Balancing the scales: achieving the optimal beta-lactam to beta-lactamase inhibitor ratio with continuous infusion piperacillin/tazobactam against extended spectrum beta-lactamase producing Enterobacterales.

Piperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against Enterobacterales. Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic approach was used to select the best kidney function model predictive of TZP clearance (CL). The probability of target attainment (PTA), cumulative fraction of response (CFR) and the ratio between piperacillin and tazobactam were computed to identify optimal dosage regimens by continuous infusion across kidney function. This study included 257 critically ill patients (79.3% male) with intra-abdominal, bloodstream, and hospital-acquired pneumonia infections in 89.5% as the primary indication. The median (min-max range) age, body weight, and estimated glomerular filtration rate (eGFR) were 66 (23-93) years, 75 (39-310) kg, and 79.2 (6.4-234) mL/min, respectively. Doses of up to 22.5 g/day were used to optimize TZP based on TDM. The 2021 chronic kidney disease epidemiology equation in mL/min best modeled TZP CL. The ratio of piperacillin:tazobactam increased from 6:1 to 10:1 between an eGFR of <20 mL/min and >120 mL/min. At conventional doses, the PTA is below 90% when eGFR is ≥100 mL/min. Daily doses of 18 g/day and 22.5 g/day by CI are expected to achieve a >80% CFR when eGFR is 100-120 mL/min and >120-160 mL/min, respectively. Inadequate piperacillin and tazobactam exposure is likely in patients with eGFR ≥ 100 mL/min. Dose regimen adjustments informed by TDM should be evaluated in this specific population.

What are the optimal pharmacokinetic/pharmacodynamic targets for ß-lactamase inhibitors? A systematic review.

BACKGROUND: Pharmacokinetic/pharmacodynamic (PK/PD) indices are widely used for the selection of optimum antibiotic doses. For ß-lactam antibiotics, fT>MIC, best relates antibiotic exposure to efficacy and is widely used to guide the dosing of ß-lactam/ß-lactamase inhibitor (BLI) combinations, often without considering any PK/PD exposure requirements for BLIs. OBJECTIVES: This systematic review aimed to describe the PK/PD exposure requirements of BLIs for optimal microbiological efficacy when used in combination with ß-lactam antibiotics. METHODS: Literature was searched online through PubMed, Embase, Web of Science, Scopus and Cochrane Library databases up to 5 June 2023. Studies that report the PK/PD index and threshold concentration of BLIs approved for clinical use were included. Narrative data synthesis was carried out to assimilate the available evidence. RESULTS: Twenty-three studies were included. The PK/PD index that described the efficacy of BLIs was fT>CT for tazobactam, avibactam and clavulanic acid and fAUC0-24/MIC for relebactam and vaborbactam. The optimal magnitude of the PK/PD index is variable for each BLI based on the companion ß-lactam antibiotics, type of bacteria and ß-lactamase enzyme gene transcription levels. CONCLUSIONS: The PK/PD index that describes the efficacy of BLIs and the exposure measure required for their efficacy is variable among inhibitors; as a result, it is difficult to make clear inference on what the optimum index is. Further PK/PD profiling of BLI, using preclinical infection models that simulate the anticipated mode(s) of clinical use, is warranted to streamline the exposure targets for use in the optimization of dosing regimens.

Pharmacokinetics of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase 1, Open-Label Study of Healthy Adults.

