Sustained co-release of ciprofloxacin and dexamethasone in rabbit maxillary sinus using polyvinyl alcohol-based hydrogel microparticle.

Topical delivery to paranasal sinuses through sustained-release stents is one of the new horizons in treating chronic rhinosinusitis (CRS). This study aims to introduce and evaluate sustained co-release of encapsulated ciprofloxacin (CIP) and dexamethasone (DEX) in polyvinyl alcohol-based carriers within the maxillary sinus of rabbit animals. DEX and CIP were loaded in a tyramine-substituted polyvinyl alcohol microparticle (PVATyr MP). The mechanical stability, degradability, and sustained-release patterns of both drugs as well as cellular cytocompatibility were assessed in vitro. The PVATyr MPs were then injected into the maxillary sinus of rabbits and they were monitored weekly for 21 days. Nasal endoscopy, MRI imaging, and tissue microscopy were used to follow the changes and compared them with the control condition. Also, the concentrations of drugs were evaluated in the maxillary sinus and blood samples over the study period. Produced PVA-based MPs possessed a relatively narrow particle size distribution (CV 7.7%) with proper physical stability until 30 days of incubation. The uniform-sized PVATyr MPs and their surrounding hydrogel showed sustained-release profiles for DEX and CIP for up to 32 days in vitro. The injected drugs-loaded hydrogel showed complete clearance from the maxillary sinus of rabbits within 28 days. The concentrations of DEX and CIP in mucosal remained within the therapeutic window when measured on days 7, 14, and 21, which were well above the plasma concentrations without any pathological changes in endoscopy, MRI imaging, and histological examinations. DEX/CIP loaded PVATyr MPs provided an effective, controlled, and safe sustained-drug delivery in both in vitro and in vivo analyses at therapeutic concentrations with minimal systemic absorption, suggesting a promising treatment approach for CRS.

Enrofloxacin pharmacokinetics in yellow catfish (Pelteobagrus fulvidraco): A comparative analysis of oral, intramuscular, and bath administration.

Enrofloxacin (ENR) residues in yellow catfish (Pelteobagrus fulvidraco) often exceed the standard due to excessive use. This study explored the pharmacokinetics of ENR and its metabolite ciprofloxacin (CIP) in yellow catfish following a single dose of 10 mg/kg body weight via intramuscular injection (IM), oral gavage (PO), or a 5-h drug bath at 10 mg/L and 25°C. High-performance liquid chromatography-mass spectrometry was used to determine the ENR and CIP concentrations in various tissues. The highest ENR concentration occurred with IM administration, peaking at 4.124 mg/L in the plasma, 8.359 mg/kg in the kidney, 6.272 mg/kg in the liver, and 5.192 mg/kg in the muscle. However, PO administration resulted in the longest metabolic time, with elimination half-lives of 56.47 h in plasma, 86.43 h in the kidney, 76.25 h in the liver, and 64.75 h in muscle. Additionally, the area under the concentration-time curve values for IM, PO, and bath administration in yellow catfish plasma were 108.36, 88.96, and 22.08 mg·h/L, respectively. These results indicate the effectiveness of all three administration methods in treating bacterial diseases in yellow catfish. The selection of an appropriate administration method depends on the minimal inhibitory concentration of ENR against pathogenic bacteria. Yellow catfish subjected to PO and IM administration require longer resting periods before they can be marketed than those receiving drug bath administration.

Positron Emission Tomography-Based Pharmacokinetic Analysis To Assess Renal Transporter-Mediated Drug-Drug Interactions of Antimicrobial Drugs.

