Population Pharmacokinetic Analyses for Tebipenem after Oral Administration of Pro-Drug Tebipenem Pivoxil Hydrobromide.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral (PO) carbapenem pro-drug that is converted to the active moiety tebipenem in the enterocytes. Tebipenem has activity against multidrug-resistant Gram-negative pathogens, including extended-spectrum beta lactamase-producing Enterobacterales, and is being developed for the treatment of patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). The objectives of these analyses were to develop a population pharmacokinetic (PK) model for tebipenem using data from three phase 1 studies and one phase 3 study and to identify covariates that described the variability in tebipenem PK. Following construction of the base model, a covariate analysis was conducted. The model was then qualified by performing a prediction-corrected visual predictive check and evaluated by using a sampling-importance-resampling procedure. The final population PK data set was composed of data from 746 subjects who provided 3,448 plasma concentrations, including 650 patients (1,985 concentrations) with cUTI/AP. The final population PK model that best described tebipenem PK was found to be a two-compartment model with linear, first-order elimination and two transit compartments to describe the rate of drug absorption after PO administration of TBP-PI-HBr. The relationship between renal clearance (CLR) and creatinine clearance (CLcr), the most clinically significant covariate, was described using a sigmoidal Hill-type function. No dose adjustments are warranted on the basis of age, body size, or sex as none of these covariates were associated with substantial differences in tebipenem exposure in patients with cUTI/AP. The resultant population PK model is expected to be appropriate for model-based simulations and assessment of pharmacokinetic-pharmacodynamic relationships for tebipenem.

Evaluation of Tebipenem Hydrolysis by ß-Lactamases Prevalent in Complicated Urinary Tract Infections.

Tebipenem pivoxil is the first orally available carbapenem antibiotic and has been approved in Japan for treating ear, nose, and throat and respiratory infections in pediatric patients. Its active moiety, tebipenem, has shown potent antimicrobial activity in vitro against clinical isolates of Enterobacterales species from patients with urinary tract infections (UTIs), including those producing extended-spectrum ß-lactamases (ESBLs) and/or AmpC ß-lactamase. In the present study, tebipenem was tested for stability to hydrolysis by a set of clinically relevant ß-lactamases, including TEM-1, AmpC, CTX-M, OXA-48, KPC, and NDM-1 enzymes. In addition, hydrolysis rates of other carbapenems, including imipenem, meropenem, and ertapenem, were determined for comparison. It was found that, similar to other carbapenems, tebipenem was resistant to hydrolysis by TEM-1, CTX-M, and AmpC ß-lactamases but was susceptible to hydrolysis by KPC, OXA-48, and NDM-1 enzymes with catalytic efficiency values (kcat/Km) ranging from 0.1 to 2 × 106 M-1s-1. This supports the reported results of antimicrobial activity of tebipenem against ESBL- and AmpC-producing but not carbapenemase-producing Enterobacterales isolates. Considering that CTX-M and AmpC ß-lactamases represent the primary determinants of multidrug-resistant complicated UTIs (cUTIs), the stability of tebipenem to hydrolysis by these enzymes supports the utility of its prodrug tebipenem, tebipenem pivoxil hydrobromide (TBP-PI-HBr), as an oral therapy for adult cUTIs.

Pharmacokinetics of benapenem for injection in subjects with mild to moderate renal impairment.

