Treatment Of Nontuberculous Mycobacteria Research Articles

Treatment for non-tuberculous mycobacteria: challenges and prospects.

Non-Tuberculous mycobacteria (NTM) are opportunistic environmental bacteria. Globally, NTM incidence is increasing and modeling suggests that, without new interventions, numbers will continue to rise. Effective treatments for NTM infections remain suboptimal. Standard therapy for Mycobacterium avium complex, the most commonly isolated NTM, requires a 3-drug regime taken for approximately 18 months, with rates of culture conversion reported between 45 and 70%, and high rates of relapse or reinfection at up to 60%. New therapeutic options for NTM treatment are urgently required. A survey of ongoing clinical trials for new NTM therapy listed on ClinicalTrials.Gov using the terms 'Mycobacterium avium', 'Mycobacterium abscessus', 'Mycobacterium intracellulare', 'Non tuberculous Mycobacteria' and 'Nontuberculous Mycobacteria' and a selection criterion of interventional studies using antibiotics demonstrates that most trials involve dose and combination therapy of the guideline based therapy or including one or more of; Amikacin, Clofazimine, Azithromycin and the anti-TB drugs Bedaquiline and Linezolid. The propensity of NTMs to form biofilms, their unique cell wall and expression of both acquired and intrinsic resistance, are all hampering the development of new anti-NTM therapy. Increased investment in developing targeted treatments, specifically for NTM infections is urgently required.

The Price of Beauty: A Literature Review on Non-Tuberculous Mycobacteria Infection After Cosmetic Procedures.

Abstract Non-tuberculous mycobacteria (NTM) infection of the skin and soft tissues is a complication of cosmetic procedures. The incidence of cutaneous NTM infections has increased significantly as aesthetic operations have become more commonplace. With the rise of cosmetic tourism, the geographic expansion of NTM infections is a major concern. Due to the unique pathogenesis of NTM infections, diagnosis and treatment remain significant challenges for clinicians. Clinical management relies on a combination of antibiotic therapy with drug susceptibility testing and appropriate surgical debridement. Some new drugs, photodynamic therapy, and bacteriophage therapy have been developed in recent years, and may improve the aesthetic outcomes. This review summarizes the cosmetic procedures prone to NTM infections in recent years and their clinical features. We propose a 2-stage treatment procedure, including a hospitalization phase and a follow-up phase. We aim to increase the alertness of clinicians to NTM infections for timely detection and treatment. Level of Evidence: 3

Plasmid-mediated drug resistance in mycobacteria: the tip of the iceberg?

Macrolides, such as clarithromycin, are crucial in the treatment of nontuberculous mycobacteria (NTM). NTM are notoriously innately drug resistant, which has made the dependence on macrolides for their treatment even more important. Not surprisingly, resistance to macrolides has been documented in some NTM, including Mycobacterium avium and Mycobacterium abscessus, which are the two NTM species most often identified in clinical isolates. Resistance is mediated by point mutations in the 23S ribosomal RNA or by methylation of the rRNA by a methylase (encoded by an erm gene). Chromosomally encoded erm genes have been identified in many of the macrolide-resistant isolates, but not in Mycobacterium chelonae. Now, Brown-Elliott et al. (J Clin Microbiol 61:e00428-23, 2023, https://doi.org/10.1128/JCM.00428-23) describe the identification of a new erm variant, erm(55), which was found either on the chromosome or on a plasmid in highly macrolide-resistant clinical isolates of M. chelonae. The chromosomal erm(55) gene appears to be associated with mobile elements; one gene is within a putative transposon and the second is in a large (37 kb) insertion/deletion. The plasmid carrying erm(55) also encodes type IV and type VII secretion systems, which are often linked on large mycobacterial plasmids and are hypothesized to mediate plasmid transfer. While the conjugative transfer of the erm(55)-containing plasmid between NTM has yet to be demonstrated, the inferences are clear, as evidenced by the dissemination of plasmid-mediated drug resistance in other medically important bacteria. Here, we discuss the findings of Brown-Elliott et al., and the potential ramifications on treatment of NTM infections.

Evaluation of omadacycline against intracellular Mycobacterium abscessus in an infection model in human macrophages.

