Oral β-Lactam Pairs for the Treatment of Mycobacterium avium Complex Pulmonary Disease.
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ABSTRACT:
SUBMITTER: Negatu DA
PROVIDER: S-EPMC11326814 | biostudies-literature | 2024 Aug
REPOSITORIES: biostudies-literature
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Oral β-Lactam Pairs for the Treatment of Mycobacterium avium Complex Pulmonary Disease.
Negatu Dereje A DA Shin Sung Jae SJ Kim Su-Young SY Jhun Byung Woo BW Dartois Véronique V Dick Thomas T
The Journal of infectious diseases 20240801 2
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 co ...[more]
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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.
| S-EPMC10789256 | biostudies-literature
Project description:Limited data are available regarding the impact of the antibiotic maintenance period on the redevelopment of nontuberculous mycobacteria-pulmonary disease (NTM-PD) after microbiological cure of Mycobacterium avium complex (MAC)-PD. This retrospective study included 631 MAC-PD patients who achieved microbiological cure between 1994 and 2021. Data on the antibiotic maintenance period, defined as the time between culture conversion and treatment completion, were collected. Redevelopment, the subsequent diagnosis of NTM-PD regardless of causative organism after microbiological cure, was investigated. Factors associated with redevelopment were analyzed after adjusting for disease severity using the body mass index, age, cavity, erythrocyte sedimentation rate, and sex (BACES) scoring system. In total, 205 (33%) patients experienced redevelopment, with a median maintenance period after culture conversion of 15.0 months (interquartile range, 13.0 to 22.0 months). A greater proportion of patients with the nodular bronchiectatic form of MAC-PD (87% versus 80%, P = 0.033) and a longer maintenance period (median 15.0 versus 14.0 months, P < 0.001) were noted in the redevelopment group compared with the nonredevelopment group. The cumulative rate of redevelopment according to the maintenance period did not differ between the >12-month and ≤12-month groups in the total patient population or the subgroups sorted according to BACES severity. No association between a maintenance period >12 months and redevelopment was identified in multivariate models. Extending the antibiotic maintenance period more than 12 months did not reduce the redevelopment rate even with adjustment for disease severity, suggesting the need to further optimize the duration of the antibiotic maintenance period. IMPORTANCE Limited data are available regarding the impact of the antibiotic maintenance period on the redevelopment of Mycobacterium avium complex-pulmonary (MAC-PD) disease after microbiological cure. To improve treatment outcomes and reduce the recurrence rate, current guidelines recommend maintenance of antibiotics for a minimum of 12 months after achievement of negative culture conversion. However, the optimal duration of antibiotic therapy for MAC-PD is not currently known. Moreover, in real-world clinical practice, total antibiotic duration is mainly impacted by the length of the maintenance period; however, it is unknown whether extending the maintenance period is beneficial for preventing redevelopment of NTM-PD. Our study may help to address concerns regarding the antibiotic maintenance period after achievement of negative culture conversion in patients with MAC-PD.
| S-EPMC9431257 | biostudies-literature
Project description:BackgroundA three-drug regimen (macrolide, ethambutol, and rifampicin) is recommended for the treatment of Mycobacterium avium complex pulmonary disease (MAC-PD). Although macrolide has proven efficacy, the role of ethambutol and rifampicin in patients without acquired immune deficiency syndrome is not proven with clinical studies. We aimed to clarify the roles of ethambutol and rifampicin in the treatment of MAC-PD.MethodsPatients treated for MAC-PD between March 1st, 2009 and October 31st, 2018 were reviewed retrospectively. Rates of culture conversion, microbiological cure, treatment failure, and recurrence were compared according to the maintenance (?6?months) of ethambutol or rifampicin with macrolide.ResultsAmong the 237 patients, 122 (51.5%) maintained ethambutol and rifampicin with macrolide, 58 (24.5%) maintained ethambutol and macrolide, 32 (13.5%) maintained rifampicin and macrolide, and 25 (10.6%) maintained macrolide only. Culture conversion was reached for 190/237 (80.2%) patients and microbiological cure was achieved for 129/177 (72.9%) who completed the treatment. Treatment failure despite ?12?months of treatment was observed in 66/204 (32.4%), and recurrence was identified in 16/129 (12.4%) who achieved microbiological cure. Compared with maintenance of macrolide only, maintenance of ethambutol, rifampicin or both with macrolide were associated with higher odds of culture conversion [odds ratio (OR), 95% confidence interval (CI): 18.06, 3.67-88.92; 15.82, 2.38-105.33; and 17.12, 3.93-74.60, respectively]. Higher odds of microbiological cure were associated with maintenance of both ethambutol and rifampicin with macrolide (OR, 95% CI: 5.74, 1.54-21.42) and macrolide and ethambutol (OR, 95% CI: 5.12, 1.72-15.24) but not macrolide and rifampicin. Maintenance of both ethambutol and rifampicin with macrolide was associated with lower odds of treatment failure (OR, 95% CI: 0.09, 0.01-0.53) compared with macrolide only, while maintenance of one of these with macrolide was not. Maintenance of both ethambutol and rifampicin or one of these with macrolide did not decrease the probability of recurrence when compared with macrolide only.ConclusionsMaintenance (?6?months) of ethambutol and rifampicin with macrolide was associated with the most favorable treatment outcomes among patients with MAC-PD. Given the association between ongoing ethambutol use and microbiological cure, clinicians should maintain ethambutol unless definite adverse events develop.
