Meropenem dosing recommendations for critically ill patients receiving continuous renal replacement therapy

PurposesTo gather available meropenem pharmacokinetics and define drug dosing regimens for Asian critically ill patients receiving CRRT.MethodsAll necessary pharmacokinetic and pharmacodynamic data from Asian population were gathered to develop mathematic models with first order elimination. Meropenem concentration-time profiles were calculated to evaluate efficacy based on the probability of target attainment (PTA) of 40%fT_>4MIC. A group of 5000 virtual patients was created and tested using Monte Carlo simulations for each dose in the models. The optimal dosing regimens were defined as the doses achieved at least 90% of the PTA.ResultsThe recommended meropenem dosing regimen for Asian critically ill patients receiving CRRT with standard (20–25 mL/kg/h) and high (35 mL/kg/h) effluent rates was 750 mg q 8 h to manage Gram negative infections with expected MIC < 2 mg/L in virtual Asian patients. Some meropenem dosages from available clinical resources could not achieve the aforementioned target. The volume of distribution, body weights and nonrenal clearance significantly contributed to drug dosing adaptation especially in the specific population.ConclusionsA meropenem regimen of 750 mg q 8 h was recommended for Asian critically ill patients receiving 2 different CRRT modalities with standard and high effluent rates. Clinical validation of these results is needed.     

Population Pharmacokinetics Study of Contezolid (MRX-I), a Novel Oxazolidinone Antibacterial Agent,in Chinese Patients

PurposeContezolid (MRX-I) is a novel oxazolidinone with potent in vitro activity against gram-positive pathogens. The aim of this study was to establish the dose-pharmacokinetic (PK) exposure-pharmacodynamic (PD)–response relationship and to quantitatively evaluate the variability of MRX-I after continuous oral administration of 600 mg BID and 800 mg BID for 14 days under fed conditions in patients with skin and skin structure infections. Another goal was to evaluate the 2 dosing regimens against methicillin-resistant Staphylococcus aureus infections based on PK/PD analysis.MethodsPK data from healthy volunteers and patients were pooled to develop a population PK model using a nonlinear mixed effect modeling method. Monte Carlo simulations were used to predict probability of target attainment (PTA) and cumulative fraction of response after single oral administration of 600 and 800 mg of MRX-I under fed conditions.FindingsThe PK profile of oral administration of MRX-I was described by using a 2-compartment model with first-order elimination. Absorption of MRX-I may be affected by food intake. Type of volunteers could affect absorption constant rate and volume of distribution in the peripheral compartment, and weight could affect volume of distribution in the central department. No obvious effect on PK parameters was identified for other factors such as age, sex, creatinine clearance, concomitant medicine, and baseline diseases. Based on Monte Carlo simulation, MRX-I 600 or 800 mg BID up to 14 days on ordinary fed status could produce satisfactory efficacy against methicillin-resistant S aureus, with cumulative fraction of response >90% for fAUC_0–24/MIC targeted at 2.3. At MIC ≤2.0 μg/mL for MRX-I 600 mg BID, or at MIC ≤4.0 μg/mL for MRX-I 800 mg BID, with continuous administration for 14 days at fed status, both regimens could obtain satisfactory clinical and antibacterial efficacy, with PTA >90%. Hence, the MRX-I regimen of 800 mg BID for 7–14 days can be recommended for confirmative clinical trials in patients with skin and skin structure infections.ImplicationsPK profiles of MRX-I were well captured by using a 2-compartment PK model, and disease status, food intake, and weight were found to significantly affect PK profiles. A dosing regimen of 800 mg BID for 7–14 days with ordinary food intake was recommended for pivotal study based on simulated fAUC_0–24/MIC and PTA values. Results suggest that dose adjustments are not necessary for patient sex in confirmatory studies. Chinese Clinical Trial Registration identifier: CTR20140056.     

