Multidrug-Resistant Enterococcus faecium Endocarditis Treated with Combination Tigecycline and High-Dose Daptomycin

Schutt, Amanda C.; Bohm, Nicole

doi:10.1345/aph.1m324

Cited by 50 publications

(35 citation statements)

References 22 publications

(2 reference statements)

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“…Multiple other case reports describe daptomycin failures, some as a result of emergence of daptomycin-resistance during treatment. 210,211 Other investigators have suggested that higher doses of daptomycin (8-10 mg·kg…”

Section: Daptomycinmentioning

confidence: 99%

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Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications

Baddour¹,

Wilson²,

Bayer³

et al. 2015

Circulation

2,467

1,421

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Background— Infective endocarditis is a potentially lethal disease that has undergone major changes in both host and pathogen. The epidemiology of infective endocarditis has become more complex with today’s myriad healthcare-associated factors that predispose to infection. Moreover, changes in pathogen prevalence, in particular a more common staphylococcal origin, have affected outcomes, which have not improved despite medical and surgical advances. Methods and Results— This statement updates the 2005 iteration, both of which were developed by the American Heart Association under the auspices of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease of the Young. It includes an evidence-based system for diagnostic and treatment recommendations used by the American College of Cardiology and the American Heart Association for treatment recommendations. Conclusions— Infective endocarditis is a complex disease, and patients with this disease generally require management by a team of physicians and allied health providers with a variety of areas of expertise. The recommendations provided in this document are intended to assist in the management of this uncommon but potentially deadly infection. The clinical variability and complexity in infective endocarditis, however, dictate that these recommendations be used to support and not supplant decisions in individual patient management.

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Section: Daptomycinmentioning

confidence: 99%

“…[211][212][213][214][215][216][217] A number of in vitro evaluations [214][215][216] suggested that ampicillin and ceftaroline in combination with daptomycin demonstrate the greatest synergistic activity compared with other β-lactam-daptomycin combinations.…”

Section: Daptomycinmentioning

confidence: 99%

Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications

Baddour¹,

Wilson²,

Bayer³

et al. 2015

Circulation

2,467

1,421

View full text Add to dashboard Cite

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“…Similar results were reproduced in other studies examining the efficacy of tigecycline in experimental enterococcal endocarditis both in rabbits (10) and in rats (14). Moreover, successful use of tigecycline combinations has been described for clinical enterococcal endocarditis (15,16). A possible explanation for the discrepancy between tigecycline's bacteriostatic nature and these promising data would be the low MICs of Gram-positive cocci that allow achievement of high AUC/MIC values.…”

supporting

confidence: 79%

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

Pontikis

Pefanis

Τσαγανός

et al. 2013

Antimicrob Agents Chemother

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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)...

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“…Several reports have demonstrated effective use of daptomycin plus tigecycline for the treatment of endocarditis caused by E. faecium (44)(45)(46). In our hands, this combination was frequently antagonistic, but again, in vivo data are required to confirm this finding.…”

Section: Discussionmentioning

confidence: 53%

In Vitro Activity of Daptomycin in Combination with β-Lactams, Gentamicin, Rifampin, and Tigecycline against Daptomycin-Nonsusceptible Enterococci

Wong-Beringer

Charlton

Miller

et al. 2015

Antimicrob Agents Chemother

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f Enterococci that are nonsusceptible (NS; MIC > 4 g/ml) to daptomycin are an emerging clinical concern. The synergistic combination of daptomycin plus beta-lactams has been shown to be effective against vancomycin-resistant Enterococcus (VRE) species in vitro. This study systematically evaluated by in vitro time-kill studies the effect of daptomycin in combination with ampicillin, cefazolin, ceftriaxone, ceftaroline, ertapenem, gentamicin, tigecycline, and rifampin, for a collection of 9 daptomycin-NS enterococci that exhibited a broad range of MICs and different resistance-conferring mutations. We found that ampicillin plus daptomycin yielded the most consistent synergy but did so only for isolates with mutations to the liaFSR system. Daptomycin binding was found to be enhanced by ampicillin in a representative isolate with such mutations but not for an isolate with mutation to the yycFGHIJ system. In contrast, ampicillin enhanced the killing of the LL-37 human antimicrobial peptide against daptomycin-NS E. faecium with either the liaFSR or yycFGHIJ mutation. Antagonism was noted only for rifampin and tigecycline and only for 2 or 3 isolates. These data add support to the growing body of evidence indicating that therapy combining daptomycin and ampicillin may be helpful in eradicating refractory VRE infections. Daptomycin is a cyclic lipopeptide antimicrobial agent with bactericidal activity against Gram-positive bacteria, including Enterococcus spp. Daptomycin is not approved by the U.S. Food and Drug Administration (FDA) for the treatment of infections caused by vancomycin-resistant Enterococcus (VRE) strains (e.g., vancomycin-resistant Enterococcus faecalis) or by vancomycin-susceptible or -resistant E. faecium strains. However, due to a limited number of available therapeutic options, daptomycin is frequently used in clinical practice for treatment of serious infections caused by these bacteria. No daptomycin resistance breakpoint has been established for the enterococci by the Clinical and Laboratory Standards Institute or the U.S. FDA. Isolates with MICs above the susceptible breakpoint of 4 g/ml are therefore referred to as daptomycin-nonsusceptible (DNS) isolates (1). The prevalence of DNS Enterococcus strains in the United States remains low, ranging from 0.02% for E. faecalis to 0.18% for E. faecium (2). Nonetheless, we and others have isolated DNS Enterococcus strains from both patients treated with and patients naive to daptomycin therapy (3-8) and much higher rates of DNS E. faecium have been reported in Europe (9).The recent description of daptomycin-susceptible Enterococcus strains for which daptomycin exhibits only bacteriostatic activity (10, 11) brings further into question the role of daptomycin for the treatment of enterococcal infections. These isolates have decreased susceptibility to daptomycin (DSD), with daptomycin MICs ranging from 3 to 4 g/ml, which is higher than the wildtype modal daptomycin MICs of 0.5 g/ml for E. faecalis and 2.0 g/ml for E. faecium (12). These isolates harbor po...

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Multidrug-Resistant Enterococcus faecium Endocarditis Treated with Combination Tigecycline and High-Dose Daptomycin

Abstract: Increasing doses of daptomycin may enhance efficacy without compromising safety, even in patients with some renal dysfunction. The combination of daptomycin and tigecycline may be useful for the treatment of multidrug-resistant E. faecium.

Cited by 50 publications

References 22 publications

Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications

Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications

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

In Vitro Activity of Daptomycin in Combination with β-Lactams, Gentamicin, Rifampin, and Tigecycline against Daptomycin-Nonsusceptible Enterococci

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