OBJECTIVE: This study evaluated the pharmacokinetic (PK) characteristics of benapenem in subjects with mild to moderate renal impairment to provide a reference for benapenem dosing regimens in this patient population. METHODS: Eighteen subjects were enrolled in this study. Each subject received a single dose of benapenem intravenously (1.0 g in 100 ml of 0.9% saline) followed by blood and urine collection to measure the concentrations of benapenem and its major metabolite. PK analysis was performed to evaluate the effect of varying degrees of renal impairment on the PK characteristics of benapenem. The safety of benapenem was also evaluated. RESULTS: In subjects with normal renal function, mild renal impairment, and moderate renal impairment, the maximum plasma benapenem concentrations were 163 ± 6.58 mg/L, 138 ± 17.4 mg/L, and 134 ± 0.11 mg/L, respectively (15.3% and 17.8% lower in subjects with mild and moderate renal impairment, respectively, than in subjects with normal renal function). The areas under the plasma concentration-time curve (AUC0-inf) were 1153.67 ± 143.2 mg·h/L, 1129.17 ± 241.41 mg·h/L, and 1316.46 ± 229.83 mg·h/L, respectively (P > 0.05); the cumulative urinary excretion rates at 72 h after dosing were 52.61 ± 8.58%, 39.42 ± 8.35%, and 29.84 ± 9.15%, respectively; and the metabolic ratio (AUC0-inf_KBP-3331/AUC0-inf_benapenem) were 3.96 ± 0.35%, 5.56 ± 0.82%, and 8.24 ± 0.85%, respectively. No drug-related adverse events (AEs), serious AEs, or AEs leading to withdrawal occurred in this study. CONCLUSION: No adjustment to benapenem dosing is needed in patients with mild to moderate renal impairment. CLINICAL TRIAL REGISTRATION: Drug clinical trial registration and information publicity platform: http://www.chinadrugtrials.org.cn/index.html . REGISTRATION NUMBER: CTR20190760.

Assessment of carbapenems in a mouse model of Mycobacterium tuberculosis infection.

We present further study of a subset of carbapenems, arising from a previously reported machine learning approach, with regard to their mouse pharmacokinetic profiling and subsequent study in a mouse model of sub-acute Mycobacterium tuberculosis infection. Pharmacokinetic metrics for such small molecules were compared to those for meropenem and biapenem, resulting in the selection of two carbapenems to be assessed for their ability to reduce M. tuberculosis bacterial loads in the lungs of infected mice. The original syntheses of these two carbapenems were optimized to provide multigram quantities of each compound. One of the two experimental carbapenems, JSF-2204, exhibited efficacy equivalent to that of meropenem, while both were inferior to rifampin. The lessons learned in this study point toward the need to further enhance the pharmacokinetic profiles of experimental carbapenems to positively impact in vivo efficacy performance.

In Vivo High Plasticity of Multi-Drug Resistant ST258 Klebsiella pneumoniae.

Carbapenemase production in Enterobacterales clinical isolates is a global threat. Multi-drug resistant Klebsiella pneumoniae harboring carbapenemases are a major concern among the hospital settings in Latin America. Aim: The aim of this study was to analyze the genetic relatedness between three isolates of K. pneumoniae recovered from one patient in the same bacteriological round on the same day, which exhibited different susceptibility profiles to carbapenems (CP) and to colistin (Col). Isolates' profiles were as follows (susceptible-S/resistant-R): CPS/ColR, CPR/ColR, and CPR/ColS. Pulse-field gel electrophoresis, multilocus sequence typing, and whole genome sequencing were performed. Conjugation assays were carried out and PCR determination in transconjugants (Tcs) was made for: blaCTX-M-groups, blaNDM, blaKPC, blaTEM, qnr alleles, aac(6')Ib-cr, ermB, and plasmid incompatibility groups (Inc). Results: All isolates belonged to the same clone, to ST258 and harbored blaCTX-M-14, blaCTX-M-15, qnrA1, qnrB1, aac(6')Ib-cr, and wzi154 (capsule-locus KL107). One isolate had additional wzi gene, wzi109 (capsule-locus KL36). In CPR isolates, the pattern was explained for blaNDM-1 or blaNDM-1/blaKPC-2 presence, and in ColR for IS5-like element insertion in mgrB at different positions. Co-mobilization of blaNDM-1/qnrA1 was associated to a different plasmid Inc (A/C-FII) in both blaNDM-1 donors. Mobilization of blaCTX-M-14 was related to IncI1 in one donor. Conclusion: These findings highlight the potential plasticity of ST258 K. pneumoniae clone. To the best of our knowledge, this is the first description of blaNDM-1/blaKPC-2-producing K. pneumoniae ST258 in Latin America.

