COVID-19 Drug Treatments Are Prone to Sequestration in Extracorporeal Membrane Oxygenation Circuits: An Ex Vivo Extracorporeal Membrane Oxygenation Study.

Drug treatments for coronavirus disease 2019 (COVID-19) dramatically improve patient outcomes, and although extracorporeal membrane oxygenation (ECMO) has significant use in these patients, it is unknown whether ECMO affects drug dosing. We used an ex vivo adult ECMO model to measure ECMO circuit effects on concentrations of specific COVID-19 drug treatments. Three identical ECMO circuits used in adult patients were set up. Circuits were primed with fresh human blood (temperature and pH maintained within normal limits). Three polystyrene jars with 75 ml fresh human blood were used as controls. Remdesivir, GS-441524, nafamostat, and tocilizumab were injected in the circuit and control jars at therapeutic concentrations. Samples were taken from circuit and control jars at predefined time points over 6 h and drug concentrations were measured using validated assays. Relative to baseline, mean (± standard deviation [SD]) study drug recoveries in both controls and circuits at 6 h were significantly lower for remdesivir (32.2% [±2.7] and 12.4% [±2.1], p < 0.001), nafamostat (21.4% [±5.0] and 0.0% [±0.0], p = 0.018). Reduced concentrations of COVID-19 drug treatments in ECMO circuits is a clinical concern. Remdesivir and nafamostat may need dose adjustments. Clinical pharmacokinetic studies are suggested to guide optimized COVID-19 drug treatment dosing during ECMO.

Peri-operative pharmacokinetics of cefazolin prophylaxis during valve replacement surgery.

OBJECTIVE: There is little prospective data to guide effective dosing for antibiotic prophylaxis during surgery requiring cardiopulmonary bypass (CPB). We aim to describe the effects of CPB on the population pharmacokinetics (PK) of total and unbound concentrations of cefazolin and to recommend optimised dosing regimens. METHODS: Patients undergoing CPB for elective cardiac valve replacement were included using convenience sampling. Intravenous cefazolin (2g) was administered pre-incision and re-dosed at 4 hours. Serial blood and urine samples were collected and analysed using validated chromatography. Population PK modelling and Monte-Carlo simulations were performed using Pmetrics® to determine the fractional target attainment (FTA) of achieving unbound concentrations exceeding pre-defined exposures against organisms known to cause surgical site infections for 100% of surgery (100% fT>MIC). RESULTS: From the 16 included patients, 195 total and 64 unbound concentrations of cefazolin were obtained. A three-compartment linear population PK model best described the data. We observed that cefazolin 2g 4-hourly was insufficient to achieve the FTA of 100% fT>MIC for Staphylococcus aureus and Escherichia coli at serum creatinine concentrations ≤ 50 µmol/L and for Staphylococcus epidermidis at any of our simulated doses and serum creatinine concentrations. A dose of cefazolin 3g 4-hourly demonstrated >93% FTA for S. aureus and E. coli. CONCLUSIONS: We found that cefazolin 2g 4-hourly was not able to maintain concentrations above the MIC for relevant pathogens in patients with low serum creatinine concentrations undergoing cardiac surgery with CPB. The simulations showed that optimised dosing is more likely with an increased dose and/or dosing frequency.

