612

Correspondence Synerglsm between fosfomycln and nalidixic add in vitro Sir, Some studies have shown a synergistic effect of fosfomycin with other antibiotics. Perea, Torres & Borobio (1978) demonstrated a high percentage of synergistic actions of fosfomycin when combined with ampiciUin or chloramphenicol respectively against Salmonella and Shigella spp. Also effective was its combination with penicillins, cephalosporins, aminoglycosides, chloramphenicol, rifampicin, lincomycin and erythromycin against Enterobacteriaceae, Pseudomonas aeruginosa, Staphybcoccus aureus and Streptococcaceae (Olay et al., 1978). The interaction of fosfomycin and nalidixic acid has been analysed on a total of 111 multiresistant Enterobacteriaceae and Pseudomonas aeruginosa strains resistant to at least 5 common chemotherapeutic agents. These strains were recently isolated from urine of hospitalized patients. Using the checker board titration technique described by Waterworth (1978), the MIC studies of the two drugs were performed by combining each of the 8 concentrations of fosfomycin (1-128 mg/1) with each of the 8 concentrations of nalidixic acid (1-128 mg/1); test medium was MuellerHinton-broth (CM 405, Oxoid). Glucose-6phosphate, which several other authors used for testing fosfomycin, was not added. Twelve of the Pseudomonas aeruginosa and 5 of the Serratia marcescens strains remained resistant to the combination of both drugs. The geometric mean [g = (xi. x , . . . x.)i] of the MIC values of the drugs alone and in combination were calculated for the other 94 strains. As can be seen from Table 1, a fourfold reduction of the MICs of both components compared with the MICs of each drug alone was observed in all strains of the

Table L MIC values of fosfomycin and nalidixic acid alone and in combination Geometric mean of MICs (mg/1) Micro organisms (No. of strains) EschericHa coli (26) Proteus mirabilis (4) Proteus stuartii (5) Proteus indole-positive (6) Bebsiella pneumoniae (10) Serratia marcescens (29) Pseudomonas aeruginosa (14)

Nalidixic acid alone

Fosfomycin alone

Nalidixic acid in combination

Fosfomycin in combination

21-45 >128 >128 >128 84-44 91-59 >128

11-93 6-72 2111 25-39 111-43 77-4 39-0

410 5-76 696 17-95 1212 9-68 6-24

2-28 1-68 4 317 25-99 3-90 9-28

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Bach, M. C , Gold, O. & Finland, M. Activity of minocycline against Nocardia asteroides: comparison with tetracycline in agar-dilution and standard disc-diffusion tests and with sulfadiazine in an experimental infection of mice. Journal Laboratory and Clinical Medicine 81: 787-93 (1973). Bach, M. G , Monaco, A. P. & Finland, M. Pulmonary nocardiosis. Therapy with minocycline and with erythromycin plus ampicillin. Journal of the American Medical Association (JAMA) 224: 2378-1381 (1973). Black, W. A. & McNellis, D. A. Comparative in vitro sensitivity of Nocardia species to fusidic acid and sulphonamides. Journal of Medical Microbiology 4: 293-5 (1971). Emmons, C. W.( Binford, C H., Utz, J. P. & Kwon-Chung, K. J. Medical Micology. Lea and Febiger, Philadelphia (1977), p. 107. Finland, M., Bach, M. C , Garner, C. & Gold, O. Synergistic action of ampiciUin and erythromycin against Nocardia asteroides: effect of time of incubation. Antimicrobial Agents and Chemotherapy 5: 344-53 (1974). Hoeprich, P. D., Brandt, D. & Parker, R. H. Nocardial brain abscess cured with cydoserioe and sulfonamides. American Journal of the Medical Sciences 255: 208-16 (1968). Hoeprich, P. D. Infectious Diseases. Harper and Row, Hargerstown (1977), p. 363. Orfanakis, M. G., Wikox, H. G. & Smith, C. B. In vitro studies of the combined effect of ampiciUin and sulfonamides on Nocardia asteroides and results of therapy in four patients. Antimicrobial Agents and Chemotherapy 1: 215-20 (1972). Peabody, J. W. & Seabury, J. H. Actionmycosis and nocardiosis. A review of basic differences in therapy. American Journal of Medicine 28: 99115 (1960). Rippon, J. N. Medical Micology. The pathogenic fungi and the pathogenic Actinomycetes. W. B. Saundcrs Company, Philadelphia, (1974), p. 35. Wallace, R. J., Septimus, E. J., Mushen, D. M. & Martin, R. R. Disk diffusion susceptibility testing of Nocardia species. Journal of Infectious Diseases 135: 568-75 (1977).