Omadacycline is an aminomethylcycline antibiotic in the tetracycline class that was approved by the US FDA in 2018 for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It is available in both IV and oral formulations. Omadacycline has broad-spectrum in vitro activity and clinical efficacy against infections caused by Gram-positive and Gram-negative pathogens. Omadacycline is being evaluated in a 3 month placebo-controlled Phase 2 clinical trial of oral omadacycline versus placebo in adults with non-tuberculous mycobacteria (NTM) pulmonary disease caused by Mycobacterium abscessus (NCT04922554). To determine if omadacycline has intracellular antimicrobial activity against NTM, bacteria that can cause chronic lung disease, in an ex vivo model of intracellular infection. Two strains of M. abscessus were used to infect THP-1 macrophages. Intracellular M. abscessus was then challenged with omadacycline and control antibiotics at multiples of the MIC over time to evaluate intracellular killing. At 16 × the MIC at 72 h, omadacycline treatment of intracellular NTM yielded a log10 reduction in cfu of 1.1 (91.74% reduction in cfu) and 1.6 (97.65% reduction in cfu) consistent with killing observed with tigecycline, whereas amikacin and clarithromycin at 16 × the MIC did not show any reduction in cfu against the intracellular M. abscessus. Omadacycline displayed intracellular activity against M. abscessus within macrophages. The activity was similar to that of tigecycline; as expected, intracellular killing was not observed with clarithromycin and amikacin.

Nontuberculous mycobacterial infections in patients with hematologic malignancies and recipients of hematopoietic stem cell transplantation.

The incidence of mycobacterial infections in patients with hematologic malignancies and hematopoietic stem cell transplant (HSCT) recipients is increasing, contributing to significant mortality and morbidity. This review explores the epidemiology, risk factors, clinical presentation, diagnosis, and treatment of nontuberculous mycobacteria (NTM) in this population. A literature search was performed using PubMed with keywords and MeSH terms pertaining to the topics of nontuberculous mycobacteria, hematologic malignancies, hematopoietic stem cell transplant, cellular therapies, chimeric antigen therapies, epidemiology, diagnosis, and treatment. Additionally, we examined the reference lists of the included articles to identify other pertinent studies. Diagnosing mycobacterial disease among patients with hematologic disease and treatment-associated immunosuppressive conditions is challenging due to the lack of distinctive clinical, radiographic, and laboratory markers, as well as the atypical manifestations compared to immunocompetent patients. Treatment involves using a combination of antibiotics for extended durations, coupled with strategies to achieve source control and reduce immunosuppression when feasible. This is complicated by the absence of clear data correlating in-vitro drug susceptibility and clinical outcome for many antimicrobials use to treat NTM, adverse drug-drug interactions, and the frequent challenges related to poor medication tolerability and toxicities. The rising incidence and corresponding clinical challenges of mycobacterial infections in this unique patient population necessitate a heightened awareness and familiarity of NTM disease by clinicians to achieve timely diagnosis and favorable treatment outcomes.

Eradication of Nontuberculous Mycobacteria in People with Cystic Fibrosis Treated with Elexacaftor/Tezacaftor/Ivacaftor: A Multicenter Cohort Study

BackgroundThe prevalence of nontuberculous mycobacteria (NTM) infections is rising in people with cystic fibrosis (pwCF). NTM infection, especially infection with Mycobacterium abscessus complex (MABC), is commonly associated with severe lung deterioration. The current treatment modalities, including multiple intravenous antibiotics, frequently fail to achieve airway eradication. Although treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to modulate the lung microbiome, data regarding its role in eradicating NTM in pwCF is lacking. Our aim was to evaluate the impact of ETI on the rate of NTM eradication in pwCF. MethodsThis retrospective multicenter cohort study included pwCF from five CF centers in Israel. PwCF aged older than 6 who had at least one positive NTM airway culture in the past two years and were treated with ETI for at least one year were included. The annual NTM and bacterial isolations, pulmonary function tests, and body mass index were analyzed before and after ETI treatment. ResultsFifteen pwCF were included (median age 20.9 years, 73.3% females, 80% pancreatic insufficient). In nine patients (66%) NTM isolations were eradicated following treatment with ETI. Seven of them had MABC. The median time between the first NTM isolation and treatment with ETI was 2.71 years (0.27-10.35 years). Eradication of NTM was associated with improved pulmonary function tests (p<0.05). ConclusionsFor the first time, we report successful eradication of NTM, including MABC, following treatment with ETI in pwCF. Additional studies are needed to assess whether treatment with ETI can result in the long-term eradication of NTM.