Preclinical Pharmacokinetic/Pharmacodynamic Studies and Clinical Trials in the Drug Development Process of EMA-Approved Antibacterial Agents: A Review.

Development of new antibacterial agents is necessary as drug-resistant bacteria are a threat to global health. In Europe, the European Medicines Agency has been guiding this development process for more than two decades. We investigated preclinical and clinical pre-approval studies to illuminate the current authorization process with emphasis on pharmacokinetic/pharmacodynamic approaches and clinical phases. All centrally authorized systemic antibacterial and antimycobacterial drugs within the European Union were included without any time restriction. Additionally, US Food and Drug Administration-approved antibiotics of the previous 3 years, which were not yet approved by the European Medicines Agency, were included. We focused on preclinical pharmacokinetic/pharmacodynamic studies and phase II and phase III clinical trials. Furthermore, we looked at the recommended dosing regimens and approved indications. In this review, we designed tree diagrams as a new means of illustrating the development process of antibiotics to relate pharmacokinetic/pharmacodynamic phase II and III studies to approved indications. We included 23 (European Medicines Agency, 18; US Food and Drug Administration, 5) antimicrobial agents. Tetracyclines, carbapenems, and cephalosporins were the leading classes. The recommended dosing intervals were significantly shorter in time- vs exposure-dependent drugs (median 8 vs 12, p = 0.006). The majority of approved indications (i.e., acute bacterial skin and soft-tissue infection, community-acquired pneumonia, complicated intra-abdominal infection, complicated urinary tract infection, and complicated skin and soft-tissue infection) used non-inferiority trials. Phase II and III clinical trials investigating community-acquired pneumonia involved the fewest patients. Some promising drugs were marketed in recent years; the individual steps to their authorizations are illuminated. We confirmed the relevance of preclinical pharmacokinetic/pharmacodynamic studies in dosing optimization and decision making in antimicrobial drug development. Non-inferiority clinical trials predominated.

Pharmacokinetics and Target Attainment of Antibiotics in Critically Ill Children: A Systematic Review of Current Literature.

BACKGROUND: Pharmacokinetics (PK) are severely altered in critically ill patients due to changes in volume of distribution (Vd) and/or drug clearance (Cl). This affects the target attainment of antibiotics in critically ill children. We aimed to identify gaps in current knowledge and to compare published PK parameters and target attainment of antibiotics in critically ill children to healthy children and critically ill adults. METHODS: Systematic literature search in PubMed, EMBASE and Web of Science. Articles were labelled as relevant when they included information on PK of antibiotics in critically ill, non-neonatal, pediatric patients. Extracted PK-parameters included Vd, Cl, (trough) concentrations, AUC, probability of target attainment, and elimination half-life. RESULTS: 50 relevant articles were identified. Studies focusing on vancomycin were most prevalent (17/50). Other studies included data on penicillins, cephalosporins, carbapenems and aminoglycosides, but data on ceftriaxone, ceftazidime, penicillin and metronidazole could not be found. Critically ill children generally show a higher Cl and larger Vd than healthy children and critically ill adults. Reduced target-attainment was described in critically ill children for multiple antibiotics, including amoxicillin, piperacillin, cefotaxime, vancomycin, gentamicin, teicoplanin, amikacin and daptomycin. 38/50 articles included information on both Vd and Cl, but a dosing advice was given in only 22 articles. CONCLUSION: The majority of studies focus on agents where TDM is applied, while other antibiotics lack data altogether. The larger Vd and higher Cl in critically ill children might warrant a higher dose or extended infusions of antibiotics in this patient population to increase target-attainment. Studies frequently fail to provide a dosing advice for this patient population, even if the necessary information is available. Our study shows gaps in current knowledge and encourages future researchers to provide dosing advice for special populations whenever possible.

Model-Informed Drug Development, Pharmacokinetic/Pharmacodynamic Cutoff Value Determination, and Antibacterial Efficacy of Benapenem against Enterobacteriaceae.

Benapenem is a novel carbapenem. The objective of this study was to determine the pharmacokinetic (PK)/pharmacodynamic (PD) cutoff values and evaluate the optimal administration regimens of benapenem for the treatment of bacterial infections via PK/PD modeling and simulation. Ertapenem was used as a control. Infected mice received an intravenous (i.v.) injection of benapenem or ertapenem of 14.6, 58.4, or 233.6 mg/kg of body weight, and the PK/PD profiles were evaluated. The MICs were determined by using a 2-fold agar dilution method. Mathematical models were developed to characterize the pharmacokinetic profile of benapenem in humans and mice. Monte Carlo simulations were employed to determine the cutoff values and the appropriate benapenem dosing regimens for the treatment of infections caused by clinical isolates of Enterobacteriaceae Two 2-compartment models were developed to describe the PK profiles of benapenem in humans and mice. A two-site binding model was applied to fit the protein binding in mouse plasma. Through correlation analysis, the percentage of the time that the free drug concentration remains above the MIC (%fT>MIC) was determined to be the indicator of efficacy. Results from the simulation showed that the probability of target attainment (PTA) against the tested isolates was over 90% with the dosing regimens studied. The PK/PD cutoff value of benapenem was 1 mg/liter at a %fT>MIC of 60% when given at a dose of 1,000 mg/day by i.v. drip for 0.5 h. The established model provides a better understanding of the pharmacological properties of benapenem for the treatment of Enterobacteriaceae infections. The proposed PK/PD cutoff value suggests that benapenem is a promising antibacterial against the Enterobacteriaceae The cutoff value of 1 mg/liter may be a useful guide for the clinical use of benapenem and for surveillance for benapenem resistance.

Antibiotic Exposure Profiles in Trials Comparing Intensity of Continuous Renal Replacement Therapy.

OBJECTIVES: To determine whether the probability of target attainment over 72 hours of initial therapy with beta-lactam (cefepime, ceftazidime, piperacillin/tazobactam) and carbapenem (imipenem, meropenem) antibiotics were substantially influenced between intensive and less-intensive continuous renal replacement therapy groups in the Acute Renal Failure Trial Network trial and The RENAL Replacement Therapy Study trial. DESIGN: The probability of target attainment was calculated using pharmacodynamic targets of percentage of time that free serum concentrations (fT): 1) were above the target organism's minimum inhibitory concentration (≥ fT > 1 × minimum inhibitory concentration); 2) were above four times the minimum inhibitory concentration (≥ % fT > 4 × minimum inhibitory concentration); and 3) were always above the minimum inhibitory concentration (≥ 100% fT > minimum inhibitory concentration) for the first 72 hours of antibiotic therapy. Demographic data and effluent rates from the Acute Renal Failure Trial Network and RENAL Replacement Therapy Study trials were used. Optimal doses were defined as the dose achieving greater than or equal to 90% probability of target attainment. SETTING: Monte Carlo simulations using demographic data from Acute Renal Failure Trial Network and RENAL Replacement Therapy Study trials. PATIENTS: Virtual critically ill patients requiring continuous renal replacement therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The pharmacodynamic target of fT greater than 1 × minimum inhibitory concentration led to similarly high rates of predicted response with antibiotic doses often used in continuous renal replacement therapy. Achieving 100% fT greater than minimum inhibitory concentration is a more stringent benchmark compared with T greater than 4 × minimum inhibitory concentration with standard antibiotic dosing. The intensity of effluent flow rates (less intensive vs intensive) did not substantially influence the probability of target attainment of antibiotic dosing regimens regardless of pharmacodynamic target. CONCLUSIONS: Antibiotic pharmacodynamic target attainment rates likely were not meaningfully different in the low- and high-intensity treatment arms of the Acute Renal Failure Trial Network and RENAL Replacement Therapy Study Investigators trials.

