a First Department of Internal Medicine, Nagoya City University, Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan; b Sumitomo Pharmaceuticals Research Center, 3-1-98 Kasugadenaka, Konohana-ku, Osaka 554-0022, Japan
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Abstract |
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Introduction |
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Materials and methods |
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The 50 clinical strains of P. aeruginosa used in this study were isolated from patients at Nagoya City University Hospital. Thirty-four were from sputum, seven from urine, four from decubitus ulcers, two from pharyngeal smears and three from other specimens.
Meropenem was obtained from Sumitomo Pharmaceuticals, Osaka, Japan; arbekacin and amikacin from Meiji Seika Kaisha, Ltd, Osaka, Japan; and netilmicin from Schering-Plough Co., Osaka, Japan.
Determination of MICs
MuellerHinton broth or agar (Nissui, Tokyo, Japan) was used in all studies. The MICs of antibiotics alone or in combination were determined using a two-fold serial agar dilution method according to the Standard Method recommended by the Japanese Society of Chemotherapy.3 In summary, serial two-fold dilutions of the antibiotics in MuellerHinton agar were inoculated with an overnight broth culture of the organism to give a final concentration of c. 106 cfu/mL. After incubating at 37°C for 20 h, the MIC was defined as the lowest concentration of antibiotic that completely inhibited visible growth. Serial two-fold concentrations ranging from 0.05 to 25 mg/L for meropenem and 0.1 to 100 mg/L for arbekacin, amikacin and netilmicin were prepared.
Determination of the combined effect of meropenem and other antibiotics
The effects of antibiotic combinations were assessed using an agar dilution chequerboard technique and fractional inhibitory concentration (FIC) indices.4 The FIC for each agent was calculated by dividing the MIC of the antibiotics when used in combination by that of the drug alone. The FIC index is the sum of the FICs of each of two antibiotics when examined in combination. A minimum FIC index of 0.5 indicates synergy, while an FIC index >2 indicates antagonism. If the minimum FIC index was >0.5 and
1, the effect of the combination was classified as additive. If the minimum FIC index was >1 and
2, the effect of the combination was classified as indifferent.
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Results |
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The MICs of each antibiotic alone for P. aeruginosa are shown in Table I. Meropenem had low MICs for P. aeruginosa (MIC50 0.39 mg/L; MIC90 3.13 mg/L) except for two resistant strains (MIC
12.5 mg/L). For most of the strains tested, arbekacin had lower MICs than did amikacin or netilmicin.
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Most minimum FIC indices were distributed in the synergic or additive range (arbekacin, 0.161.06; amikacin, 0.16 1.03; netilmicin, 0.381.13). The combinations of meropenem and aminoglycosides were effective against most of the strains tested; combinations that contained arbekacin or amikacin were more synergic than those containing netilmicin. None of the combinations had an antagonistic effect (Table II). Combinations of meropenem and aminoglycosides also had synergic or additive effects against each strain of meropenem-resistant P. aeruginosa.
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Discussion |
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Oie et al.10 reported the usefulness of a combination of two ß-lactams and amikacin or that of three ß-lactams in treating multi-drug resistant P. aeruginosa. In the present study, a combination of meropenem and aminoglycosides was also effective against two strains of meropenem-resistant P. aeruginosa. The combined effect of meropenem and arbekacin or amikacin was also examined for two more strains of meropenem-resistant P. aeruginosa; these two strains were excluded, however, because the MIC of netilmicin alone could not be determined for these strains. Synergy between meropenem and arbekacin was observed in both strains, as was either synergy or additivity between meropenem and amikacin (data not shown).
The MIC90 of meropenem in all combinations with aminoglycosides was 1.56 mg/L (Table II
), while the MIC90 of aminoglycosides in combination with meropenem was
6.25 mg/L. Such concentrations are readily achieved in human plasma after a standard dose of each antibiotic.
In conclusion, combinations of meropenem and aminoglycosides were effective against almost all P. aeruginosa strains tested, including meropenem-resistant strains, but further evaluations of bactericidal activity, in vivo activity and clinical efficacy are needed.
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Notes |
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References |
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2 . Deguchi, K., Yokota, N., Koguchi, M., Suzuki, Y., Suzuki, K., Fukayama, S. et al. (1992). Antimicrobial activities of major oral antimicrobial agents against clinically isolated microbial strains from inpatients. Japanese Journal of Antibiotics 45, 96579.[Medline]
3 . Goto, S., Jo, K., Kawakita, T., Kosakai, N., Mitsuhashi, S., Nishino, T. et al. (1981). Determination method of minimum inhibitory concentrations. Japanese Journal of Chemotherapy 29, 769.
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Totsuka, K., Shiseki, M., Kikuchi, K. & Matsui, Y. (1999). Combined effects of vancomycin and imipenem against methicillin- resistant Staphylococcus aureus (MRSA) in vitro and in vivo. Journal of Antimicrobial Chemotherapy 44, 45560.
5 . Watanabe, T., Obayashi, K., Matsui, K. & Kubota, T. (1997). Comparative studies of the bactericidal morphological and post-antibiotic effects of arbekacin and vancomycin against methicillin-resistant Staphylococcus aureus. Journal of Antimicrobial Chemotherapy 39, 4716.[Abstract]
6 . Wise, R., Ashby, J. P. & Andrews, J. M. (1989). The antibacterial activity of meropenem in combination with gentamicin or vancomicin. Journal of Antimicrobial Chemotherapy 24, Suppl. A, 2338.[ISI][Medline]
7 . Ferrara, A., Grassi, G., Grassi, F. A., Piccioni, P. D. & Gialdroni Grassi, G. (1989). Bactericidal activity of meropenem and interactions with other antibiotics. Journal of Antimicrobial Chemotherapy 24, Suppl. A, 23950.[ISI][Medline]
8 . Kropec, A., Lemmen, S., Wursthorn, M. & Daschner, F. D. (1994). Combination effect of meropenem with aminoglycosides and teicoplanin on Pseudomonas aeruginosa and enterococci. Infection 22, 3068.[ISI][Medline]
9 . Fukuchi, K., Takeda, K., Takagi, Y. & Gomi, K. (1992). Synergism of imipenem in combination with arbekacin against methicillinresistant Staphylococcus aureus and Pseudomonas aeruginosa. Japanese Journal of Chemotherapy 40, 7808.
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Oie, S., Sawa, A., Kamiya, A. & Mizuno, H. (1999). In-vitro effects of a combination antipseudomonal antibiotics against multi-drug resistant Pseudomonas aeruginosa. Journal of Antimicrobial Chemotherapy 44, 68991.
Received 14 February 2000; returned 21 May 2000; revised 12 July 2000; accepted 19 August 2000