Use of Omadacycline as a Component of Mycobacterium Abscessus Eradication in an Adolescent With Cystic Fibrosis.

Lung damage caused by non-tuberculous mycobacteria (NTM) infections can be devastating to individuals that are predisposed to chronic respiratory colonization. Cystic fibrosis patients are at increased risk for diminished lung function and increased mortality from NTM pulmonary infections. Treatment regimens are often intense and prolonged. The case described in this report is of a 16-year-old male with cystic fibrosis infected with Mycobacterium abscessus who showed evidence of severe nodular pulmonary disease on chest computerized tomography. His intensive treatment phase was complicated by neutropenia and drug resistance, leading to the use of omadacycline. Because of rapid improvement clinically and on computed tomography, he was successfully treated with a modified, less intense continuation phase that included azithromycin, omadacycline, and inhaled amikacin. The patient also was switched from tezacaftor/ivacaftor to elexacaftor/tezacaftor/ivacaftor during the course of NTM treatment.

Letter to the Editor: In Vitro Activity of Oxazolidinone Against Nontuberculous Mycobacteria in China.

Letter to the Editor: In Vitro Activity of Oxazolidinone Against Nontuberculous Mycobacteria in China.

Diagnosis and Management of Pulmonary NTM with a Focus on Mycobacterium avium Complex and Mycobacterium abscessus: Challenges and Prospects.

Nontuberculous mycobacteria (NTM) are ubiquitous. NTM can affect different organs and may cause disseminated diseases, but the pulmonary form is the most common form. Pulmonary NTM is commonly seen in patients with underlying diseases. Pulmonary Mycobacterium avium complex (MAC) is the most common NTM disease and M. abscessus (MAB) is the most challenging to treat. This review is prepared with the following objectives: (a) to evaluate new methods available for the diagnosis of pulmonary MAC or MAB, (b) to assess advances in developing new therapeutics and their impact on treatment of pulmonary MAC or MAB, and (c) to evaluate the prospects of preventive strategies including vaccines against pulmonary MAC or MAB. A literature search was conducted using PubMed/MEDLINE and multiple search terms. The search was restricted to the English language and human studies. The database query resulted in a total of 197 publications. After the title and abstract review, 64 articles were included in this analysis. The guidelines by the American Thoracic Society (ATS), European Respiratory Society (ERS), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and Infectious Diseases Society of America (IDSA) are widely applicable. The guidelines are based on expert opinion and there may be a need to broaden criteria to include those with underlying lung diseases who may not fulfill some of the criteria as 'probable cases' for better follow up and management. Some cases with only one culture-positive sputum sample or suggestive histology without a positive culture may benefit from new methods of confirming NTM infection. Amikacin liposomal inhalation suspension (ALIS), gallium containing compounds and immunotherapies will have potential in the management of pulmonary MAC and MAB. the prevalence of pulmonary NTM is increasing. The efforts to optimize diagnosis and treatment of pulmonary NTM are encouraging. There is still a need to develop new diagnostics and therapeutics.

Whole genome sequencing and prediction of antimicrobial susceptibilities in non-tuberculous mycobacteria.

Non-tuberculous mycobacteria (NTM) are opportunistic pathogens commonly causing chronic, pulmonary disease which is notoriously hard to treat. Current treatment for NTM infections involves at least three active drugs (including one macrolide: clarithromycin or azithromycin) over 12 months or longer. At present there are limited phenotypic in vitro drug susceptibility testing options for NTM which are standardised globally. As seen with tuberculosis, whole genome sequencing has the potential to transform drug susceptibility testing in NTM, by utilising a genotypic approach. The Comprehensive Resistance Prediction for Tuberculosis is a database used to predict Mycobacterium tuberculosis resistance: at present there are no similar databases available to accurately predict NTM resistance. Recent studies have shown concordance between phenotypic and genotypic NTM resistance results. To benefit from the advantages of whole genome sequencing, further advances in resistance prediction need to take place, as well as there being better information on novel drug mutations and an understanding of the impact of whole genome sequencing on NTM treatment outcomes.

