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 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.

Outcomes of Adjunctive Therapy with Open Arthrotomy for Patients with Septic Arthritis Due to Melioidosis: A Retrospective Study.

Melioidosis is a potentially fatal infection caused by the bacterium Burkholderia pseudomallei. Septic arthritis caused by this infection is uncommon and difficult to treat. The role of adjunctive open arthrotomy in this type of infection has not yet been elucidated. We conducted a retrospective study of patients with microbiologically confirmed melioidosis between January 2002 and December 2022. Patients with a clinical condition of septic arthritis and positive cultures for B. pseudomallei were included. Comparisons were made between patients who received adjunctive therapy with open arthrotomy with conventional standard treatment and those who did not in terms of clinical outcomes and hospital expenditures. Of the 478 patients diagnosed with melioidosis microbiological confirmation, 81 patients had septic arthritis, accounting for 17% of cases. Among these patients, only 36 (44%) underwent adjunctive therapy with open arthrotomy. The 14-day and 30-day in-hospital mortality and length of hospital stays of patients who underwent adjunctive therapy with open arthrotomy were more favorable than those of patients who did not receive adjunctive therapy with open arthrotomy; however, the difference was not statistically significant. Patients who underwent adjunctive therapy with open arthrotomy had lower hospital expenditures (antimicrobial and non-antimicrobial costs) than those who did not undergo open arthrotomy. Adjunctive therapy with open arthrotomy for patients with septic arthritis due to melioidosis was associated with favorable clinical outcomes and significantly lower hospital expenditures.

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.

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.

Pharmacodynamics of doripenem in critically ill patients with ventilator-associated Gram-negative bacilli pneumonia.

Several pathophysiological changes in critically ill patients are important in determining the therapeutic success of ß-lactam antibiotics. The aim of this study was to assess the population pharmacokinetics and probabilities of target attainment (PTAs) of doripenem in patients with ventilator-associated pneumonia, comparing administration by 1-h and 4-h infusion. Patients were randomised into two groups: Group I received a 1-h infusion of 0.5 g every 8 h (q8h) for seven doses; and Group II received a 4-h infusion of 0.5 g q8h for seven doses. A Monte Carlo simulation was performed to determine the PTAs. PTAs of achieving 40% T(>MIC) [exposure time during which the free drug concentration remains above the minimum inhibitory concentration (MIC)] and 75% T(>MIC) are required for effective bactericidal activity of this agent in immunocompetent and immunocompromised hosts, respectively. Values of volume of distribution and total clearance of doripenem in these patients were 17.26±1.83 L and 24.89±1.63 L/h, respectively. For pathogens with a MIC of 1 µg/mL, the PTAs of achieving 40% T(>MIC) following administration of doripenem by a 1-h and 4-h infusion of 0.5 g q8h were 92.95% and 98.32%, respectively. For pathogens with a MIC of 2 µg/mL in immunocompromised hosts, the PTAs of achieving 80% T(>MIC) following administration of doripenem by 1-h and 4-h infusion of 2 g q8h were 56.57% and 91.21%, respectively. In conclusion, these findings indicated that higher than recommended doses in this patient population, particularly neutropenic patients, would be necessary to optimise the pharmacokinetics of doripenem.

Pharmacodynamics of meropenem in critically ill patients with febrile neutropenia and bacteraemia.

The bactericidal activity of ß-lactams is determined by the time that concentrations in tissue and serum are above the minimum inhibitory concentration (T>MIC) for the pathogen. The aim of this study was to compare the probability of target attainment (PTA) and the cumulative fraction of response (CFR) for meropenem between administration by bolus injection and a 3-h infusion. The study was a randomised, three-way, cross-over design in eight febrile neutropenic patients with bacteraemia. Each subject received meropenem in three regimens consecutively: (i) a bolus injection of 1g every 8 h (q8h) for 24 h; (ii) a 3-h infusion of 1 g q8h for 24 h; and (iii) a 3-h infusion of 2 g q8h for 24h. For pathogens with an MIC of 4 µg/mL, the PTA of achieving 40% T>MIC following administration of meropenem by a bolus injection of 1g q8h, a 3-h infusion of 1 g q8h and a 3-h infusion of 2g q8h was 75.7%, 99.24% and 99.96%, respectively. Only the 3-h infusion of 2 g q8h achieved a PTA >99% for 40% T>MIC for a MIC of 8µg/mL. By referral to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) MIC distributions, the three regimens of meropenem were predicted to achieve a CFR≥90% against Escherichia coli and Klebsiella spp. In conclusion, a 3-h infusion of 2 g of meropenem q8h resulted in the highest PTA rates. The three regimens of meropenem had high probabilities of achieving optimal impact against E. coli and Klebsiella spp.