Publications by authors named "Joseph L Kuti"

200 Publications

Effect of Blood Product Resuscitation on the Pharmacokinetics of Ampicillin-Sulbactam during Orthotopic Liver Transplantation.

Surg Infect (Larchmt) 2021 Nov 24. Epub 2021 Nov 24.

Center for Anti-Infective Research and Development, Hartford Hospital, Harford, Connecticut, USA.

Ampicillin-sulbactam is a piperacillin-tazobactam-sparing alternative antibiotic administered as surgical prophylaxis during orthotopic liver transplant (OLT), but limited data are available describing its pharmacokinetics and impact of blood product resuscitation. The purpose of this study was to determine the intra-operative pharmacokinetics of ampicillin-sulbactam in patients during OLT and evaluate the effects of blood resuscitation on exposure. This was a pharmacokinetic study in 10 OLT patients receiving ampicillin-sulbactam surgical prophylaxis. A 5,000-patient Monte Carlo simulation was conducted to identify optimal ampicillin-sulbactam regimens. Linear regression assessed association between blood product administration and ampicillin exposures. Ampicillin and sulbactam concentrations best fitted two-compartment models. Mean ampicillin pharmacokinetic parameters were central compartment volume (V): 6.9 ± 2.0 L, clearance (CL): 26.6 ± 18.4 L/h, and inter-compartmental rate constants (k and k): 4.8 ± 2.6 and 2.3 ± 1.4 h. Sulbactam pharmacokinetic parameters were V: 8.1 ± 2.7 L, CL: 26.1 ± 7.4 L/h, k and k: 4.9 ± 1.0 and 2.8 ± 1.1 h. Participants received between 500 and 23,642 mL of total blood product. No statistical relations were observed between blood product administration and exposures ( 0.00-0.26). Ampicillin-sulbactam 2/1 g every two hours and 2/1 g bolus followed by 6/3 g continuous infusion provided acceptable probability of target attainment up to minimum inhibitory concentrations (MICs) of 16 and 32 mcg/mL, respectively. High and frequent ampicillin-sulbactam doses are required to maintain 100% T > MIC at relevant MICs during OLT and no impact of blood product resuscitation was observed on ampicillin exposure. These are the first data available to guide ampicillin-sulbactam dosing in patients undergoing OLT.
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http://dx.doi.org/10.1089/sur.2021.218DOI Listing
November 2021

Erratum for Crandon et al., "Comparative Efficacies of Human Simulated Exposures of Telavancin and Vancomycin against Methicillin-Resistant Staphylococcus aureus with a Range of Vancomycin MICs in a Murine Pneumonia Model".

Antimicrob Agents Chemother 2021 Nov 17;65(12):e0187821. Epub 2021 Nov 17.

Center for Anti-Infective Research and Development, Hartford Hospitalgrid.277313.3, Hartford, Connecticut.

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http://dx.doi.org/10.1128/AAC.01878-21DOI Listing
November 2021

Levofloxacin pharmacodynamics against Stenotrophomonas maltophilia in a neutropenic murine thigh infection model: implications for susceptibility breakpoint revision.

J Antimicrob Chemother 2021 Sep 20. Epub 2021 Sep 20.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.

Background: Levofloxacin displays in vitro activity against Stenotrophomonas maltophilia (STM); however, current susceptibility breakpoints are supported by limited data. We employed the murine neutropenic thigh infection model to assess levofloxacin pharmacodynamics against STM.

Methods: Twenty-six clinical STM were studied using the neutropenic murine thigh infection model. Human simulated regimens (HSR) of levofloxacin 750 mg q24h were administered over 24 h. Efficacy was measured as the change in log10 cfu/thigh at 24 h compared with 0 h. Composite cfu data were fitted to an Emax model to determine the fAUC/MIC needed for stasis and 1 log10 reduction at 24 h. Monte Carlo simulation was performed to determine PTA.

Results: Levofloxacin MICs ranged from 0.5-8 mg/L. Mean bacterial burden at 0 h was 6.21 ± 0.20 log10 cfu/thigh. In the 24 h controls, bacterial growth was 1.64 ± 0.66 log10 cfu/thigh. In isolates with levofloxacin MICs ≤1, 2 and ≥4 mg/L, changes in bacterial density following levofloxacin HSR were -1.66 ± 0.89, 0.13 ± 0.97 and 1.54 ± 0.43 log10 cfu/thigh, respectively. The Emax model demonstrated strong agreement between fAUC/MIC and change in bacterial density (R2 = 0.82). The fAUC/MIC exposure needed for stasis and 1 log10 reduction was 39.9 and 54.9, respectively. PTAs for the 1 log10 reduction threshold were 95.8, 72.2, and 26.6% at MICs of 0.5, 1 and 2 mg/L, respectively.

Conclusions: These are the first data to describe fAUC/MIC thresholds predictive of cfu reductions for levofloxacin against STM. Due to poor in vivo efficacy and PTA at MICs ≥2 mg/L, reassessment of the current susceptibility breakpoint is warranted.
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http://dx.doi.org/10.1093/jac/dkab344DOI Listing
September 2021

Optimised cefiderocol exposures in a successfully treated critically ill patient with polymicrobial Stenotrophomonas maltophilia bacteraemia and pneumonia receiving continuous venovenous haemodiafiltration.

Int J Antimicrob Agents 2021 Sep 27;58(3):106395. Epub 2021 Jun 27.

Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ijantimicag.2021.106395DOI Listing
September 2021

Pharmacokinetics and Pharmacodynamics of Ceftolozane/Tazobactam in Critically Ill Patients With Augmented Renal Clearance.

Int J Antimicrob Agents 2021 Apr 7;57(4):106299. Epub 2021 Feb 7.

Merck & Co., Inc., Kenilworth, New Jersey, USA. Electronic address:

Objective: To determine whether established ceftolozane/tazobactam (C/T) dosing is adequate for patients with augmented renal clearance (ARC) and bacterial infection.

Methods: ARC (creatinine clearance [CrCl] ≥ 130 mL/min) was confirmed by directly measured CrCl in 11 critically ill patients in a phase 1 pharmacokinetics study. Patients received 3 g C/T (ceftolozane 2 g/tazobactam 1 g) as a 60-minute intravenous infusion. Pharmacokinetic sampling occurred at 0 (predose), 1, 2, 4, 6, and 8 hours after the start of the infusion. Noncompartmental analyses were conducted on concentration data. The following pharmacodynamic targets were evaluated: time that free (unbound) drug concentrations exceeded the minimum inhibitory concentration (fT>MIC) of 4 μg/mL for ceftolozane and time that the unbound concentration exceeded the 1 μg/mL target threshold (fT>threshold = 1 µg/mL) for > 20% of the dosing interval for tazobactam. Safety was evaluated.