Telavancin pharmacokinetics and pharmacodynamics in patients with complicated skin and skin structure infections and various degrees of renal function

This study characterized the pharmacokinetic/pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved telavancin renal dose adjustment schemes. A previously published two-compartment open model with first-order elimination and a combined additive and proportional residual error model derived from 749 adult subjects in 11 clinical trials was used to simulate the individual concentration-time profiles for 10,260 subjects (NONMEM). The dosing regimens simulated were 10 mg/kg of body weight once daily for individuals with creatinine clearances (CL_CRs) of >50 ml/min, 7.5 mg/kg once daily for individuals with CL_CRs of 30 to 50 ml/min, and 10 mg/kg every 2 days for those with CL_CRs of <30 ml/min. The area under the concentration-time curve (AUC) under one dosing interval (AUC_τ) was computed as dose/CL. The probability of achieving an AUC_τ/MIC ratio of ≥219 was evaluated separately for each renal dosing scheme. Evaluation of the dosing regimens demonstrated similar AUC values across the different renal function groups. For all renal dosing strata, >90% of the simulated subjects achieved an AUC_τ/MIC ratio of ≥219 for MIC values as high as 2 mg/liter. For patients with CL_CRs of <30 ml/min, the probability of target attainment (PTA) exceeded 90% for both the AUC_0–24 (AUC from 0 to 24 h) and AUC_24–48 intervals for MICs of ≤1 mg/liter. At a MIC of 2 mg/liter, the PTAs were 89.3% and 23.6% for the AUC_0–24 and AUC_24–48 intervals, respectively. The comparable PTA profiles for the three dosing regimens across their respective dosing intervals indicate that the dose adjustments employed in phase III trials for complicated skin and skin structure infections were appropriate.     

The effect of pharmacokinetic/pharmacodynamic (PK/PD) parameters of gatifloxacin on its bactericidal activity and resistance selectivity against clinical isolates of Streptococcus pneumoniae

The impact of the pharmacokinetic/pharmacodynamic (PK/PD) parameters (the 24h area under the concentration-time curve [AUC_24h]/minimum inhibitory concentration [MIC] and maximum concentration in serum [C_max]/MIC ratio) after single oral dosing of gatifloxacin on its bactericidal activity and resistance selectivity against quinolone-susceptible clinical isolates of Streptococcus pneumoniae J-69 was investigated using an in vitro PK model. The MICs of gatifloxacin, levofloxacin, and ciprofloxacin were 0.25, 1, and 1µg/ml, respectively. When the range of AUC_24h/MIC ratios was varied from 9.0 to 36 with a constant C_max/MIC ratio of 3.4, the bactericidal activity was correlated with the AUC_24h/MIC ratios. Eradication was observed at an AUC_24h/MIC ratio of 36. On the other hand, the resistance selectivity was associated with the C_max/MIC ratio. Mutant strains were selected at a C_max/MIC ratio of 0.84, but not 1.7 with a constant AUC_24h/MIC ratio of 9.0. These results suggested that an AUC_24h/MIC ratio of 36 and a C_max/MIC ratio of 1.7 might be possible benchmarks to show enough bacterial eradication and prevention of emergence of resistant strains to gatifloxacin, respectively. When the serum concentrations after clinical oral dosing of gatifloxacin (200mg b.i.d.), levofloxacin (100mg t.i.d.), and ciprofloxacin (200mg t.i.d.) were simulated, the bactericidal activity of gatifloxacin was higher than those of levofloxacin and ciprofloxacin. Moreover, no resistant strain was obtained by the exposure to gatifloxacin and levofloxacin, whereas ciprofloxacin selected resistant strains. The clinically relevant oral dosage of gatifloxacin was anticipated to result in a high AUC_24h/MIC₉₀ ratio of 81 and a C_max/MIC₉₀ ratio of 4.4, suggesting that this agent is clinically effective in the treatment of pneumococcal infections.     

Pharmacodynamic Target Attainment for Various Ceftazidime Dosing Schemes in High-Flux Hemodialysis

Ceftazidime is a broad-spectrum cephalosporin with high-level activity against a variety of Gram-negative pathogens, including Pseudomonas aeruginosa. Improved outcomes are associated with cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%T_MIC) of >45 to 70% of the dosing interval. Optimal dosing to achieve a 90% probability of target attainment (PTA) in patients receiving high-flux hemodialysis (HFHD) is unknown. We used existing data from six anephric adults receiving hemodialysis to construct a population model with the Pmetrics package for R. From the final model''s joint probability density, we simulated the PTA for various ceftazidime dosing regimens, HFHD schedules, and organism MICs. For HFHD every 48 h and 1 g of ceftazidime given posthemodialysis, the PTA exceeds 90% for all isolates with MICs of ≤8 μg/ml, assuming a goal of 70%T_MIC. For 72-h dialysis intervals, postdialysis dosing of 1 g is adequate for achievement of the 70%T_MIC goal only for organisms with MICs of ≤4 μg/ml, while 2 g is adequate for organisms with MICs of ≤8 μg/ml. A dose of 500 mg once daily, regardless of HFHD schedule, has a 90% PTA for organisms with MICs of ≤16 μg/ml, while 1 g once daily may achieve 100% PTA even for resistant organisms with a MIC of 32 μg/ml. Therefore, to ensure maximal ceftazidime activity, once-daily dosing of 500 mg to 1 g ceftazidime in patients receiving HFHD may be preferable for critically ill patients when MIC data are unavailable and for more resistant organisms with ceftazidime MICs of 16 to 32 μg/ml.     

