Pulmonary Mycobacterium Abscessus Research Articles

Oral oxaborole MRX-5 exhibits efficacy against pulmonary Mycobacterium abscessus in mouse.

Mycobacterium abscessus (Mab) is an opportunistic pathogen common in patients with lung comorbidities and immunosuppression. There are no FDA-approved treatments, and current treatment has a failure rate exceeding 50%. The intravenous oxaborole MRX-6038 is active against Mab. This study evaluated MRX-5, the oral prodrug, against five Mab isolates in a mouse lung infection model. MRX-5 showed dose-dependent efficacy, with 15 and 45 mg/kg doses comparable to the standard of care, supporting progression to clinical trial.

Clofazimine serum concentration and safety/efficacy in nontuberculous mycobacterial pulmonary disease treatment

BackgroundClofazimine (CFZ) has shown promising effects against Mycobacterium avium-intracellulare complex pulmonary disease (MAC-PD) and Mycobacterium abscessus species pulmonary disease (MABS-PD). However, the optimal CFZ dose remains unknown. We aimed to explore the relationship between steady-state CFZ concentration and its safety and efficacy in MAC-PD and MABS-PD. MethodsThis prospective observational study focused on patients with MAC-PD and MABS-PD treated with CFZ (UMIN 000041053). To understand the safety and efficacy profile of CFZ and elucidate its optimal concentration, we analyzed CFZ-induced pigmentation grade, QTc interval, and culture conversion outcomes in relation to serum CFZ concentration using Student's t-test, a concentration-QTc model, and multivariable logistic regression analysis, respectively. In total, 64 patients (34 with MAC-PD; 30 with MABS-PD) were included. ResultsThe steady-state concentration of CFZ was higher in the moderate-to-severe pigmentation group than in the none-to-light pigmentation group (P < 0.001). At a CFZ concentration of 1 mg/L, the QTc interval was prolonged by 17.3 ms (95 % confidence interval [CI], 3.9–25.4) from baseline. Culture conversion was achieved in 33 (51.6 %) patients. The only significant predictor of culture conversion was surgery (adjusted odds ratio, 5.4; 95 % CI, 1.3–38.0). CFZ concentration and MIC of CFZ less than 0.25 mg/L were not associated with culture conversion in this study. ConclusionCFZ-induced pigmentation and QT interval prolongation are associated with serum CFZ concentrations. CFZ dosage may be optimized by monitoring serum CFZ concentration.

The epidemiology of pulmonary Mycobacterium abscessus species in Japanese population

BackgroundMycobacterium abscessus species (MABS) is now a most virulent rapidly growing mycobacteria (RGM), and the rapid increase of MABS was recently observed worldwide, including in Japan. Thus, we gathered evidences of the presence of pulmonary MABS in Japanese population from Japanese articles. Methodswe searched studies that addressed the isolation of pulmonary non-tuberculous Mycobacteria (NTM) or MABS from clinical respiratory specimens in Japan. Resultsthe ratio of MABS to NTM was 3.04% (95% confidence interval [CI]: 2.51–3.68), found using the meta-analysis of single proportions. The estimated mean age of patients infected with MABS was 67.72 years (95% CI: 65.41–70.02), found using the meta-analysis of single means. The estimated proportion of females, never smoker, and the co-infection with Mycobacterium avium complex (MAC) was 66.75% (95% CI: 59.23–73.50), 67.57% (95% CI: 62.43–72.32), and 36.74% (95% CI: 25.30–49.90), respectively. The characteristics of MABS in Japan were considerably different from that in Europe and United States from the perspective of age, gender, and complications, wherein the patients in these countries tended to be younger, had lower number of females, and had more occurrences of hereditary diseases, including cystic fibrosis (CF). Conclusionwe hypothesized that the characteristics of MABS in the Japanese were involved in those of non-CF MABS, and the distribution of gender and age of MABS were similar to that of MAC in the Japanese.

Investigating a pulmonary Mycobacterium abscessus infection outbreak among elderly inpatients in the intensive care ward.