Risk Factors for Nontuberculous Mycobacteria Infections in Solid Organ Transplant Recipients: A Multinational Case-Control Study.

Risk factors for nontuberculous mycobacteria (NTM) infections after solid organ transplant (SOT) are not well characterized. Here we aimed to describe these factors. Retrospective, multinational, 1:2 matched case-control study that included SOT recipients ≥12 years old diagnosed with NTM infection from 1 January 2008 to 31 December 2018. Controls were matched on transplanted organ, NTM treatment center, and post-transplant survival greater than or equal to the time to NTM diagnosis. Logistic regression on matched pairs was used to assess associations between risk factors and NTM infections. Analyses included 85 cases and 169 controls (59% male, 88% White, median age at time of SOT of 54 years [interquartile range {IQR} 40-62]). NTM infection occurred in kidney (42%), lung (35%), heart and liver (11% each), and pancreas transplant recipients (1%). Median time from transplant to infection was 21.6 months (IQR 5.3-55.2). Most underlying comorbidities were evenly distributed between groups; however, cases were older at the time of NTM diagnosis, more frequently on systemic corticosteroids and had a lower lymphocyte count (all P < .05). In the multivariable model, older age at transplant (adjusted odds ratio [aOR] 1.04; 95 confidence interval [CI], 1.01-1.07), hospital admission within 90 days (aOR, 3.14; 95% CI, 1.41-6.98), receipt of antifungals (aOR, 5.35; 95% CI, 1.7-16.91), and lymphocyte-specific antibodies (aOR, 7.73; 95% CI, 1.07-56.14), were associated with NTM infection. Risk of NTM infection in SOT recipients was associated with older age at SOT, prior hospital admission, receipt of antifungals or lymphocyte-specific antibodies. NTM infection should be considered in SOT patients with these risk factors.

In vitro activity of fidaxomicin against nontuberculosis mycobacteria.

Introduction. Nontuberculous mycobacteria (NTM) infections are increasing worldwide and are relatively resistant to many of the first- and second-line drugs to treat tuberculosis. Macrolide antibiotics, such as clarithromycin and azithromycin, are the key drugs for treating NTM infections. Fidaxomicin is a macrolide antibiotic that is widely used in treating Clostridium difficle (C.difficile) infections, and has high in vitro activity against Mycobacterium tuberculosis especially multidrug-resistant tuberculosis (MDR-TB) and has no cross-resistance with rifampicin.Hypothesis. Fidaxomicin may have in vitro activity against NTM strains.Aim. To find that whether the macrolide antibiotic fidaxomicin has in vitro activity against NTM strains.Methodology. Fidaxomicin used in this study was firstly tested on C. difficile reference strains and has shown to be effective and workable. And then 28 rapidly growing mycobacteria (RGM), 12 slowly growing mycobacteria (SGM) reference strains and 103 NTM clinical isolates were tested by the microplate-based AlamarBlue assay (MABA) method to determine the MICs. Fidaxomicin, rifampicin and clarithromycin were tested against M. abcessus complex subspecies 14 M. abscessus and 5 M. massiliense strains for inducible resistance determination.Results. In total, 21 out of 28 RGM and 9 of 12 SGM reference strains have the MICs of fidaxomicin at or below 1 µg ml-1. Fidaxomicin also showed low MIC values for some clinical isolates including M. abscessus complex, M. avium complex, M. fortuitum, M. kansasii and M. parascrofulaceum. Fidaxomicin also has no inducible macrolide resistance in M. abscessus complex in comparison with clarithromycin.Conclusion. Fidaxomicin has high in vitro activity against most of the NTM reference strains and some prevalent NTM clinical isolates. This promising finding warrants further investigation on the actions of fidaxomicn in vivo and as a potential antibiotic for NTM treatment.

