Publications by authors named "Jason A Roberts"

431 Publications

Personalized ß-lactam dosing in patients with coronavirus disease 2019 (COVID-19) and pneumonia: A retrospective analysis on pharmacokinetics and pharmacokinetic target attainment.

Medicine (Baltimore) 2021 Jun;100(22):e26253

Department of Anesthesiology and Intensive Care Medicine, Heidenheim General Hospital.

Abstract: Pathophysiological changes are important risk factors for critically ill patients with pneumonia manifesting sub-therapeutic antibiotic exposures during empirical treatment. The effect of coronavirus disease 2019 (COVID-19) on antibiotic dosing requirements is uncertain. We aimed to determine the effect of COVID-19 on ß-lactam pharmacokinetics (PK) and PK target attainment in critically ill patients with a personalized dosing strategy.Retrospective, single-center analysis of COVID-19 ± critically ill patients with pneumonia (community-acquired pneumonia or hospital-acquired pneumonia) who received continuous infusion of a ß-lactam antibiotic with dosing personalized through dosing software and therapeutic drug monitoring. A therapeutic exposure was defined as serum concentration between (css) 4 to 8 times the EUCAST non-species related breakpoint).Data from 58 patients with pneumonia was analyzed. Nineteen patients were tested COVID-19-positive before the start of the antibiotic therapy for community-acquired pneumonia or hospital-acquired pneumonia. Therapeutic exposure was achieved in 71% of COVID-19 patients (68% considering all patients). All patients demonstrated css above the non-species-related breakpoint. Twenty percent exceeded css above the target range (24% of all patients). The median ß-lactam clearance was 49% compared to ß-lactam clearance in a standard patient without a significant difference regarding antibiotic, time of sampling or present COVID-19 infection. Median daily doses were 50% lower compared to standard bolus dosing.COVID-19 did not significantly affect ß-lactam pharmacokinetics in critically ill patients. Personalized ß-lactam dosing strategies were safe in critically ill patients and lead to high PK target attainment with less resources.
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http://dx.doi.org/10.1097/MD.0000000000026253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183774PMC
June 2021

Nebulized Colistin in Ventilator-Associated Pneumonia and Tracheobronchitis: Historical Background, Pharmacokinetics and Perspectives.

Microorganisms 2021 May 27;9(6). Epub 2021 May 27.

Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Medicine Sorbonne University, 75012 Paris, France.

Clinical evidence suggests that nebulized colistimethate sodium (CMS) has benefits for treating lower respiratory tract infections caused by multidrug-resistant Gram-negative bacteria (GNB). Colistin is positively charged, while CMS is negatively charged, and both have a high molecular mass and are hydrophilic. These physico-chemical characteristics impair crossing of the alveolo-capillary membrane but enable the disruption of the bacterial wall of GNB and the aggregation of the circulating lipopolysaccharide. Intravenous CMS is rapidly cleared by glomerular filtration and tubular excretion, and 20-25% is spontaneously hydrolyzed to colistin. Urine colistin is substantially reabsorbed by tubular cells and eliminated by biliary excretion. Colistin is a concentration-dependent antibiotic with post-antibiotic and inoculum effects. As CMS conversion to colistin is slower than its renal clearance, intravenous administration can lead to low plasma and lung colistin concentrations that risk treatment failure. Following nebulization of high doses, colistin (200,000 international units/24h) lung tissue concentrations are > five times minimum inhibitory concentration (MIC) of GNB in regions with multiple foci of bronchopneumonia and in the range of MIC breakpoints in regions with confluent pneumonia. Future research should include: (1) experimental studies using lung microdialysis to assess the PK/PD in the interstitial fluid of the lung following nebulization of high doses of colistin; (2) superiority multicenter randomized controlled trials comparing nebulized and intravenous CMS in patients with pandrug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis; (3) non-inferiority multicenter randomized controlled trials comparing nebulized CMS to intravenous new cephalosporines/ß-lactamase inhibitors in patients with extensive drug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis.
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http://dx.doi.org/10.3390/microorganisms9061154DOI Listing
May 2021

Pharmacodynamic Evaluation of a Single Dose versus a 24-Hour Course of Multiple Doses of Cefazolin for Surgical Prophylaxis.

Antibiotics (Basel) 2021 May 19;10(5). Epub 2021 May 19.

School of Pharmacy, The University of Queensland, Woolloongabba, Brisbane, QLD 4103, Australia.

The optimal perioperative duration for the administration of cefazolin and other prophylactic antibiotics remains unclear. This study aimed to describe the pharmacodynamics of cefazolin for a single 2 g dose versus a 24 h course of a 2 g single dose plus a 1 g eight-hourly regimen against methicillin-susceptible . Static concentration time-kill assay and a dynamic in vitro hollow-fibre infection model simulating humanised plasma and interstitial fluid exposures of cefazolin were used to characterise the pharmacodynamics of prophylactic cefazolin regimens against methicillin-sensitive clinical isolates. The initial inoculum was 1 × 10 CFU/mL to mimic a high skin flora inoculum. The static time-kill study showed that increasing the cefazolin concentration above 1 mg/L (the MIC) did not increase the rate or the extent of bacterial killing. In the dynamic hollow-fibre model, both dosing regimens achieved similar bacterial killing (~3-log CFU/mL within 24 h). A single 2 g dose may be adequate when low bacterial burdens (~10 CFU/mL) are anticipated in an immunocompetent patient with normal pharmacokinetics.
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http://dx.doi.org/10.3390/antibiotics10050602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161008PMC
May 2021

Development and validation of a UHPLC-MS/MS method to measure cefotaxime and metabolite desacetylcefotaxime in blood plasma: a pilot study suitable for capillary microsampling in critically ill children.

Anal Bioanal Chem 2021 May 26. Epub 2021 May 26.

UQ Centre for Clinical Research, The University of Queensland, Herston, QLD, 4029, Australia.

