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Background Annual mortality from neonatal sepsis is an estimated 430 000–680 000 infants globally, most of which occur in low- and middle-income countries (LMICs). The WHO currently recommends a narrow-spectrum β-lactam (e.g. ampicillin) and gentamicin as first-line empirical therapy. However, available epidemiological data demonstrate high rates of resistance to both agents. Alternative empirical regimens are needed. Flomoxef and amikacin are two off-patent antibiotics with potential for use in this setting. Objectives To assess the pharmacodynamics of flomoxef and amikacin in combination. Methods The pharmacodynamic interaction of flomoxef and amikacin was assessed in chequerboard assays and a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment. The combination was further assessed in HFIM experiments mimicking neonatal plasma exposures of clinically relevant doses of both drugs against five Enterobacterales isolates with a range of flomoxef/amikacin MICs. Results Flomoxef and amikacin in combination were synergistic in bacterial killing in both assays and prevention of emergence of amikacin resistance in the HFIM. In the HFIM assessing neonatal-like drug exposures, the combination killed 3/5 strains to sterility, (including 2/5 that monotherapy with either drug failed to kill) and failed to kill the 2/5 strains with flomoxef MICs of 32 mg/L. Conclusions We conclude that the combination of flomoxef and amikacin is synergistic and is a potentially clinically effective regimen for the empirical treatment of neonatal sepsis in LMIC settings and is therefore suitable for further assessment in a clinical trial.

Background Neonatal sepsis is a serious bacterial infection of neonates, globally killing up to 680 000 babies annually. It is frequently complicated by antimicrobial resistance, particularly in low- and middle-income country (LMIC) settings with widespread resistance to the WHO’s recommended empirical regimen of ampicillin and gentamicin. Objectives We assessed the utility of flomoxef and fosfomycin as a potential alternative empirical regimen for neonatal sepsis in these settings. Methods We studied the combination in a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment and chequerboard assays. We further assessed the combination using clinically relevant regimens in the HFIM with six Enterobacterales strains with a range of flomoxef/fosfomycin MICs. Results Pharmacokinetic/pharmacodynamic modelling of the HFIM experimental output, along with data from chequerboard assays, indicated synergy of this regimen in terms of bacterial killing and prevention of emergence of fosfomycin resistance. Flomoxef monotherapy was sufficient to kill 3/3 strains with flomoxef MICs ≤0.5 mg/L to sterility. Three of three strains with flomoxef MICs ≥8 mg/L were not killed by fosfomycin or flomoxef monotherapy; 2/3 of these were killed with the combination of the two agents. Conclusions These data suggest that flomoxef/fosfomycin could be an efficacious and synergistic regimen for the empirical treatment of neonatal sepsis in LMIC settings with prevalent antimicrobial resistance. Our HFIM results warrant further assessment of the flomoxef/fosfomycin combination in clinical trials.

Purpose A series of iterative population pharmacokinetic (PK) modelling and probability of target attainment (PTA) analyses were undertaken to support dose optimization for aztreonam-avibactam, a combination antibiotic. Methods Joint PTA analyses (primary target: 60% fT>8 mg/L for aztreonam, 50% fT>2.5 mg/L for avibactam) explored the impact of patient variability, and evaluated loading doses and extended infusions, and adjustments for patients with moderate (estimated creatinine clearance [CrCL] >30 to ≤50 mL/min) and severe renal impairment (>15 to ≤30 mL/min). Achievement of >90% joint PTA, and the impact of differential renal clearance, were considerations in dose selection. Results Dose selection for phase I and phase IIa (Cohort 1) was based on PK models of avibactam in patients and of aztreonam in healthy volunteers with ‘patient-like’ assumptions. Simulations demonstrated that: 3-h and continuous infusions provide comparable PTA; with patient variability, avibactam dose is the main driver of joint PTA; loading doses support more rapid joint target attainment. Aztreonam/avibactam 500/137 mg 30-min loading dose and 1500/410 mg 3-h maintenance infusions q6h was selected for initial phase IIa evaluation in patients with complicated intra-abdominal infection. Later PTA analyses using expanded PK models supported an increased avibactam dose (500/167 mg loading; 1500/500 q6h maintenance) and were also used to select doses for renal impairment. Conclusion Aztreonam-avibactam 3-h infusions administered q6h are necessary to optimize joint PTA. Aztreonam-avibactam 500/167 mg loading 30-min infusion followed by 1500/500 mg maintenance 3-h infusions q6h (for CrCL >50 mL/min) is undergoing phase III evaluation. Clinical trial registration: NCT01689207 (September 21, 2012); NCT02655419 (January 14, 2016); NCT03329092 (November 1, 2017); NCT03580044 (July 9, 2018)

Neonatal sepsis causes up to an estimated 680,000 deaths annually worldwide, predominantly in low- and middle-income countries (LMICs). A significant and growing proportion of bacteria causing neonatal sepsis are resistant to multiple antibiotics, including the World Health Organization-recommended empiric neonatal sepsis regimen of ampicillin/gentamicin. The Global Antibiotic Research and Development Partnership is aiming to develop alternative empiric antibiotic regimens that fulfil several criteria: (1) affordable in LMIC settings; (2) activity against neonatal bacterial pathogens, including extended-spectrum β-lactamase producers, gentamicin-resistant Gram-negative bacteria, and methicillin-resistant Staphylococcus aureus (MRSA); (3) a licence for neonatal use or extensive experience of use in neonates; and (4) minimal toxicities. In this review, we identify five antibiotics that fulfil these criteria: amikacin, tobramycin, fosfomycin, flomoxef, and cefepime. We describe the available characteristics of each in terms of mechanism of action, resistance mechanisms, clinical pharmacokinetics, pharmacodynamics, and toxicity profile. We also identify some knowledge gaps: (1) the neonatal pharmacokinetics of cefepime is reliant on relatively small and limited datasets, and the pharmacokinetics of flomoxef are also reliant on data from a limited demographic range and (2) for all reviewed agents, the pharmacodynamic index and target has not been definitively established for both bactericidal effect and emergence of resistance, with many assumed to have an identical index/target to similar class molecules. These five agents have the potential to be used in novel combination empiric regimens for neonatal sepsis. However, the data gaps need addressing by pharmacokinetic trials and pharmacodynamic characterisation.

