scholarly journals Tedizolid Population Pharmacokinetics, Exposure Response, and Target Attainment

2014 ◽  
Vol 58 (11) ◽  
pp. 6462-6470 ◽  
Author(s):  
S. Flanagan ◽  
J. Passarell ◽  
Q. Lu ◽  
J. Fiedler-Kelly ◽  
E. Ludwig ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Coefficient Of Variation ◽  
Safety Data ◽  
Absolute Bioavailability ◽  
Optimum Dose ◽  
Target Attainment ◽  
Time Curve ◽  
Unbound Fraction ◽  
Once Daily ◽  
Content Type

ABSTRACTTedizolid phosphate is a novel antibacterial prodrug that is rapidly and extensively converted to its active moiety, tedizolid. We developed a population pharmacokinetics (PK) model for tedizolid using pooled data from seven densely and sparsely sampled clinical trials evaluating oral and intravenous tedizolid. Model-derived exposure estimates were evaluated for relationships to select efficacy and safety outcomes. A two-compartment model with sigmoidal absorption, absolute bioavailability, and linear elimination described the PK data well. Variability was small (clearance, 31% coefficient of variation; volume, 13.4% coefficient of variation), and absolute bioavailability was high (86%). No clinically significant covariate effects on tedizolid PK were found. Based on phase 3 data evaluating 200-mg once-daily tedizolid for acute bacterial skin and skin structure infections (ABSSSI), no relationships were seen between various efficacy outcomes and estimated tedizolid exposure; the estimated exposure range (free-drug area under the concentration-time curve over 24 h at steady state [AUCss(0–24)], 7 to 50 μg · h/ml) in these patients was modest. Safety data modeling, using once-daily doses of up to 400 mg, showed a small increase in the probability of an adverse event with increasing model-estimated tedizolid exposure; no such relationship was observed when specifically evaluating the 200-mg dose. There were no trends in neutrophil or platelet counts with increasing tedizolid exposure. Target attainment simulations for 200-mg tedizolid indicated a 98.31% probability of attaining the target measure (AUC for the free, unbound fraction of a drug [fAUC]/MIC = 3) against aStaphylococcus aureusstrain for which the MIC was ≤0.5 μg/ml. These findings support 200-mg tedizolid once daily as the optimum dose for treatment of ABSSSI.

scholarly journals Population Pharmacokinetics of Artemether, Dihydroartemisinin, and Lumefantrine in Rwandese Pregnant Women Treated for UncomplicatedPlasmodium falciparumMalaria

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Jesmin Lohy Das ◽  
Stephen Rulisa ◽  
Peter J. de Vries ◽  
Petra F. Mens ◽  
Nadine Kaligirwa ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Population Pharmacokinetics ◽  
Plasma Concentrations ◽  
Target Attainment ◽  
Time Curve ◽  
Content Type ◽  
Mixed Effects Modeling ◽  
Increased Risk ◽  
Dose Combination ◽  
Median Area

ABSTRACTThe artemisinin-based combination therapy artemether-lumefantrine is commonly used in pregnant malaria patients. However, the effect of pregnancy-related changes on exposure is unclear, and pregnancy has been associated with decreased efficacy in previous studies. This study aimed to characterize the population pharmacokinetics of artemether, its active metabolite dihydroartemisinin, and lumefantrine in 22 Rwandese pregnant women in their second (n= 11) or third (n= 11) trimester with uncomplicatedPlasmodium falciparummalaria. These patients were enrolled from Rwamagana district hospital and received the standard fixed oral dose combination of 80 mg of artemether and 480 mg of lumefantrine twice daily for 3 days. Venous plasma concentrations were quantified for all three analytes using liquid chromatography coupled with tandem mass spectroscopy, and data were analyzed using nonlinear mixed-effects modeling. Lumefantrine pharmacokinetics was described by a flexible but highly variable absorption, with a mean absorption time of 4.04 h, followed by a biphasic disposition model. The median area under the concentration-time curve from 0 h to infinity (AUC0–∞) for lumefantrine was 641 h · mg/liter. Model-based simulations indicated that 11.7% of the study population did not attain the target day 7 plasma concentration (280 ng/ml), a threshold associated with increased risk of recrudescence. The pharmacokinetics of artemether was time dependent, and the autoinduction of its clearance was described using an enzyme turnover model. The turnover half-life was predicted to be 30.4 h. The typical oral clearance, which started at 467 liters/h, increased 1.43-fold at the end of treatment. Simulations suggested that lumefantrine pharmacokinetic target attainment appeared to be reassuring in Rwandese pregnant women, particularly compared to target attainment in Southeast Asia. Larger cohorts will be required to confirm this finding.