A Comprehensive Review and Update on Epidemiology, Symptomatology and Management of Nontuberculous Mycobacteria (NTM)

Nontuberculous mycobacteria (NTM) are free-living organisms ubiquitously present in the environment. In recent times, NTM gained much importance due to the increase in incidence globally. They are potential agents in causing both pulmonary and extrapulmonary infections in both immunocompromised and immunocompetent individuals. The problem arises when the possible NTM cases are misdiagnosed as drug-resistant tuberculosis (DR-TB). Hence, it is essential to correctly identify the NTMs causing disease due to two major reasons. One is to prevent clinicians from starting anti-tuberculous drugs and the other is that treatment regimen differs for certain NTM from tuberculosis. Apart from conventional methods like smear microscopy, culture, in the current era newer diagnostic modalities like matrix-assisted laser desorption of ionization-time of flight mass spectrometry (MALDI TOF MS), line probe assay, genomic sequencing, are used in referral laboratories which allows identification and speciation of the organism. A thorough literature search was done in PubMed, Google Scholar, Cochrane Library, Embase, Scopus on nontuberculous mycobacteria. The search keywords include nontuberculous mycobacteria, atypical mycobacteria, case reports, and original articles on NTM. In this review, we have summarised the current knowledge on epidemiology, pathogenesis, clinical features, and treatment of NTM.

Chest Computed Tomography Features of Nontuberculous Mycobacterial Pulmonary Disease Versus Asymptomatic Colonization: A Cross-sectional Cohort Study.

Asymptomatic colonization by nontuberculous mycobacteria (NTM) found in sputum isolates are commonly encountered and clinicians lack a biomarker for prognosticating the risk of transition asymptomatic colonization to active clinical disease. Chest computed tomography (CT) imaging is commonly obtained in this patient population and may serve a role for this purpose. We conducted a single-center, cross-sectional study of patients followed in the NTM clinic at our center between August 2019 and August 2020. All patients had a history of NTM isolated from their airways and were cohorted as either nontuberculous mycobacteria-pulmonary disease (NTM-PD) if they met ATS/IDSA guidelines for treatment or as nontuberculous mycobacteria-colonized (NTM-C) if they did not meet ATS/IDSA criteria for NTM treatment. Patients with a chest CT were included in the analysis and CT scans were assessed for features including bronchiectasis, nodules, and cavities. Bronchiectasis severity was calculated using the modified Reiff scoring system. Univariate analyses were conducted to compare patients with NTM-C and NTM-PD. Eighty-four patients were included in the analysis and 27 were classified as NTM-C and 57 as NTM-PD. NTM-PD patients had a greater median number of lung lobes affected by bronchiectatic airways (6 [1] NTM-PD vs. 5 [3] NTM-C P=0.005) and a greater frequency of cystic bronchiectasis (17.5% NTM-PD vs. 0% NTM-PD, P=0.016). Bronchiectasis severity was higher for NTM-PD patients (7 [9] NTM-PD vs. 5 [1.5] NTM-C, P<0.001). Patients with NTM-PD have greater bronchiectatic airway involvement and the forms of bronchiectasis present are more severe compared with NTM-C patients. In addition, cavitation of lung parenchyma was a radiographic feature solely associated with NTM-PD. Features identified on chest CT may be useful as a prognostic biomarker for the risk of transition from NTM-C to NTM-PD.

Isolation of non-tuberculous mycobacteria among tuberculosis patients, a study from a tertiary care hospital in Lahore, Pakistan

BackgroundThere is scarce knowledge on the prevalence of diseases caused by non-tuberculous mycobacteria (NTM) in Pakistan. In the absence of culture and identification, acid-fast bacilli (AFB) causing NTM disease are liable to be misinterpreted as tuberculosis (TB). Introduction of nucleic acid amplification testing for Mycobacterium tuberculosis complex (MTBC) offers improved diagnostic accuracy, compared with smear microscopy, and also assists in differentiating MTBC from other mycobacteria. This study aimed to investigate the prevalence of NTM among patients investigated for TB and describe NTM disease and treatment outcomes at a tertiary care hospital in Pakistan.MethodsThis is a retrospective study, data on NTM isolates among culture-positive clinical samples over 4 years (2016–19) was retrieved from laboratory records. Information on clinical specimens processed, AFB smear results, and for the AFB positive isolates, results of species identification for MTBC, and for NTM isolates, results of species characterization and drug susceptibility testing was collected. Additional clinical data including patient characteristics, treatment regimens, and outcomes were collected for patients with NTM disease treated at Gulab Devi Hospital, Lahore.ResultsDuring the study period, 12,561 clinical specimens were processed for mycobacterial culture and 3673 (29%) were reported positive for AFB. Among these 3482 (95%) were identified as MTBC and 191 (5%) as NTM. Among NTM, 169 (88%) were isolated from pulmonary and 22 (12%) from extrapulmonary specimens. Results of NTM speciation were available for 60 isolates and included 55% (n = 33) M. avium complex and 25% (n = 15) M. abscesses. Among these patients, complete clinical records were retrieved for 12 patients with pulmonary disease including nine infected with M. avium complex and three with M. abscessus. All 12 patients had a history of poor response to standard first-line anti-TB treatment. Ten patients were cured after 18 months of treatment, whereas, one with M. abscessus infection died and another was lost to follow up.ConclusionIn TB endemic areas, NTM can be misdiagnosed as pulmonary TB leading to repeated failed anti-TB treatment and increased morbidity, emphasizing the need for improved diagnosis.