Results: Mean (SD) area under the plasma concentration-time curve from 0 to infinity, clearance and volume of distribution at steady state (V) were 236 (118) h*µg/mL, 10.4 (4.5) L/h and 30.8 (10.8) L, respectively, for ceftolozane; and 35.5 (18.5) h*µg/mL, 35.3 (16.5) L/h and 54.8 (20.1) L, respectively, for tazobactam. Clearance and V were higher for both ceftolozane and tazobactam in patients with ARC compared with healthy individuals. The mean estimated ceftolozane fT>MIC at 4 µg/mL was 86.4%; the mean estimated tazobactam fT>threshold = 1 µg/mL was 54.9%. Treatment-emergent adverse events were mild to moderate.

Conclusions: In patients with ARC, a 3 g C/T dose met respective pharmacodynamic targets for ceftolozane and tazobactam. CLINICALTRIALS.

Gov Identifier: NCT02387372.
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http://dx.doi.org/10.1016/j.ijantimicag.2021.106299DOI Listing
April 2021

A guide to therapeutic drug monitoring of β-lactam antibiotics.

Pharmacotherapy 2021 02 14;41(2):220-233. Epub 2021 Feb 14.

Center for Anti-infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.

Therapeutic drug monitoring (TDM) opens the door to personalized medicine, yet it is infrequently applied to β-lactam antibiotics, one of the most commonly prescribed drug classes in the hospital setting. As we continue to understand more about β-lactam pharmacodynamics (PD) and wide inter- and intra-patient variability in pharmacokinetics (PK), the utility of TDM has become increasingly apparent. For β-lactams, the time that free concentrations remain above the minimum inhibitory concentration (MIC) as a function of the dosing interval (%fT>MIC) has been shown to best predict antibacterial effect. Many studies have shown that β-lactam %fT>MIC exposures are often suboptimal across a wide variety of disease states and clinical settings. A limitation to implementing this practice is the general lack of understanding on how to best operationalize this intervention and interpret the results. The instrumentation and expertise needed to quantify β-lactams for TDM is rarely available locally, but certain laboratories advertise these services and perform them regularly. Familiarity with the modalities and nuances of antimicrobial susceptibility testing is crucial to establishing β-lactam concentration targets that meet the relevant exposure thresholds. Evaluation of these concentrations is best accomplished using population PK software and Bayesian modeling, for which a multitude of programs are available. While TDM of β-lactams has shown an ability to increase the rate of target attainment, there is currently limited evidence to suggest that it leads to improved clinical outcomes. Although consensus guidelines for β-lactam TDM do not exist in the United States, guidance would help to promote this important practice and better standardize the approach across institutions. Herein, we discuss the basis for β-lactam TDM, review supporting evidence, and provide guidance for implementation in specific patient populations.
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http://dx.doi.org/10.1002/phar.2505DOI Listing
February 2021

Contemporary analysis of ETEST for antibiotic susceptibility and minimum inhibitory concentration agreement against Pseudomonas aeruginosa from patients with cystic fibrosis.

Ann Clin Microbiol Antimicrob 2021 Jan 19;20(1). Epub 2021 Jan 19.

Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, 06102, CT, USA.

Objectives: Cystic fibrosis (CF) acute pulmonary exacerbations are often caused by Pseudomonas aeruginosa, including multi-drug resistant strains. Optimal antibiotic therapy is required to return lung function and should be guided by in vitro susceptibility results. There are sparse data describing ETEST performance for CF isolates using contemporary isolates, methods and interpretation, as well as novel antibiotics, such as ceftazidime-avibactam and ceftolozane-tazobactam.

Methods: Pseudomonas aeruginosa (n = 105) isolated during pulmonary exacerbation from patients with CF were acquired from 3 US hospitals. Minimum inhibitory concentrations (MICs) were assessed by reference broth microdilution (BMD) and ETEST for aztreonam, cefepime, ceftazidime, ceftazidime-avibactam, ceftolozane-tazobactam, ciprofloxacin, levofloxacin, meropenem, piperacillin-tazobactam, and tobramycin. Broth microdilution was conducted in concordance with the Clinical and Laboratory Standards Institute M100. ETEST methodology reflected package insert recommendations. Performance of ETEST strips was evaluated using the Food and Drug Administration (FDA) and Susceptibility Testing Manufacturers Association (STMA) guidance.

Results: Of the 105 P. aeruginosa included, 46% had a mucoid phenotype. ETEST MICs typically read 0-1 dilution higher than BMD for all drugs. Categorical agreement and essential agreement ranged from 64 to 93% and 63 to 86%, respectively. The majority of observed errors were minor. A single very major error occurred with ceftazidime (4.2%). For ceftazidime-vibactam, 2 very major errors were observed and both were within essential agreement. Major errors occurred for aztreonam (3.3%), cefepime (9.4%), ceftazidime-avibactam (5.3%, adjusted 2.1%), ceftolozane-tazobactam (1%), meropenem (3.3%), piperacillin-tazobactam (2.9%), and tobramycin (1.5%).

Conclusions: ETEST methods performed conservatively for most antibiotics against this challenging collection of P. aeruginosa from patients with CF.
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http://dx.doi.org/10.1186/s12941-021-00415-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816365PMC
January 2021

Imipenem/Cilastatin/Relebactam Alone and in Combination against in the Pharmacodynamic Model.