Mycobacterium abscessus is an opportunistic nontuberculous mycobacteria pathogen; however, the prevalence of nosocomial and community infections is increasing. In January 2016, several bedridden inpatients in the intensive care unit of a hospital had positive sputum smears for acid-fast bacilli, suggesting a mycobacteria outbreak. Acid-fast bacilli smear microscopy, isolation, and culturing were performed twice using sputa from each suspected intensive care unit inpatient (n = 13); in addition, medical history was obtained for each inpatient with suspected infection. Furthermore, environmental specimens were surveyed, collected, and cultured. We used DNA microarray chip analysis to identify positive mycobacterial isolates at the species level and performed whole-genome sequencing and phylogenetic tree construction. Seven inpatients had M. abscessus pulmonary infection, confirmed by 2 positive cultures; five of the inpatients had only one positive culture, while one had two negative cultures. Six of 13 ventilator condensate samples were mycobacterial culture-positive, identified as M. abscessus; the other environmental samples were negative. The M. abscessus isolates (15 sputa and 4 environmental samples) clustered together in the phylogenic analysis with only one single-nucleotide polymorphism difference. All patients were symptom-free after 8 months of multi-drug treatment. We confirmed a pulmonary M. abscessus outbreak among 12 bedridden patients in the intensive care unit through microbiological, molecular epidemiological, and environmental investigations. The possible infection source was contaminated ventilator condensate. This outbreak reemphasizes the importance of standardized ventilator maintenance and disinfection for preventing ventilator-associated pneumonia and is a reminder that nontuberculous mycobacteria-related ventilator-associated pneumonia is possible.

Omadacycline pharmacokinetics/pharmacodynamics in the hollow fiber model and clinical validation of efficacy to treat pulmonary Mycobacterium abscessus disease

BackgroundGuideline-based therapy (GBT) for pulmonary Mycobacterium abscessus (Mab) disease achieves sustained sputum culture conversion (SSCC) rates of 30%; this is reflected by poor efficacy of GBT in the hollow fiber system model of Mab (HFS-Mab), which killed ∼1.22 log10 CFU/mL. This study was performed to determine which clinical dose of omadacycline, a tetracycline antibiotic, should be used in combination therapy to treat pulmonary Mab disease for relapse-free cure. MethodsFirst, omadacycline intrapulmonary concentration-time profiles of seven daily doses were mimicked in the HFS-Mab model and exposures associated with optimal efficacy were identified. Second, 10,000 subject Monte-Carlo simulations were performed to determine whether oral omadacycline 300 mg/day achieved these optimal exposures. Third, a retrospective clinical study on omadacycline vs. primarily tigecycline-based salvage therapy was conducted to assess rates of SSCC and toxicity. Fourth, a single patient was recruited to validate the findings. ResultsOmadacycline efficacy in the HFS-Mab was 2.09 log10 CFU/mL at exposures achieved in >99% of patients on 300 mg/day omadacycline. In the retrospective study of omadacycline 300 mg/day-based combinations vs. comparators, SSCC was achieved in 8/10 vs. 1/9 (P=0.006), symptom improvement in 8/8 vs. 5/9 (P=0.033), toxicity in 0 vs. 9/9 (P<0.001), and therapy discontinuation due to toxicity in 0 vs. 3/9 (P<0.001) cases, respectively. In one prospectively recruited patient, omadacycline 300 mg/day salvage therapy achieved SSCC and symptom-resolution in 3 months. ConclusionBased on the preclinical and clinical data, omadacycline 300 mg/day in combination regimens could be appropriate for testing in Phase III trials in patients with Mab pulmonary disease.

Use of Statistical Process Control Methods for Early Detection of Healthcare Facility-Associated Nontuberculous Mycobacteria Outbreaks: A Single-Center Pilot Study.