Scant pharmacokinetic (PK) data are available on ceftazidime-avibactam (CZA) and aztreonam (ATM) in combination, and it is unknown if CZA-ATM exacerbates alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations relative to ATM alone. This phase 1 study sought to describe the PK of CZA-ATM and assess the associations between ATM exposures and ALT/AST elevations. Subjects (n = 48) were assigned to one of six cohorts (intermittent infusion [II] CZA, continuous infusion [CI] CZA, II ATM, CI ATM [8 g/daily], II CZA with II ATM [6 g/daily], and II CZA with II ATM [8 g/daily]), and study product(s) were administered for 7 days. A total of 19 subjects (40%) had ALT/AST elevations, and most (89%) occurred in the ATM/CZA-ATM cohorts. Two subjects in the CI ATM cohort experienced severe ALT/AST elevations, which halted the study. All subjects with ALT/AST elevations were asymptomatic with no other signs of liver injury, and all ALT/AST elevations resolved without sequalae after cessation of dosing. In the population PK (PopPK) analyses, CZA-ATM administration reduced total ATM clearance by 16%, had a negligible effect on total ceftazidime clearance, and was not a covariate in the avibactam PopPK model. In the exposure-response analyses, coadministration of CZA-ATM was not found to augment ALT/AST elevations. Modest associations were observed between ATM exposure (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve [AUC]) and ALT/AST elevations in the analysis of subjects in the II ATM/CZA-ATM cohorts. The findings suggest that administration of CZA-ATM reduces ATM clearance but does not exacerbate AST/ALT elevations relative to ATM alone. The results also indicate that CI ATM should be used with caution.

New ß-Lactam-ß-Lactamase Inhibitor Combinations.

The limited armamentarium against drug-resistant Gram-negative bacilli has led to the development of several novel ß-lactam-ß-lactamase inhibitor combinations (BLBLIs). In this review, we summarize their spectrum of in vitro activities, mechanisms of resistance, and pharmacokinetic-pharmacodynamic (PK-PD) characteristics. A summary of available clinical data is provided per drug. Four approved BLBLIs are discussed in detail. All are options for treating multidrug-resistant (MDR) Enterobacterales and Pseudomonas aeruginosa Ceftazidime-avibactam is a potential drug for treating Enterobacterales producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC), AmpC, and some class D ß-lactamases (OXA-48) in addition to carbapenem-resistant Pseudomonas aeruginosa Ceftolozane-tazobactam is a treatment option mainly for carbapenem-resistant P. aeruginosa (non-carbapenemase producing), with some activity against ESBL-producing Enterobacterales Meropenem-vaborbactam has emerged as treatment option for Enterobacterales producing ESBL, KPC, or AmpC, with similar activity as meropenem against P. aeruginosa Imipenem-relebactam has documented activity against Enterobacterales producing ESBL, KPC, and AmpC, with the combination having some additional activity against P. aeruginosa relative to imipenem. None of these drugs present in vitro activity against Enterobacterales or P. aeruginosa producing metallo-ß-lactamase (MBL) or against carbapenemase-producing Acinetobacter baumannii Clinical data regarding the use of these drugs to treat MDR bacteria are limited and rely mostly on nonrandomized studies. An overview on eight BLBLIs in development is also provided. These drugs provide various levels of in vitro coverage of carbapenem-resistant Enterobacterales, with several drugs presenting in vitro activity against MBLs (cefepime-zidebactam, aztreonam-avibactam, meropenem-nacubactam, and cefepime-taniborbactam). Among these drugs, some also present in vitro activity against carbapenem-resistant P. aeruginosa (cefepime-zidebactam and cefepime-taniborbactam) and A. baumannii (cefepime-zidebactam and sulbactam-durlobactam).

Mass spectrometric identification and quantification of the antibiotic clavulanic acid in broiler chicken plasma and meat as a necessary analytical tool in finding ways to increase the effectiveness of currently used antibiotics in the treatment of broiler chickens.

Clavulanic acid is a molecule with antimicrobial effect used in several livestock species treatment. Its inclusion in the treatment of infectious diseases of broilers requires determination of pharmacokinetic and pharmacodynamic parameters in order to determine the appropriate dosage for broilers and ensure safety of chicken products for human health. The present study describes the optimisation of analytical LC-MS/MS method for identification and quantification of clavulanic acid in broiler chicken plasma and meat. The limit of detection and the limit of quantification for the developed method were 3.09 µg·L-1 and 10.21 µg·L-1 for plasma and 2.57 µg·kg-1 and 8.47 µg·kg-1 for meat. The recoveries of the developed plasma and tissue extraction procedure were > 105.7% and > 95.6%, respectively. The achieved coefficient of variation of within-run precision ranged from 2.8 to 10.9% for plasma and from 6.5 to 8.5% for meat. The pharmacokinetic experiment was performed in 112 Ross broiler chickens assigned into time interval groups ranging from 10 min to 24 h in accredited animal facilities. Administered dose of clavulanic acid was 2.5 mg·kg-1 according to the manufacturer's recommendations. The pharmacokinetic parameters obtained from the experiment are as follows: Cmax = 1.82 ± 0.91 mg·L-1, Tmax = 0.25 h, T1/2 = 0.87 h, Kel = 0.80 ± 0.04 h-1, AUC0-∞ = 2.17 mg·h ·L-1.