Population Pharmacokinetics of Ganciclovir in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Treatment of cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplantation (alloHCT) patients with ganciclovir is complicated by toxicity and resistance. This study aimed to develop an intravenous ganciclovir population pharmacokinetic model for post-alloHCT patients and to determine dosing regimens likely to achieve suggested therapeutic exposure targets. We performed a prospective observational single-center pharmacokinetic study in adult alloHCT patients requiring treatment with intravenous ganciclovir for CMV viremia or disease. Samples were analyzed using a validated ultraperformance liquid chromatography method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R. Twenty patients aged 18 to 69 years were included in the study. A 2-compartment model with linear elimination from the central compartment and between occasion variability best described the data. Incorporating creatinine clearance (CLCR) estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and presence of continuous renal replacement therapy as covariates for ganciclovir clearance improved the model. Compared to current dosing recommendations, simulations demonstrated loading doses were required to achieve a target AUC24 of 80 to 120 mg.h/L on day 1 of induction therapy. Increased individualization of post-loading induction and maintenance doses based on CLCR is required to achieve the suggested exposures for efficacy (AUC24 >80/>40 mg.h/L for induction/maintenance) while remaining below the exposure thresholds for toxicity (AUC24 <120/<60 mg.h/L for induction/maintenance). Intravenous ganciclovir dosing in alloHCT patients can be guided by CLCR estimated by CKD-EPI. Incorporation of loading doses into induction dosing regimens should be considered for timely achievement of currently suggested exposures.

Antimicrobial residual drug error in the intensive care unit; a single blinded prospective observational study.

OBJECTIVE: To determine the percentage of drug remaining in discarded antibiotic vials after use. DESIGN: Blinded prospective observational trial. SETTING: 26-bed Australian metropolitan tertiary referral intensive care unit. MAIN OUTCOME MEASURES: Percentage of labelled dose remaining in the vial after discard. METHOD: Discarded antibiotic vials collected over a 7-day period in an adult intensive care unit were analysed. Each collected vial had any drug remnant washed out and made up to a known volume. A 1 ml aliquot of each vials washings was analysed using high performance liquid chromatography. From this concentration, the percentage of the drug remaining in the vial after discard was calculated. Additionally, each vial was weighed before and after washing to determine the weight of the remnant in each vial. RESULTS: A total of 311 vials comprising of 11 different drugs and 14 individual vial types were collected. The median residual drug error across all vials was 3.7 %. The drug with the highest median was piperacillin at 6.1 % (IQR 4.3) and the lowest was amoxicillin 0.2 % (IQR 0.1). The single highest value for a given vial was vancomycin (500 mg) with 33.2 % and the lowest for a given vial was 0.1 % amoxicillin (1 g). These two drugs also exhibited the greatest range between the maximum and minimum value for any drug being 32 % and 0.9 % respectively. CONCLUSIONS: Our study shows that up to a third of the intended dose may fail to reach the patient, highlighting a significant factor in the administration of antibiotics to the critically ill population. IMPLICATIONS FOR CLINICAL PRACTICE: Residual drug often remains in antibiotic vials meaning that drug is not reaching the patient. There is considerable variation in the method by which medications are reconstituted in clinical settings. Two person checks should be completed after reconstitution in order to ensure that the medication is fully reconstituted and extracted from the vial.

Population Pharmacokinetics and Dosing Simulations of Ampicillin and Sulbactam in Hospitalised Adult Patients.

BACKGROUND: The pharmacokinetic variability of ampicillin-sulbactam in adults has not been extensively described, particularly in patients with a reduced renal function (i.e., < 60 mL/min). OBJECTIVE: This study investigated the population pharmacokinetics of ampicillin and sulbactam in patients with a wide range of renal functions and sought to define dosing approaches that have a high likelihood for optimising drug exposure. METHODS: Serial blood samples were collected from 16 adult patients receiving intravenous ampicillin-sulbactam in general wards. Total ampicillin and sulbactam concentrations were measured by chromatographic assay and pharmacokinetic parameters were estimated using Pmetrics®. Monte Carlo simulations were used to evaluate the probability of target attainment (PTA) of free ampicillin and sulbactam concentrations exceeding the minimum inhibitory concentration (MIC) for 60% and 100% of the dosing interval. Fractional target attainment (FTA) was calculated against MIC distributions of common hospital pathogens. A threshold of ≥ 90% and ≥ 95% was used to define both optimal PTA and FTA, respectively. RESULTS: The median (range) age, weight, and serum creatinine of the study population was 68 (40-82) years, 62 (40-82) kg, and 1.4 (0.6-6.4) mg/dL, respectively. The pharmacokinetics of ampicillin and sulbactam were best described by a two-compartment model with serum creatinine most closely associated with clearance for both drugs. The estimated ampicillin and sulbactam clearances were 5.58 L/h and 4.79 L/h, respectively, while the volumes of distribution were 12.6 L and 15.36 L, respectively. Approved dosing regimens of ampicillin-sulbactam were sufficient against MICs ≤ 8 and ≤ 4 mg/L, respectively. A 4-h infusion enabled optimal PTA at higher MICs. For both dosing targets, optimal FTAs were obtained against Streptococcus pneumoniae. CONCLUSION: Optimal FTAs were obtained against the susceptible MIC distributions of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Applying a 4-h infusion will enhance PTA and FTA, particularly at higher MICs.