Antimicrob Agents Chemother 2020 11 17;64(12). Epub 2020 Nov 17.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA

Combination therapy may enhance imipenem/cilastatin/relebactam's (I/R) activity against and suppress resistance development. Human-simulated unbound plasma concentrations of I/R at 1.25 g every 6 h (h), colistin at 360 mg daily, and amikacin at 25 mg/kg daily were reproduced alone and in combination against six imipenem-nonsusceptible isolates in an pharmacodynamic model over 24 h. For I/R alone, the mean reductions in CFU ± the standard errors by 24 h were -2.52 ± 0.49, -1.49 ± 0.49, -1.15 ± 0.67, and -0.61 ± 0.10 log CFU/ml against isolates with MICs of 1/4, 2/4, 4/4, and 8/4 μg/ml, respectively. Amikacin alone also resulted in 24 h CFU reductions consistent with its MIC, while colistin CFU reductions did not differ. Resistant subpopulations were observed after 24 h in 1, 4, and 3 I/R-, colistin-, and amikacin-exposed isolates, respectively. The combination of I/R and colistin resulted in synergistic ( = 1) or additive ( = 2) interactions against three isolates with 24-h CFU reductions ranging from -2.62 to -4.67 log CFU/ml. The combination of I/R and amikacin exhibited indifferent interactions against all isolates, with combined drugs achieving -0.51- to -3.33-log CFU/ml reductions. No resistant subpopulations were observed during I/R and colistin combination studies, and when added to amikacin, I/R prevented the emergence of amikacin resistance. Against these six multidrug-resistant , I/R alone achieved significant CFU reductions against I/R-susceptible isolates. Combinations of I/R plus colistin resulted in additivity or synergy against some , whereas the addition of amikacin did not provide further antibacterial efficacy against these isolates.
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http://dx.doi.org/10.1128/AAC.01764-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674065PMC
November 2020

Impact of Intraoperative Cell Salvage on Concentrations of Antibiotics Used for Surgical Prophylaxis.

Antimicrob Agents Chemother 2020 11 17;64(12). Epub 2020 Nov 17.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA

Intraoperative cell salvage (IOCS) is used to administer autologous blood lost during surgery. We studied antibiotic disposition through an IOCS system for vancomycin, piperacillin, ampicillin, and cefazolin. Only 2% ± 1% of antibiotic inoculated in whole blood was recovered in the IOCS reinfusion bag, whereas 97% ± 17% was found in the waste. These observations were confirmed for ampicillin in two patients undergoing liver transplantation. Studies measuring the impact of IOCS on perioperative antibiotic concentrations are warranted.
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http://dx.doi.org/10.1128/AAC.01725-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674051PMC
November 2020

Unresolved issues in the identification and treatment of carbapenem-resistant Gram-negative organisms.

Curr Opin Infect Dis 2020 12;33(6):482-494

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.

Purpose Of Review: Carbapenem-resistant organisms (CROs), including Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacterales, are a threat worldwide. This review will cover mechanisms of resistance within CROs and challenges with identification and treatment of these organisms while pointing out unresolved issues and ongoing challenges.

Recent Findings: The treatment of CROs has expanded through newer therapeutic options. Guided utilization through genotypic and phenotypic testing is necessary in order for these drugs to target the appropriate mechanisms of resistance and select optimal antibiotic therapy.

Summary: Identification methods and treatment options need to be precisely understood in order to limit the spread and maximize outcomes of CRO infections.
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http://dx.doi.org/10.1097/QCO.0000000000000682DOI Listing
December 2020

Plazomicin: an intravenous aminoglycoside antibacterial for the treatment of complicated urinary tract infections.

Expert Rev Anti Infect Ther 2020 08 13;18(8):705-720. Epub 2020 May 13.

Center for Anti-Infective Research and Development, Harford Hospital , Hartford, CT, USA.

Introduction: Antimicrobial resistance continues to be a major public health concern due to the emergence and spread of multi-drug resistant (MDR) organisms, including extended spectrum ß-lactamase (ESBL) and carbapenemase producing Enterobacterales. Plazomicin is a novel aminoglycoside that demonstrates activity against MDR gram-negatives, including those producing ESBLs and most carbapenemases, and retains activity against aminoglycoside modifying enzymes as a result of structural modifications. The information discussed is meant to assist in identifying plazomicin's place in therapy and to expand the clinician's armamentarium.

Areas Covered: Herein, we review the pharmacology, microbiology, clinical efficacy, and safety of plazomicin. To gather relevant information, a literature search was performed using PubMed, Ovid, and Google Scholar electronic databases. Search terms used include , and AME. Additional information was obtained from FDA review documents and research abstracts presented at international conferences.

Expert Opinion: Plazomicin is a promising carbapenem or β-lactam/β-lactamase inhibitor-sparing alternative for the treatment of complicated urinary tract infections caused by MDR Enterobacterales. Although robust data for bloodstream infections and bacterial pneumonias are lacking, plazomicin may be considered in individual clinical scenarios if combination therapy is warranted provided supportive microbiological data and therapeutic drug monitoring are available.
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http://dx.doi.org/10.1080/14787210.2020.1759419DOI Listing
August 2020

Erratum for Asempa et al., " Activity of Imipenem-Relebactam Alone or in Combination with Amikacin or Colistin against Pseudomonas aeruginosa".

Antimicrob Agents Chemother 2020 04 21;64(5). Epub 2020 Apr 21.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA

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http://dx.doi.org/10.1128/AAC.00467-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179651PMC
April 2020

Lung penetration, bronchopulmonary pharmacokinetic/pharmacodynamic profile and safety of 3 g of ceftolozane/tazobactam administered to ventilated, critically ill patients with pneumonia.

J Antimicrob Chemother 2020 06;75(6):1546-1553

Merck & Co., Inc., Kenilworth, NJ, USA.

Objectives: Ceftolozane/tazobactam is approved for hospital-acquired/ventilator-associated bacterial pneumonia at double the dose (i.e. 2 g/1 g) recommended for other indications. We evaluated the bronchopulmonary pharmacokinetic/pharmacodynamic profile of this 3 g ceftolozane/tazobactam regimen in ventilated pneumonia patients.

Methods: This was an open-label, multicentre, Phase 1 trial (clinicaltrials.gov: NCT02387372). Mechanically ventilated patients with proven/suspected pneumonia received four to six doses of 3 g of ceftolozane/tazobactam (adjusted for renal function) q8h. Serial plasma samples were collected after the first and last doses. One bronchoalveolar lavage sample per patient was collected at 1, 2, 4, 6 or 8 h after the last dose and epithelial lining fluid (ELF) drug concentrations were determined. Pharmacokinetic parameters were estimated by non-compartmental analysis and pharmacodynamic analyses were conducted to graphically evaluate achievement of target exposures (plasma and ELF ceftolozane concentrations >4 mg/L and tazobactam concentrations >1 mg/L; target in plasma: ≥30% and ≥20% of the dosing interval, respectively).

Results: Twenty-six patients received four to six doses of study drug; 22 were included in the ELF analyses. Ceftolozane and tazobactam Tmax (6 and 2 h, respectively) were delayed in ELF compared with plasma (1 h). Lung penetration, expressed as the ratio of mean drug exposure (AUC) in ELF to plasma, was 50% (ceftolozane) and 62% (tazobactam). Mean ceftolozane and tazobactam ELF concentrations remained >4 mg/L and >1 mg/L, respectively, for 100% of the dosing interval. There were no deaths or adverse event-related study discontinuations.

