Nontuberculous Mycobacteria in Solid Organ Transplant Recipients

Abstract

There are now more than 125 identified species of nontuberculous mycobacteria (NTM) (1Tortoli E Impact of genotypic studies on mycobacterial taxonomy: The new mycobacteria of the 1990s.Clin Microbiol Rev. 2003; 16: 319-354Crossref PubMed Scopus (430) Google Scholar). These ubiquitous environmental organisms are found worldwide and can cause a wide spectrum of disease in humans. Incidence rates of infection with NTM are rising, partly due to improved diagnostic capabilities in the microbiology lab (2Brown BA, Wallace RJ Jr. Infections due to nontuberculous mycobacteria. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennet‘s principles and practice of infectious diseases. 6th Ed. Philadelphia, PA: Churchill-Livingstone, 2005Google Scholar, 3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar). Solid organ transplant (SOT) recipients have increased susceptibility to infection with these agents due to impaired cell-mediated immunity, but the actual frequency of these infections in transplant populations is low (4Doucette K Fishman JA Nontuberculous mycobacterial infection in hematopoetic stem cell and solid organ transplant recipients.Clin Infect Dis. 2004; 38: 1428-1439Crossref PubMed Scopus (210) Google Scholar, 5Patel R Roberts GD Keating MR et al.Infections due to nontuberculous mycobacteria in kidney, heart and liver transplant recipients.Clin Infect Dis. 1994; 19: 263-273Crossref PubMed Scopus (142) Google Scholar). Although there are no prospective studies or registries of transplant recipients to guide diagnosis and treatment, practice guidelines on the diagnosis, treatment and prevention of NTM disease by expert panels serve as a useful reference to clinicians (3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar). This document will be restricted to discussing infection with the NTM most commonly isolated from transplant recipients. These include Mycobacterium avium complex (MAC), M. kansasii, M. marinum, M. hemophilum, and the rapid growing mycobacteria: M. fortuitum, M. chelonae and M. abscessus. NTM are environmental organisms and most species have been isolated from soil or water (1Tortoli E Impact of genotypic studies on mycobacterial taxonomy: The new mycobacteria of the 1990s.Clin Microbiol Rev. 2003; 16: 319-354Crossref PubMed Scopus (430) Google Scholar, 2Brown BA, Wallace RJ Jr. Infections due to nontuberculous mycobacteria. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennet‘s principles and practice of infectious diseases. 6th Ed. Philadelphia, PA: Churchill-Livingstone, 2005Google Scholar, 3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar). Neither animal-to-human nor human-to-human transmission has been demonstrated conclusively. Although the geographic distribution of some species has been reported to be nonuniform, this may be due in part to reporting bias. When consistent laboratory methods are used, isolation rates of NTM from the environment are similar in different geographic areas (6Wolinsky E State of the art: Nontuberculous mycobacteria and associated diseases.Am Rev Resp Dis. 1979; 1979: 107-159Google Scholar, 7Falkinham JO Nontuberculous mycobacteria in the environment.Clin Chest Med. 2002; 23: 520-551Abstract Full Text Full Text PDF Scopus (314) Google Scholar). Available published literature indicates that in some transplant centers rates of infection due to Mycobacterium tuberculosis (MTB) are higher than rates due to NTM (8Lloveras J Peterson PK Simmons RL Najarian JS Mycobacterial infections in renal transplant recipients.Arch Intern Med. 1982; 142: 888-892Crossref PubMed Scopus (120) Google Scholar, 9Novick RJ Moreno-Cabral CE Stinson EB et al.Nontuberculous mycobacterial infections in heart transplant recipients: A seventeen-year experience.J Heart Transplant. 1990; 9: 357-363PubMed Google Scholar, 10McDiarmid SV Blumberg DA Remotti H et al.Mycobacterial infections after pediatric liver transplantation: A report of three cases and review of the literature.J Pediatr Gastroenterol Nutr. 1995; 20: 425-431Crossref PubMed Scopus (25) Google Scholar, 11Roy V, Weisdorf D. Typical and atypical mycobacterium. In: Bowden R, Ljungman P, Paya CV, eds. Transplant Infections, Philadelphia: Lippincott Raven, 1998.Google Scholar), but the ratio is likely to be highly variable from center to center, and dependent mainly on the burden of latent tuberculosis (TB) infection in the population served. Infection due to NTM may occur early after transplantation, but the median onset is usually a year or more after transplantation (4Doucette K Fishman JA Nontuberculous mycobacterial infection in