Transporter-mediated drug-drug interactions (DDIs) are of concern in antimicrobial drug development, as they can have serious safety consequences. We used positron emission tomography (PET) imaging-based pharmacokinetic (PK) analysis to assess the effect of different drugs, which may cause transporter-mediated DDIs, on the tissue distribution and excretion of [18F]ciprofloxacin as a radiolabeled model antimicrobial drug. Mice underwent PET scans after intravenous injection of [18F]ciprofloxacin, without and with pretreatment with either probenecid (150 mg/kg), cimetidine (50 mg/kg), or pyrimethamine (5 mg/kg). A 3-compartment kidney PK model was used to assess the involvement of renal transporters in the examined DDIs. Pretreatment with probenecid and cimetidine significantly decreased the renal clearance (CLrenal) of [18F]ciprofloxacin. The effect of cimetidine (-86%) was greater than that of probenecid (-63%), which contrasted with previously published clinical data. The kidney PK model revealed that the decrease in CLrenal was caused by inhibition of basal uptake transporters and apical efflux transporters in kidney proximal tubule cells. Changes in the urinary excretion of [18F]ciprofloxacin after pretreatment with probenecid and cimetidine resulted in increased blood and organ exposure to [18F]ciprofloxacin. Our results suggest that multiple membrane transporters mediate the tubular secretion of ciprofloxacin, with possible species differences between mice and humans. Concomitant medication inhibiting renal transporters may precipitate DDIs, leading to decreased urinary excretion and increased blood and organ exposure to ciprofloxacin, potentially exacerbating adverse effects. Our study highlights the strength of PET imaging-based PK analysis to assess transporter-mediated DDIs at a whole-body level.

Physiologically based pharmacokinetic model to predict drug concentrations of breast cancer resistance protein substrates in milk.

Many mothers need to take some medications during breastfeeding, which may carry a risk to breastfed infants. Thus, determining the amount of a drug transferred into breast milk is critical for risk-benefit analysis of breastfeeding. Breast cancer resistance protein (BCRP), an efflux transporter which usually protects the body from environmental and dietary toxins, was reported to be highly expressed in lactating mammary glands. In this study, we developed a mechanistic lactation physiologically based pharmacokinetic (PBPK) modeling approach incorporating BCRP mediated transport kinetics to simulate the concentration-time profiles of five BCRP drug substrates (acyclovir, bupropion, cimetidine, ciprofloxacin, and nitrofurantoin) in nursing women's plasma and milk. Due to the lack of certain physiological parameters and scaling factors in nursing women, we combine the bottom up and top down PBPK modeling approaches together with literature reported data to optimize and determine a set of parameters that are applicable for all five drugs. The predictive performance of the PBPK models was assessed by comparing predicted pharmacokinetic profiles and the milk-to-plasma (M/P) ratio with clinically reported data. The predicted M/P ratios for acyclovir, bupropion, cimetidine, ciprofloxacin, and nitrofurantoin were 2.48, 3.70, 3.55, 1.21, and 5.78, which were all within 1.5-fold of the observed values. These PBPK models are useful to predict the PK profiles of those five drugs in the milk for different dosing regimens. Furthermore, the approach proposed in this study will be applicable to predict pharmacokinetics of other transporter substrates in the milk.

Investigating the Impact of Crohn's Disease on the Bioaccessibility of a Lipid-Based Formulation with an In Vitro Dynamic Gastrointestinal Model.

The aim of the study was to investigate the impact of Crohn's disease (CD) on the performance of a lipid-based formulation of ciprofloxacin in a complex gastrointestinal simulator (TIM-1, TNO) and to compare the luminal environment in terms of bile salt and lipid composition in CD and healthy conditions. CD conditions were simulated in the TIM-1 system with a reduced concentration of porcine pancreatin and porcine bile. The bioaccessibility of ciprofloxacin was similar in simulated CD and healthy conditions considering its extent as well as its time course in the jejunum and ileum filtrate. Differences were observed in terms of the luminal concentration of triglycerides, monoglycerides, and fatty acids in the different TIM-1 compartments, indicating a reduction and delay in the lipolysis of formulation excipients in CD. The quantitative analysis of bile salts revealed higher concentrations for healthy conditions (standard TIM-1 fasted-state protocol) in the duodenum and jejunum TIM-1 compartments compared to published data in human intestinal fluids of healthy subjects. The reduced concentrations of bile salts in simulated CD conditions correspond to the levels observed in human intestinal fluids of healthy subjects in the fasted state.A lipidomics approach with ultra performance liquid chromatography (UPLC)/mass spectrometry (MS) has proven to be a time-efficient method to semiquantitatively analyze differences in fatty acid and bile salt levels between healthy and CD conditions. The dynamic luminal environment in CD and healthy conditions after administration of a lipid-based formulation can be simulated using the TIM-1 system. For ciprofloxacin, an altered luminal lipid composition had no impact on its performance indicating a low risk of altered performance in CD patients.

