Population Pharmacokinetics/Pharmacodynamics and Clinical Outcomes of Meropenem in Critically Ill Patients.

Several pathophysiological changes can alter meropenem pharmacokinetics in critically ill patients, thereby increasing the risk of subtherapeutic concentrations and affecting therapeutic outcomes. This study aimed to characterize the population pharmacokinetic (PPK) parameters of meropenem, evaluate the relationship between the pharmacokinetic/pharmacodynamic index of meropenem and treatment outcomes, and evaluate the different dosage regimens that can achieve 40%, 75%, and 100% of the dosing interval for which the free plasma concentrations remain above the MIC of the pathogens (fT>MIC) targets. Critically ill adult patients treated with meropenem were recruited for this study. Five blood samples were collected from each patient. PPK models were developed using a nonlinear mixed-effects modeling approach, and the final model was subsequently used for Monte Carlo simulations to determine the optimal dosage regimens. A total of 247 concentrations from 52 patients were available for analysis. The two-compartment model with linear elimination adequately described the data. The mean PPK parameters were clearance (CL) of 4.8 L/h, central volume of distribution (VC) of 11.4 L, peripheral volume of distribution (VP) of 14.6 L, and intercompartment clearance of 10.5 L/h. Creatinine clearance was a significant covariate affecting CL, while serum albumin level and shock status were factors influencing VC and VP, respectively. Although 75% of the drug-resistant infection patients had fT>MIC values of >40%, approximately 83% of them did not survive the infection. Therefore, 40% fT>MIC might not be sufficient for critically ill patients, and a higher target, such as 75 to 100% fT>MIC, should be considered for optimizing therapy. A 75% fT>MIC could be reached using approved doses administered via a 3-h infusion.

Population pharmacokinetics of oral levofloxacin in healthy volunteers and dosing optimization for multidrug-resistant tuberculosis therapy.

Levofloxacin is considered a key component of a multidrug-resistant tuberculosis (MDR-TB) regimen. However, there is considerable concern regarding the subtherapeutic concentrations of the currently used doses and the development of drug resistance. Therefore, this study aimed to describe the population pharmacokinetics (PPK) of oral levofloxacin in healthy volunteers and to evaluate the probability of target attainment (PTA) in an attempt to optimize the dosing regimens for MDR-TB therapy. Data of levofloxacin in healthy volunteers from a previous study were used to construct a PPK model. Monte Carlo simulations were performed to derive the PTAs of various regimens. A two-compartment model with linear elimination and transit absorption compartments best described the pharmacokinetics (PK) of levofloxacin. The estimated PK parameters (interindividual variability, %) were: apparent clearance 8.32 L h-1 (22.6%), apparent central volume of distribution 35.8 L (45.2%), apparent peripheral volume of distribution 39.7 L, intercompartmental clearance 40.6 L h-1 (43.8%), absorption rate constant 7.45 h-1 (150%), mean absorption transit time 0.355 h (52.4%), and total number of transit compartments 6.01 (131.9%). Monte Carlo simulations using levofloxacin 750-1000 mg yielded a probability of achieving a target free area under the concentration-time curve/minimum inhibitory concentration (MIC) of 100 at greater than 90% for Mycobacterium tuberculosis with an MIC < 0.5 mg L-1 , while a dose of 1500 mg was required for strains with an MIC of 1 mg L-1 . A higher dose of levofloxacin might be needed to treat tuberculosis. However, further studies on the efficacy and safety of this dose are needed to confirm our findings.

Isavuconazole Versus Caspofungin in the Treatment of Candidemia and Other Invasive Candida Infections: The ACTIVE Trial.