hematopoetic stem cell and solid organ transplant recipients.Clin Infect Dis. 2004; 38: 1428-1439Crossref PubMed Scopus (210) Google Scholar, 5Patel R Roberts GD Keating MR et al.Infections due to nontuberculous mycobacteria in kidney, heart and liver transplant recipients.Clin Infect Dis. 1994; 19: 263-273Crossref PubMed Scopus (142) Google Scholar). Incidence rates of NTM infection are reported as 0.16–0.38% in kidney transplant recipients and 0.04% in liver transplants, with higher rates in heart (0.24–2.8%) and lung transplants (0.46–8.0%) (4Doucette K Fishman JA Nontuberculous mycobacterial infection in hematopoetic stem cell and solid organ transplant recipients.Clin Infect Dis. 2004; 38: 1428-1439Crossref PubMed Scopus (210) Google Scholar, 12Malouf MA Lanville AR The spectrum of mycobacterial disease after lung transplantation.Am J Resp Crit Care Med. 1999; 160: 1611-1616Crossref PubMed Scopus (141) Google Scholar). Some risk factors for infection with NTM have been elucidated, though not all are well understood. Certain acquired and genetic defects in the immune system increase risk of disseminated disease. Specifically, high-risk individuals include patients with AIDS and a CD4+ T-cell count less than 50 cells/mm3, those with inherited disorders affecting the interleukin-12/interferon-γ axis, and those treated with tumor necrosis factor-a inhibitors. Underlying structural lung disease from COPD, cystic fibrosis, and bronchiectasis increase the risk of pulmonary NTM disease. With respect to solid organ transplantation, lung transplant recipients with chronic rejection have an increased risk of NTM (2Brown BA, Wallace RJ Jr. Infections due to nontuberculous mycobacteria. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennet‘s principles and practice of infectious diseases. 6th Ed. Philadelphia, PA: Churchill-Livingstone, 2005Google Scholar, 3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar, 13Wallace RJ Jr, Brown BA. Mycobacterium fortuitum, chelonae, abscessus. In Schlossberg D, ed. Tuberculosis and Nontuberculous Mycobacterial Infections, 4th Ed. Philadelphia: Saunders, 1999: 372–379.Google Scholar). NTM can cause a variety of disease manifestations. In general, chronic pulmonary disease is the most common manifestation of NTM disease, and among SOT recipients those with lung transplantation are most commonly affected. Symptoms usually include a chronic cough, dyspnea and sputum production; hemoptysis can occur especially with cavitary formation. NTM pulmonary disease can be primarily fibrocavitary (similar to TB, and characterized by infiltrates, cavities with surrounding infiltrate and fibrosis on chest imaging), primarily nodular/bronchiectatic or a combination. The most common NTM to cause pulmonary disease include M. avium, M. kansasii, M. abscessus and M. xenopi (2Brown BA, Wallace RJ Jr. Infections due to nontuberculous mycobacteria. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennet‘s principles and practice of infectious diseases. 6th Ed. Philadelphia, PA: Churchill-Livingstone, 2005Google Scholar, 4Doucette K Fishman JA Nontuberculous mycobacterial infection in hematopoetic stem cell and solid organ transplant recipients.Clin Infect Dis. 2004; 38: 1428-1439Crossref PubMed Scopus (210) Google Scholar, 12Malouf MA Lanville AR The spectrum of mycobacterial disease after lung transplantation.Am J Resp Crit Care Med. 1999; 160: 1611-1616Crossref PubMed Scopus (141) Google Scholar). Skin and soft tissue infections are a common manifestation of NTM disease in SOT patients. The NTM species that most commonly cause localized infections of the skin and subcutaneous tissue are the rapidly growing M. fortuitum, M. abscessus and M. chelonae. These rapid growing mycobacteria can also cause surgical site infections, infections associated with long-term intravenous or peritoneal catheters or infection after inoculation with environmental objects contaminated with soil or water (2Brown BA, Wallace RJ Jr. Infections due to nontuberculous mycobacteria. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennet‘s principles and practice of infectious diseases. 