Critical illness has been shown to affect the pharmacokinetics of antibiotics, which can lead to ineffective antibiotic exposure and the potential emergence of resistant bacteria. The lack of studies describing antibiotic pharmacokinetics in critically ill children has led to significant off-label dosing. This is, in part, due to the ethical and physiological challenges of removing frequent, large-volume samples from children. Capillary microsampling facilitates the collection of small volumes of blood samples to conduct clinical pharmacokinetic studies. A sensitive, rapid, and accurate ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) bioanalytical method to measure cefotaxime and desacetylcefotaxime in 2.8 μL of plasma was developed and validated. Plasma samples were treated with acetonitrile and analytes were separated using a Kinetex C8 (100 × 2.1 mm) column. The chromatographic separation was established using a gradient method, with the mobile phases consisting of acetonitrile and ammonium acetate. An electrospray ionization source interface operated in a positive mode for the multiple reaction monitoring MS/MS analysis of cefotaxime, desacetylcefotaxime, and deuterated cefotaxime (internal standard). The bioanalytical method using microsample volumes met requirements for method validation for both analytes. Cefotaxime had precision within ± 7.3% and accuracy within ± 5% (concentration range of 0.5 to 500 mg/L). Desacetylcefotaxime had precision within ± 9.5% and accuracy within ± 3.5% (concentration range of 0.2 to 10 mg/L). The bioanalytical method was applied for the quantification of cefotaxime and its metabolite to 20 capillary microsamples collected at five time points in one dosing interval from five critically ill children.
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http://dx.doi.org/10.1007/s00216-021-03411-7DOI Listing
May 2021

Microsampling to support pharmacokinetic clinical studies in pediatrics.

Pediatr Res 2021 May 22. Epub 2021 May 22.

UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia.

Background: Conventional sampling for pharmacokinetic clinical studies requires removal of large blood volumes from patients. This can result in a physiological/emotional burden for children. Microsampling to support pharmacokinetic clinical studies in pediatrics may reduce this burden.

Methods: Parents/guardians and bedside nurses completed a questionnaire describing their perception of the use of microsampling compared to conventional sampling to collect blood samples, based on their child's participation or their own role within a paired-sample pharmacokinetic clinical study. Responses were based on a seven-point Likert scale and were analyzed using frequency distributions.

Results: Fifty-one parents/guardians and seven bedside nurses completed a questionnaire. Parents/guardians (96%) and bedside nurses (100%) indicated that microsampling was highly acceptable and recommended as a method for collecting blood samples for pediatric patients. Responding to a question about the child indicating pain during the blood sampling procedure, 61% of parent/guardians reported no pain in their children, 14% remained neutral, and 26% reported that their child indicated pain; 71% of the bedside nurses slightly agreed that the children indicated pain.

Conclusions: This study strongly suggests that parents/guardians and bedside nurses prefer microsampling to conventional sampling to conduct pediatric pharmacokinetic clinical studies. Employing microsampling may support increased participation by children in these studies.

Impact: Pharmacokinetic clinical studies require the withdrawal of blood samples at multiple times during a dosing interval. This can result in a physiological or emotional burden, particularly for neonates or pediatric patients. Microsampling offers an important opportunity for pharmacokinetic clinical studies in vulnerable patient populations, where smaller sample volumes can be collected. However, microsampling is not commonly used in clinical studies. Understanding the perceptions of parents/guardians and bedside nurses about microsampling may ascertain if this technique offers an improvement to conventional blood sample collection to perform pharmacokinetic clinical studies for pediatric patients.
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http://dx.doi.org/10.1038/s41390-021-01586-4DOI Listing
May 2021

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Drug Treatment of Non-Tuberculous Mycobacteria in Cystic Fibrosis.

Clin Pharmacokinet 2021 May 13. Epub 2021 May 13.

Faculty of Medicine, University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia.

Non-tuberculous mycobacteria (NTM) are an emerging group of pulmonary infectious pathogens of increasing importance to the management of patients with cystic fibrosis (CF). NTM include slow-growing mycobacteria such as Mycobacterium avium complex (MAC) and rapidly growing mycobacteria such as Mycobacterium abscessus. The incidence of NTM in the CF population is increasing and infection contributes to significant morbidity to the patient and costs to the health system. Treating M. abscessus requires the combination of multiple costly antibiotics for months, with potentially significant toxicity associated with treatment. Although international guidelines for the treatment of NTM infection in CF are available, there are a lack of robust pharmacokinetic studies in CF patients to inform dosing and drug choice. This paper aims to outline the pharmacokinetic and pharmacodynamic factors informing the optimal treatment of NTM infections in CF.
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http://dx.doi.org/10.1007/s40262-021-01010-4DOI Listing
May 2021

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

Future Microbiol 2021 May 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 Apr 22. 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
April 2021

Prospective Cohort Study of Micafungin Population Pharmacokinetic Analysis in Plasma and Peritoneal Fluid in Septic Patients with Intra-abdominal Infections.

Antimicrob Agents Chemother 2021 Jun 17;65(7):e0230720. Epub 2021 Jun 17.

Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Nîmes, France.

The objective of this study was to describe the pharmacokinetics (PK) of micafungin in plasma and peritoneal fluid in septic patients with intra-abdominal infections. Twelve patients with secondary peritonitis in septic shock receiving 100 mg micafungin once daily were included. Total micafungin plasma and peritoneal fluid were subjected to a population pharmacokinetic analysis using Pmetrics. Monte Carlo simulations were performed considering the total area under the curve from 0 to 24 h (AUC)/MIC ratios in plasma. Micafungin concentrations in both plasma and the peritoneal exudate were best described by a three-compartmental PK model with the fat-free mass (FFM) as a covariate of clearance (CL) and the volume of the central compartment (). The mean parameter estimates (standard deviations [SD]) were 1.18 (0.40) liters/h for CL and 12.85 (4.78) liters for . The mean peritoneal exudate/plasma ratios (SD) of micafungin were 25% (5%) on day 1 and 40% (8%) between days 3 and 5. Dosing simulations supported the use of standard 100-mg daily dosing for Candida albicans (FFM, <60 kg), C. glabrata (FFM, <50 kg), and C. tropicalis (FFM, <30 kg) on the second day of therapy. There is a moderate penetration of micafungin into the peritoneal cavity (25 to 40%). For empirical treatment, a dose escalation of at least a loading dose of 150 mg depending on the FFM of patients and the species is suggested to be effective from the first day of therapy.
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http://dx.doi.org/10.1128/AAC.02307-20DOI Listing
June 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

Letter to the Editor regarding: Ceftriaxone exposure in patients undergoing extracorporeal membrane oxygenation.

Int J Antimicrob Agents 2021 May 26;57(5):106326. Epub 2021 Mar 26.

