ORCID Profile
0000-0002-8889-5579
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Publisher: AME Publishing Company
Date: 03-2018
Publisher: Springer Science and Business Media LLC
Date: 21-11-2017
Publisher: Elsevier BV
Date: 10-2019
Publisher: American Society for Microbiology
Date: 18-10-2021
DOI: 10.1128/AAC.01438-21
Abstract: Our study aimed to describe the population pharmacokinetics (PK) of piperacillin and tazobactam in patients on extracorporeal membrane oxygenation (ECMO), with and without renal replacement therapy (RRT). We also aimed to use dosing simulations to identify the optimal dosing strategy for these patient groups.
Publisher: Informa UK Limited
Date: 14-06-2018
DOI: 10.1080/17425255.2018.1484452
Abstract: Some special patient populations (e.g. critically ill, burns, hematological malignancy, post-major surgery, post-major trauma) have characteristics that lead to higher rates of failure and mortality associated with infection. Choice of effective antibiotics and optimized doses are challenging in these patients that are commonly infected by multidrug-resistant pathogens. Areas covered: A review of the importance of diagnosis and the place of newer microbiological methods (e.g. whole-genome sequencing) to ensure rapid transition from empiric to directed antibiotic therapy is provided. The effects of pathophysiological changes on antibiotic pharmacokinetics are also provided. Expert opinion: Product information dosing regimens do not address the pharmacokinetic alterations that can occur in special patient populations and increase the likelihood of therapeutic failure and the emergence of bacterial resistance. Altered dosing approaches, supplemented with the use of dosing software and therapeutic drug monitoring, may be needed to ensure optimal antibiotic exposure and better therapeutic outcomes in these patients with severe infection. Dose optimization needs to be coupled with advanced microbiological techniques that enable rapid microbiological identification and characterization of resistance mechanism to ensure that maximally effective directed therapy can be chosen.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Informa UK Limited
Date: 03-01-2019
DOI: 10.1080/17425255.2019.1563596
Abstract: One major challenge to achieving optimal patient outcome in extracorporeal membrane oxygenation (ECMO) is the development of effective dosing strategies in this critically ill patient population. Suboptimal drug dosing impacts on patient outcome as patients on ECMO often require reversal of the underlying pathology with effective pharmacotherapy in order to be liberated of the life-support device. Areas covered: This article provides a concise review of the effective use of antibiotics, analgesics, and sedative by characterizing the specific changes in PK secondary to the introduction of the ECMO support. We also discuss the barriers to achieving optimal pharmacotherapy in patients on ECMO and also the current and potential research that can be undertaken to address these clinical challenges. Expert opinion: Decreased bioavailability due to sequestration of drugs in the ECMO circuit and ECMO induced PK alterations are both significant barriers to optimal drug dosing. Evidence-based drug choices may minimize sequestration in the circuit and would enable safety and efficacy to be maintained. More work to characterize ECMO related pharmacodynamic alterations such as effects of ECMO on hepatic cytochrome system are still needed. Novel techniques to increase target site concentrations should also be explored.
Publisher: American Thoracic Society
Date: 15-09-2016
Publisher: Oxford University Press (OUP)
Date: 03-10-2015
DOI: 10.1093/JAC/DKV288
Abstract: We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic harmacodynamic and clinical outcomes between prolonged-infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies. This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries. Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT>MIC (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic harmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving β-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30) P = 0.012]. Additionally, in patients with a SOFA score of ≥9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20) P = 0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20) P = 0.025]. Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections.
