for ceftriaxone, respectively. MIC₅₀/MIC₉₀ of ceftaroline were 0.12/0.12.

Among the 60 penicillin-nonsusceptible strains, only three isolates were fully resistant to penicillin (MIC = 8 µg/ml). Table 1 shows MIC₅₀, MIC₉₀, and percent susceptibility for isolates distributed by penicillin, amoxicillin, or cefotaxime nonsusceptibility and erythromycin or levofloxacin resistance. In this study, the decrease in susceptibility to penicillin was associated with decreased susceptibility to other β-lactams, increasing MIC₉₀s to 2 µg/ml for ceftriaxone, 4 µg/ml for cefotaxime and cefepime, and 16 µg/ml for amoxicillin, cefuroxime, and ampicillin. In comparison, the influence of penicillin nonsusceptibility on ceftaroline activity was lower, with a ceftaroline MIC₉₀ of 0.25 µg/ml for penicillin-nonsusceptible strains and amoxicillin- or cefotaxime-resistant strains. Against amoxicillin- and cefotaxime-resistant strains, the ceftaroline MIC₉₀ (0.25 µg/ml) was 4 and 16 times lower, respectively, than that of ceftriaxone (1 and 4 µg/ml, respectively). Table 2 shows MIC distributions of most active β-lactams for strains nonsusceptible to penicillin, amoxicillin-resistant strains, or cefotaxime-resistant strains. With respect to non-β-lactams, ceftaroline MIC₉₀s against erythromycin- and levofloxacin-resistant strains were 0.25 µg/ml and 0.12 µg/ml, respectively.

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TABLE 1. MIC50, MIC90, and percent susceptibility to study drugs for penicillin-nonsusceptible, amoxicillin- and cefotaxime-intermediate and -resistant, and erythromycin- and levofloxacin-resistant strainsa

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TABLE 2. MIC distribution according to penicillin nonsusceptibility and amoxicillin and cefotaxime resistancea

The ceftaroline MIC₉₀ in this study was equal to that obtained in three earlier studies using broth microdilution (8, 10) or agar dilution (9), despite the absence or limited number of nonsusceptible S. pneumoniae isolates in those studies according to the new penicillin CLSI breakpoint (5). The intrinsic activity of ceftaroline against strains resistant to previous parenteral antimicrobials, together with potent anti-MRSA activity (8, 10), may represent an advantage when broader-spectrum empirical therapy is needed.

 
This study was supported by an unrestricted grant from Forest Laboratories, Inc.

 
Published ahead of print on 25 August 2008.

Top LETTER REFERENCES

 

1
1. Andriesse, G. I., and J. Verhoef. 2006. Nosocomial pneumonia: rationalizing the approach to empirical therapy. Treat. Respir. Med. 5:11-30.[CrossRef][Medline]
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2. Bouza, E., V. Pintado, S. Rivera, R. Blazquez, P. Muñoz, E. Cercenado, E. Loza, M. Rodriguez-Creixems, S. Moreno, et al. 2005. Nosocomial bloodstream infections caused by Streptococcus pneumoniae. Clin. Microbiol. Infect. 11:919-924.[CrossRef][Medline]
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3. Canet, J. J., N. Juan, M. Xercavins, N. Freixas, and J. Garau. 2002. Hospital-acquired pneumococcal bacteremia. Clin. Infect. Dis. 35:697-702.[CrossRef][Medline]
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4. Clinical and Laboratory Standards Institute. 2006. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard, 7th ed. CLSI document M7-A7. Clinical Laboratory Standards Institute, Wayne, PA.
5
5. Clinical and Laboratory Standards Institute/NCCLS. 2008. Performance standards for antimicrobial susceptibility testing; eighteenth informational supplement. CLSI/NCCLS document M100-S18. Clinical and Laboratory Standards Institute, Wayne, PA.
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6. Fenoll, A., M. J. Gimenez, O. Robledo, L. Aguilar, D. Tarrago, J. J. Granizo, and J. E. Martin-Herrero. 2008. Influence of penicillin/amoxicillin non-susceptibility on the activity of third-generation cephalosporins against Streptococcus pneumoniae. Eur. J. Clin. Microbiol. Infect. Dis. 27:75-80.[CrossRef][Medline]
7
7. Fenoll, A., M. J. Gimenez, O. Robledo, P. Coronel, M. Gimeno, J. Casal, and L. Aguilar. 2007. Activity of cefditoren against clinical isolates of Streptococcus pneumoniae showing non-susceptibility to penicillins, cephalosporins, macrolides, ketolides or quinolones. Int. J. Antimicrob. Agents 29:224-226.[CrossRef][Medline]
8
8. Iizawa, Y., J. Nagai, T. Ishikawa, S. Hashiguchi, M. Nakao, A. Miyake, and K. Okonogi. 2004. In vitro antimicrobial activity of T-91825, a novel anti-MRSA cephalosporin, and in vivo anti-MRSA activity of its prodrug, TAK-599. J. Infect. Chemother. 10:146-156.[Medline]
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9. Mushtaq, S., M. Warner, Y. Ge, K. Kaniga, and D. M. Livermore. 2007. In vitro activity of ceftaroline (PPI-0903M, T-91825) against bacteria with defined resistance mechanisms and phenotypes. J. Antimicrob. Chemother. 60:300-311.[Abstract/Free Full Text]
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10. Sader, H. S., T. R. Fritsche, K. Kaniga, Y. Ge, and R. N. Jones. 2005. Antimicrobial activity and spectrum of PPI-0903M (T-91825), a novel cephalosporin, tested against a worldwide collection of clinical strains. Antimicrob. Agents Chemother. 49:3501-3512.[Abstract/Free Full Text]

						Asunción Fenoll Spanish National Reference Pneumococcal Laboratory Instituto de Salud Carlos III ctra. Majadahonda-Pozuelo Km. 2 28220 Majadahonda, Madrid, Spain Lorenzo Aguilar* Microbiology Department School of Medicine Univ. Complutense Avda. Complutense s/n 28040 Madrid, Spain Olga Robledo Spanish National Reference Pneumococcal Laboratory Instituto de Salud Carlos III ctra. Majadahonda-Pozuelo Km. 2 28220 Majadahonda, Madrid, Spain María-José Giménez Microbiology Department School of Medicine Univ. Complutense Avda. Complutense s/n 28040 Madrid, Spain Juan-José Granizo Grana Datos SL c/ Demetrio de la Guerra 4 28223 Pozuelo de Alarcón, Madrid, Spain Donald Biek Cerexa, Inc. 1751 Harbor Bay Parkway Alameda, California 94502 David Tarragó Spanish National Reference Pneumococcal Laboratory Instituto de Salud Carlos III ctra. Majadahonda-Pozuelo Km. 2 28220 Majadahonda, Madrid, Spain
						* Phone: 34 91-3941505, Fax: 34 91-3941511, E-mail: aguilar{at}med.ucm.es

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Antimicrobial Agents and Chemotherapy, November 2008, p. 4209-4210, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00712-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fenoll, A. Articles by Tarragó, D. Search for Related Content PubMed PubMed Citation Articles by Fenoll, A. Articles by Tarragó, D.