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

ABSTRACTFor enterococcal implant-associated infections, the optimal treatment regimen has not been defined. We investigated the activity of daptomycin, vancomycin, and gentamicin (and their combinations) againstEnterococcus faecalis in vitroand in a foreign-body infection model. Antimicrobial activity was investigated by time-kill and growth-related heat production studies (microcalorimetry) as well as with a guinea pig model using subcutaneously implanted cages. Infection was established by percutaneous injection ofE. faecalisin the cage. Antibiotic treatment for 4 days was started 3 h after infection. Cages were removed 5 days after end of treatment to determine the cure rate. The MIC, the minimal bactericidal concentration (MBC) in the logarithmic phase, and the MBC in the stationary phase were 1.25, 5, and >20 μg/ml for daptomycin, 1, >64, and >64 μg/ml for vancomycin, and 16, 32, and 4 μg/ml for gentamicin, respectively.In vitro, gentamicin at subinhibitory concentrations improved the activity againstE. faecaliswhen combined with daptomycin or vancomycin in the logarithmic and stationary phases. In the animal model, daptomycin cured 25%, vancomycin 17%, and gentamicin 50% of infected cages. In combination with gentamicin, the cure rate for daptomycin increased to 55% and that of vancomycin increased to 33%. In conclusion, daptomycin was more active than vancomycin against adherentE. faecalis, and its activity was further improved by the addition of gentamicin. Despite a short duration of infection (3 h), the cure rates did not exceed 55%, highlighting the difficulty of eradicatingE. faecalisfrom implants already in the early stage of implant-associated infection.

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Activities of Fosfomycin, Tigecycline, Colistin, and Gentamicin against Extended-Spectrum-β-Lactamase-Producing Escherichia coli in a Foreign-Body Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01718-12 ◽

2013 ◽

Vol 57 (3) ◽

pp. 1421-1427 ◽

Cited By ~ 66

Author(s):

Stéphane Corvec ◽

Ulrika Furustrand Tafin ◽

Bertrand Betrisey ◽

Olivier Borens ◽

Andrej Trampuz

Keyword(s):

Escherichia Coli ◽

Foreign Body ◽

Single Agent ◽

Infection Model ◽

Minimal Bactericidal Concentration ◽

Synergistic Activity ◽

Cure Rate ◽

Gram Negative ◽

Content Type

ABSTRACTLimited antimicrobial agents are available for the treatment of implant-associated infections caused by fluoroquinolone-resistant Gram-negative bacilli. We compared the activities of fosfomycin, tigecycline, colistin, and gentamicin (alone and in combination) against a CTX-M15-producing strain ofEscherichia coli(Bj HDE-1)in vitroand in a foreign-body infection model. The MIC and the minimal bactericidal concentration in logarithmic phase (MBClog) and stationary phase (MBCstat) were 0.12, 0.12, and 8 μg/ml for fosfomycin, 0.25, 32, and 32 μg/ml for tigecycline, 0.25, 0.5, and 2 μg/ml for colistin, and 2, 8, and 16 μg/ml for gentamicin, respectively. In time-kill studies, colistin showed concentration-dependent activity, but regrowth occurred after 24 h. Fosfomycin demonstrated rapid bactericidal activity at the MIC, and no regrowth occurred. Synergistic activity between fosfomycin and colistinin vitrowas observed, with no detectable bacterial counts after 6 h. In animal studies, fosfomycin reduced planktonic counts by 4 log10CFU/ml, whereas in combination with colistin, tigecycline, or gentamicin, it reduced counts by >6 log10CFU/ml. Fosfomycin was the only single agent which was able to eradicateE. colibiofilms (cure rate, 17% of implanted, infected cages). In combination, colistin plus tigecycline (50%) and fosfomycin plus gentamicin (42%) cured significantly more infected cages than colistin plus gentamicin (33%) or fosfomycin plus tigecycline (25%) (P< 0.05). The combination of fosfomycin plus colistin showed the highest cure rate (67%), which was significantly better than that of fosfomycin alone (P< 0.05). In conclusion, the combination of fosfomycin plus colistin is a promising treatment option for implant-associated infections caused by fluoroquinolone-resistant Gram-negative bacilli.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02583-12 ◽

2013 ◽

Vol 58 (3) ◽

pp. 1284-1293 ◽

Cited By ~ 34

Author(s):

Alessandra Oliva ◽

Ulrika Furustrand Tafin ◽

Elena Maryka Maiolo ◽

Safaa Jeddari ◽

Bertrand Bétrisey ◽

...