Neonatal sepsis is an underrecognized burden on health care systems throughout the world. Antimicrobial drug resistance (AMR) is increasingly prevalent and compromises the use of currently recommended first-line agents. The development of new antimicrobial agents for neonates and children is mandated by regulatory agencies. However, there remains uncertainty about suitable development pathways, especially because of the propensity of premature babies to develop meningoencephalitis as a complication of neonatal sepsis and difficulties studying this disease in clinical settings. We developed a new platform and approach to accelerate the development of antimicrobial agents for neonatal bacterial meningoencephalitis using Pseudomonas aeruginosa as the challenge organism. We defined the pharmacodynamics of meropenem and tobramycin in these models. The percentage of partitioning of meropenem and tobramycin into the cerebrospinal fluid was comparable at 14.3 and 13.7%, respectively. Despite this similarity, there were striking differences in their pharmacodynamics. Meropenem resulted in bactericidal activity in both the cerebrospinal fluid and cerebrum, whereas tobramycin had minimal antibacterial activity. A hollow fiber infection model (HFIM) using neonatal CSF concentration time profiles yielded pharmacodynamics comparable to those observed in the rabbit model. These new experimental models can be used to estimate the pharmacodynamics of currently licensed agents and those in development and their potential efficacy for neonatal bacterial meningoencephalitis.

Purpose Ceftazidime–avibactam is a novel β-lactam/β-lactamase inhibitor combination recently approved in Europe and the USA for the treatment of adults with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), among other indications. In the phase III REPROVE trial (NCT01808092), ceftazidime–avibactam demonstrated non-inferiority to meropenem for the treatment of patients with nosocomial pneumonia (NP), including VAP. As ceftazidime–avibactam was not studied in patients with NP prior to REPROVE, selecting an appropriate dosage regimen in the “perfect storm” of NP required careful consideration of potential determinants and confounders of response specific to the NP patient population. Methods This review describes the series of preclinical studies and pharmacokinetic/pharmacodynamic (PK/PD) analyses that supported ceftazidime–avibactam dosage selection for patients with NP/VAP (2000/500 mg by 2-h intravenous infusion every 8 h, adjusted for renal function). In parallel, important considerations for antibiotic dosage selection in patients with NP are highlighted, including adequate drug penetration into the lungs, the suitability of murine-derived plasma PK/PD targets, evaluation of MIC distributions against clinical bacterial isolates from patients with NP, and consideration of PK in patients with NP, who are often critically ill. These analyses also supported the European approval of ceftazidime–avibactam for adults with HAP, including VAP, before the completion of REPROVE. Conclusions This work serves as a successful practical example of dosage design for a new antibacterial drug therapy in the indication of NP, including VAP, where previous drug therapies have failed, possibly as a result of evaluation of too few variables, thereby limiting the accuracy of pharmacodynamic predictions.

Antimicrobial resistance (particularly through extended-spectrum β-lactamase and aminoglycoside-modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, with significant mortality rates. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis, i.e., ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance. The combination was studied in a 16-arm dose-ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented the emergence of resistance, compared to monotherapy with either antibiotic. Modeling of the experimental quantitative outputs and data from checkerboard assays indicated synergy. We further assessed the combination regimen at clinically relevant doses in the HFIM with nine Enterobacterales strains with high fosfomycin and amikacin MICs and demonstrated successful kill to sterilization for 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales strains, i.e., MIC(F) × MIC(A) < 256 (where MIC(F) and MIC(A) are the fosfomycin and amikacin MICs, respectively). Monte Carlo simulations predict that a standard fosfomycin-amikacin neonatal regimen would achieve >99% probability of pharmacodynamic success for strains with MICs below this threshold. We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empirical treatment of neonatal sepsis and is suitable for further clinical assessment in a randomized controlled trial.

We thank Dr Asempa and colleagues for their comments on our recent PK-PD analyses of ANT2681 in the context of their own work on metallo-s-lactamases (1, 2).….

Cefepime-enmetazobactam is a novel β-lactam–β-lactamase inhibitor combination with broad-spectrum antimicrobial activity against a range of multidrug-resistant Enterobacteriaceae. This agent is being developed for a range of serious hospital infections. An understanding of the extent of partitioning of β-lactam–β-lactamase inhibitor combinations into the human lung is required to better understand the potential role of cefepime-enmetazobactam for the treatment of nosocomial pneumonia. A total of 20 healthy volunteers were used to study the intrapulmonary pharmacokinetics of a regimen of 2 g cefepime-1 g enmetazobactam every 8 h intravenously (2 g/1 g q8h i.v.). Each volunteer contributed multiple plasma samples and a single epithelial lining fluid (ELF) sample, obtained by bronchoalveolar lavage. Concentrations of cefepime and enmetazobactam were quantified using liquid chromatography-tandem mass spectrometry. The pharmacokinetic data were modeled using a population methodology, and Monte Carlo simulations were performed to assess the attainment of pharmacodynamic targets defined in preclinical models. The concentration-time profiles of both agents in plasma and ELF were similar. The mean ± standard deviation percentage of partitioning of total drug concentrations of cefepime and enmetazobactam between plasma and ELF was 60.59% ± 28.62% and 53.03% ± 21.05%, respectively. Using pharmacodynamic targets for cefepime of greater than the MIC and free enmetazobactam concentrations of >2 mg/liter in ELF of 20% of the dosing interval, a regimen of cefepime-enmetazobactam of 2 g/0.5 g q8h i.v. infused over 2 h resulted in a probability of target attainment of ≥90% for Enterobacteriaceae with cefepime-enmetazobactam MICs of ≤8 mg/liter. This result provides a rationale to further consider cefepime-enmetazobactam for the treatment of nosocomial pneumonia caused by multidrug-resistant Enterobacteriaceae.

