Lifelong, universal Pneumocystis jirovecii pneumonia prophylaxis: Patient uptake and adherence after kidney transplant.

INTRODUCTION: Pneumocystis jirovecii pneumonia (PJP) is a significant cause of morbidity and mortality in transplant patients yet little is known about their adherence to prophylaxis. The goal of this study was to evaluate patient uptake and long-term adherence after implementing universal, lifelong PJP prophylaxis. MATERIALS AND METHODS: This retrospective cohort study evaluated an adult kidney transplant program 18-months after initiating trimethoprim-sulfamethoxazole (TMP-SMX) 80/400 mg thrice-weekly following a cluster of PJP cases. The protocol incorporated multi-modal patient education and drug tolerability strategies to improve adherence, including a modified re-challenge strategy for TMP-SMX intolerance. Adherence was independently confirmed by the transplant pharmacist and nurse for each patient, with an a priori target ≥ 75% population on prophylaxis. RESULTS: Initial uptake was high with 237/250 (94.8%) patients starting prophylaxis. Long-term maintenance was high with 192/237 (81.0%) patients remaining on prophylaxis at 18-months. Of the remaining 45 patients who initiated prophylaxis, 36/237 (15.2%) were non-adherent and 9/237 (3.8%) discontinued prophylaxis by 18-months. Reasons for non-adherence included gastrointestinal upset, fear of drug reactions and cost; but the majority of reasons were not delineated by the patients (31/36, 86.1%). There was a statistically significant increase in serum creatinine 3.3 µmol/L (0.3-6.3 µmol/L 95% CI) and potassium 0.08 mmol/L (0.03-0.15 mmol/L 95% CI) in those prescribed TMP-SMX with only 3/237 (1.3%) patients discontinuing TMP-SMX for an increase in creatinine. CONCLUSION: High rates of patient uptake (94.8%) and long-term adherence (81.0%) were observed after implementing universal lifelong PJP prophylaxis. This may be due in part to the in-depth patient education and drug tolerability strategies employed.

Organic Anion Transporter 1 Is Inhibited by Multiple Mechanisms and Shows a Transport Mode Independent of Exchange.

The mechanism by which drugs inhibit organic anion transporter 1 (OAT1) was examined. OAT1 was stably expressed in Chinese hamster ovary (CHO) cells, and para-aminohippurate (PAH) and 6-carboxyfluorescein were the substrates. Most compounds (10 of 14) inhibited competitively, increasing the Michaelis constant (Km) without affecting the maximal transport rate (Jmax). Others were mixed-type (lowering Jmax and increasing Km) or noncompetitive (lowering Jmax only) inhibitors. The interaction of a noncompetitive inhibitor (telmisartan) with OAT1 was examined further. Binding of telmisartan to OAT1 was observed, but translocation was not. Telmisartan did not alter the plasma membrane expression of OAT1, indicating that it lowers Jmax by reducing the turnover number. PAH transport after telmisartan treatment and its washout recovered faster in the presence of 10% fetal bovine serum in the washout buffer, indicating that binding of telmisartan to OAT1 and its inhibitory effect are reversible. Together, these data suggest that telmisartan binds reversibly to a site distinct from substrate and stabilizes the transporter in a conformation unfavorable for translocation. In the absence of an exchangeable extracellular substrate, PAH efflux from CHO-OAT1 cells was relatively rapid. Telmisartan slowed PAH efflux, suggesting that some transporter-mediated efflux occurs independent of exchange. Although drug-drug interaction predictions at OAT1 assume competitive inhibition, these data show that OAT1 can be inhibited by other mechanisms, which could influence the accuracy of drug-drug interaction predictions at the transporter. Telmisartan was useful for examining how a noncompetitive inhibitor can alter OAT1 transport activity and for uncovering a transport mode independent of exchange.

Risk of Treatment Failure for Prosthetic Joint Infections: Retrospective Chart Review in an Outpatient Parenteral Antimicrobial Therapy Program.

Background: Prosthetic joint infections (PJIs) are a major complication of total joint replacement surgeries. Treatment includes surgical intervention with prolonged courses of IV antibiotics in outpatient parenteral antimicrobial therapy (OPAT) programs. The risk of PJI treatment failure is high and may be associated with various clinical factors. Objectives: To determine the rate of PJI treatment failure and to identify potential risk factors for failure in patients admitted to an OPAT program. Methods: A retrospective chart review was conducted for adult patients with PJI admitted to an OPAT program between July 1, 2013, and July 1, 2019. Treatment courses were deemed to have failed according to predetermined criteria. χ2 tests and multiple linear regression were used to examine associations of comorbidities, pathogens, and antimicrobial regimens with treatment failure. Results: In total, 100 patients associated with 137 PJI treatment courses in the OPAT program were included. Of these, 28 patients accounted for 65 of the treatment courses. Methicillin-susceptible Staphylococcus aureus was the most frequently isolated pathogen (31/137 or 22.6% of treatment courses). Patient comorbidities included body mass index of at least 30 kg/m2 (58% of patients) and diabetes (41% of patients). The overall rate of treatment failure was 56.2% (77/137 treatment courses). Selected risk factors associated with treatment failure or success were diabetes (50.9% versus 29.8%; odds ratio [OR] 4.03, 95% confidence interval [CI] 1.38-12.88, p = 0.013) and depression (32.1% versus 14.9%; OR 5.02, 95% CI 1.30-22.89, p = 0.025). Conclusions: The overall rate of PJI treatment failure in the study population was high. Patients with diabetes and depression experienced higher incidences of failure. Future investigations of comprehensive PJI management should be considered to ensure successful treatment and to minimize excessive use of health care resources.