6th Ed. Philadelphia, PA: Churchill-Livingstone, 2005Google Scholar, 13Wallace RJ Jr, Brown BA. Mycobacterium fortuitum, chelonae, abscessus. In Schlossberg D, ed. Tuberculosis and Nontuberculous Mycobacterial Infections, 4th Ed. Philadelphia: Saunders, 1999: 372–379.Google Scholar), Disease due to M. marinum (‘fish tank granuloma’) has been closely linked to contact with sea water, fresh water and home aquaria (3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar, 14Gombert ME Goldstein EJ Corrado ML et al.Disseminated Mycobacterium marinum infection after renal transplantation.Ann Intern Med. 1981; 81: 486-487Crossref Scopus (87) Google Scholar). This infection most commonly presents as a nodule at the site of inoculation, usually on an extremity. Skin and soft tissue infections due to NTM can remain localized, spread contiguously to surrounding structures, spread to regional nodes and/or disseminate. Disseminated NTM disease in patients with advanced AIDS is most often due to M. avium infection. By contrast, in transplant recipients disseminated disease is quite uncommon, but the disseminated NTM species described in renal and cardiac transplantation are M. chelonae and M. abscessus. M. hemophilum can also rarely cause disseminated disease in organ transplant recipients (2Brown BA, Wallace RJ Jr. Infections due to nontuberculous mycobacteria. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennet‘s principles and practice of infectious diseases. 6th Ed. Philadelphia, PA: Churchill-Livingstone, 2005Google Scholar, 15Saubolle MA Kiehn TE White MH et al.Mycobacterium haemophilum: Microbiology and expanding clinical and geographic spectra of disease in humans.Clin Micro Rev. 1996; 9: 435-447Crossref PubMed Google Scholar). Diagnosis relies first and foremost on inclusion of mycobacterial infection in the differential diagnosis, and obtaining relevant clinical specimens for laboratory evaluation. If respiratory disease is suspected, respiratory specimens should be sent for smear microscopy for acid fast bacilli, and for mycobacterial culture. When clinically relevant based on suspected disease sites, cerebrospinal fluid, joint fluid, effusions and abscess material should also be sent for smear and culture. Tissue specimens should be sent for smear, culture and histopathology. If disseminated disease is suspected, mycobacterial blood cultures should also be obtained. Radiographic examination can be helpful in identifying sites of disease, but no chest imaging pattern or other imaging findings are highly specific for NTM disease. With respect to mycobacteriology laboratory testing, most NTM grow readily on media designed to isolate MTB. Notable exceptions are M. marinum, M. hemophilum and some strains of M. chelonae, which grow reliably only at incubation temperatures slightly lower than customary incubation temperatures for mycobacterial cultures (2Brown BA, Wallace RJ Jr. Infections due to nontuberculous mycobacteria. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennet‘s principles and practice of infectious diseases. 6th Ed. Philadelphia, PA: Churchill-Livingstone, 2005Google Scholar). The growth of M. hemophilum also requires the presence of iron or hemin (factor X) in the medium (2Brown BA, Wallace RJ Jr. Infections due to nontuberculous mycobacteria. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennet‘s principles and practice of infectious diseases. 6th Ed. Philadelphia, PA: Churchill-Livingstone, 2005Google Scholar, 15Saubolle MA Kiehn TE White MH et al.Mycobacterium haemophilum: Microbiology and expanding clinical and geographic spectra of disease in humans.Clin Micro Rev. 1996; 9: 435-447Crossref PubMed Google Scholar). Therefore, the laboratory should be alerted if M. marinum or M. hemophilum are suspected on clinical grounds, and all skin, joint fluid and bone specimens should be incubated at 28–30°C as well as 35–37°C (III). Species identification is critical for selection of effective therapy and deciding whether to perform susceptibility testing. Knowledge of time required for growth in culture, along with the clinical presentation, may be helpful in formulating a preliminary identification (2Brown BA, Wallace RJ Jr. Infections due to nontuberculous mycobacteria. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennet‘s principles and practice of infectious diseases. 6th Ed. Philadelphia, PA: Churchill-Livingstone, 2005Google Scholar, 3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar). For example, M. chelonae, M. fortuitum and M. abscessus typically grow in culture within about 7 days (‘rapid growers’), and may cause skin and soft tissue infections or catheter-associated bacteremia. At present, commercially available NTM species identification methods require growth of mycobacteria in culture. Commercial DNA probes are available for some of the NTM including MAC, M. kansasii and M. gordonae. High-performance liquid chromatography and PCR-based methods are also used to identify NTM species (3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar). The criteria for making a firm diagnosis of invasive NTM infection vary with the involved site (3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar). Isolation of NTM