Publisher: SAGE Publications
Date: 20-06-2014
Abstract: Objective: To report the difficulty in achieving and maintaining target antibiotic exposure in critically ill patients with deep-seeded infections. Case Summary: We present a case of a 36-year-old man who was admitted to the intensive care unit with diffuse central nervous system and peripheral methicillin-sensitive Staphylococcus aureus infection (minimum inhibitory concentration MIC, 1 µg/mL). Owing to the complicated nature of the infection, sequential concentrations of free flucloxacillin were measured in plasma and cerebrospinal fluid (CSF) and used to direct antibiotic dosing. Unsurprisingly, the trough plasma concentrations of flucloxacillin were below the MIC (0.2-0.4 µg/mL), and the corresponding CSF concentrations were undetectable ( .1 µg/mL) with standard intermittent bolus dosing of 2 g every 4 hours. By administering flucloxacillin by continuous infusion (CI) and increasing the dose to 20 g daily, the plasma (2.2-5.7 µg/mL) and CSF (0.1 µg/mL) levels were increased, albeit lower than the predefined targets (plasma, 40 µg/mL CSF, 4 µg/mL). Discussion: The presence of physiological changes associated with critical illness—namely, hypoalbuminemia and augmented renal clearance—may significantly alter antibiotic pharmacokinetics, and this phenomenon may lead to suboptimal antibiotic exposure if they are not accounted for. This case also highlights the value of applying CI in such patient groups and demonstrates the significance of monitoring plasma and CSF drug concentrations in optimizing antibiotic delivery. Conclusions: Future research should aim to evaluate the utility of such drug monitoring with regard to patient outcomes and cost-effectiveness.
Publisher: American Society for Microbiology
Date: 23-06-2020
DOI: 10.1128/AAC.02584-19
Abstract: Optimal concentrations of unbound antimicrobials are essential for a maximum microbiological effect. Although hypoalbuminemia and albumin fluid resuscitation are common in critical care, the effects of different albumin concentrations on the unbound concentrations of highly protein-bound antimicrobials are not known. The aim of this study was to compare the effects of different albumin states on total and unbound concentrations of ertapenem and ceftriaxone using an ovine model. The study design was a prospective, three-phase intervention observational study.
Publisher: American Society for Microbiology
Date: 2016
DOI: 10.1128/AAC.01543-15
Abstract: Doripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a 1-hour infusion were enrolled. Serial blood s les were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients' creatinine clearance (CL CR ), such that a 30-ml/min increase in the estimated CL CR would increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CL CR of 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CL CR of ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involved.
Publisher: Springer Singapore
Date: 16-06-2017
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.IJANTIMICAG.2021.106466
Abstract: This study aimed to describe the population pharmacokinetics (PK) of cefepime during extracorporeal membrane oxygenation (ECMO) and through dosing simulations, identify a maximally effective and safe dosing strategy. Serial cefepime plasma concentrations were measured in patients on ECMO, and data were analysed using a population PK approach with Pmetrics®. Dosing simulations were used to identify the optimal dosing strategy that achieved target trough concentrations (C Based on simulations, patients with CrCL of 120 mL/min receiving 1 g 8-hourly dosing achieved a 40-44% probability of efficacy (C This study reported reduced cefepime clearance in patients receiving ECMO, resulting in an increased risk of cefepime toxicity. To avoid drug accumulation, modified dosing regimens should be used in critically ill patients on ECMO. Clinicians should adopt therapeutic drug monitoring when treating less susceptible organisms and in patients with reduced renal clearance on ECMO.
Publisher: Springer Science and Business Media LLC
Date: 25-07-2020
Publisher: Elsevier BV
Date: 06-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2019
DOI: 10.1097/FTD.0000000000000658
Abstract: Mycophenolate mofetil or enteric-coated mycophenolate sodium (EC-MPS) and steroids are used for induction and maintenance therapy in severe lupus nephritis. Blood concentrations of mycophenolic acid (MPA), the active metabolite of these drugs, vary among patients with lupus nephritis. The objective of this study was to examine whether concentration-controlled (CC) dosing (through therapeutic drug monitoring) of EC-MPS results in a higher proportion of participants achieving target exposure of MPA compared with fixed-dosing (FD). An additional aim of the study was to evaluate the influence of CC dosing on clinical outcomes. Nineteen participants were randomly assigned either to the FD or CC group. All the participants were eligible to have free and total measurements of MPA over a period of 8–12 hours on 3 different occasions. Area under the concentration–time curve between 0 and 12 hours (AUC 0-12 ) was calculated using noncompartmental methods. Dose of EC-MPS was titrated according to AUC 0-12 in the CC group. Thirty-two AUC 0-12 measurements were obtained from 9 FD and 9 CC participants. Large inter-patient variability was observed in both groups but was more pronounced in the FD group. There were no significant differences between FD and CC participants in any pharmacokinetic parameters across the study visits, except for total C 0 (FD 2.0 ± 0.3 mg/L versus CC 1.1 ± 0.3 P = 0.01) and dose-normalized C 0 (FD 2.9 ± 0.2 mg/L/g versus CC 2.1 ± 0.7 mg/L/g P = 0.04) at the second visit and total AUC 0-12 (FD 66.6 ± 6.0 mg·h/L versus CC 35.2 ± 11.4 mg·h/L P = 0.03) at the third visit. At the first study visit, 33.3% of the FD and 11.1% of the CC participants achieved the target area under the concentration–time curve ( P = 0.58). From the second visit, none of the FD participants, compared with all the CC participants, achieved target AUC 0-12 ( P = 0.01). More CC participants achieved remission compared with FD participants (absolute difference of −22.2, 95% confidence interval JOURNAL/thdm/04.03/00007691-201912000-00003/inline-formula1/v/2023-08-14T203520Z/r/image-tiff 0.19 to 0.55 P = 0.62). The mean free MPA AUC 0-12 was significantly lower in those who had complete remission. CC participants reached target AUC 0-12 quicker. Larger studies are required to test clinical efficacy.