Contexte: Les infections des prothèses articulaires (IPA) sont une complication majeure des arthroplasties totales. Le traitement comprend une intervention chirurgicale avec des séries prolongées d'antibiotiques IV dans le cadre de programmes de traitement antimicrobien parentéral ambulatoire (outpatient parenteral antimicrobial therapy; OPAT). Le risque d'échec du traitement des IPA est élevé et peut être associé à divers facteurs cliniques. Objectifs: Déterminer le taux d'échec du traitement des IPA et identifier les facteurs de risque chez les patients admis dans un programme OPAT. Méthodes: Un examen rétrospectif des dossiers de patients adultes atteints d'une IPA admis dans un programme OPAT entre le 1er juillet 2013 et le 1er juillet 2019 a été mené. L'échec d'un traitement était défini selon des critères prédéterminés. Des tests χ2 et une régression linéaire multiple ont été utilisés pour examiner les associations de comorbidités, d'agents pathogènes et de régimes antimicrobiens avec l'échec du traitement. Résultats: Au total, 100 patients associés à 137 séries de traitements des IPA au sein du programme OPAT étaient inclus. Parmi ceux-ci, 28 patients représentaient 65 des séries de traitement. Le Staphylococcus aureus sensible à la méthicilline était l'agent pathogène le plus fréquemment isolé (31/137 soit 22,6 % des séries de traitement). Les comorbidités des patients comprenaient un indice de la masse corporelle d'au moins 30 kg/m2 (58 % des patients) et un diabète (41 % des patients). Le taux global d'échec thérapeutique était de 56,2 % (77/137 séries de traitement). Les facteurs de risque sélectionnés associés à l'échec ou à la réussite du traitement étaient le diabète (50,9 % contre 29,8 %; rapport de cotes [RC] 4,03, intervalle de confiance à 95 % 1.38­12.88, p = 0,013) et la dépression (32,1 % contre 14,9 %; RC 5,02, IC à 95 % 1.30­22.89, p = 0,025). Conclusions: Le taux global d'échec du traitement de l'IPA dans la population étudiée était élevé. L'incidence des échecs chez les patients atteints de diabète et de dépression était plus élevée. Des enquêtes futures sur la prise en charge globale de l'IPA devraient être envisagées pour garantir la réussite du traitement et réduire au minimum l'utilisation excessive des ressources de soins de santé.

Organic anion transporter 2 transcript variant 1 shows broad ligand selectivity when expressed in multiple cell lines.

Organic anion transporter 2 (OAT2) is likely important for renal and hepatic drug elimination. Three variants of the OAT2 peptide sequence have been described - OAT2 transcript variant 1 (OAT2-tv1), OAT2 transcript variant 2 (OAT2-tv2), and OAT2 transcript variant 3 (OAT2-tv3). Early studies helping to define the ligand selectivity of OAT2 failed to identify the variant used, and the studies used several heterologous expression systems. In preliminary studies using OAT2-tv1, we failed to observe transport of several previously identified substrates, leading us to speculate that ligand selectivity of OAT2 differs with variant and/or heterologous expression system. The purpose was to further investigate the ligand selectivity of the OAT2 variants expressed in multiple cell types. We cloned OAT2-tv1 and OAT2-tv2, but were unsuccessful at amplifying mRNA for OAT2-tv3 from human kidney. OAT2-tv1 and OAT2-tv2 were individually expressed in human embryonic kidney (HEK), Madin-Darby canine kidney (MDCK), or Chinese hamster ovary (CHO) cells. mRNA for OAT2-tv1 and OAT2-tv2 was demonstrated in each cell type transfected with the respective construct, indicating their expression. OAT2-tv1 trafficked to the plasma membrane of all three cell types, but OAT2-tv2 did not. OAT2-tv1 transported penciclovir in all three cell types, but failed to transport para-aminohippurate, succinate, glutarate, estrone-3-sulfate, paclitaxel or dehydroepiandrosterone sulfate - previously identified substrates of OAT2-tv2. Not surprising given its lack of plasma membrane expression, OAT2-tv2 failed to transport any of the organic solutes examined, including penciclovir. Penciclovir transport by OAT2-tv1 was sensitive to large (e.g., cyclosporine A) and small (e.g., allopurinol) organic compounds, as well as organic anions, cations and neutral compounds, highlighting the multiselectivity of OAT2-tv1. The potencies with which indomethacin, furosemide, cyclosporine A and cimetidine inhibited OAT2-tv1 are in good agreement with previous studies using this variant, but inconsistent with studies using OAT2 with an unidentified sequence. This study shows that organic molecules with diverse physicochemical properties interact with OAT2-tv1, making it a likely site of drug interactions. Many previously identified substrates of OAT2 are not transported by OAT2-tv1, suggesting that variant and/or expression system may contribute. Future work should establish the expression pattern and ligand selectivity of OAT2-tv3.