from a normally sterile site such as blood or joint fluid generally offers conclusive proof of invasive disease. A biopsy showing the organism on stain and yielding it on culture is often the most secure and expeditious way to make a diagnosis of skin and soft tissue infection. The diagnosis of pulmonary infection, however, is more complex, as NTM can sometimes be cultivated from respiratory secretions without causing invasive disease. Criteria have been established to aid clinicians in deciding whether invasive lung infection is present (3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar). These criteria have been primarily developed for immunocompetent hosts with sputum or bronchoscopic isolates of MAC (3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar). The applicability of these criteria to transplant patients or to infection with other species of NTM is not proven, but they nevertheless provide a useful guide for assessing whether an isolate is clinically significant. In essence, the criteria (Table 1) propose that invasive pulmonary disease with NTM can only be reliably diagnosed when, in a symptomatic individual, radiographic evidence of chest disease (nodular or cavitary opacities, or multifocal bronchiectasis with multiple nodules) is supported by histological evidence of tissue invasion, isolation of the organism in large quantities or persistent isolation of the organism over time (3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar). M. hemophilum should be considered if a specimen is AFB smear positive but has no growth on routine (unsupplemented) mycobacterial culture media.Table 1American thoracic society/infectious diseases society of America criteria for diagnosing NTM lung diseaseClinical (both required)1. Pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution computed tomography scan that shows multifocal bronchiectasis with multiple small nodules, and2. Appropriate exclusion of other diagnosesMicrobiologic1. Positive culture results from at least two separate expectorated sputum samples. If the results from one are nondiagnostic, consider repeat sputum AFB smears and cultures, or2. Positive culture result from at least one bronchial wash or lavage, or3. Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) and positive culture for NTM, or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputum sample or bronchial washing that is culture positive for NTM Open table in a new tab Rifabutin, clarithromycin and azithromycin are effective prophylactic agents for MAC in individuals with AIDS (16Nightingale SD Cameron DW Gordin FM et al.Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS.N Engl J Med. 1993; 329: 828-833Crossref PubMed Scopus (376) Google Scholar, 17Pierce M Crampton S Henry D et al.A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients advance acquired immunodeficiency syndrome.N Engl J Med. 1996; 335: 384-391Crossref PubMed Scopus (277) Google Scholar, 18Havlir DV Dubé MP Sattler FR et al.Prophylaxis against Mycobacterium avium complex with weekly azithromycin, daily rifabutin or both.N Engl J Med. 1996; 335: 392-398Crossref PubMed Scopus (299) Google Scholar) (AI). Prophylaxis has not been systematically studied for other NTM species. In lung transplant recipients, there is emerging evidence that NTM colonization pretransplant may be associated with overt NTM disease posttransplant (19Kesten S Chapparo C Mycobacterial infections in lung transplant recipients.Chest. 1999; 115: 741-745Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Patients with cystic fibrosis undergoing lung transplantation and known to be colonized with rapidly growing mycobacteria should be considered for posttransplant chemoprophylaxis with azithromycin to prevent surgical site infections (III). Similarly, patients infected or colonized with MAC prior to lung transplant should be considered for multidrug MAC therapy prior to lung transplantation (III). For other situations, there is insufficient evidence to recommend routine prophylaxis (III). The treatment of NTM infections is complex and in constant evolution. The preferred therapies vary according to species, so it is critical to have accurate identification to initiate empiric therapy and determine the need for susceptibility testing (III). Susceptibility testing is generally only available at reference laboratories. The National Committee of Clinical Laboratory Standards (NCCLS) recently published tentative guidelines for such testing (20NCCLS: Susceptibility testing of Mycobacteria, Nocardia and other Aerobic Actinomycetes. Approved Standard, Wayne PA: NCCLS:2003. Document No. M24-A.Google Scholar). Susceptibility testing