A Population Pharmacokinetics and Pharmacodynamic Approach To Optimize Tazobactam Activity in Critically Ill Patients.

The percentage of the time that the free drug concentration remains above a concentration threshold (%fT > concentration threshold) has frequently been identified to be the optimal pharmacokinetic (PK)-pharmacodynamic (PD) target of interest for tazobactam using in vitro infection models. Similar in vitro models suggested that an 85% fT > concentration threshold of 2 µg/ml for tazobactam is required to demonstrate a 2-log10-unit decrease in the number of CFU per milliliter from that at the baseline at 24 h for high-level ß-lactamase-producing Escherichia coli strains. The objective of this study was to characterize the tazobactam concentrations in a cohort of critically ill patients with Gram-negative bacterial infections, determine if traditional dosing regimens achieve a prespecified PK/PD target of an 80% fT > concentration threshold of 2 µg/ml, and propose alternative dosing regimens. Hospitalized critically ill adult patients receiving piperacillin-tazobactam (TZP) for a culture-positive Gram-negative bacterial infection were eligible to consent for study inclusion. Two blood samples were drawn, one during the midpoint of the dosing interval and one at the time of the trough concentration once the patient achieved PK steady state. A population PK model was developed using Phoenix NLME (v8.1) software to characterize the observed concentration-time profile of tazobactam, explore potential covariates to explain the variability in the clearance and volume parameters, and to simulate potential dosing regimens that would achieve the PK/PD target. The PK of tazobactam were adequately described by a one-compartment model with first-order elimination in 18 patients who provided consent. The final model incorporated creatinine clearance as a covariate on clearance. Simulations demonstrated target attainments of less than 50% for tazobactam using traditional dosing regimens (4/0.5 g over 30 min every 6 h). Target attainments of greater than 75% were achieved when using extended infusion times of 4 to 6 h or when administering TZP as a continuous infusion (16/2 g over 24 h). Traditional tazobactam dosing regimens fail to achieve conservative PK/PD targets in critically ill patients. Increases in the tazobactam dose or prolongation of the infusion rate may be warranted to achieve activity against ß-lactamase-producing Gram-negative bacteria.

Considerations in the Selection of Renal Dosage Adjustments for Patients with Serious Infections and Lessons Learned from the Development of Ceftazidime-Avibactam.

An extensive clinical development program (comprising two phase 2 and five phase 3 trials) has demonstrated the efficacy and safety of ceftazidime-avibactam in the treatment of adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), and hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP). During the phase 3 clinical program, updated population pharmacokinetic (PK) modeling and Monte Carlo simulations using clinical PK data supported modified ceftazidime-avibactam dosage adjustments for patients with moderate or severe renal impairment (comprising a 50% increase in total daily dose compared with the original dosage adjustments) to reduce the risk of subtherapeutic drug exposures in the event of rapidly improving renal function. The modified dosage adjustments were included in the ceftazidime-avibactam labeling information at the time of initial approval and were subsequently evaluated in the final phase 3 trial (in patients with HAP, including VAP), providing supportive data for the approved U.S. and European ceftazidime-avibactam dosage regimens across renal function categories. This review describes the analyses supporting the ceftazidime-avibactam dosage adjustments for renal impairment and discusses the wider implications and benefits of using modeling and simulation to support dosage regimen optimization based on emerging clinical evidence.

Safety and Pharmacokinetic Characterization of Nacubactam, a Novel ß-Lactamase Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers.

