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Aims: The purpose of the study was to assess the status of emerging therapeutic drug monitoring (TDM) of anti‐infective agents in Australian hospitals. Methods: A nationwide cross‐sectional survey of all Australian hospitals operating in the public and private health sector was conducted between August and September 2019. The survey consisted of questions regarding institutional TDM practice for anti‐infective agents and clinical vignettes specific to β‐lactam antibiotics. Results: Responses were received from 82 unique institutions, representing all Australian states and territories. All 29 (100%) of principal referral (major) hospitals in Australia participated. Five surveys were partially complete. Only 25% (20/80) of hospitals had TDM testing available on‐site for any of the eight emerging TDM candidates considered: β‐lactam antibiotics, anti‐tuberculous agents, flucytosine, fluoroquinolones, ganciclovir, human immunodeficiency virus (HIV) drugs, linezolid and teicoplanin. A considerable time lag was noted between TDM sampling and reporting of results. With respect to β‐lactam antibiotic TDM, variable indications, pharmacodynamic targets and sampling times were identified. The three greatest barriers to local TDM performance were found to be (1) lack of timely assays/results, (2) lack of institutional‐wide expertise and/or training and (3) lack of guidelines to inform ordering of TDM and interpretation of results. The majority of respondents favoured establishing national TDM guidelines and increasing access to dose prediction software, at rates of 89% and 96%, respectively. Conclusion: Translating emerging TDM evidence into daily clinical practice is slow. Concerted efforts are required to address the barriers identified and facilitate the implementation of standardised practice. [ABSTRACT FROM AUTHOR]

Antifungal agents can have complex dosing and the potential for drug interaction, both of which can lead to subtherapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy and haemopoietic stem cell transplant recipients. Antifungal agents can also be associated with significant toxicities when drug concentrations are too high. Suboptimal dosing can be minimised by clinical assessment, laboratory monitoring, avoidance of interacting drugs, and dose modification. Therapeutic drug monitoring (TDM) plays an increasingly important role in antifungal therapy, particularly for antifungal agents that have an established exposure‐response relationship with either a narrow therapeutic window, large dose‐exposure variability, cytochrome P450 gene polymorphism affecting drug metabolism, the presence of antifungal drug interactions or unexpected toxicity, and/or concerns for non‐compliance or inadequate absorption of oral antifungals. These guidelines provide recommendations on antifungal drug monitoring and TDM‐guided dosing adjustment for selected antifungal agents, and include suggested resources for identifying and analysing antifungal drug interactions. Recommended competencies for optimal interpretation of antifungal TDM and dose recommendations are also provided. [ABSTRACT FROM AUTHOR]

Objectives: Candidaemia carries a mortality of up to 40% and may be related to increasing complexity of medical care. Here, we determined risk factors for the development of candidaemia. Methods: We conducted a prospective, multi‐centre, case‐control study over 12 months. Cases were aged ≥18 years with at least one blood culture positive for Candida spp. Each case was matched with two controls, by age within 10 years, admission within 6 months, admitting unit, and admission duration at least as long as the time between admission and onset of candidaemia. Results: A total of 118 incident cases and 236 matched controls were compared. By multivariate analysis, risk factors for candidaemia included neutropenia, solid organ transplant, significant liver, respiratory or cardiovascular disease, recent gastrointestinal, biliary or urological surgery, central venous access device, intravenous drug use, urinary catheter and carbapenem receipt. Conclusions: Risk factors for candidaemia derive from the infection source, carbapenem use, host immune function and organ‐based co‐morbidities. Preventive strategies should target iatrogenic disruption of mucocutaneous barriers and intravenous drug use. [ABSTRACT FROM AUTHOR]

There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combination therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug–drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections. [ABSTRACT FROM AUTHOR]

Candida auris is an emerging drug‐resistant yeast responsible for hospital outbreaks. This statement reviews the evidence regarding diagnosis, treatment and prevention of this organism and provides consensus recommendations for clinicians and microbiologists in Australia and New Zealand. C. auris has been isolated in over 30 countries (including Australia). Bloodstream infections are the most frequently reported infections. Infections have crude mortality of 30–60%. Acquisition is generally healthcare‐associated and risks include underlying chronic disease, immunocompromise and presence of indwelling medical devices. C. auris may be misidentified by conventional phenotypic methods. Matrix‐assisted laser desorption ionisation time‐of‐flight mass spectrometry or sequencing of the internal transcribed spacer regions and/or the D1/D2 regions of the 28S ribosomal DNA are therefore required for definitive laboratory identification. Antifungal drug resistance, particularly to fluconazole, is common, with variable resistance to amphotericin B and echinocandins. Echinocandins are currently recommended as first‐line therapy for infection in adults and children ≥2 months of age. For neonates and infants <2 months of age, amphotericin B deoxycholate is recommended. Healthcare facilities with C. auris should implement a multimodal control response. Colonised or infected patients should be isolated in single rooms with Standard and Contact Precautions. Close contacts, patients transferred from facilities with endemic C. auris or admitted following stay in overseas healthcare institutions should be pre‐emptively isolated and screened for colonisation. Composite swabs of the axilla and groin should be collected. Routine screening of healthcare workers and the environment is not recommended. Detergents and sporicidal disinfectants should be used for environmental decontamination. [ABSTRACT FROM AUTHOR]