Therapeutic concentration of ciprofloxacin and transfer across the human term placenta.

BACKGROUND: Pregnant women have an increased risk of infections, and early and decisive treatment is preferred to prevent complications. Although ciprofloxacin is very commonly used, safety aspects of maternal treatment during pregnancy are limited, and avoidance of its use during late pregnancy is recommended. OBJECTIVE: The aim is to estimate maternal-to-fetal transfer clearance of ciprofloxacin at a therapeutic concentration and to determine fetal exposure to maternally administered ciprofloxacin. STUDY DESIGN: Transplacental pharmacokinetics were determined with an ex vivo placental model, which is a reliable experimental model for estimating fetal drug exposure. Human placentas from uncomplicated term pregnancies were collected after delivery and a suitable cotyledon was cannulated. Ciprofloxacin was added at a therapeutic concentration (1.6 µg/mL) to the maternal compartment, and antipyrine was included as a reference drug (10.0 µg/mL). Samples were collected from the maternal and fetal compartment at 12 time points (-2 to 180 minutes), and the integrity and metabolic parameters were measured consecutively. Drug concentrations were determined using ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: A total of 5 human placentas from healthy term pregnancies were collected after delivery and cannulated with success. Ciprofloxacin crossed the placenta; its mean concentration in the fetal compartment was 0.3 µg/mL, accounting for 22% (0.29/1.30; range, 15%-31%) of the maternal concentration after 3 hours. The fetal/maternal ciprofloxacin concentration ratio increased gradually over time and reached 0.53. The transfer clearance for ciprofloxacin was 0.28 mL/min (range, 0.21-0.41 mL/min) during the first hour and 0.21 mL/min (range, 0.14-0.26 mL/min) during the following 2 hours. After end perfusion, the mean tissue concentration and proportion of ciprofloxacin were 0.7 µg/g and 11% (14/130; range, 7%-14%), respectively. CONCLUSION: Ciprofloxacin crossed the placenta at a slow, constant rate, indicating moderate fetal exposure. This study verifies an accumulation of ciprofloxacin in the placenta that may lengthen the duration of fetal exposure. These results are an essential element of fetal risk assessment, but further studies are needed to estimate fetal safety.

Coadministration of tizanidine and ciprofloxacin: a retrospective analysis of the WHO pharmacovigilance database.

PURPOSE: Tizanidine, an alpha-adrenergic substance with antinociceptive and antihypertensive effects, is extensively metabolized via cytochrome P450 (CYP) 1A2. Therefore, coadministration with potent CYP1A2 inhibitors, such as ciprofloxacin, is contraindicated. However, both drugs are broadly utilized in various countries. Their concomitant use bears an inherent high risk for clinically significant symptoms, especially in multimorbid patients experiencing polypharmacy. This study aims to investigate the impact of coadministration of tizanidine and ciprofloxacin using real-world pharmacovigilance data and to raise awareness of this potentially underestimated safety issue. METHODS: We conducted a retrospective study including Individual Case Safety Reports (ICSR) registered until March 1, 2017, in the World Health Organization (WHO) global database. Demographic data, drug administration information, the course of the adverse drug reaction (ADR), its severity, and outcomes were analyzed for cases reporting ciprofloxacin comedication. RESULTS: In 91 (2.0%) of the identified 4192 worldwide ICSR on tizanidine, coadministration of ciprofloxacin was reported. Most of the patients were female (n = 59, 64.8%) with a median age of 54 years (range 13-85 years). The countries contributing most reports were the USA (n = 54, 59.3%) and Switzerland (n = 16, 17.6%). ADRs reported most often affected the nervous system and the cardiac function, especially with large tizanidine doses or drugs with CNS and cardiovascular depressant effects. In two cases, a fatal outcome was reported. CONCLUSION: Despite the existing formal contraindication, the concomitant use of tizanidine and ciprofloxacin can be observed in real-world clinical practice. Reactions mainly affected the central nervous and the cardiovascular system resulting in potentially severe adverse effects. The concomitant use of tizanidine and ciprofloxacin should absolutely be avoided.

