Management of Drug Toxicity in Mycobacterium avium Complex Pulmonary Disease: An Expert Panel Survey.
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ABSTRACT:
SUBMITTER: van Ingen J
PROVIDER: S-EPMC8491833 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundIn Japan, Mycobacterium avium complex lung disease (MAC-LD) is the most common in nontuberculous mycobacterial lung disease. Patients often experience adverse events, resulting in the discontinuation of treatment, which causes treatment failure. The JADER (Japanese Adverse Drug Event Report) database is a database of adverse events that allows us to collect real-world data on adverse events. We can collect large-scale data cost-effectively and detect signals of potential adverse events such as reporting odds ratio (ROR) by using spontaneous reporting systems. In this study, we aimed to elucidate the adverse events of clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) using the JADER database.MethodsWe included cases of MAC-LD between April 2004 and June 2017. We investigated sex, age, and medications that may have caused the adverse events, outcomes, and time of onset. We calculated the safety signal index as the ROR. Time-to-event analysis was performed using the Weibull distribution.ResultsThe total number of adverse events of CAM, EB, and RFP was 2780, with 806 patients. In the overall adverse events, hematologic and lymphatic disorders were the most common adverse events, with 17.3%, followed by eye disorders (16.6%), and hepatobiliary disorders (14.0%). The outcomes were as follows: recovery, 40.0%; remission, 27.1%; non-recovery, 11.2%; and death, 7.1%. Regarding the most common onset time of CAM, EB, and RFP was within 120 days at 40%, 181-300 days at 43.6%, and within 120 days at 88.5%. For CAM, the RORs of infections and infestations, hepatobiliary system disorders, and immune system disorders were 4.13 (95% confidence interval [CI], 2.3-7.44), 2.61 (95% CI, 1.39-4.91), and 2.38 (95% CI, 1.04-5.44). For EB, the ROR of eye disorders was 215.79 (95% CI, 132.62-351.12). For RFP, the RORs of renal and urinary tract disorders and investigations were 7.03 (95% CI, 3.35-14.77) and 6.99 (95% CI, 3.22-15.18). The β value of EB was 2.07 (95% CI, 1.48-2.76), which was classified as a wear-out failure type.ConclusionsFor MAC-LD, the adverse event which has the highest ROR is infections and infestations in CAM, eye disorders in EB, renal and urinary tract disorders in RFP. Adverse events of EB occur after 180 days, whereas the adverse events of CAM and RFP occur early in the course of treatment.
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Project description:Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.
| S-EPMC4003341 | biostudies-literature
Project description:Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and an important cause of disease. The most common species causing pulmonary disease are members of Mycobacterium avium complex (MAC). MAC pulmonary disease (MAC-PD) can be chronic, debilitating, costly, and associated with a high mortality. However, MAC diagnoses are often delayed due to the nonspecific presentation of MAC-PD and radiological findings that overlap with other pulmonary diseases. Patients with risk factors and who meet the diagnostic criteria-which include clinical, radiological, and microbiologic criteria-should be considered for treatment. Diagnosis requires 2 or more positive sputum cultures or 1 bronchoscopic specimen culture. The recommendation for those who are treated is a 3-drug regimen including macrolide, rifamycin, and ethambutol that is continued for 12 months beyond sputum culture conversion to negative. MAC-PD is difficult to treat, with frequent drug-related side effects and suboptimal treatment outcomes. Refractory and recurrent disease is common, leading to lifelong follow-up of patients. There are limited treatment options for patients with macrolide-resistant or refractory disease. Amikacin liposome inhalation suspension is recommended for treatment-refractory patients whose cultures remain positive after 6 months of guideline-based therapy. Among the research priorities to improve patient outcomes and quality of life are developing new, more rapid diagnostic tests, investigating biomarkers associated with disease progression, and identifying new drugs and routes of administration as well as new, shorter, and better-tolerated regimens.
| S-EPMC7566660 | biostudies-literature
Project description:BACKGROUND:Multidrug therapy is essential for preventing respiratory failure in patients with highly progressive Mycobacterium avium complex pulmonary disease (MAC-PD). However, the prognosis and long-term outcome following combination therapy is poorly understood. METHODS:We retrospectively evaluated the clinical characteristics and long-term outcomes in patients with chemo-naïve progressive MAC-PD, hospitalized for first-line multidrug therapy. RESULTS:Among 125 patients, 86 (68.8%) received standardized treatment (rifampicin, ethambutol, clarithromycin), 25 (20.0%) received a fluoroquinolone (FQ)-containing regimen, and 53 (42.4%) received aminoglycoside injection. The sputum conversion rate was 80.0%, and was independently associated with standardized treatment. The incidence of refractory disease (45.6%) was independently and negatively associated with standardized regimen and aminoglycoside use. Choice of an FQ-containing regimen was not associated with positive outcome. Clarithromycin resistance occurred in 16.8% and was independently associated with refractory disease. MAC-PD-associated death occurred in 3.3% of patients with non-cavitary nodular bronchiectasis (NB) and 21.3% with cavitary MAC-PD over a median follow-up period of 56.4 months. The rates of MAC-PD-associated death were comparable between cavitary-NB and fibrocavitary disease. Concurrent chronic pulmonary aspergillosis (CPA) occurred in 13 (17.3%) patients with cavitary MAC-PD, and age, diabetes mellitus, and CPA were independent risk factors for mortality. CONCLUSIONS:Standardized intensive multidrug treatment reduces disease progression and persistence in progressive MAC-PD. Cavitary NB may differ from, rather than being just an advanced stage of, non-cavitary NB. The high incidence and significant mortality of CPA in cavitary MAC-PD highlight the need for early diagnosis and treatment.
| S-EPMC7291046 | biostudies-literature
Project description:How to identify MAC-PD patients with limited treatment options: an expert consensus https://bit.ly/3QwLQ8T.