Nacubactam is a novel ß-lactamase inhibitor with dual mechanisms of action as an inhibitor of serine ß-lactamases (classes A and C and some class D) and an inhibitor of penicillin binding protein 2 in Enterobacteriaceae The safety, tolerability, and pharmacokinetics of intravenous nacubactam were evaluated in single- and multiple-ascending-dose, placebo-controlled studies. Healthy participants received single ascending doses of nacubactam of 50 to 8,000 mg, multiple ascending doses of nacubactam of 1,000 to 4,000 mg every 8 h (q8h) for up to 7 days, or nacubactam of 2,000 mg plus meropenem of 2,000 mg q8h for 6 days after a 3-day lead-in period. Nacubactam was generally well tolerated, with the most frequently reported adverse events (AEs) being mild to moderate complications associated with intravenous access and headache. There was no apparent relationship between drug dose and the pattern, incidence, or severity of AEs. No clinically relevant dose-related trends were observed in laboratory safety test results. No serious AEs, dose-limiting AEs, or deaths were reported. After single or multiple doses, nacubactam pharmacokinetics appeared linear, and exposure increased in an approximately dose-proportional manner across the dose range investigated. Nacubactam was excreted largely unchanged into urine. Coadministration of nacubactam with meropenem did not significantly alter the pharmacokinetics of either drug. These findings support the continued clinical development of nacubactam and demonstrate the suitability of meropenem as a potential ß-lactam partner for nacubactam. (The studies described in this paper have been registered at ClinicalTrials.gov under NCT02134834 [single ascending dose study] and NCT02972255 [multiple ascending dose study].).

Pharmacokinetics and Efficacy of Ceftazidime-Avibactam in the Treatment of Experimental Pneumonia Caused by Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae in Persistently Neutropenic Rabbits.

Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) is an emerging global public health threat that causes life-threatening pneumonia and bacteremia. Ceftazidime-avibactam (CZA) represents a promising advance for the treatment of serious infections caused by KPC-Kp We investigated the pharmacokinetics and efficacy of ceftazidime-avibactam in the treatment of experimental KPC-Kp pneumonia in persistently neutropenic rabbits. For single-dose and multidose (administration every 8 h) pharmacokinetics, rabbits received ceftazidime-avibactam intravenous infusions at 60/15, 90/22.5, and 120/30 mg/kg of body weight. Ceftazidime mean area under the concentration-time curves (AUCs) ranged from 287 to 608 µg·h/ml for a single dose and from 300 to 781 µg·h/ml for multiple doses. Avibactam AUCs ranged from 21 to 48 µg·h/ml for a single dose and from 26 to 48 µg·h/ml for multiple doses. KPC-Kp pneumonia was established by direct endotracheal inoculation. Treatments consisted of ceftazidime-avibactam at 120/30 mg/kg every 6 h, a polymyxin B (PMB) loading dose of 2.5 mg/kg followed by 1.5 mg/kg every 12 h q12h, or no treatment (untreated controls [UC]). There were significant reductions in the residual bacterial burden, lung weights, and pulmonary hemorrhage scores in CZA- and PMB-treated rabbits for a 7-day or a 14-day (P ≤ 0.01) course in comparison with those in the UC. These results corresponded to significant decreases in the bacterial burden in bronchoalveolar lavage fluid after a 7-day or a 14-day treatment (P ≤ 0.01). The outcomes demonstrated an improved response at 14 days versus that at 7 days. There was significantly prolonged survival in rabbits treated with CZA for 14 days in comparison with that in the PMB-treated or UC rabbits (P ≤ 0.05). This study demonstrates that ceftazidime-avibactam displays linear dose-proportional exposures simulating those seen from human plasma pharmacokinetic profiles, is active for the treatment of experimental KPC-Kp pneumonia in persistently neutropenic rabbits, and provides an experimental foundation for the treatment of severely immunocompromised patients with this life-threatening infection.

A novel mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model describing ceftazidime/avibactam efficacy against ß-lactamase-producing Gram-negative bacteria.