Population pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing regimens.

PURPOSE: This study aimed to characterize pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing scheme. METHODS: Children treated with ciprofloxacin were included. Pharmacokinetics were described using non-linear mixed-effect modelling and validated with an external dataset. Monte Carlo simulations investigated dosing regimens to achieve a target AUC0-24 h/MIC ratio ≥ 125. RESULTS: A total of 189 children (492 concentrations) were included. A two-compartment model with first-order absorption and elimination best described the data. An allometric model was used to describe bodyweight (BW) influence, and effects of estimated glomerular filtration rate (eGFR) and age were significant on ciprofloxacin clearance. CONCLUSION: The recommended IV dose of 10 mg/kg q8h, not exceeding 400 mg q8h, would achieve AUC0-24 h to successfully treat bacteria with MICs ≤ 0.25 (e.g. Salmonella, Escherichia coli, Proteus, Haemophilus, Enterobacter, and Klebsiella). A dose increase to 600 mg q8h in children > 40 kg and to 15 mg/kg q8h (max 400 mg q8h, max 600 mg q8h if augmented renal clearance, i.e., eGFR > 200 mL/min/1.73 m2) in children < 40 kg would be needed for the strains with highest MIC (16% of Pseudomonas aeruginosa and 47% of Staphylococcus aureus). The oral recommended dose of 20 mg/kg q12h (not exceeding 750 mg) would cover bacteria with MICs ≤ 0.125 but may be insufficient for bacteria with higher MIC and a dose increase according bodyweight and eGFR would be needed. These doses should be prospectively confirmed, and a therapeutic drug monitoring could be used to refine them individually.

Adsorption of vancomycin, gentamycin, ciprofloxacin and tygecycline on the filters in continuous renal replacement therapy circuits: in full blood in vitro study.

The aim of this study was to assess the in vitro adsorption of antibiotics: vancomycin, gentamicin, ciprofloxacin and tigecycline on both polyethyleneimine-treated polyacrylonitrile membrane of AN69ST filter and polysulfone membrane of AV1000 filter using porcine blood as a model close to in vivo conditions. The porcine blood with antibiotic dissolved in it was pumped into hemofiltration circuit (with AN69ST or AV1000 filter), ultrafiltration fluid was continuously returned to the reservoir containing blood with antibiotic. Blood samples to determine antibiotic concentrations were taken at minutes 0, 5, 15, 30, 45, 60, 90 and 120 from the pre- blood pump of the hemofiltration circuit. To assess possible spontaneous degradation of the drug in the solution there was an additional reservoir prepared for each antibiotic, containing blood with the drug, which was not connected to the circuit. In the case of vancomycin, ciprofloxacine and tigecycline, a statistically significant decrease in the drug concentration in the hemofiltration circuit in comparison to initial value as well as to the concentrations in the control blood was observed, both for polyacrylonitrile and plolysulfone membrane. In the case of gentamicin, significant adsorption was noted only on polyacrylonitrile membrane. Our studies demonstrated that in full blood adsorption of antibiotics may be big enough to be of clinical significance. In particular in the case of polyacrylonitrile membrane.

[Ciprofloxacin: pharmacokinetics and a potential for therapeutic monitoring].

Ciprofloxacin is a broad-spectrum bactericidal antibiotic with a concentration-dependent antimicrobial effect. Ciprofloxacin penetrates well into tissues, providing good efficacy against many Gram-negative microorganisms. Due to its good antibacterial efficacy and tolerability, it is often used in the treatment of critically ill. However, high interindividual variability in pharmacokinetics is reported in this population, especially in volume of distribution, clearance, and elimination half-life. Interindividual variability across patient groups results in difficult achievement of the therapeutic goal, mostly described as AUC/MIC ≥ 125. The usual dosing is 400 mg after 8-12 hours intravenously for one hour. In critically ill patients, the lower dose proved to be insufficient. In these patients, doses of at least 1 200 mg/day are required. An initial dose of 800 mg increases the probability of achieving the therapeutic goal by 35-45 %. Although many authors mention the possibility of using therapeutic drug monitoring to achieve the therapeutic goal, there are only few trials describing its benefits.