In Vivo Pharmacodynamic Study of Cefiderocol, a Novel Parenteral Siderophore Cephalosporin, in Murine Thigh and Lung Infection Models.

The pharmacokinetic (PK) and pharmacodynamic (PD) parameters which correlated with the in vivo efficacy of cefiderocol were evaluated using neutropenic murine thigh and lung infection models in which the infections were caused by a variety of Gram-negative bacilli. The dose fractionation study using the thigh infection model in which the infection was caused by Pseudomonas aeruginosa showed that the cumulative percentage of a 24-h period that the free drug concentration in plasma exceeds the MIC (%fT>MIC) rather than the free peak level divided by the MIC (fCmax/MIC) and the area under the free concentration-time curve over 24 h divided by the MIC (fAUC/MIC) was the PK/PD parameter that best correlated with efficacy. The study with multiple carbapenem-resistant strains revealed that the %fT>MIC determined in iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) better reflected the in vivo efficacy of cefiderocol than the %fT>MIC determined in cation-adjusted Mueller-Hinton broth (CAMHB). The mean %fT>MIC of cefiderocol required for a 1-log10 reduction against 10 strains of Enterobacteriaceae and 3 strains of Pseudomonas aeruginosa in the thigh infection models were 73.3% and 77.2%, respectively. The mean %fT>MIC for Enterobacteriaceae, P. aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia in the lung infection model were 64.4%, 70.3%, 88.1%, and 53.9%, respectively. These results indicate that cefiderocol has potent efficacy against Gram-negative bacilli, including carbapenem-resistant strains, irrespective of the bacterial species, in neutropenic thigh and lung infection models and that the in vivo efficacy correlated with the in vitro MIC under iron-deficient conditions.

Safety, Pharmacokinetics, and Food Effect of Tebipenem Pivoxil Hydrobromide after Single and Multiple Ascending Oral Doses in Healthy Adult Subjects.

Tebipenem pivoxil hydrobromide (TBPM-PI-HBr, formerly SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-ß-lactamase-producing Enterobacteriaceae The safety and pharmacokinetics (PK) of tebipenem were studied after administration of single and multiple ascending oral doses of TBPM-PI-HBr in fed and fasted states. Healthy adults received single oral doses of TBPM-PI-HBr at 100 mg to 900 mg or placebo (n = 108) or multiple doses of 300 mg or 600 mg every 8 h or placebo (n = 16) for 14 days. In the single-ascending-dose (SAD) phase, mean tebipenem plasma concentrations increased in a linear and dose proportional manner for doses of 100 to 900 mg and were comparable in the fasted and fed states for the 300- and 600-mg doses. In the MAD phase, tebipenem maximum concentration (Cmax) was reached within 1.5 h and was dose proportional on day 1 and higher than dose proportional (2.7-fold) on day 14. AUC was more than 2-fold greater on day 1 (2.7-fold) and day 14 (2.5-fold) for 600 mg q8h than for 300 mg q8h. Approximately 55% to 60% of tebipenem was recovered in the urine. TBPM-PI-HBr was well tolerated; mild, transient diarrhea was the most commonly reported adverse event. TBPM-PI-HBr provides an orally bioavailable carbapenem option to treat serious infections caused by MDR Enterobacteriaceae and has the potential to decrease the need for intravenous antibiotic therapy in the hospital or outpatient setting. (This study has been registered at ClinicalTrials.gov under identifier NCT03395249.).

A validated UPLC-MS/MS method for determination of tebipenem in human plasma and its application to a pharmacokinetic study in healthy volunteers.