KU Leuven Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; Pharmacy Department, University Hospitals Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1016/j.ijantimicag.2021.106326DOI Listing
May 2021

Microfluidic assembly of pomegranate-like hierarchical microspheres for efflux regulation in oral drug delivery.

Acta Biomater 2021 05 24;126:277-290. Epub 2021 Mar 24.

School of Pharmacy, The University of Queensland, Woolloongabba 4102, Australia; School of Materials Science and Engineering, The University of New South Wales, Sydney 2052, NSW, Australia. Electronic address:

Herein, a multi-functional nano-in-micro hierarchical microsphere system is demonstrated for controlling the intestinal efflux pumps that affect the oral bioavailability of many therapeutic drugs. The hierarchical particles were generated by a co-flow microfluidic device and consisted of porous silica nanoparticles packed in Eudragit® polymeric matrix. Meropenem (MER), a last-resort antibacterial drug, was loaded into porous silica (MCM-48) with a loading capacity of 34.3 wt%. In this unique materials combination, MCM-48 enables ultrahigh loading of a hydrophilic MER, while the Eudragit® polymers not only protect MER from gastric pH but also act as an antagonist for p-glycoprotein protein efflux pumps to reduce the efflux of MER back into the gastrointestinal lumen. We investigated the in-vitro temporal MER release and bidirectional (absorptive and secretory) drug permeation model across the Caco-2 monolayer. The bioavailability of MER was significantly improved by all of the prepared formulations (i.e. increased absorptive transport and reduced secretory transport). The Eudragit® RSPO formulated MER-MCM showed the best performance with an efflux ratio (i.e. secretory transport/absorptive transport) of 0.35, which is 7.4 folds less than pure MER (2.62). Lastly, the prepared formulations were able to retain the antibacterial activity of MER against Staphylococcus aureus and Pseudomonas aeruginosa. STATEMENT OF SIGNIFICANCE: Meropenem (MER) is a last resort antibiotic used for the treatment of drug-resistant and acute infections and only available as intravenous injectable dosage due to its poor chemical and thermal stability, and ultra-poor oral bioavailability because of the efflux action of P-glycoprotein (P-gp) pumps. Multifunctional colloidal micro/nanoparticles can help to solve these issues. Herein, we designed pomegranate-like hierarchical microspheres comprised of porous silica nanoparticles and enteric Eudragit® polymers (Eudragit®S100, Eudragit®RSPO, and Eudragit®RS100) using a co-flow microfluidic device. Our formulations allow for ultrahigh loading of hydrophilic MER, protects MER from gastric pH, and also block P-gp efflux pumps for enhanced MER permeation/retention with Eudragit®RSPO - showing 13.9-folds higher permeation and 7.4-folds reduction in efflux ratio in a bi-directional Caco-2 monolayer culture system.
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http://dx.doi.org/10.1016/j.actbio.2021.03.042DOI Listing
May 2021

Provider perspectives on beta-lactam therapeutic drug monitoring programs in the critically ill: a protocol for a multicenter mixed-methods study.

Implement Sci Commun 2021 Mar 24;2(1):34. Epub 2021 Mar 24.

Knowledge and Evaluation Research (KER) Unit, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.

Background: Beta-lactams (i.e., penicillins, cephalosporins, carbapenems, monobactams) are the most widely used class of antibiotics in critically ill patients. There is substantial interpatient variability in beta-lactam pharmacokinetics which renders their effectiveness and safety largely unpredictable. One strategy to ensure achievement of therapeutic concentrations is drug level testing ("therapeutic drug monitoring"; TDM). While studies have suggested promise with beta-lactam TDM, it is not yet widely available or implemented. This protocol presents a mixed-methods study designed to examine healthcare practitioners' perspectives on the use and implementation of beta-lactam TDM in the critically ill.

Methods: An explanatory sequential mixed-methods design will be used [QUANT → qual]. First, quantitative data will be collected through a web-based questionnaire directed at clinicians at three academic medical centers at different phases of beta-lactam TDM implementation (not yet implemented, partially implemented, fully implemented). The sampling frame will include providers from a variety of disciplines that interact with drug level testing and interpretation in the critical care environment including pharmacists, intensivists, infectious diseases experts, medical/surgical trainees, and advanced practice providers. Second, approximately 30 individuals will be purposively sampled from survey respondents to conduct in-depth qualitative interviews to explain and expand upon the results from the quantitative strand. Normalization Process Theory and the Consolidated Framework for Implementation Science will be used to guide data analysis.

Discussion: These data will be used to answer two specific questions: "What are ICU practitioners' perspectives on implementing beta-lactam TDM?" and "What factors contribute to the success of beta-lactam TDM program implementation?" Results of this study will be used to design future implementation strategies for beta-lactam TDM programs in the critically ill.

Trial Registration: NCT04755777 .
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http://dx.doi.org/10.1186/s43058-021-00134-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992791PMC
March 2021

An international survey on aminoglycoside practices in critically ill patients: the AMINO III study.

Ann Intensive Care 2021 Mar 19;11(1):49. Epub 2021 Mar 19.

Department of Intensive Care Medicine, Division of Anesthesiology, Intensive Care, Pain and Emergency Medicine, Nîmes University Hospital, Place du Professeur Robert Debré, 30 029, Nîmes cedex 9, France.

Background: While aminoglycosides (AG) have been used for decades, debate remains on their optimal dosing strategy. We investigated the international practices of AG usage specifically regarding dosing and therapeutic drug monitoring (TDM) in critically ill patients. We conducted a prospective, multicentre, observational, cohort study in 59 intensive-care units (ICUs) in 5 countries enrolling all ICU patients receiving AG therapy for septic shock.

Results: We enrolled 931 septic ICU patients [mean ± standard deviation, age 63 ± 15 years, female 364 (39%), median (IQR) SAPS II 51 (38-65)] receiving AG as part of empirical (761, 84%) or directed (147, 16%) therapy. The AG used was amikacin in 614 (66%), gentamicin in 303 (33%), and tobramycin in 14 (1%) patients. The median (IQR) duration of therapy was 2 (1-3) days, the number of doses was 2 (1-2), the median dose was 25 ± 6, 6 ± 2, and 6 ± 2 mg/kg for amikacin, gentamicin, and tobramycin respectively, and the median dosing interval was 26 (23.5-43.5) h. TDM of C and C was performed in 437 (47%) and 501 (57%) patients, respectively, after the first dose with 295 (68%) patients achieving a C/MIC > 8 and 353 (71%) having concentrations above C recommended thresholds. The ICU mortality rate was 27% with multivariable analysis showing no correlation between AG dosing or pharmacokinetic/pharmacodynamic target attainment and clinical outcomes.