Modification and validation of liquid chromatographic method for the quantification of ciprofloxacin in human plasma and its application to a bioavailability study.

A new simple, accurate, precise and sensitive liquid chromatographic method for the analysis of Ciprofloxacin in human plasma, suitable for quantification of drug was developed and validated using HPLC-UV method. The analyte was chromatographically separated from endogenous plasma components on a C-18 reversed phase column (5µm, 25cm × 0.46cm) and detected at 278nm. The sample pretreatment was carried out with acetonitrile on 200µl of plasma. The Lower limit of quantification (LLOQ) was 0.04 µg/ml with linearity in the range 0.04-4 µg/ml and coefficient of correlation value (R2)>0.995. The method was successfully validated as per current FDA guidance for necessary parameters and applied to a pilot bioavailability study conducted on six healthy volunteers with marketed Ciprofloxacin 250mg immediate release tablets. The plasma concentrations were subjected to non-compartmental analysis for calculation of pharmacokinetic parameters like Cmax, Tmax, AUCo-t, AUC 0-∞ and t½ etc. The mean values of Cmax and Tmax were found to be 1.35±0.09µg/ml and 1.25±0.27h respectively while for other pharmacokinetic parameters including AUCo-t, AUC0-∞ were found to be 5.98±0.96 µg/ml×h and 6.34±1.07µg/ml×h. The drug exhibited half-life (t½) of 3.94±0.33h. The obtained results proved the suitability of the method for routine pharmacokinetic studies of Ciprofloxacin.

The Impact of Breast Cancer Resistance Protein (BCRP/ABCG2) on Drug Transport Across Caco-2 Cell Monolayers.

Breast cancer resistance protein (BCRP) is expressed on the apical membrane of small intestinal epithelial cells and functions as an efflux pump with broad substrate recognition. Therefore, quantitative evaluation of the contribution of BCRP to the intestinal permeability of new chemical entities is very important in drug research and development. In this study, we assessed the BCRP-mediated efflux of several model drugs in Caco-2 cells using WK-X-34 as a dual inhibitor of P-glycoprotein (P-gp) and BCRP and LY335979 as a selective inhibitor of P-gp. The permeability of daidzein was high with an apparent permeability coefficient for apical-to-basal transport (P AB) of 20.3 × 10-6 cm/s. In addition, its efflux ratio (ER) was 1.55, indicating that the contribution of BCRP to its transport is minimal. Estrone-3-sulfate and ciprofloxacin showed relatively higher ER values (>2.0), whereas their BCRP-related absorptive quotient (AQ BCRP) was 0.21 and 0.3, respectively. These results indicate that BCRP does not play a major role in regulating the permeability of estrone-3-sulfate and ciprofloxacin in Caco-2 cells. Nitrofurantoin showed a P AB of 1.8 × 10-6 cm/s, and its ER was 7.6. However, the AQ BCRP was 0.37, suggesting minimal contribution of BCRP to nitrofurantoin transport in Caco-2 cells. In contrast, topotecan, SN-38, and sulfasalazine had low P AB values (0.81, 1.13, and 0.19 × 10-6 cm/s, respectively), and each AQ BCRP was above 0.6, indicating that BCRP significantly contributes to the transport of these compounds in Caco-2 cells. In conclusion, Caco-2 cells are useful to accurately estimate the contribution of BCRP to intestinal drug absorption. SIGNIFICANCE STATEMENT: We performed an in vitro assessment of the contribution of breast cancer resistance protein (BCRP) to the transport of BCRP and/or P-glycoprotein (P-gp) substrates across Caco-2 cell monolayers using absorptive quotient, which has been proposed to represent the contribution of drug efflux transporters to the net efflux. The present study demonstrates that the combined use of a BCRP/P-gp dual inhibitor and a P-gp selective inhibitor is useful to estimate the impact of BCRP and P-gp on the permeability of tested compounds in Caco-2 cells.

