Publications by authors named "Aaron J Heffernan"

14 Publications

  • Page 1 of 1

Association Between Urine Output and Mortality in Critically Ill Patients: A Machine Learning Approach.

Crit Care Med 2021 Sep 22. Epub 2021 Sep 22.

School of Medicine, Griffith University, Southport, QLD, Australia. Department of Intensive Care, Alfred Hospital, Melbourne, VIC, Australia. Centre for Transformative Innovation, Faculty of Business and Law, Swinburne University of Technology, Hawthorn, VIC, Australia. Department of Data Science and AI, Faculty of Information Technology, Monash University, Melbourne, VIC, Australia. School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia. Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation, Melbourne, VIC, Australia. Department of Cardiology, Alfred Hospital, Melbourne, VIC, Australia. Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.

Objectives: Current definitions of acute kidney injury use a urine output threshold of less than 0.5 mL/kg/hr, which have not been validated in the modern era. We aimed to determine the prognostic importance of urine output within the first 24 hours of admission to the ICU and to evaluate for variance between different admission diagnoses.

Design: Retrospective cohort study.

Setting: One-hundred eighty-three ICUs throughout Australia and New Zealand from 2006 to 2016.

Patients: Patients greater than or equal to 16 years old who were admitted with curative intent who did not regularly receive dialysis. ICU readmissions during the same hospital admission and patients transferred from an external ICU were excluded.

Measurements And Main Results: One hundred and sixty-one thousand nine hundred forty patients were included with a mean urine output of 1.05 mL/kg/hr and an overall in-hospital mortality of 7.8%. A urine output less than 0.47 mL/kg/hr was associated with increased unadjusted in-hospital mortality, which varied with admission diagnosis. A machine learning model (extreme gradient boosting) was trained to predict in-hospital mortality and examine interactions between urine output and survival. Low urine output was most strongly associated with mortality in postoperative cardiovascular patients, nonoperative gastrointestinal admissions, nonoperative renal/genitourinary admissions, and patients with sepsis.

Conclusions: Consistent with current definitions of acute kidney injury, a urine output threshold of less than 0.5 mL/kg/hr is modestly predictive of mortality in patients admitted to the ICU. The relative importance of urine output for predicting survival varies with admission diagnosis.
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http://dx.doi.org/10.1097/CCM.0000000000005310DOI Listing
September 2021

A Systematic Review of Intravenous β-Hydroxybutyrate Use in Humans - A Promising Future Therapy?

Front Med (Lausanne) 2021 21;8:740374. Epub 2021 Sep 21.

Department of Intensive Care Medicine, North Bristol NHS Trust, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom.

Therapeutic ketosis is traditionally induced with dietary modification. However, owing to the time delay involved, this is not a practical approach for treatment of acute conditions such as traumatic brain injury. Intravenous administration of ketones would obviate this problem by rapidly inducing ketosis. This has been confirmed in a number of small animal and human studies. Currently no such commercially available product exists. The aim of this systematic review is to review the safety and efficacy of intravenous beta-hydroxybutyrate. The Web of Science, PubMed and EMBASE databases were searched, and a systematic review undertaken. Thirty-five studies were included. The total beta-hydroxybutyrate dose ranged from 30 to 101 g administered over multiple doses as a short infusion, with most studies using the racemic form. Such dosing achieves a beta-hydroxybutyrate concentration >1 mmol/L within 15 min. Infusions were well tolerated with few adverse events. Blood glucose concentrations occasionally were reduced but remained within the normal reference range for all study participants. Few studies have examined the effect of intravenous beta-hydroxybutyrate in disease states. In patients with heart failure, intravenous beta-hydroxybutyrate increased cardiac output by up to 40%. No studies were conducted in patients with neurological disease. Intravenous beta-hydroxybutyrate has been shown to increase cerebral blood flow and reduce cerebral glucose oxidation. Moreover, beta-hydroxybutyrate reduces protein catabolism and attenuates the production of counter-regulatory hormones during induced hypoglycemia. An intravenous beta-hydroxybutyrate formulation is well tolerated and may provide an alternative treatment option worthy of further research in disease states.
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http://dx.doi.org/10.3389/fmed.2021.740374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490680PMC
September 2021

Dose optimisation of antibiotics used for meningitis.

Curr Opin Infect Dis 2021 Sep 15. Epub 2021 Sep 15.