Nontuberculous mycobacteria (NTM) are emerging pathogens increasingly implicated in healthcare facility-associated (HCFA) infections and outbreaks. We analyzed the performance of statistical process control (SPC) methods in detecting HCFA NTM outbreaks. We retrospectively analyzed 3 NTM outbreaks that occurred from 2013 to 2016 at a tertiary care hospital. The outbreaks consisted of pulmonary Mycobacterium abscessus complex (MABC) acquisition, cardiac surgery-associated extrapulmonary MABC infection, and a bronchoscopy-associated pseudo-outbreak of Mycobacterium avium complex (MAC). We analyzed monthly case rates of unique patients who had positive respiratory cultures for MABC, non-respiratory cultures for MABC, and bronchoalveolar lavage cultures for MAC, respectively. For each outbreak, we used these rates to construct a pilot moving average (MA) SPC chart with a rolling baseline window. We also explored the performance of numerous alternative control charts, including exponentially weighted MA, Shewhart, and cumulative sum charts. The pilot MA chart detected each outbreak within 2 months of outbreak onset, preceding actual outbreak detection by an average of 6 months. Over a combined 117 months of pre-outbreak and post-outbreak surveillance, no false-positive SPC signals occurred (specificity, 100%). Prospective use of this chart for NTM surveillance could have prevented an estimated 108 cases of NTM. Six high-performing alternative charts detected all outbreaks during the month of onset, with specificities ranging from 85.7% to 94.9%. SPC methods have potential to substantially improve HCFA NTM surveillance, promoting early outbreak detection and prevention of NTM infections. Additional study is needed to determine the best application of SPC for prospective HCFA NTM surveillance in other settings.

FATAL MYCOBACTERIUM ABSCESSUS INFECTION WITH BRONCHOESOPHAGEAL FISTULA

TOPIC: Chest Infections TYPE: Fellow Case Reports INTRODUCTION: Mycobacterium abscessus is known as the most prevalent rapidly growing non-tuberculous mycobacterium (NTM) (1). It is difficult to treat as it has numerous ways to evade the host immune system. Risk factors for infection include immunodeficiencies, smoking, and pulmonary disorders including cystic fibrosis and bronchiectasis. Tigecycline has been recommended as part of a multi-drug regimen therapy. However, the efficacy of multiple regimens is still being evaluated. Some of the novel therapies include b-lactamase inhibitors as well as macrophage therapy (1). CASE PRESENTATION: We present a 69-year-old female with a past medical history of blindness, atrial fibrillation, anemia, breast cancer with metastasis to the lungs and bones who comes in for generalized weakness from her oncologist office. She was noted to have a significantly worsening consolidation of the left lung with cavitation. (Figure 1 and 2). Furthermore, it showed a small area of communication between the left main stem bronchus and esophagus. Bronchoscopy was performed which showed a broncho-esophageal fistula (Figure 3). Cultures were positive for Pseudomonas aeruginosa which was sensitive and treated with cefepime. Due to the severity of the left lung consolidation, the patient was transferred to a tertiary hospital for placement of a bronchial and esophageal stent. Despite placement of stents, she passed of hypoxic respiratory failure after placement of the stents. A postmortum acid fast culture from the sputum and bronchial alveolar lavage grew Mycobacterium abscessus. Further speciation, macrolide, and additional antibiotic sensitivities were not ordered when culture was sent to National Jewish Laboratory in Denver, CO. DISCUSSION: In this case, the cavitary findings and severe lung consolidation appeared to be clinically out of proportion with the patient's community acquired Pseudomonas aeruginosa infection. Furthermore, a broncho-esophageal fistula has not been seen with Pseudomonas infections. So, the late finding of the Mycobacterium abscessus infection clarified why the patient had such a severe infection and fistula. Acquired broncho-esophageal fistulas are rare and there is one case of an esophago-pulmonary fistula reported in the Japanese literature (3). In this patient, we present a fatal case of a Mycobacterium abscessus and Pseudomonas aeruginosa with a broncho-esophageal fistula. Pseudomonas aeruginosa co-infection has been listed as a risk factor, which contributed to the development of the fistula (1). It is important to consider additional testing with severe pulmonary infections with only Pseudomonas aeruginosa. CONCLUSIONS: Broncho-esophageal fistula has been rarely reported in the literature. So, we felt it was important to report this case of Mycobacterium abscessus and Pseudomonas aeruginosa co-infection causing a consolidation, cavitary lesion and a denouveau broncho-esophageal fistula. REFERENCE #1: Johansen, M.D., Herrmann, JL. & Kremer, L. Non-tuberculous mycobacteria and the rise of Mycobacterium abscessus. Nat Rev Microbiol 18, 392–407 (2020). https://doi.org/10.1038/s41579-020-0331-1 REFERENCE #2: Strnad L, Winthrop KL. Treatment of Mycobacterium abscessus Complex. Semin Respir Crit Care Med. 2018 Jun;39(3):362-376. doi: 10.1055/s-0038-1651494. Epub 2018 Aug 2. PMID: 30071551. REFERENCE #3: Kokuho N, Hayashi H, Matsuyama M, Miura Y, Hayashihara K, Saito T. [A case of pulmonary Mycobacterium abscessus disease complicated with esophago-pulmonary fistula causing repeated exacerbation]. Nihon Kokyuki Gakkai Zasshi. 2010 Sep;48(9):696-701. Japanese. PMID: 20954373. DISCLOSURES: No relevant relationships by Justin Ching, source=Web Response