BACKGROUND: Isavuconazole was compared to caspofungin followed by oral voriconazole in a Phase 3, randomized, double-blind, multinational clinical trial for the primary treatment of patients with candidemia or invasive candidiasis. METHODS: Adult patients were randomized 1:1 to isavuconazole (200 mg intravenous [IV] three-times-daily [TID] for 2 days, followed by 200 mg IV once-daily [OD]) or caspofungin (70 mg IV OD on day 1, followed by 50 mg IV OD [70 mg in patients > 80 kg]) for a maximum of 56 days. After day 10, patients could switch to oral isavuconazole (isavuconazole arm) or voriconazole (caspofungin arm). Primary efficacy endpoint was successful overall response at the end of IV therapy (EOIVT) in patients with proven infections who received ≥1 dose of study drug (modified-intent-to-treat [mITT] population). The pre-specified noninferiority margin was 15%. Secondary outcomes in the mITT population were successful overall response at 2 weeks after the end of treatment, all-cause mortality at days 14 and 56, and safety. RESULTS: Of 450 patients randomized, 400 comprised the mITT population. Baseline characteristics were balanced between groups. Successful overall response at EOIVT was observed in 60.3% of patients in the isavuconazole arm and 71.1% in the caspofungin arm (adjusted difference -10.8, 95% confidence interval -19.9--1.8). The secondary endpoints, all-cause mortality, and safety were similar between arms. Median time to clearance of the bloodstream was comparable between groups. CONCLUSIONS: This study did not demonstrate non-inferiority of isavuconazole to caspofungin for primary treatment of invasive candidiasis. Secondary endpoints were similar between both groups. CLINICAL TRIALS REGISTRATION: NCT00413218.

Population pharmacokinetics and pharmacodynamics of piperacillin in critically ill patients during the early phase of sepsis.

This study aimed to characterize the population pharmacokinetics (PKs) of piperacillin and investigate probability of target attainment (PTA) and cumulative fraction of response (CFR) of various dosage regimens in critically ill patients during the early phase of sepsis. Forty-eight patients treated with piperacillin/tazobactam were recruited. Five blood samples were drawn before and during 0-0.5, 0.5-2, 2-4 and 4-6 or 8 h after administration. Population PKs was analyzed using NONMEM®. The PTA of 90%fT>MIC target and CFR were determined by Monte Carlo simulation. The two compartment model best described the data. Piperacillin clearance (CL) was 5.37 L/h, central volume of distribution (V1) was 9.35 L, and peripheral volume of distribution was 7.77 L. Creatinine clearance (CLCr) and mean arterial pressure had a significant effect on CL while adjusted body weight had a significant impact on V1. Subtherapeutic concentrations can occur during the early phase of sepsis in critically ill patients with normal renal function. The usual dosage regimen, 4 g of piperacillin infused over 0.5 h every 6 h, could not achieve the target for susceptible organisms with MIC 16 mg/L in patients with CLCr ≥ 60 mL/min. Our proposed regimen for the patients with CLCr 60-120 mL/min was an extended 2 h infusion of 4 g of piperacillin every 6 h. Most regimens provided CFR ≥ 90% for the E. coli infection while there was no dosage regimen achieved a CFR of 90% for the P. aeruginosa infection.

Population Pharmacokinetics and Pharmacodynamics Modeling of Oral Levofloxacin.

Background: Levofloxacin, a fluoroquinolone, is an isomer of ofloxacin with an extensive spectrum of antimicrobial efficacy. In common with other fluoroquinolones, the main pharmacokinetic/pharmacodynamic (PK/PD) index that correlates with its therapeutic efficacy is the area under the plasma time-concentration curve (AUC)/the minimum inhibitory concentration (MIC) ratios. Objective: To evaluate the population PK and determine the efficacy of various dosage regimens in achieving the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of oral levofloxacin when prescribed as the switching therapy after intravenous levofloxacin treatment. Material and Method: The PK studies were conducted in 45 healthy volunteers who received one 500 mg tablet of levofloxacin and PTAs were determined by using a Monte Carlo simulation. The dosage regimens were predicted to achieve CFR greater than or equal to 90% by referral to the MIC distributions database of the European Committee on Antimicrobial Susceptibility Testing. Results: The population PKs of levofloxacin were; the volume of distribution (V) = 101.71±1.41 L, total clearance (CL) = 8.51±1.43 L/hour and the area under the plasma time-concentration curve from 0 to 24 hours (AUC0-24 ) = 66.19±1.30 mg*hour/L. The predicted CFRs for a target AUC0-24 /MIC ratio of 30 for S. aureus and S. pneumoniae were 83.12% and 92.63%, respectively for 500 mg levofloxacin, and 84.96% and 98.17%, respectively for 750 mg levofloxacin. The predicted CFRs for a target AUC0-24 /MIC ratio of 125 for E. coli and Klebsiella spp. were 84.25% and 88.81%, respectively for 500 mg levofloxacin and 86.00% and 91.34%, respectively for 750 mg levofloxacin. Conclusion: The population PKs of levofloxacin in the present study were similar to the values obtained from the previous study. Both 500 mg qd and 750 mg qd of oral levofloxacin dosage regimens had a high probability of achieving optimal impact against S. pneumoniae, but only the 750 mg qd dosage regimen achieved optimal exposure against Klebsiella spp.