Conclusion: Short courses of high AG doses are mainly used in ICU patients with septic shock, although wide variability in AG usage is reported. We could show no correlation between PK/PD target attainment and clinical outcome. Efforts to optimize the first AG dose remain necessary. Trial registration Clinical Trials, NCT02850029, registered on 29th July 2016, retrospectively registered, https://www.clinicaltrials.gov.
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http://dx.doi.org/10.1186/s13613-021-00834-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979853PMC
March 2021

A Loading Micafungin Dose in Critically Ill Patients Undergoing Continuous Veno-Venous Hemofiltration or Continuous Veno-Venous Hemodiafiltration: A Population Pharmacokinetic Analysis.

Ther Drug Monit 2021 Feb 8. Epub 2021 Feb 8.

Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, Centre Hospitalier Universitaire (CHU) Nîmes, Nîmes, France Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Univ Montpellier, Montpellier, France Equipe d'accueil 2992 Caractéristiques Féminines des Interfaces Vasculaires (IMAGINE), Faculté de médecine, Univ Montpellier, Montpellier, France Laboratoire de Biochimie, CHU Nîmes, Hôpital Carémeau, Nîmes, France Department of Anesthesia and Surgical Intensive Care, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain Universidad Autónoma de Madrid, Madrid, Spain Pharmacy Department. Hospital del Mar, Parc de Salut Mar, Barcelona, Spain. Infectious Pathology and Antimicrobials Research Group (IPAR). Institut Hospital del Mar d'Investigacions Mèdiques (IMIM). Pharmacy Department. Hospital del Mar, Parc de Salut Mar, Barcelona, Spain. Universitat Auto[Combining Grave Accent]noma de Barcelona, Barcelona, Spain. UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia Pharmacy Department, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.

Background: In the present study, the authors aimed to compare the pharmacokinetics (PK) of micafungin in critically ill patients receiving continuous veno-venous hemofiltration (CVVH, 30 mL/kg/h) with those of patients receiving equidoses of hemodiafiltration (CVVHDF, 15 mL/kg/h + 15 mL/kg/h) and determine the optimal dosing regimen using the developed model.

Methods: Patients with septic shock undergoing continuous renal replacement therapy (CRRT) and receiving a conventional dose of 100 mg micafungin once daily were eligible for inclusion. Total micafungin plasma concentrations from eight CVVH sessions and eight CVVHDF sessions were subjected to a population PK analysis using Pmetrics. Validation of the model performance was reinforced by external validation. Monte Carlo simulations were performed considering the total ratio of free drug area under the curve (AUC) over 24 h to the minimum inhibitory concentration (MIC) (AUC0-24/MIC) in plasma.

Results: The median total body weight (min-max) was 94.8 (66-138) kg. Micafungin concentrations were best described by a two-compartmental PK model. No covariates, including CRRT modality (CVVH or CVVHDF), were retained in the final model. The mean parameter estimates (standard deviation) were 0.96 (0.32) L/h for clearance and 14.8 (5.3) L for the central compartment volume. External validation confirmed the performance of the developed PK model. Dosing simulations did not support the use of standard 100 mg daily dosing, except for Candida albicans on the second day of therapy. A loading dose of 150 mg followed by 100 mg daily reached the probability of target attainment for all C. albicans and C. glabrata, but not for C. krusei and C. parapsilosis.

Conclusions: No difference was observed in micafungin PK between equidoses of CVVH and CVVHDF. A loading dose of 150 mg is required to achieve the PK/PD target for less susceptible Candida species from the first day of therapy.
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http://dx.doi.org/10.1097/FTD.0000000000000874DOI Listing
February 2021

Model-Informed Drug Development for Anti-Infectives: State of the Art and Future.

Clin Pharmacol Ther 2021 Apr 9;109(4):867-891. Epub 2021 Mar 9.

Certara, Princeton, New Jersey, USA.

Model-informed drug development (MIDD) has a long and rich history in infectious diseases. This review describes foundational principles of translational anti-infective pharmacology, including choice of appropriate measures of exposure and pharmacodynamic (PD) measures, patient subpopulations, and drug-drug interactions. Examples are presented for state-of-the-art, empiric, mechanistic, interdisciplinary, and real-world evidence MIDD applications in the development of antibacterials (review of minimum inhibitory concentration-based models, mechanism-based pharmacokinetic/PD (PK/PD) models, PK/PD models of resistance, and immune response), antifungals, antivirals, drugs for the treatment of global health infectious diseases, and medical countermeasures. The degree of adoption of MIDD practices across the infectious diseases field is also summarized. The future application of MIDD in infectious diseases will progress along two planes; "depth" and "breadth" of MIDD methods. "MIDD depth" refers to deeper incorporation of the specific pathogen biology and intrinsic and acquired-resistance mechanisms; host factors, such as immunologic response and infection site, to enable deeper interrogation of pharmacological impact on pathogen clearance; clinical outcome and emergence of resistance from a pathogen; and patient and population perspective. In particular, improved early assessment of the emergence of resistance potential will become a greater focus in MIDD, as this is poorly mitigated by current development approaches. "MIDD breadth" refers to greater adoption of model-centered approaches to anti-infective development. Specifically, this means how various MIDD approaches and translational tools can be integrated or connected in a systematic way that supports decision making by key stakeholders (sponsors, regulators, and payers) across the entire development pathway.
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http://dx.doi.org/10.1002/cpt.2198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014105PMC
April 2021

A validated LC-MS/MS method for the simultaneous quantification of the novel combination antibiotic, ceftolozane-tazobactam, in plasma (total and unbound), CSF, urine and renal replacement therapy effluent: application to pilot pharmacokinetic studies.

Clin Chem Lab Med 2021 Apr 25;59(5):921-933. Epub 2020 Nov 25.

UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia.

