Papers by Cornelia Landersdorfer
Journal of Antimicrobial Chemotherapy, 2021
Antimicrobial agents and chemotherapy, 2017
We previously optimized imipenem and tobramycin combination regimens against a double-resistant c... more We previously optimized imipenem and tobramycin combination regimens against a double-resistant clinical isolate by using infection models, mechanism-based pharmacokinetic/pharmacodynamic modeling (MBM), and Monte Carlo simulations. The current study aimed to evaluate these regimens in a neutropenic murine thigh infection model and to characterize the time course of bacterial killing and regrowth via MBM. We studied monotherapies and combinations of imipenem with tobramycin against the double-resistant clinical isolate by using humanized dosing schemes. Viable count profiles of total and resistant populations were quantified over 24 h. Tobramycin monotherapy (7 mg/kg every 24 h [q24h] as a 0.5-h infusion) was ineffective. Imipenem monotherapies (continuous infusion of 4 or 5 g/day with a 1-g loading dose) yielded 2.47 or 2.57 log CFU/thigh killing at 6 h. At 24 h, imipenem at 4 g/day led to regrowth up to the initial inoculum (4.79 ± 0.26 log CFU/thigh), whereas imipenem at 5 g/day ...
Antimicrobial Agents and Chemotherapy
Hypermutable Pseudomonas aeruginosa isolates (hypermutators) have been identified in patients wit... more Hypermutable Pseudomonas aeruginosa isolates (hypermutators) have been identified in patients with cystic fibrosis (CF). Hypermutators display a greatly increased mutation rate, an enhanced ability to become resistant to antibiotics during treatment and are associated with reduced lung function in patients. Their prevalence has been established amongst patients with CF, but has not been determined for patients with CF in Australia. This study aimed to determine the prevalence of hypermutable P. aeruginosa isolates from adult patients with CF from a healthcare institution in Australia, and to characterize the genetic diversity and antibiotic susceptibility of these isolates. A total of 59 P. aeruginosa clinical isolates from patients with CF were characterized. For all isolates, rifampicin mutation frequencies and susceptibility to a range of antibiotics were determined. Of the 59 isolates, 13 (22%) were hypermutable. Whole genome sequences were determined for all hypermutable isolat...
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, Jan 7, 2017
Fimasartan is a novel angiotensin II receptor blocker. Our aims were to characterize the time-cou... more Fimasartan is a novel angiotensin II receptor blocker. Our aims were to characterize the time-course of the antihypertensive activity of fimasartan via a new population pharmacokinetic/pharmacodynamic model and to define its optimal dose range. We simultaneously modelled all fimasartan plasma concentrations and 24-h ambulatory blood pressure monitoring (ABPM) data from 39 patients with essential hypertension and 56 healthy volunteers. Patients received placebo, 20, 60, or 180mg fimasartan every 24h for 28days and healthy volunteers received placebo or 20 to 480mg as a single oral dose or as seven doses every 24h. External validation was performed using data on 560 patients from four phase II or III studies. One turnover model each was used to describe diastolic and systolic blood pressure. The input rates into these compartments followed a circadian rhythm and were inhibited by fimasartan. The average predicted (observed) diastolic blood pressure over 24-h in patients decreased by 1...
Clinical pharmacokinetics, 2017
Lithium is a well-established treatment for bipolar I disorder in adults. However, there is a pau... more Lithium is a well-established treatment for bipolar I disorder in adults. However, there is a paucity of information on its pharmacokinetics/pharmacodynamics in children and adolescents. We aimed to develop the first lithium dosage regimens based on population pharmacokinetics/pharmacodynamics for paediatric patients. Lithium concentrations, Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Improvement (CGI-I) scores over 24 weeks were available from 61 paediatric patients with bipolar I disorder. The population pharmacokinetics/pharmacodynamics were co-modelled. Concentrations and clinical effects following several dosage regimens were predicted by Monte Carlo simulations. The pharmacokinetics were well characterised by a two compartment model with linear elimination. Including the effect of total body weight (TBW) or lean body weight (LBW) on clearance and volume of distribution decreased the unexplained inter-individual variability by up to 12 %. The population mean...
Antimicrobial Agents and Chemotherapy, 2016
Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in ... more Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large-animal model with pulmonary architecture similar to that of humans. Six merino sheep (34 to 43 kg body weight) received an intravenous or pulmonary dose of 4 to 8 mg/kg CMS (sodium) or 2 to 3 mg/kg colistin (sulfate) in a 4-way crossover study. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) samples by high-performance liquid chromatography (HPLC). ELF concentrations were calculated via the urea method. CMS and colistin were comodeled in S-ADAPT. Following intravenous CMS or colistin administration, no concentrations were quantifiable in BALF samples. Elimi...