Severe Pulmonary Mycobacterium abscessus Cases Due to Co-Infection with Other Microorganisms Well Treated by Clarithromycin and Sitafloxacin in Japan

BackgroundMycobacterium abscessus frequently causes severe infections, yet its pathophysiological features and treatment regimens have not been established.Case ReportWe present five cases of severe pneumonia due to Mycobacterium abscessus infection in Japan. All cases were diabetic patients, with possible acceleration to pneumonia due to co-infection with other microorganisms. However, following a short period of hospitalization and combination therapy with intravenous imipenem/cilastatin and amikacin, all the cases were successfully treated as outpatients with oral clarithromycin and sitafloxacin.ConclusionM. abscessus infections can become severe in the presence of diabetes mellitus and co-infection with other chronic infectious organisms. Sitafloxacin might be a key drug in the treatment of M. abscessus infection in future.

Prevalence and speciation of non-tuberculous mycobacteria among pulmonary and extrapulmonary tuberculosis suspects in South India

Background and objectivesNon tuberculous mycobacteria (NTM) is an emerging opportunistic pathogen increasing globally and indistinguishable from tuberculosis (TB), which remains a challenge particularly in developing countries. This study aimed to identify the prevalence and diversity of NTM among both pulmonary TB (PTB) and extrpulmonary TB (EPTB) clinical isolates from south India. MethodologyA total of 7633 specimens from TB suspects (PTB, n = 4327 and EPTB, n = 3306) were collected during the study period (July 2018–March 2020) in a tertiary care hospital. The study specimens were subjected to Ziehl Neelsen (ZN) staining and Auramine phenol (AP) staining followed by Lowenstein–Jensen (LJ) and mycobacteria growth indicator tube (MGIT) culture. The MPT64 immunochromatographic test (ICT) was performed among mycobacterial cultures and ICT negative isolates were subjected to Line Probe Assay (LPA). In addition, 53 (PTB, 48 and EPTB, 5) NTM MGIT positive cultures were collected from Intermediate Reference Laboratory (IRL), Puducherry and subjected to LPA for speciation. ResultsOf the 7633 TB suspects, 0.6% were diagnosed as NTM diseases and 5.5% with Mycobacterium tuberculosis (MTBC). NTM infection was observed among 0.7% (31/4327) of PTB and 0.4% (14/3306) of EPTB. MTBC was detected among 6.1% (264/4327) of PTB and 4.6% (153/3306) of EPTB. Among 98 NTM cultures, 80.6% of isolates were recovered from PTB and 19.4% from EPTB specimens. Among pulmonary specimens, Mycobacterium intracellulare (26.6%), Mycobacterium abscessus (17.7%) and Mycobacterium kansasii (12.7%) were the most frequently detected species, while Mycobacterium intracellulare (21.1%), Mycobacterium scrofulaceum (15.8%) and Mycobacterium fortuitum (10.5%) were common in extrapulmonary specimens. ConclusionThe frequency of NTM infection among TB suspects was low at a South Indian tertiary care hospital. The most predominant NTM species isolated from both pulmonary and extrapulmonary specimens was M. intracellulare.

877. Use of Statistical Process Control Charts for Early Detection of Healthcare Facility-Associated Nontuberculous Mycobacterial Outbreaks

