Comparative inactivation of isepamicin, amikacin, and gentamicin by nine beta-lactams and two beta-lactamase inhibitors, cilastatin and heparin

Abstract

This study was undertaken to compare the susceptibility to inactivation of isepamicin with amikacin and gentamicin when. exposed to different beta-lactams, ,I-lactamase inhibitors, and heparin. The aminoglycosides (5; 10, 20, and 50 ,g/ml) were incubated in human serum with ampicillin, azlocillin, aztreonam, carbenicillin, ceftazidime, piperacillin, and ticarcillin (100 and 600 ,ug/ml) and with clavulanate, cilastatin, 1:1 imipenemcilastatin? oxacilin, and sulbactam (20 and 120 ,ug/ml) for 48 h at 37°C. Aminoglycoside concentrations were measured by fluorescence polarization immunoassay (FPI) after 0, 8, and 48 h of incubation and by radial difibsion bipassay after 48 h of incubation. Each of the three aminoglycosides was also added to whole blood tontaihing either hebarin (100 U/ml) or 0.5% EDTA as a control and assayed after 6 h by FPI. The degree of inactivation of isepamicin by the beta-lactams was significantly less than that by amikacin (P < 0.003) and gentamAicih,(P < O.0.X2) when determined by bioassay. Piperacillin, carbenicillin, and azlocillin produced the greatest amount of inactivation, and cilastatin and oxacillin produced the least. A similar pattern was observed when the degree of inactivation ywvs measured by FPI. A significant difference in the degree of inactivation was noted between isepanticin and gentamicin (P < 0.003 at 8 h and P < 0.006 at 48 h) but not between isepamicin and amikacin (P> Q.7 at 8h and P > 0.08 at 48 h). Aminoglycoside determinations by FPI were not influenced by the,pirestnce of heparin. In summary, isepamicin was found to be at least as stable as amikacin against inactivration by beta-lactam compounds and Il-lactamase inhibitors. Heparin (100 U/ml) did not influence aminoglycoside determinations by FPL Aminoglycoside antibiotics interact with beta-lactam compounds and heparinr (11,12,14). The mechanism for the interaction with beta-lactams is thought to consist of a nuc1 ophilic opening of the beta-lactam ring by an amino group, leading to formation of. an amide, with loss of biological activity of both (2). Heparin in contrast binds by ionic ijiteraction only, a process that is reversible by dilution (12). The concentrations of heparin that are used therapeutically are too low for this to occur in vivo, but sufficient concentrations can be reached in blood collection tubes (12).The inactivation of aminoglycosides by beta-lactam antibiotics is clinically relevant for patients with renal failure, in whom beta-lactams can accumulate to high concentrations and inactivate an aminoglycoside given concomitantly (4,11,16). Loss of the aminoglycoside due to in vitro inactivation can also occur when specimens containing both compounds are processed after delay (14). Tissue culture media frequently contain both types of antibiotics, and inactivation can limit the time for storage and exchange of media.Isepamicin is an aminoglycoside with increased stability against enzymatic degradation and low oto-and nephrotoxicity (9). Its sensitivity to inactivation by beta-lactam compounds ...

Effect of concomitant administration of piperacillin on the dispositions of isepamicin and gentamicin in patients with end-stage renal disease

“…DISCUSSION Aminoglycosides have been used with extended-spectrum penicillins to provide wider antibacterial coverage against gram-negative bacilli through a synergistic effect (2,3,16,25,31,32). It is known, however, that the combined use may result in chemical inactivation of the aminoglycoside, leading to a loss in antibiotic activity (12,28). In vitro studies have demonstrated that the rate of inactivation is related to the incubation period, temperature, presence of solutes, and ,-lactam concentration (6,11,12,(21)(22)(23).…”

Plazomicin—a New Aminoglycoside—for Treating Complicated Urinary Tract Infections

“…Plazomicin against carbapenem susceptible A. baumannii (n = 8) and carbapenem resistant A. baumannii (n = 69) showed MIC values ranging from 0.5-16 μg/mL and 0.5-64 μg/mL, respectively (40). The AG inactivation by beta-lactam antibiotics has been observed in vivo and in vitro (41). Similar to other AGs, plazomicin showed lower in vitro efficacy against Stenotrophomonas maltophilia.…”

In vitro Activity of Isepamicin (Sch 21420), a New Aminoglycoside

“…Further more, Walterspiel et al [10] compared the inactivation of isepamicin, amikacin and gen tamicin by nine (1-lactams and two (l-lactam in- hibitors and concluded that isepamicin was su perior to gentamicin and at least as stable as amikacin, a property that constitutes an ad vantage in the monitoring of drug levels in pa tients with renal failure [11]. Studies on the post-antibiotic effect have shown that isepa micin was similar to netilmicin and gentamicin but had a faster activity [12].…”