Keyword(s):

Foreign Body ◽

Enterococcus Faecalis ◽

Infection Model ◽

Content Type ◽

Inhibition Of Growth ◽

Planktonic Bacteria ◽

Biofilm Bacteria ◽

Time Kill

ABSTRACTEnterococcal 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 adherentEnterococcus faecalis(ATCC 19433)in vitroand in a foreign-body infection model. The MIC/MBClogvalues were 32/>512 μg/ml for fosfomycin, 4/>64 μg/ml for rifampin, 1/2 μg/ml for ampicillin, 2/>256 μg/ml for linezolid, 16/32 μg/ml for gentamicin, 1/>64 μg/ml for vancomycin, and 1/5 μg/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 ≈4 log10CFU/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 adherentE. faecalis, whereas in combination with daptomycin it cured 17% and with fosfomycin it cured 25% of cages. Emergence of fosfomycin resistance was not observedin vivo. In conclusion, fosfomycin showed activity against planktonic and adherentE. faecalis. Its role against enterococcal biofilms should be further investigated, especially in combination with rifampin and/or daptomycin treatment.

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Role of Rifampin against Propionibacterium acnes BiofilmIn Vitroand in an Experimental Foreign-Body Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05552-11 ◽

2012 ◽

Vol 56 (4) ◽

pp. 1885-1891 ◽

Cited By ~ 113

Author(s):

Ulrika Furustrand Tafin ◽

Stéphane Corvec ◽

Bertrand Betrisey ◽

Werner Zimmerli ◽

Andrej Trampuz

Keyword(s):

Foreign Body ◽

Propionibacterium Acnes ◽

Penicillin G ◽

Infection Model ◽

Minimal Bactericidal Concentration ◽

Content Type ◽

Planktonic Form ◽

Cure Rates

ABSTRACTPropionibacterium acnesis an important cause of orthopedic-implant-associated infections, for which the optimal treatment has not yet been determined. We investigated the activity of rifampin, alone and in combination, against planktonic and biofilmP. acnes in vitroand in a foreign-body infection model. The MIC and the minimal bactericidal concentration (MBC) were 0.007 and 4 μg/ml for rifampin, 1 and 4 μg/ml for daptomycin, 1 and 8 μg/ml for vancomycin, 1 and 2 μg/ml for levofloxacin, 0.03 and 16 μg/ml for penicillin G, 0.125 and 512 μg/ml for clindamycin, and 0.25 and 32 μg/ml for ceftriaxone. TheP. acnesminimal biofilm eradication concentration (MBEC) was 16 μg/ml for rifampin; 32 μg/ml for penicillin G; 64 μg/ml for daptomycin and ceftriaxone; and ≥128 μg/ml for levofloxacin, vancomycin, and clindamycin. In the animal model, implants were infected by injection of 109CFUP. acnesin cages. Antimicrobial activity onP. acneswas investigated in the cage fluid (planktonic form) and on explanted cages (biofilm form). The cure rates were 4% for daptomycin, 17% for vancomycin, 0% for levofloxacin, and 36% for rifampin. Rifampin cured 63% of the infected cages in combination with daptomycin, 46% with vancomycin, and 25% with levofloxacin. While all tested antimicrobials showed good activity against planktonicP. acnes, for eradication of biofilms, rifampin was needed. In combination with rifampin, daptomycin showed higher cure rates than with vancomycin in this foreign-body infection model.

