Treatment of experimental endocarditis caused by a beta-lactamase-producing strain of Enterococcus faecalis with high-level resistance to gentamicin

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Penicillin-"virgin" strains of Enterococcus faecalis collected from a population of individuals with no previous antibiotic exposure were subjected in vitro to penicillin delivered as repeated pulses, stepwise increasing concentrations, or sustained levels of a single concentration. Changes in resistance to penicillin were assessed by determination of MICs, and time-kill studies were performed to evaluate changes in tolerance to the bactericidal effects of penicillin. Isogenic clones, derived from various exposure regimens, which exhibited changes in either resistance or tolerance were further examined for changes in penicillin-binding proteins. Exposure to repeated pulses of penicillin resulted in the development of tolerance to penicillin without changes in the level of resistance. Clones derived from a regimen of stepwise increases in the penicillin concentration acquired both increased penicillin resistance and tolerance. Clones selected after prolonged continuous exposure to a fixed concentration of penicillin displayed minimally increased resistance to penicillin, but they retained the lytic, nontolerant response to the bactericidal effect of penicillin. Clones which acquired tolerance to the bactericidal effect of penicillin without changes in penicillin resistance exhibited a penicillin-binding protein pattern identical to that of the parental strain. Increased labeling of several penicillin-binding proteins accompanied the development of increased penicillin resistance in both penicillin-tolerant and nontolerant strains. Exposure of E. faecalis to penicillin in repeated pulses of brief duration, for prolonged periods at a constant concentration, or in stepwise graded concentrations can result in the selection of clones with increased resistance to the inhibitory or bactericidal effects of penicillin, or both. These observations may be relevant to the selection of dosing regimens for penicillin in the treatment of enterococcal infections, when bactericidal synergism cannot be achieved with penicillin-aminoglycoside combinations.

Section: Discussionmentioning

confidence: 99%

Antimicrobial susceptibility changes in Enterococcus faecalis following various penicillin exposure regimens

Hodges

Zighelboim-Daum

Eliopoulos

et al. 1992

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“…Experimental endocarditis was established as described previously (6). Two enterococcal strains were used in these experiments: vancomycin-susceptible strain E. faecalis 1310 and vancomycin-resistant (VanA) strain E. faecium A1221.…”

mentioning

confidence: 99%

Activities of Taurolidine In Vitro and in Experimental Enterococcal Endocarditis

Torres-Viera

Thauvin-Eliopoulos

Souli

et al. 2000

In vitro, the antimicrobial agent taurolidine inhibited virtually all of the bacteria tested, including vancomycin-resistant enterococci, oxacillin-resistant staphylococci, and Stenotrophomonas maltophilia, at concentrations between 250 and 2,000 g/ml. Taurolidine was not effective in experimental endocarditis. While it appears unlikely that this antimicrobial would be useful for systemic therapy, its bactericidal activity and the resistance rates found (<10 ؊9 ) are favorable indicators for its possible development for topical use.With the continuing emergence of multiply antibiotic-resistant organisms, the need to develop new therapeutic agents remains evident. Taurolidine [bis-(1,1-dioxoperhydro-1,2,4-thiadiazinyl-4)methane], a derivative of the amino acid taurine, is an antimicrobial agent which inhibits and kills a broad range of microorganisms in vitro, albeit at high concentrations (3,4,9,11,13). This compound acts through mechanisms unlike those described for other currently available antimicrobials. Specifically, it is believed that methylol derivatives interact with components of bacterial cell walls resulting in irreparable injury (4). Taurolidine also appears to have immunoregulatory properties, blunting lipopolysaccharide-induced tumor necrosis factor and interleukin-1 release from human peripheral blood mononuclear cells (2) and also reducing adherence of bacteria to human epithelial cells in vitro (5). The compound has been given to humans both intravenously (i.v.) and by peritoneal lavage (1, 12).The purpose of the present study was to examine the in vitro activity of taurolidine against a broad variety of bacterial species, including antibiotic-resistant strains. We also evaluated the activity of taurolidine in vivo in experimental endocarditis using two strains of enterococci, one of which was a vancomycin-resistant strain of Enterococcus faecium.Most of the bacterial strains used in this study were routine isolates collected by our clinical microbiology laboratory during 1997. Additional strains from our collection were included based upon specific resistance traits. Taurolidine was provided by Wallace Laboratories, Cranbury, N.J. Antimicrobial reference standards of ciprofloxacin, imipenem, and cefotaxime were provided by Bayer Corporation, West Haven, Conn.; Merck & Co., Inc., West Point, Pa.; and Hoechst Marion Roussel, Inc., Kansas City, Mo., respectively. Vancomycin was obtained from Eli Lilly & Co., Indianapolis, Ind. MICs were determined by agar dilution (7, 8) on Mueller-Hinton II agar (BBL Microbiology Systems, Cockeysville, Md.) except as noted otherwise. Agar was supplemented with 5% sheep blood for streptococci and diphtheroids. Inocula were ca. 10 4 (10 5 for anaerobes) CFU/spot. Plates were incubated in room air and read at 18 to 20 h, except for lactobacilli, Leuconostoc spp., Pediococcus spp., and pneumococci, which were incubated in 5% CO 2 and examined for growth at 24 h. Anaerobes were incubated for 48 h on brucella agar in an atmosphere produced by Gas-Pak Plus (BBL). Time-...