BackgroundNontuberculous mycobacteria (NTM) are increasingly implicated in healthcare facility-associated (HCFA) outbreaks. However, systematic methods for NTM surveillance and outbreak detection are lacking and represent an emerging need. We examined how statistical process control (SPC) might perform in NTM outbreak detection.MethodsSPC charts were optimized for surgical site infection surveillance and adapted to analyze 3 NTM outbreaks that occurred from 2013-2016 at a single hospital. The first 2 outbreaks occurred contemporaneously and consisted of pulmonary Mycobacterium abscessus complex (MABC) acquisition and cardiac surgery-associated extrapulmonary MABC infection, respectively. The third outbreak was a pseudo-outbreak of Mycobacterium avium complex (MAC) at a bronchoscopy suite.We retrospectively analyzed monthly rates of unique patients who had: 1) positive respiratory cultures for MABC obtained on hospital day 3 or later; 2) positive non-respiratory cultures for MABC; and 3) positive bronchoalveolar lavage (BAL) cultures for MAC collected at the bronchoscopy suite. For each outbreak, we used these rates to construct a standardized moving average (MA) SPC chart with MA span of 3 months. Rolling baselines were estimated from average rates for months 7 through 12 prior to each monthly data point. SPC detection was indicated by the first data point above the upper control limit (UCL) of 3 standard deviations. Traditional surveillance detection was defined as the time of outbreak detection by routine infection control procedures.ResultsSPC detection occurred 5, 4, and 9 months prior to traditional surveillance outbreak detection for the three outbreaks, respectively (Figures 1 and 2). Prospective NTM surveillance using the MA chart potentially would have prevented an estimated 19 cases of pulmonary MABC, 9 cases of extrapulmonary MABC, and 80 cases of BAL MAC isolation (Table). No data points exceeded the UCL during 95 cumulative months of post-outbreak surveillance, suggesting low burden of false positive SPC signals.Figure 1. Use of a moving average statistical process control (SPC) chart for early detection of hospital-associated outbreaks of pulmonary Mycobacterium abscessus complex (MABC) and cardiac surgery-associated extrapulmonary MABC infection. The pulmonary chart analyzes cases of hospital-onset respiratory isolation of MABC. The extrapulmonary chart analyzes cases of positive non-respiratory cultures for MABC. CL, center line; LCL, lower control limit; UCL, upper control limit. Figure 2. Use of a moving average statistical process control (SPC) chart for early detection of a pseudo-outbreak of Mycobacterium avium complex (MAC) that occurred at a bronchoscopy suite. The chart analyzes cases of MAC isolated from bronchoalveolar lavage cultures. CL, center line; LCL, lower control limit; UCL, upper control limit. Table. Estimated cases of hospital-associated nontuberculous mycobacteria that would have been prevented by prospective surveillance with a moving average statistical process control (SPC) chart. ConclusionA single MA SPC chart detected 3 HCFA NTM outbreaks an average of 6 months earlier than traditional surveillance. SPC has potential to improve NTM surveillance, promoting early cluster detection and prevention of HCFA NTM.Disclosures All Authors: No reported disclosures

Immune defects in patients with pulmonary Mycobacterium abscessus disease without cystic fibrosis.

The prevalence of Mycobacterium abscessus infections in non-cystic fibrosis (CF) patients has increased in recent years. In this study, we investigate whether immune defects explain the apparent susceptibility to this opportunistic infection in non-CF patients.We performed stimulations of peripheral blood mononuclear cells and whole blood from 13 patients with M. abscessus pulmonary disease and 13 healthy controls to investigate their cytokine production after 24 h and 7 days.Patients were predominantly women (54%) with a mean age of 59 years; 62% had nodular bronchiectatic disease. Many patients had predisposing pulmonary diseases, such as COPD (46%), and asthma (23%). Patients with COPD showed an impaired interleukin (IL)-6 response to M. abscessus and a reduced IL-17 response to Candida, together with a M. abscessus-specific enhanced IL-22 production. Patients without COPD showed higher levels of interleukin-1 receptor antagonist (IL-1Ra), an anti-inflammatory molecule. Within the non-COPD patients, those with bronchiectasis showed defective interferon (IFN)-γ production in response to Candida albicans.In conclusion, susceptibility to M. abscessus is likely determined by a combination of immunological defects and predisposing pulmonary disease. The main defect in the innate immune response was a shift of the ratio of IL-1β to IL-1Ra, which decreased the bioactivity of this pathway in the adaptive immune response. In the adaptive immune response there was defective IL-17 and IFN-γ production. Patients with COPD and bronchiectasis showed different cytokine defects. It is therefore crucial to interpret the immunological results within the clinical background of the patients tested.

Antibacterial activity of high-dose nitric oxide against pulmonary Mycobacterium abscessus disease.