Enterobacteriaceae that produce metallo-β-lactamases (MBLs) are an emerging threat to public health. The metallo-β-lactamase inhibitor (MBLi) ANT2681 inhibits the enzymatic activity of MBLs through interaction with the dinuclear zinc ion cluster present in the active site that is common to these enzymes. ANT2681 is being codeveloped, with meropenem as the partner β-lactam, as a novel combination therapy for infections caused by MBL-producing bacteria. The pharmacokinetics/pharmacodynamics of meropenem-ANT2681 were studied in a murine neutropenic thigh model of NDM-producing Enterobacteriaceae. Dose-ranging studies were performed with both meropenem and ANT2681. Dose fractionation experiments were performed to identify the relevant pharmacodynamic index of ANT2681 when coadministered with meropenem. A background of meropenem at 50 mg/kg of body weight every 4 h (q4h) subcutaneously (s.c.) had minimal antibacterial effect. On this background, half-maximal effect was observed with an ANT2681 dose of 89 mg/kg q4h intravenously (i.v.). The dose fractionation study showed that area under the concentration-time curve (AUC) was the relevant pharmacodynamic index for the inhibitor. The magnitude of the meropenem-ANT2681 exposure required to achieve stasis was explored using 5 NDM-producing strains. A 3-dimensional surface fitted to the pharmacodynamic data from the 5 strains suggested that stasis was achieved with an fT > potentiated meropenem MIC of 40% and ANT2681 AUC of 700 mg · h/liter. These data and analyses provide the underpinning evidence for the combined use of meropenem and ANT2681 for clinical infections.

Klebsiella pneumoniae strains that produce extended-spectrum beta lactamases (ESBLs) are a persistent public health threat. There are relatively few therapeutic options, and there is undue reliance on carbapenems. Alternative therapeutic options are urgently required. A combination of cefepime and the novel beta lactamase inhibitor enmetazobactam is being developed for the treatment of serious infections caused by ESBL-producing organisms. The pharmacokinetics-pharmacodynamics (PK-PD) of cefepime-enmetazobactam against ESBL-producing K. pneumoniae was studied in a neutropenic murine pneumonia model. Dose-ranging studies were performed. Dose fractionation studies were performed to define the relevant PD index for the inhibitor. The partitioning of cefepime and enmetazobactam into the lung was determined by comparing the area under the concentration-time curve (AUC) in plasma and epithelial lining fluid. The magnitude of drug exposure for cefepime-enmetazobactam required for logarithmic killing in the lung was defined using 3 ESBL-producing strains. Cefepime, given as 100 mg/kg of body weight every 8 h intravenously (q8h i.v.), had minimal antimicrobial effect. When this background regimen of cefepime was combined with enmetazobactam, a half-maximal effect was induced with enmetazobactam at 4.71 mg/kg q8h i.v. The dose fractionation study suggested both fT > threshold and fAUC:MIC are relevant PD indices. The AUCELF:AUCplasma ratio for cefepime and enmetazobactam was 73.4% and 61.5%, respectively. A ≥2-log kill in the lung was achieved with a plasma and ELF cefepime fT > MIC of ≥20% and enmetazobactam fT > 2 mg/liter of ≥20% of the dosing interval. These data and analyses provide the underpinning evidence for the combined use of cefepime and enmetazobactam for nosocomial pneumonia.

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.

Klebsiella pneumoniae strains that produce extended-spectrum beta lactamases (ESBLs) are a persistent public health threat. There are relatively few therapeutic options, and there is undue reliance on carbapenems. Alternative therapeutic options are urgently required. A combination of cefepime and the novel beta lactamase inhibitor enmetazobactam is being developed for the treatment of serious infections caused by ESBL-producing organisms. The pharmacokinetics-pharmacodynamics (PK-PD) of cefepime-enmetazobactam against ESBL-producing K. pneumoniae was studied in a neutropenic murine pneumonia model. Dose-ranging studies were performed. Dose fractionation studies were performed to define the relevant PD index for the inhibitor. The partitioning of cefepime and enmetazobactam into the lung was determined by comparing the area under the concentration-time curve (AUC) in plasma and epithelial lining fluid. The magnitude of drug exposure for cefepime-enmetazobactam required for logarithmic killing in the lung was defined using 3 ESBL-producing strains. Cefepime, given as 100 mg/kg of body weight every 8 h intravenously (q8h i.v.), had minimal antimicrobial effect. When this background regimen of cefepime was combined with enmetazobactam, a half-maximal effect was induced with enmetazobactam at 4.71 mg/kg q8h i.v. The dose fractionation study suggested both fT > threshold and fAUC:MIC are relevant PD indices. The AUC(ELF):AUC(plasma) ratio for cefepime and enmetazobactam was 73.4% and 61.5%, respectively. A ≥2-log kill in the lung was achieved with a plasma and ELF cefepime fT > MIC of ≥20% and enmetazobactam fT > 2 mg/liter of ≥20% of the dosing interval. These data and analyses provide the underpinning evidence for the combined use of cefepime and enmetazobactam for nosocomial pneumonia.

Agriculture is the most essential and the oldest practice of food supply for human survival. With the increases in population, food demands also increases. Therefore, the activities of agriculture have to be increased to meet increasing demand of the food supply. The increase of agricultural activities with improper planning has adverse effect to our ecological diversity. Also with the introduction of new strategies, the environment pollution is become the main problem that human is facing today. This article attempt to highlights the advantages and disadvantages of new innovative agricultural practices and its effects on environment. Through this paper, we attempt to explain how an agricultural system has been modified from the Vedic period to modern technological farming practices with new scientific innovation and invention. Here, we are also mentioned the latest artificial intelligence that could be used in agricultural field to make the agriculture smart and sustain the environment.

Ceftazidime‐avibactam is a novel β‐lactam/β‐lactamase inhibitor combination for the treatment of serious infections caused by resistant gram‐negative pathogens. Population pharmacokinetic (PopPK) models were built to incorporate pharmacokinetic (PK) data from five phase III trials in patients with complicated intra‐abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial (including ventilator‐associated) pneumonia. Ceftazidime and avibactam pharmacokinetics were well‐described by two‐compartment disposition models, with creatinine clearance (CrCL) the key covariate determining clearance variability. Steady‐state ceftazidime and avibactam exposure for most patient subgroups differed by ≤ 20% vs. healthy volunteers. Probability of PK/pharmacodynamic (PD) target attainment (free plasma ceftazidime > 8 mg/L and avibactam > 1 mg/L for ≥ 50% of dosing interval) was ≥ 94.9% in simulations for all patient subgroups, including indication and renal function categories. No exposure‐microbiological response relationship was identified because target exposures were achieved in almost all patients. These modeling results support the approved ceftazidime‐avibactam dosage regimens (2000‐500 mg every 8 hours, adjusted for CrCL ≤ 50 mL/min).