University of Queensland Centre for Clinical Research, Faculty of Medicine, University of Queensland, Herston School of Medicine and Dentistry, Griffith University, Southport Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France.

Purpose Of Review: Central nervous system (CNS) infections such as ventriculitis and meningitis are associated with significant morbidity and mortality. In part, this may be due to increased difficulties in achieving a therapeutic antibiotic concentration at the site of infection due to both the pharmacokinetic (PK) changes observed during critical illness and the reduced antibiotic penetration through the blood brain barrier. This paper reviews the pharmacodynamics (PD) and CNS PKs of antibiotics used for Gram-negative bacterial CNS infections to provide clinicians with practical dosing advice.

Recent Findings: Recent PK studies have shown that currently used intravenous antibiotic dosing regimens may not achieve a therapeutic exposure within the CNS, even for reportedly 'susceptible' bacteria per the current clinical meningitis breakpoints. Limited data exist for new β-lactam antibiotic/β-lactamase inhibitor combinations, which may be required for multidrug resistant infections. Intraventricular antibiotic administration, although not a new concept, has further evidence demonstrating improved patient outcomes compared with intravenous therapy alone, despite the ongoing paucity of PK studies guiding dosing recommendations.

Summary: Clinicians should obtain the bacterial minimum inhibitory concentration when treating patients with CNS Gram-negative bacterial infections and consider the underlying PK/PD principles when prescribing antibiotics. Therapeutic drug monitoring, where available, should be considered to guide dosing. Intraventricular therapy should also be considered for patients with ventricular drains to optimise clinical outcomes.
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http://dx.doi.org/10.1097/QCO.0000000000000783DOI Listing
September 2021

Epidemiology of extended-spectrum β-lactamase and metallo-β-lactamase-producing in South Asia.

Future Microbiol 2021 05 7;16:521-535. Epub 2021 May 7.

Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Queensland, 4103, Australia.

To determine the prevalence of extended-spectrum β-lactamase (ESBL) and metallo-β-lactamase (MBL)-producing in South Asia. A systematic review and meta-analysis of data published in PubMed, EMBASE, Web of Science and Scopus. The pooled prevalence of ESBL and MBL-producing in South Asia were 33% (95% CI: 27-40%) and 17% (95% CI: 12-24%), respectively. The prevalence of type was 58% (95% CI: 49-66%) with being the most prevalent (51%, 95% CI: 40-62%) variant. The most prevalent MBL variant was (33%, 95% CI: 20-50%). This study suggests a high prevalence of ESBLs and MBLs among clinical isolates. Comprehensive resistance surveillance is required to guide clinicians prescribing antibiotics in South Asia.
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http://dx.doi.org/10.2217/fmb-2020-0193DOI Listing
May 2021

Semi-mechanistic PK/PD modelling of meropenem and sulbactam combination against carbapenem-resistant strains of Acinetobacter baumannii.

Eur J Clin Microbiol Infect Dis 2021 Sep 22;40(9):1943-1952. Epub 2021 Apr 22.

Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, Pharmacy Australia Centre of Excellence, University of Queensland, Level 4, 20 Cornwall Street, Woolloongabba, QLD, 4102, Australia.

Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are commonly used. In this study, we explored the potential efficacy of meropenem-sulbactam combination (MEM/SUL) against CR-AB. The checkerboard method was used to screen for synergistic activity of MEM/SUL against 50 clinical CR-AB isolates. Subsequently, time-kill studies against two CR-AB isolates were performed. Time-kill data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Subsequently, Monte Carlo simulations were performed to estimate the probability of 2-log kill, 1-log kill or stasis at 24-h following combination therapy. The MEM/SUL demonstrated synergy against 28/50 isolates. No antagonism was observed. The MIC50 and MIC of MEM/SUL were decreased fourfold, compared to the monotherapy MIC. In the time-kill studies, the combination displayed synergistic killing against both isolates at the highest clinically achievable concentrations. At concentrations equal to the fractional inhibitory concentration, synergism was observed against one isolate. The PK/PD model adequately delineated the data and the interaction between meropenem and sulbactam. The effect of the combination was driven by sulbactam, with meropenem acting as a potentiator. The simulations of various dosing regimens revealed no activity for the monotherapies. At best, the MEM/SUL regimen of 2 g/4 g every 8 h demonstrated a probability of target attainment of 2-log kill at 24 h of 34%. The reduction in the MIC values and the achievement of a moderate PTA of a 2-log reduction in bacterial burden demonstrated that MEM/SUL may potentially be effective against some CR-AB infections.
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http://dx.doi.org/10.1007/s10096-021-04252-zDOI Listing
September 2021

Impact of the Epithelial Lining Fluid Milieu on Amikacin Pharmacodynamics Against Pseudomonas aeruginosa.

