Population Pharmacokinetics of Finafloxacin in Healthy Volunteers and Patients with Complicated Urinary Tract Infections

ABSTRACTFinafloxacin is a novel fluoroquinolone with increased antibacterial activity at acidic pH and reduced susceptibility to several resistance mechanisms. A phase II study revealed a good efficacy/safety profile in patients with complicated urinary tract infections (cUTIs), while the pharmacokinetics was characterized by highly variable concentration-versus-time profiles, suggesting the need for an elaborated pharmacokinetic model. Data from three clinical trials were evaluated: 127 healthy volunteers were dosed orally (n= 77) or intravenously (n= 50), and 139 patients with cUTI received finafloxacin intravenously. Plasma (2,824 samples from volunteers and 414 samples from patients) and urine (496 samples from volunteers and 135 samples patients) concentrations were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). NONMEM was used to build a population pharmacokinetic model, and pharmacokinetic/pharmacodynamic relationships were investigated via simulations and logistic regression. A two-compartment model with first-order elimination described the data best (central volume of distribution [Vc] and peripheral volume of distribution [Vp] of 47 liters [20%] and 43 liters [67%], respectively, and elimination clearance and intercompartmental clearance of 21 liters/h [54%] and 2.8 liters/h [57%], respectively [median bootstrap estimates {coefficients of variation}]).Vcincreased with body surface area, and clearance was reduced in patients (−29%). Oral absorption was described best by parallel first- and zero-order processes (bioavailability of 75%). No pharmacodynamic surrogate parameter of clinical/microbiological outcome could be identified, which depended exclusively on the MIC of the causative pathogens. Despite the interindividual variability, the present data set does not support covariate-based dose adjustments. Based on the favorable safety and efficacy data, the clinical relevance of the observed variability appears to be limited. (This study has been registered at ClinicalTrials.gov under identifier NCT01928433.)

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Validity of the Minimum Data Set in Identifying Urinary Tract Infections in Residents of Long-Term Care Facilities

Journal of the American Geriatrics Society ◽

10.1111/j.1532-5415.2004.52206.x ◽

2004 ◽

Vol 52 (5) ◽

pp. 707-711 ◽

Cited By ~ 23

Author(s):

Kurt B. Stevenson ◽

James W. Moore ◽

Barbara Sleeper

Keyword(s):

Urinary Tract ◽

Urinary Tract Infections ◽

Long Term Care ◽

Minimum Data Set ◽

Term Care ◽

Data Set ◽

Minimum Data ◽

Care Facilities ◽

Tract Infections

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Identifying the risk factors for catheter-associated urinary tract infections: a large cross-sectional study of six hospitals

BMJ Open ◽

10.1136/bmjopen-2018-022137 ◽

2019 ◽

Vol 9 (2) ◽

pp. e022137 ◽

Cited By ~ 21

Author(s):

Allison S Letica-Kriegel ◽

Hojjat Salmasian ◽

David K Vawdrey ◽

Brett E Youngerman ◽

Robert A Green ◽

...

Keyword(s):

Risk Factors ◽

Urinary Tract ◽

Urinary Tract Infections ◽

Large Data ◽

Time Range ◽

Healthcare Associated Infection ◽

Cross Sectional ◽

Data Set ◽

Paediatric Hospital ◽

Tract Infections

MotivationCatheter-associated urinary tract infections (CAUTI) are a common and serious healthcare-associated infection. Despite many efforts to reduce the occurrence of CAUTI, there remains a gap in the literature about CAUTI risk factors, especially pertaining to the effect of catheter dwell-time on CAUTI development and patient comorbidities.ObjectiveTo examine how the risk for CAUTI changes over time. Additionally, to assess whether time from catheter insertion to CAUTI event varied according to risk factors such as age, sex, patient type (surgical vs medical) and comorbidities.DesignRetrospective cohort study of all patients who were catheterised from 2012 to 2016, including those who did and did not develop CAUTIs. Both paediatric and adult patients were included. Indwelling urinary catheterisation is the exposure variable. The variable is interval, as all participants were exposed but for different lengths of time.SettingUrban academic health system of over 2500 beds. The system encompasses two large academic medical centres, two community hospitals and a paediatric hospital.ResultsThe study population was 47 926 patients who had 61 047 catheterisations, of which 861 (1.41%) resulted in a CAUTI. CAUTI rates were found to increase non-linearly for each additional day of catheterisation; CAUTI-free survival was 97.3% (CI: 97.1 to 97.6) at 10 days, 88.2% (CI: 86.9 to 89.5) at 30 days and 71.8% (CI: 66.3 to 77.8) at 60 days. This translated to an instantaneous HR of. 49%–1.65% in the 10–60 day time range. Paraplegia, cerebrovascular disease and female sex were found to statistically increase the chances of a CAUTI.ConclusionsUsing a very large data set, we demonstrated the incremental risk of CAUTI associated with each additional day of catheterisation, as well as the risk factors that increase the hazard for CAUTI. Special attention should be given to patients carrying these risk factors, for example, females or those with mobility issues.

