Mycobacterium abscessus and other nontuberculous mycobacteria: evolving respiratory pathogens in cystic fibrosis: a case report and review.

Abstract: Cystic fibrosis (CF) is a risk factor for the development of nontuberculous mycobacteria (NTM) infection. Prevalence of these organisms varies from center to center with the predominance of affected patients being in the adult population. The difficulty in diagnosing NTM infection in CF involves the overlap between signs and symptoms of underlying CF lung disease with its variable pathogens and the signs and symptoms attributable to pulmonary disease caused by NTM. Bacterial overgrowth, especially with Pseudomonas aeruginosa, is problematic, leading to the difficulty in recovering mycobacteria from sputum. There is varying opinion whether the presence of NTM in pulmonary secretions of patients with CF indicates infection or colonization from an environmental organism. This report describes a 14-year-old asymptomatic female patient with CF with minimal bronchiectasis on high-resolution computed tomography scan of the chest who clinically deteriorated over the next 29 months after acquiring Mycobacterium abscessus to the point of being listed for lung transplantation. As more is discovered about NTM, the pathogenicity and virulence of these organisms should be considered in the setting of CF and treated.

Key Words: cystic fibrosis, Mycobacterium abscessus, nontuberculous mycobacteria

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Cystic fibrosis (CF) is a common life-shortening autosomal recessive disease in the white population, with approximately 1 in 2,500 live births in this group. (1) Patients with CF have very viscous respiratory and gastrointestinal secretions as a result of a decrease in the cystic fibrosis transmembrane conductance regulator protein, which regulates chloride and liquid secretion across epithelial surfaces and resorption of sodium and liquid. These thick respiratory secretions occlude the airway and ductal lumens, leading to recurrent pulmonary infections, pancreatic insufficiency, and intestinal obstruction. The most common respiratory pathogens in CF are Staphylococcus aureus and Pseudomonas aeruginosa, but new pathogens are evolving, such as nontuberculous mycobacteria (NTM), Stenotrophomonas maltophilia, Burkholderia cepacia, and Achromobacter xylosoxidans. (2-4) NTM are ubiquitous organisms found in soil, dust, and drinking water systems. (5,6) It is unclear how NTM is acquired, but it appears that person-to-person transmission is unlikely. (5,6) The mode of acquisition for those with CF is unknown, and the under-standing of the factors associated with the development of NTM infection is incomplete.

Case Report

A 14-year-old female with cystic fibrosis and a history of allergic bronchopulmonary aspergillosis, asymptomatic at baseline with infrequent pulmonary exacerbations, presented with cough, fever, and depressed pulmonary function on spirometry (FVC 59% and FE[V.sub.1] 50% of predicted compared with usual baseline of 114 and 106% of predicted). Chest radiography revealed development of a small cavitary lesion in the left upper lobe. She was hospitalized for broad-coverage intravenous antibiotics targeting S. aureus, which had been isolated in her sputum for several years. With a new cavitary lesion, sputum was sent for acid-fast bacteria (AFB). Bacterial sputum cultures once again grew S. aureus; and the AFB smear was positive with Mycobacterium abscessus ultimately being identified. Flexible fiberoptic bronchoscopy with bronchoalveolar lavage was performed and confirmed that M abscessus predominated in the left upper lobe. High-resolution computed tomography (HRCT) of the chest (Fig. 1) revealed advancement of bronchiectasis as compared with a study scan obtained 8 months earlier with the development of multiple pulmonary nodules in the left upper lobe, the right middle lobe, and the left lower lobe with a tree-in-bud configuration in the right middle lobe. With no significant improvement with the antibiotics targeting S. aureus, antimicrobial therapy was then directed against M abscessus with intravenous cefoxitin and amikacin and oral clarithromycin. The patient's clinical symptoms improved quickly after an antimycobacterial agent was started, with minimal improvement in pulmonary function. She was discharged home to complete an 8-week course of intravenous cefoxitin and amikacin with continuing oral clarithromycin (500 mg) twice daily. She was later switched to aerosolized amikacin (500 mg) twice daily at the end of the 8-week period of intravenous therapy with continuation of clarithromycin. Over the next 29 months, she continued with intermittent symptoms of cough, fever, and depressed pulmonary function requiring three admissions to the hospital for inpatient and outpatient intravenous antimycobacterial coverage directed against M abscessus. Aerosolized amikacin (500 mg) twice daily and clarithromycin (500 mg) twice daily were continued when she was not receiving intravenous treatment. During these hospitalizations, acute allergic bronchopulmonary aspergillosis exacerbation was ruled out, and antimicrobial coverage targeted both S aureus and M abscessus with each organism continuing to be isolated on sputum cultures. Twenty-nine months after M abscessus was isolated from her sputum, HRCT of the chest was repeated and revealed significant worsening of her bronchiectasis in all lung fields, with the development of large multiloculated cysts in the right upper lobe (Fig. 2) and a thick-walled cavitary lesion (Fig. 3) with an air fluid level in the superior segment of the left lower lobe. The cavitary lesion was drained under computed tomography guidance because of her supplemental oxygen requirement, fever, and minimal response to medical therapy. With progressing lung disease, she was evaluated and listed for lung transplantation.