Conclusions: In ventilated pneumonia patients, 3 g of ceftolozane/tazobactam q8h yielded ELF exposures considered adequate to cover ceftolozane/tazobactam-susceptible respiratory pathogens.
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http://dx.doi.org/10.1093/jac/dkaa049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225904PMC
June 2020

Assessment of Meropenem and Vaborbactam Room Temperature and Refrigerated Stability in Polyvinyl Chloride Bags and Elastomeric Devices.

Clin Ther 2020 04 3;42(4):606-613. Epub 2020 Mar 3.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA. Electronic address:

Purpose: Meropenem and vaborbactam is an intravenous beta-lactam/beta-lactamase inhibitor combination antibiotic active against multidrug resistant gram-negative bacteria. It may be a suitable treatment for inpatient and outpatient management of infections, and the intravenous admixture stability is therefore important for optimal utilization. The purpose of this study was to determine the stability of meropenem and vaborbactam in polyvinyl chloride (PVC) infusion bags and elastomeric pumps at room and refrigerated temperatures.

Methods: Meropenem and vaborbactam vials were reconstituted according to manufacturer instructions and diluted in PVC infusion bags to final concentrations of 4, 8, and 16 mg/mL and in elastomeric pumps to 11.4 mg/mL (n = 5 replicates per concentration and per temperature). PVC bags and elastomeric pumps were stored at room temperature (~24 °C) or in the refrigerator (~4 °C) and sampled over 12 and 144 h, respectively. Stability was defined as the duration that meropenem and vaborbactam concentrations remained ≥90% of the original concentrations.

Findings: All room temperature replicates across the tested concentrations retained meropenem and vaborbactam stability over 12 h and displayed concentration-dependent degradation. Refrigerated studies resulted in meropenem and vaborbactam stability at all tested concentrations up to 120 h.

Implications: Meropenem and vaborbactam in PVC bags (4, 8, and 16 mg/mL) and elastomeric pumps (11.4 mg/mL) were stable for 12 h at room temperature and 120 h when refrigerated. These stability data allow for enhanced flexibility in the preparation, storage, wastage, and administration of meropenem and vaborbactam in the hospital and outpatient setting.
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http://dx.doi.org/10.1016/j.clinthera.2020.01.021DOI Listing
April 2020

Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation.

Antimicrob Agents Chemother 2019 12 20;64(1). Epub 2019 Dec 20.

Center for Anti-Infective Research and Development, Hartford Hospital, Harford, Connecticut, USA

Adults with cystic fibrosis (CF) frequently harbor , which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients ( = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment ( ) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight ( ) normalized by the median observed value (  =   × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CL + CL × CRCL), where CL represents nonrenal clearance and CL represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: , 4.92  ± 0.76 liters · kg; CL, 0.59  ± 0.30 liters · h; CL, 5.97 × 10 ± 1.24 × 10; (volume of the peripheral compartment), 3.77  ± 1.41 liters; (intercompartmental clearance), 4.08  ± 2.17 liters · h The free area under the concentration-time curve (AUC) values for 7.5 and 10 mg/kg were 30  ± 4.6 and 52  ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a AUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.).
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http://dx.doi.org/10.1128/AAC.01914-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187619PMC
December 2019

Effect of Clinically Meaningful Antibiotic Concentrations on Recovery of Escherichia coli and Klebsiella pneumoniae Isolates from Anaerobic Blood Culture Bottles with and without Antibiotic Binding Resins.

J Clin Microbiol 2019 12 22;57(12). Epub 2019 Nov 22.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA

Blood cultures are routinely collected in pairs of aerobic and anaerobic bottles. Artificial sterilization of Gram-negative bacteria in aerobic bottles containing clinically meaningful antibiotic concentrations has previously been observed. This study assessed recovery from anaerobic bottles with and without antibiotic binding resins. We studied the recovery of and when exposed to meropenem, imipenem, cefepime, cefazolin, levofloxacin, and piperacillin-tazobactam in resin-containing BacT/Alert FN Plus and BD Bactec Plus anaerobic/F bottles as well as resin-free BacT/Alert SN and BD Bactec standard anaerobic bottles. Bottles were inoculated with bacteria and whole blood containing peak, midpoint, or trough concentrations and incubated for up to 120 hours in their respective detection systems. In resin-containing bottles, recovery was observed in 10/24 (42%), 17/24 (71%), and 18/24 (75%) ( = 0.034) of those exposed to peak, midpoint, and trough concentrations, respectively. In resin-containing bottles, recovery was observed in 8/16 (50%), 10/16 (63%), and 10/16 (63%) ( = 0.710), respectively. No growth was detected in bottles containing cefepime regardless of concentration, while recovery was observed in the presence of all concentrations of cefazolin and piperacillin-tazobactam. Recovery in bottles with meropenem and imipenem was more frequently observed in BacT/Alert FN Plus bottles compared with Bactec Plus bottles. Resin-free bottles demonstrated significantly lower recovery than bottles containing binding resin. Clinical concentrations of certain antibiotics can adversely affect detection of and in anaerobic blood culture bottles. Obtaining blood cultures immediately before a dose and utilizing resin-containing anaerobic bottles will maximize the likelihood of recovery.
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http://dx.doi.org/10.1128/JCM.01344-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879289PMC
December 2019

Assessment of the Physical Compatibility of Eravacycline and Common Parenteral Drugs During Simulated Y-site Administration.

Clin Ther 2019 10 7;41(10):2162-2170. Epub 2019 Sep 7.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA. Electronic address:

Purpose: Eravacycline is a broad-spectrum, intravenous fluorocycline antibiotic approved for the treatment of complicated intra-abdominal infections in adults. A 60-minute infusion is recommended for each infused dose. Compatibility data that may allow convenient Y-site administration of eravacycline with other parenteral medications are unavailable. We aimed to determine the physical compatibility of eravacycline with other intravenous medications by simulated Y-site administration.

Methods: Eravacycline was reconstituted according to published prescribing information and diluted with 0.9% sodium chloride to a concentration of 0.6 mg/mL. Simulated Y-site administration was performed by mixing 5 mL of eravacycline with an equal volume of 51 other intravenous medications, including crystalloid and carbohydrate hydration fluids and 20 antimicrobials. Secondary medications were assessed at the upper range of concentrations considered standard for intravenous infusion. Mixtures underwent visual inspection and turbidity measurement immediately on mixture and at 3 subsequent time points (30, 60, and 120 minutes after admixture), and pH was measured at 60 minutes for comparison with the baseline value of the secondary medication.

