Abscessus Disease Research Articles

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.

Novel drug combination for Mycobacterium abscessus disease therapy identified in a Drosophila infection model

Mycobacterium abscessus is known to be the most drug-resistant Mycobacterium and accounts for ∼80% of pulmonary infections caused by rapidly growing mycobacteria. This study reports a new Drosophila melanogaster-M. abscessus infection model that can be used as an in vivo efficacy model for anti-M. abscessus drug potency assessment. D. melanogaster were challenged with M. abscessus, and infected flies were fed with a fly medium containing tigecycline, clarithromycin, linezolid, clofazimine, moxifloxacin, amikacin, cefoxitin, dinitrobenzamide or metronidazole at different concentrations (0, 100 and 500 mg/L). The survival rates of infected flies were plotted and bacterial colonization/dissemination in fly bodies was monitored by cfu determination and green fluorescent protein epifluorescence. The D. melanogaster-M. abscessus model enabled an assessment of the effectiveness of antibiotic treatment. Tigecycline was the best drug for extending the lifespan of M. abscessus-infected Drosophila, followed by clarithromycin and linezolid. Several different combinations of tigecycline, linezolid and clarithromycin were tested to determine the best combination. Tigecycline (25 mg/L) plus linezolid (500 mg/L) was the best drug combination and its efficacy was superior to conventional regimens, not only in prolonging infected fly survival but also against M. abscessus colonization and dissemination. This D. melanogaster-M. abscessus infection/curing methodology may be useful for the rapid evaluation of potential drug candidates. In addition, new combinations using tigecycline and linezolid should be considered as possible next-generation combination therapies to be assessed in higher organisms.

Pulmonary Mycobacterium abscessus disease in a patient receiving low-dose methotrexate for treatment of early rheumatoid arthritis

A 70-year-old woman with methotrexate (MTX)-refractory rheumatoid arthritis (RA) was referred to our hospital for introduction of biological therapy. On high-resolution computed tomography scans, the patient exhibited abnormal findings such as bronchiectasis and centrilobular small nodules, which were highly suggestive of pulmonary nontuberculous mycobacterial (NTM) disease. Although mycobacterial cultures of sputum specimens yielded negative results, cultures of bronchoalveolar lavage fluids grew Mycobacterium abscessus. Frequent follow-up chest radiographs indicated that the patient's pulmonary disease became rapidly worse in 1month following dose escalation of MTX and administration of low-dose prednisolone. Oral clarithromycin and levofloxacin, chosen on the basis of in vitro susceptibility testing, led to a dramatic recovery from this potentially life-threatening complication. Through our experience with this case, we have learned that (1) pulmonary M. abscessus disease can progress rapidly, even during nonbiological anti-RA therapy; (2) regular follow-up chest radiographs are useful to ensure timely implementation of anti-NTM treatment; (3) bronchoscopic testing should be considered when patients are suspected of pulmonary NTM disease but do not meet the diagnostic criteria; and (4) early isolation, identification, and susceptibility testing of causative NTM species are critical for favorable outcomes.

Serial CT Findings ofMycobacterium massiliensePulmonary Disease Compared withMycobacterium abscessusDisease after Treatment with Antibiotic Therapy

To present the serial computed tomographic (CT) findings of lung abnormalities in Mycobacterium massiliense pulmonary disease compared with those in Mycobacterium abscessus disease. The institutional review board approved this retrospective study and waived informed consent. Serial chest CT scans of M massiliense (n = 34) and M abscessus (n = 24) pulmonary diseases were retrospectively reviewed. Patients were treated with clarithromycin-containing combination antibiotics regimen, and sputum examinations were performed regularly. CT scans were obtained at the beginning of antibiotic therapy, at the end of 4-week hospitalization, and at the time of 12-month antibiotic therapy. All patients with M massiliense disease had sputum conversion during treatment, whereas 50% of patients with M abscessus disease had sputum conversion. The most common CT findings of M massiliense disease at presentation were cellular bronchiolitis (n = 34, 100%), bronchiectasis (n = 34, 100%), consolidation (n = 33, 97%), nodules (n = 32, 94%), and cavities (n = 15, 44%). These findings were similar in M abscessus disease. Thirty (88%) patients with M massiliense disease had decrease in overall CT score at 12-month therapy, whereas only eight (33%) patients with M abscessus disease had a decrease (P < .0001). Improvement was noticeable in cellular bronchiolitis and cavity in M massiliense disease. Common CT findings of M massiliense diseases overlap with those of M abscessus disease. However, responses to antibiotic treatment are much different; in M massiliense disease, negative sputum conversion is accomplished in all patients and serial CT scans show improvement in most patients.