BACKGROUND: Diazabicyclooctanes (DBOs) are an increasingly important group of non ß-lactam ß-lactamase inhibitors, employed clinically in combinations such as ceftazidime/avibactam. The dose finding of such combinations is complicated using the traditional pharmacokinetic/pharmacodynamic (PK/PD) index approach, especially if the ß-lactamase inhibitor has an antibiotic effect of its own. OBJECTIVES: To develop a novel mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model for ceftazidime/avibactam against Gram-negative pathogens, with the potential for combination dosage simulation. METHODS: Four ß-lactamase-producing Enterobacteriaceae, covering Ambler classes A, B and D, were exposed to ceftazidime and avibactam, alone and in combination, in static time-kill experiments. A PKPD model was developed and evaluated using internal and external evaluation, and combined with a population PK model and applied in dosage simulations. RESULTS: The developed PKPD model included the effects of ceftazidime alone, avibactam alone and an 'enhancer' effect of avibactam on ceftazidime in addition to the ß-lactamase inhibitory effect of avibactam. The model could describe an extensive external Pseudomonas aeruginosa data set with minor modifications to the enhancer effect, and the utility of the model for clinical dosage simulation was demonstrated by investigating the influence of the addition of avibactam. CONCLUSIONS: A novel mechanism-based PKPD model for the DBO/ß-lactam combination ceftazidime/avibactam was developed that enables future comparison of the effect of avibactam with other DBO/ß-lactam inhibitors in simulations, and may be an aid in translating PKPD results from in vitro to animals and humans.

Impact of renal impairment and human organic anion transporter inhibition on pharmacokinetics, safety and tolerability of relebactam combined with imipenem and cilastatin.

AIMS: Two phase 1, open-label studies were conducted to investigate the effect of renal impairment (RI) and organic anion transporter (OAT) inhibition on pharmacokinetics (PK) and safety of relebactam (REL) plus imipenem/cilastatin (IMI). METHODS: Study PN005 evaluated the PK of REL (125 mg) plus IMI (250 mg) in participants with RI vs healthy controls. Study PN019 evaluated the PK of REL (250 mg) and imipenem (500 mg; dosed as IMI) with/without probenecid (1 g; OAT inhibitor) in healthy adults. RESULTS: Geometric mean ratios (RI/healthy matched controls) of area under the concentration-time curve from time 0 to infinity (AUC0-∞ ; 90% confidence interval) for REL, imipenem and cilastatin increased as RI increased from mild (1.6 [1.1, 2.4], 1.4 [1.1, 1.8] and 1.6 [1.0, 2.5], respectively) to severe (4.9 [3.4, 7.0], 2.5 [1.9, 3.3] and 5.6 [3.6, 8.6], respectively). For all 3 analytes, plasma and renal clearance decreased and corresponding plasma apparent terminal half-life increased with increasing RI. Geometric mean ratios ([probenecid+IMI/REL]/[IMI/REL]) of plasma exposure for REL and imipenem were 1.24 (1.19, 1.28) and 1.16 (1.13, 1.20), respectively. The dose fraction excreted (fe) in the urine decreased progressively from mild to severe RI. Probenecid reduced renal clearance of REL and imipenem by 25 and 31%, respectively. Compared with IMI/REL, coadministration of IMI/REL with probenecid yielded lower fe for REL and imipenem. In both studies, treatment was well tolerated; there were no serious adverse events or discontinuations due to adverse events. CONCLUSION: RI increased plasma exposure and similarly decreased clearance of REL, imipenem and cilastatin; IMI/REL dose adjustment (fixed-ratio) will be required for patients with RI. Probenecid had no clinically meaningful impact on the PK of REL or imipenem.

Single-Center Evaluation of the Pharmacokinetics of WCK 5222 (Cefepime-Zidebactam Combination) in Subjects with Renal Impairment.