A Simulated Application of the Hartford Hospital Aminoglycoside Dosing Nomogram for Plazomicin Dosing Interval Selection in Patients With Serious Infections Caused by Carbapenem-Resistant Enterobacterales

PurposeIn the Phase III Study of Plazomicin Compared With Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CARE), plazomicin was studied for the treatment of critically ill patients with infections caused by carbapenem-resistant Enterobacterales. Initial plazomicin dosing was guided by creatinine clearance (CrCl) and subsequent doses adjusted by therapeutic drug monitoring to achieve AUC_0–24 exposures within a target range (210–315 mg?h/L). We applied the Hartford nomogram to evaluate whether this clinical tool could reduce plazomicin troughs levels and increase the proportion of patients within the target AUC range.MethodsThirty-seven patients enrolled in cohorts 1 or 2 of CARE were eligible for analyses. Observed 10-hour concentrations after the initial dose were plotted on the Hartford nomogram to determine an eligible dosing interval group (q24h, q36h or q48h). On the basis of baseline CrCl, a 15- or 10-mg/kg dose was simulated with the nomogram-recommended dosing interval. The proportion of patients in each dosing interval group with a trough ≥3 mg/L (trough threshold associated with serum creatinine increases ≥0.5 mg/dL in product label) was quantified. Simulated interval-normalized AUC_0–24 was compared with the target AUC range.FindingsAmong the 28 patients with a CrCl ≥60 mL/min, the nomogram recommended every-24-hour dosing in 61% and an extended-interval (q36h or q48h) in 39% of patients. For patients with a CrCl ≥30–59 mL/min (n = 9), the nomogram recommended every-24-hour dosing and an extended-interval in 22% and 78% of patients, respectively. Among both renal function cohorts, exposure simulation with the nomogram significantly reduced the proportion of patients with trough concentrations ≥3 mg/L (CrCl ≥60 mL/min cohort: 91% vs 9%, P < 0.001; CrCl ≥30–59 mL/min cohort, 100% vs 0%, P < 0.001). Relative to the observed mean (SD) AUC_0–24 of 309 mg?h/mL (96 mg?h/mL), simulation of extended intervals resulted in a mean interval-normalized AUC_0–24 of 210 mg?h/mL (40 mg?h/mL) in all patients eligible for an extended interval, resulting in a similar proportion (49% vs 54%) of patients within the target AUC_0–24 range after the first dose.ImplicationsApplication of the Hartford nomogram successfully reduced the likelihood of elevated plazomicin trough concentrations while improving AUC exposures in these patients with carbapenem-resistant Enterobacterales infections.     

An initial dosing method for teicoplanin based on the area under the serum concentration time curve required for MRSA eradication

Teicoplanin is a glycopeptide antibacterial agent that has a long serum half-life and therefore takes time to achieve steady-state conditions. An appropriate initial dosing is needed for teicoplanin to promptly reach an effective serum trough concentration. However, little information is available on tailoring the initial dosing for patients with various characteristics. The objective of this study was to develop a nomogram for determining teicoplanin initial dose to promptly reach an effective trough concentration (≥13 μg/mL). A logistic regression analysis was performed to test whether the area under the concentration time curve (AUC) is a significant predictor of microbiological response (persistence 0; eradication 1). The study included 24 adult patients with methicillin-resistant Staphylococcus aureus infections [minimal inhibitory concentration (MIC) for the isolates was <2 μg/mL). Each AUC was estimated using individual dose, creatinine clearance (CL_cr), and body weight data. The target value, which gives about a 0.9 microbiological eradication probability, was 750 μg h/mL for AUC from zero to 24 h (AUC_0–24 h). Using published population pharmacokinetic parameters, the dose required to achieve the AUC_0–24 h target was calculated as dose (mg) = 750 × (0.00498 × CL_cr (mL/min) + 0.00426 × body weight (kg). For various combinations of CL_cr and body weight, we checked the calculated doses using a therapeutic drug monitoring (TDM)-supporting software and developed a nomogram. The nomogram would be useful for initial dose adjustment to promptly reach an effective serum trough concentration and avoid adverse events of teicoplanin.     