Oral ciprofloxacin activity against ceftriaxone-resistant Escherichia coli in an in vitro bladder infection model.

OBJECTIVES: Pharmacodynamic profiling of oral ciprofloxacin dosing for urinary tract infections caused by ceftriaxone-resistant Escherichia coli isolates with ciprofloxacin MIC ≥ 0.25 mg/L. BACKGROUND: Urine-specific breakpoints for ciprofloxacin do not exist. However, high urinary concentrations may promote efficacy in isolates with low-level resistance. METHODS: Ceftriaxone-resistant E. coli urinary isolates were screened for ciprofloxacin susceptibility. Fifteen representative strains were selected and tested using a dynamic bladder infection model. Oral ciprofloxacin dosing was simulated over 3 days (250 mg daily, 500 mg daily, 250 mg 12 hourly, 500 mg 12 hourly and 750 mg 12 hourly). The model was run for 96 h. Primary endpoint was change in bacterial density at 72 h. Secondary endpoints were follow-up change in bacterial density at 96 h and area-under-bacterial-kill-curve. Bacterial response was related to exposure (AUC0-24/MIC; Cmax/MIC). PTA was determined using Monte-Carlo simulation. RESULTS: Ninety-three clinical isolates demonstrated a trimodal ciprofloxacin MIC distribution (modal MICs at 0.016, 0.25 and 32 mg/L). Fifteen selected clinical isolates (ciprofloxacin MIC 0.25-512 mg/L) had a broad range of quinolone-resistance genes. Following ciprofloxacin exposure, E. coli ATCC 25922 (MIC 0.008 mg/L) was killed in all dosing experiments. Six isolates (MIC ≥ 16 mg/L) regrew in all experiments. Remaining isolates (MIC 0.25-8 mg/L) regrew variably after an initial period of killing, depending on simulated ciprofloxacin dose. A >95% PTA, using AUC0-24/MIC targets, supported 250 mg 12 hourly for susceptible isolates (MIC ≤ 0.25 mg/L). For isolates with MIC ≤ 1 mg/L, 750 mg 12 hourly promoted 3 log10 kill at the end of treatment (72 h), 1 log10 kill at follow-up (96 h) and 90% maximal activity (AUBKC0-96). CONCLUSIONS: Bladder infection modelling supports oral ciprofloxacin activity against E. coli with low-level resistance (ciprofloxacin MIC ≤ 1 mg/L) when using high dose therapy (750 mg 12 hourly).

Plasma and Interstitial Fluid Pharmacokinetics of Prophylactic Cefazolin in Elective Bariatric Surgery Patients.