Introduction Mycobacterium abscessus is an emerging pulmonary pathogen with limited treatment options. Nitric oxide (NO) demonstrates antibacterial activity against various bacterial species, including mycobacteria. In this study, we evaluated the effect of adjunctive inhaled NO therapy, using a novel NO generator, in a CF patient with pulmonary M. abscessus disease, and examined heterogeneity of response to NO in vitro.MethodsIn the compassionate-use treatment, a 24-year-old CF patient with pulmonary M. abscessus was treated with two courses of adjunctive intermittent NO, first at 160 p.p.m. for 21 days and subsequently by escalating the dose up to 240 p.p.m. for 8 days. Methemoglobin, pulmonary function, 6 min walk distance (6MWD), qualify of life and sputum microbiology were assessed. In vitro susceptibility tests were performed against patient’s isolate and comparison clinical isolates and quantified by Hill’s slopes calculated from time–kill curves.Results M. abscessus lung infection eradication was not achieved, but improvements in selected qualify of life domains, lung function and 6MWD were observed during the study. Inhaled NO was well tolerated at 160 p.p.m. Dosing at 240 p.p.m. was stopped due to adverse symptoms, although methemoglobin levels remained within safety thresholds. In vitro susceptibility tests showed a dose-dependent NO effect on M. abscessus susceptibility and significant heterogeneity in response between M. abscessus clinical isolates. The patient’s isolate was found to be the least susceptible strain in vitro.Conclusion These results demonstrate heterogeneity in M. abscessus susceptibility to NO and suggest that longer treatment regimens could be required to see the reduction or eradication of more resistant pulmonary strains.

Outcomes of pulmonary Mycobacterium abscessus infection.

Treatment of Mycobacterium abscessus pulmonary disease (PD) is challenging with frequent side effects and uncertain rates of success. We performed a retrospective review of all patients at our center with at least one respiratory sample positive for M. abscessus between 2014 and 2019. Electronic health records were reviewed to determine factors associated with M. abscessus infection and clinical outcomes. Thirty-seven patients were identified including 24 with cystic fibrosis (CF), 10 with bronchiectasis, two with chronic obstructive PD (COPD), and one with asthma. American Thoracic Society/Infectious Diseases Society of America criteria for nontuberculous mycobacteria PD were met in 21/37 (56.8%) of cases. Evidence of Aspergillus lung disease was noted in 18 (75.0%) CF patients compared with 3 (23.1%) non-CF patients (P = 0.005). Induction therapy for M. abscessus was given to 22/37 (59.5%) patients (18/24 [75%] with CF and 4/13 [30.8%] without CF). Median duration of induction therapy was 6 weeks (range 3-12). Maintenance antibiotic therapy was prescribed to 17/22 (77.3%) of treated patients. Culture conversion was seen in 15/24 (62.5%) of CF patients compared with 3/13 (23.1%) in the non-CF group (P = 0.034). Culture conversion occurred in 10/22 (45.5%) of treated patients compared with 8/15 (53.3%) untreated patients. Three patients (8.1%) died during follow-up: one with CF and two with COPD. Culture conversion following isolation of M. abscessus from respiratory samples not only is more common in CF than in patients without CF but also frequently occurs spontaneously in both groups. Targeted treatment for M. abscessus did not clearly impact rates of culture conversion.

Incidence possibility of pulmonary Mycobacterium abscessus infection in an endemic area: onion diagram with overlapping analysis

Background Mycobacterium abscessus is a new emerging mycobacterial infection with drug resistance problem. An endemic area of this infection is Thailand, a tropical country in Indochina. The incidence of this infection is not well estimated. Materials and methods In the present study, the authors reappraised on the available epidemiological data in an endemic area aiming at finding incidence possibility of pulmonary M. abscessus infection. The path probability assessment was done, and the onion diagram was finally constructed. In additional, overlapping analysis was also performed. Results The incidence possibility of pulmonary M. abscessus infection in this endemic area is equal to 0.15% of overall suspected cases of nontuberculous mycobacterial infections. Conclusion In our setting, there is considerably high possibility of pulmonary M. abscessus infection among suspected cases of nontuberculous mycobacterial infections.

Top Questions in the Diagnosis and Treatment of Pulmonary M. abscessus Disease.