Levofloxacin pharmacokinetics and pharmacodynamics in patients with severe burn injury

Levofloxacin pharmacokinetics were studied in 11 patients with severe burn injuries. Patients (values are means +/- standard deviations; age, 41 +/- 17 years; weight, 81 +/- 12 kg; creatinine clearance, 114 +/- 40 ml/min) received intravenous levofloxacin at 750 mg (n = 10 patients) or 500 mg (n = one patient) once daily. Blood samples were collected on day 1 of levofloxacin therapy; eight patients were studied again on days 4 to 6. The pharmacodynamic probability of target attainment (PTA) was evaluated by Monte Carlo simulation. Mean systemic clearance, half-life, and area under the concentration-time curve over 24 h after levofloxacin at 750 mg were 9.0 +/- 3.2 liters/h, 7.8 +/- 1.6 h, and 93 +/- 31 mg . h/liter, respectively. There were no differences in pharmacokinetic parameters between day 1 and day 4; however, large intrapatient and interpatient variability was observed. Levofloxacin pharmacokinetics in burned patients were similar to those reported in other critically ill populations. Levofloxacin at 750 mg achieved >90% PTA for gram-negative and gram-positive pathogens with MICs of < or =0.5 microg/ml and MICs of < or =1 microg/ml, respectively. However, satisfactory PTA was not obtained with less-susceptible gram-negative organisms with MICs of 1 microg/ml or any organism with a MIC of > or =2 microg/ml. The results of this study indicate that levofloxacin should be administered at 750 mg/day for treatment of systemic infections in severely burned patients. However, even 750 mg/day may be inadequate for gram-negative organisms with MICs of 1 to 2 microg/ml even though they are defined as susceptible. Alternative antibiotics or treatment strategies should be considered for infections due to these pathogens.     

Pharmacodynamic evaluation of tosufloxacin against Streptococcus pneumoniae in an in vitro model simulating serum concentration

We compared the antibacterial effects and the emergence of resistance to tosufloxacin or levofloxacin for Streptococcus pneumoniae by simulating the serum concentration according to the Japanese clinical regimens using an in vitro pharmacokinetic-pharmacodynamic model. For quinolone-susceptible strain ATCC49619, tosufloxacin showed bactericidal activity, given that both the AUC_0–24h/MIC ratios at the dosage of 150 mg t.i.d. and 300 mg b.i.d. of tosufloxacin tosilate were 138 and 193, and the C_max/MIC ranges were 7.93–10.2 and 15.9–17.6, respectively, which were greater than those of levofloxacin (100 mg t.i.d. and 200 mg b.i.d.). The greater area above the killing curves (AAKCs) or shorter time to achieve 99.9% killing (99.9% KT) in both models of tosufloxacin than those of levofloxacin was related to their larger AUC_0–24h/MIC and C_max/MIC. Exposure of only 100 mg t.i.d. of levofloxacin led to outgrowth of the parC mutants, which were twofold less susceptible to levofloxacin than the parent strain. Neither of the tosufloxacin tosilate regimens resulted in isolation of resistant mutants of this strain. For the parC mutant strain D-3197, both the AUC_0–24h/MIC and C_max/MIC ratios of tosufloxacin were greater than those of levofloxacin, which resulted in comparable or better bactericidal activity as compared to those of levofloxacin. However, both fluoroquinolones and both regimens led to outgrowth of resistant mutants, which possessed a mutation in gyrA in addition to parC. In conclusion, tosufloxacin is superior to levofloxacin in bactericidal activity against S. pneumoniae in the Japanese clinical regimens, especially in the quinolone-susceptible strain, without emergence of resistant subpopulations.     