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late-stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well-established and regulatory-acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4-5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP-Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)-based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well-designed dose-finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale.

This post-hoc analysis compared the pharmacokinetics and clinical outcomes of ceftaroline fosamil 600 mg every 12 (q12h) versus every 8 hours (q8h) in patients with acute bacterial skin and skin-structure infection (ABSSSI) and signs of sepsis. Clinical outcomes at test-of-cure in patients with ABSSSI and systemic inflammatory signs/systemic inflammatory response syndrome (SIRS) as well as ceftaroline minimum inhibitory concentrations (MICs) against baseline pathogens were compared between the COVERS trial (ceftaroline fosamil 600 mg q8h, 2-h infusion) and the CANVAS 1 and 2 trials (ceftaroline fosamil 600 mg q12h, 1-h infusion). Ceftaroline exposure among patients in COVERS with or without markers of sepsis was compared using population pharmacokinetic modelling. In COVERS, 62% (312/506) and 41% (208/506) of ceftaroline fosamil-treated patients had ≥1 systemic inflammatory sign or SIRS, respectively, compared with 55% (378/693) and 22% (155/693), respectively, in the CANVAS trials. Clinical cure rates for the modified intent-to-treat population in COVERS and CANVAS were similar for ceftaroline fosamil-treated patients with ≥1 sign of sepsis [82% (255/312) and 85% (335/394)] and for those with SIRS [84% (168/199) and 85% (131/155)]. Ceftaroline MIC distributions were similar across trials. Sepsis did not affect predicted individual steady-state ceftaroline exposure. Clinical cure rates in patients with ≥1 systemic inflammatory sign or SIRS were comparable for both ceftaroline fosamil dosage regimens. Pathogen susceptibilities to ceftaroline were similar across trials. Ceftaroline exposure was not affected by disease severity. Ceftaroline fosamil 600 mg q12h is a robust dosage regimen for most ABSSSI patients with sepsis [ClinicalTrials.gov ID: NCT01499277, NCT00424190, NCT00423657].

Avibactam is a non-β-lactam β-lactamase inhibitor that has been approved in combination with ceftazidime for the treatment of complicated intra-abdominal infections, complicated urinary tract infections, and nosocomial pneumonia, including ventilator-associated pneumonia. In Europe, ceftazidime-avibactam is also approved for the treatment of Gram-negative infections with limited treatment options. Selection and validation of the ceftazidime-avibactam dosage regimen was guided by an iterative process of population pharmacokinetic (PK) modelling, whereby population PK models for ceftazidime and avibactam were developed using PK data from clinical trials and updated periodically. These models were used in probability of target attainment (PTA) simulations using joint pharmacodynamic (PD) targets for ceftazidime and avibactam derived from preclinical data. Joint PTA was calculated based on the simultaneous achievement of the individual PK/PD targets (50% free time above the ceftazidime-avibactam MIC for ceftazidime and free time above a critical avibactam threshold concentration of 1 mg/liter for avibactam). The joint PTA analyses supported a ceftazidime-avibactam dosage regimen of 2,000 + 500 mg every 8 h by 2-h intravenous infusion for patients with creatinine clearance (CLCR) >50 ml/min across all approved indications and modified dosage regimens for patients with CLCR ≤50 ml/min. Subgroup simulations for individual phase 3 patients showed that the dosage regimen was robust, with high target attainment (>95%) against MICs ≤8 mg/liter achieved regardless of older age, obesity, augmented renal clearance, or severity of infection. This review summarizes how the approved ceftazidime-avibactam dosage regimens were developed and validated using PK/PD targets, population PK modeling, and PTA analyses.

Tebipenem pivoxil HBr (TBPM-PI-HBr) is a novel orally bioavailable carbapenem. The active moiety is tebipenem. Tebipenem pivoxil is licensed for use in Japan in children with ear, nose, and throat infections and respiratory infections. The HBr salt was designed to improve drug substance and drug product properties, including stability. TBPM-PI-HBr is now being developed as an agent for the treatment of complicated urinary tract infections (cUTI) in adults. The pharmacokinetics-pharmacodynamics of tebipenem were studied in a well-characterized neutropenic murine thigh infection model. Plasma drug concentrations were measured using liquid chromatography-tandem mass spectrometry. Dose fractionation experiments were performed after establishing dose-response relationships. The magnitude of drug exposure required for stasis was established using 11 strains of Enterobacteriaceae (Escherichia coli, n = 6; Klebsiella pneumoniae, n = 5) with a variety of resistance mechanisms. The relationship between drug exposure and the emergence of resistance was established in a hollow-fiber infection model (HFIM). Tebipenem exhibited time-dependent pharmacodynamics that were best described by the free drug area under the concentration-time curve (fAUC(0-24))/MIC corrected for the length of the dosing interval (fAUC(0–24)/MIC · 1/tau). The pharmacodynamics of tebipenem versus E. coli and K. pneumoniae were comparable, as was the response of strains possessing extended-spectrum β-lactamases versus the wild type. The median fAUC(0-24)/MIC · 1/tau value for the achievement of stasis in the 11 strains was 23. Progressively more fractionated regimens in the HFIM resulted in the suppression of resistance. An fAUC(0-24)/MIC · 1/tau value of 34.58 to 51.87 resulted in logarithmic killing and the suppression of resistance. These data and analyses will be used to define the regimen for a phase III study of adult patients with cUTI.