Mycobacterium abscessus disease is particularly challenging to treat, given the intrinsic drug resistance of this species and the limited data on which recommendations are based, resulting in a greater reliance on expert opinion. We address several commonly encountered questions and management considerations regarding pulmonary Mycobacterium abscessus disease, including the role of subspecies identification, diagnostic criteria for determining disease, interpretation of drug susceptibility test results, approach to therapy including the need for parenteral antibiotics and the role for new and repurposed drugs, and the use of adjunctive strategies such as airway clearance and surgical resection.

Systematic Review and Meta-analyses of the Effect of Chemotherapy on Pulmonary Mycobacterium abscessus Outcomes and Disease Recurrence.

ABSTRACTIn pharmacokinetic/pharmacodynamic models of pulmonary Mycobacterium abscessus complex, the recommended macrolide-containing combination therapy has poor kill rates. However, clinical outcomes are unknown. We searched the literature for studies published between 1990 and 2017 that reported microbial outcomes in patients treated for pulmonary M. abscessus disease. A good outcome was defined as sustained sputum culture conversion (SSCC) without relapse. Random effects models were used to pool studies and estimate proportions of patients with good outcomes. Odds ratios (OR) and 95% confidence intervals (CI) were computed. Sensitivity analyses and metaregression were used to assess the robustness of findings. In 19 studies of 1,533 patients, combination therapy was administered to 508 patients with M. abscessus subsp. abscessus, 204 with M. abscessus subsp. massiliense, and 301 with M. abscessus with no subspecies specified. Macrolide-containing regimens achieved SSCC in only 77/233 (34%) new M. abscessus subsp. abscessus patients versus 117/141 (54%) M. abscessus subsp. massiliense patients (OR, 0.108 [95% CI, 0.066 to 0.181]). In refractory disease, SSCC was achieved in 20% (95% CI, 7 to 36%) of patients, which was not significantly different across subspecies. The estimated recurrent rates per month were 1.835% (range, 1.667 to 3.196%) for M. abscessus subsp. abscessus versus 0.683% (range, 0.229 to 1.136%) for M. abscessus subsp. massiliense (OR, 6.189 [95% CI, 2.896 to 13.650]). The proportion of patients with good outcomes was 52/223 (23%) with M. abscessus subsp. abscessus versus 118/141 (84%) with M. abscessus subsp. massiliense disease (OR, 0.059 [95% CI, 0.034 to 0.101]). M. abscessus subsp. abscessus pulmonary disease outcomes with the currently recommended regimens are atrocious, with outcomes similar to those for extensively drug-resistant tuberculosis. Therapeutically, the concept of nontuberculous mycobacteria is misguided. There is an urgent need to craft entirely new treatment regimens.

Mycobacterium abscessus Displays Fitness for Fomite Transmission.

Mycobacterium abscessus is a rapidly growing nontuberculous mycobacterium (NTM) increasingly reported in soft tissue infections and chronic lung diseases, including cystic fibrosis. The environmental source of M. abscessus has not been definitively identified, but NTM have been detected in soil and water. To determine the potential of soil-derived M. abscessus as an infectious source, we explored the association, growth, and survival of M. abscessus with defined mineral particulates, including kaolin, halloysite, and silicone dioxide, and house dust as possible M. abscessus fomites. M. abscessus physically associated with particulates, and the growth of M. abscessus was enhanced in the presence of both kaolin and house dust. M. abscessus survived desiccation for 2 weeks but was not viable after 3 weeks. The rate of decline of M. abscessus viability during desiccation was reduced in the presence of house dust. The evidence for enhanced growth and survival of M. abscessus during alternating growth and drying periods suggests that dissemination could occur when in wet or dry environments. These studies are important to understand environmental survival and acquisition of NTM.IMPORTANCE The environmental source of pulmonary Mycobacterium abscessus infections is not known. Fomites are nonliving carriers of infectious agents and may contribute to acquisition of M. abscessus This study provides evidence that M. abscessus growth is enhanced in the presence of particulates, using kaolin, an abundant natural clay mineral, and house dust as experimental fomites. Moreover, M. abscessus survived desiccation for up to 2 weeks in the presence of house dust, kaolin, and several chemically defined mineral particulates; mycobacterial viability during extended periods of dessication was enhanced by the presence of house dust. The growth characteristics of M. abscessus with particulates suggest that a fomite mechanism of transmission may contribute to M. abscessus acquisition, which may lead to strategies to better control infections by M. abscessus and related organisms.