scholarly journals Population Pharmacokinetics of AZD-5847 in Adults with Pulmonary Tuberculosis

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Abdullah Alsultan ◽  
Jennifer J. Furin ◽  
Jeannine Du Bois ◽  
Elana van Brakel ◽  
Phalkun Chheng ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Compartment Model ◽  
Time Curve ◽  
Free Concentration ◽  
Unbound Fraction ◽  
Once Daily ◽  
Two Compartment Model ◽  
Recent Phase

ABSTRACT AZD-5847 is a new oxazolidinone derivative under development for the treatment of tuberculosis (TB). Here we describe the population pharmacokinetics (PK) of AZD-5847 in patients with tuberculosis based on a recently completed phase II study. The study included 60 patients with drug-susceptible TB. Patients were randomized to four dosages (500 mg once daily, 1,200 mg once daily, 500 mg twice daily, and 800 mg twice daily). Patients were intensively sampled on days 1 and 14. AZD-5847 pharmacokinetics were best described with a two-compartment model with lag time (T lag) for absorption. AZD-5847 bioavailability was nonlinear and plateaued at 800 mg. We performed deterministic simulation to compare the PK/pharmacodynamics (PD) of AZD-5847, linezolid, and sutezolid. AZD-5847 PK/PD in terms of both area under the concentration-time curve for the free, unbound fraction (fAUC)/MIC and time the free concentration was above the MIC (fT>MIC) were less favorable than those for linezolid and sutezolid. This could help explain the poor bactericidal activity of AZD-5847 in the recent phase II study.

scholarly journals Population Pharmacokinetics and Pharmacodynamics of Levofloxacin in Acutely Hospitalized Older Patients with Various Degrees of Renal Function

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
Pier Giorgio Cojutti ◽  
Virginia Ramos-Martin ◽  
Isabella Schiavon ◽  
Paolo Rossi ◽  
Massimo Baraldo ◽  
...  
Keyword(s):  
Renal Function ◽  
Clinical Outcome ◽  
Creatinine Clearance ◽  
Population Pharmacokinetics ◽  
Older Patients ◽  
Classification And Regression Tree ◽  
Therapeutic Drug ◽  
Time Curve ◽  
Content Type ◽  
Cart Analysis