Correspondence

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and penicillin and Staphylococcus aureus (Eagle & Musselman, 1948; Yourassowsky, Van der Linden, Lismont & Schoutens, 1975). Paradoxical effects with aminoglycoside antibiotics were noted when routine MICs were determined in the clinical laboratory of the Bronx-Lebanon Hospital Center. During a recent study on the ratio of MIC to the minimum antibacterial concentration (MAC), growth has also been observed with aminoglycosides at concentrations above the MIC while there was no growth at lower concentrations (Lorian & De Freitas, 1979). This paper studies in detail such paradoxical effects with aminoglycosides. Ten strains each of Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus faecalis, and twenty-six strains of E. coli were tested. All strains were isolated from specimens References submitted to the clinical laboratory. The Olay, T., Rodriguez, H., Oliver, L. E., Vicente, organisms were identified by standard laboraM. V. & Queccdo, M. C. R. Interaction of tory methods (Lennette, Spaulding & Trunat, fosfomycin with other antimicrobial agents: in vitro and in vivo studies. Journal of Antimicrobial 1947), and were biotyped using API 20E (Analytab Products, Plainview, N.Y.) (Smith Chemotherapy 4: 569-76 (1978). Perea, E. J., Torres, M. A. & Borobio, M. V. et al., 1972), and an antibiogram to 14 Synergism of fosfomycin-ampicillin and fosfo- antibacterial agents (Bauer et ah, 1966) to mycin-chloramphenicol against salmonella and avoid the possibility of testing identical strains. shigella. Antimicrobial Agents and Chemo- All strains studied were susceptible to amitherapy 13: 705-9 (1978). kacin, gentamicin, and tobramycin. The Waterworth, P. M. Tests of combined antibacterial organisms were grown in trypticase soy broth action. In Laboratory methods in antimicrobial (TSB) (BBL), and on trypticase soy agar chemotherapy. (Reeves, D. S., Phillips, I., (TSA) (BBL). MacConkey medium with 3% Williams, J. D. & Wise, R. Eds). Livingstone, Edinburgh, London, New York (1978), pp. agar (BBL) was used for colony forming unit (CFU) counts with P. mirabilis. 41-9. Amikacin (Bristol), gentamicin (Schering), and tobramycin (Lilly) were dissolved in Paradoxical effect of amlnoglycoslde antibiotics sterile distilled water. on the growth of Gram-negative bacilli Minimum inhibitory concentrations were determined by plating 0-05 ml of a 1 :100 Sir, Antibacterial activity is usually proportional dilution of an 18 hour broth culture (TSB) to drug concentration, and the minimum on a series of TSA plates containing twofold bactericidal concentration (MBQ is usually dilutions of either amikacin, gentamicin, or equal to, or up to four times the minimum tobramycin. The MIC was defined as the inhibitory concentration (MIC) (Eagle & lowest drug concentration associated with no Musselman, 1948; Shah, Hectderks & Stille, bacterial growth after incubation at 37°C 1977). Penicillin is known to show a para- for 24 h. Each strain was grown in TSB for 18 h at doxical effect that is a decrease instead of an increase in bactericidal activity with strepto- 37°C. A 0-5 ml aliquot of a 1 :10 dilution was cocci at concentrations well above the MBC added to a 250 ml TSB and incubated in a (Eagle & Musselman, 1948; Eagle, 1951). 37°C water bath for one hour, except for Such paradoxical effects were also observed P. aeruginosa, S. aureus, and S. faecalis, with ampicillin and Streptococcus faecalis which were incubated for 2 h. Subsequently, (Yourassowsky, Van der Linden & Schoutens, 4-5 ml were added to 0-5 ml TSB containing 1976), carbenicillin and Proteus mirabilis antibiotic concentrations calculated to produce (Yourassowsky, Van der Linden & Schoutens, 1/4 to 32 times the MIC of each strain. Control 1976), mecillinam and Providencia stuartii tubes containing 0-5 ml TSB without anti(Kerry, Hamilton-Miller & Brumfitt, 1976), biotic were also prepared for each strain.

different species (Table I). The effectiveness of combined action against Scrratia marcescens is especially favourable, strains resistant to nalidixic acid (e.g. Proteus mirabilis) also become susceptible when using the combination with fosfomycin, and vice versa. Antagonism was not observed. The combination of fosfomycin with other antibiotics has been suggested as a means of retarding the development of resistance to this antibiotic; it is not clear, whether this is true for the combination described. Even more uncertain are the molecular basis of the effect and the possible therapeutic consequences. U. ULLMANN Department of Microbiology, Institute of Hygiene of the University Tubingen, West Germany

Synergism between fosfomycin and nalidixic acid in vitro.

612 Correspondence Synerglsm between fosfomycln and nalidixic add in vitro Sir, Some studies have shown a synergistic effect of fosfomycin with other...
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