Emergence of Teicoplanin Resistance During Therapy of Staphylococcus aureus Endocarditis

Abstract

Serial isolates of Staphylococcus aureus showing two- to eightfold increases in teicoplanin minimum inhibitory concentrations (MICs) and twofold or less increases in MICs of other glycopeptides were recovered from the blood of a patient with endocarditis in whom drug therapy was unsuccessful. Comparable resistance emerged during teicoplanin treatment of rabbits with endocarditis caused by the original susceptible parent strain. For the parent strain, spontaneous resistance to teicoplanin at concentrations of 2-10 times the MIC was detected in vitro at frequencies of 10(-7) to 10(-9). Similar results were found for isolates of S. aureus from other geographic locations. Resistance was constitutive and not plasmid mediated, and its acquisition was not associated with changes in cytoplasmic membrane proteins. Teicoplanin was less effective than vancomycin at inhibiting peptidoglycan synthesis in resistant strains, suggesting that there is differential interference with the access of teicoplanin to or interaction with its target(s). Alternatively, teicoplanin and vancomycin may differ in some detail(s) of their mechanism of action against S. aureus.

Bactericidal activities of teicoplanin, vancomycin, and gentamicin alone and in combination against Staphylococcus aureus in an in vitro pharmacodynamic model of endocarditis

“…A clinical isolate of S. aureus (isolate 12871) was obtained (prior to antibiotic treatment) from a patient being treated for endocarditis at Detroit Receiving Hospital. This isolate was originally methicillin and teicoplanin susceptible; however, following 10 days of teicoplanin administered at a dose of 6 mg/kg of body weight, the MIC of teicoplanin increased eightfold (28 concentration was expressed as the ratio of the antibiotic concentration in the cryoprecipitate, thrombin, or cryoprecipitate-thrombin mixture to that in SMHB multiplied by 100. Minimal adsorption of antibiotics to this system has been reported previously (29).…”

“…VOL. 38,1994 on April 27, 2019 by guest http://aac.asm.org/ Downloaded from vegetation, decreased antibiotic activity under anaerobic and acidic conditions, impaired host defenses at the site of infection, the high degree of virulence of some infecting pathogens, and the development of resistance (4,14,28). These problems have been highlighted with the recent failure of teicoplanin for the treatment of endocarditis caused by susceptible strains of S. aureus (10,22).…”

“…Conditions in the in vitro model of endocarditis were designed to simulate the pharmacokinetics of teicoplanin, vancomycin, and gentamicin in humans. The clinical isolate studied (S. aureus 12871) was chosen because the isolate developed teicoplanin resistance during therapy with teicoplanin at 3 mg/kg (28).…”

“…Infective endocarditis continues to be a difficult therapeutic problem because of the poor penetration of antibiotics, large inoculum size, the development of resistance, and the lack of host defense at the infection site (4,10,14,22,28,33). In the case of endocarditis caused by Staphylococcus aureus, the treatment choices remain extremely limited.…”

“…Vancomycin has been the mainstay of treatment for methicillin-resistant S. aureus (4). Teicoplanin is an investigational glycopeptide antibiotic with a spectrum of activity and mechanism of action similar to those of vancomycin (8,28). Like vancomycin, teicoplanin's killing activity is not concentration dependent (1).…”