ABSTRACT A retrospective study was conducted in a large sample of acutely hospitalized older patients who underwent therapeutic drug monitoring during levofloxacin treatment. The aim was to assess the population pharmacokinetics (popPK) and pharmacodynamics of levofloxacin among older patients. PopPK and Monte Carlo simulation were performed to define the permissible doses in older patients according to various degrees of renal function. Classification and regression tree (CART) analysis was used to detect the cutoff 24-hour area under the concentration-time curve (AUC24)/MIC ratio that best correlated with the clinical outcome. The probability of target attainment (PTA) of this value was calculated against different pathogens. A total of 168 patients were included, and 330 trough and 239 peak concentrations were used for the popPK analysis. Creatinine clearance (CrCL) was the only covariate that improved the model fit (levofloxacin CL = 0.399 + 0.051 × CrCLCKD-EPI [creatinine clearance estimated by means of the chronic kidney disease epidemiology]). Drug doses ranged between 500 mg every 48 h and 500 mg every 12 h in relation to different renal functions. The identified cutoff AUC24/MIC ratio (≥95.7) was the only covariate that correlated with a favorable clinical outcome in multivariate regression analysis (odds ratio [OR], 20.85; 95% confidence interval [CI], 1.56 to 186.73). PTAs were optimal (>80%) against Escherichia coli and Haemophilus influenzae, borderline against Staphylococcus aureus, and suboptimal against Pseudomonas aeruginosa. The levofloxacin doses defined in our study may be effective for the treatment of infections due to bacterial pathogens, with an MIC of ≤0.5 mg/liter in older patients with various degrees of renal function, while minimizing the toxicity risk. Conversely, the addition of another active antimicrobial should be considered whenever treating infections caused by less susceptible pathogens.

scholarly journals Pharmacokinetics of Tedizolid in an Obese Patient after Bariatric Surgery

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Matthieu Grégoire ◽  
Julia Brochard Libois ◽  
Denis Waast ◽  
Benjamin Gaborit ◽  
Marc Dauty ◽  
...  
Keyword(s):  
Bariatric Surgery ◽  
Bypass Surgery ◽  
Obese Woman ◽  
Total Plasma ◽  
Time Curve ◽  
Once Daily ◽  
Content Type ◽  
Concentration Time ◽  
Target Ratio ◽  
Plasma Peak

ABSTRACT An obese woman was treated with oral tedizolid 200 mg once daily for pseudoarthrosis 10 years after Roux-en-Y bypass surgery. Total plasma peak concentration was 2.12 mg/liter 3 h after intake, and area under the concentration-time curve from 0 to 24 h (AUC 0–24 ) was 28.3 mg/liter · h. The AUC 0–24 /MIC ratio for unbound concentrations and for sensitive Staphylococcus and Streptococcus strains was ≥10.8, higher than the target ratio of 3. These results support the use of tedizolid without adjustment after bariatric surgery.

scholarly journals Efficacy of NZ2114, a Novel Plectasin-Derived Cationic Antimicrobial Peptide Antibiotic, in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

2011 ◽  
Vol 55 (11) ◽  
pp. 5325-5330 ◽  
Author(s):  
Yan Q. Xiong ◽  
Wessam Abdel Hady ◽  
Antoine Deslandes ◽  
Astrid Rey ◽  
Laurent Fraisse ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Maximum Effect ◽  
Peptide Antibiotic ◽  
Time Curve ◽  
Cationic Antimicrobial Peptide ◽  
Unbound Fraction ◽  
Methicillin Resistant ◽  
Content Type ◽  
Conventional Antibiotics

ABSTRACTCationic antimicrobial peptides (CAPs) play important roles in host immune defenses. Plectasin is a defensin-like CAP isolated from the saprophytic fungusPseudoplectania nigrella. NZ2114 is a novel variant of plectasin with potent activity against Gram-positive bacteria. In this study, we investigated (i) thein vivopharmacokinetic and pharmacodynamic (PK/PD) characteristics of NZ2114 and (ii) thein vivoefficacy of NZ2114 in comparison with those of two conventional antibiotics, vancomycin or daptomycin, in an experimental rabbit infective endocarditis (IE) model due to a methicillin-resistantStaphylococcus aureus(MRSA) strain (ATCC 33591). All NZ2114 regimens (5, 10, and 20 mg/kg of body weight, intravenously [i.v.], twice daily for 3 days) significantly decreased MRSA densities in cardiac vegetations, kidneys, and spleen versus those in untreated controls, except in one scenario (5 mg/kg, splenic MRSA counts). The efficacy of NZ2114 was clearly dose dependent in all target tissues. At 20 mg/kg, NZ2114 showed a significantly greater efficacy than vancomycin (P< 0.001) and an efficacy similar to that of daptomycin. Of importance, only NZ2114 (in 10- and 20-mg/kg regimens) prevented posttherapy relapse in cardiac vegetations, kidneys, and spleen, while bacterial counts in these target tissues continued to increase in vancomycin- and daptomycin-treated animals. Thesein vivoefficacies were equivalent and significantly correlated with three PK indices investigated:fCmax/MIC (the maximum concentration of the free, unbound fraction of a drug in serum divided by the MIC),fAUC/MIC (where AUC is the area under the concentration-time curve), andf%T>MIC(%T>MICis the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions), as analyzed by a sigmoid maximum-effect (Emax) model (R2> 0.69). The superior efficacy of NZ2114 in this MRSA IE model suggests the potential for further development of this compound for treating serious MRSA infections.