WCK 5222 is a novel ß-lactam-ß-lactam-enhancer combination of cefepime (FEP) and zidebactam (ZID). ZID is a novel ß-lactam enhancer with a dual action of binding to Gram-negative penicillin-binding protein 2 (PBP2) and ß-lactamase inhibition. WCK 5222 is being developed as a new therapeutic option for the treatment of complicated multidrug-resistant Gram-negative pathogen infections. We investigated the effect of renal impairment on the pharmacokinetics (PK) and safety of WCK 5222 in 48 subjects based on Cockcroft-Gault-estimated creatinine clearance (CLCR). We enrolled mild (n = 6; CLCR, 60 to <90 ml/min), moderate (n = 6; CLCR, 30 to <60 ml/min), and severe (n = 6; CLCR, <30 ml/min; not on dialysis) impairment, end-stage renal disease (ESRD) on hemodialysis (HD) (n = 6), and matched normal controls (n = 24; CLCR, ≥90 ml/min). Healthy control subjects and mild and moderate renal impairment subjects received a single 60-min intravenous (i.v.) infusion of 3 g WCK 5222 (2 g FEP/1 g ZID); severe renal impairment and HD subjects received a single 60-min i.v. infusion of 1.5 g WCK 5222 (1 g FEP plus 0.5 g ZID). Body and renal clearance decreased, and plasma half-life (t1/2) and the area under the concentration-time curve from time zero extrapolated to infinity (AUC0-∞ [h µg/ml]) increased in a graded relationship with severity of renal impairment for both FEP and ZID. Our findings suggest that dose adjustments for WCK 5222 will be required according to the degree of renal impairment. Overall, WCK 5222 (FEP-ZID) was found to be safe and well tolerated in subjects with normal and impaired renal function. (This study has been registered at ClinicalTrials.gov under identifier NCT02942810.).

Pharmacokinetics/Pharmacodynamics of Vaborbactam, a Novel Beta-Lactamase Inhibitor, in Combination with Meropenem.

Vaborbactam is a novel beta-lactamase inhibitor with activity against important beta-lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as Vabomere for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant Enterobacteriaceae The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model, as well as in an in vitro hollow-fiber infection model, in combination with a fixed exposure of meropenem using KPC-containing strains of Enterobacteriaceae For both models, the meropenem dosage regimen was designed to simulate a 2-g dose administered every eight hours (q8h) by 3-h infusion. Vaborbactam dosage regimens were designed to produce a wide range of 24-h areas under the concentration-time curves (AUCs) in the thigh infection model. However, for the hollow-fiber model, the AUCs were limited to values of 192, 320, or 550 mg · h/liter. In both the animal and in vitro models, the PK-PD parameter that best described the antibacterial activity of vaborbactam, when administered in combination with meropenem at exposures equivalent to 2 g dosed q8h by 3-h infusion in humans, was the 24-h free vaborbactam AUC/meropenem-vaborbactam (with vaborbactam at 8 mg/liter) MIC ratio. The magnitude of this ratio for bacteriostasis was 9 to 12 and the magnitude to observe a 1-log kill was 18 to 38. In addition, a magnitude greater than 24 suppressed the development of resistance in the in vitro hollow-fiber model.

Role of transporters in the disposition of a novel ß-lactamase inhibitor: relebactam (MK-7655).

OBJECTIVES: To identify the transporters involved in renal elimination of relebactam, and to assess the potential of relebactam as a perpetrator or victim of drug-drug interactions (DDIs) for major drug transporters. METHODS: A series of bidirectional transport, uptake and inhibition studies were conducted in vitro using transfected cell lines and membrane vesicles. The inhibitory effects of relebactam on major drug transporters, as well as the inhibitory effects of commonly used antibiotics/antifungals on organic anion transporter (OAT) 3-mediated uptake of relebactam, were assessed. RESULTS: Relebactam was shown to be a substrate of OAT3, OAT4, and multidrug and toxin extrusion (MATE) proteins MATE1 and MATE2K. Relebactam did not show profound inhibition across a panel of transporters, including organic anion-transporting polypeptides 1B1 and 1B3, OAT1, OAT3, organic cation transporter 2, MATE1, MATE2K, breast cancer resistance protein, multidrug resistance protein 1 and the bile salt export pump. Among the antibiotics/antifungals assessed for potential DDIs, probenecid demonstrated the most potent in vitro inhibition of relebactam uptake; however, such in vitro data did not translate into clinically relevant DDIs, suggesting that relebactam can be co-administered with OAT inhibitors, such as probenecid. CONCLUSIONS: Overall, relebactam has low potential to be a victim or perpetrator of DDIs with major drug transporters.

Individualizing piperacillin/tazobactam dosing in adult patients with cystic fibrosis: can tobramycin measurements help?