Risk factors for Mycobacterium abscessus infection in cystic fibrosis patients; a case–control study

Mycobacterium abscessus is a nontuberculous mycobacterium that is increasingly recognized as an opportunistic pathogen in cystic fibrosis (CF) patients. Factors that predispose CF patients to infection by this environmental bacterium remain unknown. In a case–control study of 22 CF patients with M. abscessus infection and 22 CF controls, we investigated risk factors for MAB infection as well as the positioning of MAB infection in relation to the other pathogens infecting CF patients. No clear risk factors were found; steroid treatment and CF related diabetes were equally common among cases and controls. M. abscessus disease affects CF patients of varying age, lung function and co-morbidities. Antimicrobial maintenance therapy did not prevent M. abscessus infection. A history of Stenotrophomonas maltophilia infection was significantly more frequent among cases than among controls and there may be a relation with Aspergillus fumigatus infection, or both may be signs of advanced lung damage that predisposes to MAB disease. The absence of clear risk factors and the omnipresence of MAB in the environment suggest that MAB infection in CF patients is a random event. Its symptoms and impact on lung function seem to warrant treatment.

Coexistence of lung cancer and active pulmonary mycobacteriosis

The aim of this study is to clarify the clinical and pathological anatomical picture of cases in which lung cancer and active pulmonary mycobacteriosis are intermingled in the same lobe of the lung. We analyzed clinicopathological data on 11 cases in which lung cancer and active pulmonary mycobacteriosis are intermingled in the same lung lobe out of 61 admitted cases of coexisting lung cancer and active pulmonary mycobacteriosis, encountered at National Hospital Organization Tokyo National Hospital during the period from 1991 to 2003. The subjects were 10 men and 1 woman, with a mean age of 68 years. The species of mycobacteriosis were M. tuberculosis in 6 and nontuberculous mycobacteriosis in 5 (M. avium disease and M. abscessus disease in 2 each, and M. kansasii disease in 1). The frequency of the mixture was 13% (6/45) in patients with lung cancer and tuberculosis and was 31% (5/16) in patients with lung cancer and nontuberculous mycobacteriosis. Radiographic findings revealed that both cancer shadows and mycobacteriosis shadows are identified in 8 of the 11 patients, whereas cancer shadows were recognized but mycobacteriosis shadows could not be pointed out in the remaining 3 patients. We divided 7 cases (5 resection scases and 2 autopsy cases) with the mixture of cancer and mycobacteriosis into 2 types from the macroscopic images: (1) type A (4 cases, the foci of lung cancer and tuberculosis, which were separated originally, progressed mutually, and has adjoined), and (2) type B (2 cases, the foci of mycobacteriosis existed within or in the edge of the foci of lung cancer). There were 3 nontuberculous mycobacteriosis cases and 1 tuberculosis case in type A, and 2 tuberculosis cases and 1 nontuberculous mycobacteriosis in type B. In nontuberculous mycobacteriosis cases, cancer and mycobacteriosis had often adjoined under the conditions of preexisting lung disease, such as a lung cyst, whereas in tuberculosis cases, it was characteristically shown that the wall of encapsulated caseous nodules was destroyed by cancer invasion, and that the tuberculous nodules were reactivated. These findings seemed to be related to exogenous infection of nontuberculous mycobacteriosis to the injured lungs and to endogenous reactivation of tuberculosis from inactive tuberculous lesions. Lung cancer and active pulmonary mycobacteriosis are often seen intermingled in the same lung lobe, and the mixture pictures of the two diseases are variable. The physicians should carefully note about the mixture of lung cancer and mycobacteriosis, though the findings are not clear on the chest plain radiographs.