Data Revues 00916749 V131i2ss S009167491203062x, Jan 26, 2013
RATIONALE: Immunotherapy can induce immunological changes that can result in long-term remission ... more RATIONALE: Immunotherapy can induce immunological changes that can result in long-term remission of symptoms after treatment discontinuation. The loss of skin test reactivity may be a marker for successful desensitization. We have evaluated the relationship between cumulative allergen doses and the loss of skin test reactivity with a retrospective review of our records. METHODS: Records were reviewed from sequential immunotherapy started in 2008; selecting those who had undergone repeat skin testing between 12-24 month on maintenance dosing. Mixing of skin prick positive allergens targeted the Joint Task Force immunotherapy practice parameter-recommended ''optimal'' dosing ranges for most major allergens. Recommended maintenance dosing frequency was 0.5cc bimonthly, but varied. RESULTS: 77 patients received subcutaneous immunotherapy containing, on average, 19 allergens per patient There was no significant difference in allergen number between groups (p50.73). Serial skin testing changes were compared between those who had received monthly immunotherapy > 0.49cc (group 1) and 0.1-0.49cc (group 2). Groups 1 & 2 received maintenance immunotherapy for a similar average of 16.8 and 16.7 months respectively (p50.76). There was a significant 15.7% difference in mean loss of skin test reactivity between groups (p50.015). A greater than 50% loss of reactivity was seen in 59% of group 1 and 17.6% of group 2. The average administered volumes for groups 1 & 2 were 0.84cc/mo. and 0.35cc/mo. respectively. CONCLUSIONS: Multi-allergen immunotherapy, targeting JTF-recommended ''optimal'' dosing recommendations, commonly results in the loss of skin test reactivity. Cumulative allergen doses of only 2-3 fold lower than recommended often failed to induce skin test sensitivity loss.
Clinical Pharmacokinetics, May 5, 2015
Current Opinion in Microbiology, 2013
There is an urgent need for novel antibiotics to treat life-threatening infections caused by bact... more There is an urgent need for novel antibiotics to treat life-threatening infections caused by bacterial 'superbugs'. Validated in vitro pharmacokinetic/pharmacodynamic (PK/PD) and animal infection models have been employed to identify the most predictive PK/PD indices and serve as key tools in the antibiotic development process. The results obtained can be utilized for optimizing study designs in order to minimize the cost and duration of clinical trials. This review outlines the key in vitro PK/PD and animal infection models which have been extensively used in antibiotic discovery and development. These models have shown great potential in accelerating drug development programs and will continue to make significant contributions to antibiotic development.
Current Opinion in Infectious Diseases, 2012
Purpose of review-Increased emergence of bacterial resistance and the decline in newly developed ... more Purpose of review-Increased emergence of bacterial resistance and the decline in newly developed antibiotics have necessitated the reintroduction of previously abandoned antimicrobial agents active against multidrug-resistant bacteria. Having never been subjected to contemporary drug development procedures, these 'old' antibiotics require redevelopment in order to optimize therapy. This review focuses on colistin as an exemplar of a successful redevelopment process and briefly discusses two other old antibiotics, fusidic acid and fosfomycin. Recent findings-Redevelopment of colistin led to an improved understanding of its chemistry, pharmacokinetics and pharmacodynamics, enabling important steps towards optimizing its clinical use in different patient populations. A scientifically based dosing algorithm was developed for critically ill patients, including those with renal impairment. As nephrotoxicity is a dose-limiting adverse event of colistin, rational combination therapy with other antibiotics needs to be investigated. Summary-The example of colistin demonstrated that state-of-the-art analytical, microbiological and pharmacokinetic/pharmacodynamic methods can facilitate optimized use of 'old' antibiotics in the clinic. Similar methods are now being applied to fosfomycin and fusidic acid in order to optimize therapy. To improve and preserve the usefulness of these antibiotics rational approaches for redevelopment need to be followed.
Clinical Pharmacokinetics, 2009
Chemotherapy, 2002
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Chemotherapy, 2011
availability of ciprofloxacin by 12% and achieved significantly (p ! 0.05) higher concentrations ... more availability of ciprofloxacin by 12% and achieved significantly (p ! 0.05) higher concentrations at 3 h in ejaculate, prostatic, seminal, and vaginal fluid compared to ciprofloxacin. Conclusion: Modeling suggested that ciprofloxacin inhibited the tubular reabsorption of levofloxacin due to a 12-fold higher affinity for a putative tubular reabsorption transporter compared to levofloxacin. This pharmacokinetic interaction was not clinically relevant.