Background: Ribavirin is used in the treatment of respiratory paramyxovirus infection in lung transplant recipients; however, its pharmacokinetic profile in the transplant population is unknown despite the potential for alterations due to underlying pathology. Furthermore, the ability of current regimens to meet exposure targets has not been established.Objectives: This study examined the pharmacokinetics of ribavirin in a lung transplant population for which current and alternative dosing regimens were assessed.Methods: Population pharmacokinetic modelling was conducted in NONMEM using concentration-time data from 24 lung transplant recipients and 6 healthy volunteers. Monte Carlo simulation was used to assess the ability of dosing regimens to achieve pre-specified target concentrations.Results and Conclusions: A three-compartment model with first-order elimination most adequately described ribavirin concentration-time data, with CLCR and patient type (i.e. lung transplant) identified as significant covariates in the model. Simulations indicate that current regimens achieve efficacious concentrations within 24 h of treatment initiation that increase to supra-therapeutic levels over the treatment period. A regimen of 8 mg/kg q6h orally for 48 h followed by 8 mg/kg q24h orally for the remainder of the treatment period was predicted to result in >90% of patients exhibiting concentrations within the defined target range throughout the entire treatment course. Additional work to formally establish target therapeutic concentrations is required; however, this study provides a valuable first step in determining optimal ribavirin treatment regimens for paramyxovirus infections in the lung transplant population. [ABSTRACT FROM AUTHOR]

