Gentamicin Improves the Activities of Daptomycin and Vancomycin against Enterococcus faecalis In Vitro and in an Experimental Foreign-Body Infection Model

Borens

et al. 2014

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bWe investigated the activities of fluconazole, caspofungin, anidulafungin, and amphotericin B against Candida species in planktonic form and biofilms using a highly sensitive assay measuring growth-related heat production (microcalorimetry). C. albicans, C. glabrata, C. krusei, and C. parapsilosis were tested, and MICs were determined by the broth microdilution method. The antifungal activities were determined by isothermal microcalorimetry at 37°C in RPMI 1640. For planktonic Candida, heat flow was measured in the presence of antifungal dilutions for 24 h. Candida biofilm was formed on porous glass beads for 24 h and exposed to serial dilutions of antifungals for 24 h, and heat flow was measured for 48 h. The minimum heat inhibitory concentration (MHIC) was defined as the lowest antifungal concentration reducing the heat flow peak by >50% (>90% for amphotericin B) at 24 h for planktonic Candida and at 48 h for Candida biofilms (measured also at 24 h). Fluconazole (planktonic MHICs, 0.25 to >512 g/ml) and amphotericin B (planktonic MHICs, 0.25 to 1 g/ml) showed higher MHICs than anidulafungin (planktonic MHICs, 0.015 to 0.5 g/ml) and caspofungin (planktonic MHICs, 0.125 to 0.5 g/ml). Against Candida species in biofilms, fluconazole's activity was reduced by >1,000-fold compared to its activity against the planktonic counterparts, whereas echinocandins and amphotericin B mainly preserved their activities. Fluconazole induced growth of planktonic C. krusei at sub-MICs. At high concentrations of caspofungin (>4 g/ml), paradoxical growth of planktonic C. albicans and C. glabrata was observed. Microcalorimetry enabled real-time evaluation of antifungal activities against planktonic and biofilm Candida organisms. It can be used in the future to evaluate new antifungals and antifungal combinations and to study resistant strains.

Section: Discussionsupporting

confidence: 57%

Activities of Fluconazole, Caspofungin, Anidulafungin, and Amphotericin B on Planktonic and Biofilm Candida Species Determined by Microcalorimetry

Maiolo

Borens

et al. 2014

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“…First, the infection inoculum was reduced from 10 5 to 10 4 CFU/ cage, and second, the duration of infection was shortened to 3 h, based on a previous study involving E. faecalis (10). If treatment was started after an infection duration of 24 h, no cure of cage infections was achieved with any antibiotic or combination regimen (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…While rifampin combination treatment has been established for staphylococcal implant-associated infections (9), an optimal treatment for enterococcal infections has not been determined. Despite gentamicin-containing regimens showing activity against Enterococcus faecalis biofilms in an experimental foreign-body infection model, the failure rates remain high (10).…”

mentioning

confidence: 99%

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Activities of Fosfomycin and Rifampin on Planktonic and Adherent Enterococcus faecalis Strains in an Experimental Foreign-Body Infection Model

Oliva

Maiolo

et al. 2014

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c Enterococcal implant-associated infections are difficult to treat because antibiotics generally lack activity against enterococcal biofilms. We investigated fosfomycin, rifampin, and their combinations against planktonic and adherent Enterococcus faecalis (ATCC 19433) in vitro and in a foreign-body infection model. The MIC/MBC log values were 32/>512 g/ml for fosfomycin, 4/>64 g/ml for rifampin, 1/2 g/ml for ampicillin, 2/>256 g/ml for linezolid, 16/32 g/ml for gentamicin, 1/>64 g/ml for vancomycin, and 1/5 g/ml for daptomycin. In time-kill studies, fosfomycin was bactericidal at 8؋ and 16؋ MIC, but regrowth of resistant strains occurred after 24 h. With the exception of gentamicin, no complete inhibition of growth-related heat production was observed with other antimicrobials on early (3 h) or mature (24 h) biofilms. In the animal model, fosfomycin alone or in combination with daptomycin reduced planktonic counts by Ϸ4 log 10 CFU/ml below the levels before treatment. Fosfomycin cleared planktonic bacteria from 74% of cage fluids (i.e., no growth in aspirated fluid) and eradicated biofilm bacteria from 43% of cages (i.e., no growth from removed cages). In combination with gentamicin, fosfomycin cleared 77% and cured 58% of cages; in combination with vancomycin, fosfomycin cleared 33% and cured 18% of cages; in combination with daptomycin, fosfomycin cleared 75% and cured 17% of cages. Rifampin showed no activity on planktonic or adherent E. faecalis, whereas in combination with daptomycin it cured 17% and with fosfomycin it cured 25% of cages. Emergence of fosfomycin resistance was not observed in vivo. In conclusion, fosfomycin showed activity against planktonic and adherent E. faecalis. Its role against enterococcal biofilms should be further investigated, especially in combination with rifampin and/or daptomycin treatment.

“…This animal model has been previously used for studying the activity of antimicrobial combinations against implant-associated infections and is predictive for clinical outcome (14)(15)(16)(17)(18)(19) …”

mentioning

confidence: 99%

High Activity of Fosfomycin and Rifampin against Methicillin-Resistant Staphylococcus aureus Biofilm In Vitro and in an Experimental Foreign-Body Infection Model

Mihăilescu

Corvec

et al. 2014

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103

e Increasing antimicrobial resistance reduces treatment options for implant-associated infections caused by methicillin-resistant Staphylococcus aureus (MRSA). We evaluated the activity of fosfomycin alone and in combination with vancomycin, daptomycin, rifampin, and tigecycline against MRSA (ATCC 43300) in a foreign-body (implantable cage) infection model. The MICs of the individual agents were as follows: fosfomycin, 1 g/ml; daptomycin, 0.125 g/ml; vancomycin, 1 g/ml; rifampin, 0.04 g/ ml; and tigecycline, 0.125 g/ml. Microcalorimetry showed synergistic activity of fosfomycin and rifampin at subinhibitory concentrations against planktonic and biofilm MRSA. In time-kill curves, fosfomycin exhibited time-dependent activity against MRSA with a reduction of 2.5 log 10 CFU/ml at 128 ؋ the MIC. In the animal model, planktonic bacteria in cage fluid were reduced by <1 log 10 CFU/ml with fosfomycin and tigecycline, 1.7 log 10 with daptomycin, 2.2 log 10 with fosfomycin-tigecycline and fosfomycin-vancomycin, 3.8 log 10 with fosfomycin-daptomycin, and >6.0 log 10 with daptomycin-rifampin and fosfomycin-rifampin. Daptomycin-rifampin cured 67% of cage-associated infections and fosfomycin-rifampin cured 83%, whereas all single drugs (fosfomycin, daptomycin, and tigecycline) and rifampin-free fosfomycin combinations showed no cure of MRSA cageassociated infections. No emergence of fosfomycin resistance was observed in animals; however, a 4-fold increase in fosfomycin MIC (from 2 to 16 g/ml) occurred in the fosfomycin-vancomycin group. In summary, the highest eradication of MRSA cageassociated infections was achieved with fosfomycin in combination with rifampin (83%). Fosfomycin may be used in combination with rifampin against MRSA implant-associated infections, but it cannot replace rifampin as an antibiofilm agent.