Avibactam is a non-β-lactam β-lactamase inhibitor intended for use as a fixed-dose combination with ceftazidime for the treatment of certain serious Gram-negative infections. As avibactam is primarily excreted unchanged in the urine, renal impairment may affect its pharmacokinetics. This phase 1 study investigated the effect of renal impairment and hemodialysis on avibactam pharmacokinetics and safety. Healthy controls and subjects with increasing degrees of renal impairment received a single 30-minute intravenous (IV) infusion of avibactam (100 mg). Anuric subjects requiring hemodialysis received the same infusion pre- and posthemodialysis, separated by a 7- to 14-day washout. Blood and urine samples were collected, and pharmacokinetics were analyzed using noncompartmental methods. The relationships between avibactam total plasma clearance (CL) or renal clearance (CLR ) and creatinine clearance (CrCL) were evaluated by linear correlation analysis. Safety was also monitored. Increasing severity of renal impairment was associated with decreasing CL and CLR and increasing exposure and terminal half-life (t1/2 ). Avibactam CL and CLR demonstrated an approximately linear relationship with CrCL comparable to that previously observed for ceftazidime. In patients requiring hemodialysis, >50% of the administered avibactam was removed during a 4-hour hemodialysis session, demonstrating that avibactam should be administered after hemodialysis. No new safety findings were reported. To conclude, avibactam dose adjustment is warranted in patients with renal impairment based on the severity of impairment. Because the slope of the linear relationship between avibactam total plasma CL and CrCL is similar to that of ceftazidime, renal impairment dose adjustments should maintain the currently advised 4:1 ratio of ceftazidime:avibactam.

Ceftaroline, the active form of the prodrug ceftaroline fosamil, is approved for use in adults with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infections (ABSSSI) in the United States and for similar indications in Europe. Pharmacokinetic (PK) data from 5 pediatric (birth to MIC) for pediatric dose regimens. With dose regimens of 8 mg/kg every 8 hours (q8h) in children aged 2 months to 90% of children were predicted to achieve a target of 36% fT>MIC at an MIC of 2 mg/L, and >97% were predicted to achieve 44% fT>MIC at an MIC of 1 mg/L. Thus, high PK/pharmacodynamic target attainment would be maintained in children for targets associated with 1-log kill of Staphylococcus aureus and Streptococcus pneumoniae. The predicted ceftaroline exposures for these dose regimens were similar to those in adults given 600 mg q12h ceftaroline fosamil. This work contributed to the approval of dose regimens for children aged 2 months to

Introduction: low card retention and utilization has been shown by different studies determining immunization coverage in developing countries. The present study aims at assessing the prevalence of vaccination card retention of children between 12 to 23 months age by their parents in a rural area of Tripura. Material and Methods: a community based cross-sectional study has been conducted among parents of 330 children of 12 to 23 months using Lot Quality Assurance Sampling (LQAS) technique in Mohanpur, the rural field practice area under Department of Community Medicine, Agartala Government Medical College. Data was collected using pre-designed semi-structured questionnaire and analysed using computer software SPSS version 20.0. Univariate analysis was done to find the factors associated with non-retention of vaccination card. Results: the prevalence of vaccination card retention is found to be 97.9%. Majority (71.4%) said that they have lost the card and rest 28.6% of the parents mentioned that the card is with the local ASHA. Card retention was higher among children with higher educational status of both the parents and those children who were delivered institutionally. Conclusion: the present study reveals that vaccination card retention byparents of thestudy children is higher than previously conducted studies elsewhere.

Background: Professional college students being at the base of the hierarchy of professional occupation may be vulnerable to harassment, discrimination and abuse regarding their gender. The present study was conducted with the objective to assess the prevalence and pattern of Gender discrimination among professional college students in Agartala, and to study their emotional response towards gender discrimination. Methods: This cross-sectional study was conducted between September to November, 2015 among students of 5 randomly selected Professional colleges of Agartala. Sample size was calculated and 450 professional college students were included in the study. Results: The present study revealed that the prevalence of gender discrimination among the professional college students was 12.45% with both the males and females being victims of gender discrimination (6.80% vs 5.56%, p value 0.77). There was a significant difference in the type of discrimination experienced by the male and female students (p value-0.01) and male faculties were the main perpetrators of gender discrimination. Regarding the emotional response towards gender discrimination majority of the students complained of frustration (28.57%) followed by helplessness (26.78%) and depression (23.21%). Conclusions: Gender discrimination can be controlled in the college premises with collective efforts to minimize the belief that one sex has rights, leadership qualities, and academic status greater than that of the other sex.

Clinical susceptibility breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa for the ceftazidime-avibactam dosage regimen of 2,000/500 mg every 8 h (q8h) by 2-h intravenous infusion (adjusted for renal function) have been established by the FDA, CLSI, and EUCAST as susceptible (MIC, ≤8 mg/liter) and resistant (MIC, >8 mg/liter). The key supportive data from pharmacokinetic/pharmacodynamic analyses, in vitro surveillance, including molecular understanding of relevant resistance mechanisms, and efficacy in regulatory clinical trials are collated and analyzed here.

Objectives Our objective was to develop population pharmacokinetic (PK) models for ceftazidime and avibactam in the plasma and epithelial lining fluid (ELF) of healthy volunteers and to compare ELF concentrations to plasma PK/pharmacodynamic (PD) targets. Methods Plasma and ELF population PK models were developed for ceftazidime and avibactam concentration data from 42 subjects (NCT01395420). Two- and three-compartment plasma PK models were fitted to ceftazidime and avibactam plasma PK data, and different plasma–ELF linked models were evaluated. Using best-fitting models, plasma and ELF concentration–time profiles were simulated for 1000 subjects. ELF concentration–time profiles for ceftazidime/avibactam 2000–500 mg every 8 h were compared with plasma PK/PD targets for ceftazidime (50% of time above [fT >] 8 mg/l) and avibactam (50% fT > 1 mg/l). Results Three-compartment PK models best fitted the plasma concentration data for ceftazidime and avibactam. ELF data for both drugs were best described by a direct response (instantaneous equilibrium) model. Ceftazidime plasma–ELF relationships were best described by a saturable Michaelis–Menten model. For avibactam, departure from plasma–ELF relationship linearity was more modest than for ceftazidime. ELF:plasma penetration ratios of both ceftazidime (52%) and avibactam (42%) at plasma concentrations relevant for efficacy (~ 8 mg/l for ceftazidime and ~ 1 mg/l for avibactam) were greater than previously calculated using non-compartmental area under the curve (AUC) methods, which average across the entire concentration range. Ceftazidime and avibactam ELF exposures exceeded their respective plasma PK/PD time-above-threshold targets by the dosing interval mid-point in most subjects. Conclusions This compartmental modelling analysis suggests ELF exposures of both ceftazidime and avibactam exceed levels required for efficacy in plasma.