Guidelines for surgical prophylactic dosing of cefazolin in bariatric surgery vary in terms of recommended dose. This study aimed to describe the plasma and interstitial fluid (ISF) cefazolin pharmacokinetics in patients undergoing bariatric surgery and to determine an optimum dosing regimen. Abdominal subcutaneous ISF concentrations (measured using microdialysis) and plasma samples were collected at regular time points after administration of cefazolin 2 g intravenously. Total and unbound cefazolin concentrations were assayed and then modeled using Pmetrics. Monte Carlo dosing simulations (n = 5,000) were used to define cefazolin dosing regimens able to achieve a fractional target attainment (FTA) of >95% in the ISF suitable for the MIC for Staphylococcus aureus in isolates of ≤2 mg · L-1 and for a surgical duration of 4 h. Fourteen patients were included, with a mean (standard deviation [SD]) bodyweight of 148 (35) kg and body mass index (BMI) of 48 kg · m-2. Cefazolin protein binding ranged from 14 to 36% with variable penetration into ISF of 58% ± 56%. Cefazolin was best described as a four-compartment model including nonlinear protein binding. The mean central volume of distribution in the final model was 18.2 (SD 3.31) L, and the mean clearance was 32.4 (SD 20.2) L · h-1. A standard 2-g dose achieved an FTA of >95% for all patients with BMIs ranging from 36 to 69 kg · m-2. A 2-g prophylactic cefazolin dose achieves appropriate unbound plasma and ISF concentrations in obese and morbidly obese bariatric surgery patients.

Oral fosfomycin activity against Klebsiella pneumoniae in a dynamic bladder infection in vitro model.

INTRODUCTION: The use of oral fosfomycin for urinary tract infections (UTIs) caused by non-Escherichia coli uropathogens is uncertain, including Klebsiella pneumoniae, the second most common uropathogen. METHODS: A multicompartment bladder infection in vitro model was used with standard media and synthetic human urine (SHU) to simulate urinary fosfomycin exposure after a single 3 g oral dose (fAUC0-72 16884 mg·h/L, t½ 5.5 h) against 15 K. pneumoniae isolates including ATCC 13883 (MIC 2 to >1024 mg/L) with a constant media inflow (20 mL/h) and 4-hourly voiding of each bladder. The impact of the media (CAMHB + G6P versus SHU) on fosfomycin MIC measurements, drug-free growth kinetics and regrowth after fosfomycin administration was assessed. A low and high starting inoculum (5.5 versus 7.5 log10 cfu/mL) was assessed in the bladder infection model. RESULTS: Compared with CAMHB, isolates in SHU had a slower growth rate doubling time (37.7 versus 24.1 min) and reduced growth capacity (9.0 ± 0.3 versus 9.4 ± 0.3 log10 cfu/mL), which was further restricted with increased inflow rate (40 mL/h) and more frequent voids (2-hourly). Regrowth was commonly observed in both media with emergence of fosfomycin resistance promoted by a high starting inoculum in CAMHB (MIC rise to ≥1024 mg/L in 13/14 isolates). Resistance was rarely detected in SHU, even with a high starting inoculum (MIC rise to ≥1024 mg/L in 2/14 isolates). CONCLUSIONS: Simulated in an in vitro UTI model, the regrowth of K. pneumoniae urinary isolates was inadequately suppressed following oral fosfomycin therapy. Efficacy was further reduced by a high starting inoculum.

In vitro effect of synovial fluid from patients undergoing arthroplasty surgery on MRSA biofilm formation.

BACKGROUND: Bacterial biofilm is a key component in the pathogenesis of prosthetic joint infection (PJI). Synovial fluid has been shown to have inhibitory activity against planktonic bacteria. However, the contribution of synovial fluid in prevention of Staphylococcus aureus (including MRSA) planktonic and biofilm forms is unknown. OBJECTIVES: To test the antibacterial and antibiofilm activities of synovial fluid, including that containing cefazolin, against MSSA and MRSA. MATERIALS AND METHODS: We determined the antiplanktonic and antibiofilm activities of synovial fluid collected from patients given preoperative cefazolin while undergoing elective arthroplasty surgery. MICs of cefazolin were determined for planktonic and biofilm cultures of biofilm-forming strains of MSSA and MRSA. RESULTS: Synovial fluid inhibited planktonic and biofilm cultures of MSSA and MRSA. Cefazolin-containing synovial fluid had greater antibacterial and antibiofilm activities than the same cefazolin concentration in glucose LB (GLB) broth. MSSA and MRSA MICs of cefazolin suspended in synovial fluid were 0.7 mg/L. The MICs of cefazolin diluted in GLB broth were higher, measuring 1.4 mg/L for MSSA and 23 mg/L for MRSA. CONCLUSIONS: Synovial fluid containing cefazolin inhibited biofilm- and planktonic-state MRSA cultures. This may explain the apparent effect of cefazolin in the prevention of MRSA PJI.

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

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.

Clinically Relevant Epithelial Lining Fluid Concentrations of Meropenem with Ciprofloxacin Provide Synergistic Killing and Resistance Suppression of Hypermutable Pseudomonas aeruginosa in a Dynamic Biofilm Model.

Treatment of exacerbations of chronic Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) is highly challenging due to hypermutability, biofilm formation, and an increased risk of resistance emergence. We evaluated the impact of ciprofloxacin and meropenem as monotherapy and in combination in the dynamic in vitro CDC biofilm reactor (CBR). Two hypermutable P. aeruginosa strains, PAOΔmutS (MIC of ciprofloxacin [MICciprofloxacin], 0.25 mg/liter; MICmeropenem, 2 mg/liter) and CW44 (MICciprofloxacin, 0.5 mg/liter; MICmeropenem, 4 mg/liter), were investigated for 120 h. Concentration-time profiles achievable in epithelial lining fluid (ELF) following FDA-approved doses were simulated in the CBR. Treatments were ciprofloxacin at 0.4 g every 8 h as 1-h infusions (80% ELF penetration), meropenem at 6 g/day as a continuous infusion (CI) (30% and 60% ELF penetration), and their combinations. Counts of total and less-susceptible planktonic and biofilm bacteria and MICs were determined. Antibiotic concentrations were quantified by an ultrahigh-performance liquid chromatography photodiode array (UHPLC-PDA) assay. For both strains, all monotherapies failed, with substantial regrowth and resistance of planktonic (≥8 log10 CFU/ml) and biofilm (>8 log10 CFU/cm2) bacteria at 120 h (MICciprofloxacin, up to 8 mg/liter; MICmeropenem, up to 64 mg/liter). Both combination treatments demonstrated synergistic bacterial killing of planktonic and biofilm bacteria of both strains from ∼48 h onwards and suppressed regrowth to ≤4 log10 CFU/ml and ≤6 log10 CFU/cm2 at 120 h. Overall, both combination treatments suppressed the amplification of resistance of planktonic bacteria for both strains and of biofilm bacteria for CW44. The combination with meropenem at 60% ELF penetration also suppressed the amplification of resistance of biofilm bacteria for PAOΔmutS Thus, combination treatment demonstrated synergistic bacterial killing and resistance suppression against difficult-to-treat hypermutable P. aeruginosa strains.

Pharmacokinetics of Sulfamethoxazole and Trimethoprim During Venovenous Extracorporeal Membrane Oxygenation: A Case Report.

Extracorporeal membrane oxygenation (ECMO) therapy could affect drug concentrations via adsorption onto the oxygenator and/or associated circuit. We describe a case of a 33-year-old man with severe respiratory failure due to Pneumocystis jirovecii infection on a background of recently diagnosed human immunodeficiency virus infection. He required venovenous ECMO therapy for refractory respiratory failure. Intravenous sulfamethoxazole-trimethoprim (100 and 20 mg/kg/day) was administered in a dosing regimen every 6 hours. Pre-oxygenator, post-oxygenator, and arterial blood samples were collected after antibiotic administration and were analyzed for total sulfamethoxazole and trimethoprim concentrations. The peak sulfamethoxazole and trimethoprim concentrations were 122 mg/L and 5.3 mg/L, respectively. The volume of distribution for sulfamethoxazole was 0.37 and 2.30 L/kg for trimethoprim. The clearance for sulfamethoxazole was 0.35 ml/minute/kg and for trimethoprim was 1.64 ml/minute/kg. The pharmacokinetics of sulfamethoxazole and trimethoprim appear not to be affected by ECMO therapy, and dosing adjustment may not be required.

Prophylactic Cefazolin Dosing in Women With Body Mass Index >35 kg·m-2 Undergoing Cesarean Delivery: A Pharmacokinetic Study of Plasma and Interstitial Fluid.

BACKGROUND: Obesity is a risk factor for surgical site infection after cesarean delivery. There is inadequate pharmacokinetic data available regarding prophylactic cefazolin dosing in obese pregnant women. We aimed to describe the plasma and interstitial fluid (ISF) pharmacokinetics of cefazolin in obese women undergoing elective cesarean delivery and use dosing simulations to predict optimal dosing regimens. METHODS: Eligible women were scheduled for elective cesarean delivery at term, with a body mass index (BMI) of >35 kg·m. Plasma and ISF samples were collected following 2 g of intravenous cefazolin. Concentrations were determined using liquid chromatography-mass spectrometry. Population pharmacokinetic modeling and Monte Carlo dosing simulations were performed using Pmetrics. Total and unbound cefazolin concentrations in plasma and ISF were compared with the minimum inhibitory concentration at which 90% of isolates are inhibited (MIC90) of cefazolin for Staphylococcus aureus, 2 mg·L. The fractional target attainment (FTA) of dosing regimens to achieve a pre-established target of 95% unbound ISF concentrations >2 mg·L throughout a 3-hour duration of the surgery was calculated. RESULTS: The 12 women recruited had a median (interquartile range [IQR]) BMI of 41.5 (39.7-46.6) kg·m and a median (IQR) gestation of 38.7 weeks (37.9-39.0). For each timepoint up to 180 minutes, the median across subjects of total and unbound plasma concentration of cefazolin remained above 2 mg·L. The minimum observed total plasma concentration was 31.7 mg·L and plasma unbound concentration was 7.7 mg·L (observed in the same participant). For each timepoint up to 150 minutes, the median across subjects of unbound ISF concentrations remained above 2 mg·L. The minimum observed unbound ISF concentration was 0.7 mg·L (observed in 1 participant). In 2 participants, the ISF concentration of cefazolin was not maintained above 2 mg·L. The mean (± standard error [SE]) penetration of cefazolin (calculated as area under the concentration-time curve for the unbound fraction of drug [fAUC]tissue/fAUCplasma) into the ISF was 0.884 ± 1.11. Simulations demonstrated that FTA >95% was achieved in patients weighing 90-150 kg by an initial 2 g dose with redosing of 2 g at 2 hours. FTA was improved to >99% when an initial 3 g dose was repeated at 2 hours. CONCLUSIONS: To maintain adequate ISF antibiotic concentrations in obese pregnant women, our results suggest that redosing of cefazolin may be required. When wound closure has not occurred within 2 hours, redosing is suggested, following either a 2 or 3 g initial bolus. These preliminary results require validation in a larger population.

The pharmacokinetics of meropenem and piperacillin-tazobactam during sustained low efficiency haemodiafiltration (SLED-HDF).

OBJECTIVE: We analysed the pharmacokinetics of meropenem and piperacillin-tazobactam in patients undergoing a standardised session of sustained low efficiency haemodiafiltration (SLED-HDF) to inform the dosing of these drugs in an acute setting. PARTICIPANTS: Six stable patients with end-stage kidney disease. METHODS: An open-label pilot pharmacokinetic study of meropenem and piperacillin-tazobactam. SLED-HDF was undertaken for 4 h. Plasma drug concentrations were measured pre- and post-filter and in the effluent at multiple time points. The pharmacokinetic data was analysed using non-compartmental methods. The fraction of time that individual plasma concentration profiles were predicted to remain above the MIC break-points for commonly isolated gram-negative pathogens during a prolonged SLED-HDF session was assessed using two targets; fT > MIC (fraction of time above the MIC) and the more aggressive fT > 4 × MIC (fraction of time above 4 × MIC). RESULTS: Meropenem total and SLED-HDF clearance ranged from 141 to 180 mL/min and 126-205 mL/min, respectively. Piperacillin total and SLED-HDF clearance values ranged from 131 to 252 mL/min and 135-162 mL/min, respectively. Our results suggest that prolonged SLED-HDF (12 h) will only maintain a sufficient meropenem and piperacillin-tazobactam plasma concentration to achieve a target of fT > MIC for gram-negative pathogens (MIC 2 mg/L-meropenem, 8 mg/L-piperacillin-tazobactam) for less than 40% of the time. Plasma concentrations would be inadequate to achieve the more aggressive target of 100 % fT > 4xMIC target recommended for critically unwell patients. CONCLUSIONS: The pharmacokinetic data obtained from this pilot study demonstrate significant quantities of meropenem and piperacillin are removed during a SLED-HDF session. This may lead to subtherapeutic concentrations of piperacillin and meropenem over the duration of HDF session. TRIAL REGISTRATION: Australasian Clinical Trials Registry Network (ACTRN12616000078459).

Population Pharmacokinetics of Periarticular Ketorolac in Adult Patients Undergoing Total Hip or Total Knee Replacement Surgery.

BACKGROUND: Ketorolac tromethamine has been used for joint infiltration by the orthopedic surgeons as a part of postoperative multimodal analgesia. The objective of this study is to investigate the pharmacokinetic properties of S (-) and R (+) enantiomers of ketorolac in adult patients undergoing total hip (THA) and knee arthroplasty (TKA). METHODS: Adult patients with normal preoperative renal function received a periarticular infiltration of 30 mg of ketorolac tromethamine along with 100 mL of 0.2% ropivacaine and 1 mg of epinephrine at the end of their THA or TKA surgery. Blood samples were taken from a venous cannula at various time points after infiltration. Pharmacokinetic modeling was performed using PMetrics 1.5.0. RESULTS: From 18 participants, 104 samples were analyzed. The peak plasma concentration for S (-) ketorolac was found to be lower than that of R (+) ketorolac, for both THA (0.19-1.22 mg/L vs 0.39-1.63 mg/L, respectively) and TKA (0.28-0.60 mg/L vs 0.48-0.88 mg/L, respectively). The clearance of the S (-) ketorolac enantiomer was higher than R (+) ketorolac (4.50 ± 2.27 vs 1.40 ± 0.694 L/h, respectively). CONCLUSIONS: Our study demonstrates that with periarticular infiltration, S (-) ketorolac was observed to have increased clearance rate and highly variable volume of distribution and lower peak plasma concentration compared to R (+) ketorolac.

A research pathway for the study of the delivery and disposition of nebulised antibiotics: an incremental approach from in vitro to large animal models.

BACKGROUND: Nebulised antibiotics are frequently used for the prevention or treatment of ventilator-associated pneumonia. Many factors may influence pulmonary drug concentrations with inaccurate dosing schedules potentially leading to therapeutic failure and/or the emergence of antibiotic resistance. We describe a research pathway for studying the pharmacokinetics of a nebulised antibiotic during mechanical ventilation using in vitro methods and ovine models, using tobramycin as the study antibiotic. METHODS: In vitro studies using a laser diffractometer and a bacterial-viral filter were used to measure the effect of the type and size of tracheal tubes and antibiotic concentration on the particle size distribution of the tobramycin 400 mg (4 ml; 100 mg/ml) and 160 mg (4 ml, 40 mg/ml) aerosol and nebulised mass delivered. To compare the regional drug distribution in the lung of two routes (intravenous and nebulised) of drug administration of tobramycin 400 mg, technetium-99m-labelled tobramycin 400 mg with planar nuclear medicine imaging was used in a mechanically ventilated ovine model. To measure tobramycin concentrations by intravenous and nebulised tobramycin 400 mg (4 ml, 100 mg/ml) administration in the lung interstitial space (ISF) fluid and blood of mechanically ventilated sheep, the microdialysis technique was used over an 8-h duration. RESULTS: Tobramycin 100 mg/ml achieved a higher lung dose (121.3 mg) compared to 40 mg/ml (41.3 mg) solution. The imaging study with labelled tobramycin indicated that nebulised tobramycin distributed more extensively into each lung zone of the mechanically ventilated sheep than intravenous administration. A higher lung ISF peak concentration of tobramycin was observed with nebulised tobramycin (40.8 mg/l) compared to intravenous route (19.0 mg/l). CONCLUSIONS: The research methods appear promising to describe lung pharmacokinetics for formulations intended for nebulisation during mechanical ventilation. These methods need further validation in an experimental pneumonia model to be able to contribute toward optimising dosing regimens to inform clinical trials and/or clinical use.

