The Food and Drug Administration's (FDA's) Drug Safety Surveillance During the COVID-19 Pandemic.

Introduction: On 4 February, 2020, the Secretary of the Department of Health and Human Services declared a public health emergency related to coronavirus disease 2019 (COVID-19), and on 27 March, 2020 declared circumstances existed to justify the authorization of the emergency use of drug and biological products (hereafter, "drugs") for COVID-19. At the outset of the pandemic with uncertainty relating to the virus, many drugs were being used to treat or prevent COVID-19, resulting in the US Food and Drug Administration's (FDA's) need to initiate heightened surveillance across these drugs.

Objective: We aimed to describe the FDA's approach to monitoring the safety of drugs to treat or prevent COVID-19 across multiple data sources and the subsequent actions taken by the FDA to protect public health.

Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation.

Adults with cystic fibrosis (CF) frequently harbor , which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients ( = 18) admitted for exacerbations received 3 doses of telavancin 7.

Development of Neutropenic Murine Models of Iron Overload and Depletion To Study the Efficacy of Siderophore-Antibiotic Conjugates.

Siderophore-antibiotic conjugates have increased activity in low-iron environments where bacteria express siderophores and associated transporters. The host immune hypoferremic response reduces iron availability to bacteria; however, patients with iron overload or deficiency may have altered ability to restrict iron, which may affect the efficacy of siderophore-antibiotic conjugates. models of infection with iron overload and deficiency are needed to perform this assessment.

Efficacy of Humanized Cefiderocol Exposure Is Unaltered by Host Iron Overload in the Thigh Infection Model.

Cefiderocol is a siderophore-cephalosporin conjugate with greater potency under iron-depleted conditions. During infection, iron is scarce in host tissue; however, it is not known whether iron overload in the host, such as in cases of hereditary hemochromatosis, alters the efficacy of cefiderocol. We compared cefiderocol efficacy between iron-overloaded and standard murine thigh infection models.

Efficacy of human-simulated bronchopulmonary exposures of cefepime, zidebactam and the combination (WCK 5222) against MDR Pseudomonas aeruginosa in a neutropenic murine pneumonia model.

Objectives: WCK 5222 combines cefepime with zidebactam, a β-lactam enhancer that binds PBP2 and inhibits class A and C β-lactamases. The efficacy of human-simulated bronchopulmonary exposures of WCK 5222 against MDR Pseudomonas aeruginosa was investigated in a neutropenic murine pneumonia model.

Methods: Nineteen MDR isolates of P.

Comparative Antibacterial Activity of Human-Simulated Exposures of Cefiderocol and Ceftazidime against in the Murine Thigh Model.

Cefiderocol is a novel siderophore cephalosporin that utilizes bacterial ferric iron transports to cross the outer membrane. Cefiderocol shows high stability against all classes of β-lactamases, rendering it extremely potent against carbapenem- and multidrug-resistant Gram-negative organisms. Using a neutropenic murine thigh model, we compared the efficacies of human-simulated exposures of cefiderocol (2 g Q8H 3 h infusion) and ceftazidime (2 g Q8H 2 h infusion) against , an emerging opportunistic Gram-negative organism associated with serious and often fatal nosocomial infections.

Monte Carlo Simulation Methodologies for β-Lactam/β-Lactamase Inhibitor Combinations: Effect on Probability of Target Attainment Assessments.

Monte Carlo simulations (MCSs) are used in antibiotic development to predict the probability of pharmacodynamic target attainment (PTA) for a dosing regimen. However, for β-lactam/β-lactamase inhibitor combinations (BL-BLICs), methods for linking simulated concentration profiles of the β-lactam (BL) and β-lactamase inhibitor (BLI) components are rarely described. Using a previously defined pharmacokinetic model of ceftazidime/avibactam from critically ill patients, we performed four 5000-patient MCSs using different methods of increasing complexity to couple the BL and BLI components and compared PTA for ceftazidime and avibactam targets of >70% fT>MIC and >70% fT>1 mg/L, respectively, at MICs from 1 to 128 mg/L.

In vitro activity of ampicillin and ceftriaxone against ampicillin-susceptible Enterococcus faecium.

Objectives: To assess activity of the combination of ceftriaxone and ampicillin against clinical isolates of ampicillin-susceptible Enterococcus faecium.

Methods: Ampicillin-susceptible E. faecium (n = 29) and Enterococcus faecalis (n = 10) collected from locations in the USA and France were used for this analysis.

Comparative efficacy of human-simulated epithelial lining fluid exposures of tedizolid, linezolid and vancomycin in neutropenic and immunocompetent murine models of staphylococcal pneumonia.

Objectives: Few antibiotics are approved to treat Staphylococcus aureus pneumonia. Tedizolid is an oxazolidinone with potent in vitro activity against S. aureus and is currently under investigation for hospital-acquired and ventilator-associated bacterial pneumonia.

Optimizing Antibiotic Administration for Pneumonia.

Pneumonia, including community-acquired bacterial pneumonia, hospital-acquired bacterial pneumonia, and ventilator-acquired bacterial pneumonia, carries unacceptably high morbidity and mortality. Despite advances in antimicrobial therapy, emergence of multidrug resistance and high rates of treatment failure have made optimization of antibiotic efficacy a priority. This review focuses on pharmacokinetic and pharmacodynamic approaches to antibacterial optimization within the lung environment and in the setting of critical illness.

Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime/Avibactam in Critically Ill Patients.

Background: The pharmacokinetics, especially the volume of distribution (Vd), of ß-lactam antibiotics can be altered in critically ill patients. This can lead to decreased serum concentrations and a reduction in clinical cures. Ceftazidime/avibactam (CZA) is a new antimicrobial agent utilized in critically ill patients although its pharmacokinetics has not been well defined in these patients.

Pharmacodynamics of Daptomycin against Enterococcus faecium and Enterococcus faecalis in the Murine Thigh Infection Model.

The Clinical and Laboratory Standards Institute (CLSI) daptomycin MIC susceptibility breakpoint for the treatment of enterococcal infections is ≤4 μg/ml. However, patients receiving daptomycin for the treatment of infections caused by enterococci with MICs of ≤4 μg/ml may experience treatment failures. We assessed the pharmacodynamics of daptomycin against enterococci in a neutropenic murine thigh infection model and determined the exposures necessary for bacteriostasis and a 1-log-CFU reduction of and We further characterized daptomycin efficacy at clinically achievable exposures.

Physical compatibility of plazomicin with select i.v. drugs during simulated Y-site administration.

Purpose: The results of a study to determine the physical compatibility of plazomicin sulfate solution during simulated Y-site administration with 92 i.v. drugs are reported.

Novel pharmacotherapy for the treatment of hospital-acquired and ventilator-associated pneumonia caused by resistant gram-negative bacteria.

Introduction: Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are among the most prevalent infections in hospitalized patients, particularly those in the intensive care unit. Importantly, the frequency of multidrug resistant (MDR) Gram-negative (GN) bacteria as the bacteriologic cause of HABP/VABP is increasing. These include MDR Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem resistant Enterobacteriaceae (CRE).

Physical Compatibility of Meropenem and Vaborbactam With Select Intravenous Drugs During Simulated Y-site Administration.

Purpose: Meropenem/vaborbactam is a novel intravenous antibiotic combining the carbapenem, meropenem, with a novel β-lactamase inhibitor, vaborbactam. Meropenem/vaborbactam is administered as a 3-hour infusion given every 8 hours, thereby potentially restricting an intravenous line for 9 h/d. Intravenous medications may be given concurrently via Y-site when compatibility data are available.