Population Pharmacokinetics and Pharmacodynamics Modeling To Optimize Dosage Regimens of Sulbactam in Critically Ill Patients with Severe Sepsis Caused by Acinetobacter baumannii.

Sulbactam is being considered as an alternative concomitant medication with other effective antibiotics for the treatment of multidrug-resistant (MDR) Acinetobacter baumannii infections. Pathophysiological changes in critically ill patients with severe sepsis, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors in determining therapeutic success. The aims of this study were (i) to examine the population PK parameters and (ii) to assess the probability of target attainment (PTA) for sulbactam in patients with severe sepsis caused by A. baumannii PK studies were carried out following administration of 2 g of sulbactam every 12 h on the 4th day of drug administration in 27 patients, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the plasma drug concentration remained above the MIC (T>MIC) and 60% T>MIC The central and peripheral volumes of distribution were 14.56 and 9.55 liters, respectively, and total clearances of sulbactam were 2.26 liters/h and 7.64 liters/h in patients aged >65 years and ≤65 years, respectively. The high PTAs (≥90%) for targets of 40% T>MIC and 60% T>MIC with a MIC of 4 µg/ml were observed when sulbactam was administered by a 4-h infusion of 1 g every 12 h and 1 g every 8 h, respectively. Sulbactam would be an alternative antibiotic option to coadminister with colistin for the treatment of infections caused by MDR A. baumannii However, for pathogens with MICs of >4 µg/ml, higher dosage regimens of sulbactam are required.

Population pharmacokinetics and Monte Carlo dosing simulations of meropenem during the early phase of severe sepsis and septic shock in critically ill patients in intensive care units.

Pathophysiological changes during the early phase of severe sepsis and septic shock in critically ill patients, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors influencing therapeutic success. The aims of this study were (i) to reveal the population PK parameters and (ii) to assess the probability of target attainment (PTA) for meropenem. The PK studies were carried out following administration of 1 g of meropenem every 8 h during the first 24 h of severe sepsis and septic shock in nine patients, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the free plasma drug concentration remains above the MIC (fT>MIC) and 80% fT>MIC. The volume of distribution (V) and total clearance (CL) of meropenem in these patients were 23.7 liters and 7.82 liters/h, respectively. For pathogens with MICs of 4 µg/ml, the PTAs of 40% fT>MIC following administration of meropenem as a 1-h infusion of 1 g every 8 h and a 4-h infusion of 0.5 g every 8 h were 92.52% and 90.29%, respectively. For pathogens with MICs of 2 µg/ml in immunocompromised hosts, the PTAs of 80% fT>MIC following administration of 1-h and 4-h infusions of 2 g of meropenem every 8 h were 84.32% and 94.72%, respectively. These findings indicated that the V of meropenem was greater and the CL of meropenem was lower than the values obtained in a previous study with healthy subjects. The maximum recommended dose, i.e., 2 g of meropenem every 8 h, may be required for treatment of life-threatening infections in this patient population.

Population pharmacokinetics and dosing simulations of imipenem in serious bacteraemia in immunocompromised patients with febrile neutropenia.