Objectives: Novel treatment options for some carbapenem-resistant Gram-negative pathogens have been identified by the World Health Organization as being of the highest priority. Ceftolozane-tazobactam is a novel cephalosporin-beta-lactamase inhibitor combination antibiotic with potent bactericidal activity against the most difficult-to-treat multi-drug resistant and extensively drug resistant Gram-negative pathogens. This study aimed to develop and validate a liquid chromatography - tandem mass spectrometry method for the simultaneous quantification of ceftolozane and tazobactam in plasma (total and unbound), renal replacement therapy effluent (RRTE), cerebrospinal fluid (CSF) and urine.

Methods: Analytes were separated using mixed-mode chromatography with an intrinsically base-deactivated C18 column and a gradient mobile phase consisting of 0.1% formic acid, 10 mM ammonium formate and acetonitrile. The analytes and internal standards were detected using rapid ionisation switching between positive and negative modes with simultaneous selected reaction monitoring.

Results: A quadratic calibration was obtained for plasma (total and unbound), RRTE and CSF over the concentration range of 1-200 mg/L for ceftolozane and 0.5-100 mg/L for tazobactam, and for urine the concentration range of 10-2,000 mg/L for ceftolozane and 5-1,000 mg/L for tazobactam. For both ceftolozane and tazobactam, validation testing for matrix effects, precision and accuracy, specificity and stability were all within the acceptance criteria of ±15%.

Conclusions: This methodology was successfully applied to one pilot pharmacokinetic study in infected critically ill patients, including patients receiving renal replacement therapy, and one case study of a patient with ventriculitis, where all patients received ceftolozane-tazobactam.
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http://dx.doi.org/10.1515/cclm-2020-1196DOI Listing
April 2021

Evaluation of Meropenem-Ciprofloxacin Combination Dosage Regimens for the Pharmacokinetics of Critically Ill Patients With Augmented Renal Clearance.

Clin Pharmacol Ther 2021 Apr 12;109(4):1104-1115. Epub 2021 Mar 12.

Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.

Augmented renal clearance (ARC, creatinine clearance > 130 mL/minute) makes difficult achievement of effective concentrations of renally cleared antibiotics in critically ill patients. This study examined the synergistic killing and resistance suppression for meropenem-ciprofloxacin combination dosage regimens against Pseudomonas aeruginosa isolates within the context of ARC. Clinically relevant meropenem and ciprofloxacin concentrations, alone and in combinations, were studied against three clinical isolates with a range of susceptibilities to each of the antibiotics. Isolate Pa1280 was susceptible to both meropenem and ciprofloxacin, Pa1284 had intermediate susceptibility to meropenem and was susceptible to ciprofloxacin, and CR380 was resistant to meropenem and had intermediate susceptibility to ciprofloxacin. Initially, isolates were studied in 72-hour static-concentration time-kill (SCTK) studies. Subsequently, the pharmacokinetic profiles expected in patients with ARC receiving dosage regimens, including at the highest approved daily doses (meropenem 6 g daily divided and administered as 0.5-hour infusions every 8 hours, or as a continuous infusion; ciprofloxacin 0.4 g as 1-hour infusions every 8 hours), were examined in a dynamic hollow-fiber infection model (HFIM) over 7-10 days. In both SCTK and HFIM, combination regimens were generally synergistic and suppressed growth of less-susceptible subpopulations, these effects being smaller for isolate CR380. The time-courses of total and less-susceptible bacterial populations in the HFIM were well-described by mechanism-based models, which enabled conduct of Monte Carlo simulations to predict likely effectiveness of approved dosage regimens at different creatinine clearances. Optimized meropenem-ciprofloxacin combination dosage regimens may be a viable consideration for P. aeruginosa infections in critically ill patients with ARC.
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http://dx.doi.org/10.1002/cpt.2191DOI Listing
April 2021

PLGA encapsulated γ-cyclodextrin-meropenem inclusion complex formulation for oral delivery.

Int J Pharm 2021 Mar 1;597:120280. Epub 2021 Feb 1.

School of Pharmacy, The University of Queensland, Woolloongabba 4102, Australia. Electronic address:

Meropenem (MER) is one of the last resort antibiotics used to treat resistant bacterial infections. However, the clinical effectiveness of MER is hindered due to chemical instability in aqueous solution and gastric pH, and short plasma half-life. Herein, a novel multi-material delivery system based on γ-cyclodextrin (γ-CD) and poly lactic-co-glycolic acid (PLGA) is demonstrated to overcome these challenges. MER showed a saturated solubility of 14 mg/100 mL in liquid CO and later it was loaded into γ-CD to form the inclusion complex using the liquid CO method. The γ-CD and MER inclusion complex (MER-γ-CD) was encapsulated into PLGA by the well-established double emulsion solvent evaporation method. The formation of the inclusion complex was confirmed using FTIR, XRD, DSC, SEM, and H NMR and docking study. Further, MER-γ-CD loaded PLGA nanoparticles (MER-γ-CD NPs) were characterized by SEM, DLS, and FTIR. The drug loading and entrapment efficiency for MER-γ-CD were 21.9 and 92. 2% w/w, respectively. However, drug loading and entrapment efficiency of MER-γ-CD NPs was significantly lower at up to 3.6 and 42.1% w/w, respectively. In vitro release study showed that 23.6 and 27.4% of active (non-degraded drug) and total drug (both degraded and non-degraded drug) were released from MER-γ-CD NPs in 8 h, respectively. The apparent permeability coefficient (Papp) (A to B) for MER, MER-γ-CD, and MER-γ-CD NPs were 2.63 × 10 cm/s, 2.81 × 10 cm/s, and 2.92 × 10 cm/s respectively. For secretory transport, the Papp (B to A) were 1.47 × 10 cm/s, 1.53 × 10 cm/s, and 1.58 × 10 cm/s for MER, MER-γ-CD and MER-γ-CD NPs respectively. Finally, the MER-γ-CD inclusion complex and MER-γ-CD NPs retained MER's antibacterial activities against Staphylococcus aureus and Pseudomonas aeruginosa. Overall, this work demonstrates the significance of MER-γ-CD NPs to protect MER from gastric pH with controlled drug release, while retaining MER's antibacterial activity.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120280DOI Listing
March 2021

A Systematic Review of the Clinical Pharmacokinetics, Pharmacodynamics and Toxicodynamics of Ganciclovir/Valganciclovir in Allogeneic Haematopoietic Stem Cell Transplant Patients.