Drugs R D 2021 Jun 2;21(2):203-215. Epub 2021 Apr 2.

Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Cornwall St, Woolloongabba, QLD, 4102, Australia.

Background: Even though nebulised administration of amikacin can achieve high epithelial lining fluid concentrations, this has not translated into improved patient outcomes in clinical trials. One possible reason is that the cellular and chemical composition of the epithelial lining fluid may inhibit amikacin-mediated bacterial killing.

Objective: The objective of this study was to identify whether the epithelial lining fluid components inhibit amikacin-mediated bacterial killing.

Methods: Two amikacin-susceptible (minimum inhibitory concentrations of 2 and 8 mg/L) Pseudomonas aeruginosa isolates were exposed in vitro to amikacin concentrations up to 976 mg/L in the presence of an acidic pH, mucin and/or surfactant as a means of simulating the epithelial lining fluid, the site of bacterial infection in pneumonia. Pharmacodynamic modelling was used to describe associations between amikacin concentrations, bacterial killing and emergence of resistance.

Results: In the presence of broth alone, there was rapid and extensive (> 6 - log) bacterial killing, with emergence of resistance identified in amikacin concentrations < 976 mg/L. In contrast, the rate and extent of bacterial killing was reduced (≤ 5 - log) when exposed to an acidic pH and mucin. Surfactant did not appreciably impact the bacterial killing or resistance emergence when compared with broth alone for either isolate. The combination of mucin and an acidic pH further reduced the rate of bacterial killing, with the maximal bacterial killing occurring 24 h following initial exposure compared with approximately 4-8 h for either mucin or an acidic pH alone.

Conclusions: Our findings indicate that simulating the epithelial lining fluid antagonises amikacin-mediated killing of P. aeruginosa, even at the high concentrations achieved following nebulised administration.
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http://dx.doi.org/10.1007/s40268-021-00344-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017437PMC
June 2021

Host Diagnostic Biomarkers of Infection in the ICU: Where Are We and Where Are We Going?

Curr Infect Dis Rep 2021 12;23(4). Epub 2021 Feb 12.

Department of Intensive Care, Gold Coast University Hospital, Gold Coast, QLD Australia.

Purpose Of Review: Early identification of infection in the critically ill patient and initiation of appropriate treatment is key to reducing morbidity and mortality. On the other hand, the indiscriminate use of antimicrobials leads to harms, many of which may be exaggerated in the critically ill population. The current method of diagnosing infection in the intensive care unit relies heavily on clinical gestalt; however, this approach is plagued by biases. Therefore, a reliable, independent biomarker holds promise in the accurate determination of infection. We discuss currently used host biomarkers used in the intensive care unit and review new and emerging approaches to biomarker discovery.

Recent Findings: White cell count (including total white cell count, left shift, and the neutrophil-leucocyte ratio), C-reactive protein, and procalcitonin are the most common host diagnostic biomarkers for sepsis used in current clinical practice. However, their utility in the initial diagnosis of infection, and their role in the subsequent decision to commence treatment, remains limited. Novel approaches to biomarker discovery that are currently being investigated include combination biomarkers, host 'sepsis signatures' based on differential gene expression, site-specific biomarkers, biomechanical assays, and incorporation of new and pre-existing host biomarkers into machine learning algorithms.

Summary: To date, no single reliable independent biomarker of infection exists. Whilst new approaches to biomarker discovery hold promise, their clinical utility may be limited if previous mistakes that have afflicted sepsis biomarker research continue to be repeated.
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http://dx.doi.org/10.1007/s11908-021-00747-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880656PMC
February 2021

Ceftriaxone dosing in patients admitted from the emergency department with sepsis.

Eur J Clin Pharmacol 2021 Feb 24;77(2):207-214. Epub 2020 Sep 24.

University of Queensland Centre for Clinical Research, Faculty of Medicine, University of Queensland, Herston, Australia.