For recently licensed antibiotics, such as the cephalosporin ceftaroline fosamil, probability of target attainment (PTA) curves, showing the percentage of patients reaching a predefined pharmacokinetic (PK)/pharmacodynamic (PD) target at different bacterial minimum inhibitory concentrations (MICs), have been used to support and justify dose recommendations across patient populations. However, information on PTA for older antibiotics is limited. A retrospective analysis was conducted to construct PTA curves for 4 antibiotics against Staphylococcus aureus in patients with complicated skin and soft tissue infections (cSSTIs). PK models for vancomycin, linezolid, daptomycin, and ceftriaxone were selected from the literature based on large numbers of subjects with covariates representative of patients in Europe and/or the United States. An existing model was available for ceftaroline fosamil. Standard and high-dosage regimens were used to compare the PTA of each antibiotic at MIC values 0.03 to 64 mg/L for a simulated set of patients with cSSTI caused by S. aureus. These were compared to proportions of S. aureus isolates at each MIC from global surveillance data. Ceftaroline achieved PTAs >99.9% for bacteriostatic and bactericidal targets at the MIC90 (1 mg/L), whereas the comparators failed to achieve PTAs >90%, at bacteriostatic or bactericidal targets, even when clinical doses were increased beyond those recommended. PTA analysis can be used to compare different drugs with the same simulated patient dataset, subject to availability of an appropriate PK model and robust exposure targets. This analysis shows that some antibiotics commonly used to treat cSSTIs may fail to reach high PTAs relative to contemporary MIC90 estimates.

Efficacy of ceftaroline fosamil, the prodrug of the active metabolite ceftaroline, was demonstrated in a phase 3 study of hospitalized Asian patients with Pneumonia Outcomes Research Team (PORT) risk class III-IV community-acquired pneumonia (NCT01371838). The objectives of the current analysis were to expand an existing ceftaroline and ceftaroline fosamil population pharmacokinetic (PK) model with data from this phase 3 study and a phase 1 study (NCT01458743) assessing ceftaroline PK in healthy Chinese volunteers and to evaluate the probability of PK/pharmacodynamic (PK/PD) target attainment (PTA) in Asian patients with community-acquired pneumonia (CAP) treated with ceftaroline fosamil. The ceftaroline plasma concentration-time course was simulated for 5000 Asian patients with CAP for different renal function subgroups using the final model. PTA was calculated for Streptococcus pneumoniae, Staphylococcus aureus, and non-extended-spectrum β-lactamase-producing Enterobacteriaceae. PTA was also evaluated for ceftaroline MIC90 values of isolates collected from Asia-Pacific surveillance studies (2012-2014) and for EUCAST and FDA/CLSI ceftaroline susceptibility break points. The final model reasonably described the ceftaroline PK. Race was not found to be a significant covariate impacting ceftaroline PK, suggesting similar ceftaroline PK in Asian and Western populations when corrected for body weight. High PTAs (90%-100%) were predicted for Asian patients with CAP treated with ceftaroline fosamil, covering MIC90 values of target CAP pathogens from the region. Similarly, >90% PTAs were predicted at EUCAST and FDA/CLSI clinical break points for these pathogens. These results support the use of the ceftaroline fosamil dosing regimens approved in Europe and the United States in Asian patients with PORT III-IV CAP.

Avibactam is a novel non-β-lactam β-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 β-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 β-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 (% f T>C T ). The magnitude of the C T and the time that this threshold needed to be exceeded to elicit particular PD endpoints varied depending on the model and the partner β-lactam. This review describes the preclinical studies used to determine the avibactam PK/PD target in combination with its β-lactam partners.

Objectives To describe the pharmacokinetic/pharmacodynamic (PK/PD) modelling and microbiological data that were used to support the recent European approval of ceftaroline fosamil 600 mg q8h by 2 h intravenous (iv) infusion for patients with complicated skin and soft tissue infections (cSSTIs) caused by Staphylococcus aureus with ceftaroline MICs of 2 or 4 mg/L, and the associated EUCAST MIC breakpoint update for q8h dosing (intermediate = 2 mg/L and resistant >2 mg/L). Methods A population PK model for ceftaroline and ceftaroline fosamil was developed using PK data from 21 clinical studies. The final model was used to simulate PTA in patients with cSSTI receiving ceftaroline fosamil 600 mg q12h by 1 h iv infusion or 600 mg q8h by 2 h iv infusion. PTA was calculated by MIC for S. aureus PK/PD targets derived from preclinical studies (27% fT>MIC for stasis, 31% fT>MIC for 1 log10 kill and 35% fT>MIC for 2 log10 kill) and compared with S. aureus ceftaroline MIC distributions from a 2013 global surveillance study. Results The final population PK model based on 951 subjects adequately described ceftaroline and ceftaroline fosamil PK. High PTA (>90%) was predicted for the ceftaroline fosamil 600 mg q12h dosage regimen against S. aureus isolates with ceftaroline MICs ≤2 mg/L. Greater than 90% PTA was predicted for the ceftaroline fosamil 600 mg q8h dosage regimen against S. aureus with ceftaroline MICs ≤4 mg/L. Conclusions The approved ceftaroline fosamil dosage regimens for adults and adolescents with cSSTI achieve high PTA against S. aureus at the associated EUCAST breakpoints.