scholarly journals Pharmacodynamics of Imipenem in Combination with β-Lactamase Inhibitor MK7655 in a Murine Thigh Model

2014 ◽  
Vol 59 (2) ◽  
pp. 790-795 ◽  
Author(s):  
Eleftheria Mavridou ◽  
Ria J. B. Melchers ◽  
Anita C. H. A. M. van Mil ◽  
E. Mangin ◽  
Mary R. Motyl ◽  
...  
Keyword(s):  
Dose Fractionation ◽  
Maximum Effect ◽  
Significant Activity ◽  
Beta Lactamase ◽  
Time Curve ◽  
Unbound Fraction ◽  
Content Type ◽  
Concentration Time ◽  
Lactamase Inhibitor

ABSTRACTMK7655 is a newly developed beta-lactamase inhibitor of class A and class C carbapenemases. Pharmacokinetics (PK) of imipenem-cilastatin (IMP/C) and MK7655 were determined for intraperitoneal doses of 4 mg/kg to 128 mg/kg of body weight. MIC and pharmacodynamics (PD) studies of MK7655 were performed against several beta-lactamase producingPseudomonas aeruginosaandKlebsiella pneumoniaestrains to determine its effectin vitroandin vivo. Neutropenic mice were infected in each thigh 2 h before treatment with an inoculum of approximately 5 × 106CFU. They were treated with IMP/C alone (every 2 hours [q2h], various doses) or in combination with MK7655 in either a dose fractionation study or q2h for 24 h and sacrificed for CFU determinations. IMP/MK7655 decreased MICs regarding IMP MIC. The PK profiles of IMP/C and MK7655 were linear over the dosing range studied and comparable with volumes of distribution (V) of 0.434 and 0.544 liter/kg and half-lives (t1/2) of 0.24 and 0.25 h, respectively. Protein binding of MK7655 was 20%. A sigmoidal maximum effect (Emax) model was fit to the PK/PD index responses. The effect of the inhibitor was not related to the maximum concentration of drug in serum (Cmax)/MIC, and model fits forT>MICand area under the concentration-time curve (AUC)/MIC were comparable (R2of 0.7 and 0.75), but there appeared to be no significant relationship of effect with dose frequency. Escalating doses of MK7655 and IMP/C showed that the AUC of MK7655 required for a static effect was dependent on the dose of IMP/C and the MIC of the strain, with a mean area under the concentration-time curve for the free, unbound fraction of the drug (fAUC) of 26.0 mg · h/liter. MK7655 shows significant activityin vivoand results in efficacy of IMP/C in otherwise resistant strains. The exposure-response relationships found can serve as a basis for establishing dosing regimens in humans.

scholarly journals Population Pharmacokinetics, Exposure–Response, and Probability of Target Attainment Analyses for Tedizolid in Adolescent Patients With Acute Bacterial Skin and Skin Structure Infections