Background: Empirical models to predict ß-lactam pharmacokinetics (PK) using information from routine aminoglycoside therapeutic drug monitoring (TDM) have been proposed for critically ill patients; however, no such models exist for patients with cystic fibrosis (CF). Objectives: To investigate whether PK parameters of tobramycin could be used to predict those of piperacillin. Methods: A non-interventional, open-label PK study was conducted in hospitalized adults treated with piperacillin/tazobactam and tobramycin for acute pulmonary exacerbations of CF. Six serum samples per patient were collected and analysed. One- and two-compartment population PK models with linear, Michaelis-Menten or mixed elimination were evaluated for both drugs within the PmetricsTM package for R. Models were developed and compared iteratively using the log-likelihood and Akaike information criterion (AIC) objective functions. Results: Nine primarily female (n = 8) and Caucasian (100%) adult CF patients were enrolled. The median (IQR) age, height, weight and serum creatinine of included patients was 31 (27-32) years, 51.4 (49.9-55.8) kg, 162.6 (160.0-165.1) cm and 0.6 (0.5-0.6) mg/dL, respectively. The final model with the lowest objective function values consisted of one compartment with first-order elimination for tobramycin and two compartments with mixed-order elimination for piperacillin with the elimination rate constant of piperacillin modelled as a linear function of the elimination rate constant of tobramycin. Conclusions: A relationship was identified between the elimination rate constants of tobramycin and piperacillin. Validation of this relationship in larger studies of adult patients with CF is needed before application to the precision dosing of piperacillin/tazobactam in this patient population.

Pharmacokinetics of ticarcillin-clavulanate in premature infants.

Ticarcillin-clavulanate covers a broad spectrum of pathogens that are common in premature infants. In infants <30 weeks gestational age, pharmacokinetic data to guide ticarcillin-clavulanate dosing are lacking. We enrolled 15 premature infants <30 weeks gestational age, determined pharmacokinetic parameters, and performed dosing simulations to determine optimal dosing for ticarcillin-clavulanate. The infants had a median (range) postnatal age (PNA) of 18 days (6-44 days) and gestational age of 25 weeks (23-28 weeks). Clearance was lower in infants with a PNA <14 days (0.050 L/kg/h [range 0.043-0.075]) compared with a PNA ≥14-45 days (0.078 L/kg/h [0.047-0.100]), consistent with maturation of renal function. Dosing simulations determined that ticarcillin 75 mg/kg q12h (PNA <14 days) or q8h (PNA ≥ 14-45 days) achieved the target exposure for organisms with a minimum inhibitory concentration ≤16 µ/mL in >90% of simulated infants. For highly resistant organisms (minimum inhibitory concentration 32 µg/mL), increased dosing frequency or extended infusion are necessary.

Scaling beta-lactam antimicrobial pharmacokinetics from early life to old age.

AIMS: Beta-lactam dose optimization in critical care is a current priority. We aimed to review the pharmacokinetics (PK) of three commonly used beta-lactams (amoxicillin ± clavulanate, piperacillin-tazobactam and meropenem) to compare PK parameters reported in critically and noncritically ill neonates, children and adults, and to investigate whether allometric and maturation scaling principles could be applied to describe changes in PK parameters through life. METHODS: A systematic review of PK studies of the three drugs was undertaken using MEDLINE and EMBASE. PK parameters and summary statistics were extracted and scaled using allometric principles to 70 kg individual for comparison. Pooled data were used to model clearance maturation and decline using a sigmoidal (Hill) function. RESULTS: A total of 130 papers were identified. Age ranged from 29 weeks to 82 years and weight from 0.9-200 kg. PK parameters from critically ill populations were reported with wider confidence intervals than those in healthy volunteers, indicating greater PK variability in critical illness. The standard allometric size and sigmoidal maturation model adequately described increasing clearance in neonates, and a sigmoidal model was also used to describe decline in older age. Adult weight-adjusted clearance was achieved at approximately 2 years postmenstrual age. Changes in volume of distribution were well described by the standard allometric model, although amoxicillin data suggested a relatively higher volume of distribution in neonates. CONCLUSIONS: Critical illness is associated with greater PK variability than in healthy volunteers. The maturation models presented will be useful for optimizing beta-lactam dosing, although a prospective, age-inclusive study is warranted for external validation.