High virulent clinical isolates of Mycobacterium abscessus from patients with the upper lobe fibrocavitary form of pulmonary disease

Pulmonary disease caused by nontuberculous mycobacteria (NTM), including Mycobacterium abscessus, can be classified into two distinct types of clinical disease; the upper lobe fibrocavitary (UC) form and nodular bronchiectatic (NB) form. However, the relationship between mycobacterial strain virulence and disease type in the pulmonary M. abscessus diseases has not been reported. To determine the differential virulence between strains causing two forms of disease, we obtained clinical isolates from patients with the UC and NB form of pulmonary disease caused by M. abscessus. In present study, we investigated the intracellular growth of clinical isolates in macrophages and their pathogenicity in C57BL/6 mice. For the isolates from the UC form, intracellular macrophage growth was faster and higher levels of cytokines were induced in macrophages than for those from NB form. Moreover, severe lung inflammation was only observed in mice intranasally infected with the isolate from the UC form with the increase of bacterial load. These findings suggest that M. abscessus isolates from the UC form of pulmonary disease are more virulent than those from NB form. This differential virulence of clinical strains may be one of the important factors involved in the determination of the disease form of pulmonary M. abscessus disease.

Clinical relevance of Mycobacterium chelonae–abscessus group isolation in 95 patients

To determine the clinical relevance of Mycobacterium chelonae-abscessus group isolation from clinical samples. We retrospectively reviewed medical files of all patients from whom these mycobacteria were isolated between January 1999 and January 2005 and re-identified the isolates by rpoB sequencing. We applied the American Thoracic Society (ATS) diagnostic criteria to establish clinical relevance. Ninety-five patients were traced (56 M. chelonae, 25 Mycobacterium abscessus, 8 Mycobacterium massiliense, 6 Mycobacterium bolletii). Most isolates were cultured from pulmonary samples in patients with pre-existing pulmonary disease. Among patients with pulmonary isolates, 27% (20/74) meets ATS criteria; M. abscessus is most relevant (50%; 9/18), followed by M. massiliense (29%; 2/7), M. bolletii (20%; 1/5) and M. chelonae (18%; 8/44). Extrapulmonary disease presented as disseminated skin disease, eye disease specific for M. chelonae and otomastoiditis for M. abscessus. Treatment, especially for pulmonary M. abscessus disease, yielded limited results. One-fourth of the patients with pulmonary M. chelonae-abscessus group isolates met the ATS criteria; this percentage differs by species. Species distribution and clinical relevance differ from other regions. M. abscessus isolation in cystic fibrosis patients warrants special attention. Current ATS criteria might be too lenient to diagnose M. chelonae-abscessus group disease.

Pneumonectomy for nontuberculous mycobacterial infections

Background Pneumonectomy is considered in the treatment of nontuberculous mycobacterial infections when an entire lung is affected. However, this procedure carries high morbidity. We report on our experience in using pneumonectomy for treating patients with nontuberculous mycobacterial infections. Methods Between 1983 and 2002, 53 patients infected with nontuberculous mycobacteria underwent 55 pulmonary resections. Of these patients, 11 (3 men, 8 women) underwent pneumonectomy (5 right, 6 left). Median age was 57 years (range, 43 to 69 years). Mycobacterium avium complex disease occurred in 10 patients and Mycobacterium abscessus disease in 1. Indications for pneumonectomy included multiple cavities in one lung and destruction of an entire lung. The bronchial stump was covered with a latissimus dorsi muscle flap in 7 patients and with an intercostal pedicle flap in 2. Results Operating time ranged from 142 to 477 minutes (median, 360 minutes). The median intraoperative blood loss was 555 mL (range, 130 to 1,245 mL). There was no operative mortality. Bronchopleural fistula occurred in 3 patients. All fistulas were observed after right pneumonectomy, and were treated by reclosure of the bronchus. Empyema occurred in 1 patient, who was treated with irrigation. All patients achieved sputum-negative status after surgery. Two late deaths occurred. One patient died of respiratory failure 11 months after surgery. A second patient, the only patient who had recurrent disease, died of respiratory failure 4 years postoperatively. Conclusions Despite bronchial stump protection, right pneumonectomy carries a risk for bronchopleural fistula. Nonetheless, pneumonectomy can result in high cure rates in patients with nontuberculous mycobacterial infections.