Failure of the Amikacin, Cefoxitin, and Clarithromycin Combination Regimen for Treating Pulmonary Mycobacterium abscessus Infection.

In a hollow-fiber model, we mimicked the drug exposures achieved in the lungs of humans treated with standard amikacin, clarithromycin, and cefoxitin combination therapy for Mycobacterium abscessus infection. At optimal dosing, a kill rate of -0.09 (95% confidence interval, -0.04 to 0.03) log10 CFU per ml/day was achieved over the first 14 days, after which there was regrowth due to acquired drug resistance. Thus, the standard regimen quickly failed. A new regimen is needed.

Moxifloxacin's Limited Efficacy in the Hollow-Fiber Model of Mycobacterium abscessus Disease.

Current regimens used to treat pulmonary Mycobacterium abscessus disease have limited efficacy. There is an urgent need for new drugs and optimized combinations and doses. We performed hollow-fiber-system studies in which M. abscessus was exposed to moxifloxacin lung concentration-time profiles similar to human doses of between 0 and 800 mg/day. The minimum bactericidal concentration and MIC were 8 and 2 mg/liter, respectively, in our M. abscessus strain, suggesting bactericidal activity. Measurement of the moxifloxacin concentrations in each hollow-fiber system revealed an elimination rate constant (kel) of 0.11 ± 0.05 h(-1) (mean ± standard deviation) (half-life of 9.8 h). Inhibitory sigmoid maximal effect (Emax) modeling revealed that the highest Emax was 3.15 ± 1.84 log10 CFU/ml on day 3, and the exposure mediating 50% of Emax (EC50) was a 0- to 24-h area under the concentration time curve (AUC0-24)-to-MIC ratio of 41.99 ± 31.78 (r(2) = 0.99). The EC80 was an AUC0-24/MIC ratio of 102.11. However, no moxifloxacin concentration killed the bacteria to burdens below the starting inoculum. There was regrowth beyond day 3 in all doses, with replacement by a resistant subpopulation that had an MIC of >32 mg/liter by the end of the experiment. A quadratic function best described the relationship between the AUC0-24/MIC ratio and the moxifloxacin-resistant subpopulation. Monte Carlo simulations of 10,000 patients revealed that the 400- to 800-mg/day doses would achieve or exceed the EC80 in ≤12.5% of patients. The moxifloxacin susceptibility breakpoint was 0.25 mg/liter, which means that almost all M. abscessus clinical strains are moxifloxacin resistant by these criteria. While moxifloxacin's efficacy against M. abscessus was poor, formal combination therapy studies with moxifloxacin are still recommended.

Amikacin Pharmacokinetics/Pharmacodynamics in a Novel Hollow-Fiber Mycobacterium abscessus Disease Model.

The treatment of pulmonary Mycobacterium abscessus disease is associated with very high failure rates and easily acquired drug resistance. Amikacin is the key drug in treatment regimens, but the optimal doses are unknown. No good preclinical model exists to perform formal pharmacokinetics/pharmacodynamics experiments to determine these optimal doses. We developed a hollow-fiber system model of M. abscessus disease and studied amikacin exposure effects and dose scheduling. We mimicked amikacin human pulmonary pharmacokinetics. Both amikacin microbial kill and acquired drug resistance were linked to the peak concentration-to-MIC ratios; the peak/MIC ratio associated with 80% of maximal kill (EC80) was 3.20. However, on the day of the most extensive microbial kill, the bacillary burden did not fall below the starting inoculum. We performed Monte Carlo simulations of 10,000 patients with pulmonary M. abscessus infection and examined the probability that patients treated with one of 6 doses from 750 mg to 4,000 mg would achieve or exceed the EC80. We also examined these doses for the ability to achieve a cumulative area under the concentration-time curve of 82,232 mg · h/liter × days, which is associated with ototoxicity. The standard amikacin doses of 750 to 1,500 mg a day achieved the EC80 in ≤ 21% of the patients, while a dose of 4 g/day achieved this in 70% of the patients but at the cost of high rates of ototoxicity within a month or two. The susceptibility breakpoint was an MIC of 8 to 16 mg/liter. Thus, amikacin, as currently dosed, has limited efficacy against M. abscessus. It is urgent that different antibiotics be tested using our preclinical model and new regimens developed.