Findings: Eravacycline was physically compatible with 41 parenteral drugs (80%) by simulated Y-site administration. Incompatibility was observed with albumin, amiodarone hydrochloride, ceftaroline fosamil, colistimethate sodium, furosemide, meropenem, meropenem/vaborbactam, micafungin sodium, propofol, and sodium bicarbonate.

Implications: Eravacycline for injection was physically compatible with most parenteral medications assessed. Pharmacists and nurses should be knowledgeable of the observed incompatibilities with eravacycline to prevent the unintentional mixing of incompatible intravenous medications.
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http://dx.doi.org/10.1016/j.clinthera.2019.08.005DOI Listing
October 2019

Development of Daptomycin Susceptibility Breakpoints for Enterococcus faecium and Revision of the Breakpoints for Other Enterococcal Species by the Clinical and Laboratory Standards Institute.

Clin Infect Dis 2020 03;70(6):1240-1246

Department of Pathology, University of Texas Health Sciences Center at San Antonio.

Daptomycin is one of the few treatment options for infections caused by enterococci that are resistant to ampicillin and vancomycin, such as vancomycin-resistant Enterococcus faecium. The emergence and clinical significance of daptomycin-resistant enterococci and evolving microbiologic, pharmacokinetic-pharmacodynamic, and clinical data indicated that the pre-2019 Clinical and Laboratory Standards Institute (CLSI) susceptible-only breakpoint of ≤4 μg/mL for daptomycin and enterococci was no longer appropriate. After analyzing data that are outlined in this article, the CLSI Subcommittee on Antimicrobial Susceptibility Testing established new breakpoints for daptomycin and enterococci. For E. faecium, a susceptible dose-dependent (SDD) breakpoint of ≤4 μg/mL was established based on an increased dosage of 8-12 mg/kg/day (≥8 μg/mL-resistant). CLSI suggests infectious diseases consultation to guide daptomycin use for the SDD category. For Enterococcus faecalis and other enterococcal species, revised breakpoints of ≤2 μg/mL-susceptible, 4 μg/mL-intermediate, and ≥8 μg/mL-resistant were established based on a standard dosage of 6 mg/kg/day.
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http://dx.doi.org/10.1093/cid/ciz845DOI Listing
March 2020

Monte Carlo Simulation Methodologies for β-Lactam/β-Lactamase Inhibitor Combinations: Effect on Probability of Target Attainment Assessments.

J Clin Pharmacol 2020 02 18;60(2):172-180. Epub 2019 Aug 18.

Center for Anti-Infective Research and Development, Hartford Hospital, Harford, Connecticut, USA.

Monte Carlo simulations (MCSs) are used in antibiotic development to predict the probability of pharmacodynamic target attainment (PTA) for a dosing regimen. However, for β-lactam/β-lactamase inhibitor combinations (BL-BLICs), methods for linking simulated concentration profiles of the β-lactam (BL) and β-lactamase inhibitor (BLI) components are rarely described. Using a previously defined pharmacokinetic model of ceftazidime/avibactam from critically ill patients, we performed four 5000-patient MCSs using different methods of increasing complexity to couple the BL and BLI components and compared PTA for ceftazidime and avibactam targets of >70% fT>MIC and >70% fT>1 mg/L, respectively, at MICs from 1 to 128 mg/L. Method A ignored all covariates and correlations, whereas methods B, C, and D enhanced associations by adding (B) pharmacokinetic parameter correlation within each drug only; (C) pharmacokinetic parameter correlation within each drug and creatinine clearance (CRCL); and (D) pharmacokinetic parameter correlation within each drug, CRCL, and pharmacokinetic parameter correlation between drugs. Method D produced a simulated patient population that best recapitulated the observed relationships between pharmacokinetic parameters in actual patients. Ceftazidime/avibactam PTA at MIC 8 mg/L (the susceptibility break point) and 16 mg/L ranged from 92.4% to 98.3% and 80.2% to 88.4%, respectively. PTA was lowest with method A, whereas PTA estimates were similar for all other methods. Compared with ignoring all pharmacokinetic parameter associations, the inclusion of covariate relationships and parameter correlation between both components of ceftazidime/avibactam leads to fewer patients with discordant pharmacokinetic parameters and results in higher PTA. Consideration of these methodologies should guide future MCS analyses for BL-BLIC.
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http://dx.doi.org/10.1002/jcph.1510DOI Listing
February 2020

Application of the Hartford Hospital Nomogram for Plazomicin Dosing Interval Selection in Patients with Complicated Urinary Tract Infection.

Antimicrob Agents Chemother 2019 10 23;63(10). Epub 2019 Sep 23.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA

Plazomicin is a new FDA-approved aminoglycoside antibiotic for complicated urinary tract infections (cUTI). In the product labeling, trough-based therapeutic drug management (TDM) is recommended for cUTI patients with renal impairment to prevent elevated trough concentrations associated with serum creatinine increases of ≥0.5 mg/dl above baseline. Herein, the utility of the Hartford nomogram to prevent plazomicin trough concentrations exceeding the TDM trough of 3 μg/ml and optimize the area under the curve (AUC) was assessed. The AUC reference range was defined as the 5th to 95th percentile AUC observed in the phase 3 cUTI trial (EPIC) (121 to 368 μg · h/ml). Observed 10-h plazomicin concentrations from patients in EPIC ( = 281) were plotted on the nomogram to determine an eligible dosing interval (every 24 h [q24h], q36h, q48h). Based on creatinine clearance (CLcr), a 15- or 10-mg/kg of body weight dose was simulated with the nomogram-derived interval. The nomogram recommended an extended interval (q36h and q48h) in 31% of patients. Compared with the 15 mg/kg q24h regimen received by patients with CLcr of ≥60 ml/min in EPIC, the nomogram-derived interval reduced the proportion of patients with troughs of ≥3 μg/ml (q36h, 27% versus 0%,  = 0.021; q48h, 57% versus 0%,  = 0.002) while significantly increasing the number of patients within the AUC range. Compared with the 8 to 12 mg/kg q24h regimen (received by patients with CLcr of >30 to 59 ml/min in EPIC), the nomogram-derived interval significantly reduced the proportion of troughs of ≥3μg/ml in the q48h cohort (72% versus 0%,  < 0.001) while maintaining a similar proportion of patients in the AUC range. Simulated application of the Hartford nomogram optimized plazomicin exposures in patients with cUTI while reducing troughs to <3 μg/ml.
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http://dx.doi.org/10.1128/AAC.00148-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761540PMC
October 2019

Recovery of Gram-Negative Bacteria from Aerobic Blood Culture Bottles Containing Antibiotic Binding Resins after Exposure to β-Lactam and Fluoroquinolone Concentrations.

