a Department of Pharmacy b Clinical Laboratory, Yamaguchi University Hospital, 1144 Kogushi, Ube 755, Japan
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Abstract |
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Introduction |
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Materials and methods |
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We requested five hospitals in Yamaguchi Prefecture, Japan to supply non-replicate strains of P. aeruginosa, isolated from patients with infection between December 1994 and May 1998, that were possibly resistant to piperacillin, meropenem, ceftazidime, aztreonam andamikacin. A total of 36 strains were provided and re-examined for identification (Gram's stain, morphology, oxidationfermentation test, cytochrome oxidase test and API system) and antimicrobial sensitivity. Of the 36 strains, six multi-drug resistant P. aeruginosa strains showing the following antibiotic resistance pattern were used in this experiment: piperacillin, MIC> 64 mg/L; meropenem, MIC> 8 mg/L; ceftazidime, MIC> 16 mg/L; aztreonam, MIC> 16 mg/L; amikacin, MIC> 8 mg/L. The sources of the six strains were bronchial secretion (four strains), urine (one) and blood (one).
Susceptibility tests
MICs were determined after 18 h incubation at 37°C by dilution on Sensitivity Disc Agar-N (Nissui Pharm., Tokyo, Japan). The following antibiotics were tested: piperacillin (Toyama Chemicals, Tokyo, Japan), meropenem (Sumitomo Pharmaceuticals, Tokyo), ceftazidime (Glaxo Japan Co., Tokyo), aztreonam (Eisai Co., Tokyo) and amikacin (Banyu Pharmaceuticals, Tokyo). These antibiotics were provided in the form of a freeze-dried amorphous powder. The inocula (104 cfu/spot) were plated using a multipoint inoculator (Sakuma Co., Tokyo). The MIC was defined as the lowest antibiotic concentration that inhibited visible growth. P. aeruginosa IFO 3919 was used as a reference strain.
The effects of the combination of two or three drugs among the above five types of antibiotics were evaluated. The antibiotic concentration was set as follows: piperacillin, 64 mg/L; meropenem, 8 mg/L; ceftazidime, 16 mg/L; aztreonam, 16 mg/L; amikacin, 4 mg/L. The presence or absence of growth on Sensitivity Disc Agar-N was determined by a method similar to that used for the measurement of MIC.
Data analysis
The effects against the six P. aeruginosa strains were compared (between the combinations of two drugs and those of three drugs, and between the combinations of three drugs not including amikacin and three drugs including amikacin) by the chi-square test, using the number of growth-inhibited strains as a variable.
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Results |
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The Table shows the MICs of the five types of drugs used for the six multi-drug resistant P. aeruginosa strains, and the presence or absence of growth inhibition by the combination of two or three drugs among the five drugs. P. aeruginosa Nos 1 and 3 were obtained from patients treated in the same hospital, but four other isolates were obtained, respectively, from patients treated in four different hospitals. The combinations of two ß-lactam antibiotics inhibited growth of one to three strains. The combinations of one ß-lactam antibiotic and amikacin inhibited growth of two to four strains. Among the combinations of three ß-lactam antibiotics, piperacillin + meropenem + ceftazidime and piperacillin + meropenem + aztreonam inhibited growth of four strains, while piperacillin + ceftazidime + aztreonam and meropenem + ceftazidime + aztreonam inhibited growth of five strains. The combinations of two ß-lactam drugs and amikacin also inhibited growth of five strains.
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Discussion |
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In this study, the combinations of two ß-lactam antibiotics and amikacin were moderately effective against multi-drug resistant P. aeruginosa. Roussel-Delvallez et al.,9 who performed a 24 h timekill study, also showed potentiation effects of a three-drug combination of imipenem + (ticarcillin + clavulanic acid) + amikacin on multi-drug resistant P. aeruginosa. Therefore, the combination of two ß-lactam antibiotics and amikacin is worth considering for multi-drug resistant P. aeruginosa infection. In some patients receiving nephrotoxic drugs such as amphotericin B, cisplatin or cyclosporin, since administration of amikacin is inappropriate, piperacillin + ceftazidime + aztreonam or meropenem + ceftazidime + aztreonam may be effective.
In this study, the three-drug combinations of two ß-lactam antibiotics and amikacin was ineffective against one of the six multi-drug resistant P. aeruginosa isolates. Even when the amikacin concentration was increased from 4 to 32 mg/L, these three-drug combinations were ineffective against this strain (data not shown). A future question may be what combinations of antibiotics should be used for such multi-drug resistant P. aeruginosa strains?
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Acknowledgments |
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Notes |
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References |
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Received 18 February 1999; returned 29 April 1999; revised 19 May 1999; accepted 27 June 1999