Significant Publications on Infectious Diseases Pharmacotherapy in 2022.

Purpose: To provide summarization of the most significant infectious diseases (ID) pharmacotherapy articles published in peer-reviewed literature in 2022. Summary: Members of the Houston Infectious Diseases Network (HIDN) nominated notable articles providing significant contributions to ID pharmacotherapy in 2022. Article nominations included those pertaining to general ID, as well as those including coronavirus disease 2019 (COVID-19), and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) pharmacotherapy. A total of 71 articles were nominated by HIDN. Members: 68 articles pertaining to general ID pharmacotherapy and 3 articles focusing on HIV/AIDS. To aid selection of the most these most notable articles of 2022, a survey was created and distributed to members of the Society of Infectious Diseases Pharmacists (SIDP). Of the 153 SIDP members who participated in the survey, there were 128 recorded votes for the top 10 general ID pharmacotherapy articles and 30 votes recorded for the top HIV/AIDS article. The most notable publications are summarized. Conclusion: Post pandemic significant advances in antimicrobial stewardship and infectious disease states continues to occur in a world recently focused on the coronavirus disease 2019 (COVID-19) global pandemic. Continuous growth in publication of ID-related articles over the past year lends towards the aims of this review to aid clinicians in remaining current on key practice-changing ID pharmacotherapy publications from 2022.

Decarbamoylation of acetylcholinesterases is markedly slowed as carbamoyl groups increase in size.

Carbamates are esters of substituted carbamic acids that react with acetylcholinesterase (AChE) by initially transferring the carbamoyl group to a serine residue in the enzyme active site accompanied by loss of the carbamate leaving group followed by hydrolysis of the carbamoyl enzyme. This hydrolysis, or decarbamoylation, is relatively slow, and half-lives of carbamoylated AChEs range from 4 min to more than 30 days. Therefore, carbamates are effective AChE inhibitors that have been developed as insecticides and as therapeutic agents. We show here, in contrast to a previous report, that decarbamoylation rate constants are independent of the leaving group for a series of carbamates with the same carbamoyl group. When the alkyl substituents on the carbamoyl group increased in size from N-monomethyl- to N,N-dimethyl-, N-ethyl-N-methyl-, or N,N-diethyl-, the decarbamoylation rate constants decreased by 4-, 70-, and 800-fold, respectively. We suggest that this relationship arises as a result of active site distortion, particularly in the acyl pocket of the active site. Furthermore, solvent deuterium oxide isotope effects for decarbamoylation decreased from 2.8 for N-monomethylcarbamoyl AChE to 1.1 for N,N-diethylcarbamoyl AChE, indicating a shift in the rate-limiting step from general acid-base catalysis to a likely conformational change in the distorted active site.

Single incision laparoscopic surgery approach for obscure small intestine bleeding localized by CT guided percutaneous injection of methylene blue.

INTRODUCTION: Traditionally, localization of small intestine sources of obscure gastrointestinal bleeding has been a challenge. Advances in the field of endoscopy with the introduction of capsule endoscopy and radiographic imaging with computed tomography angiography and visceral angiography have facilitated more accurate visualization of the small intestine. If a bleeding lesion is identified on angiography and surgery is indicated, the use of methylene blue for enteric mapping is very effective to aid intraoperative localization of the culprit. However, when this is not an option, more invasive surgical techniques are required. PRESENTATION OF CASE: We present a new technique used in a patient with angiodysplasia of the small intestine, in where preoperative localization was done using percutaneous computed tomography (CT) guided injection of methylene blue dye. This allowed us to perform a single incision laparoscopic small intestine resection of the culprit.

Interactions between the peripheral site and the acylation site in acetylcholinesterase.

Acetylcholinesterase (AChE) hydrolyzes its physiological substrate acetylcholine at one of the highest known catalytic rates. Two sites of ligand interaction have been identified: an acylation site or A-site at the base of the active site gorge, and a peripheral site or P-site at its mouth. Despite a wealth of information about the AChE structure and the role of specific residues in catalysis, an understanding of the catalytic mechanism and the role of the P-site has lagged far behind. In recent years we have clarified how the P- and A-sites interact to promote catalysis. Our studies have revealed that the P-site mediates substrate trapping and that ligand binding to the P-site can result in steric blockade of the A-site as well as allosteric activation. We have demonstrated this activation only for the acylation step of the catalytic reaction, but others have proposed that it involves the deacylation step. To investigate this point, we have measured the reaction of carbamoyl esters (carbamates) with AChE. With these slowly hydrolyzed substrates, the carbamoylation (acylation) and decarbamoylation (deacylation) steps can be resolved and analyzed separately. Carbamoylcholine is one of the closest structural analogs of acetylcholine, and we monitored these steps in continuous mixed assays with acetylthiocholine as a reporter substrate. At high concentrations of carbamoylcholine, decarbamoylation was inhibited but no activation of carbamoylation was observed. However, high concentrations of acetylthiocholine had no effect on the decarbamoylation rate constants. We concluded that the binding of acetylthiocholine to the P-site does not activate deacylation reactions.