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Infections Due to Non-Tuberculous Mycobacteria (NTM)

Posted on: Wednesday, 24 November 2004, 03:00 CST

The membership list of genus mycobacterium is ever expanding and it has grown to 95 in year 2003. While leprosy and tuberculosis are specific diseases caused by mycobacteria, other members are usually saprophytes but can be opportunistic and at times deadly pathogens. These other mycobacteria are referred to as atypical mycobactcria, non-tuberculous mycobacteria (NTM) or mycobacteria other than tubercle bacilli (MOTT). These organisms can produce localized disease in the lungs, lymph glands, skin, wounds or bone. Occasionally they may produce disseminated disease. Of the more than 90 known species of NTM, about one third have been associated with disease in humans. The species causing human disease are : Mycobacterium avium, M. intracellulare, M. kansasii, M. paratuberculosis, M. scrofulaceum, M. simiae, M. habana, M. interjectum, M. xenopi, M. heckeshornense, M. szulagai, M. fortuitum, M. immunogenum, M. chelonae, M. marinum, M. genavense, M. haemophilum, M. celatum, M. conspicuum, M. malmoense, M. ulcerans, M. smegmatis, M. wolinskyi, M. goodii, M. thermoresistible, M. neoaurum, M. vaccae, M.paluster, M. elephantis, M. bohemicam and M. septicum. Isolation of the mycobacterium from representative specimens and their rapid identification is very important as the treatment strategy for tuberculosis and other mycobacterioses is different. Several biochemical, chemical (lipid) and molecular techniques have been developed for rapid identification of these species. Along with suggestive clinical features, poor response to antitubercular treatment and repeated isolation of the organisms from the clinical specimens these techniques can help in establishing correct diagnosis. Further, many drugs like rifampicin, rifabutin, ethambutol, clofazimine, amikacin, new generation quinolones and macrolides effective against mycobacterial infections are available that can be used in appropriate combinations and dosage to treat these infections.

Key words Atypical mycobacteria - MOTT - non-tuberculous mycobacteria

Genus Mycobacterium has 95 well characterized species1. Over the centuries two well known mycbacterial species, namely, Mycobacterium tuberculosis and M.leprae have been the known causes of immense human suffering. Most of other mycobacteria are present in the environment as saprophytes. Their pathogenic potential has been recognized since the beginning of last century2. These organisms in the past have been called atypical mycobacteria. the term first coined by Pinner3. These have been increasingly recognised to cause pulmonary and non pulmonary infections3-8, which is in part explained by the increase in the number of susceptible/ immunocomproinized individuals such as those suffering from acquired immuno deficiency syndrome (AIDS) and is also due to better recognition of their role through more sensitive and specific techniques9,10. The diseases caused by these mycobacteria have varied manifestations, are not usually transmitted from man to man and have been broadly grouped as mycobacterioses. In the immunocompromised individuals the infections clue to non- tuberculous mycobacteria (NTM) have been observed to be an important cause of morbidity and mortality in western countries9. Besides being known as atypical, these mycobacterial species have been given various names like anonymous, nontuberculous, environmental, opportunistic and mycobacteria other than tubercle bacilli (MOTT). None of these terms have been universally accepted and the name NTM seems to be more acceptable. It has been endorsed by American Thoracic Society (ATS) in their statement9,10.

Distribution in the environment

The distribution of NTM and the incidence of disease caused by them is perhaps not fully understood in most parts of the world. NTM are widely distributed in nature" and have been isolated from natural water, tap water, soil, water used in showers and surgical solutions. In United States most of isolates were M. avium, M. kansasii and M. fortuitumu. There have been some reports from Japan13, UK14 and India15-21. In most of Indian studies M. tuberculosis has been found as major cause of mycobacterial infections and the proportion of NTM has been considered low. Species like M.fortuitum, M. avium, M. scrofulaceiim etc., have been isolated in different studies17-21. As the culture with strict criteria is still not routinely done in most parts of India and there is a tendency to ignore such isolates as cotaminants, it would be difficult to comment on the exact magnitude of the problem. Though M.tuberculosis has been observed to be the main secondary infection in the reported cases of AIDS in India22 the future scenario is yet to unfold.