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Results of a Multicenter Population Pharmacokinetic Study of Ciprofloxacin in Children with Complicated Urinary Tract Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00517-18 ◽

2018 ◽

Vol 62 (9) ◽

Cited By ~ 2

Author(s):

Kevin Meesters ◽

Robin Michelet ◽

Reiner Mauel ◽

Ann Raes ◽

Jan Van Bocxlaer ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Body Weight ◽

Urinary Tract ◽

Urinary Tract Infections ◽

Complicated Urinary Tract Infection ◽

Fat Free Mass ◽

Population Pharmacokinetic ◽

Content Type ◽

Tract Infections ◽

Significant Covariates

ABSTRACTResistance rates for ciprofloxacin, which is labeled for treating complicated urinary tract infections in children, are rapidly rising. As there is limited knowledge on developmental pharmacology of ciprofloxacin, the primary aim of this study was to develop a population pharmacokinetic model for ciprofloxacin in children treated for complicated urinary tract infections. Children to whom ciprofloxacin was prescribed, intravenous (10 to 15 mg/kg body weight every 12 h) orper os(15 to 20 mg/kg every 12 h), were enrolled. One hundred eight serum and 119 urine samples were obtained during 10 intravenous and 13 oral courses of ciprofloxacin in 22 patients (age range, 0.31 to 15.51 years). A one-compartment model best described our data. Fat-free mass and glomerular filtration rate (estimated by a formula using cystatin C and creatinine), standardized for body surface area, were significant covariates for ciprofloxacin clearance. In our population, ciprofloxacin clearance is 0.16 to 0.43 liter/h/kg of body weight, volume of distribution 0.06 to 2.88 liters/kg, and bioavailability 59.6%. All of our patients had a clinical cure of their infection. Based on target attainment simulations across doses, all children reached the pharmacodynamic target forEnterobacteriaceae, but on average only 53% did forPseudomonas aeruginosaand 3% forStaphylococcus aureus, at the 15-mg/kg oral dose. For treating urinary tract infections caused byPseudomonas aeruginosa, oral doses should be at least 20 mg/kg. Furthermore, in our population, fat-free mass and kidney function should be considered, as they prove to be significant covariates for ciprofloxacin clearance and, hence, exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT02598362.)

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Population Pharmacokinetic Analyses for BC-3781 Using Phase 2 Data from Patients with Acute Bacterial Skin and Skin Structure Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02033-13 ◽

2014 ◽

Vol 59 (1) ◽

pp. 282-288 ◽

Cited By ~ 19

Author(s):

C. M. Rubino ◽

B. Xue ◽

S. M. Bhavnani ◽

W. T. Prince ◽

Z. Ivezic-Schoenfeld ◽

...

Keyword(s):

Renal Function ◽

Body Size ◽

Phase 1 ◽

Compartment Model ◽

Volume Of Distribution ◽

Population Pharmacokinetic ◽

Phase 2 ◽

Data Set ◽

Skin Structure ◽

Population Pk

ABSTRACTBC-3781, a pleuromutilin antimicrobial agent, is being developed for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia. Data from a phase 2 study of patients with ABSSSI were used to refine a previous population pharmacokinetic (PK) model and explore potential predictors of PK variability. The previously derived population PK model based on data from three phase 1 studies was applied to sparse sampling data from a phase 2 ABSSSI study and modified as necessary. Covariate analyses were conducted to identify descriptors (e.g., body size, renal function, age) associated with interindividual variability in PK. All population PK analyses were conducted by using Monte Carlo parametric expectation maximization implemented in S-ADAPT 1.5.6. The population PK data set contained 1,167 concentrations from 129 patients; 95% of the patients had 5 or more PK samples (median, 11). The previous population PK model (three-compartment model with first-order elimination and nonlinear protein binding) provided an acceptable and unbiased fit to the data from the 129 patients. Population PK parameters were estimated with acceptable precision; individual clearance values were particularly well estimated (median individual precision of 9.15%). Graphical covariate evaluations showed no relationships between PK and age or renal function but modest relationships between body size and clearance and volume of distribution, which were not statistically significant when included in the population PK model. This population PK model will be useful for subsequent PK-pharmacodynamic analyses and simulations conducted to support phase 3 dose selection. (This study has been registered at ClinicalTrials.gov under registration no. NCT01119105.)

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Population Pharmacokinetic (PPK) Analysis of ZTI-01 (Fosfomycin for Injection) Using Data from Healthy Subjects and Patients with Complicated Urinary Tract Infections (cUTI)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.1378 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S529-S529 ◽

Cited By ~ 1

Author(s):

Michael Trang ◽

Evelyn J Ellis-Grosse ◽

Paul B Eckburg ◽

David Skarinsky ◽

Sujata M Bhavnani ◽

...

