BACKGROUND:Oral and ocular medications are frequently used in the treatment of allergic rhinitis (AR). As part of the update of the Allergic Rhinitis and its Impact on Asthma (ARIA)-EAACI guidelines, this manuscript presents the ARIA-EAACI 2024-2025 recommendations for oral and ocular treatments. METHODS:The ARIA-EAACI 2024-2025 guideline panel issued recommendations following the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) evidence-to-decision framework. Several sources of evidence were used to inform panel judgements and recommendations, including systematic reviews, mHealth and pharmacovigilance data as well as a survey on costs. RESULTS:Eight guideline questions concerning oral treatments for AR and three questions concerning ocular treatments were addressed. These questions led to the recommendations. Overall, these questions concern the choice between different classes of medication. They also discuss the role of oral antihistamines (OAH), leukotriene receptor antagonists (LTRA), ocular antihistamines (OcAH) and ocular mast cell stabilisers. Four questions had not been previously evaluated in ARIA guidelines, while, for the other four, there was a change in the strength or directionality of the recommendations. Overall, these guidelines recommend using intranasal corticosteroids over OAH and using OAH over LTRA. Moreover, they suggest using OAH over OcAH and suggest being against adding LTRA to OAH. Finally, considerations for choosing between different individual OAHs are presented. CONCLUSION:This ARIA-EAACI 2024-2025 article supports patients, their caregivers and healthcare professionals in choosing oral and ocular treatments for AR. Decisions on treatment should consider the clinical variability of the disease, patients' values and the affordability of medications.
PURPOSE:Amikacin (AMK) is a widely used therapeutic drug monitoring (TDM)-recommended treatment for nontuberculous mycobacterial pulmonary disease (NTM-PD). However, its optimal dosage and TDM target remain unclear. In this study, we aimed to clarify the relationship between AMK exposure, ototoxicity, and efficacy. METHODS:Patients with NTM-PD treated with AMK at Fukujuji Hospital were retrospectively included in this study. The correlation between AMK exposure, measured by peak and trough levels and the area under the concentration-time curve (AUC), ototoxicity, and culture conversion was analyzed using the Mann-Whitney U test and Cox regression analysis. A population pharmacokinetic/pharmacodynamic (PPK/PD) model was developed to predict ototoxicity using TDM measurements. RESULTS:A total of 185 patients were enrolled. The median AMK dose and observation period were 500 (interquartile range [IQR], 500-600) mg/day and 45.8 (IQR, 31.3-76.5) months, respectively. Ototoxicity and culture conversion were observed in 39% and 54% of the enrolled patients, respectively, after initiating AMK. The median time to the development of ototoxicity was 69 (IQR; 43-97) days. Neither ototoxicity nor culture conversion was associated with pharmacokinetic parameter of AMK exposure, including its minimum inhibitory concentration. However, the cumulative AUC was significantly higher in patients who developed ototoxicity (P < 0.001) than in those without ototoxicity. The developed PPK/PD model enabled calculation of cumulative AUC from TDM data and prediction of ototoxicity onset. CONCLUSION:Cumulative AMK exposure was associated with ototoxicity, and our findings allow prediction of ototoxicity onset using AMK TDM data.
Mycobacterium avium complex (MAC) is the leading cause of non-tuberculous mycobacterial pulmonary disease (NTM-PD), a chronic infection with a heterogeneous clinical course. Although murine models of MAC-PD exist, faithfully reproducing the progressive pathology and variable treatment responses of the disease remains challenging. Here, we assessed the virulence of five clinical MAC strains in immunocompetent BALB/c mice, including a newly identified highly virulent isolate, NBRC112750. Two strains, FKJ-1 and NBRC112750, induced progressive pulmonary infection characterized by rising bacterial loads and extensive lung involvement over 25 weeks postinfection. In BALB/c mice, both strains produced necrotizing granulomas resembling those observed in M. tuberculosis-infected C3HeB/FeJ mice, characterized by neutrophilic infiltration, foamy macrophages, and collagen encapsulation. We further established an inhalation-based infection model using FKJ-1, in which low-dose exposure reproducibly generated necrotizing granulomas. Despite demonstrating in vitro drug susceptibility, FKJ-1 responded poorly to standard antimicrobial, therapy indicating strain-dependent variability in treatment efficacy. Together, these findings establish a murine model that accurately reflects the critical pathological and therapeutic features of MAC-PD and provides a valuable platform for studying MAC pathogenesis and evaluating novel therapies.IMPORTANCEThe global incidence of pulmonary disease (PD) caused by non-tuberculous mycobacteria, particularly Mycobacterium avium complex (MAC), is increasing. However, the mechanisms underlying its pathological heterogeneity and variable treatment outcomes remain poorly understood. Here, we establish a murine model that recapitulates the key features of progressive MAC-PD, including necrotizing granuloma formation. We also demonstrate strain-specific differences in treatment responses despite comparable in vitro drug susceptibility. Notably, highly virulent strains induced necrotizing granulomatous lesions similar to those observed in patients with tuberculosis or MAC-PD. This study provides a valuable in vivo platform for investigating host-pathogen interactions, elucidating strain-dependent pathogenesis, and optimizing treatment strategies for MAC-PD.
INTRODUCTION:Macrolides are key drugs for treating Mycobacterium avium pulmonary disease, and combination chemotherapy is essential to preventing macrolide resistance. However, the concentrations of concomitant agents required to suppress resistance emergence remain undefined. Therefore, we aimed to quantify the concentration-dependent effects of companion drugs on macrolide resistance using an improved time-kill assay and pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. METHODS:Time-kill assays were performed using M. avium ATCC 700898 exposed to azithromycin alone or in combination with ethambutol, rifampicin, amikacin, or clofazimine. Total and resistant bacterial populations were quantified over 28 days. A pharmacodynamic model describing the dynamics of susceptible and resistant subpopulations was linked to a pharmacokinetic model incorporating alveolar macrophage exposure to simulate resistance emergence and bactericidal activity under various dosing regimens. RESULTS:Macrolide resistance most frequently emerged at 2-4× the minimum inhibitory concentration (MIC) of azithromycin, whereas resistance was less frequent at 8-16× MIC or sub-MIC levels. The addition of companion drugs suppressed resistance emergence even at sub-MIC levels. PK/PD simulations (excluding clofazimine) demonstrated that standard-dose ethambutol prevented macrolide resistance regardless of whether the regimen was administered daily or three times weekly. In contrast, the addition of rifampicin or amikacin further reduced bacterial burden compared with the macrolide-plus-ethambutol regimen. CONCLUSION:This study defines the concentration-dependent contributions of concomitant agents to macrolide resistance suppression in M. avium and establishes a quantitative PK/PD framework for evaluating resistance emergence. The findings provide mechanistic insights that may help optimize combination dosing strategies for M. avium pulmonary disease.
