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

Yim, Juwon; Smith, Jordan R.; Rybak, Michael J.

doi:10.1002/phar.1922

Cited by 79 publications

(59 citation statements)

References 67 publications

(156 reference statements)

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“…In vitro studies showed lower MICs for Gramnegative bacteria on exposure to combination drugs than to monotherapies and delay in resistance emergence [30]. Combination therapies possess potential additional benefits of a wider activity spectrum and a synergistic effect and so may be effective in combating infections and improving clinical outcomes [31,32]. Real-life data in patients with multidrug-resistant Gram-negative infections seems to suggest that medical doctors use combination therapies to increase effectiveness and reduce resistance risk [33].…”

Section: Discussionmentioning

confidence: 99%

Estimating the association between antibiotic exposure and colonization with extended-spectrum β-lactamase-producing Gram-negative bacteria using machine learning methods: a multicentre, prospective cohort study

Tacconelli

Górska

Angelis

et al. 2020

Clinical Microbiology and Infection

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Extended-spectrum b-lactamaseIncidence rate Machine learning a b s t r a c t Objectives: The aim of the study was to measure the impact of antibiotic exposure on the acquisition of colonization with extended-spectrum b-lactamase-producing Gram-negative bacteria (ESBL-GNB) accounting for individual-and group-level confounding using machine-learning methods. Methods: Patients hospitalized between September 2010 and June 2013 at six medical and six surgical wards in Italy, Serbia and Romania were screened for ESBL-GNB at hospital admission, discharge, antibiotic start, and after 3, 7, 15 and 30 days. Primary outcomes were the incidence rate and predictive factors of new ESBL-GNB colonization. Random forest algorithm was used to rank antibiotics according to the risk of selection of ESBL-GNB colonization in patients not colonized before starting antibiotics. Results: We screened 10 034 patients collecting 28 322 rectal swab samples. New ESBL-GNB colonization incidence with and without antibiotic treatment was 22/1000 and 9/1000 exposure-days, respectively. In the adjusted regression analyses, antibiotic exposure (hazard ratio (HR) 2.38; 95% CI 1.29e4.40), age 60 e69 years (HR 1.19; 95% CI 1.05e1.34), and spring season (HR 1.25; 95% CI 1.14e1.38) were independently associated with new colonization. Monotherapy ranked higher als combination therapy in promoting ESBL-GNB colonization. Among monotherapy, cephalosporins ranked first followed by tetracycline (second), macrolide (fourth) and cotrimoxazole (seventh). Overall the ranking of cephalosporins was lower when used in combination. Among combinations not including cephalosporins, quinolones plus carbapenems ranked highest (eighth). Among sequential therapies, quinolones ranked highest (tenth) when prescribed within 30 days of therapy with cephalosporins. Conclusions: Impact of antibiotics on selecting ESBL-GNB at intestinal level varies if used in monotherapy or combination and according to previous antibiotic exposure. These finding should be explored in future clinical trials on antibiotic stewardship interventions.

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Section: Discussionmentioning

confidence: 99%

Estimating the association between antibiotic exposure and colonization with extended-spectrum β-lactamase-producing Gram-negative bacteria using machine learning methods: a multicentre, prospective cohort study

Tacconelli

Górska

Angelis

et al. 2020

Clinical Microbiology and Infection

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“…The increasing use of linezolid, one of the last-resort antibiotics, enhances the selective pressure for developing resistance to it in VRE strains (22). Currently, the speed of research and development of novel antimicrobial agents cannot keep pace with the increasing antibiotic resistance rates, so more and more unconventional combinations for the infection of VRE seem to be attractive options (23). The study conducted by Luther et al showed that the combination of linezolid and gentamicin combination enhanced antimicrobial activity against VRE (20).…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of linezolid-plus-fosfomycin against vancomycin-susceptible and -resistant enterococci in vitro and in vivo of a Galleria mellonella larval infection model

