Comparison of 5-Episisomicin (Sch 22591), Gentamicin, Sisomicin, and Tobramycin in Treatment of Experimental Pseudomonas Infections in Mice

Sch 22591 (5-episisomicin), gentamicin, sisomicin, and tobramycin were compared for their ability to protect mice from lethal intraperitoneal challenge with 12 Pseudomonas strains, all susceptible to each of the aminoglycosides (minimal inhibitory concentrations and minimal bactericidal concentrations were </=6.2 mug/ml). Median 50% protective doses were 5.8, 6.4, 7.7, and 17.8 mg/kg for Sch 22591, tobramycin, sisomicin, and gentamicin, respectively. Those for Sch 22591 were significantly lower than gentamicin in five protection tests and significantly lower than both gentamicin and tobramycin in one test. Microbial analysis of the therapeutic effect indicated that protection from lethality by each of the four aminoglycosides was associated with either a complete eradication or a reduction in the number of challenge bacteria in both the heart blood and peritoneum. In rare instances, challenge isolates exhibiting decreased susceptibility to one or more of the aminoglycosides were recovered from animals. However, this in vivo selection of resistance did not appear related to either the aminoglycoside used in therapy or the outcome of therapy, and resistant isolates were recovered as frequently from untreated animals as from those receiving one of the four aminoglycosides.