J Clin Microbiol 2019 10 24;57(10). Epub 2019 Sep 24.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA

Blood culture bottles containing antibiotic binding resins are routinely used to minimize artificial sterilization in the presence of antibiotics. However, the resin binding kinetics can differ between antibiotics and concentrations. This study assessed the impact of clinically meaningful peak, midpoint, and trough concentrations of meropenem, imipenem, cefepime, cefazolin, levofloxacin, and piperacillin-tazobactam on the recovery of , , and from resin-containing BacT/Alert FA Plus and Bactec Aerobic/F blood culture bottles. -inoculated bottles alarmed positive in 4/20 (20%), 16/20 (80%), and 20/20 (100%) of those with peak, midpoint, and trough concentrations of antipseudomonal agents, respectively ( ≤ 0.001). was recovered from 8/24 (33%), 11/24 (46%), and 14/24 (58%) of bottles with peak, midpoint, and trough concentrations, respectively ( = 0.221). was recovered from 8/16 (50%) at all concentrations of the studied antibiotics ( = 1.0). BacT/Alert and Bactec bottles inoculated with antibiotics and had similar times to detection (TTD) ( = 0.352); however, antibiotic-containing BacT/Alert bottles had a shorter TTD compared with antibiotic-containing Bactec bottles for ( = 0.026) and ( ≤ 0.001). Pathogen recovery in BacT/Alert FA Plus and Bactec Aerobic/F blood culture bottles containing antibiotic binding resins was greatly reduced in the presence of antibiotics, especially at higher concentrations. These data support the practice of drawing blood cultures immediately before an antibiotic dose to maximize the chances of pathogen recovery.
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http://dx.doi.org/10.1128/JCM.00849-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760962PMC
October 2019

Pharmacodynamics of daptomycin in combination with other antibiotics for the treatment of enterococcal bacteraemia.

Int J Antimicrob Agents 2019 Sep 5;54(3):346-350. Epub 2019 Jul 5.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA; Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut, USA. Electronic address:

Daptomycin is commonly prescribed in combination with other antibiotics for treatment of enterococcal bacteraemia. Whilst a free drug area under the concentration-time curve to minimum inhibitory concentration (fAUC/MIC) ratio >27.4 is associated with 30-day survival with daptomycin monotherapy, it is unknown whether receipt of other antibiotics affects this threshold. Data were pooled from seven published trials assessing outcomes in daptomycin-treated enterococcal bacteraemia, including patients receiving daptomycin (≥72 h) and any β-lactam, intravenous aminoglycoside, linezolid, tigecycline and/or vancomycin. Exposures were calculated using a published population pharmacokinetic model based on creatinine clearance, 90% protein binding and daptomycin Etest MIC. The fAUC/MIC threshold predictive of 30-day survival was determined by classification and regression tree analysis. Following pooling of data, 240 adults were included; 137 (57.1%) were alive at 30 days. A majority of patients were immunosuppressed (65.8%) and received a β-lactam (94.6%). Examining the threshold in low-acuity patients (n = 135) to control for co-morbidities, these patients were more likely to survive when fAUC/MIC >12.3 was achieved (63.2% vs. 20.0%; P = 0.015). The difference remained significant in a multivariable logistic regression model that controlled for infection source and immunosuppression (P = 0.017). This threshold is 2-fold lower than that observed with daptomycin monotherapy. Probabilities of threshold attainment using a 10 mg/kg/day dose were 100% for isolates with MICs ≤ 2 mg/L and 95.2% for a 12 mg/kg/day dose for MICs of 4 mg/L. These data support the use of high-dose daptomycin in combination with another antibiotic for treatment of enterococcal bacteraemia.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.07.002DOI Listing
September 2019

Activity of Imipenem-Relebactam Alone or in Combination with Amikacin or Colistin against Pseudomonas aeruginosa.

Antimicrob Agents Chemother 2019 09 23;63(9). Epub 2019 Aug 23.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA

Relebactam is a novel class A/C β-lactamase inhibitor that restores imipenem activity against multidrug-resistant and carbapenem-nonsusceptible Time-kill analyses were performed to evaluate the potential role of imipenem-relebactam in combination with amikacin or colistin against Ten clinical isolates (9 imipenem nonsusceptible) with imipenem-relebactam MICs ranging from 1/4 to 8/4 μg/ml were included. The isolates had varied susceptibilities to imipenem (1 to 32 μg/ml), amikacin (4 to 128 μg/ml), and colistin (0.5 to 1 μg/ml). Duplicate 24-h time-kill studies were conducted using the average steady-state concentrations (ss) observed after the administration of imipenem-relebactam at 500 mg/250 mg every 6 hours (q6h) alone and in combination with the ss of 25 mg/kg of body weight/day amikacin and 360 mg/day colistin in humans. Imipenem-relebactam alone resulted in 24-h bacterial densities of -2.93 ± 0.38, -1.67 ± 0.29, +0.38 ± 0.96, and +0.15 ± 0.65 log CFU/ml at imipenem-relebactam MICs of 1/4, 2/4, 4/4, and 8/4 μg/ml, respectively. No synergy was demonstrated against the single imipenem-susceptible isolate. Against the imipenem-nonsusceptible isolates ( = 9), imipenem-relebactam combined with amikacin resulted in synergy (-2.61 ± 1.50 log CFU/ml) against all amikacin-susceptible isolates and in two of three amikacin-intermediate (i.e., MIC, 32 μg/ml) isolates (-2.06 ± 0.19 log CFU/ml). Synergy with amikacin was not observed when the amikacin MIC was >32 μg/ml. Imipenem-relebactam combined with colistin demonstrated synergy in eight out of the nine imipenem-resistant isolates (-3.17 ± 1.00 log CFU/ml). Against these 10  isolates, imipenem-relebactam combined with either amikacin or colistin resulted in synergistic activity against the majority of strains. Further studies evaluating combination therapy with imipenem-relebactam are warranted.
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http://dx.doi.org/10.1128/AAC.00997-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709505PMC
September 2019

Evaluation of Plazomicin, Tigecycline, and Meropenem Pharmacodynamic Exposure against Carbapenem-Resistant Enterobacteriaceae in Patients with Bloodstream Infection or Hospital-Acquired/Ventilator-Associated Pneumonia from the CARE Study (ACHN-490-007).