“…(i.e., continuous versus intermittent antibiotic infusion or faecalis has been achieved with imipenem (6), vancomycin the interval between doses), differences in animal models (3,6,7,25), teicoplanin (3,25), penicillin-clavulanic acid (7), and physiology (i.e., rabbit model versus rat model), the and ampicillin-sulbactam (3,6). Several injection of the bacterial inoculum or removal of the catheter during infection), and, finally, the duration of therapy (4,5,20).…”

Section: Discussionmentioning

confidence: 99%

Comparison of ampicillin-sulbactam with vancomycin for treatment of experimental endocarditis due to a beta-lactamase-producing, highly gentamicin-resistant isolate of Enterococcus faecalis

Lavoie

Wong

Coudron

et al. 1993

whether treatment was continued for 3 or 7 days. The addition of gentamicin was not associated with increased killing in rabbits infected with the aminoglycoside-resistant isolate. Both high-dose ampicillin-sulbactam and vancomycin regimens demonstrated significant, continued reduction in bacterial titers with the longer periods of treatment (P c 0.05); 7-day treatment with high-dose ampicillin-sulbactam produced a greater reduction in bacterial titers in vegetation than 7-day treatment with vancomycin (P c 0.05). We conclude that ampicillinsulbactam and vancomycin are equally effective in the treatment of experimental endocarditis due to 13-lactamase-producing, highly gentamicin-resistant E. faecalis. The optimum therapy for such infections in humans is not known.Increasing antibiotic resistance has complicated the treatment of serious infections due to enterococci, particularly those due to Enterococcus faecalis. Such infections require a bactericidal therapy, which is usually obtained only with a synergistic combination of a cell-wall-active agent, such as a P-lactam antibiotic or vancomycin, and an aminoglycoside for cure (9,13,(20)(21)(22)24). The emergence of high-level aminoglycoside resistance and the appearance of 1-lactamase-producing strains of E. faecalis (15) and Enterococcus faecium (1) are noteworthy for two reasons: (i) the number of treatment options is reduced because synergism is not observed when aminoglycosides to which the organism has demonstrated high-level resistance are used (12), and (ii) ,-lactamase production has been shown to influence the clinical outcome of infections due to these organisms (23). We have previously shown that ampicillin-sulbactam was bactericidal by the time-kill method for 13 of 20 ,-lactamaseproducing, highly gentamicin-resistant strains of E. faecalis, while bactericidal activity was absent with vancomycin against all 20 strains (10). Currently, the optimum treatment of serious infections caused by I-lactamase-producing, highly gentamicin-resistant E. faecalis has not been determined. In the studies reported herein, we evaluated the efficacy of ampicillin-sulbactam and vancomycin (each alone * Corresponding author. and in combination with gentamicin) in the treatment of experimental aortic valve endocarditis caused by a 3-lactamase-producing, highly gentamicin-resistant isolate of E. faecalis and compared these data with the results obtained in the treatment of experimental endocarditis caused by a non-p-lactamase-producing, gentamicin-susceptible E. faecalis isolate.(This study was presented in part at the 92nd General Meeting of the American Society for Microbiology, 1992 [8].) MATERIALS AND METHODS Bacterial strain. E. faecalis E-48, a ,-lactamase-producing, gentamicin-resistant isolate, was used to inoculate rabbits. The MICs for E. faecalis E-48 were as follows: ampicillin, 4 ,ug/ml; sulbactam, .8 ,ug/ml; ampicillin-sulbactam, 1 ,ug of ampicillin per ml; vancomycin, 4 ,ug/ml; and gentamicin, .2,000 ,ug/ml. In addition, several rabbits were inoculated wi...