The aims of this study were to i) reveal the population pharmacokinetics; and ii) assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) (defined as the expected population PTA for a specific drug dose and a specific population of microorganisms) of imipenem in febrile neutropenic patients with bacteraemia. Ten patients were randomised into two groups: Group I received a 0.5-h infusion of 0.5 g of imipenem every 6 h (q6h) for 8 doses; and Group II received a 4-h infusion of 0.5 g q6h for 8 doses. A Monte Carlo simulation was performed to determine the PTA. The volume of distribution and total clearance of imipenem were 20.78 ± 1.35 l and 23.19 ± 1.34 l/h, respectively. Only a 4-h infusion of 1 g q6h regimen achieved a PTA >93% for 80% T>MIC for a MIC of 2 µg/ml. A 4-h infusion of all simulated regimens and a 0.5-h infusion of 0.5 g q6h and 1 g q6h achieved targets (CFR ≥ 90%) against Escherichia coli and Klebsiella spp. However, against Pseudomonas aeruginosa and Acinetobacter spp., no regimens achieved their targets. In conclusion, the results indicate that a higher than manufacturer's dosage recommendation is required to maximize the activity of imipenem.

Vancomycin Dosing Regimen by Monte Carlo Simulation in Patients on Intermittent High-Efficiency Hemodialysis (HEHD).

OBJECTIVE: To evaluate the effective vancomycin dosing regimens by Monte Carlo simulation among patients on intermittent high-efficiency hemodialysis (HEHD). MATERIAL AND METHOD: The present study was conducted on eight end-stage renal disease patients receiving HEHD. The patients received an initial dose of vancomycin 1 g followedby 500 mg immediately after HEHD session for a supplementation. Blood samplings were obtained to investigate vancomycin pharmacokinetic parameters. A Monte Carlo simulation was performed to determine the percentage of probability of target attainment (PTA) achieving AUC24/MIC ratio greater than or equal to 400 as the target of achievement of antimicrobial activity. RESULTS: A loading dose (LD) of vancomycin of 20 mg per kilogram of dry weight (DW) with or without a supplementation had the optimum effectiveness for pathogens with MICs not greater than 0.5 mg/L. For pathogens with an MIC of 1.0 mg/L, the LD of 25 mg/kgDW followed by 20 or 25 mg/kgDW supplementation was achieved the target in some cases. Therefore, the LD of 30 mg/kgDW followed by 25 mg/kgDW or the LD of 35 mg/kgDW with 10, 20 or 25 mg/kgDW supplementation was required to achieve the target of antimicrobial activity. CONCLUSION: From the present study, the lowest vancomycin dosing regimen that had the optimum effectiveness was a 35 mg/kgDW LD followed by 10 mg/kgDW supplementation. This regimen is recommended to treat pathogens with MICs not greater than 1.0 mg/L.

Initial dosage regimen of vancomycin for septic shock patients: a pharmacokinetic study and Monte Carlo simulation.

OBJECTIVE: To evaluate the pharmacokinetic parameters of vancomycin in septic shock patients and to determine the vancomycin dosage to achieve requisite pharmacokinetic/pharmacodynamic (PK/PD) target against methicillin resistant Staphylocccus aureus (MRSA) in patients with septic shock. MATERIAL AND METHOD: Pharmacokinetic parameters of vancomycin in 12 septic shock patients were assessed. Then, the Monte Carlo simulation was performed to calculate the probabilities of target attainment (PTAs) to reach target AUC0-24/MIC of 400 and 450 mg.h/L. RESULTS: The total clearance (CL) and the volume of the central compartment (Vc) of vancomycin was 3.34±1.39 L/h and 0.14±1.43 L/kg, respectively. For Staphylococcalspp. with low MICs of 0.125 and 0.5 mg/L, the administration of vancomycin 30 mg/kg as the loading dose, followed by the maintenance dose of 20 mg/kg every six, eight, 12, and 24 hours achieved >90% PTAs to reach target AUC0-24/MlC: For pathogens with MIC of 1, and 1.5 mg/L, the vancomycin maintenance dose of 20 mg/kg every six, eight, and 12 hours and every six and eight hours respectively to achieve >90% PTA. CONCLUSION: High dose ofvancomycin is required to achieve PK/PD target for treatment of MRSA septic shock, especially if MRSA MIC is higher than 1 mg/L.