Clin Pharmacokinet 2021 Jun 30;60(6):727-739. Epub 2021 Jan 30.

Faculty of Medicine and Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, University of Queensland Centre for Clinical Research (UQCCR), The University of Queensland, St Lucia, QLD, Australia.

Background: Ganciclovir (GCV) and valganciclovir (VGCV) are the first-line agents used to prevent and treat cytomegalovirus (CMV) infection in allogeneic haematopoietic stem cell transplant (alloHCT) patients.

Objective: The aim of this work was to describe available data for the clinical pharmacokinetics, pharmacodynamics and toxicodynamics of GCV and VGCV and the potential of a therapeutic drug monitoring strategy to improve outcomes in the alloHCT population.

Methods: We systematically reviewed the pharmacokinetics (dose-exposure), pharmacodynamics (exposure-efficacy) and toxicodynamics (exposure-toxicity) of GCV and VGCV in alloHCT patients with CMV infection. Studies including alloHCT patients treated for CMV infection reporting the pharmacokinetics, pharmacodynamics and toxicodynamics of GCV or VGCV were searched for using the PUBMED and EMBASE databases from 1946 to 2019. Only studies involving participants > 12 years of age and available in the English language were included.

Results: A total of 179 patients were included in the 14 studies that met the inclusion criteria, of which 6 examined GCV pharmacokinetics only, while 8 also examined GCV pharmacodynamics and toxicodynamics. Reported pharmacokinetic parameters showed considerable interpatient variability and were different from other populations, such as solid organ transplant and human immunodeficiency virus-infected patients. Only one study found a correlation between neutropenia and elevated peak and trough GCV concentrations, with no other significant pharmacodynamic and toxicodynamic relationships identified. While therapeutic drug monitoring of GCV is performed in some institutions, no association between GCV therapeutic drug monitoring and clinical outcomes was identified.

Conclusion: Further studies of the pharmacokinetics, pharmacodynamics and toxicodynamics of GCV/VGCV in alloHCT patients are required to identify a more robust therapeutic range and to subsequently quantify the potential value of therapeutic drug monitoring of GCV/VGCV in the alloHCT population.
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http://dx.doi.org/10.1007/s40262-020-00982-zDOI Listing
June 2021

Population Pharmacokinetics Analysis of Amikacin Initial Dosing Regimen in Elderly Patients.

Antibiotics (Basel) 2021 Jan 20;10(2). Epub 2021 Jan 20.

Department of Clinical Infectious Diseases, Aichi Medical University, Aichi 480-1195, Japan.

There are limited data of amikacin pharmacokinetics (PK) in the elderly population. Hence, we aimed to describe the population PK of amikacin in elderly patients (>70 years old) and to establish optimized initial dosing regimens. We simulated individual maximum concentrations in plasma (Cmax) and minimal concentrations (Cmin) for several dosing regimens (200-2000 mg every 24, 48, and 72 h) for patients with creatinine clearance (CCr) of 10-90 mL/min and analyzed efficacy (Cmax/minimal inhibitory concentration (MIC) ≥ 8) for MICs of 4, 8, and 16 mg/L and safety (Cmin < 4 mg/L). A one-compartment model best described the data. CCr was the only covariate associated with amikacin clearance. The population PK parameter estimates were 2.25 L/h for clearance and 18.0 L for volume of distribution. Dosing simulations recommended the dosing regimens (1800 mg) with dosing intervals ranging 48-72 h for patients with CCr of 40-90 mL/min based on achievement of both efficacy for the MIC of 8 mg/L and safety. None of the dosing regimens achieved the targets for an MIC of 16 mg/L. We recommend the initial dosing regimen using a nomogram based on CCr for an MIC of ≤8 mg/L in elderly patients with CCr of 40-90 mL/min.
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http://dx.doi.org/10.3390/antibiotics10020100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909551PMC
January 2021

Liquid CO Formulated Mesoporous Silica Nanoparticles for pH-Responsive Oral Delivery of Meropenem.

ACS Biomater Sci Eng 2021 05 7;7(5):1836-1853. Epub 2021 Jan 7.

School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia.

Meropenem (MER) is an effective broad-spectrum antibiotic currently only available in the parenteral form requiring frequent drug preparation and administration due to its extremely poor stability. The unavailability of oral Meropenem is primarily due to its ultrapoor handling and processing stability, hydrophilic nature that inhibits the passive diffusion across the gastrointestinal (GI) epithelium, degradation in the harsh gastric environment, and GI expulsion through enterocyte efflux glycoproteins. In this regard, we have developed an oral drug delivery system that confines MER into mesoporous silica nanoparticles (MSNs i.e, MCM-41 ∼141 nm) using a novel liquid carbon dioxide (CO) method. MER was efficiently encapsulated within pristine, phosphonate (negatively charged MSN), and amine (positively charged MSN) modified MSNs with loading capacity ranging between 25 % and 31 %. Next, the MER-MCM-NH particles were electrostatically coated with Eudragit S100 enteric polymer that protected MER against gastric pH (pH 1.9) and enabled site-specific delivery in the small intestine (pH 6.8). Cellular uptake results in RAW 264.7 macrophage, Caco-2, and LS174T cells confirming the efficient cellular uptake of nanoparticles in all three cell lines. More importantly, the bidirectional transport (absorptive and secretory) of MER across Caco-2 monolayer was significantly improved for both MSN-based formulations, particularly MSNs coated with a polymer (Eud-MER-MCM-NH) where permeability was significantly enhanced (∼2.4-fold) for absorptive transport and significantly reduced (∼1.8-fold) for secretory transport. Finally, antibacterial activity [minimum inhibitory concentration (MIC)] and time-kill assay against and showed that drug-loaded nanoparticles were able to retain antibacterial activity comparable to that of free MER in a solution at equivalent dose. Thus, Eudragit-coated silica nanoparticles could offer a promising and novel solution for oral delivery of Meropenem and other such drugs.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01284DOI Listing
May 2021

Population Pharmacokinetics of Levetiracetam in Patients with Traumatic Brain Injury and Subarachnoid Hemorrhage Exhibiting Augmented Renal Clearance.

Clin Pharmacokinet 2021 May 11;60(5):655-664. Epub 2021 Jan 11.

University of Queensland Centre for Clinical Research, The University of Queensland, Building 71/918, Royal Brisbane & Women's Hospital Campus, Herston, QLD, 4029, Australia.