Pharmacokinetic and Pharmacodynamic Characteristics of Vancomycin and Meropenem in Critically Ill Patients Receiving Sustained Low-efficiency Dialysis

PurposeAntibiotic dosing is challenge in critically ill patients undergoing renal replacement therapy. Our aim was to evaluate the pharmacokinetic and pharmacodynamic (PK/PD) characteristics of meropenem and vancomycin in patients undergoing SLED.MethodsConsecutive ICU patients undergoing SLED and receiving meropenem and/or vancomycin were prospectively evaluated. Serial blood samples were collected before, during, and at the end of SLED sessions. Antimicrobial concentrations were determined using a validated HPLC method. Noncompartmental PK analysis was performed. AUC was determined for vancomycin. For meropenem, time above MIC was calculated.FindingsA total of 24 patients receiving vancomycin and 21 receiving meropenem were included; 170 plasma samples were obtained. Median serum vancomycin and meropenem concentrations before SLED were 24.5 and 28.0 μg/mL, respectively; after SLED, 14 and 6 μg/mL. Mean removal was 42% with vancomycin and 78% with meropenem. With vancomycin, 19 (83%), 16 (70%), and 15 (65%) patients would have achieved the target (AUC_0–24 >400) considering MICs of 1, 2, and 4 mg/L, respectively. With meropenem, 17 (85%), 14 (70%), and 10 (50%) patients would have achieved the target (100% of time above MIC) if infected with isolates with MICs of 1, 4, and 8 mg/L, respectively.ImplicationsSLED clearances of meropenem and vancomycin were 3-fold higher than the clearance described by continuous methods. Despite this finding, overall high PK/PD target attainments were obtained, except for at higher MICs. We suggest a maintenance dose of 1 g TID or BID of meropenem. With vancomycin, a more individualized approach using therapeutic drug monitoring should be used, as commercial assays are available     

Evaluation by Monte Carlo simulation of levofloxacin dosing for complicated urinary tract infections caused by Escherichia coli or Pseudomonas aeruginosa

We evaluated, by Monte Carlo simulation, 500-mg once-daily, 100-mg thrice-daily, 200-mg twice-daily, and 200-mg thrice-daily dose regimens of levofloxacin (LVFX), for the ratio of area under the concentration–time curve for 24 h (AUC_0–24) to minimum inhibitory concentration (MIC) (AUC_0–24/MIC) and the ratio of maximum plasma concentration (C _max) to MIC (C _max/MIC), which predict microbiological outcomes, and the C _max/MIC, which inhibits fluoroquinolone resistance selection, in complicated urinary tract infections (UTIs) with Escherichia coli or Pseudomonas aeruginosa. Monte Carlo simulation was performed for 10000 cases using the pharmacokinetic data of patients with complicated UTIs and the LVFX MIC distributions for E. coli or P. aeruginosa clinical strains. The probabilities of achieving the AUC_0–24/MIC target (66.2–67.9%) and the C _max/MIC target (64.5–67.5%) to eradicate E. coli were similar among the 4 regimens. In eradication of P. aeruginosa, the 200-mg thrice-daily and the once-daily dose regimens produced higher probabilities of achieving the AUC_0–24/MIC target (57.5%) and C _max/MIC target (55.1%), respectively. For the probabilities of achieving the C _max/MIC targets that prevent the emergence of fluoroquinolone resistance, the once-daily dose regimen (66.8%) did not differ from the other multiple-dose regimens (62.3–66.2%) in E. coli, whereas the former regimen (44.2%) was superior to the latter regimens (10.8–31.7%) in P. aeruginosa. The 500-mg once-daily dose regimen of LVFX, which produced the larger AUC_0–24 and higher C _max, could ensure the efficacy of eradication of uropathogens and reduce the risk of fluoroquinolone resistance selection in complicated UTIs.     

The Pharmacodynamics of Prolonged Infusion β-Lactams for the Treatment of Pseudomonas aeruginosa Infections: A Systematic Review

PurposePseudomonas aeruginosa is a commonly isolated nosocomial pathogen for which treatment options are often limited for multidrug-resistant isolates. In addition to newer available antimicrobial agents active against P. aeruginosa, strategies such as extended (eg, prolonged or continuous) infusion have been suggested to optimize the pharmacokinetic and pharmacodynamic profiles of β-lactams. Literature regarding clinical outcomes for extended infusion β-lactams has been controversial; however, this use seems most beneficial in patients with severe illness. Prolonged infusion of β-lactams (eg, 3- to 4-hour infusion) can enhance the pharmacodynamic target attainment via increasing the amount of time throughout the dosing interval to which the free drug concentration remains above the MIC (minimum inhibitory concentration) of the organism (fT > MIC). This systematic review summarizes current literature related to the probability of target attainment (PTA) of various antipseudomonal β-lactam regimens administered as prolonged infusions in an effort to provide guidance in selecting optimal dosing regimens and infusion times for the treatment of P. aeruginosa infections.MethodsA literature search for all pertinent studies was performed by using the PubMed database (with no year limit) through March 31, 2019.FindingsThirty-nine studies were included. Although many standard antipseudomonal β-lactam intermittent infusion regimens can provide adequate PTA against most susceptible isolates, prolonged infusion may enhance percent fT > MIC for organisms with higher MICs (eg, nonsusceptible) or patients with altered pharmacokinetic profiles (eg, obese, critically ill, those with febrile neutropenia).ImplicationsProlonged infusion β-lactam regimens can enhance PTA against nonsusceptible P. aeruginosa isolates and may provide a potential therapeutic option for multidrug-resistant infections. Before implementing prolonged infusion antipseudomonal β-lactams, institutions should consider the half-life of the antibiotic, local incidence of P. aeruginosa infections, antibiotic MIC distributions or MICs isolated from individual patients, individual patient characteristics that may alter pharmacokinetic variables, and PTA (eg, critically ill), as well as implementation challenges.     

