Investigational drugs in phase I and phase II clincial trials for the treatment of hospital-acquired pneumonia

Falcó, Vicenç; Burgos, Joaquín; Papiol, Elisabeth; Ferrer, Ricard; Almirante, Benito

doi:10.1517/13543784.2016.1168803

Cited by 10 publications

(1 citation statement)

References 97 publications

(70 reference statements)

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“…The right choice of the antimicrobial treatment is key to the prognosis of patients with VAP (Craven et al, 2014). The increase of multi-drug resistant organisms in HAP/VAP, especially gram-negative bacilli, make the selection of effective drugs more difficult (Falco et al, 2016). A total of 36 kinds of antibiotics were investigated for the treatment of VAP.…”

Section: Discussionmentioning

confidence: 99%

Clinical Trials Focusing on Drug Control and Prevention of Ventilator-Associated Pneumonia: A Comprehensive Analysis of Trials Registered on ClinicalTrials.gov

Chen

Quan

et al. 2019

Front. Pharmacol.

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Objective: Clinical trials have emerged as the main force in driving the development of medicine. However, little is known about the current status of clinical trials regarding drug control and prevention of ventilator-associated pneumonia (VAP). This study aimed at providing a comprehensive landscape of these trials on the basis of ClinicalTrials.gov . Methods: A cross-sectional, descriptive study of clinical trials on drug control and prevention of VAP which have been registered on the ClinicalTrials.gov up to 25 th August 2018 was conducted. Results: A total of 109 eligible trials were identified. Trials were started from 1998 to 2018, and most trials focused on adult patients. More than half trials were completed, while only 11.9% trials had results available. Sample sizes were relatively large, with a median enrollment of 146. Universities were listed as the primary sponsor for 36.7% trials, industry for 28.4% trials and hospitals for 19.3% trials. Of the 109 VAP trials, 37 trials were from in Europe, 36 in North America and 27 in Asia. Among the 97 interventional trials, 32 were phase 3 trials, 21 were phase 4 trials, and 16 were phase 2 trials. Most interventional trials were randomized trials with a parallel assignment, and 57.7% trials were blinded. Of the 12 observational trials, 9 were cohort studies, and 10 trials were prosepctive studies. Drugs about oral care, preemptive antibiotics and probiotics were most investigated for prevention. A total of 61 trials investigated drugs for the treatment of VAP, mainly focused on antibiotics. A total of 36 kinds of antibiotics were investigated for monotherapy or combination therapy. Beta-lactams were most studied, followed by aminoglycosides and polypeptides. Conclusion: Most clinical trials registered on ClinicalTrials.gov about drugs for VAP were interventional trials with the purpose for treatment. A high proportion of interventional trials were randomized, parallel assigned and masked. Our analysis highlights the need for improvement in completeness of study results on the ClinicalTrials.gov .

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Section: Discussionmentioning

confidence: 99%

Clinical Trials Focusing on Drug Control and Prevention of Ventilator-Associated Pneumonia: A Comprehensive Analysis of Trials Registered on ClinicalTrials.gov

Chen

Quan

et al. 2019

Front. Pharmacol.

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Ventilator-Associated Pneumonias

Arrington

2018

Healthcare-Associated Infections in Children

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Clinical Pharmacokinetics and Pharmacodynamics of Ceftazidime–Avibactam Combination: A Model-Informed Strategy for its Clinical Development

Zhuang

et al. 2018

Clin Pharmacokinet

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Avibactam is a non-β-lactam, β-lactamase inhibitor of the diazabicyclooctane class that covalently acylates its β-lactamase targets, encompassing extended spectrum of activities that cover serine β-lactamases but not metallo-β-lactamases. Ceftazidime and avibactam have complementary pharmacokinetic (PK) profiles. Both drugs have a half-life of approximately 2 h, making them suitable to be combined in a fixed-dose combination ratio of 4:1 (ceftazidime:avibactam). Renal clearance is the primary elimination pathway of both ceftazidime and avibactam, and dose adjustment is required in patients with moderate and severe renal impairment. Population PK models of ceftazidime and avibactam were developed separately and incorporated body weight, disease state, ethnicity, and renal function (creatinine clearance) as covariates of clearance and volume of distribution. The clinical dosing regimen of ceftazidime/avibactam combination was determined from population PK model simulations in the patient population for dosing regimens that can achieve sufficient joint probability of target attainment for ceftazidime minimum inhibitory concentration (MIC) of 8 mg/L at a fixed 4 mg/L avibactam concentration (MIC ≤ 8/4 mg/L); 8 mg/L is the breakpoint of ceftazidime in Enterobacteriaceae and Pseudomonas aeruginosa for the target pharmacodynamic indices of ceftazidime and avibactam of 50% time at which the free ceftazidime concentration is above the MIC (fT > MIC) and 50% time at which the free avibactam is above a threshold concentration of 1 mg/L (fT > C). Whereas the static index approach does not take into account the changing potency of ceftazidime in the presence of changing avibactam concentration, a mathematical model based on kill-curve kinetics was utilized to validate the dose selection in humans. The clinical dosing regimen of 2/0.5 g ceftazidime/avibactam administered every 8 h as a 2-h intravenous infusion in patients with normal renal function, with dose adjustment in renal impairment, demonstrated statistical non-inferiority to carbapenem in phase III studies on the treatment of complicated intra-abdominal infection, complicated urinary tract infection, and nosocomial pneumonia, including ceftazidime non-susceptible Gram-negative pathogens. The success of the phase III studies validated the dose selection and exposure target that were associated with efficacy based on a model-informed approach.

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Investigational drugs in phase I and phase II clincial trials for the treatment of hospital-acquired pneumonia

Cited by 10 publications

References 97 publications

Clinical Trials Focusing on Drug Control and Prevention of Ventilator-Associated Pneumonia: A Comprehensive Analysis of Trials Registered on ClinicalTrials.gov

Clinical Trials Focusing on Drug Control and Prevention of Ventilator-Associated Pneumonia: A Comprehensive Analysis of Trials Registered on ClinicalTrials.gov

Ventilator-Associated Pneumonias

Clinical Pharmacokinetics and Pharmacodynamics of Ceftazidime–Avibactam Combination: A Model-Informed Strategy for its Clinical Development

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