Pharmacokinetics of intravenous piperacillin/tazobactam among patients with peritoneal dialysis-associated peritonitis.

Currently, pharmacokinetic information on intravenous (IV) piperacillin/tazobactam in patients with peritoneal dialysis-associated peritonitis (PD peritonitis) is limited. This study employed a prospective single-dose pharmacokinetic design to assess the pharmacokinetics of IV piperacillin/tazobactam in these patients. Four patients with PD peritonitis who received an IV loading dose of 4000 mg/500 mg piperacillin/tazobactam were enrolled in this study. The concentrations of piperacillin and tazobactam in plasma, peritoneal dialysis fluid (PDF) and urine were determined by high-performance liquid chromatography. Non-compartmental methods were used for pharmacokinetic analysis. During a 6-h dwell time for chronic ambulatory peritoneal dialysis (CAPD), 9.23 ± 4.01% of the piperacillin was recovered in the PDF. This result is greater than that observed in patients without peritonitis in prior research. Piperacillin's PD clearance (CLPD), steady-state volume of distribution (Vss) and terminal half-life (t 1/2) were 5.79 ± 2.55 mL/min, 24.35 ± 11.26 L and 5.74 ± 1.53 h, respectively. These values are also higher than those of patients without peritonitis in a prior study. Eight hours following the loading dosage, the plasma and PDF piperacillin concentrations of all patients (98.25 ± 26.03 and 52.70 ± 22.99 mg/L, respectively) surpassed the Pseudomonas aeruginosa and Enterobacterales Clinical and Laboratory Standards Institute susceptible breakpoints. In summary, the CLPD, Vss and t 1/2 for piperacillin were found to be greater in patients with PD peritonitis than in CAPD patients without peritonitis when compared with the results of a previous study. The IV loading dose of 4000 mg/500 mg piperacillin/tazobactam is sufficient to treat peritonitis caused by susceptible P. aeruginosa and Enterobacterales. The multiple-dose pharmacokinetics of IV piperacillin and tazobactam in this specific patient group should be further investigated.

Pharmacodynamics modeling to optimize dosage regimens of sulbactam.

The aim of this study was to reveal population pharmacokinetics and assess the efficacies of various dosage regimens of sulbactam in terms of the probability of target attainment with this agent over a range of MICs. Monte Carlo simulations were performed to determine the probability of attaining specific pharmacodynamic targets. The results indicated that a regimen consisting of a 4-h infusion of 3 g of sulbactam every 8 h would be an alternative treatment option for less-susceptible pathogens.

Pharmacodynamics of imipenem in critically ill patients with ventilator-associated pneumonia.

BACKGROUND: Drug dispositions are altered in critically ill patients, including ventilator-associated pneumonia (VAP) when compared with healthy subjects leading to fluctuations of plasma concentrations. OBJECTIVE: To compare the probability of target attainment (PTA) and cumulative fraction of response (CFR) for imipenem between administration by 0.5-hour and 2-hour infusions. MATERIAL AND METHOD: The present study was a randomized three-way crossover in nine patients with VAP Each patient received imipenem in three regimens consecutively: (i) a 0.5-hour infusion of 0.5 g every six hours for 24 hours; (ii) a 2-hour infusion of 0.5 g every six hours for 24 hours; and (iii) a 2-hour infusion of 1 g every six hours for 24 hours. Monte Carlo simulation was performed to determine the PTA at various regimens and the study used susceptibility patterns obtained from EUCAST and MYSTIC for assessment of CFR. RESULTS: For an MIC of 2 microg/ml, the PTAs achieving 40% T > MIC following a 0.5-hour infusion of 0.5 g, a 2-hour infusion of 0.5 g, and a 2-hour infusion of 1 g were 90.93%, 98.97%, and 100%, respectively. Only a 2-hour infusion of 1 g achieved 98.75% of the PTA of 40% T > MGC for an MIC of 4 microg/ml. All regimens were predicted to achieve CFR > 99% against E. coli and Klebsiella spp. CONCLUSION: A 2-hour infusion of 1 g regimen was predicted to have the highest PTA rates. All regimens achieved a high CFR against E. coli and Klebsiella spp.

