Efficacy of Macrolides and Telithromycin against Leptospirosis in a Hamster Model

Abstract

Human studies support the use of ␤-lactams and tetracyclines in the treatment of leptospirosis. Additional agents from these and other classes of antimicrobials also have in vitro activity against Leptospira species, though corroborating in vivo data are limited or lacking. We evaluated the therapeutic efficacy of azithromycin, clarithromycin, and telithromycin in a lethal hamster model of leptospirosis using Leptospira interrogans serogroup Canicola serovar Portlandvere. A range of dosages for each antimicrobial was given to the infected animals on days 2 through 7 (5 days) of the 21-day survival model. All untreated control animals survived less than 10 days from infection. Leptospirosis is an acute febrile illness caused by spirochetes of the genus Leptospira whose clinical manifestations can range from asymptomatic infection to death. Current treatment of leptospirosis includes symptomatic support with or without directed antimicrobial administration, depending on the severity and duration of symptoms (12). Specific antimicrobial therapy for leptospirosis has been examined for over 60 years (13,17). Antimicrobials of choice include penicillin, doxycycline, cefotaxime, and ceftriaxone (7,13,16,20,22). This is based on randomized, controlled human studies that have demonstrated the efficacy of these drugs in reducing symptoms and leptospiruria but not necessarily in improving survival. Amoxicillin, ampicillin, and erythromycin have been suggested in less-severe disease, although no randomized, controlled human data are available to support this recommendation (23). Additional antimicrobials, primarily ␤-lactams and fluoroquinolones, have shown treatment efficacy in various animal models (1,4,5,6,9,19,24). However, to date, neither animal model nor human trial has addressed the efficacy of most other modern antimicrobials in leptospirosis. Such agents might provide equal or superior efficacy, with easier administration, fewer contraindications (e.g., doxycycline's contraindication in pregnancy or restriction of penicillin use due to allergy), and fewer adverse events (e.g., doxycycline's associated phototoxicity and gastrointestinal side effects) than the proven options. This report describes our experience in using macrolides and telithromycin in treating acute leptospirosis in a lethal hamster model. MATERIALS AND METHODSAnimal model. The animal model utilized was adapted from previously published work by Alexander and Rule (1). Female golden Syrian hamsters (Mesocricetus auratus) weighing 50 to 100 g (Harlan, Indianapolis, IN) were inoculated intraperitoneally with 0.5 ml of Ellinghausen-McCullough-Johnson-Harris (EMJH) medium (Becton Dickinson, Sparks, MD) containing 10 5 leptospires. Leptospira interrogans serogroup Canicola serovar Portlandvere (CA-12-029/ CDC Nic 1808) was used for all trials (obtained from David Haake, University of California Los Angeles). This strain was maintained by hamster passage and recovered between passages in semisolid EMJH medium. Inoculum was produced by subculture of these ...

Antimicrobial Susceptibilities of Geographically Diverse Clinical Human Isolates ofLeptospira

“…A correlation of in vitro susceptibility data to treatment outcomes in humans is lacking, although the results of in vivo animal studies with strain 11 have correlated well with the results of our in vitro testing (7,12,13).…”

In Vitro and In Vivo Activity of First Generation Cephalosporins Against Leptospira

“…A group of five hamsters was left untreated as a negative control, and a group of nine hamsters was treated with doxycycline (5 mg/kg, IP, daily) as positive control. 16 All hamsters were observed multiple times a day during the 21-day study period, and any study animal showing significant pain or distress or characteristics of a moribund state was humanely euthanized. Blood cultures were obtained from each hamster at the time of death.…”

“…Using our previously developed model, 74 female golden Syrian hamsters ( Mesocricetus auratus ) weighing 80-110 g (Harlan, Indianapolis, IN) were inoculated intraperitoneally (IP) with 0.5 mL EMJH medium containing 10 5 leptospires ( L. interrogans serovar Canicola/Portlandvere strain CA-12-029/CDC Ni 1808). [15][16][17] On study days 2-6, groups of 10 animals were treated by daily IP injection with cefazolin or cephalexin in concentrations of 5, 25, or 50 mg/kg. A group of five hamsters was left untreated as a negative control, and a group of nine hamsters was treated with doxycycline (5 mg/kg, IP, daily) as positive control.…”

Efficacy of the Rabbit Polyclonal Anti-leptospira Antibody against Homotype or Heterotype Leptospira Infection in Hamster

“…However, antibiotics residue and the probability of multidrug resistance are concerns, which may influence the safety of patients while using the antibiotic therapy. For example, James E. Moon and Zhang W reported that nearly all animals exhibited diarrhea after some types of antibiotic therapies [12,13]. Therefore, an urgent need exists for novel therapeutic agents directed against Leptospira without severe side-effects.…”