Population pharmacokinetics and target attainment of ciprofloxacin in critically ill patients.

PURPOSE: To develop and validate a population pharmacokinetic model of ciprofloxacin intravenously in critically ill patients, and determine target attainment to provide guidance for more effective regimens. METHODS: Non-linear mixed-effects modelling was used for the model development and covariate analysis. Target attainment of an ƒAUC0-24/MIC ≥ 100 for different MICs was calculated for standard dosing regimens. Monte Carlo simulations were performed to define the probability of target attainment (PTA) of several dosing regimens. RESULTS: A total of 204 blood samples were collected from 42 ICU patients treated with ciprofloxacin 400-1200 mg/day, with median values for age of 66 years, APACHE II score of 22, BMI of 26 kg/m2, and eGFR of 58.5 mL/min/1.73 m2. The median ƒAUC0-24 and ƒCmax were 29.9 mg•h/L and 3.1 mg/L, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model. We did not find any significant covariate to add to the structural model. The proportion of patients achieving the target ƒAUC0-24/MIC ≥ 100 were 61.9% and 16.7% with MICs of 0.25 and 0.5 mg/L, respectively. Results of the PTA simulations suggest that a dose of ≥ 1200 mg/day is needed to achieve sufficient ƒAUC0-24/MIC ratios. CONCLUSIONS: The model described the pharmacokinetics of ciprofloxacin in ICU patients adequately. No significant covariates were found and high inter-individual variability of ciprofloxacin pharmacokinetics in ICU patients was observed. The poor target attainment supports the use of higher doses such as 1200 mg/day in critically ill patients, while the variability of inter-individual pharmacokinetics parameters emphasizes the need for therapeutic drug monitoring to ensure optimal exposure.

Emerging contaminants in water used for maize irrigation: Economic and food safety losses associated with ciprofloxacin and glyphosate.

Chemicals used to assure agricultural production and the feasibility of planting sites often end up in bodies of water used for crop irrigation. In a pot study, we investigated the consequences associated with the irrigation of maize with water contaminated by ciprofloxacin (Cipro; 0, 0.2, 0.8, 1.4 and 2.0 µg l-1) and/or glyphosate (0, 5, 25 and 50 mg l-1) on yields and food safety. Glyphosate in concentrations ≥25 mg l-1 prevented plant establishment, regardless of Cipro presence. Evaluations made at the V5 stage of plants reveal that Cipro concentrations ≥0.8 µg l-1 and glyphosate decreased photosynthesis and induced changes in leaf anatomy and stem biophysical properties that may contribute to decreased kernel yields. When those chemicals were applied together, kernel yield reductions were accentuated, evidencing their interactive effects. Irrigation with contaminated water resulted in accumulations of Cipro and glyphosate (as well as its metabolite, aminomethylphosphonic acid) in plant tissues. Accumulation of these chemicals in plant tissues such as leaves and kernels is a problem, since they are used to feed animals and humans. Moreover, these chemicals are of potential toxicological concern, principally due to residue accumulations in the food chain. Specially, the antibiotic residue accumulations in maize tissues can assist the induction of antibiotic resistance in dangerous bacteria. Therefore, we point out the urgency of monitoring the quality of water used for crop irrigation to avoid economic and food-quality losses.

Pharmacokinetic profile analyses for inhaled drugs in humans using the lung delivery and disposition model.