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Ampicillin in Combination with Ceftaroline, Cefepime, or Ceftriaxone Demonstrates Equivalent Activities in a High-Inoculum Enterococcus faecalis Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03126-15 ◽

2016 ◽

Vol 60 (5) ◽

pp. 3178-3182 ◽

Cited By ~ 10

Author(s):

Megan K. Luther ◽

Louis B. Rice ◽

Kerry L. LaPlante

Keyword(s):

Combination Therapy ◽

Enterococcus Faecalis ◽

Pharmacodynamic Model ◽

Infection Model ◽

Vancomycin Resistant Enterococcus ◽

Content Type ◽

Time Profiles ◽

Concentration Time ◽

Vancomycin Resistant

ABSTRACTAmpicillin-ceftriaxone combination therapy has become a predominant treatment for seriousEnterococcus faecalisinfections, such as endocarditis. Unfortunately, ceftriaxone use is associated with future vancomycin-resistant enterococcus colonization. We evaluatedE. faecalisin anin vitropharmacodynamic model against simulated human concentration-time profiles of ampicillin plus ceftaroline, cefepime, ceftriaxone, or gentamicin. Ampicillin-cefepime and ampicillin-ceftaroline demonstrated activities similar to those of ampicillin-ceftriaxone againstE. faecalis.

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Edwardsiella tarda Eta1, anIn Vivo-Induced Antigen That Is Involved in Host Infection

Infection and Immunity ◽

10.1128/iai.00063-12 ◽

2012 ◽

Vol 80 (8) ◽

pp. 2948-2955 ◽

Cited By ~ 30

Author(s):

Yun Sun ◽

Wen-Jiang Zheng ◽

Yong-Hua Hu ◽

Bo-Guang Sun ◽

Li Sun

Keyword(s):

Early Stage ◽

Paralichthys Olivaceus ◽

Cellular Level ◽

Host Cells ◽

Edwardsiella Tarda ◽

Pcr Analysis ◽

Logarithmic Phase ◽

Content Type

ABSTRACTEdwardsiella tarda, a Gram-negative bacterium, is a severe fish pathogen that can also infect humans. In this study, we identified, viain vivo-induced antigen technology, anE. tardaantigen, Eta1, and analyzed its function in a Japanese flounder (Paralichthys olivaceus) model. Eta1 is composed of 226 residues and shares homology with putative bacterial adhesins. Quantitative real-time reverse transcriptase (RT)-PCR analysis indicated that when culturedin vitro,eta1expression was growth phase dependent and reached maximum at mid-logarithmic phase. During infection of flounder lymphocytes,eta1expression was drastically increased at the early stage of infection. Compared to the wild type, theeta1-defective mutant, TXeta1, was unaffected in growth but exhibited attenuated overall virulence, reduced tissue dissemination and colonization capacity, and impaired ability to invade flounder lymphocytes and to block the immune response of host cells. The lost virulence of TXeta1 was restored when a functionaleta1gene was reintroduced into the strain. Western blot and immunodetection analyses showed that Eta1 is localized to the outer membrane and exposed on the surface ofE. tardaand that recombinant Eta1 (rEta1) was able to interact with flounder lymphocytes. Consistent with these observations, antibody blocking of Eta1 inhibitedE. tardainfection at the cellular level. Furthermore, when used as a subunit vaccine, rEta1 induced strong protective immunity in flounder against lethalE. tardachallenge. Taken together, these results indicate that Eta1 is anin vivo-induced antigen that mediates pathogen-host interaction and, as a result, is required for optimal bacterial infection.

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Efficacy of Daptomycin-Cloxacillin Combination in Experimental Foreign-Body Infection Due to Methicillin-Resistant Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00127-12 ◽

2012 ◽

Vol 56 (7) ◽

pp. 3806-3811 ◽

Cited By ~ 22

Author(s):