Avibactam is a novel non-β-lactam β-lactamase inhibitor that has been shown to restore the in vitro activity of ceftazidime against pathogens producing Ambler class A, C, and some class D β-lactamases. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of avibactam alone or with ceftazidime in healthy Japanese subjects. In this Phase I, double-blind study (NCT01291602), 16 healthy Japanese males, mean age 28.8 years, were randomized in a 2:2:1 ratio to receive avibactam 500 mg (n = 6), ceftazidime 2000 mg plus avibactam 500 mg (n = 7), or placebo (n = 3), each administered as a 100 ml intravenous infusion over 2 h, once on Day 1, every 8 h on Days 3-6, and once on Day 7. There were no deaths or serious adverse events. Nine treatment-emergent adverse events were reported in three subjects in the avibactam group - including one elevation in transaminase levels, and three vital signs events (tachycardia, palpitations, and orthostatic hypotension) - and one in the ceftazidime-avibactam group. All events were considered mild. After single or multiple dosing, plasma concentrations of avibactam and ceftazidime declined in a multi-exponential manner. No plasma concentration accumulation was observed, and the majority of avibactam was excreted unchanged in urine within 24 h. No clinically relevant changes in intestinal bacterial flora were observed. In conclusion, avibactam alone and ceftazidime-avibactam were generally well tolerated in healthy male Japanese subjects, and avibactam pharmacokinetics were comparable whether administered alone or in combination with ceftazidime.

Introduction It is very important to analyze the factors which acts as obstacle in achieving 100% immunization among children. Lot Quality Assurance Sampling (LQAS) is one of the effective method to assess such barriers. Aim To assess the full immunization coverage among 12 to 23-month old children of rural field practice area under Department of Community Medicine, Agartala Government Medical College and identify the factors for failure of full immunization. Materials and methods A community based cross-sectional study was conducted from November 2013 to October 2014 on children aged 12 to 23 months old of area under Mohanpur Community health centre. Using LQAS technique 330 samples were selected with multi-stage sampling, each sub-centre being one lot and two calculated to be the decision value. Data was collected using pre-designed pre-tested questionnaire during home visit and verifying immunization card and analysed by computer software SPSS version 21.0. Results The full immunization coverage among 12 to 23 months old children of Mohanpur area was found as 91.67%. Out of all the 22 sub-centres, 36.36% was found under performing as per pre-fixed criteria and the main reasons for failure of full immunization in those areas are unawareness of need of subsequent doses of vaccines and illness of the children. Conclusion LQAS is an effective method to identify areas of under-performance even though overall full immunization coverage is high.

BACKGROUND: Patient's satisfaction is a measure of the quality of services offered by a hospital. OBJECTIVES: To determine the level of satisfaction of patients attending OPD of AGMC & GBP Hospital, to identify the determinants of satisfaction and to formulate recommendations for improvement. METHODOLOGY: A hospital based cross-sectional study was conducted during 17th August to 17th September 2013 using a pretested structured interview schedule among 515 patients attending OPD of AGMC and GBP Hospital recruited by concurrent sampling and ensuring probability proportionate to size representation based upon previous three month's turnover. STATISTICAL ANALYSIS: Data entry and analysis were performed in computer using SPSS 15. Descriptive statistics and Chi-square test were used for presenting data and testing the significance. RESULTS: Cleanliness of OPD was satisfactory to 54.2% patients, 54.8% were satisfied with ventilation, 48.5% were satisfied with queuing and 49.9% were satisfied with the sitting facility of OPD. Clinical care was felt satisfactory by 75.9%, 70.5% were satisfied with the explanation of the disease & prescription given by the doctor, 72.4% patients did not get any medicine from the hospital and 17.5% patients were unaware about the enquiry services. Toilet was unsatisfactory to 26.6%, drinking water was unsatisfactory to 24.7% and the services of RSBY (Rastriya Swasthya Bima Yojana) help desk were unsatisfactory to 50% patients. Overall services of OPD were felt satisfactory by 57.5% patients and 30.3% felt it average. CONCLUSION: Cleanliness, ventilation, sitting facility, enquiry services, drinking water, toilet, RSBY help desk etc. of AGMC OPD require improvement.

Avibactam, a novel non-β-lactam β-lactamase inhibitor with activity against Ambler class A, class C, and some class D enzymes is being evaluated in combination with various β-lactam antibiotics to treat serious bacterial infections. The in vivo mass balance recovery and metabolite profile of [(14)C] avibactam (500 mg/1-h infusion) was assessed in six healthy male subjects, and a series of in vitro experiments evaluated the metabolism and drug-drug interaction potential of avibactam. In the mass balance study, measurement of plasma avibactam (using a validated liquid chromatography-tandem mass spectrometry method) and total radioactivity in plasma, whole blood, urine, and feces (using liquid scintillation counting) indicated that most of the avibactam was excreted unchanged in urine within 12 hours, with recovery complete (>97% of the administered dose) within 96 hours. Geometric mean avibactam renal clearance (158 ml/min) was greater than the product of unbound fraction of drug and glomerular filtration rate (109.5 ml/min), suggesting that active tubular secretion accounted for some renal elimination. There was no evidence of metabolism in plasma and urine, with unchanged avibactam the major component in both matrices. Avibactam demonstrated in vitro substrate potential for organic anion transporters 1 and 3 (OAT1 and OAT3) proteins expressed in human embryonic kidney 293 cells (Km > 1000 μM; >10-fold the Cmax of a therapeutic dose), which could account for the active tubular secretion observed in vivo. Avibactam uptake by OAT1 and OAT3 was inhibited by probenecid, a potent OAT1/OAT3 inhibitor. Avibactam did not interact with various other membrane transport proteins or cytochrome P450 enzymes in vitro, suggesting it has limited propensity for drug-drug interactions involving cytochrome P450 enzymes.