Pharmacodynamics of meropenem in critically ill patients with ventilator-associated pneumonia.

BACKGROUND: Pharmacokinetic changes have been found in critically ill patients, including ventilator-associated pneumonia (VAP) when compared with healthy volunteers leading to fluctuation of plasma concentrations. OBJECTIVE: To compare the probability of target attainment (PTA) and cumulative fraction of response (CFR) for meropenem between administration by a bolus injection and a 3-hour infusion. MATERIAL AND METHOD: The study was a randomized three-way crossover in nine patients with VAP. Each patient received meropenem in three regimens consecutively: (i) a bolus injection of 1 g every eight hours (q8h) for 24 hours; (ii) a 3-hour infusion of 1 g q8h for 24 hours; and (iii) a 3-hour infusion of 2 g q8h for 24 hours. The pharmacodynamic analysis of meropenem was performed to determine the PTA by using the Monte Carlo simulation and the study used susceptibility patterns obtained from EUCAST and MYSTIC for assessment of CFR. RESULTS: For an MIC of 4 microg/ml, the PTAs achieving 40% T > MIC following a bolus injection of 1 g q8h, a 3-hour infusion of 1 g q8h, and a 3-hour infusion of 2 g q8h were 87.71%, 98.80%, and 99.90%, respectively. Only the 3-hour infusion regimens were predicted to achieve a CFR > or = 90% against E. coli, Klebsiella spp., P. aeruginosa, and Acinetobacter spp. CONCLUSION: A 3-hour infusion of 2 g of meropenem regimen was predicted to have the highest PTA rates. Only the prolonged infusion regimens achieved a high CFR against E. coli, Klebsiella spp., P. aeruginosa, and Acinetobacter spp.

Impact of therapeutic plasma exchange on meropenem pharmacokinetics.

STUDY OBJECTIVE: The aim of this study was to investigate the impact of therapeutic plasma exchange (TPE) on the plasma concentrations and pharmacokinetic (PK) patterns of meropenem. DESIGN: Prospective, open-label, PK study. SETTING: Academic tertiary care medical center. PATIENTS: Eleven patients who underwent TPE. MEASUREMENTS: A single-center PK study was conducted on adult patients who underwent TPE. All patients received two phases of meropenem administration for research purposes. Meropenem PK studies were carried out after the administration of a single dose of 1 g of meropenem in the patients during TPE (phase 1) and compared with meropenem 1 g administration in the same patients without TPE (phase 2), which served as the control phase with an at least 72-h wash-out period separating the phases. MAIN RESULTS: The total clearance (CL) of meropenem during TPE was greater than the values obtained from the same patients without TPE (13.37 ± 6.23 L/h during TPE vs. 8.42 ± 2.84 L/h without TPE). The mean drug fraction eliminated during TPE was 14.22 ± 11.03%, and the mean amount of drug removed by the TPE was 142.23 ± 110.31 mg. CONCLUSIONS: These results indicate that the TPE had an impact on the elimination of meropenem in patients during the exchange procedure. The CL of meropenem during TPE was greater than the values obtained from the control phase without TPE.

NONMEM population pharmacokinetics and Monte Carlo dosing simulations of imipenem in critically ill patients with life-threatening severe infections during support with or without extracorporeal membrane oxygenation in an intensive care unit.

STUDY OBJECTIVES: The objectives of this study were (i) to determine the population pharmacokinetic (PK) of imipenem in critically ill patients with life-threatening severe infections, (ii) to investigate the impact of extracorporeal membrane oxygenation (ECMO) on the population PK of imipenem during support with ECMO compared to those without ECMO support, and (iii) to assess the probability of target attainment (PTA) for finding the optimal dosage regimens of imipenem in critically ill patients with life-threatening severe infections. DESIGN: Open-label, PK study. SETTING: Academic tertiary care medical center. PATIENTS: Fifty critically ill patients with or without ECMO by pooling data from previously published studiesand unpublished data from 14 patients. INTERVENTION AND MEASUREMENTS: The population PK of imipenem was determined using NONMEM and a Monte Carlo simulation was performed to determine the PTAs of achieving 40% and 75% exposure times during which the plasma drug concentrations remained above the MIC. MAIN RESULTS: The values of volume of distribution and total clearance were 30.5 L and 13.3 L/h, respectively. The ECMO circuit did not show a significant influence on the PK parameters of imipenem. For pathogens with a MIC of 4 mg/L, the PTA target of 75% fT>MIC in patients with normal renal function was achieved when the imipenem was administered by a 4-h infusion of 1 g q6h. CONCLUSION: The ECMO circuit had little effect on enhancing the PK changes of imipenem that had already occurred in these patients. A high dosage of imipenem may be required for achieving the PK/pharmacodynamic targets against less susceptible pathogens, however, the dosage regimens in patients with renal impairment may not need to be as high as those required in patients with normal renal function. ClinicalTrials.gov: NCT03858387.

Effects of long-term use of HAART on oral health status of HIV-infected subjects.

BACKGROUND: The aim of this study was to determine the effects of long-term use of highly active antiretroviral therapy (HAART) on oral health status of HIV-infected subjects. METHODS: Oral examination and measurement of saliva flow rate of both unstimulated and wax-stimulated whole saliva were performed in HIV-infected subjects with and without HAART, and in non-HIV individuals. The following data were recorded; duration and risk of HIV infection, type and duration of HAART, CD4 cell count, viral load, presence of orofacial pain, oral dryness, oral burning sensation, oral lesions, cervical caries, and periodontal pocket. Multiple logistic regression analysis was performed to determine the effects of long-term use of HAART on oral health status of HIV-infected subjects. RESULTS: One hundred and fifty-seven HIV-infected subjects - 99 on HAART (age range 23-57 years, mean 39 years) and 58 not on HAART (age range 20-59 years, mean 34 years) - and 50 non-HIV controls (age range 19-59 years, mean 36 years) were enrolled. The most common HAART regimen was 2 NRTI + 2 NNRTI. HIV-infected subjects without HAART showed greater risks of having orofacial pain, oral dryness, oral lesions, and periodontal pockets than those with short-term HAART (P < 0.01). The subjects with long-term HAART were found to have a greater risk of having oral lesions than those with short-term HAART (P < 0.05). The unstimulated and stimulated salivary flow rates of the subjects with HAART were significantly lower than in those without HAART (P < 0.05). CONCLUSION: We conclude that long-term HAART has adverse effects on oral health status of HIV-infected subjects.

Comparative study of pharmacokinetics/ pharmacodynamics of ciprofloxacin between 400 mg intravenously every 8 h and 400 mg intravenously every 12 h in patients with gram negative bacilli bacteremia.

OBJECTIVE: To compare the ratio of the area under the concentration-time curve at 24 hours to the minimum inhibitory concentration value (24-h AUC/MIC) of ciprofloxacin between 400 mg intravenously every 8 h and 400 mg intravenously every 12 h. MATERIAL AND METHOD: A prospective, randomized, two-way crossover study of 10 patients with gram-negative bacilli bacteremia was conducted. All patients were randomized to receive ciprofloxacin in both regimens consecutively: (i) 400 mg intravenously every 8 h for four doses; (ii) 400 mg intravenously every 12 h for four doses. Ciprofloxacin pharmacokinetic studies were carried out after the start of both regimens. RESULTS: For the ciprofloxacin 400 mg intravenously every 8 h regimen, the 24-h AUC/MIC at MICs of 0.5 and 1 microg/ml were 218.63 +/- 78.75 and 109.31 +/- 39.37, respectively. For the ciprofloxacin 400 mg intravenously every 12 h regimen, the 24-h AUC/MIC at MICs of 0.5 and +/- microg/ml were 144.07 +/- 57.02 and 72.03 +/- 28.51, respectively. After 14 days of ciprofloxacin treatment, the gram-negative bacilli infections were eradicated in all patients. Moreover, during both regimens, no adverse events related to the use of ciprofloxacin were observed. CONCLUSION: Both ciprofloxacin 400 mg every 8 h and 400 mg every 12 h regimens can provide good coverage for pathogens with the susceptibility breakpoint of ciprofloxacin with an MIC of 0.5 microg/ml. For pathogens with an MIC of 1.0 microg/ml, only ciprofloxacin 400 mg every 8 h regimen can provide a 24-h AUC/MIC ratio greater than 100.

Comparison of continuous infusion versus intermittent infusion of vancomycin in patients with methicillin-resistant Staphylococcus aureus.

OBJECTIVE: To compare the pharmacokinetics of vancomycin administration by continuous infusion and intermittent infusion. MATERIAL AND METHOD: A prospective, randomized, two-way crossover study of 12 patients with methicillin-resistant Staphylococcus aureus infections was conducted. All patients were randomized to receive vancomycin in both regimens consecutively: (i) infusion of 15 mg/kg of vancomycin as a loading dose for 1 h followed by 30 mg/kg of vancomycin as a continuous infusion over 24 h for 48 h; and (ii) intermittent infusion of 15 mg/kg of vancomycin for 1 h every 12 h for 48 h. Vancomycin pharmacokinetic studies were carried out during hours 24-48 after the start of both regimens. RESULTS: For the continuous infusion regimen, the mean highest steady-state concentration was 24.88 +/- 12.75 microg/ml and the mean lowest steady-state concentration was 19.89 +/- 10.15 microg/ml. For the intermittent infusion regimen, the mean peak and trough serum concentrations were 55.02 +/- 17.36 and 12.43 +/- 12.86 microg/ml, respectively. After 10 days of vancomycin treatment, the MRSA infections were eradicated in all patients. Moreover, during both methods of infusion, no adverse events related to the use of vancomycin were observed. CONCLUSION: Either continuous infusion or intermittent infusion can be used as an effective mode of vancomycin administration to achieve bactericidal activity.

Pharmacokinetics and Monte Carlo Dosing Simulations of Imipenem in Critically Ill Patients with Life-Threatening Severe Infections During Support with Extracorporeal Membrane Oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO), a cardiopulmonary bypass device, has been found to increase the profound pathophysiological changes associated with life-threatening severe infections in patients with multiple comorbidities, which results in alterations of pharmacokinetic patterns for antibiotics. OBJECTIVES: The aims of this study were (1) to determine the pharmacokinetics of imipenem and (2) to assess the probability of target attainment (PTA) for imipenem in critically ill patients with life-threatening severe infections during support with ECMO. METHODS: The pharmacokinetic studies were carried out following administration of 0.5 g of imipenem every 6 h on the 4th dose of drug administration in 10 patients and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the plasma drug concentrations remained above minimum inhibitory concentration (T > MIC) and 80% T > MIC. RESULTS: The median values of volume of distribution and total clearance (CL) of imipenem in these patients were 13.98 L and 9.78 L/h, respectively. A high PTA (≥ 90%) for a target of 80% with a MIC of 4 µg/mL in patients with CLCR 60-120 mL/min and flow rate of ECMO circuit 3-5.5 L/min was observed when imipenem was administered by a 4-h infusion of 1 g every 6 h. CONCLUSIONS: A high dosage regimen such as 1 g every 6 h of imipenem may be required to achieve pharmacodynamic targets against less susceptible pathogens in this patient population. CLINICALTRIAL. GOV IDENTIFIER: NCT03776305, date of registration: 11 December 2018.