Efficacy of Tigecycline Alone and in Combination with Gentamicin in the Treatment of Experimental Endocarditis Due to Linezolid-Resistant Enterococcus faecium

Abstract

bWe evaluated the efficacy of tigecycline in a rabbit model of experimental endocarditis caused by a linezolid-resistant clinical strain of Enterococcus faecium. Tigecycline-treated animals had a 2.8-log 10 -CFU/g reduction in microbial counts in excised vegetations compared with controls. Addition of gentamicin caused a further arithmetical reduction in colony counts. The therapeutic effect was sustained 5 days after completion of treatment, as shown by relapse studies performed in treatment groups. Optimal treatment of multidrug-resistant (MDR) Enterococcus faecium endocarditis is an unresolved issue (1). Such an infection occurs primarily in the hospital environment, where rates of resistance to linezolid might reach 11 to 16% (2, 3) although still being less than 1% in the community (4). We evaluated the efficacy of tigecycline and explored the synergistic potential with gentamicin in a rabbit model of endocarditis caused by a linezolidresistant strain of ⌭. faecium.The bacterial isolate was collected during a vancomycin-resistant Enterococcus (VRE) outbreak (5). It harbored at least one copy of the G2576U mutation of 23S rRNA, which is linked to linezolid resistance. The isolate was esp gene positive as shown by PCR (5). MICs and minimal bactericidal concentrations (MBCs) were determined by broth microdilution, following CLSI guidelines (6). A time-kill assay was performed to evaluate the in vitro bactericidal effect of tigecycline and its combination with gentamicin against a high bacterial inoculum. CLSI definitions were used for interpretation of results (7).The optimal pharmacokinetic/pharmacodynamic (PK/PD) indicator of tigecycline activity is the area under the concentration-time curve (AUC)/MIC ratio (8). Human pharmacokinetic studies have shown that AUC values after 50-to 100-mg intravenous (i.v.) injections in steady state are between 3 and 5 mg · h/liter (9). A previous study (10) has documented that tigecycline dosing in rabbits has a linear relationship with AUC and that a single 7-mg/kg-of-body-weight dose produces an AUC of 9.5 mg · h/liter. Thus, we predicted that a 4-mg/kg dose would be appropriate and performed a confirmatory pharmacokinetic study, using an agar diffusion assay, with Bacillus subtilis ATCC 6633 as the indicator of tigecycline concentration. Blood was drawn from 2 healthy animals at serial time points after a single i.v. infusion of 4 mg/kg tigecycline. The maximum concentration of drug in serum (C max ) and AUC from 0 to 12 h (AUC 0 -12 ) were calculated.The study was approved by the Veterinary Directorate of the Prefecture of Athens (Athens, Greece).Endocarditis was induced to study animals at time zero as previously described (11). On day 1, rabbits were infected by intravenous administration of 10 8 CFU of the enterococcal strain. On day 2, animals were assigned to the following treatment groups: A, control (n ϭ 14); B, tigecycline (n ϭ 15); C, tigecycline plus gentamicin (n ϭ 15); D, tigecycline test of relapse (ToR) (n ϭ 12); E, tigecycline plus gentamicin ToR (n ϭ 13)...

Efficacy of tigecycline–colistin combination in the treatment of carbapenem-resistant Klebsiella pneumoniae endocarditis

“…Tigecycline, a novel glycylcycline, has been shown in experimental studies to be effective against a broad range of multidrug-resistant (MDR) Enterobacteriaceae such as carbapenem-resistant K. pneumoniae, either alone or in combination with other antimicrobial agents [3,4]. Moreover, several experimental reports suggest that it can be a possible salvage therapeutic option to treat IE due to MDR bacteria [5,6]. Here we report the case of patient admitted to the ICU of Habib Bourguiba University Hospital because of severe head injury.…”

Role of Combination Antimicrobial Therapy for Vancomycin‐Resistant Enterococcus faecium Infections: Review of the Current Evidence

“…Tigecycline has also been evaluated in combination with gentamicin. In a rabbit model of endocarditis caused by VRE faecium , tigecycline produced a significant decrease in bacterial load of vegetation in comparison to no treatment, and addition of gentamicin led to further reduction in colony count . Interestingly, sustainable antimicrobial activity of tigecycline alone and in combination with gentamicin was observed on day 5 after completion of treatment.…”

“…In a rabbit model of endocarditis caused by VRE faecium, tigecycline produced a significant decrease in bacterial load of vegetation in comparison to no treatment, and addition of gentamicin led to further reduction in colony count. 69 Interestingly, sustainable antimicrobial activity of tigecycline alone and in combination with gentamicin was observed on day 5 after completion of treatment. Similarly, in an in vitro, time-kill analysis including two strains of VRE faecium evaluating tigecycline and tigecycline combinations, addition of gentamicin improved bactericidal activity of tigecycline against both strains, even though the degree of enhancement was minimal in one strain.…”

Enterococcal Endocarditis Revisited

“…Immunosuppression, prior surgery and previous exposure to β-lactam antibiotics have been recently identified as the predictors of linezolid resistance development against vancomycin-resistant enterococci [175], and no worse outcomes have been found for those strains developing resistance to linezolid [176,177]. Tigecycline, alone or combined with gentamicin, has shown good activity against linezolid-resistant E. faecium strains [178]. However, some authors suggest using linezolid with precaution in VRE endocarditis until more data are made available [43].…”