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| S-EPMC8266509 | biostudies-literature
Project description:BackgroundThe number of patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) is rapidly increasing globally, especially in the older population. However, there is a dearth of evidence regarding the impact of aging on the treatment outcomes of NTM-PD.MethodsWe analyzed consecutive patients who satisfied the diagnostic criteria for Mycobacterium avium complex (MAC)-PD and received antibiotic treatment between January 2009 and December 2020 at a tertiary referral hospital in Korea. The main outcomes were (1) long-term treatment success, defined by negative culture conversion for more than 12 months; and (2) adverse drug reactions (ADRs). Multivariable logistic regression model was used to evaluate the association between age and main outcomes.ResultsA total of 614 patients (median age, 65 years, interquartile range [IQR] 57-73 years; men, 35.3%) were included. Median treatment duration (530 days, IQR 290-678 days; P for trend < 0.001) and long-term treatment success (P for trend = 0.026) decreased, whereas ADRs (P for trend < 0.001) increased significantly with age. Multivariable analyses demonstrated that age ≥ 80 years was an independent factor associated with ADRs (adjusted odds ratio [aOR] 3.29; 95% confidence interval [CI] 1.05-10.28) and worse treatment outcome (aOR 0.42; 95% CI 0.19-0.91).ConclusionsAging is associated with worse treatment outcome and frequent ADRs of patients with MAC-PD. Individualized treatment with reduced-intensity may be a reasonable alternative for older adults.
| S-EPMC9284708 | biostudies-literature
Project description:The Mycobacterium abscessus complex (MABC) comprises rapidly growing mycobacteria and has received increasing attention recently, with an increasing number of associated infections reported worldwide. However, the clinical features of MABC pulmonary disease (MABC-PD), especially in terms of the chest computed tomography (CT) findings, are not fully understood. Thus, this retrospective, cross-sectional study aimed to evaluate the clinical background and chest high-resolution CT (HRCT) findings of MABC-PD in comparison with those of Mycobacterium avium complex PD (MAC-PD). Accordingly, 36 patients with MABC-PD and 65 patients with MAC-PD (defined according to the American Thoracic Society criteria), who were newly diagnosed at four major hospitals in Okinawa (Japan) between January 2012 and December 2017, were analyzed. With respect to their clinical background, only cardiovascular diseases were significantly more common in patients with MABC-PD than in those with MAC-PD (38.9% vs. 18.5%, p = 0.0245). HRCT revealed a significantly higher incidence of low attenuation in patients with MABC-PD than in those with MAC-PD (63.9% vs. 10.8%, p<0.0001). On analyzing only never-smokers (20 and 47 patients with MABC-PD and MAC-PD, respectively), this significant difference remained (65.0% vs. 8.5%, p<0.0001), suggesting MABC infection itself caused low attenuation. In terms of the distribution of abnormal shadows, the involvement of the right lower, left upper, and left lower lobes was more common in patients with MABC-PD than in those with MAC-PD. Furthermore, the mean number of involved lung lobes was significantly higher in patients with MABC-PD than in those with MAC-PD (5.6 vs. 4.7, p<0.001). Although further studies are needed, we assume that the aforementioned radiological features of MABC-PD are due to the high virulence of MABC.
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Project description:Non-tuberculous mycobacteria are widely distributed in environments and are capable of infecting humans, particularly those with a compromised immune system. The most prevalent species that cause nontuberculous mycobacterial lung diseases are slow-growing bacteria from the Mycobacterium avium complex (MAC), mainly M. avium or M. intracellulare. The key treatment of MAC infections includes macrolides, ethambutol, and rifampicin; however, the therapy outcomes are unsatisfactory. Phenotypic drug susceptibility testing is a conditional recommendation prior to treatment, and critical concentrations for clarithromycin, amikacin, moxifloxacin, and linezolid have been established. In this review, data from studies on the determination of MIC of clinical isolates using the broth microdilution method were summarized. A significant variation in the MIC distributions from different studies was found. The main reasons could impact the findings: insufficient reproducibility of the phenotypic testing and variation in species lineages identified in different laboratories, which could have various intrinsic susceptibility to drugs. For most of the drugs analyzed, the MICs are too high, which could undermine the treatment efficiency. Further improvement of treatment outcomes demands the validation of microbiological resistance criteria together with the identification of molecular mechanisms of resistance.
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Project description:Cure rates for pulmonary disease caused by the Mycobacterium avium complex (MAC) are poor. While β-lactam are front line antibiotics against Mycobacterium abscessus pulmonary disease, they have not been used or recommended to treat MAC lung infections. Through a comprehensive screen of oral β-lactams, we have discovered that selected pairs combining either a penem/carbapenem or penicillin with a cephalosporin are strongly bactericidal at clinically achieved concentrations. These dual β-lactam combinations include tebipenem and sulopenem, both in phase 3, and Food and Drug Administration-approved amoxicillin and cefuroxime. They could therefore immediately enter clinical trials or clinical practice.
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