is generally recommended for all species of rapidly growing mycobacteria (III). Limited susceptibility testing is recommended by the NCCLS for M. avium complex (clarithromycin) and M. kansasii (rifampin), especially in patients who have received prior treatment (III). For MAC isolates, susceptibility testing of the antituberculous agents is not recommended because of the lack of correlation between testing results and clinical outcomes. The treatment of infections due to NTM may be complicated by interactions between immunosuppressive drugs and rifamycins. The rifamycins have excellent activity against many NTM, but they are potentially hepatotoxic and caution is advised when using them in patients with liver transplants or reduced hepatic function. The rifamycins are also powerful inducers of the microsomal enzymes that metabolize cyclosporine, tacrolimus and sirolimus. Thus, it may be necessary to increase levels of immunosuppressive drugs two- or threefold, or even higher, to maintain adequate concentrations and prevent emergence of mycobacterial resistance (21Finch CK Chrisman CR Baciewicz AM Self TH Rifampin and rifabutin drug interactions: An update.Arch Int Med. 2002; 162: 985-992Crossref PubMed Scopus (208) Google Scholar) (AIII). If adequate concentrations of immunosuppressive drugs cannot be maintained, it may be necessary to choose an alternative agent. Rifabutin is a less potent inducer of CYP3A4 than rifampin and it appears to have less of an effect on cyclosporine and tacrolimus serum concentrations than rifampin. Rifabutin has been shown to be as effective as rifampin for mycobacterial infections due to MAC and MTB and for these infections should probably be the preferred agent in transplant patients (3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar, 22McGregor MM Olliaro P Wolmarons L et al.Efficacy and safety of rifabutin in the treatment of patients with newly diagnosed pulmonary tuberculosis.Am J Resp Crit Care Med. 1996; 154: 1462-1467Crossref PubMed Scopus (87) Google Scholar) (I). Clarithromycin has an opposite effect on the concentrations of calcineurin inhibitors, blocking their metabolism and raising their levels (23Ferrari SL Goffin E Mourad M Wallemacq P Squifflet J-P Pirson Y The interaction between clarithromycin and cyclosporine in kidney transplant recipients.Transplantation. 1994; 58: 725-727Crossref PubMed Scopus (39) Google Scholar). Azithromycin has much less of an effect than clarithromycin on cyclosporine and tacrolimus levels, but it may be still prudent to closely monitor levels of calcineurin inhibitors whenever azithromycin is initiated (III). When clarithromycin and rifamycins are used together, clarithromycin will partially, but not completely offset the effect of the rifamycin on the calcinuerin inhibitor (24Plemmons RM McAllister K Garces MC Ward RL Osteomyelitis due to Mycobacterium haemophilum in a cardiac transplant patient: Case report and analysis of interactions among clarithromycin, rifampin and cyclosporine.Clin Infect Dis. 1997; 24: 995-997Crossref PubMed Scopus (35) Google Scholar). Overall, when macrolides and rifamycins are used together for NTM treatment in patients on calcineurin inhibitors, the preferred combination is azithromycin plus rifabutin. However, this regimen requires balancing drug–drug interactions, tolerability and antimicrobial potency, with close monitoring of calcineurin inhibitor levels. Surgical excision has been used to treat localized skin infections caused by NTM (3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar). Because transplant recipients have a tendency to develop disseminated infection, surgery as a therapeutic modality should be reserved for relatively small skin lesions or those that are not responding to chemotherapy (III). Surgical drainage should be considered in patients with abscess formation. In patients with mycobacteremia or catheter-associated mycobacterial infections, the catheter should be removed to optimize likelihood for cure (III). The development of resistance during therapy is a recognized problem when mycobacterial infections are treated with only a single active drug (25Wallace Jr, RJ Tanner D Brennan PJ Brown B Clinical Trial of clarithromycin for cutaneous (disseminated) infection due to Mycobacterium chelonae.Ann Intern Med. 1993; 119: 482-486Crossref PubMed Scopus (223) Google Scholar, 26Chaisson RE Benson CA Dube MP et al.Clarithromycin therapy for bacteremic Mycobacterium avium complex disease.N Engl J Med. 1994; 121: 905-911Google Scholar). Mutational resistance has been described for clarithromycin, azithromycin, rifpampin and amikacin when used for NTM infections (3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar). Thus, it is generally advisable to initiate therapy with more than one active agent. In cases where the illness is life threatening or the infectious burden of organisms is high, treatment with three or more drugs may be necessary (III). The recommended drugs for treatment are listed in Table 2. First line drugs are the best available agents. Second line drugs have good in vitro activity, but are either more toxic than the first line drugs or are treatments for which there is little or no accumulated clinical experience in transplant recipients. Third line drugs are those that possess activity only against a minority of isolates. The recommendations have been abstracted from recently published society guidelines, reviews and clinical trials (2Brown BA, Wallace RJ Jr. Infections due to nontuberculous mycobacteria. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennet‘s principles and practice of infectious diseases. 6th Ed. Philadelphia, PA: Churchill-Livingstone, 2005Google Scholar, 3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar, 27Campbell IA, Jenkins PA. Mycobacterium kansasii. In: Schlossberg D, ed. Tuberculosis and Nontuberculous Mycobacterial Infections, 4th Ed. Philadelphia: Saunders, 1999: 380–385.Google Scholar, 28Shafran SD Singer J Zarowny DP et al.A comparison of two regimens for treatment of Mycobacterium avium complex bacteremia in AIDS: Rifabutin, ethambutol and clarithromycin versus rifampin, ethambutol, clofazamine and ciprofloxacin.N Engl J Med. 1996; 335: 377-383Crossref PubMed Scopus (281) Google Scholar, 29Bernard L Vincent V Lortholary O et al.Mycobacterium kansasii septic arthritis: French retrospective study of 5 years and review.Clin Infect Dis. 1999; 29: 1455-1460Crossref PubMed Scopus (49) Google Scholar). Although clinical information on the use of either linezolid (30Brown-Elliot BA Wallace Jr, RJ Blinkhorn R Crist CJ Mann LB Successful treatment of disseminated Mycobacteriuim chelonae infection with linezolid.Clin Infect Dis. 2001; 33: 1433-1434Crossref PubMed Scopus (79) Google Scholar) or tigecyline (31Fernández-Roblas R Martín-de-Hijas NZ Fernández-Martinez AI García-Almeida D Gadea I Estaban J In vitro activities of tigecycline and 10 other antimicrobials against nonpigmented rapidly growing mycobacteria.Antimicrob Agents Chemother. 2008; 52: 4184-4186Crossref PubMed Scopus (36) Google Scholar, 32Wallace Jr, RJ Brown-Elliott BA Crist CJ Mann L Wilson RW Comparison of the in vitro activity of the glycylcycline tigecycline (formerly GAR-936) with those of tetracycline, minocycline, and doxycycline against isolates of nontuberculous mycobacteria.Atimicrob Agents Chemother. 2002; 46: 3164-3167Crossref PubMed Scopus (194) Google Scholar) is limited, good in vitro activity has led to these drugs’ inclusion as a second line option for the treatment of rapid growing mycobacteria. Ultimately, the decision about which drugs to use must be made on clinical grounds. Even for infection with organisms such as MAC, for which considerable clinical trial data is available in patients with HIV infection, many questions remain. Thus, in an individual patient, there may be uncertainty about whether to treat MAC infection with a standard three drug regimen that includes a macrolide, a rifamycin and ethambutol, or choose a potentially less toxic regimen that omits the rifamycin or replaces with a second line drug such as a fluoroquinolone. In patients with AIDS, over a relatively short follow-up period of 6 months, a two drug regimen of clarithromycin and ethambutol yielded an equivalent clinical response to a three drug regimen that added rifabutin. However, the two drug regimens were associated with a higher rate of resistance development (33Gordin FM Sullam PM Shafran SD et al.A randomized placebo-controlled study of rifabutin added to a regimen of clarithromycin and ethambutol for treatment of disseminated infection with Mycobacerium avium complex.Clin Inf Dis. 1999; 28: 1080-1085Crossref PubMed Scopus (120) Google Scholar). Based on these data, in SOT patients it may be prudent to favor the more intensive (e.g. three drug) regimens in patients who are critically ill, appear to have high organism loads or are very heavily immunosuppressed and reserve the less intensive (e.g. in this instance two drug) regimens for more stable patients with lesser burden of mycobacterial disease.Table 2Recommended treatment regimens for NTMPathogenRecommended regimen (see reference [3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar] for additional discussion)Other drugs that may be activeRoutine susceptibility testing recommended in previously untreated