C. Garrigós ◽

O. Murillo ◽

J. Lora-Tamayo ◽

R. Verdaguer ◽

F. Tubau ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Foreign Body ◽

Infection Model ◽

Cure Rate ◽

Methicillin Resistant ◽

Content Type ◽

Resistant Strains ◽

High Doses ◽

Rat Tissue

ABSTRACTDespite the use of daptomycin alone at high doses (greater than 6 mg/kg of body weight/day) against difficult-to-treat infections, clinical failures and resistance appeared. Recently, the combination daptomycin-cloxacillin showed enhanced efficacy in clearing bacteremia caused by methicillin-resistantStaphylococcus aureus(MRSA). The aim of this study was to evaluate the efficacy of daptomycin at usual and high doses (equivalent to 6 and 10 mg/kg/day in humans, respectively) in combination with cloxacillin in a rat tissue cage infection model by MRSA and to compare its efficacy to that of daptomycin-rifampin. We used MRSA strain ATCC BAA-39. In the log- and stationary-phase kill curves, daptomycin-cloxacillin improved the bactericidal activity of daptomycin, especially in log phase. Forin vivostudies, therapy was administered intraperitoneally for 7 days with daptomycin at 100 mg/kg/day and 45/mg/kg/day (daptomycin 100 and daptomycin 45), daptomycin 100-cloxacillin at 200 mg/kg/12 h, daptomycin 45-cloxacillin, and daptomycin 100-rifampin at 25 mg/kg/12 h. Daptomycin-rifampin was the best therapy (P< 0.05). Daptomycin 45 was the least effective treatment and did not protect against the emergence of resistant strains. There were no differences between the two dosages of daptomycin plus cloxacillin in any situation, and both protected against resistance. The overall effect of the addition of cloxacillin to daptomycin was a significantly greater cure rate (against adhered bacteria) than that for daptomycin alone. In conclusion, daptomycin-cloxacillin enhanced modestly thein vivoefficacy of daptomycin alone against foreign-body infection by MRSA and was less effective than daptomycin plus rifampin. The benefits of adding cloxacillin to daptomycin should be especially evaluated against infections by rifampin-resistant MRSA and for protection against the emergence of daptomycin nonsusceptibility.

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Linezolid Alone or Combined with Rifampin against Methicillin-Resistant Staphylococcus aureus in Experimental Foreign-Body Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00775-08 ◽

2008 ◽

Vol 53 (3) ◽

pp. 1142-1148 ◽

Cited By ~ 83

Author(s):

Daniela Baldoni ◽

Manuel Haschke ◽

Zarko Rajacic ◽

Werner Zimmerli ◽

Andrej Trampuz

Keyword(s):

Staphylococcus Aureus ◽

Foreign Body ◽

Test Organism ◽

Stationary Growth Phase ◽

Minimal Bactericidal Concentration ◽

Logarithmic Phase ◽

Methicillin Resistant ◽

Bacterial Regrowth ◽

Planktonic Bacteria

ABSTRACT We investigated the activity of linezolid, alone and in combination with rifampin (rifampicin), against a methicillin-resistant Staphylococcus aureus (MRSA) strain in vitro and in a guinea pig model of foreign-body infection. The MIC, minimal bactericidal concentration (MBC) in logarithmic phase, and MBC in stationary growth phase were 2.5, >20, and >20 μg/ml, respectively, for linezolid; 0.01, 0.08, and 2.5 μg/ml, respectively, for rifampin; and 0.16, 0.63, >20 μg/ml, respectively, for levofloxacin. In time-kill studies, bacterial regrowth and the development of rifampin resistance were observed after 24 h with rifampin alone at 1× or 4× the MIC and were prevented by the addition of linezolid. After the administration of single intraperitoneal doses of 25, 50, and 75 mg/kg of body weight, linezolid peak concentrations of 6.8, 12.7, and 18.1 μg/ml, respectively, were achieved in sterile cage fluid at ≈3 h. The linezolid concentration remained above the MIC of the test organism for 12 h with all doses. Antimicrobial treatments of animals with cage implant infections were given twice daily for 4 days. Linezolid alone at 25, 50, and 75 mg/kg reduced the planktonic bacteria in cage fluid during treatment by 1.2 to 1.7 log10 CFU/ml; only linezolid at 75 mg/kg prevented bacterial regrowth 5 days after the end of treatment. Linezolid used in combination with rifampin (12.5 mg/kg) was more effective than linezolid used as monotherapy, reducing the planktonic bacteria by ≥3 log10 CFU (P < 0.05). Efficacy in the eradication of cage-associated infection was achieved only when linezolid was combined with rifampin, with cure rates being between 50% and 60%, whereas the levofloxacin-rifampin combination demonstrated the highest cure rate (91%) against the strain tested. The linezolid-rifampin combination is a treatment option for implant-associated infections caused by quinolone-resistant MRSA.