Fluoroquinolone susceptibility, resistance, and pharmacodynamics versus clinical isolates of Streptococcus pneumoniae from Indiana

The in vitro activity and pharmacodynamics (AUC_0–24/MIC) of levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin were evaluated against 307 clinical isolates of Streptococcus pneumoniae from Indianapolis, Indiana. Organisms were collected between January 1999 and April 2000, and MICs were determined by broth microdilution. Serum concentration-time profiles were simulated for the following oral regimens administered once daily: levofloxacin 500 mg and 750 mg; gatifloxacin 400 mg; moxifloxacin 400 mg; gemifloxacin 320 mg. Free 24 h area under the serum concentration-time curves (AUC_0–24) were calculated, and the average AUC_0–24/MIC was calculated for each regimen. Differences in AUC_0–24/MIC among agents were determined by analysis of variance (Scheffe post-hoc test, p < 0.05). Overall, gemifloxacin was the most potent agent tested. Five (1.7%), 4 (1.3%), and 2 (0.7%) isolates were resistant to levofloxacin, gatifloxacin, and moxifloxacin, respectively. None of the isolates was resistant to gemifloxacin. Gemifloxacin AUC_0–24/MIC was significantly greater than all other regimens (p < 0.0001), with the exception of moxifloxacin. However, the percent of isolates for which an AUC_0–24/MIC ≥ 30–50 can be achieved is similar for gemifloxacin, moxifloxacin, gatifloxacin, and levofloxacin 750 mg. Large comparative studies are needed to determine if the differences in AUC_0–24/MIC among fluoroquinolones are clinically significant.     

Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients

Pharmacokinetic exposure and the MIC of fluoroquinolones are important determinants of their efficacy against Mycobacterium tuberculosis. Population modeling was used to describe the steady-state plasma pharmacokinetics of moxifloxacin in 241 tuberculosis (TB) patients in southern Africa. Monte Carlo simulations were applied to obtain the area under the unbound concentration-time curve from 0 to 24 h (fAUC_0–24) after daily doses of 400 mg or 800 mg moxifloxacin and 800 mg ofloxacin. The MIC distributions of ofloxacin and moxifloxacin were determined for 197 drug-resistant clinical isolates of Mycobacterium tuberculosis. For a specific MIC, the probability of target attainment (PTA) was determined for target fAUC_0–24/MIC ratios of ≥53 and ≥100. The PTAs were combined with the MIC distributions to calculate the cumulative fraction of response (CFR) for multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Even with the less stringent target ratio of ≥53, moxifloxacin at 400 mg and ofloxacin at 800 mg achieved CFRs of only 84% and 58% for multidrug-resistant isolates with resistance to an injectable drug, while the 800-mg moxifloxacin dose achieved a CFR of 98%. Using a target ratio of ≥100 for multidrug-resistant strains (without resistance to injectable agents or fluoroquinolones), the CFR was 88% for moxifloxacin and only 43% for ofloxacin, and the higher dose of 800 mg moxifloxacin was needed to achieve a CFR target of >90%. Our results indicate that moxifloxacin is more efficacious than ofloxacin in the treatment of MDR-TB. Further studies should determine the optimal pharmacodynamic target for moxifloxacin in a multidrug regimen and clarify safety issues when it is administered at higher doses.     