Avibactam Pharmacokinetic/Pharmacodynamic Targets.

Avibactam is a novel non-ß-lactam ß-lactamase inhibitor that has been approved in the United States and Europe for use in combination with ceftazidime. Combinations of avibactam with aztreonam or ceftaroline fosamil have also been clinically evaluated. Until recently, there has been very little precedence of which pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitudes are appropriate to use for ß-lactamase inhibitors in population PK modeling for analyzing potential doses and susceptibility breakpoints. For avibactam, several preclinical studies using different in vitro and in vivo models have been conducted to identify the PK/PD index of avibactam and the magnitude of exposure necessary for effect in combination with ceftazidime, aztreonam, or ceftaroline fosamil. The PD driver of avibactam critical for restoring the activity of all three partner ß-lactams was found to be time dependent rather than concentration dependent and was defined as the time that the concentration of avibactam exceeded a critical concentration threshold (%fT>CT). The magnitude of the CT and the time that this threshold needed to be exceeded to elicit particular PD endpoints varied depending on the model and the partner ß-lactam. This review describes the preclinical studies used to determine the avibactam PK/PD target in combination with its ß-lactam partners.

Intrapulmonary Pharmacokinetics of Relebactam, a Novel ß-Lactamase Inhibitor, Dosed in Combination with Imipenem-Cilastatin in Healthy Subjects.

This phase I study assessed the intrapulmonary pharmacokinetic profiles of relebactam (MK-7655), a novel ß-lactamase inhibitor, and imipenem. Sixteen healthy subjects received 250 mg relebactam with 500 mg imipenem-cilastatin, given intravenously every 6 h for 5 doses, and were randomized to bronchoscopy/bronchoalveolar lavage at 0.5, 1, 1.5, or 3 h after the last dose (4 subjects per time point). Both drugs penetrated the epithelial lining fluid (ELF) to a similar degree, with the profiles being similar in shape to the corresponding plasma profiles and with the apparent terminal half-lives in plasma and ELF being 1.2 and 1.3 h, respectively, for relebactam and 1.0 h in both compartments for imipenem. The exposure (area under the concentration-time curve from time zero to infinity) in ELF relative to that in plasma was 54% for relebactam and 55% for imipenem, after adjusting for protein binding. ELF penetration for relebactam was further analyzed by fitting the data to a two-compartment pharmacokinetic model to capture its behavior in plasma, with a partitioning coefficient capturing its behavior in the lung compartment. In this model, the time-invariant partition coefficient for relebactam was found to be 55%, based on free drug levels. These results support the clinical evaluation of relebactam with imipenem-cilastatin for the treatment of bacterial pneumonia.

Activity of Meropenem-Vaborbactam in Mouse Models of Infection Due to KPC-Producing Carbapenem-Resistant Enterobacteriaceae.

Meropenem-vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae The objective of these studies was to evaluate the efficacy of meropenem alone and in combination with vaborbactam in mouse thigh and lung infection models. Thighs or lungs of neutropenic mice were infected with KPC-producing carbapenem-resistant Enterobacteriaceae, with meropenem MICs ranging from ≤0.06 to 8 mg/liter in the presence of 8 mg/liter vaborbactam. Mice were treated with meropenem alone or meropenem in combination with vaborbactam every 2 h for 24 h to provide exposures comparable to 2-g doses of each component in humans. Meropenem administered in combination with vaborbactam produced bacterial killing in all strains tested, while treatment with meropenem alone either produced less than 0.5 log CFU/tissue of bacterial killing or none at all. In the thigh model, 11 strains were treated with the combination of meropenem plus vaborbactam (300 plus 50 mg/kg of body weight). This combination produced from 0.8 to 2.89 logs of bacterial killing compared to untreated controls at the start of treatment. In the lung infection model, two strains were treated with the same dosage regimen of meropenem and vaborbactam. The combination produced more than 1.83 logs of bacterial killing against both strains tested compared to untreated controls at the start of treatment. Overall, these data suggest that meropenem-vaborbactam may have utility in the treatment of infections due to KPC-producing carbapenem-resistant Enterobacteriaceae.