Background: Menstrual cycle is a regular coordinated physiological change in non-pregnant women. The variation of hormonal concentrations during different phases of the menstrual cycle has a profound influence on autonomic and metabolic activities. The present study was designed to assess the cardiovascular sympathetic functions during different phases of menstrual cycle in normal healthy eumenorrheic females.Methods: Fifty females in the age group of 18-25 years were selected for the study. Non-invasive cardiovascular sympathetic function tests were performed during different phases of the menstrual cycle using RMS Polyrite D.Results: Results were analyzed using paired ‘t’ test. Resting blood pressure, blood pressure response to isometric handgrip test and cold pressor test were statistically significant higher (p-value

Background: India is currently in need of large number of public health specialists to combat the double burden of communicable and non-communicable diseases. But it was seen that medical students are less interested in a career as a public health specialists. This study aimed to assess the preferences of subjects for future specialization among medical students and to understand their attitude towards Community Medicine as a future career.Methods: A cross-sectional study was done among 200 MBBS students selected by stratified random sampling at Agartala Govt. Medical College of Tripura during April to May 2018. Data were analyzed using SPSS (version 25.0).Results: Medicine was the most preferred subject (35%) for specialization followed by obstetrics and gynecology (16%) and surgery (15%). About 4% of the participants opted Community Medicine for future specialization. Lack of personal satisfaction, lack of future career prospective and lack of opportunity to earn name and money ranked top most cause for not choosing Community Medicine as a career.Conclusions: Preference of Community Medicine for future specialization was very limited among medical students. Interest on Community Medicine as a career among MBBS students can be improved by proper counseling and modification of curriculum.

Potential effects of supratherapeutic doses of intravenous (IV) ceftazidime-avibactam and ceftaroline fosamil-avibactam on cardiac repolarization were assessed in a thorough QT/QTc study. This was a double-blind, randomized, placebo-controlled, four-period crossover Phase I study (NCT01290900) in healthy males (n = 51). Subjects received, in randomized order and separated by ≥3 days washout: single doses of IV ceftaroline fosamil 1,500 mg with avibactam 2,000 mg; IV ceftazidime 3,000 mg with avibactam 2,000 mg; oral moxifloxacin 400 mg (open-label positive control); and IV placebo (saline). Least square mean and two-sided 90% confidence intervals (CI) for change from baseline in Fridericia-corrected QT interval (ΔQTcF) for active treatments versus placebo were estimated at 10 time points over 24 hours. The upper bound of the two-sided 90% CI for placebo-corrected ΔQTcF did not exceed 10 milliseconds at any time point over 24 hours for ceftaroline fosamil-avibactam or ceftazidime-avibactam. The lower bound of the two-sided 90% CI for the difference between moxifloxacin and placebo in ΔQTcF over 1-4 hours was >5 milliseconds, confirming assay sensitivity. Pharmacokinetics results confirmed achievement of supratherapeutic plasma concentrations. No safety concerns were raised. In conclusion, supratherapeutic doses of ceftaroline fosamil-avibactam or ceftazidime-avibactam were not associated with QT/QTc prolongation in this study population.

This study aimed to investigate the pharmacokinetics (PK), safety, and tolerability of a single dose of ceftazidime-avibactam in pediatric patients. A phase I, multicenter, open-label PK study was conducted in pediatric patients hospitalized with an infection and receiving systemic antibiotic therapy. Patients were enrolled into four age cohorts (cohort 1, ≥12 to C max ), and area under the concentration-time curve from time zero to infinity (AUC 0–∞ ) were similar across all cohorts for both drugs. Six patients (18.8%) reported an adverse event, all mild or moderate in intensity. No deaths or serious adverse events occurred. The single-dose PK of ceftazidime and avibactam were comparable between each of the 4 age cohorts investigated and were broadly similar to those previously observed in adults. No new safety concerns were identified. (This study has been registered at ClinicalTrials.gov under registration no. NCT01893346.)

The purpose of this study was to determine the maximum-tolerated dose (MTD), pharmacokinetics and safety profile for two different dosing regimens of barasertib, a selective inhibitor of Aurora B Kinase. In this Phase I trial, patients with advanced solid malignancies were treated with escalating doses of barasertib, administered as either a 48-h continuous infusion or as two 2-h infusions on consecutive days, both every 14 days of a 28-day cycle. Thirty-five patients were treated. The MTDs were 150 mg as a 48-h continuous infusion and 220 mg administered as two 2-h infusions (110 mg/day, days 1, 2, 15 and 16), with neutropenia the dose-limiting toxicity (DLT) of each schedule. Common Terminology Criteria of Adverse Events (CTCAE) grade ≥ 3 neutropenia (with or without fever) occurred in 34 % of patients overall. Other adverse events, many of hematologic or gastrointestinal etiology, were of mild or moderate intensity. No objective tumor responses were observed, although stable disease was observed in 23 % of patients. Systemic exposure to barasertib-hQPA, the more active moiety to which barasertib is converted, was observed by 1 and 6 h into the 2-h and continuous infusion, respectively, and exhibited linear pharmacokinetics. In summary, barasertib was generally well tolerated, with neutropenia the most frequent and dose-limiting toxicity, irrespective of schedule. Future development of barasertib will depend on better definition of its therapeutic index. © 2012 Springer Science+Business Media, LLC.

We assessed pharmacokinetic and safety profiles of ceftazidime-avibactam administered ± metronidazole, and whether drug-drug interactions exist between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole. The first study (NCT01430910) involved two cohorts of healthy subjects. Cohort 1 received ceftazidime-avibactam (2000-500 mg) as a single infusion or as multiple intravenous infusions over 11 days to evaluate ceftazidime-avibactam pharmacokinetics. Cohort 2 received ceftazidime, avibactam, or ceftazidime-avibactam over 4 days to assess drug-drug interaction between ceftazidime and avibactam. The second study (NCT01534247) assessed interaction between ceftazidime-avibactam and metronidazole in subjects receiving ceftazidime-avibactam (2000-500 mg), metronidazole (500 mg), or metronidazole followed by ceftazidime-avibactam over 4 days. In all studies, subjects received a single-dose on the first and final days, and multiple-doses every 8 h on intervening days. Concentration-time profiles for ceftazidime and avibactam administered as single- or multiple-doses separately or together with/without metronidazole were similar. There was no evidence of time-dependent pharmacokinetics or accumulation. In both interaction studies, 90% confidence intervals for geometric least squares mean ratios of area under the curve and maximum plasma concentrations for each drug were within the predefined interval (80-125%) indicating no drug-drug interaction between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole. There were no safety concerns. In conclusion, pharmacokinetic parameters and safety of ceftazidime, avibactam, and metronidazole were similar after single and multiple doses with no observed drug-drug interaction between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole.