Optimization of an in vitro Pseudomonas aeruginosa Biofilm Model to Examine Antibiotic Pharmacodynamics at the Air-Liquid Interface.

Pseudomonas aeruginosa is an important cause of lower respiratory tract infections, such as ventilator-associated bacterial pneumonia (VABP). Using inhaled antibiotics to treat VABP can achieve high drug concentrations at the infection site while minimizing systemic toxicities. Despite the theoretical advantages, clinical trials have failed to show a benefit for inhaled antibiotic therapy in treating VABP. A potential reason for this discordance is the presence of biofilm-embedded bacteria in lower respiratory tract infections. Drug selection and dosing are often based on data from bacteria grown planktonically. In the present study, an in vitro air-liquid interface pharmacokinetic/pharmacodynamic biofilm model was optimized to evaluate the activity of simulated epithelial lining fluid exposures of inhaled and intravenous doses of polymyxin B and tobramycin against two P. aeruginosa strains. Antibiotic activity was also determined against the P. aeruginosa strains grown planktonically. Our study revealed that inhaled antibiotic exposures were more active than their intravenous counterparts across biofilm and planktonic populations. Inhaled exposures of polymyxin B and tobramycin exhibited comparable activity against planktonic P. aeruginosa. Although inhaled polymyxin B exposures were initially more active against P. aeruginosa biofilms (through 6 h), tobramycin was more active by the end of the experiment (48 h). Together, these data slightly favor the use of inhaled tobramycin for VABP caused by biofilm-forming P. aeruginosa that are not resistant to either antibiotic. The optimized in vitro air-liquid interface pharmacokinetic/pharmacodynamic biofilm model may be beneficial for the development of novel anti-biofilm agents or to optimize antibiotic dosing for infections such as VABP.

Multicenter Evaluation of an MIC-Based Aztreonam and Ceftazidime-Avibactam Broth Disk Elution Test.

Due to limited therapeutic options, there is a clinical need to assess the in vitro activity of the combination of aztreonam (ATM) and ceftazidime-avibactam (CZA) to guide the therapeutic management of multidrug-resistant (MDR) Gram-negative organism infections. We set out to develop a practical MIC-based broth disk elution (BDE) method to determine the in vitro activity of the combination ATM-CZA using readily available supplies and compare it to reference broth microdilution (BMD). For the BDE method, a 30-µg ATM disk, a 30/20-µg CZA disk, both disks in combination, and no disks were added to 4 separate 5-mL cation-adjusted Mueller-Hinton broth (CA-MHB) tubes, using various manufacturers. Three testing sites performed both BDE and reference BMD testing of bacterial isolates in parallel from a single 0.5 McFarland standard inoculum and after overnight incubation, assessed them for growth (not susceptible) or no growth (susceptible) at a final concentration of 6/6/4 µg/mL ATM-CZA. During the first phase, the precision and accuracy of the BDE were analyzed by testing 61 Enterobacterales isolates at all sites. This testing yielded 98.3% precision between sites, with 98.3% categorical agreement and 1.8% major errors (ME). During the second phase, at each site, we evaluated unique, clinical isolates of metallo-ß-lactamase (MBL)-producing Enterobacterales (n = 75), carbapenem-resistant Pseudomonas aeruginosa (n = 25), Stenotrophomonas maltophilia (n = 46), and Myroides sp. (n = 1). This testing resulted in 97.9% categorical agreement, with 2.4% ME. Different results were observed for different disk and CA-MHB manufacturers, requiring a supplemental ATM-CZA-not-susceptible quality control organism to ensure the accuracy of results. The BDE is a precise and effective methodology for determining susceptibility to the combination ATM-CZA.

Sugammadex-induced anaphylactic reaction: A systematic review.

Perioperative anaphylaxis is a rare, but life-threatening hypersensitivity reaction for patients undergoing surgical procedures. Sugammadex is a relatively new drug used to reverse the neuromuscular blockade of specific anesthetics in surgery. Several case reports indicate that there may be a risk of anaphylaxis associated with the use of sugammadex This review examines the literature in order to evaluate the strength of the association between sugammadex use and anaphylaxis. A query of PubMed, EMBASE, and Web of Science was conducted using a combination of terms to identify relevant articles from inception until March 9, 2020. We included any primary study that identified sugammadex as a probable causative agent based on the World Allergy Organization diagnostic criteria for anaphylaxis. A total of 24 articles were reviewed. Across the three randomized controlled trials, there were only four cases of anaphylaxis identified. Incidence of anaphylaxis was reported in only one trial at 0.33%. Two retrospective observational studies conducted in Japan identified cases of anaphylaxis, with incidences of 0.02 and 0.04%. Among 19 case reports and series, 25 patient cases of anaphylaxis were confirmed via allergy testing to be caused by sugammadex or sugammadex-rocuronium complex. Commonly reported symptoms included hypotension, erythema, and decreased oxygen saturation. Based on the findings of this review, there appears to be a rare, but serious, association of sugammadex-induced perioperative anaphylaxis with an incidence between 0.02 and 0.04% in observational studies. It is unclear whether sugammadex on its own or in complex with rocuronium triggers this reaction, but it is clearly involved in inducing anaphylaxis. Further population studies are needed to get a more accurate global incidence rate, and more detailed allergy testing is required to better describe which step of the sugammadex reversal pathway initiates the anaphylactic attack.

The importance of pharmacokinetics and pharmacodynamics in antimicrobial drug development and their influence on the success of agents developed to combat resistant gram negative pathogens: A review.

A deep understanding of an antimicrobial's critical pharmacokinetic and pharmacodynamic properties is crucial towards optimizing its use in patients and bolstering the drug development program. With the growing threat of antimicrobial resistance and decline in antimicrobial development, the advancement of complex and rigorous pharmacokinetic and pharmacodynamic studies over a short time span has renewed confidence in the value of pharmacokinetic and pharmacodynamic studies and allowed it to become fundamental component of a robust drug development program with high chances of successful approval. In addition, recent guidance by various regulatory bodies have reinforced that a strong and dedicated focus on pharmacokinetics and pharmacodynamics throughout research and development lead to the use of an optimized dosing regimen in Phase 3 trials, improving the probability of drug approval. The objective of this review is to demonstrate the importance of pharmacokinetic and pharmacodynamic studies in the drug development decision-making process by highlighting the developments in pharmacokinetic and pharmacodynamic methods and discuss the role of pharmacokinetic and pharmacodynamic studies in antimicrobial successes and failures.