Discussion

Patients with abnormal pulmonary anatomy, including bullae or cavities, have an increased incidence of NTM pulmonary disease. (7) Mycobacterium avium-intracellulare complex (MAC) is most commonly isolated in sputum, but M. abscessus, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, and others have been reported. (8-12) NTM is not a reportable disease in the United States; thus, estimates of incidence and prevalence have been unreliable. A recent 21-center prospective study of NTM in patients with CF older than 10 years of age demonstrated a prevalence of 13%, with MAC (72%) and M abscessus (16%) being the two most common organisms isolated. (12) This multicenter study also demonstrated that patients with CF with NTM were significantly more likely to be older (average age of 26 years), have a higher FE[V.sub.1], have a lower body mass index, and have S aureus on sputum culture and were less likely to have P aeruginosa in their sputum. (12) This was the first study to examine geographic distribution of NTM in a defined population, and geographic variability to the prevalence of NTM was found, ranging from 7 to 24%. (12) All 21 participating centers recovered NTM, and most of the centers with a prevalence of 15% or greater were in coastal states. (12)

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Mycobacteria are difficult to culture from the sputum of patients with CF because of overgrowth of the AFB by other pathogens, such as P aeruginosa, and decontamination procedures reduce recovery of specimens. Sputum for AFB culture in CF has traditionally involved decontamination with 0.25% N-acetyl-L-cysteine and 1% sodium hydroxide. (13) More recent studies show 5% oxalic acid as an adjunct decreases bacterial overgrowth. (14) A later study demonstrated that oxalic acid treatment may reduce recovery of NTM from sputum with low numbers of acid-fast bacilli with recommendations that only specimens with bacterial overgrowth be decontaminated with oxalic acid. (15) Isolating NTM in patients with CF is difficult in itself, but diagnosing infection when an organism is recovered remains controversial. Specialists question whether the isolation of NTM on sputum indicates infection or colonization. Several authors have supported the diagnosis of NTM infection if it persistently is isolated in sputum culture. (8,10-11)

In 1997, the American Thoracic Society (ATS) published a consensus statement that identified CF as a risk factor for NTM pulmonary disease in HIV-seronegative patients and provided recommendations on the laboratory and clinical diagnosis for NTM. (16) The preferred method for laboratory identification includes the use of fluorochrome staining and growth in liquid media as well as on Middlebrook 7H10 or 7H11 agar with rapid identification methods available using commercial DNA probes and high-pressure liquid chromatography. (16) The ATS further recommended (1) no susceptibility testing for initial MAC isolates except in patients who have failed prior macrolide therapy or prophylaxis; (2) susceptibility testing of M abscessus, M chelonae, and M fortuitum should not be performed with antituberculous agents but against amikacin, doxycycline, imipenem, fluoroquinolones, sulfonamide, cefoxitin, and clarithromycin; and (3) testing M. kansasii isolates against rifampin only. (16) Three criteria must be satisfied to diagnose NTM pulmonary disease in HIV-seronegative patients: (1) clinical signs and symptoms of cough, fever, fatigue, weight loss, hemoptysis, and dyspnea with exclusion of other disease; (2) radiographic findings on chest radiography (infiltrates, nodules, or cavitation) or HRCT of the chest abnormalities (nodules and/or multifocal bronchiectasis); and (3) bacteriologic isolation of the NTM organism on sputum/bronchial washings or tissue biopsy. (16) The chest radiography in NTM pulmonary disease caused by rapidly growing mycobacteria, including M abscessus, M chelonae, and M fortuitum, is likely to show multilobar, patchy, reticulonodular, or mixed interstitial-alveolar infiltrates with upper lobe predominance, with cavitation seen in only 15% of cases. (17)

No guidelines exist for the treatment of NTM pulmonary disease in the CF population. For MAC pulmonary disease in HIV-seronegative patients, the 1997 ATS consensus statement recommended empiric treatment with daily azithromycin or clarithromycin, ethambutol, and a rifamycin (rifampin or rifabutin). (16) In the setting of extensive disease, streptomycin is added to this regimen two to three times per week for 8 weeks for the first 2 to 3 months of therapy. (16) Monotherapy for MAC pulmonary disease has yielded resistant strains. (18-20) M. abscessus is a more virulent organism and is more difficult to treat. (16,21) Combination therapy is needed for M. abscessus with clarithromycin (15 to 30 mg/kg, maximum dose of 1 g daily), amikacin (10 to 15 mg/kg divided twice daily to achieve serum levels of 20 [micro]g/mL), and cefoxitin (200 mg/kg, maximum dose of 12 g daily) for 2 to 4 weeks for empiric treatment pending sensitivities. (7,16) Further recommendations for treatment include following sputum cultures to assess response and treatment for at least 12 months after cultures are negative with longer treatment or chronic suppressive treatment if necessary. (7) Recommended suppressive therapy includes oral clarithromycin and aerosolized amikacin (500 mg in 2 to 3 mL of normal saline twice daily). (21, 22) Avoidance of clarithromycin monotherapy for M abscessus and the closely related M chelonae is recommended with concerns of developing macrolide resistance. (23-26) The most common underlying conditions associated with development of macrolide resistance in M abscessus with clarithromycin therapy were cystic fibrosis and disseminated cutaneous disease. (25)