Infect Dis Ther 2019 Sep 28;8(3):383-396. Epub 2019 Jun 28.

Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT, 06102, USA.

Introduction: CARE was a Phase 3, randomized study evaluating the efficacy and safety of plazomicin-based combination therapy compared with colistin-based combination therapy for the treatment of patients with bloodstream infections or hospital-acquired/ventilator-associated pneumonia due to carbapenem-resistant Enterobacteriaceae (CRE). Adjunctive therapies included either tigecycline or meropenem. We sought to understand the contribution of tigecycline and meropenem to plazomicin-treated-patient outcomes by determining their observed pharmacodynamic exposures against baseline pathogens.

Methods: Blood samples collected for plazomicin therapeutic monitoring were assayed for tigecycline and meropenem concentrations. Population pharmacokinetic models were constructed for each antibiotic. Using the individual Bayesian posterior or a covariate-based model, concentration time profiles were simulated to estimate the pharmacodynamic exposures for each patient. Pharmacodynamic thresholds for plazomicin, tigecycline, and meropenem were a total area under the curve to minimum inhibitory concentration ratio (AUC/MIC) ≥ 85, free (f) AUC/MIC ≥ 0.9, and free time above the MIC (fT > MIC) of ≥ 40%, respectively.

Results: Fifteen plazomicin-treated patients were included (12 received tigecycline, 4 received meropenem, 1 received both). Microbiological response was observed in 13 (86.7%) and clinical efficacy was achieved in 11 (73.3%). Plazomicin achieved its pharmacodynamic target in all 15 patients. Meropenem fT > MIC was 0% in all 4 patients, and tigecycline fAUC/MIC was ≥ 0.9 in 9 (75%) patients. Overall, 6 (40%) of 15 patients had a tigecycline or meropenem exposure below the requisite thresholds. Microbiological response and clinical efficacy were observed in 100% (6/6) and 83.3% (5/6) of patients with low threshold attainment by tigecycline and meropenem dosing regimens, respectively.

Conclusions: Plazomicin successfully achieved its requisite pharmacodynamic exposure, and these data suggest that optimization of tigecycline and meropenem therapy was not required for the combination to achieve microbiological response and clinical efficacy against serious CRE infections.

Trial Registration: ClinicalTrials.gov number, NCT01970371.

Funding: Achaogen, Inc.
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http://dx.doi.org/10.1007/s40121-019-0251-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702525PMC
September 2019

A Simulated Application of the Hartford Hospital Aminoglycoside Dosing Nomogram for Plazomicin Dosing Interval Selection in Patients With Serious Infections Caused by Carbapenem-Resistant Enterobacterales.

Clin Ther 2019 08 24;41(8):1453-1462. Epub 2019 Jun 24.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA. Electronic address:

Purpose: In the Phase III Study of Plazomicin Compared With Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CARE), plazomicin was studied for the treatment of critically ill patients with infections caused by carbapenem-resistant Enterobacterales. Initial plazomicin dosing was guided by creatinine clearance (CrCl) and subsequent doses adjusted by therapeutic drug monitoring to achieve AUC exposures within a target range (210-315 mg∙h/L). We applied the Hartford nomogram to evaluate whether this clinical tool could reduce plazomicin troughs levels and increase the proportion of patients within the target AUC range.

Methods: Thirty-seven patients enrolled in cohorts 1 or 2 of CARE were eligible for analyses. Observed 10-hour concentrations after the initial dose were plotted on the Hartford nomogram to determine an eligible dosing interval group (q24h, q36h or q48h). On the basis of baseline CrCl, a 15- or 10-mg/kg dose was simulated with the nomogram-recommended dosing interval. The proportion of patients in each dosing interval group with a trough ≥3 mg/L (trough threshold associated with serum creatinine increases ≥0.5 mg/dL in product label) was quantified. Simulated interval-normalized AUC was compared with the target AUC range.

Findings: Among the 28 patients with a CrCl ≥60 mL/min, the nomogram recommended every-24-hour dosing in 61% and an extended-interval (q36h or q48h) in 39% of patients. For patients with a CrCl ≥30-59 mL/min (n = 9), the nomogram recommended every-24-hour dosing and an extended-interval in 22% and 78% of patients, respectively. Among both renal function cohorts, exposure simulation with the nomogram significantly reduced the proportion of patients with trough concentrations ≥3 mg/L (CrCl ≥60 mL/min cohort: 91% vs 9%, P < 0.001; CrCl ≥30-59 mL/min cohort, 100% vs 0%, P < 0.001). Relative to the observed mean (SD) AUC of 309 mg∙h/mL (96 mg∙h/mL), simulation of extended intervals resulted in a mean interval-normalized AUC of 210 mg∙h/mL (40 mg∙h/mL) in all patients eligible for an extended interval, resulting in a similar proportion (49% vs 54%) of patients within the target AUC range after the first dose.

Implications: Application of the Hartford nomogram successfully reduced the likelihood of elevated plazomicin trough concentrations while improving AUC exposures in these patients with carbapenem-resistant Enterobacterales infections.
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http://dx.doi.org/10.1016/j.clinthera.2019.04.038DOI Listing
August 2019

Carbapenem-Nonsusceptible Isolates from Intensive Care Units in the United States: a Potential Role for New β-Lactam Combination Agents.