Drug susceptibiity testing of nontuberculous mycobacteria by broth microdilution method

Introduction-Incidence of Nontuberculous mycobacteria (NTM) has been increasing in past few years. Treatment of NTM differs from Mycobacterium tuberculosis. For proper treatment, it's important to carry out Drug Susceptibility Testing of NTM. Method of DST for NTM is different from MTB and is not available in most laboratories. Method-We performed DST on 122 isolates of NTM. Amikacin, Ciprofloxacin, Trimethoprim, Doxycycline, Moxifloxacin, Clarithromycin, Minocycline and Cefoxitin were used for Rapid Growing Mycobacteria (RGM) and Rifampicin, Clarithromycin, Ethambutol, Isoniazid and Moxifloxacin for Slow Growing Mycobacteria (SGM). M. avium Complex (MAC) was tested against Clarithromycin. Minimum inhibitor concentration was calculated as recommended by standard Clinical and Laboratory Standards Institute (CLSI) and Resazurin Microtitre Assay (REMA). Result-Most of Rapid Growing Mycobacteria were sensitive to Amikacin (76.1%) and Moxifloxacin (46.47%) while Slow Growing Mycobacteria showed only 33.3% sensitivity to Rifampicin and Moxifloxacin and 42% to Clarithromycin. M. avium-intracellulare complex showed 45–50% sensitivity to Clarithromycin. Overall, 98% concordance (Kappa = 0.98; almost perfect; 95% CI = 0.966 to 0.996) was seen between standard and REMA method of DST of NTM. Conclusion-Rapid growers showed good sensitivity to Amikacin and Moxifloxacin, while only one third SGM showed sensitivity to Rifampicin, Moxifloxacin and Clarithromycin. For proper management of NTM of eastern Rajasthan its important to know the DST profile in our area to initiate empirical therapy till the results of specific patient are available. REMA was found to give excellent concordance with standard method.

Repurposing Avermectins and Milbemycins against Mycobacteroides abscessus and Other Nontuberculous Mycobacteria.

Infections caused by nontuberculous mycobacteria (NTM) are increasing worldwide, resulting in a new global health concern. NTM treatment is complex and requires combinations of several drugs for lengthy periods. In spite of this, NTM disease is often associated with poor treatment outcomes. The anti-parasitic family of macrocyclic lactones (ML) (divided in two subfamilies: avermectins and milbemycins) was previously described as having activity against mycobacteria, including Mycobacterium tuberculosis, Mycobacterium ulcerans, and Mycobacterium marinum, among others. Here, we aimed to characterize the in vitro anti-mycobacterial activity of ML against a wide range of NTM species, including Mycobacteroides abscessus. For this, Minimum Inhibitory Concentration (MIC) values of eight ML were determined against 80 strains belonging to nine different NTM species. Macrocyclic lactones showed variable ranges of anti-mycobacterial activity that were compound and species-dependent. Milbemycin oxime was the most active compound, displaying broad-spectrum activity with MIC lower than 8 mg/L. Time kill assays confirmed MIC data and showed bactericidal and sterilizing activity of some compounds. Macrocyclic lactones are available in many formulations and have been extensively used in veterinary and human medicine with suitable pharmacokinetics and safety properties. This information could be exploited to explore repurposing of anti-helminthics for NTM therapy.