Another potential therapeutic option for NTM pulmonary disease was identified by Wallace et al. (27) when linezolid was found to have activity against the rapidly growing mycobacteria, including M chelonae, M abscessus, and M fortuitum. M abscessus had the least susceptibility (23% of the isolates had minimum inhibitory concentrations 8 [micro]g/mL or less). Linezolid, an oxazolidinone with activity against Grampositive organisms, was used effectively in the treatment of a patient with disseminated M chelonae. (28) Close monitoring of the susceptibility patterns is needed with NTM because they have a high propensity to develop antibiotic resistance. When M abscessus lung disease progresses, limited therapeutic options are available to prevent or slow disease progression. Surgical resection should be considered for patients with severe localized disease that is failing to respond to therapy and a FE[V.sub.1] greater than 30% predicted. (7) The other rapidly growing mycobacteria are usually less virulent and are more susceptible to multiple oral agents than M abscessus; treatment based on in vitro susceptibility tests can often lead to clinical cure. (16)

Percutaneous drainage of a complicated abscess should be considered in the setting of failure to respond to adequate medical therapy, development of sepsis despite adequate medical therapy, enlarging abscess in the setting of treatment, imminent rupture of the abscess, and failure to wean from mechanical ventilation. However, transthoracic drainage of an intrapulmonary abscess can potentially lead to extrapulmonary seeding of the infecting organism, which can lead to significant morbidity or mortality if lung transplantation is later needed. As lung disease progresses in CF, lung transplantation is often needed with opportunistic infections leading to morbidity and mortality due to immunosuppressive therapy. Nontuberculous mycobacterial infections are emerging as important pathogens in organ transplant recipients, with a recent review of revealing NTM infections being common after lung transplantation (6.5%, 17 of 261 patients), with both pulmonary and extrapulmonary infections observed. (29) This study also identified NTM infections as a potential cause of graft dysfunction with mycobacterial infections occurring in association with other infections in patients with severe graft dysfunction. (29) M abscessus was reported as the cause of a fatal pulmonary infection in a 20-year-old patient 15 days after bilateral lung transplantation; the colonization of the multidrug-resistant mycobacterium in the patient was not clearly identified before lung transplantation. (30) Repeated attempts of identifying M abscessus from a variety of clinical specimens were needed to reach the correct diagnosis in a lung transplant recipient who had an empyema. (31)

Conclusion

The survival rate for patients with CF has dramatically improved over the past 50 years because of advancement in therapy, including antibiotics and airway clearance techniques with improved nutrition. Accompanying these advancements is the emergence of new respiratory pathogens such as NTM and others including S maltophilia, B cepacia, and A xylosoxidans. Although there is a strong association between NTM and older patients with CF this case illustrates the presence and the potential aggressiveness of M abscessus in the pediatric patient population. Therapeutic options are limited in NTM pulmonary disease, with linezolid being a potential option; however, its susceptibility against M abscessus was lacking. Macrolide monotherapy for M abscessus in the CF population should be avoided, with the development of resistance a potential risk. Physicians should be cognizant of both established and evolving respiratory pathogens in the CF population and their developing therapies.

Woe to the man whose heart has not learned while young to hope, to
love--and to put its trust in life.
--Joseph Conrad

Accepted February 14, 2005.

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RELATED ARTICLE: Key Points

* The familiar respiratory pathogens in cystic fibrosis are Staphylococcus aureus and Pseudomonas aeruginosa, but new pathogens including nontuberculous mycobacteria, Stenotrophomonas maltophilia, Burk-holderia cepacia, and Achromobacter xylosoxidans are evolving.

* Linezolid, an oxazolidinone, was found to have excellent activity against rapidly growing mycobacteria; however, Mycobacterium abscessus had poor susceptibility.

* Macrolide monotherapy for nontuberculous mycobacteria should be avoided in the setting of cystic fibrosis with the development of macrolide resistance being a risk.

* Nontuberculous mycobacterial infection is common after lung transplantation and may be an unrecognized cause of graft dysfunction.

Don Hayes, Jr, MD

From the Departments of Medicine and Pediatrics, University of Wisconsin Medical School, Clinical Sciences Center, Madison, WI.

There was no financial support.

The author has no commercial or proprietary interest in any drug, device, or equipment mentioned in this case report.

Reprint requests to Dr. Don Hayes, Jr., University of Wisconsin Medical School, Clinical Sciences Center, Room K4/938, 600 Highland Ave., Madison, WI 53792. Email: [e-mail].