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Construction and Application of aluxABCDEReporter System for Real-Time Monitoring of Enterococcus faecalis Gene Expression and Growth

Applied and Environmental Microbiology ◽

10.1128/aem.02018-12 ◽

2012 ◽

Vol 78 (19) ◽

pp. 7003-7011 ◽

Cited By ~ 18

Author(s):

Sabina Leanti La Rosa ◽

Dzung B. Diep ◽

Ingolf F. Nes ◽

Dag Anders Brede

Keyword(s):

Real Time ◽

Enterococcus Faecalis ◽

Galleria Mellonella ◽

Viable Cell ◽

Model Systems ◽

Infection Model ◽

Broad Host Range ◽

Reporter System ◽

Content Type

ABSTRACTThe present work describes the construction of a novel molecular tool for luciferase-based bioluminescence (BL) tagging ofEnterococcus faecalis. To this end, a vector (pSL101) and its derivatives conferring a genetically encoded bioluminescent phenotype on all tested strains ofE. faecaliswere constructed. pSL101 harbors theluxABCDEoperon from pPL2luxand the pREG696 broad-host-range replicon andaxe-txetoxin-antitoxin cassette, providing segregational stability for long-term plasmid persistence in the absence of antibiotic selection. The bioluminescent signals obtained from three highly expressed promoters correlated linearly (R2> 0.98) with the viable-cell count. We employedlux-taggedE. faecalisstrains to monitor growth in real time in milk and urinein vitro. Furthermore, bioluminescence imaging (BLI) was used to visualize the magnitude of the bacterial burden during infection in theGalleria mellonellamodel system. To our knowledge, pSL101 is the first substrate addition-independent reporter system developed for BLI ofE. faecalisand an efficient tool for spatiotemporal tracking of bacterial growth and quantitative determination of promoter activity in real time, noninvasively, in infection model systems.

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From (p)ppGpp to (pp)pGpp: Characterization of Regulatory Effects of pGpp Synthesized by the Small Alarmone Synthetase of Enterococcus faecalis

Journal of Bacteriology ◽

10.1128/jb.00324-15 ◽

2015 ◽

Vol 197 (18) ◽

pp. 2908-2919 ◽

Cited By ~ 58

Author(s):

Anthony O. Gaca ◽

Pavel Kudrin ◽

Cristina Colomer-Winter ◽

Jelena Beljantseva ◽

Kuanqing Liu ◽

...

Keyword(s):

