In vitro activity of meropenem, imipenem, cefepime and ceftazidime against Pseudomonas aeruginosa isolates from cystic fibrosis patients

John C. Christensona,*, E. Kent Korgenskib and Judy A. Dalyb,c

a Department of Paediatrics, Division of Infectious Diseases and Geographic Medicine, b Clinical Microbiology Laboratory, Primary Children's Medical Center and c Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
We studied 67 Pseudomonas aeruginosa isolates from cystic fibrosis patients, and compared their in vitro susceptibility to two carbapenems (meropenem and imipenem) and two cephalosporins (cefepime and ceftazidime). The carbapenems were more effective in vitro than the cephalosporins: 92.5% of isolates were susceptible to the former and 77.6% to the latter. Essentially no difference was found between meropenem and imipenem. More discrepancies were seen between cefepime and ceftazidime: four of 67 isolates (6.0%) were more susceptible to cefepime than to ceftazidime, while eight (11.9%) were more susceptible to ceftazidime than to cefepime.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Chronic lung infection in patients with cystic fibrosis (CF) is usually associated with a limited number of organisms. With the advent of anti-staphylococcal antimicrobial therapy, Pseudomonas aeruginosa emerged as the most important bacterial pathogen in lung disease of CF patients.1 Chronic infection with P. aeruginosa causes lung destruction which may shorten the lifespan of affected individuals.2 The cornerstone of CF care remains the aggressive use of oral, nebulized and intravenous antibiotics. The aim of antimicrobial therapy is to improve lung function and clinical well-being by decreasing the bacterial load and delaying lung destruction. Studies have suggested that two new antimicrobial agents, meropenem and cefepime, may be more effective than the antimicrobials currently available for treating P. aeruginosa infections in CF patients.27 We studied the in vitro susceptibility of P. aeruginosa strains isolated from CF patients and compared meropenem with imipenem, and cefepime with ceftazidime.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Sixty-seven P. aeruginosa isolates collected at the Primary Children's Medical Center in Salt Lake City, UT, USA (a paediatric tertiary care medical centre serving the Intermountain Western United States) were used in this study. All isolates were from sputum cultures collected from CF patients between November 1996 and February 1997.

Susceptibility testing was performed using the disc diffusion method as described by the NCCLS.8 Briefly, all inocula were prepared from a pure agar plate culture, with isolates that were 18–24 h old. Organisms were prepared in 0.85% saline and adjusted to match a 0.5 McFarland standard with a photometer. All organisms were tested on Mueller–Hinton agar (Becton Dickinson, Cockeysville, MD, USA). Discs containing 10 µg of imipenem or meropenem, or 30 µg of ceftazidime or cefepime were obtained from Becton Dickinson. Zone diameters were measured after incubation of plates in ambient air at 35°C for 16–18 h. Interpretation of zone diameters for cefepime, ceftazidime and imipenem as susceptible, intermediate or resistant was based upon NCCLS guidelines.9 Interpretation of zone diameters for meropenem was based upon the manufacturer's guidelines.10 Escherichia coli ATCC 25922 and P. aeruginosa ATCC 27853 were included as quality control strains following the protocol described above.

The activity of other antimicrobial agents commonly used to treat pulmonary infections in CF patients was tested using the technique described above. NCCLS guidelines were used to interpret the results.9

The majority of CF patients in our institution receive antimicrobial therapy consisting of combinations of ticarcillin–clavulanic acid and tobramycin or ceftazidime and tobramycin. Nebulized colistin and tobramycin are also commonly used. Specific details of antimicrobial therapy for each patient submitting sputum specimens for culture were not collected.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Table IGo shows the activity of the two carbapenems and of cefepime and ceftazidime against the 67 isolates of P. aeruginosa. Sixty-two (92.5%) of the isolates were susceptible to both meropenem and imipenem and four (6.0%) were resistant to both agents. Only one isolate was less susceptible to meropenem than to imipenem.


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Table I. In vitro sensitivity of 67 isolates of P. aeruginosa to (A) meropenem and imipenem and (B) cefepime and ceftazidime
 
Fifty-two (77.6%) of the isolates were susceptible and three (4.5%) were resistant to both cefepime and ceftazidime. Minor category interpretation differences occurred with 11 (16.4%) of the 67 isolates. One isolate (1.5%) was resistant to cefepime and susceptible to ceftazidime. Overall, more of the 67 isolates were susceptible to meropenem/ imipenem than to cefepime/ceftazidime (92.5 and 77.6%, respectively).

Data on the in vitro susceptibility of P. aeruginosa isolates to other antimicrobial agents was available for 55 of the isolates. These data are presented in Table IIGo. Many of our isolates were resistant to trimethoprim– sulphamethoxazole, amikacin and tobramycin. The majority (>=80%) of isolates tested were susceptible to the ß-lactam antibiotics tested. Forty-two per cent of the P. aeruginosa isolates were mucoid in phenotype. No difference in susceptibility was observed between mucoid and non-mucoid isolates.


