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Antimicrobial Agents and Chemotherapy, October 2004, p . 4002-4005, Vol . 48, No . 10 Determination of Susceptibilities of 26 Leptospira sp . Serovars to 24 Antimicrobial Agents by a Broth Microdilution TechniqueClinton K . Murray and Duane R . Hospenthal* Infectious Disease Service, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, Texas Received 7 April 2004/ Returned for modification 6 June 2004/ Accepted 23 June 2004
Clinical trials of antimicrobial agents against leptospirosis are limited to penicillin, doxycycline, and ceftriaxone (4, 7, 11, 15) . Although no survival benefit has been shown with these agents, symptom improvement, including resolution of fever and leptospiruria, has been documented . The ever-growing armamentarium of antimicrobial agents used as empirical therapies for acute febrile illnesses necessitates the assessment of newer antimicrobial agents against leptospirosis . In vitro antibiotic susceptibility testing, typically done on a limited scale using macrodilution techniques and small numbers of serovars, has been reported (3, 6, 8, 10, 12-14) . We have developed an in vitro broth microdilution technique by which a more efficient evaluation of a greater number of antimicrobial agents and Leptospira serovars can be accomplished (9) . In this study we assess the in vitro activity of 24 antimicrobial agents against 26 Leptospira serovars . (This work was presented in part at the 52nd Annual Meeting of the American Society of Tropical Medicine and Hygiene, Philadelphia, Penn., December 2003.) Twenty-six Leptospira serovars, representing seven species and 18 serogroups, were obtained from the Veterinary Command Food and Drug Analysis Laboratory, Fort Sam Houston, Texas (Table 1) . These strains originated at the USDA National Veterinary Services Laboratories, Ames, Iowa . Although the majority of these were initially recovered from human infections, all have been maintained by subculture as laboratory strains for many years . The organisms were maintained and the inocula were prepared as previously described (9) .
The median MICs from three experiments using the strains indicated in Table 1 are reported in Table 2 . The observed reproducibility of drug-serovar combinations revealed that 84% (527 of 624) of test results fell within two dilutions of each other . The reproducibility increases to 94% if amoxicillin, ampicillin, and penicillin G are excluded from this comparison .
Delays inherent in the diagnosis of leptospirosis, a potentially fatal infection, often dictate empirical therapy for acute febrile illness . As the differential diagnosis of an acute febrile illness in any particular setting may be expansive, numerous antimicrobial agents are often used as initial therapies . Only three drugs have been evaluated for leptospirosis in randomized human trials (4, 7, 11, 15) . Determination of the antileptospiral activity of newer agents is needed . Currently there is no standard method to assess in vitro antimicrobial agents for antileptospiral activity; however, we have recently described a broth microdilution method which is more rapid than the traditional macrodilution method (9) . Our assessment by broth microdilution of 24 antimicrobial agents against 26 Leptospira serovars found that many antimicrobial agents have excellent in vitro activity . Included in our testing were the traditional antileptospiral drugs penicillin G, ceftriaxone, and doxycycline and representative agents from many other classes of agents . As classes of antimicrobial agents, carbapenems, cephalosporins (with the exception of cefdinir), fluoroquinolones, and macrolides (and telithromycin) had lower MICs than the traditional agents . All agents with the exception of aztreonam had MICs equal to or less than that of penicillin G, the accepted treatment alternative for severe disease . The overall reproducibility seen in our study was excellent, although amoxicillin, ampicillin, and penicillin G had greater variability than the other antimicrobial agents tested . Serovar-specific diagnosis is virtually never available for therapy of acute infection, so an assortment of Leptospira spp . were included in our study to allow observation of potential strain-to-strain and species-to-species variability . We noted no clinically significant strain-to-strain or species-to-species variability . A variety of antimicrobials have shown variable therapeutic activity in small in vitro and in vivo (animal) studies; however, these studies are limited by the numbers of antimicrobials and/or isolates of Leptospira spp . examined at one time (1-3, 5, 6, 8, 10, 12-14, 16) . Through our broth microdilution study, we delivered reproducible results and allowed more convenient testing with greater throughput than previous macrodilution methods . Presently correlation of in vitro susceptibility to outcome is lacking in treatment trials for leptospirosis . Future study, including animal and human treatment or prophylaxis trials, can now be pursued to determine if any of these agents will be useful in the therapy of leptospirosis .
The views expressed herein are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S . government .
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0.01 µg/ml
3.13 µg/ml