Background And Objective: Patients with severe trauma exhibit augmented renal clearance, which can alter the dosing requirement of renally eliminated drugs. This study aimed to develop a population pharmacokinetic model for levetiracetam in patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage, and use it to describe optimal dosing regimens.

Methods: This was a prospective open-label observational study. Critically ill adult patients with severe traumatic brain injury or aneurysmal subarachnoid hemorrhage without renal dysfunction and receiving levetiracetam were eligible. Serial levetiracetam plasma concentrations were analyzed to develop a population pharmacokinetic model and perform dosing simulations.

Results: A two-compartment model best described the concentration-time data from 30 patients. The mean ± standard deviation parameter estimates were bioavailability (F) of 0.8 ± 0.2, absorption rate constant of 2.4 ± 2 h, clearance 2.5 ± 1.1 L/h, central volume of distribution 8.9 ± 3.0 L/h, and transfer rate constraints of 1.8 ± 1.1 h from central to peripheral compartments and 0.7 ± 0.3 h from peripheral to central compartments. For the simulated intermittent dosing regimens, on average, the median trough concentration reduced by 50% for every 40-mL/min/1.73 m increase in urinary creatinine clearance. Simulated doses of at least 6 g/day were required for some levels of augmented renal clearance.

Conclusions: Patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage with augmented renal clearance are at risk of not achieving target levetiracetam plasma concentrations. We suggest dose titration guided by measured creatinine clearance, and/or, therapeutic drug monitoring if available, to minimize the risk of seizures.
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http://dx.doi.org/10.1007/s40262-020-00979-8DOI Listing
May 2021

Australian National Enterovirus Reference Laboratory annual report, 2019.

Commun Dis Intell (2018) 2020 Nov 21;44. Epub 2020 Nov 21.

National Enterovirus Reference Laboratory, Victorian Infectious Diseases Reference Laboratory, Doherty Institute, 792 Elizabeth St, Melbourne 3000, Victoria, Australia.

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http://dx.doi.org/10.33321//cdi.2020.44.94DOI Listing
November 2020

Comparative lung distribution of radiolabeled tobramycin between nebulized and intravenous administration in a mechanically-ventilated ovine model, an observational study.

Int J Antimicrob Agents 2021 Feb 21;57(2):106232. Epub 2020 Nov 21.

UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia; Department of Intensive Care Medicine, Royal Brisbane & Women's Hospital, Brisbane, Australia; Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Australia; Department of Pharmacy, Royal Brisbane & Women's Hospital, Brisbane, Australia.

Background: Ventilator-associated pneumonia is common and is treated using nebulized antibiotics. Although adequate pulmonary biodistribution is important for antibiotic effect, there is a lack of data for both intravenous (IV) and nebulized antibiotic administration during mechanical ventilation.

Objective: To describe the comparative pulmonary regional distribution of IV and nebulized technetium-99m-labeled tobramycin (Tc-tobramycin) 400 mg in a mechanically-ventilated ovine model.

Methods: The study was performed in a mechanically-ventilated ovine model. Tc-tobramycin 400 mg was obtained using a radiolabeling process. Computed tomography (CT) was performed. Ten sheep were given Tc-tobramycin 400 mg via either an IV (five sheep) or nebulized (five sheep) route. Planar images (dorsal, ventral, left lateral and right lateral) were obtained using a gamma camera. Blood samples were obtained every 15 min for 1 h (4 time points) and lung, liver, both kidney, and urine samples were obtained post-mortem.

Results: Ten sheep were anesthetized and mechanically ventilated. Whole-lung deposition of nebulized Tc-tobramycin 400 mg was significantly lower than with IV (8.8% vs. 57.1%, P<0.001). For both administration routes, there was significantly lower deposition in upper lung zones compared with the rest of the lungs. Dorsal deposition was significantly higher with nebulized Tc-tobramycin 400 mg compared with IV (68.9% vs. 58.9%, P=0.003). Lung concentrations of Tc-tobramycin were higher with IV compared with nebulized administration. There were significantly higher concentrations of Tc-tobramycin in blood, liver and urine with IV administration compared with nebulized.

Conclusions: Nebulization resulted in lower whole and regional lung deposition of Tc-tobramycin compared with IV administration and appeared to be associated with low blood and extra-pulmonary organ concentrations.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106232DOI Listing
February 2021

Optimization of Ganciclovir use in allogeneic hematopoietic cell transplant recipients - the role of therapeutic drug monitoring.

Expert Rev Anti Infect Ther 2021 Jun 17;19(6):707-718. Epub 2020 Dec 17.

Departments of Infectious Diseases, The National Centre for Infections in Cancer, Peter MacCallum Cancer Centre Melbourne, Australia.

: Cytomegalovirus (CMV) is an opportunistic infectious complication that can occur after allogeneic hematopoietic cell transplantation (HCT). The mainstay of treatment and prevention of this infection is ganciclovir and its ester prodrug valganciclovir. There is conflicting evidence on the clinical utility of routine ganciclovir therapeutic drug monitoring (TDM) as a means to optimize treatment.: This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of ganciclovir and valganciclovir, and to explore the evidence and challenges surrounding ganciclovir TDM within the allogeneic HCT cohort.: Ganciclovir TDM is important to optimize efficacy in selected patient groups where there are variable pharmacokinetic factors or inadequate response to treatment. However, defined pharmacokinetic exposures which correlate with treatment efficacy and toxicity remain elusive. Prospective clinical studies in specific patient groups are required to clarify this issue. Alternative TDM targets such as the intracellular ganciclovir triphosphate should be explored as they may prove to have better correlation with clinical outcomes and adverse effects. With recent advances in CMV immune monitoring, novel approaches integrating TDM with specific CMV immune phenotyping in a predictive model will be advantageous in optimizing ganciclovir dosing by combining TDM with a risk stratification approach.
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http://dx.doi.org/10.1080/14787210.2021.1851193DOI Listing
June 2021

Oral meropenem for superbugs: challenges and opportunities.

Drug Discov Today 2021 Feb 13;26(2):551-560. Epub 2020 Nov 13.