Population pharmacokinetics and pharmacodynamics of sitafloxacin in patients with community-acquired respiratory tract infections

An optimal dosage regimen of sitafloxacin was considered based on a pharmacokinetics and pharmacodynamics (PK–PD) analysis in patients with community-acquired respiratory tract infections (RTI). A population pharmacokinetic analysis of sitafloxacin was conducted using clinical data of five clinical pharmacology studies and one clinical PK–PD study in patients with RTIs. The pharmacokinetic parameters in individual patients were estimated by the Bayesian method to examine any correlation between pharmacokinetics and bacteriological efficacy. Efficacy data were obtained from the clinical PK–PD study, in which 50 or 100 mg sitafloxacin was administered twice daily for 7 days. In addition, an efficacy was simulated for a hypothetical dose regimen of 100 mg once daily. The fAUC_0–24h/MIC and the fC _max/MIC of sitafloxacin at a dose of 50 mg twice daily were 117.5 ± 78.0 and 7.3 ± 4.7 (mean ± SD), respectively. As a result of the univariate logistic regression analysis, the larger the value of fAUC_0–24h/MIC or fC _max/MIC becomes, the higher the bacteriological efficacies. The eradication rates for fAUC_0–24h/MIC ≥ 30 and for fC _max/MIC ≥ 2 were 96.4 % and 96.3 %, respectively. The PK–PD target values of sitafloxacin for the treatment of mild to moderate RTIs were considered to be fAUC_0–24h/MIC ≥ 30 and fC _max/MIC ≥ 2. The PK–PD parameters at the regimen of 50 or 100 mg twice daily in patients with RTIs reached the target values. Furthermore, a 100 mg once-daily regimen was expected to show similar efficacy based on the PK–PD simulations.     

Pharmacokinetics and Pharmacodynamics of Levornidazole in Patients With Intra-abdominal AnaerobicInfection

Purpose

The pharmacokinetic (PK) and pharmacodynamic characteristics of levornidazole were studied in patients with intra-abdominal anaerobic infection to provide the rationale of new clinical dosing regimen of levornidazole.

Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance?

IntroductionThe aim of this study was to explore the impact of augmented creatinine clearance and differing minimum inhibitory concentrations (MIC) on piperacillin pharmacokinetic/pharmacodynamic (PK/PD) target attainment (time above MIC (fT_>MIC)) in critically ill patients with sepsis receiving intermittent dosing.MethodsTo be eligible for enrolment, critically ill patients with sepsis had to be receiving piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6 hours for presumed or confirmed nosocomial infection without significant renal impairment (defined by a plasma creatinine concentration greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood samples were drawn to determine unbound plasma piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CL_CR). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% fT_>MIC was calculated for varying MIC and CL_CR values.ResultsIn total, 48 patients provided data. Increasing CL_CR values were associated with lower trough plasma piperacillin concentrations (P < 0.01), such that with an MIC of 16 mg/L, 100% fT_>MIC would be achieved in only one-third (n = 16) of patients. Mean piperacillin clearance was approximately 1.5-fold higher than in healthy volunteers and correlated with CL_CR (r = 0.58, P < 0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% fT_>MIC, was noted with increasing CL_CR measures.ConclusionsStandard intermittent piperacillin-tazobactam dosing is unlikely to achieve optimal piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CL_CR can be employed as a useful tool to determine whether piperacillin PK/PD target attainment is likely with a range of MIC values.     

Population Pharmacokinetics and AUC-Guided Dosing of Tobramycin in the Treatment of Infections Caused by Glucose-Nonfermenting Gram-Negative Bacteria

PurposeTobramycin (TOB) exhibits variable pharmacokinetic properties due to the clinical condition of patients. This study aimed to investigate the AUC-guided dosing of TOB based on population pharmacokinetic analysis in the treatment of infections caused by Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia.MethodsThis retrospective study was conducted between January 2010 and December 2020 after obtaining approval from our institutional review board. For 53 patients who received therapeutic drug monitoring of TOB, a population pharmacokinetic model was developed with covariates of estimated glomerular filtration rate using serum creatinine (eGFRcre) on clearance (CL) and weight on both CL and V_d in exponential error modeling (CL = 2.84 × [weight/70] × eGFRcre^0.568, interindividual variability [IIV] = 31.1%; V_d = 26.3 × [weight/70], IIV = 20.2%; residual variability = 28.8%).FindingsThe final regression model for predicting 30-day mortality was developed with risk factors of AUC during a 24-hour period after the first dose to MIC ratio (odds ratio [OR] = 0.996; 95% CI, 0.968–1.003) and serum albumin (OR = 0.137; 95% CI, 0.022–0.632). The final regression model for predicting acute kidney injury was developed with the risk factors of C-reactive protein (OR = 1.136; 95% CI, 1.040–1.266) and AUC during a 72-hour period after the first dose (OR = 1.004; 95% CI, 1.000–1.001). A dose of 8 or 15 mg/kg was beneficial for achievement of AUC during a 24-hour period after the first dose/MIC >80 and trough concentration <1 µg/mL in patients with preserved kidney function and TOB CL >4.47 L/h/70 kg in the events of MIC of 1 or 2 µg/mL, respectively. We propose that the first dose of 15, 11, 10, 8, and 7 mg/kg for eGFRcre >90, 60 to 89, 45 to 59, 30 to 44, and 15 to 29 mL/min/1.73 m² be followed by therapeutic drug monitoring at peak and 24 hours after the first dose.ImplicationsThis study suggests that TOB use encourages the replacement of trough- and peak-targeted dosing with AUC-guided dosing.     

