This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chen, Y.
Right arrow Articles by Saiman, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, Y.
Right arrow Articles by Saiman, L.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, June 2005, p. 2510-2511, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2510-2511.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

In Vitro Activity of Doripenem (S-4661) against Multidrug-Resistant Gram-Negative Bacilli Isolated from Patients with Cystic Fibrosis

Yunhua Chen,1 Elizabeth Garber,1 Qiuqu Zhao,1 Yigong Ge,2 Matthew A. Wikler,2 Koné Kaniga,2 and Lisa Saiman1*

Department of Pediatrics, Columbia University, New York, New York,1 Peninsula Pharmaceuticals, Inc., Alameda, California2

Received 12 November 2004/ Returned for modification 12 January 2005/ Accepted 9 February 2005


arrow
ABSTRACT
 
Doripenem 50% inhibitory concentrations (MIC50) and 90% inhibitory concentrations (MIC90) for multidrug-resistant strains of mucoid Pseudomonas aeruginosa (n = 200 strains), nonmucoid P. aeruginosa (n = 200), and Burkholderia cepacia complex (n = 200) isolated from patients with cystic fibrosis were 8 and 32, 8 and 64, and 8 and 32 µg/ml, respectively. Doripenem had somewhat better activity than established antimicrobial agents.


arrow
TEXT
 
Patients with cystic fibrosis (CF) can be chronically infected with several pathogens, including Staphylococcus aureus, nontypeable Haemophilus influenzae, and P. aeruginosa; by 18 years of age, 80% of patients are infected with P. aeruginosa (3). With time, P. aeruginosa converts to a mucoid phenotype which often heralds deterioration in respiratory status. Approximately 4% of patients in the United States become infected with Burkholderia cepacia complex, which can be particularly virulent and is associated with increased mortality (4).

The aggressive use of oral, intravenous, and aerosolized antibiotics has substantially contributed to the increased life expectancy for patients with CF. Several classes of intravenously administered agents are available to treat patients with CF experiencing acute pulmonary exacerbations. However, there is a need for additional therapeutic agents, particularly for the treatment of multidrug-resistant gram-negative pathogens (8). Multidrug resistance in CF strains is defined as resistance to all of the agents in two of three classes of antibiotics, i.e., quinolones, aminoglycosides, and beta-lactam agents, including monobactams and carbapenems (9).

Doripenem is a carbapenem in clinical development for serious bacterial infections. It has potent in vitro activity against a wide range of gram-positive and gram-negative clinical isolates (2, 5, 11) and in vivo efficacy in various animal models (10). We studied the in vitro activity of doripenem against 600 multidrug-resistant clinical strains of P. aeruginosa and B. cepacia complex isolated from patients with CF and compared its activity with seven other conventional antipseudomonal antibiotics.

These isolates were sent to the CF Referral Center at Columbia University, which has established a large collection of multidrug-resistant isolates from patients with CF in the United States. In all, 200 mucoid P. aeruginosa, 200 nonmucoid P. aeruginosa, and 200 B. cepacia complex strains isolated from 2001 through 2003 (each from a unique patient with CF) were tested in this study. Antimicrobial susceptibility testing was performed using a commercially prepared (TREK Diagnostic Systems, Cleveland, OH) broth microdilution assay (6). The studies were not performed in replicate. Interpretative criteria for susceptibility breakpoints for non-Enterobacteriaceae, including P. aeruginosa and B. cepacia, were used and are shown in Table 1 (7). The breakpoint for imipenem was used tentatively for doripenem for comparative purposes, because National Committee for Clinical Laboratory Standards susceptibility criteria for doripenem are not yet available (7).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Activity of doripenem compared with conventional agents against 600 multidrug-resistant strains of P. aeruginosa and B. cepacia complex isolated from patients with cystic fibrosis

The activity of the eight antimicrobial agents against these clinical isolates is shown in Table 1. Overall, doripenem exhibited the lowest 50% inhibitory concentration (MIC50) and lowest 90% inhibitory concentration (MIC90) values (8 and 32 µg/ml for mucoid P. aeruginosa, 8 and 64 µg/ml for nonmucoid P. aeruginosa, and 8 and 32 µg/ml for B. cepacia complex strains). The proportions of P. aeruginosa isolates susceptible to doripenem and tobramycin were comparable (40% versus 49% of mucoid and 33% versus 34% of nonmucoid strains, respectively). Less than one-third of the P. aeruginosa strains were susceptible to imipenem (26%), aztreonam, piperacillin, ceftazidime, and cefepime. Ceftazidime and doripenem were the two most active agents against B. cepacia complex strains, inhibiting 43% and 25%, respectively.

In addition, we assessed cross-resistance between doripenem and tobramycin among P. aeruginosa strains, as tobramycin is frequently used for patients with CF. In all, 43% (173 of 400) of P. aeruginosa strains were resistant to tobramycin (MIC ≥ 16 µg/ml) and of these 173 strains, 54% were susceptible or intermediately susceptible to doripenem (MIC ≤ 8 µg/ml). Similarly, 49% (197 of 400) of strains were resistant to doripenem and of these 197 strains, 59% were susceptible or intermediately susceptible to tobramycin.

The selected strains represent problematic clinical isolates for patients with CF, as therapeutic options are limited because of multidrug resistance. These strains were obtained from patients across the United States, which supports the notion that multidrug resistance is widespread in this patient population. While accurate rates for multidrug-resistant strains of P. aeruginosa and B. cepacia complex are unavailable, from 1996 to 2003 the CF Referral Center (http://synergy.columbia.edu) processed approximately 20,000 strains from 6,700 patients from 140 CF care centers in the United States.