Keyword(s):

Urinary Tract ◽

Urinary Tract Infections ◽

Healthy Subjects ◽

Population Pharmacokinetic ◽

Using Data ◽

Tract Infections

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Population Pharmacokinetic Modeling of Itraconazole and Hydroxyitraconazole for Oral SUBA-Itraconazole and Sporanox Capsule Formulations in Healthy Subjects in Fed and Fasted States

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00973-15 ◽

2015 ◽

Vol 59 (9) ◽

pp. 5681-5696 ◽

Cited By ~ 32

Author(s):

Ahmad Y. Abuhelwa ◽

David J. R. Foster ◽

Stuart Mudge ◽

David Hayes ◽

Richard N. Upton

Keyword(s):

Single Dose ◽

Healthy Subjects ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Oral Absorption ◽

Compartment Model ◽

Time Dependent ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Size Estimation

ABSTRACTItraconazole is an orally active antifungal agent that has complex and highly variable absorption kinetics that is highly affected by food. This study aimed to develop a population pharmacokinetic model for itraconazole and the active metabolite hydroxyitraconazole, in particular, quantifying the effects of food and formulation on oral absorption. Plasma pharmacokinetic data were collected from seven phase I crossover trials comparing the SUBA-itraconazole and Sporanox formulations of itraconazole. First, a model of single-dose itraconazole data was developed, which was then extended to the multidose data. Covariate effects on itraconazole were then examined before extending the model to describe hydroxyitraconazole. The final itraconazole model was a 2-compartment model with oral absorption described by 4-transit compartments. Multidose kinetics was described by total effective daily dose- and time-dependent changes in clearance and bioavailability. Hydroxyitraconazole was best described by a 1-compartment model with mixed first-order and Michaelis-Menten elimination for the single-dose data and a time-dependent clearance for the multidose data. The relative bioavailability of SUBA-itraconazole compared to that of Sporanox was 173% and was 21% less variable between subjects. Food resulted in a 27% reduction in bioavailability and 58% reduction in the transit absorption rate constant compared to that with the fasted state, irrespective of the formulation. This analysis presents the most extensive population pharmacokinetic model of itraconazole and hydroxyitraconazole in the literature performed in healthy subjects. The presented model can be used for simulating food effects on itraconazole exposure and for performing prestudy power analysis and sample size estimation, which are important aspects of clinical trial design of bioequivalence studies.

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A clinical prediction tool for extended-spectrum β-lactamase-producing Enterobacteriaceae urinary tract infection

BMC Infectious Diseases ◽

10.1186/s12879-022-07040-y ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Hui Liu ◽

Suishan Qiu ◽

Minghao Chen ◽

Jun Lyu ◽

Guangchao Yu ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Urinary Tract ◽

Urinary Tract Infections ◽

Clinical Decision Making ◽

Susceptibility Testing ◽

Empirical Treatment ◽

Data Set ◽

Extended Spectrum ◽

Tract Infections

Abstract Background Prevalence of extended-spectrum beta-lactamase-producing-Enterobacteriaceae (ESBL-E) has risen in patients with urinary tract infections. The objective of this study was to determine explore the risk factors of ESBL-E infection in hospitalized patients and establish a predictive model. Methods This retrospective study included all patients with an Enterobacteriaceae-positive urine sample at the first affiliated hospital of Jinan university from January 2018 to December 2019. Antimicrobial susceptibility patterns of ESBL-E were analyzed, and multivariate analysis of related factors was performed. From these, a nomogram was established to predict the possibility of ESBL-E infection. Simultaneously, susceptibility testing of a broad array of carbapenem antibiotics was performed on ESBL-E cultures to explore possible alternative treatment options. Results Of the total 874 patients with urinary tract infections (UTIs), 272 (31.1%) were ESBL-E positive. In the predictive analysis, five variables were identified as independent risk factors for ESBL-E infection: male gender (OR = 1.607, 95% CI 1.066–2.416), older age (OR = 4.100, 95% CI 1.678–12.343), a hospital stay in preceding 3 months (OR = 1.872, 95% CI 1.141–3.067), invasive urological procedure (OR = 1.810, 95% CI 1.197–2.729), and antibiotic use within the previous 3 months (OR = 1.833, 95% CI 1.055–3.188). In multivariate analysis, the data set was divided into a training set of 611 patients and a validation set of 263 patients The model developed to predict ESBL-E infection was effective, with the AuROC of 0.650 (95% CI 0.577–0.725). Among the antibiotics tested, several showed very high effectiveness against ESBL-E: amikacin (85.7%), carbapenems (83.8%), tigecycline (97.1%) and polymyxin (98.2%). Conclusions The nomogram is useful for estimating a UTI patient’s likelihood of infection with ESBL-E. It could improve clinical decision making and enable more efficient empirical treatment. Empirical treatment may be informed by the results of the antibiotic susceptibility testing.

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