Stress Tolerance ◽

Enterococcus Faecalis ◽

Second Messengers ◽

Stringent Response ◽

Synthetase Activity ◽

Protective Effects ◽

Content Type ◽

Regulatory Effects ◽

Complex Target

ABSTRACTThe bacterial stringent response (SR) is a conserved stress tolerance mechanism that orchestrates physiological alterations to enhance cell survival. This response is mediated by the intracellular accumulation of the alarmones pppGpp and ppGpp, collectively called (p)ppGpp. InEnterococcus faecalis, (p)ppGpp metabolism is carried out by the bifunctional synthetase/hydrolaseE. faecalisRel (RelEf) and the small alarmone synthetase (SAS) RelQEf. Although Rel is the main enzyme responsible for SR activation inFirmicutes, there is emerging evidence that SASs can make important contributions to bacterial homeostasis. Here, we showed that RelQEfsynthesizes ppGpp more efficiently than pppGpp without the need for ribosomes, tRNA, or mRNA. In addition to (p)ppGpp synthesis from GDP and GTP, RelQEfalso efficiently utilized GMP to form GMP 3′-diphosphate (pGpp). Based on this observation, we sought to determine if pGpp exerts regulatory effects on cellular processes affected by (p)ppGpp. We found that pGpp, like (p)ppGpp, strongly inhibits the activity ofE. faecalisenzymes involved in GTP biosynthesis and, to a lesser extent, transcription ofrrnBbyEscherichia coliRNA polymerase. Activation ofE. coliRelA synthetase activity was observed in the presence of both pGpp and ppGpp, while RelQEfwas activated only by ppGpp. Furthermore, enzymatic activity of RelQEfis insensitive to relacin, a (p)ppGpp analog developed as an inhibitor of “long” RelA/SpoT homolog (RSH) enzymes. We conclude that pGpp can likely function as a bacterial alarmone with target-specific regulatory effects that are similar to what has been observed for (p)ppGpp.IMPORTANCEAccumulation of the nucleotide second messengers (p)ppGpp in bacteria is an important signal regulating genetic and physiological networks contributing to stress tolerance, antibiotic persistence, and virulence. Understanding the function and regulation of the enzymes involved in (p)ppGpp turnover is therefore critical for designing strategies to eliminate the protective effects of this molecule. While characterizing the (p)ppGpp synthetase RelQ ofEnterococcus faecalis(RelQEf), we found that, in addition to (p)ppGpp, RelQEfis an efficient producer of pGpp (GMP 3′-diphosphate).In vitroanalysis revealed that pGpp exerts complex, target-specific effects on processes known to be modulated by (p)ppGpp. These findings provide a new regulatory feature of RelQEfand suggest that pGpp may represent a new member of the (pp)pGpp family of alarmones.

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Pharmacodynamics of Daptomycin against Enterococcus faecium and Enterococcus faecalis in the Murine Thigh Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00506-18 ◽

2018 ◽

Vol 62 (10) ◽

Cited By ~ 9

Author(s):

James M. Kidd ◽

Kamilia Abdelraouf ◽

Tomefa E. Asempa ◽

Romney M. Humphries ◽

David P. Nicolau

Keyword(s):

Enterococcus Faecalis ◽

Enterococcus Faecium ◽

Hill Equation ◽

Infection Model ◽

Free Drug Concentration ◽

Time Curve ◽

Content Type ◽

Concentration Time ◽

The Hill ◽

Susceptibility Breakpoint

ABSTRACT The Clinical and Laboratory Standards Institute (CLSI) daptomycin MIC susceptibility breakpoint for the treatment of enterococcal infections is ≤4 μg/ml. However, patients receiving daptomycin for the treatment of infections caused by enterococci with MICs of ≤4 μg/ml may experience treatment failures. We assessed the pharmacodynamics of daptomycin against enterococci in a neutropenic murine thigh infection model and determined the exposures necessary for bacteriostasis and a 1-log10-CFU reduction of Enterococcus faecalis and Enterococcus faecium. We further characterized daptomycin efficacy at clinically achievable exposures. Six E. faecium and 6 E. faecalis isolates (daptomycin MICs, 0.5 to 32 μg/ml) were studied. Daptomycin was administered at various doses over 24 h to achieve area under the free drug concentration-time curve-to-MIC ratios (fAUC0–24/MIC) ranging from 1 to 148. Daptomycin regimens that simulate mean human exposures following doses of 6, 8, and 10 mg/kg of body weight/day were also studied. Efficacy was assessed by the differences in the number of log10 CFU per thigh at 24 h. The Hill equation was used to estimate the fAUC0–24/MIC required to achieve bacteriostasis and a 1-log10-CFU reduction. For E. faecium, a 1-log10-CFU reduction required an fAUC0–24/MIC of 12.9 (R2 = 0.71). For E. faecalis, a 1-log10-CFU reduction was not achieved, while the fAUC0–24/MIC required for stasis was 7.2 (R2 = 0.8). With a human-simulated regimen of 6 mg/kg/day, a 1-log10-CFU reduction was observed in 3/3 E. faecium isolates with MICs of <4 μg/ml and 0/3 E. faecium isolates with MICs of ≥4 μg/ml; however, a 1-log10-CFU reduction was not achieved for any of the 6 E. faecalis isolates. These results, alongside clinical data, prompt a reevaluation of the current breakpoint.

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