A validated UHPLC-MS/MS method for the measurement of riluzole in plasma and myocardial tissue samples.

Through blocking the cardiac persistent sodium current, riluzole has the potential to prevent myocardial damage post cardiac bypass surgery. A sensitive UHPLC-MS/MS method was developed and validated for quantitation of riluzole and 5-methoxypsoralen in human plasma and myocardial tissue homogenate using a liquid-liquid extraction with dichloromethane. The chromatographic separation was achieved using Shimadzu Shim-pack XR-ODS III, 2.0 × 50 mm, 1.6 µm column with a gradient mobile phase comprising methanol and ammonium acetate buffer pH 3.6 in purified water. The analyte and internal standard were separated within 3.5 min. Riluzole quantitation was achieved using the mass transitions of 235-138 for riluzole and 217-156 for 5-methoxypsoralen. The method was linear for riluzole plasma concentrations from 0.2 to 500 ng/mL and myocardial tissue homogenate concentrations from 0.2 to 100 ng/mL. The method developed was successfully applied to a clinical study for patients receiving riluzole while undergoing cardiac bypass surgery.

Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study.

INTRODUCTION: Vital drugs may be degraded or sequestered in extracorporeal membrane oxygenation (ECMO) circuits, with lipophilic drugs considered to be particularly vulnerable. However, the circuit effects on protein-bound drugs have not been fully elucidated. The aim of this experimental study was to investigate the influence of plasma protein binding on drug disposition in ex vivo ECMO circuits. METHODS: Four identical ECMO circuits comprising centrifugal pumps and polymethylpentene oxygenators and were used. The circuits were primed with crystalloid, albumin and fresh human whole blood and maintained at a physiological pH and temperature for 24 hours. After baseline sampling, known quantities of study drugs (ceftriaxone, ciprofloxacin, linezolid, fluconazole, caspofungin and thiopentone) were injected into the circuit to achieve therapeutic concentrations. Equivalent doses of these drugs were also injected into four polypropylene jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the controls and the ECMO circuits over 24 hours, and the concentrations of the study drugs were quantified using validated chromatographic assays. A regression model was constructed to examine the relationship between circuit drug recovery as the dependent variable and protein binding and partition coefficient (a measure of lipophilicity) as explanatory variables. RESULTS: Four hundred eighty samples were analysed. There was no significant loss of any study drugs in the controls over 24 hours. The average drug recoveries from the ECMO circuits at 24 hours were as follows: ciprofloxacin 96%, linezolid 91%, fluconazole 91%, ceftriaxone 80%, caspofungin 56% and thiopentone 12%. There was a significant reduction of ceftriaxone (P = 0.01), caspofungin (P = 0.01) and thiopentone (P = 0.008) concentrations in the ECMO circuit at 24 hours. Both protein binding and partition coefficient were highly significant, with the model possessing a high coefficient of determination (R (2) = 0.88, P <0.001). CONCLUSIONS: Recovery of the highly protein-bound drugs ceftriaxone, caspofungin and thiopentone was significantly lower in the ECMO circuits at 24 hours. For drugs with similar lipophilicity, the extent of protein binding may determine circuit drug loss. Future clinical population pharmacokinetic studies should initially be focused on drugs with greater lipophilicity and protein binding, and therapeutic drug monitoring should be strongly considered with the use of such drugs.