The kinetic clarification of lung disposition for inhaled drugs in humans via pharmacokinetic (PK) modeling aids in their development and regulation for systemic and local delivery, but remains challenging due to its multiplex nature. This study exercised our lung delivery and disposition kinetic model to derive the kinetic descriptors for the lung disposition of four drugs [calcitonin, tobramycin, ciprofloxacin and fluticasone propionate (FP)] inhaled via different inhalers from the published PK profile data. With the drug dose delivered to the lung (DTL) estimated from the corresponding γ-scintigraphy or in vivo predictive cascade impactor data, the model-based curve-fitting and statistical moment analyses derived the rate constants of lung absorption (ka ) and non-absorptive disposition (knad ). The ka values differed substantially between the drugs (0.05-1.00 h-1 ), but conformed to the lung partition-based membrane diffusion except for FP, and were inhaler/delivery/deposition-independent. The knad values also varied widely (0.03-2.32 h-1 ), yet appeared to be explained by the presence or absence of non-absorptive disposition in the lung via mucociliary clearance, local tissue degradation, binding/sequestration and/or phagocytosis, and to be sensitive to differences in lung deposition. For FP, its ka value of 0.2 h-1 was unusually low, suggesting solubility/dissolution-limited slow lung absorption, but was comparable between two inhaler products. Thus, the difference in the PK profile was attributed to differences in the DTL and the knad value, the latter likely originating from different aerosol sizes and regional deposition in the lung. Overall, this empirical, rather simpler model-based analysis provided a quantitative kinetic understanding of lung absorption and non-absorptive disposition for four inhaled drugs from PK profiles in humans.

Population pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin in clinically diseased or injured Eastern box turtles (Terrapene carolina carolina), yellow-bellied sliders (Trachemys scripta scripta), and river cooters (Pseudemys concinna).

Enrofloxacin is frequently administered to turtles in wildlife clinics during rehabilitation due to its wide spectrum of antibacterial activity and availability of injectable formulations. However, sufficient pharmacokinetic data to guide dosing are lacking. The objective of this study was to determine pharmacokinetic parameters of enrofloxacin and its active metabolite, ciprofloxacin, in chelonians presenting injured to a wildlife clinic. Thirty-six Eastern box turtles (EBT, Terrapene carolina carolina), 23 yellow-bellied sliders (YBS, Trachemys scripta scripta), and 13 river cooters (RC, Pseudemys concinna) received a single subcutaneous injection of enrofloxacin at 10 mg/kg. Blood samples were collected between 0 and 240 hr postinjection. Pharmacokinetic parameters were determined using nonlinear mixed-effects modeling (NMLE). Overall elimination half-life (T½) was over 75 hr, and varied among species. T½ was 63 hr in EBT and 79 hr in YBS, which is longer than in previous reports. The volume of distribution (steady-state) was 1.4 L/kg across turtle species, but highly variable-ranging from 0.4 L/kg in RC to 1.9 L/kg in YBS. Antibiotic concentrations were above a minimum inhibitory concentration value of 0.5 µg/ml for over 200 hr. These results indicate variable pharmacokinetic parameters for enrofloxacin among turtle species, which will help guide appropriate dosing protocols in injured turtles.

Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin in freshwater crocodiles (Crocodylus siamensis) after intravenous and intramuscular administration.

To the best of the authors' knowledge, pharmacokinetic information to establish suitable therapeutic plans for freshwater crocodiles is limited. Therefore, the purpose of this study was to clarify the pharmacokinetic characteristics of enrofloxacin (ENR) in freshwater crocodiles, Crocodylus siamensis, following single intravenous and intramuscular administration at a dosage of 5 mg/kg body weight (b.w.). Blood samples were collected at assigned times up to 168 hr. The plasma concentrations of ENR and its metabolite ciprofloxacin (CIP) were measured by liquid chromatography tandem-mass spectrometry. The concentrations of ENR and CIP in the plasma were quantified up to 144 hr after both the administrations. The half-life was long (43-44 hr) and similar after both administrations. The absolute i.m. bioavailability was 82.65% and the binding percentage of ENR to plasma protein ranged from 9% to 18% with an average of 10.6%. Percentage of CIP (plasma concentrations) was 15.9% and 19.9% after i.v. and i.m. administration, respectively. Based on the pharmacokinetic data, susceptibility break point and PK-PD indexes, i.m. single administration of ENR at a dosage of 5 mg/kg b.w. might be appropriate for treatment of susceptible bacteria (MIC > 1 µg/mL) in freshwater crocodiles, C. siamensis.

Fluoroquinolones in Drug-Resistant Tuberculosis: Culture Conversion and Pharmacokinetic/Pharmacodynamic Target Attainment To Guide Dose Selection.