Pharmacotherapy Modifications Due to Drug Interactions with Concomitant Fungal Prophylaxis and Nontuberculous Mycobacteria Treatment after Transplant

Introduction Patients undergoing orthotopic heart transplant (OHT) have a 0.2 to 2.8% rate of infection with nontuberculous mycobacteria (NTM) in the year after transplant. Rifamycins, particularly rifampin, remain the backbone of NTM therapy; rifampin therapy can be especially challenging in solid organ transplant (SOT) due to potent CYP3A4 induction. Rifabutin, an alternative rifamycin, though less studied, is commonly substituted for rifampin in SOT due to less drug-drug interactions (DDI). Rifabutin is also a CYP3A4 substrate which can be impacted by concomitant CYP3A4 inhibitors. We report a case of an OHT recipient requiring systemic fungal prophylaxis while on rifabutin for pulmonary NTM. Case Report He is a 44-year old Caucasian male on 12 months of NTM treatment with rifabutin, azithromycin, and ethambutol who presented for OHT in his final month of treatment for pulmonary Mycobacterium kansasii. After OHT, he was started on high-dose steroids and triple-drug immunosuppression (IS). His NTM regimen was extended for another month. In addition to his IS regimen, isavuconazole was initiated for fungal prophylaxis rather than standard protocol posaconazole, for less CYP3A4 inhibition of rifabutin. Due to DDI, he required close therapeutic drug monitoring (TDM) to attain tacrolimus levels of 10-12ng/mL, requiring 10-15 mg/day (0.11-0.16 mg/kg/day) on the CYP3A4 inhibitor/inducer regimen. Rifabutin also remained therapeutic (0.3mcg/ml) on 300mg daily despite isavuconazole inhibition. After completion of rifabutin, tacrolimus requirements reduced to 6mg/day (0.06 mg/kg/day) with isavuconazole CYP3A4 inhibition alone. No breakthrough fungal infections occurred during isavuconazole prophylaxis despite the potential for rifabutin CYP3A4 induction. Summary Use of moderate CYP3A4 inhibitor isavuconazole with rifabutin did not result in rifabutin toxicity, particularly the shared ocular effects of ethambutol, and permitted effective systemic fungal prophylaxis. The degree of reduced exposure of isavuconazole inhibition due to a concomitant CYP3A4 induction of rifabutin remains unknown and requires monitoring for breakthrough infections. Close TDM may permit concomitant administration of significantly interacting CYP3A4 inhibitors, inducers, and substrates in complicated SOT patients.

Editorial: Coronavirus disease 2019 (COVID-19) - advances in epidemiology, diagnostics, treatments, host-directed therapies, pathogenesis, vaccines, and ongoing challenges.

Editorial: Coronavirus disease 2019 (COVID-19) - advances in epidemiology, diagnostics, treatments, host-directed therapies, pathogenesis, vaccines, and ongoing challenges.

Atypical mycobacterial infections - management and when to treat.

Infections caused by nontuberculous mycobacteria (NTM) are increasing for several reasons, including diagnostic advances, increased awareness and a larger at-risk population. NTM pulmonary disease is surpassing tuberculosis (TB) in some low incidence areas. This review summarizes the latest literature and guidelines and aims to be a concise source outlining treatment and management of NTM lung infections, integrating established treatment paradigms with novel pharmacological interventions. Recent additions to NTM treatment are inhaled liposomal amikacin and the anti-TB drug bedaquiline. Several other new or repurposed treatments are being explored in vitro, in animal models and in clinical trials, including novel beta-lactamase inhibitor/lactam combinations, dual-lactam combinations, efflux pump inhibitors, novel antimicrobials, inhaled clofazimine suspension and bacteriophages. Patients with NTM pulmonary disease are mainly female and older with significant delay between diagnosis and treatment being common. Treatment varies according to causative organism, drug susceptibilities, radiological type and disease severity. Underlying chronic conditions, drug intolerances and interactions require careful consideration. In all cases, at least three drugs should be used to minimize acquisition of drug resistance, and all patients should receive a minimum of 12 months of treatment. Expert advice should be taken. NTM treatment is longer than TB treatment, more likely to fail and more likely to cause toxicity. The relatively small numbers of patients affected by each NTM species has limited research. Novel treatments hold promise; nevertheless, it is likely that new solutions for NTM management will stem from the TB pipeline for the foreseeable future.