| S-EPMC6849249 | biostudies-literature
Project description:BackgroundThe impact of co-infection with other pathogenic microorganisms after initiation of treatment for Mycobacterium avium complex pulmonary disease (MAC-PD) has not been clearly described. This study sought to clarify the clinical outcomes of co-infection with MAC after antimycobacterial therapy for MAC.MethodsCo-infection status was defined as the detection of pathogenic microorganisms other than MAC in at least two consecutive sputum cultures 6-24 months after initiation of treatment. Chest computed tomography (CT) findings and culture results were compared between co-infection and MAC alone groups.ResultsThe co-infection and MAC alone groups comprised 12 and 36 patients, respectively. The proportion of patients with sputum culture positive for MAC after 24 months of therapy did not differ significantly between the two groups [25% (3/12) vs. 16.7% (6/36); p = 0.671]. The proportion of patients with improved chest CT score after 24 months of starting treatment compared to baseline was significantly lower for the co-infection group than for the MAC alone group [16.7% (2/12) vs. 79.4% (27/34); p < 0.001]. In the co-infection group, median CT score values at 12 and 24 months did not differ from baseline. However, the MAC alone group showed significant improvement at 12 and 24 months compared with baseline.ConclusionsIn the patient group with co-infection of other pathogenic microorganisms after treatment initiation for MAC there was no impact on therapeutic efficacy compared to the MAC alone group. However, therapeutic intervention interfered with improvement in chest CT findings such as nodule formation, bronchiectasis, infiltration, and cavitary lesions.
| S-EPMC9036801 | biostudies-literature
Project description:Bioactive forms of oral β-lactams were screened in vitro against Mycobacterium abscessus with and without the bioactive form of the oral β-lactamase inhibitor avibactam ARX1796. Sulopenem was equally active without avibactam, while tebipenem, cefuroxime, and amoxicillin required avibactam for optimal activity. Systematic pairwise combination of the four β-lactams revealed strong bactericidal synergy for each of sulopenem, tebipenem, and cefuroxime combined with amoxicillin in the presence of avibactam. These all-oral β-lactam combinations warrant clinical evaluation.
| S-EPMC9487536 | biostudies-literature
Project description:BackgroundAlthough the "unclassifiable type" is categorized as one of the radiologic classifications in Mycobacterium avium complex (MAC) pulmonary disease (PD), there have been few studies of this type thus far. We aimed to investigate the radiologic subtypes and treatment outcome of unclassifiable type MAC-PD.MethodsNinety-six patients with unclassifiable type MAC-PD who initiated a macrolide-containing regimen from 2001 to 2020 were identified at a tertiary referral center in South Korea. Among these 96 patients, 1-year culture conversion rate was analyzed for 48 patients who received standard treatment (three-drug oral-antibiotic combination with or without an injectable agent) for ≥ 1 year.ResultsThe mean age of the 96 patients was 65.4 ± 10.8 years, and 72.9% of them were male. These patients were classified into four major radiologic subtypes; the most common subtype was the focal cavity subtype (n = 31, 32.3%), followed by the focal mass or nodule (n = 23, 24.0%), consolidation upon emphysema (n = 21, 21.9%), and bronchiolitis (n = 21, 21.9%) subtypes. For the 48 patients who received standard treatment for ≥ 1 year, the overall rate of culture conversion at 1-year was 93.8%. All patients in the focal cavity subtype and focal mass or nodule subtype categories achieved 1-year culture conversion. Additionally, 1-year culture conversion rate was 92.9% in consolidation upon emphysema subtype and 75.0% in bronchiolitis subtype.ConclusionUnclassifiable type MAC-PD can be radiologically further categorized into four major radiologic subtypes. The treatment outcome of all of these subtypes seems to be favorable.
