isepamicin and Endocarditis

The effect of production of the aminoglycoside 6'-N-acetyltransferase [AAC(6')-IB] in Klebsiella pneumoniae on the outcome of amikacin and isepamicin treatment of rabbits with experimental endocarditis was assessed. Isogenic high-level (Hi) and low-level (Lo) AAC(6')-Ib-producing transconjugants (T) were constructed from clinical isolates with plasmid-borne resistance determinants. The MICs of amikacin and isepamicin, their bactericidal effects, and AAC(6')-Ib production appeared to be well correlated among the clinical isolates and the transconjugants. The susceptibility data determined in vitro, with MICs (in micrograms per milliliter) of amikacin and isepamicin for LoT and HiT of 4 and 0.5 and 32 and 8, respectively, were, however, not predictive of the in vivo efficacies of the drugs. While amikacin and isepamicin caused reductions in bacterial densities (log10 CFU per gram of cardiac vegetation) of 5.1 and 4.8 of the fully susceptible recipient strain (MICs of amikacin and isepamicin, 0.5 and 0.25, respectively), the reductions in density of both LoT and HiT caused by the two drugs (2.7 and 2.4 and 2.9 and 2.2, respectively) were only marginally significant, if at all. There was no significant difference (P > 0.05) when the reductions in density of LoT and HiT by either drug were compared or when the efficacies of the two drugs in reducing the density of any strain [non-AAC(6')-producing, LoT, or HiT] were compared (P > 0.5). It is concluded that AAC(6')-Ib in K.pneumoniae, even when produced at a low level and not conferring resistance to amikacin and isepamicin in vitro, compromises the efficacies of both drugs in vivo and possibly does so beyond the experimental model studied here.

Topics: Acetyltransferases; Amikacin; Animals; Anti-Bacterial Agents; Colony Count, Microbial; Drug Resistance, Microbial; Endocarditis; Female; Genes, Bacterial; Gentamicins; Klebsiella Infections; Klebsiella pneumoniae; Male; Mice; Rabbits

The pharmacokinetics and efficacy of isepamicin were compared with those of amikacin and gentamicin in a rabbit model of endocarditis due to Klebsiella pneumoniae CF104 producing beta-lactamase TEM-3 and aminoglycoside acetyltransferase AAC(6')-IV. Only isepamicin and gentamicin, alone or combined with ceftriaxone, were effective as determined by titration of viable bacteria in vegetations. Variants highly resistant to ceftriaxone without change in MICs of aminoglycosides were isolated at the end of each therapeutic regimen except with the most effective one (ceftriaxone plus gentamicin). Examination of the bacterial outer membrane proteins as well as the 50% inhibition of the beta-lactamase activity in intact and sonified cells suggested a permeability defect as being responsible for the increased MICs of ceftriaxone. The activity of isepamicin was superior to that of amikacin against the TEM-3-AAC(6')-IV-producing strain. The combination of gentamicin plus ceftriaxone was the most effective regimen in terms of efficacy and prevention of emergence of resistant strains. Suboptimal aminoglycoside monotherapy might be responsible for selection of permeability mutants to beta-lactams.

Topics: Acetyltransferases; Amikacin; Animals; Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; beta-Lactamases; beta-Lactams; Cell Membrane Permeability; Disease Models, Animal; Drug Therapy, Combination; Endocarditis; Female; Gentamicins; Klebsiella pneumoniae; Mutation; Rabbits