Activity of Isepamicin and Selection of Permeability Mutants to β-Lactams during Aminoglycoside Therapy of Experimental Endocarditis Due to Klebsiella pneumoniae CF104 Producing an Aminoglycoside Acetyltransferase 6′ Modifying Enzyme and a TEM-3 β-Lactamase

• Published in: The Journal of infectious diseases 1994-06, Vol.169 (6), p.1318-1324
• Main Authors: Mainardi, Jean-Luc, Zhou, Xiang Yang, Goldstein, Fred, Mohler, Jacqueline, Farinotti, Robert, Gutmann, Laurent, Carbon, Claude
• Format: Article
• Language: English
• Subjects: Acetyltransferases - biosynthesis; Amikacin - pharmacokinetics; Amikacin - therapeutic use; Aminoglycosides; Animals; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - therapeutic use; Antibacterials; Antibiotics; Bacteria; Bacterial Outer Membrane Proteins - analysis; beta-Lactamases - biosynthesis; beta-Lactams; Cell Membrane Permeability; Disease Models, Animal; Drug Therapy, Combination - pharmacokinetics; Drug Therapy, Combination - therapeutic use; Endocarditis; Endocarditis - drug therapy; Endocarditis - microbiology; Female; Gentamicins - pharmacokinetics; Gentamicins - therapeutic use; Inoculum; Klebsiella pneumoniae; Klebsiella pneumoniae - drug effects; Klebsiella pneumoniae - enzymology; Klebsiella pneumoniae - genetics; Major Articles; Medical treatment; Mutation; Pharmacokinetics; Rabbits; Vegetation
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/169.6.1318

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 β-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 β-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 β-lactams.