Over the past several years, there has been increasing clinical experience with carbapenem antibiotics for patients with CF. Much of this interest has focused on meropenem for management of acute pulmonary exacerbations, in part because of its superior activity against B. cepacia complex and because of its activity against multidrug-resistant strains of P. aeruginosa (1). Overall, we have noted that 40% of multidrug-resistant strains of P. aeruginosa and 29% of B. cepacia complex strains processed by the CF Referral Center are susceptible to meropenem (L. Saiman, unpublished data). In this study, comparable proportions of P. aeruginosa (37%) and B. cepacia complex strains (25%) were susceptible to doripenem.

In conclusion, doripenem exhibited somewhat better in vitro activity against multidrug-resistant strains isolated from patients with CF than other conventional antipseudomonal agents. Future studies of doripenem should assess the inhibitory effect of CF sputum on doripenem's potency, the pharmacokinetics of doripenem in patients with CF, and the concentration of doripenem achievable within the lung following intravenous administration. Such studies would support the potential role of doripenem for treatment of acute pulmonary exacerbations associated with P. aeruginosa and B. cepacia complex, particularly when combined with another effective agent.


arrow
ACKNOWLEDGMENTS
 
This work was funded by Peninsula Pharmaceuticals Inc.


arrow
FOOTNOTES
 
* Corresponding author. Mailing address: Columbia University, 622 West 168th St., PH4W-470, New York, NY 10032. Phone: (212) 305-9446. Fax: (212) 305-9491. E-mail: LS5{at}columbia.edu. Back


arrow
REFERENCES
 
    1
  1. Blumer, J., L. Saiman, M. W. Konstan, and D. Melnick. The efficacy and safety of meropenem and tobramycin versus ceftazidime and tobramycin in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis. Chest, in press.
    2. 2
  2. Ge, Y., M. A. Wikler, D. F. Sahm, R. S. Blosser-Middleton, and J. A. Karlowsky. 2004. In vitro antimicrobial activity of doripenem, a new carbapenem. Antimicrob. Agents Chemother. 48:1384-1396.[Abstract/Free Full Text]
    3. 3
  3. Gilligan, P. H. 1991. Microbiology of airway disease in patients with cystic fibrosis. Clin. Microbiol. Rev. 4:35-51.[Abstract/Free Full Text]
    4. 4
  4. LiPuma, J. J. 1998. Burkholderia cepacia epidemiology and pathogenesis: implications for infection control. Curr. Opin. Pulm. Med. 4:337-341.[CrossRef][Medline]
    5. 5
  5. Mushtaq, S., Y. Ge, and D. M. Livermore. 2004. Comparative activities of doripenem versus isolates, mutants, and transconjugants of Enterobacteriaceae and Acinetobacter spp. with characterized beta-lactamases. Antimicrob. Agents Chemother. 48:1313-1319.[Abstract/Free Full Text]
    6. 6
  6. National Committee for Clinical Laboratory Standards. 2002. NCCLS document M100-S12: performance standards for antimicrobial susceptibility testing. Twelfth informational supplement, p. 43-44. NCCLS, Wayne, PA.
    7. 7
  7. National Committee for Clinical Laboratory Standards. 2004. NCCLS document M100-S14: performance standards for antimicrobial susceptibility testing. Fourteenth informational supplement, vol. 24 (No. 1), p. 36-38, 102-104. NCCLS, Wayne, PA.
    8. 8
  8. Saiman, L., F. Mehar, W. W. Niu, H. C. Neu, K. J. Shaw, G. Miller, and A. Prince. 1996. Antibiotic susceptibility of multiply resistant Pseudomonas aeruginosa isolated from patients with cystic fibrosis, including candidates for transplantation. Clin. Infect. Dis. 23:532-537.[Medline]
    9. 9
  9. Saiman, L., J. Siegel, and the CF Foundation Consensus Conference on Infection Control Participants. 2003. Infection control recommendations for patients with cystic fibrosis: microbiology, important pathogens, and infection control practices to prevent patient-to-patient transmission. Infect. Control Hosp. Epidemiol. 24:S1-S52.
    10. 10
  10. Tsuji, M., Y. Ishii, A. Ohno, S. Miyazaki, and K. Yamaguchi. 1998. In vitro and in vivo antibacterial activities of S-4661, a new carbapenem. Antimicrob Agents Chemother. 42:94-99.[Abstract/Free Full Text]
    11. 11
  11. Watanabe, A., H. Takahashi, T. Kikuchi, T. Kobayashi, K. Gomi, S. Fujimura, Y. Tokue, and T. Nukiwa. 2000. Comparative in vitro activity of S-4661, a new parenteral carbapenem, and other antimicrobial agents against respiratory pathogens. Chemotherapy 46:184-187.[CrossRef][Medline]

Antimicrobial Agents and Chemotherapy, June 2005, p. 2510-2511, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2510-2511.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Baughman, R. P. (2009). The Use of Carbapenems in the Treatment of Serious Infections. J Intensive Care Med 24: 230-241 [Abstract]  
  • Kim, A., Banevicius, M. A., Nicolau, D. P. (2008). In Vivo Pharmacodynamic Profiling of Doripenem against Pseudomonas aeruginosa by Simulating Human Exposures. Antimicrob. Agents Chemother. 52: 2497-2502 [Abstract] [Full Text]  
  • Credito, K. L., Ednie, L. M., Appelbaum, P. C. (2008). Comparative Antianaerobic Activities of Doripenem Determined by MIC and Time-Kill Analysis. Antimicrob. Agents Chemother. 52: 365-373 [Abstract] [Full Text]  

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chen, Y.
Right arrow Articles by Saiman, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, Y.
Right arrow Articles by Saiman, L.

Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»