Aim: Tacrolimus is a CYP3A4 substrate with a narrow therapeutic index that requires dose adjustment when used with voriconazole, a recognized CYP3A4 inhibitor. Interactions involving flucloxacillin and tacrolimus or voriconazole individually have been shown to result in decreased concentrations of the latter two drugs. Tacrolimus concentrations have been reported to be unaffected by flucloxacillin when voriconazole is administered; however, this has not been extensively investigated., Methods: Retrospective review of voriconazole and tacrolimus concentrations and subsequent dose adjustment following flucloxacillin administration., Results: Eight transplant recipients (five lung, two re-do lung, one heart) received concurrent flucloxacillin, voriconazole and tacrolimus. Voriconazole trough concentrations were measured before flucloxacillin initiation in three of eight patients and all trough concentrations were therapeutic. Following flucloxacillin initiation, all eight patients exhibited subtherapeutic concentrations of voriconazole (median concentration 0.15 mg/L [interquartile range (IQR) 0.10-0.28]). In five patients, voriconazole concentrations remained subtherapeutic despite dose increases, and treatment for two patients was changed to alternative antifungal agents. All eight patients required tacrolimus dose increases to maintain therapeutic concentrations after flucloxacillin initiation. Median total daily dose prior to flucloxacillin treatment was 3.5 mg [IQR 2.0-4.3] and this increased to 13.5 mg [IQR 9.5-20] (P=0.0026) during flucloxacillin treatment. When flucloxacillin was ceased, the median tacrolimus total daily dose reduced to 2.2 mg [IQR 1.9-4.7]. Supra-therapeutic tacrolimus concentrations were observed in seven patients after flucloxacillin discontinuation (median concentration 19.7 μg/L [IQR 17.9-28.0])., Conclusion: A significant three-way interaction was shown between flucloxacillin, voriconazole and tacrolimus, resulting in subtherapeutic voriconazole concentrations, and requiring substantial tacrolimus dose increases. Administration of flucloxacillin to patients receiving voriconazole should be avoided. Tacrolimus concentrations should be closely monitored, and dosing adjusted during and after flucloxacillin administration., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Purpose: Reduced exposure to echinocandins has been reported in specific patient populations, such as critically ill patients; however, fixed dosing strategies are still used. The present review examines the accumulated evidence supporting echinocandin therapeutic drug monitoring (TDM) and summarizes available assays and sampling strategies., Methods: A literature search was conducted using PubMed in December 2020, with search terms such as echinocandins, anidulafungin, caspofungin, micafungin, or rezafungin with pharmacology, pharmacokinetics (PKs), pharmacodynamics (PDs), drug-drug interactions, TDM, resistance, drug susceptibility testing, toxicity, adverse drug reactions, bioanalysis, chromatography, and mass spectrometry. Data on PD/PD (PK/PD) outcome markers, drug resistance, PK variability, drug-drug interactions, assays, and TDM sampling strategies were summarized., Results: Echinocandins demonstrate drug exposure-efficacy relationships, and maximum concentration/minimal inhibitory concentration ratio (Cmax/MIC) and area under the concentration-time curve/MIC ratio (AUC/MIC) are proposed PK/PD markers for clinical response. The relationship between drug exposure and toxicity remains poorly clarified. TDM could be valuable in patients at risk of low drug exposure, such as those with critical illness and/or obesity. TDM of echinocandins may also be useful in patients with moderate liver impairment, drug-drug interactions, hypoalbuminemia, and those undergoing extracorporeal membrane oxygenation, as these conditions are associated with altered exposure to caspofungin and/or micafungin. Assays are available to measure anidulafungin, micafungin, and caspofungin concentrations. A limited-sampling strategy for anidulafungin has been reported., Conclusions: Echinocandin TDM should be considered in patients at known risk of suboptimal drug exposure. However, for implementing TDM, clinical validation of PK/PD targets is needed., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Bayesian forecasting software can assist in guiding therapeutic drug monitoring (TDM)-based dose adjustments for amikacin to achieve therapeutic targets. This study aimed to evaluate amikacin prescribing and TDM practices, and to determine the suitability of the amikacin model incorporated into the DoseMeRx® software as a replacement for the previously available software (Abbottbase®)., Methods: Patient demographics, pathology, amikacin dosing history, amikacin concentrations and Abbottbase® predicted TDM targets (area under the curve up to 24 hours, maximum concentration and trough concentration) were collected for adults receiving intravenous amikacin (2012-2017). Concordance with the Australian Therapeutic Guidelines was assessed. Observed and predicted amikacin concentrations were compared to determine the predictive performance (bias and precision) of DoseMeRx®. Amikacin TDM targets were predicted by DoseMeRx® and compared to those predicted by Abbottbase®., Results: Overall, guideline compliance for 63 courses of amikacin in 47 patients was suboptimal. Doses were often lower than recommended. For therapy >48 h, TDM sample collection timing was commonly discordant with recommendations, therapeutic target attainment low and 34% of dose adjustments inappropriate. DoseMeRx® under-predicted amikacin concentrations by 0.9 mg/L (95% confidence interval [CI] -1.4 to -0.5) compared with observed concentrations. However, maximum concentration values (n = 19) were unbiased (-1.7 mg/L 95%CI -5.8 to 0.8) and precise (8.6% 95%CI 5.4-18.1). Predicted trough concentration values (n = 7) were, at most, 1 mg/L higher than observed. Amikacin area under the curve values estimated using Abbottbase® (181 mg h/L 95%CI 161-202) and DoseMeRx® (176 mg h/L 95%CI 152-199) were similar (P = .59)., Conclusion: Amikacin dosing and TDM practice was suboptimal compared with guidelines. The model implemented by DoseMeRx® is satisfactory to guide amikacin dosing., (© 2020 The British Pharmacological Society.)

Aims: Dose-prediction software can optimise vancomycin therapy, improving therapeutic drug monitoring processes and reducing drug toxicity. Success of software in hospitals may be dependent on prescriber uptake of software recommendations. This study aimed to identify the perceived psychosocial and environmental barriers and facilitators to prescriber acceptance of dose-prediction software., Methods: Semi-structured interviews, incorporating prescribing scenarios, were undertaken with 17 prescribers. Participants were asked to prescribe the next maintenance dose of vancomycin for a scenario(s) and then asked if they would accept a recommendation provided by a dose-prediction software. Interviews further explored opinions of dose-prediction software. Interview transcripts were analysed using an inductive approach to identify themes and the Theoretical Domains Framework was used to synthesise barriers and facilitators to software acceptance., Results: When presented with software recommendations, half of the participants were comfortable with accepting the recommendation. Key barriers to acceptance of software recommendations aligned with 2 Theoretical Domains Framework domains: Knowledge (uncertainty of software capability) and Beliefs about Consequences (perceived impact of software on clinical outcomes and workload). Key facilitators aligned with 2 domains: Beliefs about Consequences (improved efficiency) and Social Influences (influence of peers). A novel domain, Trust, was identified as influential., Conclusion: Prescribers reported barriers to acceptance of dose-prediction software aligned with limited understanding of, and scepticism about, software capabilities, as well as concerns about clinical outcomes. Identification of key barriers and facilitators to acceptance provides essential information to design of implementation strategies to support the introduction of this intervention into the workplace., (© 2020 The British Pharmacological Society.)