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Project description:BackgroundClofazimine is suggested as a promising drug for the treatment of nontuberculous mycobacterial pulmonary disease. However, the role of clofazimine in severe Mycobacterium avium complex pulmonary disease (MAC-PD) remains unclear. In this study, we investigated the treatment outcomes of patients with severe MAC-PD treated with regimens containing clofazimine.MethodsThis study included patients diagnosed with severe MAC-PD at Seoul National University Hospital who underwent anti-mycobacterial treatment between 1 January 2011 and 31 December 2022. We assessed the rate of culture conversion within 6 months and microbiological cure in patients receiving clofazimine-containing regimens, considering the dose and duration of clofazimine administration.ResultsA total of 170 patients with severe MAC-PD, treated with regimens containing clofazimine, were included in the analysis. The median age of patients was 68 years (interquartile range, 59-75 years), with a female predominance (n = 114 [67.1%]). Cavities were identified in 121 patients (71.2%). Within 6 months, 77 patients (45.3%) achieved culture conversion, and 84 of 154 (54.6%) patients attained microbiological cure. The dose of clofazimine (100 mg vs 50 mg) was not associated with culture conversion (adjusted odds ratio [aOR], 0.64 [95% confidence interval {CI}, .29-1.42]) or microbiological cure (aOR, 1.21 [95% CI, .52-2.81]). The microbiological cure rate reached 71.0% when clofazimine was administered for 6-12 months, compared to 23.1% when administered for <6 months.ConclusionsClofazimine demonstrated a relatively favorable efficacy in severe MAC-PD, regardless of the maintenance dose. This effect was more pronounced when administered for a duration exceeding 6 months.
| S-EPMC10849115 | biostudies-literature
Project description:The treatment responses and outcomes in patients with Mycobacterium avium-intracellulare complex pulmonary disease (MAC-PD) remain uncertain. This retrospective study was conducted in Taiwan between 2011 and 2020. A microbiological cure was defined as the requirement for a minimum of three consecutive negative cultures following culture conversion that continued until the completion of anti-MAC treatment. A total of 97 patients with MAC-PD were enrolled in this study. The sputum smear-negative conversion rate was 40% (19/47). Thirty (31%) patients achieved sputum culture-negative conversion rates within 3 years after treatment initiation. All patients with negative sputum culture conversion rates achieved microbiological cure. Patients treated with a macrolide + rifamycin + ethambutol (M + R + EMB)-based regimen had a higher microbiological cure rate than the other patients (39% vs 17%, P = 0.023). Patients with persistently positive sputum smears after 6 months of treatment had a lower microbiological cure rate than those with negative sputum smears (6% vs 44%, P < 0.001). Among 30 patients with microbiological cure, the median time from sputum culture conversion to treatment completion was 221.5 (0-483) days, and the 1-year relapse rate was 17%. Treatment with the M + R + EMB-based regimen was associated with a higher microbiological cure rate, and patients with persistently positive sputum smears after 6 months of treatment had a lower microbiological cure rate. IMPORTANCE The treatment responses and outcomes in patients with Mycobacterium avium-intracellulare complex pulmonary disease (MAC-PD) remain uncertain. In this study, patients with MAC-PD treated with a macrolide + rifamycin + ethambutol (M + R + EMB)-based regimen had a higher microbiological cure rate than those treated with other regimens. After 6 months of treatment, patients with persistently positive sputum smears had a lower microbiological cure rate than those with negative sputum smears. Among patients with microbiological cure, the median time from sputum culture conversion to treatment completion was 221.5 days (range, 0-483), and the 1-year relapse rate was 17%.
| S-EPMC10581154 | biostudies-literature
Project description:The combination of rifamycin (RFP), ethambutol (EB), and macrolides is currently the standard regimen for treatment of Mycobacterium avium complex pulmonary disease (MAC-PD). However, poor adherence to the standardized regimens recommended by current guidelines have been reported. We undertook a single-centred retrospective cohort study to evaluate the long-term outcomes in 295 patients with MAC-PD following first line treatment with standard (RFP, EB, clarithromycin [CAM]) or alternative (EB and CAM with or without fluoroquinolones (FQs) or RFP, CAM, and FQs) regimens. In this cohort, 80.7% were treated with standard regimens and 19.3% were treated with alternative regimens. After heterogeneity was statistically corrected using propensity scores, outcomes were superior in patients treated with standard regimens. Furthermore, alternative regimens were significantly and independently associated with sputum non-conversion, treatment failure and emergence of CAM resistance. Multivariate cox regression analysis revealed that older age, male, old tuberculosis, diabetes mellitus, higher C-reactive protein, and cavity were positively associated with mortality, while higher body mass index and M. avium infection were negatively associated with mortality. These data suggest that, although different combination regimens are not associated with mortality, first line administration of a standard RFP + EB + macrolide regimen offers the best chance of preventing disease progression in MAC-PD patients.
| S-EPMC7807086 | biostudies-literature