Identification of factors affecting meropenem pharmacokinetics in critically ill patients: Impact of inflammation on clearance

IntroductionThe purpose of this study was to explore factors influencing meropenem pharmacokinetics (PKs) in critically ill patients by developing a population PK model and to determine the optimal dosing strategy.MethodsThis prospective observational study involved 12 critically ill patients admitted to the intensive care unit and treated with meropenem 1 g infused over 1 h every 8 h. Blood samples were collected on days 1, 2, and 5 immediately prior to dosing, and at 1, 2, 4, and 6 h after the start of infusion. Population PK parameters were estimated using nonlinear mixed-effects model software.ResultsMeropenem PK was adequately described using a two-compartment model. Typical values of total and inter-compartmental clearance were 9.30 L/h and 9.70 L/h, respectively, and the central and peripheral compartment volumes of distribution were 12.61 L and 7.80 L, respectively. C-reactive protein (CRP) was identified as significant covariate affecting total meropenem clearance. The probability of target attainment (PTA) predicted by Monte Carlo simulations varied according to the patients’ CRP. The PTA of 100% time above the minimum inhibitory concentration ≤2 mg/L for bacteria was achieved after a dose of 1 and 2 g infused over 4 h every 8 h in patients with CRP of 30 and 5 mg/dL, respectively.ConclusionThe findings of this study suggest that CRP might be helpful in managing meropenem dosing in critically ill patients. Higher doses and extended infusion may be required to achieve optimal pharmacodynamic targets.     

Meropenem Population Pharmacokinetics in Critically Ill Patients with Septic Shock and Continuous Renal Replacement Therapy: Influence of Residual Diuresis on Dose Requirements

Meropenem dosing in critically ill patients with septic shock and continuous renal replacement therapy (CRRT) is complex, with the recommended maintenance doses being 500 mg to 1,000 mg every 8 h (q8h) to every 12 h. This multicenter study aimed to describe the pharmacokinetics (PKs) of meropenem in this population to identify the sources of PK variability and to evaluate different dosing regimens to develop recommendations based on clinical parameters. Thirty patients with septic shock and CRRT receiving meropenem were enrolled (153 plasma samples were tested). A population PK model was developed with data from 24 patients and subsequently validated with data from 6 patients using NONMEM software (v.7.3). The final model was characterized by CL = 3.68 + 0.22 · (residual diuresis/100) and V = 33.00 · (weight/73)^2.07, where CL is total body clearance (in liters per hour), residual diuresis is the volume of residual diuresis (in milliliters per 24 h), and V is the apparent volume of distribution (in liters). CRRT intensity was not identified to be a CL modifier. Monte Carlo simulations showed that to maintain concentrations of the unbound fraction (f_u) of drug above the MIC of the bacteria for 40% of dosing interval T (referred to as 40% of the ƒ_uT_>MIC), a meropenem dose of 500 mg q8h as a bolus over 30 min would be sufficient regardless of the residual diuresis. If 100% of the ƒ_uT_>MIC was chosen as the target, oligoanuric patients would require 500 mg q8h as a bolus over 30 min for the treatment of susceptible bacteria (MIC < 2 mg/liter), while patients with preserved diuresis would require the same dose given as an infusion over 3 h. If bacteria with MICs close to the resistance breakpoint (2 to 4 mg/liter) were to be treated with meropenem, a dose of 500 mg every 6 h would be necessary: a bolus over 30 min for oligoanuric patients and an infusion over 3 h for patients with preserved diuresis. Our results suggest that residual diuresis may be an easy and inexpensive tool to help with titration of the meropenem dose and infusion time in this challenging population.