School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia. Electronic address:

An increase in the number of multidrug-resistant microbial strains is the biggest threat to global health and is projected to cause >10 million deaths by 2055. The carbapenem family of antibacterial drugs are an important class of last-resort treatment of infections caused by drug-resistant bacteria and are only available as an injectable formulation. Given their instability within the gut and poor permeability across the gut wall, oral carbapenem formulations show poor bioavailability. Meropenem (MER), a carbapenem antibiotic, has broad-spectrum antibacterial activity, but suffers from the above-mentioned issues. In this review, we discuss strategies for improving the oral bioavailability of MER, such as inhibiting tubular secretion, prodrug formulations, and use of nanomedicine. We also highlight challenges and emerging approaches for the development of oral MER.
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http://dx.doi.org/10.1016/j.drudis.2020.11.004DOI Listing
February 2021

Vancomycin Serum Concentration after 48 h of Administration: A 3-Years Survey in an Intensive Care Unit.

Antibiotics (Basel) 2020 Nov 10;9(11). Epub 2020 Nov 10.

Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, 30029 Nîmes, France.

The present study assessed the proportion of intensive care unit (ICU) patients who had a vancomycin serum concentration between 20 and 25 mg/L after 24-48 h of intravenous vancomycin administration. From 2016 to 2018, adult ICU patients with vancomycin continuous infusion (CI) for any indication were included. The primary outcome was the proportion of patients with a first-available vancomycin serum concentration between 20-25 mg/L at 24 h (D2) or 48 h (D3). Of 3894 admitted ICU patients, 179 were included. A median loading dose of 15.6 (interquartile range (IQR) = (12.5-20.8) mg/kg) was given in 151/179 patients (84%). The median daily doses of vancomycin infusion for D1 and D2 were 2000 [(IQR (1600-2000)) and 2000 (IQR (2000-2500)) mg/d], respectively. The median duration of treatment was 4 (2-7) days. At D2 or D3, the median value of first serum vancomycin concentration was 19.8 (IQR (16.0-25.1)) with serum vancomycin concentration between 20-25 mg/L reported in 43 patients (24%). Time spent in the ICU before vancomycin initiation was the only risk factor of non-therapeutic concentration at D2 or D3. Acute kidney injury occurred significantly more when vancomycin concentration was supra therapeutic at D2 or D3. At D28, 44 (26%) patients had died. These results emphasize the need of appropriate loading dose and regular monitoring to improve vancomycin efficacy and avoid renal toxicity.
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http://dx.doi.org/10.3390/antibiotics9110793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698174PMC
November 2020

Cerebrospinal Fluid Penetration of Ceftolozane-Tazobactam in Critically Ill Patients with an Indwelling External Ventricular Drain.

Antimicrob Agents Chemother 2020 12 16;65(1). Epub 2020 Dec 16.

University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia

The aim of this study was to describe the pharmacokinetics of ceftolozane-tazobactam in plasma and cerebrospinal fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (≥18 years) with an indwelling external ventricular drain received a single intravenous dose of 3.0 g ceftolozane-tazobactam. Serial plasma and CSF samples were collected for measurement of unbound ceftolozane and tazobactam concentration by liquid chromatography. Unbound concentration-time data were modeled in R using Pmetrics. Dosing simulations were performed using the final model. A three-compartment model adequately described the data from 10 patients. For ceftolozane, the median (interquartile range [IQR]) area under the unbound concentration-time curve from time zero to infinity (AUC) in the CSF and plasma were 30 (19 to 128) h·mg/liter and 323 (183 to 414) h·mg/liter, respectively. For tazobactam, these values were 5.6 (2 to 24) h·mg/liter and 52 (36 to 80) h·mg/liter, respectively. Mean ± standard deviation (SD) CSF penetration ratios were 0.2 ± 0.2 and 0.2 ± 0.26 for ceftolozane and tazobactam, respectively. With the regimen of 3.0 g every 8 h, a probability of target attainment (PTA) of ≥0.9 for 40% T in the CSF was possible only when MICs were ≤0.25 mg/liter. The CSF cumulative fractional response for -susceptible MIC distribution was 73%. The tazobactam PTA for the minimal suggested exposure of 20% T was 12%. The current maximal dose of ceftolozane-tazobactam (3.0 g every 8 h) does not provide adequate CSF exposure for treatment of Gram-negative meningitis or ventriculitis unless the MIC for the causative pathogen is very low (≤0.25 mg/liter).
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http://dx.doi.org/10.1128/AAC.01698-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927828PMC
December 2020

A Systematic Review of Studies Reporting Antibiotic Pharmacokinetic Data in the Cerebrospinal Fluid of Critically Ill Patients with Uninflamed Meninges.

Antimicrob Agents Chemother 2020 12 16;65(1). Epub 2020 Dec 16.

University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia

Ventriculostomy-associated infections in critically ill patients remain therapeutically challenging because of drug- and disease-related factors that contribute to suboptimal antibiotic concentrations in cerebrospinal fluid. Optimal antibiotic dosing for the treatment and prevention of such infections should be based on robust and contextually specific pharmacokinetic data. The objects of this study were to describe and critically appraise studies with reported antibiotic concentrations or pharmacokinetic data in cerebrospinal fluid of critically ill patients without meningeal inflammation. We systematically reviewed the literature to identify published reports and studies describing antibiotic concentrations, pharmacokinetics, and pharmacokinetics/pharmacodynamics in cerebrospinal fluid of critically ill patients with uninflamed meninges. Fifty-eight articles met the inclusion criteria. There was significant heterogeneity in methodologies and results. When available, antibiotic pharmacokinetic parameters displayed large intersubject variability. Intraventricular dosing achieved substantially higher antibiotic concentrations in cerebrospinal fluid than did intravenous doses. Few studies conducted a robust pharmacokinetic analysis and described relevant clinical pharmacokinetic/pharmacodynamic indices and exposure targets in cerebrospinal fluid. Robust and clinically relevant antibiotic pharmacokinetic data describing antibiotic disposition in cerebrospinal fluid are necessary. Such studies should use a standardized approach to accurately describe pharmacokinetic variability. These data should ideally be tied to clinical outcomes whereby therapeutic targets in the cerebrospinal fluid can be better defined. Altered dosing strategies, in conjunction with exploring the utility of therapeutic drug monitoring, can then be developed to optimize antibiotic exposure with the goal of improving outcomes in this difficult-to-treat patient group.
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http://dx.doi.org/10.1128/AAC.01998-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927803PMC
December 2020