Publisher: S. Karger AG
Date: 2019
DOI: 10.1159/000502474
Abstract: Extra-corporeal membrane oxygenation (ECMO) therapy could affect effective drug concentrations via adsorption onto the oxygenator or associated circuit. We describe a case of a 25-year-old female who required a veno-arterial ECMO therapy for refractory cardiac arrest due to massive pulmonary embolism. She had mild renal dysfunction as a result of the cardiac arrest. A total of 2 g of intravenous cefazolin 8-hourly was administered. Pre- and post-oxygenator blood s les were collected at 0, 1, 4, and 8 h post antibiotic administration. S les were analyzed for total and unbound cefazolin concentrations. Protein binding was ∼60%. Clearance was reduced due to impaired renal function. The pharmacokinetics of cefazolin appear to not be affected by ECMO therapy and dosing adjustment may not be required.
Publisher: Oxford University Press (OUP)
Date: 24-12-2015
DOI: 10.1093/JAC/DKV412
Abstract: The objectives of this study were to determine the effects of obesity on unbound trough concentrations and on the achievement of pharmacokinetic (PK) harmacodynamic (PD) targets of piperacillin and meropenem in critically ill patients. This study retrospectively analysed therapeutic-drug-monitoring data from ICU databases in Australia, Germany and Spain, as well as from a large PK study. The presence of obesity was defined as a BMI ≥30 kg/m(2), and patients were also categorized based on level of renal function. The presence of obesity was compared with unbound piperacillin and meropenem trough concentrations. We also used logistic regression to describe factors associated with the achievement of the PK/PD targets, an unbound concentration maintained above the MIC breakpoint (100% fT>MIC and 100% fT>4×MIC) of Pseudomonas aeruginosa. In all, 1400 patients were eligible for inclusion in the study. The median age and weight were 67 years (IQR 52-76 years) and 79 kg (69-90 kg), respectively, and 65% of participants were male. Significantly lower median piperacillin trough concentrations [29.4 mg/L (IQR 17.0-58.0 mg/L)] were found in obese patients compared with non-obese patients [42.0 mg/L (21.5-73.5 mg/L)] (P = 0.001). There was no difference for meropenem trough concentrations [obese 10.3 mg/L (IQR 4.8-16.0 mg/L) versus non-obese 11.0 mg/L (4.3-18.5 mg/L) P = 0.296]. Using logistic regression, we found that the presence of obesity was not associated with achievement of 100% fT>MIC, but the use of prolonged infusion, a creatinine clearance ≤100 mL/min, increasing age and female gender were for various PK/PD targets for both piperacillin and meropenem (P < 0.05). This large dataset has shown that the presence of obesity in critically ill patients may affect piperacillin, but not meropenem, unbound trough concentrations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2017
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.IJANTIMICAG.2018.10.011
Abstract: The spread of multidrug-resistant bacteria is an ever-growing concern, particularly among Gram-negative bacteria because of their intrinsic resistance and how quickly they acquire and spread new resistance mechanisms. Treating infections caused by Gram-negative bacteria is a challenge for medical practitioners and increases patient mortality and cost of care globally. This vulnerability, along with strategies to tackle antimicrobial resistance development, prompts the development of new antibiotic agents and exploration of alternative treatment options. This article summarises the new antibiotics that have recently been approved for Gram-negative bacterial infections, looks down the pipeline at promising agents currently in phase I, II, or III clinical trials, and introduces new alternative avenues that show potential in combating multidrug-resistant Gram-negative bacteria.