patients?Additional commentsM. avium complexAzithromycin 250–300 mg/day plus rifabutin 300 mg/day plus ethambutol 15 mg/kg/day.Rifampin, clarithromycin, amikacin, streptomycin, moxifloxacinYes—clarithromycin onlyAddition of aminoglycoside three times weekly early in therapy may increase efficacy. Adjunctive measures (e.g. mucus clearance, smoking cessation) may be helpful.M. kansasiiRifabutin 300 mg/day plus ethambutol 15 mg/kg/day plus isoniazid 5 mg/kg/day (max 300 mg/day) plus pyridoxine 50 mg/day.Rifampin, clarithromycin, azithromycin, moxifloxacin, streptomycin, amikacin, sulfamethoxazoleYes—rifampin only. If resistant to rifampin, additional drugs should be tested.Most strains of M. kansasii are inhibited by concentrations of isoniazid achievable in serum even though may be reported as resistant to isoniazid.M. marinumAzithromycin 250 mg/day plus ethambutol 15 mg/kg/day. Consider addition of rifabutin for extensive disease.Rifampin, rifabutin, clarithromycin, sulfonamides, trimethoprim-sulfamethoxazole, doxycycline, minocyclineNo, unless patient clinically failing treatment.No comparative trials of treatment regimens.Consider surgical debridement of disease involving closed spaces of hand, or if treatment failure.M. hemophilumAzithromycin 250–300 mg/day plus rifabutin 300 mg/day plus ciprofloxacin 500–750 mg bid.Clarithromycin, rifampin, doxycycline, sulfonamidesNo standardized susceptibility methods; interpret susceptibility data with caution.M. fortuitumBased on in vitro drug resistance data. Two drugs generally recommended.Clarithromycin, azithromycin, levofloxacin, moxifloxacin, doxycycline, minocycline, sulfonamides, amikacin, imipenem, tigecyclineYesAll isolates contain an inducible erythromycin methylase gene that confers susceptibility to macrolides; use macrolides with caution (reference [3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar]).M. chelonaeBased on in vitro drug susceptibility data. Two drugs generally recommended, typically azithromycin plus one other agent.Clarithromycin, Azithromycin, linezolid, tobramycin, imipenem, tigecyclineYesSurgery should be considered for abscess formation or if drug therapy difficult; infected foreign bodies should be removed.M. abscessusBased on in vitro drug susceptibility data. Typically azithromycin plus a parenteral agent, or two parenteral agents.Azithromycin, clarithromycin, amikacin, cefoxitin, linezolid, imipenem, tigecyclineYesLimited data on oral regimen of macrolide plus linezolid. M. abscessus lung disease difficult to cure. Open table in a new tab Amikacin and other aminoglycosides have excellent in vitro activity against many NTM. In transplant recipients receiving nephrotoxic immunosuppressive regimens, these agents should be used sparingly and reserved for situations in which less toxic therapies are either not available or have failed. Aminoglycosides are included in Table 1 as possible first line drugs for rapid growing mycobacteria because these organisms often demonstrate a high degree of resistance to other antimicrobials (3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar). Table 3 lists the dosing schedules for drugs in Table 2.Table 3Dosing regimens and drug interactionsDrugAdult doseDrug interactionDose alteration for renal dysfunction1The degree of alteration for renal dysfunction reflects the creatinine clearance at which dose reduction is first necessary: It is minimal when dose reduction is only necessary for CrCl ≤10 cc/min, mild for CrCl ≤ 30 cc/min, moderate for CrCl ≤50 cc/min and major for CrCl ≤ 70 cc/min.Clarithromycin500 mg BID PO2Three times weekly dosing has been used successfully to treat MAC in patients without HIV infection (34). Doses used have been clarithromycin (1000 mg), azithromycin (600 mg), ethambutol (25 mg/kg) and rifabutin (300–600 mg) (30).Calcineurin inhibitors and rifamycinsMildAzithromycin250–300 mg daily PO2Three times weekly dosing has been used successfully to treat MAC in patients without HIV infection (34). Doses used have been clarithromycin (1000 mg), azithromycin (600 mg), ethambutol (25 mg/kg) and rifabutin (300–600 mg) (30).Calcineurin inhibitors and rifamycinsNone1200 mg/week (prophylaxis)Ethambutol15 mg/kg/day PO2Three times weekly dosing has been used successfully to treat MAC in patients without HIV infection (34). Doses used have been clarithromycin (1000 mg), azithromycin (600 mg), ethambutol (25 mg/kg) and rifabutin (300–600 mg) (30).MildRifampin600 mg/daily PO or IVCalcineurin inhibitors and macrolidesNoneRifabutin150–300 mg/day POCalcineurin inhibitors and macrolidesNoneCiprofloxacin500–750 mg BID POCyclosporine (mild)ModerateLevofloxacin500–750 mg QD PO or IVNo dosage adjustment