J Clin Microbiol 2019 08 26;57(8). Epub 2019 Jul 26.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA

, a frequent pathogen in the intensive care unit (ICU), has the propensity to develop antibiotic resistance. In particular, carbapenem-nonsusceptible (NS) poses tremendous challenges, and new antibiotics will be needed to treat this phenotype. Here we determine carbapenem nonsusceptibility rates for contemporary isolates from U.S. ICUs and activities of new β-lactam combination agents. Between July 2017 and June 2018, consecutive nonduplicate isolates from blood and respiratory tract sources were recovered from patients admitted to the ICUs of 36 geographically diverse U.S. hospitals. Antimicrobial susceptibility to the following antipseudomonal agents was tested: ceftazidime, imipenem, meropenem, ceftazidime-avibactam, and imipenem-relebactam (an investigational β-lactam/β-lactamase inhibitor). MICs and susceptibility rates were measured using Clinical and Laboratory Standards Institute reference broth microdilution methodology. Among the 538 consecutive ICU isolates collected, carbapenem nonsusceptibility was observed for 35% of the isolates and was more common among respiratory tract versus bloodstream specimens. Susceptibility rates, MIC values, and MIC values were as follows: ceftazidime-avibactam, 92.8%, 2 μg/ml, and 8 μg/ml; imipenem-relebactam, 91.5%, 0.25 μg/ml, and 2 μg/ml; ceftazidime, 77.1%, 4 μg/ml, and 64 μg/ml; meropenem, 72.7%, 1 μg/ml, and 16 μg/ml; imipenem, 67.1%, 2 μg/ml, and 16 μg/ml. Most (>75%) of the carbapenem-NS isolates were susceptible to ceftazidime-avibactam and imipenem-relebactam. In these U.S. hospital ICUs, carbapenem-NS isolates from respiratory sources were frequently observed. Novel β-lactam combination agents appear to retain active susceptibility profiles against these isolates and may play a role in the treatment of infections caused by carbapenem-NS strains.
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http://dx.doi.org/10.1128/JCM.00535-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663898PMC
August 2019

Pharmacodynamics of a Novel Ceftibuten-Clavulanate Combination Antibiotic against Enterobacteriaceae.

Antimicrob Agents Chemother 2019 07 24;63(7). Epub 2019 Jun 24.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA

A novel antibiotic combination of the oral cephalosporin ceftibuten (CTB) and the β-lactamase inhibitor clavulanate (CLA) is currently in development for urinary tract infections, including those caused by extended-spectrum-β-lactamase (ESBL)-producing organisms. This study aimed to identify the pharmacodynamic index and magnitude of this index for CLA, when combined with a fixed CTB exposure (∼59% free time above the CTB-CLA MIC) against ESBL-producing and (CTB-CLA MICs of 0.25/0.125 to 1/0.5 μg/ml) using the chemostat model. Dose fractionation studies identified the time that free CLA concentrations remained above a threshold concentration (>threshold) to be the best pharmacodynamic index ( = 0.85) compared with the free area under the curve (AUC)/threshold ratio ( = 0.62) and free maximum concentration/threshold ratio ( = 0.37). For isolates, stasis and 1-log CFU reductions were achieved at 30.9 and 47.9% >CTB concentrations of the 2:1 CTB-CLA MIC (>MIC here), respectively. For isolates, stasis and 1-log CFU reductions were achieved at 51.9 and 92.0% >MIC, respectively. These data inform exposure requirements for CLA combined with CTB for optimizing pharmacodynamics against and should be useful in designing dosage regimens for this combination antibiotic.
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http://dx.doi.org/10.1128/AAC.00144-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591603PMC
July 2019

Where should antibiotic gradient diffusion strips be crossed to assess synergy? A comparison of the standard method with a novel method using steady-state antimicrobial concentrations.

Int J Antimicrob Agents 2019 May 14;53(5):698-702. Epub 2019 Mar 14.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA; Division of Infectious Diseases, Hartford Hospital, Hartford, CT, USA. Electronic address:

Multi-drug resistance among Pseudomonas aeruginosa in hospitals, and particularly intensive care units, has achieved alarming rates. Some combination antimicrobial therapies have demonstrated promising synergistic effects and an ability to overcome resistance without increasing drug-related toxicities. Nevertheless, rapid and feasible methods to identify synergy have not been routinely implemented in clinical microbiology laboratories. Synergistic activity of meropenem plus tobramycin or levofloxacin against clinical P. aeruginosa isolates (N=21) was assessed by two different methods using gradient diffusion strips (GDSs). A 90° angle was created at the intersection of the minimum inhibitory concentration (MIC) of each drug by the standard method, and by a novel method, the cross was placed at clinically relevant steady-state concentrations (C) based on recommended dosing regimens. Fractional inhibitory concentration indexes were determined to describe antibiotic interactions. Time-kill analyses were performed over 24 h in duplicate for instances of discordance between the standard cross method and the novel method. Synergy between meropenem and tobramycin by the novel method was observed in one (4.8%) isolate and between meropenem and levofloxacin in two (9.5%) isolates. Agreement with the standard method was 86-100% for meropenem plus tobramycin and meropenem plus levofloxacin combinations, respectively. Time-kill studies resulted in agreement with GDSs crossed at C in two of three instances of discordance between GDS methods. This novel method of synergy testing that involves crossing GDSs at steady-state concentrations may be a rapid and feasible tool for routine practice. Further comparisons of this novel procedure with time-kill methods are needed.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.03.006DOI Listing
May 2019

Reply to Cheng and Chuang.

Clin Infect Dis 2019 08;69(5):903-904

Center for Anti-infective Research and Development, Hartford Hospital, Connecticut.

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http://dx.doi.org/10.1093/cid/ciz081DOI Listing
August 2019

Patient preferences for treatment of acute bacterial skin and skin structure infections in the emergency department.

BMC Health Serv Res 2018 Dec 4;18(1):932. Epub 2018 Dec 4.

Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT, 06102, USA.

Background: Limited research has assessed patient preferences for treatment disposition and antibiotic therapy of acute bacterial skin and skin structure infection (ABSSSI) in the emergency department (ED). Understanding patient preference for the treatment of ABSSSI may influence treatment selection and improve satisfaction.

Methods: A survey was conducted across 6 US hospital EDs. Patients with ABSSSI completed a baseline survey assessing preferences for antibiotic therapy (intravenous versus oral) and treatment location. A follow-up survey was conducted within 30-40 days after ED discharge to reassess preferences and determine satisfaction with care.

Results: A total of 94 patients completed both baseline and follow-up surveys. Sixty (63.8%) participants had a history of ABSSSI, and 69 (73.4%) were admitted to the hospital. Treatment at home was the most common preference reported on baseline and follow-up surveys. Patients with higher education were 82.2% less likely to prefer treatment in the hospital. Single dose intravenous therapy was the most commonly preferred antibiotic regimen on baseline and follow-up surveys (39.8 and 19.1%, respectively). Median satisfaction scores for care in the ED, hospital, home, and with overall antibiotic therapy were all 8 out of a maximum of 10.

Conclusions: In these patients, the most common preference was for outpatient care and single dose intravenous antibiotics. Patient characteristics including higher education, younger age, and current employment were associated with these preferences. Opportunities exist for improving ABSSSI care and satisfaction rates by engaging patients and offering multiple treatment choices.
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http://dx.doi.org/10.1186/s12913-018-3751-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278032PMC
December 2018
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