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The effectiveness of ziracin (SCH27899), a novel everninomicin, was at first investigated against lethal pneumonia caused by a penicillin-susceptible Streptococcus pneumoniae strain. A single intravenous injection of ziracin at a dose of 60 mg/kg of body weight given at 18 h postinfection protected 100% mice and led to the complete clearance of bacteria from their lungs. The activity of ziracin was observed to be the same as that of ceftriaxone: the 50% protective doses (PD(50)s) of ziracin and ceftriaxone were 24.8 and 24.6 mg/kg, respectively. Evaluation of this therapy with leukopenic mice showed that a single injection of ziracin protected 75% of these mice. A delay in therapy with ziracin, which was initiated at 48 h postinfection with 30 mg/kg given once daily for 3 days, resulted in an 83% survival rate of immunocompetent mice. The efficacy of ziracin was further compared to that of vancomycin against lethal pneumonia caused by a penicillin-resistant S. pneumoniae strain in leukopenic mice. The PD(50)s of ziracin and vancomycin were 40.5 and 44.2 mg/kg, respectively. Treatment with ziracin at 30 mg/kg once daily for 2 days (initiated 18 h postinfection) yielded an 83% survival rate and achieved complete eradication of the bacteria. The results were the same as those obtained with vancomycin administered at 15 mg/kg twice daily for 2 days. It is notable that the high survival rates for mice treated with ziracin were associated with effective eradication of the bacteria and rapid recovery of pulmonary tissues from pneumonia. The pharmacokinetic properties of ziracin, ceftriaxone, and vancomycin were estimated following intravenous administration of a single dose of 30 mg/kg to immunocompetent mice. The half-life of ziracin was observed to be longer than those of ceftriaxone and vancomycin (2.3 h versus 1.0 and 0.36 h in the bloodstream and 3 h versus 1.9 and 0. 45 h in lung tissues). The areas under the concentration-time curves (AUCs) in lung tissue for ziracin versus those for ceftriaxone and vancomycin were 36 microg. h/g versus 20 and 9.5 microg. h/g. The prolonged half-life and high AUC for ziracin in tissue contributed to its excellent in vivo activities.

antimicrobial agents and chemotherapy

In Vivo Activity and Pharmacokinetics of Ziracin (SCH27899), a New Long-Acting Everninomicin Antibiotic, in a Murine Model of Penicillin-Susceptible or Penicillin-Resistant Pneumococcal Pneumonia