2021 ◽  
Author(s):  
Dan Li ◽  
Philip E. Sabato ◽  
Benjamin Guiastrennec ◽  
Aziz Ouerdani ◽  
Hwa-Ping Feng ◽  
...  
Keyword(s):  
Body Weight ◽  
Phase 1 ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Target Attainment ◽  
Time Curve ◽  
Once Daily ◽  
Skin Structure ◽  
Lower Body Weight ◽  
Safety Event

Tedizolid phosphate is an oxazolidinone antibacterial agent approved for treatment of gram-positive acute bacterial skin and skin structure infections (ABSSSIs) in patients aged ≥12 years. To support the use of tedizolid phosphate in adolescents with ABSSSIs, a population pharmacokinetic (PK) model, developed using adult and pediatric data, was updated to include PK data from a phase 3 clinical trial (PN012) that evaluated the safety and efficacy of once-daily oral or intravenous 200-mg tedizolid phosphate in adolescents (12 to <18 years) with ABSSSIs, along with emerging data from a phase 1 trial (PN013) in children (2 to <12 years). Updated PK parameter estimates remained similar to the previous model. Body weight was a statistically significant covariate on clearance and volume parameters, with no clinically meaningful effects on exposure in adolescents. Tedizolid exposures in adolescents from PN012 were slightly higher with largely overlapped area under the concentration–time curve distribution compared with adults from previous phase 2 and 3 trials. The probability of PK/pharmacodynamic target attainment at the minimum inhibitory concentration susceptibility breakpoint of 0.5 μg/mL for Staphylococcus and Streptococcus was 100%. As most participants from the PN012 trial were cured, no significant exposure–efficacy relationship was identified. Tedizolid exposures were similar between participants with and without a safety event from PN012; no clear relationship was detected between exposure and safety. Despite lower body weight and higher exposures in adolescents, safety profiles in adolescents were similar to adults. These results support the 200-mg, once-daily intravenous or oral dose of tedizolid phosphate in adolescents with ABSSSIs.

scholarly journals Toward Harmonization of Voriconazole CLSI and EUCAST Breakpoints for Candida albicans Using a Validated In Vitro Pharmacokinetic/Pharmacodynamic Model

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Maria-Ioanna Beredaki ◽  
Panagiota-Christina Georgiou ◽  
Maria Siopi ◽  
Lamprini Kanioura ◽  
David Andes ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Simulation Analysis ◽  
Maximal Activity ◽  
Wild Type ◽  
Time Curve ◽  
Unbound Fraction ◽  
Content Type ◽  
Interval Probability

ABSTRACT CLSI and EUCAST susceptibility breakpoints for voriconazole and Candida albicans differ by one dilution (≤0.125 and ≤0.06 mg/liter, respectively) whereas the epidemiological cutoff values for EUCAST (ECOFF) and CLSI (ECV) are the same (0.03 mg/liter). We therefore determined the pharmacokinetic/pharmacodynamic (PK/PD) breakpoints of voriconazole against C. albicans for both methodologies with an in vitro PK/PD model, which was validated using existing animal PK/PD data. Four clinical wild-type and non-wild-type C. albicans isolates (voriconazole MICs, 0.008 to 0.125 mg/liter) were tested in an in vitro PK/PD model. For validation purposes, mouse PK were simulated and in vitro PD were compared with in vivo outcomes. Human PK were simulated, and the exposure-effect relationship area under the concentration-time curve for the free, unbound fraction of a drug from 0 to 24 h (fAUC0–24)/MIC was described for EUCAST and CLSI 24/48-h methods. PK/PD breakpoints were determined using the fAUC0–24/MIC associated with half-maximal activity (EI50) and Monte Carlo simulation analysis. The in vitro 24-h PD EI50 values of voriconazole against C. albicans were 2.5 to 5 (1.5 to 17) fAUC/MIC. However, the 72-h PD were higher at 133 (51 to 347) fAUC/MIC for EUCAST and 94 (35 to 252) fAUC/MIC for CLSI. The mean (95% confidence interval) probability of target attainment (PTA) was 100% (95 to 100%), 97% (72 to 100%), 83% (35 to 99%), and 49% (8 to 91%) for EUCAST and 100% (97 to 100%), 99% (85 to 100%), 91% (52 to 100%), and 68% (17 to 96%) for CLSI for MICs of 0.03, 0.06, 0.125, and 0.25 mg/liter, respectively. Significantly, >95% PTA values were found for EUCAST/CLSI MICs of ≤0.03 mg/liter. For MICs of 0.06 to 0.125 mg/liter, trough levels 1 to 4 mg/liter would be required to attain the PK/PD target. A PK/PD breakpoint of C. albicans voriconazole at the ECOFF/ECV of 0.03 mg/liter was determined for both the EUCAST and CLSI methods, indicating the need for breakpoint harmonization for the reference methodologies.