for levofloxacin or cyclosporine required when administered concomitantlyModerateMoxifloxacin400 mg QD PO or IVNoneAmikacin10–12 mg/kg3In most instances it is preferable to administer streptomycin and aminoglycosides three times a week in transplant recipients who are over age 50 or taking calcineurin inhibitors.Potentiation of renal toxicityMajorIM or IVStreptomycin0.5–1.0 g IM or IV3In most instances it is preferable to administer streptomycin and aminoglycosides three times a week in transplant recipients who are over age 50 or taking calcineurin inhibitors.MajorIsoniazid300 mg/day POMinimalClofazamine100–200 mg daily PONoneEthionamide250 mg BID (start) POMay increase rifabutinMild500 mg BID (max) POToxicityCycloserine250–500 mg BID POModerateCapreomycin500–1000 mg IM five times weekMay potentiate renalMajorIMToxicityMinocycline100 mg BID PONoneDoxycycline100 mg BID PONoneTigecycline100 mg IV × 1, then 50 mg IV q 12 hNoneSulfamethoxazole or TMP/SMX1.0 g q 8–12 h POModerateCefoxitin8–12 gm/day IV in divided dosesModerateImipenem500 mg q 6 h IVMajorTobramycin5 mg/kg daily IV or IM3In most instances it is preferable to administer streptomycin and aminoglycosides three times a week in transplant recipients who are over age 50 or taking calcineurin inhibitors.May potentiate renal toxicityMajorTMP–SMX, trimethoprim–sulfamethoxazole.1 The degree of alteration for renal dysfunction reflects the creatinine clearance at which dose reduction is first necessary: It is minimal when dose reduction is only necessary for CrCl ≤10 cc/min, mild for CrCl ≤ 30 cc/min, moderate for CrCl ≤50 cc/min and major for CrCl ≤ 70 cc/min.2 Three times weekly dosing has been used successfully to treat MAC in patients without HIV infection (34Griffith DE Brown BA Cegielski P Murphy DT Wallace Jr, RJ Early results (at 6 months) with intermittent clarithromycin-including regimens for lung disease due to Mycobacterium avium complex.Clin Infect Dis. 2000; 30: 288-292Crossref PubMed Scopus (97) Google Scholar). Doses used have been clarithromycin (1000 mg), azithromycin (600 mg), ethambutol (25 mg/kg) and rifabutin (300–600 mg) (30Brown-Elliot BA Wallace Jr, RJ Blinkhorn R Crist CJ Mann LB Successful treatment of disseminated Mycobacteriuim chelonae infection with linezolid.Clin Infect Dis. 2001; 33: 1433-1434Crossref PubMed Scopus (79) Google Scholar).3 In most instances it is preferable to administer streptomycin and aminoglycosides three times a week in transplant recipients who are over age 50 or taking calcineurin inhibitors. Open table in a new tab TMP–SMX, trimethoprim–sulfamethoxazole. Most NTM disease in SOT patients requires prolonged treatment (2Brown BA, Wallace RJ Jr. Infections due to nontuberculous mycobacteria. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennet‘s principles and practice of infectious diseases. 6th Ed. Philadelphia, PA: Churchill-Livingstone, 2005Google Scholar, 3Griffith DE Aksamit T Brown-Elliot B et al.An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4301) Google Scholar). Reductions in immunosuppression doses may be necessary to sufficiently clear the infection. Pulmonary disease due to MAC or M. kansasii should be treated until sputum cultures obtained over 12 consecutive months are negative; this is also a reasonable goal for M. abscessus pulmonary disease. Skin and soft tissue infections generally require treatment of at least 3–6 months duration, depending on severity and structures involved. Close clinical follow-up after discontinuation of antimicrobial agents is important. Appendix II also notes major drug interactions with immunosuppressive agents and other antimycobacterial drugs, as well as the degree of dose adjustment required for renal dysfunction. These are presented as a general guide and not intended to replace the package insert or standard pharmacological references. Prospective trials of treatment or prevention of infections caused by NTM are probably not feasible in transplant populations due to the low incidence of the infections. Risk factors for the development of these infections are poorly defined. Studies of risk factors for these infections would provide useful information, but would require the compilation of data from multiple centers over a period of many years. The management of patients with NTM infections will be aided by development of novel antimicrobial agents with potent activity, as well as general advances in their clinical microbiology especially in the areas of rapid diagnosis and susceptibility testing. Subramanian AK.: Grant/Research Support, Pfizer, Chimerix, Adamas; Consultant/Scientific Advisor, Viropharma. Dorman SE.: The author has nothing to disclose.