Many important drugs exhibit substantial variability in pharmacokinetics and pharmacodynamics leading to a loss of the desired clinical outcomes or significant adverse effects. Forecasting drug exposures using pharmacometric models can improve individual target attainment when compared with conventional therapeutic drug monitoring (TDM). However, selecting the "correct" model for this model-informed precision dosing (MIPD) is challenging. We derived and evaluated a model selection algorithm (MSA) and a model averaging algorithm (MAA), which automates model selection and finds the best model or combination of models for each patient using vancomycin as a case study, and implemented both algorithms in the MIPD software "TDMx." The predictive performance (based on accuracy and precision) of the two algorithms was assessed in (i) a simulation study of six distinct populations and (ii) a clinical dataset of 180 patients undergoing TDM during vancomycin treatment and compared with the performance obtained using a single model. Throughout the six virtual populations the MSA and MAA (imprecision: 9.9-24.2%, inaccuracy: less than ± 8.2%) displayed more accurate predictions than the single models (imprecision: 8.9-51.1%; inaccuracy: up to 28.9%). In the clinical dataset, the predictive performance of the single models applying at least one plasma concentration varied substantially (imprecision: 28-62%, inaccuracy: -16 to 25%), whereas the MSA or MAA utilizing these models simultaneously resulted in unbiased and precise predictions (imprecision: 29% and 30%, inaccuracy: -5% and 0%, respectively). MSA and MAA approaches implemented in TDMx might thereby lower the burden of fit-for-purpose validation of individual models and streamline MIPD., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

This study evaluated the ability of a pilot therapeutic drug monitoring (TDM) Advisory Service to facilitate vancomycin therapeutic target attainment within a real-world clinical setting. The Service provided area under the concentration-time curve (AUC)-guided vancomycin dose recommendations, using Bayesian forecasting software and clinical expertise, to prescribers at an Australian hospital. A retrospective audit of intravenous vancomycin therapy (> 48 hours) in adults (≥ 18 years old) was undertaken over a 54-month period to evaluate attainment of established vancomycin pharmacokinetic/pharmacodynamic targets (AUC over 24 hours / minimum inhibitory concentration: 400-600) before (36-month period) and after (18-month period) Service implementation. Interrupted time series analysis was employed to evaluate monthly measures of the median proportion of therapy spent within the target range. Indices of time to target attainment were also assessed before and after Service implementation. The final cohort comprised 1,142 courses of vancomycin (816 patients); 835 courses (596 patients) and 307 courses (220 patients) administered before and after Service implementation, respectively. Prior to piloting the Service, the median proportion of time in the target range was 40.1% (95% CI, 34.3-46.0%); this increased by 10.4% (95% CI, 1.2-19.6%, P = 0.03) after the Service, and was sustained throughout the post-Service evaluation period. Post-Service target attainment at 48-72 hours after initiation of therapy was increased (7.8%, 95% CI, 1.3-14.3%, P = 0.02). The findings of this study provide evidence that a consultative TDM Service can facilitate attainment of vancomycin therapeutic targets; however, optimization of the Service may further improve the use of vancomycin., (© 2020 The Authors. Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Background: Respiratory syncytial virus (RSV) causes serious respiratory tract infections in lung transplant (LTx) recipients, is associated with development of bronchiolitis obliterans syndrome, and has no proven effective therapy. We evaluated the efficacy, safety, and cost-effectiveness of oral ribavirin for the treatment of RSV infection after LTx., Methods: Between December 2011 and May 2014, 52 LTx recipients developed 56 episodes of symptomatic RSV infection, which was diagnosed by positive RSV polymerase chain reaction on nasopharyngeal swabs. An intravenous (IV) loading dose of ribavirin (33 mg/kg) was given in 52 of 56 episodes; an equivalent oral loading dose was given in 2 episodes. Oral ribavirin (20 mg/kg/day) was given by day 2 in 53 of 56 episodes. Median duration of therapy was 8 days (range 6-31 days)., Results: Mean forced expiratory volume in 1 sec decreased from 2.38 ± 0.78 liters to 2.07 ± 0.85 liters (p < 0.001) at presentation, recovered to 2.26 ± 0.82 liters at cessation of ribavirin, and was maintained at 2.31 ± 0.81 liters within 3 months. New-onset bronchiolitis obliterans syndrome developed in 1 of 38 patients (2.6%) at 3 months. Anemia worsened in 23 episodes, and de novo anemia developed in 5 episodes. Mean hemoglobin decreased from 118 ± 16 g/liter to 113 ± 21 g/liter (p = 0.015). There were 4 late deaths. Compared with IV therapy, mean drug cost saving was US $6,035 per episode, and mean inpatient bed days was reduced by 6.7 days (p < 0.001)., Conclusions: To our knowledge, we report the largest series of LTx recipients treated with oral ribavirin for RSV. Oral ribavirin appears to be an effective, well-tolerated alternative to IV or inhaled ribavirin; provides considerable cost savings and reduces length of hospital stay. Potential long-term benefits in preventing development of chronic lung allograft dysfunction are yet to be determined., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)