Failure of beta-lactam antibiotics and marked efficacy of fluoroquinolones in treatment of murine Yersinia pseudotuberculosis infection

Abstract

The treatment of yersiniosis by beta-lactams is questionable considering the proven failure of newer beta-lactams for treating murine Yersinia enterocolitica infection. Another modality of experimental treatment was performed with a virulent strain of Y. pseudotuberculosis (nonproducer of beta-lactamase) highly susceptible (in terms of MICs) to amoxicillin, cefotaxime, ceftriaxone, imipenem, doxycycline, gentamicin, and ofloxacin. The in vivo comparative efficacy of these drugs was evaluated in a standardized and reproducible mouse model of systemic infection. Each single antibiotic was injected intravenously once, at 30 h after intravenous inoculation of the infective strain, and then repeatedly (at 30, 52, and 76 h postinfection). In vivo results were measured by counting the viable bacteria recovered from the whole spleens of mice sacrificed at selected times. Cefotaxime, even at high doses (250 mg/kg of body weight), was totally ineffective. Amoxicillin and imipenem at high doses (200 and 100 mg/kg, respectively) and ceftriaxone at usual doses (20 mg/kg) were active only in stopping bacterial proliferation to a more or less slight degree. Ceftriaxone was able to reduce viable counts in the spleen only at high doses (200 mg/kg), as were gentamicin (20 mg/kg) and doxycycline (125 mg/kg). Ofloxacin at the low dose of 5 mg/kg was demonstrated to be very effective by the very significant decrease observed in bacterial numbers from 10(6) to 10(3) CFU per spleen. The pharmacological parameters do not in themselves explain all the discrepancies between the in vitro and in vivo activities of beta-lactams on yersiniae. No emergence of beta-lactam-resistant organisms, which could explain the failure of beta-lactams, was detected. Thus, their use should be delayed in the therapy of human yersinosis until further investigations are carried out. The fluoroquinolone appeared more active and rapid than reference drugs in the treatment of murine yersinosis, which confirms initial clinical results.