Purpose: Unbound ceftriaxone pharmacokinetics in adult patients have been poorly characterised. The objective of this study is to determine the ceftriaxone dose that achieves an unbound trough concentration ≥ 0.5 mg/L in > 90% of adult patients receiving once-daily dosing presenting to the emergency department (ED) with sepsis.

Methods: We performed a prospective single-centre pharmacokinetic study. A single unbound plasma ceftriaxone concentration was obtained from each patient using blood collected as part of routine clinical practice within the first dosing interval. Samples were analysed using a validated ultra-high pressure liquid chromatography method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R.

Results: A ceftriaxone concentration obtained throughout the first dosing interval was available for fifty adult patients meeting sepsis criteria. Using this concentration time-curve data, a pharmacokinetic model was developed with acceptable predictive performance per the visual predictive check. Simulations show that a 1-g once-daily dose is unlikely to achieve the minimum therapeutic ceftriaxone exposure in > 90% patients with a creatinine clearance ≥ 60 mL/min. However, a 2-g once-daily dose will provide a therapeutic exposure for target pathogens infecting patients with a creatinine clearance ≤ 140 mL/min.

Conclusions: Ceftriaxone administered as a 1-g once-daily dose is unlikely to achieve a therapeutic exposure in > 90% of patients presenting to the ED with sepsis. Increasing the ceftriaxone dose to 2 g once daily will likely achieve the desired exposure against target pathogens. Future clinical trials are required to determine any potential clinical benefit of optimised ceftriaxone dosing.
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http://dx.doi.org/10.1007/s00228-020-03001-zDOI Listing
February 2021

Pharmacodynamic Analysis of Meropenem and Fosfomycin Combination Against Carbapenem-Resistant in Patients with Normal Renal Clearance: Can It Be a Treatment Option?

Microb Drug Resist 2021 Apr 8;27(4):546-552. Epub 2020 Sep 8.

Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, University of Queensland, Brisbane, Queensland, Australia.

Combination therapy may be a treatment option against carbapenem-resistant (CR-AB) infections. In this study, we explored the utility of fosfomycin in combination with meropenem (FOS/MEM) against CR-AB isolates. Screening of synergistic activity of FOS/MEM was performed using the checkerboard assay. A pharmacokinetic/pharmacodynamic analysis was performed for various FOS/MEM regimens using Monte Carlo simulations. The minimum inhibitory concentration (MIC) required to inhibit the growth of 50% of the isolates (MIC) and MIC required to inhibit the growth of 90% of the isolates (MIC) of FOS and MEM were reduced fourfold and twofold, respectively. The combination was synergistic against 14/50 isolates. No antagonism was observed. Sixteen out of fifty isolates had MEM MICs of ≤8 mg/L when subjected to combination therapy, compared to none with monotherapy. Forty-one out of 50 isolates had FOS MICs of ≤128 mg/L when subjected to combination therapy, compared to 17/50 isolates with monotherapy. The cumulative fraction response for MEM and FOS improved from 0% to 40% and 40% to 80%, with combination therapy, respectively. Addition of MEM improved the activity of FOS against the CR-AB isolates. FOS/MEM could be a plausible option to treat CR-AB for a small fraction of isolates.
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http://dx.doi.org/10.1089/mdr.2020.0197DOI Listing
April 2021

Pharmacodynamic Evaluation of Plasma and Epithelial Lining Fluid Exposures of Amikacin against Pseudomonas aeruginosa in a Dynamic Hollow-Fiber Infection Model.

Antimicrob Agents Chemother 2020 08 20;64(9). Epub 2020 Aug 20.

Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.

Given that aminoglycosides, such as amikacin, may be used for multidrug-resistant infections, optimization of therapy is paramount for improved treatment outcomes. This study aims to investigate the pharmacodynamics of different simulated intravenous amikacin doses on susceptible to inform ventilator-associated pneumonia (VAP) and sepsis treatment choices. A hollow-fiber infection model with two isolates (MICs of 2 and 8 mg/liter) with an initial inoculum of ∼10 CFU/ml was used to test different amikacin dosing regimens. Three regimens (15, 25, and 50 mg/kg) were tested to simulate a blood exposure, while a 30 mg/kg regimen simulated the epithelial lining fluid (ELF) for potential respiratory tract infection. Data were described using a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Whole-genome sequencing was used to identify mutations associated with resistance emergence. While bacterial density was reduced by >6 logs within the first 12 h in simulated blood exposures following this initial bacterial kill, there was amplification of a resistant subpopulation with ribosomal mutations that were likely mediating amikacin resistance. No appreciable bacterial killing occurred with subsequent doses. There was less (<5 log) bacterial killing in the simulated ELF exposure for either isolate tested. Simulation studies suggested that a dose of 30 and 50 mg/kg may provide maximal bacterial killing for bloodstream and VAP infections, respectively. Our results suggest that amikacin efficacy may be improved with the use of high-dose therapy to rapidly eliminate susceptible bacteria. Subsequent doses may have reduced efficacy given the rapid amplification of less-susceptible bacterial subpopulations with amikacin monotherapy.
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http://dx.doi.org/10.1128/AAC.00879-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449155PMC
August 2020