Fluoroquinolones are group A drugs in tuberculosis guidelines. We aim to compare the culture conversion between new-generation (levofloxacin and moxifloxacin) and old-generation (ciprofloxacin and ofloxacin) fluoroquinolones, develop pharmacokinetic models, and calculate target attainment for levofloxacin and moxifloxacin. We included three U.S. tuberculosis centers. Patients admitted between 1984 and 2015, infected with drug-resistant tuberculosis, and who had received fluoroquinolones for ≥28 days were included. Demographics, sputum cultures and susceptibility, treatment regimens, and serum concentrations were collected. A time-to-event analysis was conducted, and Cox proportional hazards model was used to compare the time to culture conversion. Using additional data from ongoing studies, pharmacokinetic modelling and Monte Carlo simulations were performed to assess target attainment for different doses. Overall, 124 patients received fluoroquinolones. The median age was 40 years, and the median weight was 60 kg. Fifty-six patients (45%) received old-generation fluoroquinolones. New-generation fluoroquinolones showed a faster time to culture conversion (median 16 versus 40 weeks, P = 0.012). After adjusting for isoniazid and clofazimine treatment, patients treated with new-generation fluoroquinolones were more likely to have culture conversion (adjusted hazards ratio, 2.16 [95% confidence interval, 1.28 to 3.64]). We included 178 patients in the pharmacokinetic models. Levofloxacin and moxifloxacin were best described by a one-compartment model with first-order absorption and elimination. At least 1,500 to 1,750 mg levofloxacin and 800 mg moxifloxacin may be needed for maximum kill at the current epidemiologic cutoff values. In summary, new-generation fluoroquinolones showed faster time to culture conversion compared to the old generation. For optimal target attainment at the current MIC values, higher doses of levofloxacin and moxifloxacin may be needed.

DAV131A Protects Hamsters from Lethal Clostridioides difficile Infection Induced by Fluoroquinolones.

Fluoroquinolone treatments induce dysbiosis of the intestinal microbiota, resulting in loss of resistance to colonization by exogenous bacteria such as Clostridioides difficile that may cause severe diarrhea in humans and lethal infection in hamsters. We show here that DAV131A, a charcoal-based adsorbent, decreases the intestinal levels of the fluoroquinolone antibiotics levofloxacin and ciprofloxacin in hamsters, protects their intestinal microbiota, and prevents lethal infection by C. difficile.

Antibiotics and efflux: combined spectrofluorimetry and mass spectrometry to evaluate the involvement of concentration and efflux activity in antibiotic intracellular accumulation.

Background: In Gram-negative bacteria, passing through the double membrane barrier to reach the inhibitory concentration inside the bacterium is a pivotal step for antibiotic activity. Spectrofluorimetry has been developed to follow fluoroquinolone accumulation inside bacteria using intrinsic bacterial fluorescence as an internal standard. However, adaptation for non-fluorescent antibiotics is needed; quantitative methods based on MS offer the possibility of expanding the detection range obtained by spectrofluorimetry. Objectives: To validate, with spectrofluorimetry, the use of MS to measure antibiotic accumulation in cells and to determine the relationship between antibiotic concentrations and the amount of intrabacterial accumulation in different efflux backgrounds on the same batch of molecules. Methods: Spectrofluorimetry was performed in parallel with MS on the same samples to measure the ciprofloxacin and fleroxacin accumulation in cells expressing various efflux pump levels. A microplate protocol was set up to determine the antibiotic accumulation as a function of external antibiotic concentrations. Results: A correlation existed between the data obtained with spectrofluorimetry and MS, whatever the efflux pump or tested antibiotic. The results highlighted different dynamics of uptake between ciprofloxacin and fleroxacin as well as the relationship between the level of efflux activity and antibiotic accumulation. Conclusions: We have developed a microplate protocol and cross-validated two complementary methods: spectrofluorimetry, which contains a reliable internal standard; and MS, which allows detection of low antibiotic amounts. These assays allow study of the dose effect and the efflux impact on the intrabacterial accumulation of antibiotics.