et al. 2019

Preprint

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25Objective: To explore the in vitro and in vivo antibacterial activity of 26 linezolid/fosfomycin combination against vancomycin-susceptible and -resistant 27 enterococci (VSE and VRE), providing theoretical basis for the treatment of VRE. 28Methods: The checkerboard method and time-kill curve study were used to evaluate 29 the synergistic effect of linezolid combined with fosfomycin against VSE and VRE. 30The transmission electron microscopy (TEM) was employed to observe the bacterial 31 cell morphology followed by each drug alone and in combination, elucidating the 32 possible result of antibiotic combination therapy. The Galleria mellonella infection 33 model was constructed to demonstrate the in vivo efficacy of linezolid plus 34 fosfomycin for VSE and VRE infection.35 Results: The fractional inhibitory concentration index (FICI) values of all strains 36 suggested that linezolid showed synergy or additivity in combination with fosfomycin 37 against five of the six strains. Time-kill experiments demonstrated that the 38 combination of linezolid-fosfomycin at 1MIC or 2MIC led to higher degree of 39 bacterial killing without regrowth for all isolates tested than each monotherapy. TEM 40 imaging showed that the combination treatment damaged the bacterial cell 41 morphology more obviously than each drug alone. In the Galleria mellonella infection 42 model, the enhanced survival rate of the combination treatment was revealed 43 compared to linezolid monotherapy (P<0.05). 44 Conclusions: Our data manifest that the combination of linezolid and fosfomycin may 45 be a possible therapeutic regimen for VRE infection. The combination displays 46 excellent bacterial killing and inhibits amplification of fosfomycin-resistant 47 subpopulations.48

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“…This approach fits with the call to action to assess whether single-target antibacterials can be used in combination to overcome resistance (34). Combination antimicrobial therapy, a mainstay for tuberculosis, is becoming increasingly common for other difficult-to-treat infections (35).…”

Section: Discussionmentioning

confidence: 99%

In Vivo and In Vitro Effects of a ClpP-Activating Antibiotic against Vancomycin-Resistant Enterococci

Gandt

Griffith

Lister

et al. 2018

Antimicrob Agents Chemother

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Antibiotics with novel bactericidal mechanisms of action are urgently needed. The antibiotic acyldepsipeptide 4 (ADEP4) activates the ClpP protease and causes cells to self-digest. The effects of ADEP4 and ClpP activation have not been characterized sufficiently for the enterococci, which are important pathogens known for high levels of acquired and intrinsic antibiotic resistance. In the present study, ADEP4 was found to be potently active against both and, with MICs of 0.016 μg/ml and 0.031 μg/ml, respectively. ClpP purified from was found to bind ADEP4 in a surface plasmon resonance analysis, and ClpP activation by ADEP4 was demonstrated biochemically with a β-casein digestion assay. In addition, ClpP was crystallized in the presence of ADEP4, revealing ADEP4 binding to ClpP in the activated state. These results confirm that the anti-enterococcal activity of ADEP4 occurs through ClpP activation. In killing curve assays, ADEP4 was found to be bactericidal against stationary-phase vancomycin-resistant (VRE) strain V583, and resistance development was prevented when ADEP4 was combined with multiple classes of approved antibiotics. ADEP4 in combination with partnering antibiotics also eradicated mature VRE biofilms within 72 h of treatment. Biofilm killing with ADEP4 antibiotic combinations was superior to that with the clinically used combinations ampicillin-gentamicin and ampicillin-daptomycin. In a murine peritoneal septicemia model, ADEP4 alone was as effective as ampicillin. ADEP4 coadministered with ampicillin was significantly more effective than either drug alone. These data suggest that ClpP-activating antibiotics may be useful for treating enterococcal infections.

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

Cited by 79 publications

References 67 publications

Estimating the association between antibiotic exposure and colonization with extended-spectrum β-lactamase-producing Gram-negative bacteria using machine learning methods: a multicentre, prospective cohort study

Estimating the association between antibiotic exposure and colonization with extended-spectrum β-lactamase-producing Gram-negative bacteria using machine learning methods: a multicentre, prospective cohort study

Pharmacodynamics of linezolid-plus-fosfomycin against vancomycin-susceptible and -resistant enterococci in vitro and in vivo of a Galleria mellonella larval infection model

In Vivo and In Vitro Effects of a ClpP-Activating Antibiotic against Vancomycin-Resistant Enterococci

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