Antimicrobial Agents and Chemotherapy, 2009
Probenecid interacts with transport processes of drugs at several sites in the body. For most qui... more Probenecid interacts with transport processes of drugs at several sites in the body. For most quinolones, renal clearance is reduced by concomitant administration of probenecid. The interaction between gemifloxacin and probenecid has not yet been studied. We studied the extent, time course, site(s), and mechanism of this interaction. Seventeen healthy volunteers participated in a randomized, two-way crossover study. Subjects received 320 mg gemifloxacin as an oral tablet without and with 4.5 g probenecid divided in eight oral doses. Drug concentrations in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry. WinNonlin was used for noncompartmental analysis, compartmental modeling, and statistics, and NONMEM was used for visual predictive checks. Concomitant administration of probenecid increased plasma gemifloxacin concentrations and amounts excreted in urine compared to baseline amounts. Data are average estimates (percent coefficients of variation). Modeling showed a competitive inhibition of the renal tubular secretion of gemifloxacin by probenecid as the most likely mechanism of the interaction. The estimated K m and V max for the saturable part of renal elimination were 9.16 mg/liter (20%) and 113 mg/h (21%), respectively. Based on the molar ratio, the affinity for the renal transporter was 10-fold higher for gemifloxacin than for probenecid. Since probenecid reached an ϳ200-times-higher area under the molar concentration-time curve from 0 to 24 h than gemifloxacin, probenecid inhibited the active tubular secretion of gemifloxacin. Probenecid also reduced the nonrenal clearance of gemifloxacin from 25.2 (26%) to 21.0 (23%) liters/h. Probenecid inhibited the renal tubular secretion of gemifloxacin, most likely by a competitive mechanism, and slightly decreased nonrenal clearance of gemifloxacin.
Antimicrobial Agents and Chemotherapy, 2009
Moxifloxacin is a fluoroquinolone with a broad spectrum of activity and good penetration into man... more Moxifloxacin is a fluoroquinolone with a broad spectrum of activity and good penetration into many tissues, including bone. Penetration of moxifloxacin into bone has not yet been studied using compartmental modeling techniques. Therefore, we determined the rate and extent of bone penetration by moxifloxacin and evaluated its pharmacodynamic profile in bone via Monte Carlo simulation. Twenty-four patients (10 males, 14 females) undergoing total hip replacement received 400 mg moxifloxacin orally 2 to 7 h prior to surgery. Blood and bone specimens were collected. Bone samples were pulverized under liquid nitrogen by a cryogenic mill, including an internal standard. Drug concentrations were analyzed by high-performance liquid chromatography. We used ADAPT II (results reported), NONMEM, and WinBUGS for pharmacokinetic analysis. Monte Carlo simulation was performed to reverse engineer the necessary area under the free concentration-time curve fAUCSERUM/MIC in serum and total AUCBONE/MIC ...
The AAPS Journal, 2011
Mechanistic modeling greatly benefits from automated pre-and post-processing of model code and mo... more Mechanistic modeling greatly benefits from automated pre-and post-processing of model code and modeling results. While S-ADAPT provides many state-of-the-art parametric population estimation methods, its pre-and post-processing capabilities are limited. Our objective was to develop a fully automated, open-source pre-and post-processor for nonlinear mixed-effects modeling in S-ADAPT. We developed a new translator tool (SADAPT-TRAN) based on Perl scripts. These scripts (a) automatically translate the core model components into robust Fortran code, (b) perform extensive mutual error checks across all input files and the raw dataset, (c) extend the options of the Monte Carlo Parametric Expectation Maximization (MC-PEM) algorithm, and (d) improve the numerical robustness of the model code. The post-processing scripts automatically summarize the results of one or multiple models as tables and, by generating problem specific R scripts, provide an extended series of standard and covariatestratified diagnostic plots. The SADAPT-TRAN package substantially improved the efficiency to specify, debug, and evaluate models and enhanced the flexibility of using the MC-PEM algorithm for parallelized estimation in S-ADAPT. The parameter variability model can take any combination of normally, lognormally, or logistically distributed parameters and the SADAPT-TRAN package can automatically generate the Fortran code required to specify between occasion variability. Extended estimation features are available to avoid local minima, estimate means with negligible variances, and estimate variances for fixed means. The SADAPT-TRAN package significantly facilitated model development in S-ADAPT, reduced model specification errors, and provided useful error messages for beginner and advanced users. This benefit was greatest for complex mechanistic models.
Journal of Materials Chemistry B
This report details the synthesis of lipidated 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers v... more This report details the synthesis of lipidated 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers via an optimised Cu(0)-mediated reversible-deactivation radical polymerisation approach, and the use of these oligomers as a versatile functional platform for...
Pharmaceutics
Hypermutable Pseudomonas aeruginosa strains have a greatly increased mutation rate and are preval... more Hypermutable Pseudomonas aeruginosa strains have a greatly increased mutation rate and are prevalent in chronic respiratory infections. Initially, we systematically evaluated the time-course of total and resistant populations of hypermutable (PAO∆mutS) and non-hypermutable (PAO1) P. aeruginosa strains in 48-h static concentration time-kill studies with two inocula. Both strains were exposed to clinically relevant concentrations of important antibiotics (aztreonam, ceftazidime, imipenem, meropenem, tobramycin, and ciprofloxacin) in monotherapy. The combination of tobramycin and ciprofloxacin was subsequently assessed in 48-h static concentration time-kill studies against PAO1, PAO∆mutS, and two hypermutable clinical P. aeruginosa strains. Mechanism-based mathematical modelling was conducted to describe the time-course of total and resistant bacteria for all four strains exposed to the combination. With all monotherapies, bacterial regrowth and resistant populations were overall more ...
Pharmaceutics
The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ consid... more The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound β-lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for β-lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 ± 5.4kg) and six healthy volunteers (LBM: 53.1 ± 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and compositi...
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Papers by Cornelia Landersdorfer