A rapid and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determining tebipenem (TBPM) in human plasma. Plasma samples were prepared following a single-step protein precipitation method using acetonitrile and 3-morpholinopropanesulfonic acid (MOPS, pH 7.0, 50 mM) which equal volume of plasma samples were added for stabilizing the analyte. Separation was achieved using an ACQUITY UPLC BEH C18 (1.7 µm, 2.1 × 50 mm) column. A repeated gradient program was employed for reducing the carryover effect, and the total chromatographic run time was 3.0 min. Method validation results showed TBPM was linear in its analytical range i.e. between 0.1-20 µg/mL (r2>0.99), and the lower limit of quantification (LLOQ) was 0.1 µg/mL. The intra-run and inter-run precision (coefficient of variation, CV) was within 3.81%, and the accuracy (relative error, RE) was within ± 8.56%. The carryover was restricted below 8.1%. Matrix effects were minimal, and recovery of TBPM was 90.19-95.74%. The stability of TBPM in plasma sample stored at room temperature (25 °C) for 4 h, at -20 °C for 3 days, at -80 °C for 30 days, five freeze-thaw cycles at -80 °C and processed samples at auto sampler vials (8 °C) for 24 h were within 91.11-106.33%. Finally, the validated method was successfully applied to a pharmacokinetic study of TBPM in healthy volunteers after oral administration of tebipenem pivoxil (TBPM-PI).

Modeling Ertapenem: the impact of body mass index on distribution of the antibiotic in the body.

Ertapenem is an antibiotic commonly used to treat a broad spectrum of infections and is part of a broader class of antibiotics called carbapenems. Unlike other carbapenems, ertapenem has a longer half-life and thus only has to be administered once a day. Previously, a physiologically-based pharmacokinetic (PBPK) model was developed to investigate the uptake, distribution, and elimination of ertapenem following a single one gram dose in normal height, normal weight males. Due to the absorption properties of ertapenem, the amount of fat in the body can influence how the drug binds, how quickly the drug passes through the body, and thus how effective the drug might be. Thus, we have revised the model so that it is applicable to males and females of differing body mass index (BMI). Simulations were performed to consider the distribution of the antibiotic in males and females with varying body mass indexes. These results could help to determine if there is a need for altered dosing regimens in the future.

Cyclodextrins as multifunctional excipients: Influence of inclusion into ß-cyclodextrin on physicochemical and biological properties of tebipenem pivoxil.

A novel approach for drug design based on the oral carbapenem analog tebipenem pivoxil (TP) has been proposed. The formation of the tebipenem pivoxil-ß-cyclodextrin (TP-ß-CD) complex resulted in changes concerning physicochemical properties of TP, which is significant for planning the development of an innovative pharmaceutical formulation as well as in the modifications of biological activity profile of the studied delivery system. The inclusion of TP into ß-cyclodextrin (ß-CD) was confirmed by spectral (infrared and Raman spectroscopies) and thermal method (differential scanning calorimetry). Precise indications of TP domains responsible for interaction with ß-CD were possible through a theoretical approach. The most important physicochemical modifications obtained as an effect of TP inclusion were changes in solubility and its rate depending on acceptor fluids, and an increase in chemical stability in the solid state. Biologically essential effects of TP and ß-CD interactions were decreased TP permeability through Caco-2 cell monolayers with the use of efflux effect inhibition and increased antibacterial activity. The proposed approach is an opportunity for development of the treatment in resistant bacterial infections, in which along with physicochemical modifications induced by a drug carrier impact, a carrier synergy with a pharmacological potential of an active pharmaceutical substance could be used.

A First-in-Human Safety, Tolerability, and Pharmacokinetics Study of Benapenem in Healthy Chinese Volunteers.