Publisher: Future Medicine Ltd
Date: 03-2022
Abstract: Background: A successful antimicrobial stewardship program (ASP) is sustained through improving antimicrobial prescribing by changing prescribing behavior. This requires a better understanding of hospital stakeholders’ views regarding antimicrobial resistance (AMR), antimicrobial use and participation in ASP activities. Objectives: Identify perceptions and attitudes among physicians and pharmacists in a public hospital toward AMR, prescription and ASP. Methods: A questionnaire consisting of 45 items was distributed to physicians and pharmacists in a 320-bed public hospital. All responses were formatted into the Likert scale. Results: A total of 78 respondents (73% response rate) completed the questionnaire. The majority of the respondents perceived AMR within hospital as less of a severe problem, and factors outside hospital were considered to be greater contributors to AMR. In addition, interprofessional conflict was identified as a serious concern in relation to implementing ASP. Conclusion: This finding indicates the need to address existing perceptions and attitudes toward ASP activities that may h er its successful implementation in Indonesia.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2013
Publisher: Wiley
Date: 02-06-2020
DOI: 10.1002/PHAR.2413
Publisher: Georg Thieme Verlag KG
Date: 02-02-2015
Abstract: The recent surge in multidrug-resistant pathogens combined with the diminishing antibiotic pipeline has created a growing need to optimize the use of our existing antibiotic armamentarium, particularly in the management of intensive care unit (ICU) patients. Optimal and timely pharmacokinetic harmacodynamic (PK/PD) target attainment has been associated with an increased likelihood of clinical and microbiological success in critically ill patients. Emerging data, mostly from in vitro and in vivo studies, suggest that optimization of antibiotic therapy should not only aim to maximize clinical outcomes but also to include the suppression of resistance. The development of antibiotic dosing regimens that adheres to the PK/PD principles may prolong the clinical lifespan of our existing antibiotics by minimizing the emergence of resistance. This article summarizes the relevance of PK/PD characteristics of different antibiotic classes on the development of antibiotic resistance. On the basis of the available data, we propose dosing recommendations that can be adopted in the clinical setting, to maximize therapeutic success and limit the emergence of resistance in the ICU.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2012
Abstract: There is controversy over whether traditional intermittent bolus dosing or continuous infusion of beta-lactam antibiotics is preferable in critically ill patients. No significant difference between these two dosing strategies in terms of patient outcomes has been shown yet. This is despite compelling in vitro and in vivo pharmacokinetic harmacodynamic (PK/PD) data. A lack of significance in clinical outcome studies may be due to several methodological flaws potentially masking the benefits of continuous infusion observed in preclinical studies. In this review, we explore the methodological shortcomings of the published clinical studies and describe the criteria that should be considered for performing a definitive clinical trial. We found that most trials utilized inconsistent antibiotic doses and recruited only small numbers of heterogeneous patient groups. The results of these trials suggest that continuous infusion of beta-lactam antibiotics may have variable efficacy in different patient groups. Patients who may benefit from continuous infusion are critically ill patients with a high level of illness severity. Thus, future trials should test the potential clinical advantages of continuous infusion in this patient population. To further ascertain whether benefits of continuous infusion in critically ill patients do exist, a large-scale, prospective, multinational trial with a robust design is required.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2016
DOI: 10.1007/S00134-015-4188-0
Abstract: This study aims to determine if continuous infusion (CI) is associated with better clinical and pharmacokinetic harmacodynamic (PK/PD) outcomes compared to intermittent bolus (IB) dosing in critically ill patients with severe sepsis. This was a two-centre randomised controlled trial of CI versus IB dosing of beta-lactam antibiotics, which enrolled critically ill participants with severe sepsis who were not on renal replacement therapy (RRT). The primary outcome was clinical cure at 14 days after antibiotic cessation. Secondary outcomes were PK/PD target attainment, ICU-free days and ventilator-free days at day 28 post-randomisation, 14- and 30-day survival, and time to white cell count normalisation. A total of 140 participants were enrolled with 70 participants each allocated to CI and IB dosing. CI participants had higher clinical cure rates (56 versus 34 %, p = 0.011) and higher median ventilator-free days (22 versus 14 days, p MIC than the IB arm on day 1 (97 versus 70 %, p < 0.001) and day 3 (97 versus 68 %, p < 0.001) post-randomisation. There was no difference in 14-day or 30-day survival between the treatment arms. In critically ill patients with severe sepsis not receiving RRT, CI demonstrated higher clinical cure rates and had better PK/PD target attainment compared to IB dosing of beta-lactam antibiotics. Continuous beta-lactam infusion may be mostly advantageous for critically ill patients with high levels of illness severity and not receiving RRT. Malaysian National Medical Research Register ID: NMRR-12-1013-14017.