Pharmacodynamic evaluation of intermittent versus extended and continuous infusions of piperacillin/tazobactam in a hollow-fibre infection model against Klebsiella pneumoniae.

J Antimicrob Chemother 2020 09;75(9):2633-2640

Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.

Objectives: To compare bacterial killing and the emergence of resistance to piperacillin/tazobactam, administered by intermittent versus prolonged infusion (i.e. extended or continuous), for ceftriaxone-resistant Klebsiella pneumoniae clinical isolates in an in vitro dynamic hollow-fibre infection model (HFIM).

Methods: K. pneumoniae 68 (Kp68; MIC = 8 mg/L, producing SHV-106 and DHA-1) and K. pneumoniae 69 (Kp69; MIC = 1 mg/L, producing CTX-M-14) were studied in the HFIM over 7 days (initial inoculum ~107 cfu/mL). Six piperacillin/tazobactam dosing regimens for Kp68 (4/0.5 g 8 hourly as 0.5 and 4 h infusions, 12/1.5 g/24 h continuous infusion, 4/0.5 g 6 hourly as 0.5 and 3 h infusions and 16/2 g/24 h continuous infusion) and three piperacillin/tazobactam dosing regimens for Kp69 (4/0.5 g 8 hourly as 0.5 and 4 h infusions and 12/1.5 g/24 h continuous infusion) were simulated (piperacillin clearance = 14 L/h, creatinine clearance = 100 mL/min). Total and resistant populations and MICs were quantified/determined.

Results: For Kp68, all simulated dosing regimens exhibited approximately 4 log10 of bacterial killing at 8 h followed by regrowth to approximately 1011 cfu/mL within 24 h. The MICs for resistant subpopulations exceeded 256 mg/L at 72 h. Similarly, for Kp69, all simulated dosing regimens exhibited approximately 4 log10 of bacterial killing over 8 h; however, only the continuous infusion prevented bacterial regrowth.

Conclusions: Compared with intermittent infusion, prolonged infusion did not increase initial bacterial killing and suppression of regrowth of plasmid-mediated AmpC- and ESBL-producing K. pneumoniae. However, continuous infusion may suppress regrowth of some ESBL-producing susceptible K. pneumoniae, although more data are warranted to confirm this observation.
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http://dx.doi.org/10.1093/jac/dkaa211DOI Listing
September 2020

What Antibiotic Exposures Are Required to Suppress the Emergence of Resistance for Gram-Negative Bacteria? A Systematic Review.

Clin Pharmacokinet 2019 11;58(11):1407-1443

Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.

Background: The rates of antibiotic resistance in Gram-negative bacteria are increasing. One method to minimize resistance emergence may be optimization of antibiotic dosing regimens to achieve drug exposure that suppress the emergence of resistance.

Objective: The aim of this systematic review was to describe the antibiotic exposures associated with suppression of the emergence of resistance for Gram-negative bacteria.

Methods: We conducted a search of four electronic databases. Articles were included if the antibiotic exposure required to suppress the emergence of resistance in a Gram-negative bacterial isolate was described. Among studies, 57 preclinical studies (in vitro and in vivo) and 2 clinical studies 59 included investigated the monotherapy of antibiotics against susceptible and/or intermediate Gram-negative bacteria.