The objective of this trial was to investigate the safety, tolerability, and pharmacokinetics (PK) of benapenem administered by single or multiple intravenous infusions in healthy Chinese volunteers. The trial was divided into 3 parts. In part A, 94 subjects were enrolled in a double-blind, placebo-controlled, sequential-ascending-single-dose study. The subjects were randomly assigned to groups receiving placebo or benapenem for injection at doses of 62.5, 125, 250, 500, 1,000, 2,000, or 3,000 mg. The effects of intravenous infusion time on the subjects of 250-, 500-, and 1,000-mg groups were explored. In part B, 12 subjects were enrolled in a single-dose PK study under fasting conditions and received 250, 500, or 1,000 mg of benapenem for injection. In part C, 36 subjects were given 250, 500, and 1,000 mg of benapenem for injection once daily for 7 consecutive days. The results showed that benapenem for injection was well tolerated during the studies. The major observed adverse events were mild, and all were resolved spontaneously without any medical intervention. Benapenem was mainly excreted through the kidneys in the form of parent molecule and metabolites. The PK and safety profiles of benapenem in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (Part A, part B, and part C have been registered at ClinicalTrials.gov under identifiers NCT03588156, NCT03578588, and NCT03570970, respectively.).

Population Pharmacokinetic Analyses for Ertapenem in Subjects with a Wide Range of Body Sizes.

Despite a number of studies reporting that ertapenem pharmacokinetic parameters differ considerably in obese patients from those in healthy volunteers, functions describing the relationships between this agent's pharmacokinetics and indicators of body size have not been developed. The aim of this analysis was to develop an ertapenem population pharmacokinetic model using data from a previously described study in normal-weight, obese, and morbidly obese healthy volunteers. A single ertapenem 1-g dose administered intravenously was evaluated in 30 subjects within different body mass index (BMI) categories. The population pharmacokinetic model was developed using the first-order conditional estimation method with interaction (FOCE-I) algorithm within NONMEM. The ability of age, sex, renal function, and various body size measures (total body weight, height, body mass index, ideal body weight, fat-free mass, and body surface area [BSA]) to explain a portion of the interindividual variability on select pharmacokinetic parameters was explored using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). The data were best described using a linear three-compartment model with total body weight as a covariate on clearance (CL = 1.79 · [weight/95.90]0.278) and BSA as a covariate on central volume (Vc = 4.76 · [BSA/2.06]1.86). After accounting for fixed effects, the estimated interindividual variability was very low (<10% for all clearance and volume terms). Goodness-of-fit diagnostics indicated a precise and unbiased fit to the data. Using the developed population pharmacokinetic model and simulation, reliable estimates of ertapenem serum exposures, which can be utilized to evaluate various dosing regimens in subjects with a wide range of body sizes, are expected.

Characterization of SPR994, an Orally Available Carbapenem, with Activity Comparable to Intravenously Administered Carbapenems.

Carbapenems are potent antibacterials with broad-spectrum activity. However, poor oral absorption generally confines this important drug class to in-hospital use by intravenous (IV) administration. The continued rise in drug resistant pathogens creates a need for alternative oral therapies with broad-spectrum activity. SPR994 is a novel formulation of the orally bioavailable pivoxil prodrug of SPR859 (tebipenem) and is being developed as the first oral carbapenem for treatment of complicated urinary tract infections (cUTIs) in adults. Herein, we describe characteristics beneficial to oral administration and compare the in vitro and in vivo activity of SPR859 or SPR994 with IV carbapenems.

Pharmacokinetics and Pharmacodynamics of Fosfomycin and Its Activity against Extended-Spectrum-ß-Lactamase-, Plasmid-Mediated AmpC-, and Carbapenemase-Producing Escherichia coli in a Murine Urinary Tract Infection Model.