Publisher: Wiley
Date: 17-01-2023
DOI: 10.1002/PHAR.2753
Abstract: The aim of this study was to compare the achievement of therapeutic pharmacokinetic–pharmacodynamic (PK‐PD) exposure targets for beta‐lactam antibiotics using product information dosing or guideline‐based dosing for the treatment of serious infections. In silico study. ID‐ODS TM (In idually Designed Optimum Dosing Strategies). None. In silico product information and guideline‐based dosing simulations for cefepime, ceftazidime, flucloxacillin, meropenem, and piperacillin/tazobactam were performed using pharmacokinetic models from seriously ill patient populations. The median simulated concentration at 48 and 96 h was used to measure the probability of target attainment (PTA) to achieve predefined therapeutic and toxicity PK‐PD targets. A multiple linear regression model was constructed to identify the effect of guideline‐based dosing covariates on achieving pre‐defined therapeutic targets. In total, 480 dosing simulations were performed. The PTA percentage with guideline‐based dosing at 48 and 96 h was 80% and 68%, respectively, yielding significantly higher results when compared to product information dosing (48.45% and 49%, respectively), p 0.001 at both time points. At 48 h, predefined toxicity thresholds were exceeded in 4.7% and 0% of simulations for guideline‐based and product information‐based dosing, respectively ( p = 0.002). eGFR was significantly associated with the % PTA by guideline‐based dosing, with eGFR values of 20 and 50 ml/min both statistically significant in leading to an increase in PTA. Our study demonstrated that achievement of PK‐PD exposures associated with an increased likelihood of effectiveness was more likely to occur with guideline‐based dosing especially at 48 h.
Publisher: SMW Supporting Association
Date: 10-10-2016
Publisher: American Society for Microbiology
Date: 18-01-2022
DOI: 10.1128/AAC.01377-21
Abstract: Our study aimed to describe the population pharmacokinetics (PK) of vancomycin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO), including those receiving concomitant renal replacement therapy (RRT). Dosing simulations were used to recommend maximally effective and safe dosing regimens.
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.IJANTIMICAG.2021.106431
Abstract: Extracorporeal membrane oxygenation (ECMO) can affect antimicrobial pharmacokinetics. This case report describes a 33-year-old male with newly diagnosed acquired immunodeficiency syndrome presenting in acute severe type 1 respiratory failure. On investigation, the patient had positive cultures for Candida albicans from respiratory specimens and high blood cytomegalovirus titres, and required venovenous ECMO therapy for refractory respiratory failure. Intravenous fluconazole (6 mg/kg, 24-h) and ganciclovir (5 mg/kg, 12-h) was commenced. Pre-oxygenator, post-oxygenator and arterial blood s les were collected after antibiotic administration, and were analysed for total fluconazole and ganciclovir concentrations. Although there was a 40% increase in the volume of distribution for fluconazole relative to healthy volunteers, the pharmacodynamic targets for prophylaxis were still met. The area under the curve exposure of ganciclovir (50.78 mg•h/L) achieved target thresholds. The ECMO circuit had no appreciable effect on achievement of therapeutic exposures of fluconazole and ganciclovir.
No related grants have been discovered for Mohd-Hafiz Abdul-Aziz.