Results: The pharmacokinetic/pharmacodynamic (PK/PD) indices reported to suppress the emergence of antibiotic resistance for various classes were β-lactam antibiotic minimum concentration to minimum inhibitory concentration (C/MIC) ≥ 4; aminoglycoside maximum concentration to MIC (C/MIC) ratio ≥ 20; fluoroquinolones, area under the concentration-time curve from 0 to 24 h to mutant prevention concentration (AUC/MPC) ≥ 35; tetracyclines, AUC to MIC (AUC/MIC) ratio ≥ 50; polymyxin B, AUC/MIC ≥ 808; and fosfomycin, AUC/MIC ≥ 3136. However, the exposures required to suppress the emergence of resistance varied depending on the specific antibiotic tested, the duration of the experiment, the bacterial species and the specific bacterial isolate tested. Importantly, antibiotic exposures required to suppress the emergence of resistance generally exceeded that associated with clinical efficacy.

Conclusion: The benefits of implementing such high PK/PD targets must be balanced with the potential risks of antibiotic-associated toxicity.
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http://dx.doi.org/10.1007/s40262-019-00791-zDOI Listing
November 2019

Intrapulmonary pharmacokinetics of antibiotics used to treat nosocomial pneumonia caused by Gram-negative bacilli: A systematic review.

Int J Antimicrob Agents 2019 Mar 23;53(3):234-245. Epub 2018 Nov 23.

Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Woolloongabba, Queensland, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Queensland 4006, Australia.

Background: Knowledge of antibiotic concentrations achievable in the epithelial lining fluid (ELF) will help guide antibiotic dosing for treating patients with Gram-negative bacillary ventilator-associated pneumonia (VAP).

Objective: To compare: (1) the ELF:serum penetration ratio of antibiotics in patients with pneumonia, including VAP, with that in healthy study participants; and (2) the ELF and/or tracheal aspirate antibiotic concentrations following intravenous and nebuliser delivery.

Methods: Web of Science, EMBASE and PubMed databases were searched and a systematic review undertaken.

Results: Fifty-two studies were identified. ELF penetration ratios for aminoglycosides and most β-lactam antibiotics administered intravenously were between 0.12 and 0.57, whereas intravenous colistin may be undetectable in the ELF. In contrast, estimated mean fluoroquinolone ELF penetration ratios of up to 1.31 were achieved. Importantly, ELF penetration ratios appear reduced in critically ill patients with pneumonia compared with in healthy volunteers receiving intravenous ceftazidime, levofloxacin and fosfomycin; thus, dose adjustment is likely to be required in critically ill patients. In contrast to the systemic administration route, nebulisation of antibiotics achieves high ELF concentrations. Nebulised 400 mg twice-daily amikacin resulted in a median peak ELF steady-state concentration of 976.01 mg/L (interquartile range 410.3-2563.1 mg/L). Similarly, nebulised 1 million international units of colistin resulted in a peak ELF concentration of 6.73 mg/L (interquartile range 4.80-10.10 mg/L).

Conclusion: Further pharmacokinetic studies investigating the mechanisms for ELF penetration in infected patients and healthy controls are needed to guide antibiotic dosing in VAP and to determine the potential benefits of nebulised therapy.
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http://dx.doi.org/10.1016/j.ijantimicag.2018.11.011DOI Listing
March 2019

How to optimize antibiotic pharmacokinetic/pharmacodynamics for Gram-negative infections in critically ill patients.

Curr Opin Infect Dis 2018 12;31(6):555-565

Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Woolloongabba, Queensland, Australia.

Purpose Of Review: Optimized antibiotic dosing regimens improve survival rates in critically ill patients. However, dose optimization is challenging because of fluctuating antibiotic pharmacokinetics both between patients and within a single patient. This study reviews the pharmacokinetic changes that occur in critically ill patients, along with the pharmacodynamics and toxicodynamics of antibiotics commonly used for the treatment of Gram-negative bacterial infections to formulate a recommendation for antibiotic dosing at the bedside.

Recent Findings: Recent studies highlight that critically ill patients do not achieve therapeutic antibiotic exposures with standard antibiotic dosing. Although dose increases are required, the method of administration, such as the use of β-lactam antibiotic continuous infusions and nebulized aminoglycoside administration, may improve efficacy and limit toxicity. In addition, the increased availability of therapeutic drug monitoring and antibiotic dosing software allow the formulation of individualized dosing regimens at the bedside.

Summary: When prescribing antibiotic doses, the clinician should consider antibiotic pharmacokinetic and pharmacodynamic principles. Before initiating high-dose antibiotic therapy, therapeutic drug monitoring may be considered to assist the clinician to optimize antibiotic treatment and minimize potential toxicity.
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http://dx.doi.org/10.1097/QCO.0000000000000494DOI Listing
December 2018
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