Fosfomycin has become an attractive treatment alternative for urinary tract infections (UTIs) due to increasing multidrug resistance (MDR) in Escherichia coli In this study, we evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) indices of fosfomycin and its in vivo activity in an experimental murine model of ascending UTI. Subcutaneous administration of fosfomycin showed that the mean peak plasma concentrations of fosfomycin were 36, 280, and 750 mg/liter following administration of a single dose of 0.75, 7.5, and 30 mg/mouse, respectively, with an elimination half-life of 28 min, and urine peak concentrations of 1,100, 33,400, and 70,000 mg/liter expected to be sustained above 1 mg/liter (MIC of the test strain, NU14) for 5, 8, and 9.5 h, respectively. The optimal PK/PD indices for reducing urine colony counts (number of CFU per milliliter) were determined to be the area under the concentration-time curve/MIC from 0 to 72 h and the maximum concentration/MIC on the basis of the dose-dependent bloodstream PK and the results of an evaluation of six dosing regimens. With a dosing regimen of 15 mg/mouse twice (every 36 h), fosfomycin significantly reduced the number of CFU per milliliter of all susceptible strains in urine, including clinical MDR strains, except for one clinical strain (P = 0.062). Variable degrees of reduction were observed in the bladder and kidneys. No significant reductions in the number of CFU per milliliter were observed with the resistant strains. In conclusion, fosfomycin shows concentration-dependent in vivo activity, and the results suggest that fosfomycin is an effective alternative to carbapenems in treating MDR E. coli in uncomplicated UTIs. The data on the effectiveness of fosfomycin against the MDR isolates along with the results of PK/PD modeling should facilitate the further development of improved recommendations for its clinical use.

Elimination of Doripenem during Dialysis and Pharmacokinetic Evaluation of Posthemodialysis Dosing for Patients Undergoing Intermittent Renal Replacement Therapy.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa and Enterobacteriaceae Current dosing regimens recommend the administration of 0.25 to 0.5 g once daily in patients undergoing intermittent renal replacement therapy. As patients are usually dialyzed thrice weekly, we aimed to investigate a 1-g posthemodialysis regimen, thus reducing treatment costs and enhancing patient compliance. A second objective of this trial was to describe the pharmacokinetics of intradialytic doripenem. Ten oliguric or anuric patients in need of intermittent renal replacement therapy were included in this trial. All patients suffered from a septic episode. The mean hemofilter clearance was 123.46 ± 42.03 ml/min, and the total body clearance between hemodialysis sessions was 16.79 ± 6.02 ml/min. The average prehemodialysis trough concentration was 2.4 ± 1.3 mg/liter, while the EUCAST resistance breakpoint for Enterobacteriaceae is set at 2 mg/liter. The interpatient variability was considerably higher than the intrapatient variability. Apart from one patient who suffered an allergic reaction, doripenem was tolerated well by all patients. Our data indicate that posthemodialysis administration of 1 g of doripenem results in sufficient plasma levels in anuric but not oliguric patients during the entire dosing interval. (This trial was registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

Dissemination and Characteristics of a Novel Plasmid-Encoded Carbapenem-Hydrolyzing Class D ß-Lactamase, OXA-436, Found in Isolates from Four Patients at Six Different Hospitals in Denmark.

The diversity of OXA-48-like carbapenemases is continually expanding. In this study, we describe the dissemination and characteristics of a novel carbapenem-hydrolyzing class D ß-lactamase (CHDL) named OXA-436. In total, six OXA-436-producing Enterobacteriaceae isolates, including Enterobacter asburiae (n = 3), Citrobacter freundii (n = 2), and Klebsiella pneumoniae (n = 1), were identified in four patients in the period between September 2013 and April 2015. All three species of OXA-436-producing Enterobacteriaceae were found in one patient. The amino acid sequence of OXA-436 showed 90.4 to 92.8% identity to the amino acid sequences of other acquired OXA-48-like variants. Expression of OXA-436 in Escherichia coli and kinetic analysis of purified OXA-436 revealed an activity profile similar to that of OXA-48 and OXA-181, with activity against penicillins, including temocillin; limited or no activity against extended-spectrum cephalosporins; and activity against carbapenems. The blaOXA-436 gene was located on a conjugative ∼314-kb IncHI2/IncHI2A plasmid belonging to plasmid multilocus sequence typing sequence type 1 in a region surrounded by chromosomal genes previously identified to be adjacent to blaOXA genes in Shewanella spp. In conclusion, OXA-436 is a novel CHDL with functional properties similar to those of OXA-48-like CHDLs. The described geographical spread among different Enterobacteriaceae and the plasmid location of blaOXA-436 illustrate its potential for further dissemination.