scholarly journals Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Sujata M. Bhavnani ◽  
Jeffrey P. Hammel ◽  
Elizabeth A. Lakota ◽  
M. Courtney Safir ◽  
Brian D. VanScoy ◽  
...  
Keyword(s):  
Compartment Model ◽  
Simulated Patients ◽  
Population Pharmacokinetic ◽  
Total Drug ◽  
Target Attainment ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time

ABSTRACT ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m2) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log10 CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. Percent probabilities of PK­PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at MIC values above the MIC90 value for K. pneumoniae (8 μg/ml), P. aeruginosa (4 μg/ml), and S. aureus (0.5 μg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m2. ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m2, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.

scholarly journals Sequential Evolution of Vancomycin-Intermediate Resistance Alters Virulence in Staphylococcus aureus: Pharmacokinetic/Pharmacodynamic Targets for Vancomycin Exposure

2015 ◽  
Vol 60 (3) ◽  
pp. 1584-1591 ◽  
Author(s):  
Justin R. Lenhard ◽  
Tanya Brown ◽  
Michael J. Rybak ◽  
Calvin J. Meaney ◽  
Nicholas B. Norgard ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Galleria Mellonella ◽  
Infection Model ◽  
Bacterial Reduction ◽  
Accessory Gene ◽  
Time Curve ◽  
Bacterial Killing ◽  
Unbound Fraction ◽  
Content Type ◽  
Intermediate Resistance

Staphylococcus aureuspossesses exceptional virulence and a remarkable ability to adapt in the face of antibiotic therapy. We examined thein vitroevolution ofS. aureusin response to escalating vancomycin exposure by evaluating bacterial killing and the progression of resistance. A hollow-fiber infection model was utilized to simulate human doses of vancomycin increasing from 0.5 to 4 g every 12 h (q12h) versus a high inoculum (108CFU/ml) of methicillin-resistantS. aureus(MRSA) USA300 and USA400. Host-pathogen interactions usingGalleria mellonellaand accessory gene regulator (agr) expression were studied in serially obtained isolates. In both USA300 and USA400 MRSA isolates, vancomycin exposure up to 2 g q12h resulted in persistence and regrowth, whereas 4 g administered q12h achieved sustained killing against both strains. As vancomycin exposure increased from 0.5 to 2 g q12h, the bacterial population shifted toward vancomycin-intermediate resistance, and collateral increases in the MICs of daptomycin and televancin were observed over 10 days. Guideline-recommended exposure of a ratio of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC (fAUC/MIC ratio) of 200 displayed a 0.344-log bacterial reduction in area, whereasfAUC/MICs of 371 and 554 were needed to achieve 1.00- and 2.00-log reductions in area, respectively. The stepwise increase in resistance paralleled a decrease inG. mellonellamortality (P= 0.021) and a gradual decline of RNAIII expression over 10 days. Currently recommended doses of vancomycin resulted in amplification of resistance and collateral damage to other antibiotics. Decreases inagrexpression and virulence during therapy may be an adaptive mechanism ofS. aureuspersistence.

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