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Table II. In vitro susceptibility data of 55 isolates of P. aeruginosa to commonly used antimicrobial agents (expressed as percentages)
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Our results demonstrate that meropenem and imipenem are more effective in vitro than cefepime and ceftazidime against the isolates of P. aeruginosa from our population of CF patients: 92.5% of isolates were susceptible to both of the carbapenems and 77.6% to both of the cephalosporins. Meropenem has been reported to be more active in vitro against P. aeruginosa from CF patients than imipenem,11 but we found no significant difference between meropenem and imipenem using interpretative guidelines. One isolate was slightly less susceptible to meropenem than to imipenem. Other investigators have observed this same finding in a few clinical isolates from CF patients.12 The mechanism behind this observation in our isolate is not known, but a selective decreased affinity for a penicillin-binding protein (possibly PBP-3) may be involved.

More discrepancies were seen when comparing cefepime with ceftazidime. Four (6.0%) of the 67 isolates were more susceptible to cefepime than to ceftazidime, but eight (11.9%) showed the reverse pattern.

Based on our data, meropenem and cefepime may be of value for the treatment of pulmonary exacerbations in patients with CF, especially in those patients infected with multiple organisms such as Staphylococcus aureus and P. aeruginosa.


    Acknowledgments
 
We thank the microbiologists of the Primary Children's Medical Center for their valuable contributions to this project.


    Notes
 
* Correspondence address. University of Utah School of Medicine, Department of Paediatrics, Division of Infectious Diseases and Geographic Medicine, 50 North Medical Drive, Room 2R022, Salt Lake City, UT 84132, USA. Tel: +1-801-581-6791; Fax: +1-801-585-3789; E-mail: john.c.christenson{at}hsc.utah.edu Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Gilligan, P. H. (1991). Microbiology of airway disease in patients with cystic fibrosis. Clinical Microbiology Reviews 4, 35–51.[ISI][Medline]

2 . Webb, A. K. (1995). The treatment of pulmonary infection in cystic fibrosis. Scandinavian Journal of Infectious Diseases 96, Suppl., 24–7.

3 . Arrieta, A. (1997). Use of meropenem in the treatment of serious infections in children: review of the current literature. Clinical Infectious Diseases 24, Suppl. 2, S207–12.[ISI][Medline]

4 . Ballestero, S., Fernandez-Rodriquez, A., Villaverde, R., Escobar, H., Perez-Diaz, J. C. & Baquero, F. (1996). Carbapenem resistance in Pseudomonas aeruginosa from cystic fibrosis patients. Journal of Antimicrobial Chemotherapy 38, 39–45.[Abstract]

5 . Byrne, S., Maddison, J., Connor, P., Doughty, I., Dodd, M., Jenney, M. et al. (1995). Clinical evaluation of meropenem versus ceftazidime for the treatment of Pseudomonas spp. infections in cystic fibrosis patients. Journal of Antimicrobial Chemotherapy 36, Suppl. A, 135–43.[ISI][Medline]

6 . Huls, C. E., Prince, R. A., Seilheimer, D. K. & Bosso, J. A. (1993). Pharmokinetics of cefepime in cystic fibrosis patients. Antimicrobial Agents and Chemotherapy 37, 1414–6.[Abstract]

7 . Barradell, L. B. & Bryson, H. M. (1994). Cefepime: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 47, 471–505.[ISI][Medline]

8 . National Committee for Clinical Laboratory Standards. (1997). Performance Standards for Antimicrobial Disk Susceptibility Tests—Sixth Edition: Approved Standard M2-A6. NCCLS, Villanova, PA.

9 . National Committee for Clinical Laboratory Standards. (1997). Performance Standards for Antimicrobial Susceptibility Tests: Approved Standard M100-S7. NCCLS, Villanova, PA.

10 . Zeneca Pharmaceuticals. (1996). Susceptibility Test Criteria. Zeneca Pharmaceuticals. Wilmington, DE.

11 . Bauernfeind, A., Jungwirth, R. & Schweighart, S. (1989). In-vitro activity of meropenem, imipenem, the penem HRE 664 and ceftazidime against clinical isolates from West Germany. Journal of Antimicrobial Chemotherapy 24, Suppl. A, 73–84.

12 . Ballestero, S., Fernandez-Rodriguez, A., Villaverde, R., Escobar, H., Perez-Diaz, J. C. & Baquero, F. (1996). Carbapenem resistance in Pseudomonas aeruginosa from cystic fibrosis patients. Journal of Antimicrobial Chemotherapy 38, 39–45.[Abstract]

Received 9 July 1999; returned 11 November 1999; revised 22 December 1999; accepted 17 January 2000