Predisposing factors

It is a common observation that environmental mycobacteria cause disease in individuals who offer some opportunity due to altered local or systemic immunity3,4,9,10,23-26. Chronic obstructive pulmonary diseases, emphysema, pneumoconiosis, bronchiectasis, cystic fibrosis, thoracic scoliosis, aspiration due to oesophageal disease, previous gastrecromy and chronic alcoholism are some of conditions which have been linked to disease due to NTM. While the reasons may be less clear in conditions like adenitis in children, such factors may be quite obvious in other conditions like bronchiectasis, surgical procedures, injections, break in skin surface due to wounds and generalized immune deficiency states like AIDS, use of immunosuppressive agents as used in transplant patients etc9,10. The mechanisms of pathogenesis of NTM are not very clear and have not been adequately investigated. The lipid rich outer envelope of the organisms may be important as first defence but specific moeities on the surface may be the important factors. Very low CD4 counts in AIDS patients and defective cytokine response(s) have been linked to severe infections due to M.avium from the common sources like potable water26.

Clinical manifestations

Of the 95 known species of mycobactcria, nearly one third have been observed to be associated with disease in humans. The species of NTM associated with human disease are : M.avium, M. inlracellulare25-30, M.kan.sasii3133, M.paratuberculsis34-36, M.scrofulaceum31', M.simiae7,8 M.habana7, M.interjeclum38, M.xenopi3941, M.heckeshornense42, M.szulga43, M.fortuitum18,44,45, M.immunogenum46, M.chelonae20,47, M.marinum48-50, M.genavense51,52,M. bohemicum53,M.haemophilum54-56, M.celalum57, M.conspicuum58, M.malmoenxe59,60, M.ulcerans61, M.smegmatis62, M.wolinskyi and M.goodii63, M.thermoresislible64, M.neoaurum65, M.vaccae66, M.palustre67, M.elephantis68, and M.septicum68 and M.nonchromogenicum70.

Non-tuberculous mycobactcria have been reported to cause localized or disseminated disease depending on local predisposition and/or degree of immune deficit3,4-9. In non-HIV patients, different NTM may cause localized pulmonary disease, adenitis, soft tissue infections, infections of joints/bones, bursae, skin ulcers and generalized disease in individuals like leukaemia, transplant patients etc3,4,9. In AIDS patients the manifestations may range from localized to disseminated disease9,71. Clinical features will include local organ specific signs and symptoms to persistent high grade fever, night sweats, anaemia and weight loss in addition to nonspecific symptoms of malaise, anorexia, diarrhoea, myalgia and occasional painful adenopathy.

(a) Pulmonary infections duc Io NTM: M.aviumintracellulare complex (MAC) strains have been a major cause of pulmonary and other infections in the pre-AlDS era also9,10. MAC infections were commonly seen in chronic bronchitis, bronchicctasis and in chronic obstructive airway disease in the pre-AIDS era in geriatric patients. Since long, M. kansasii has been considered an important cause of pulmonary disease4,9. M.scrofiilaceuni has been shown to be the cause of localized pulmonary infections9,10. M. kansasii, an unusual bacterium with optimal growth temperature of 45 C has been encountered as a pathogen in patients with other underlying lung diseases39-41. One instance of an outbreak of pulmonary disease due to this organism from hot water supply of a hospital has been reported9. M.simiae3,4,9, M.habaiuf, M.szulgai19,43 M.forluiliim(TM), M.vaccae66 , M.malmoense59,60 are other pathogens reported to be associated with pulmonary infections. M.heckeshornense is a new slow growing species of mycobactcria which has been shown to be associated with cavitary disease in immunocompetent individuals42.

(b) Lymph glands: MAC isolates have been reported to be the cause of lymphadenitis9,10. M. scrofiilaceiim whose distribution in nature closely resembles that of M.avhim, has also been found to be a common cause of cervical lymphadenitis in western countries9 and has been reported from India as well-'. M.bohemicuim53, M.sziilgain and M. interjectiim, a new species resembling M.scrofuhtceiim have been isolated (Vom eases of lymphadenitis21.

(c) Bone, joints and hursae: MAC isolates, M.szulgai43 M.fortuitum3,4,9 M.non-chroniogeniciim and M.kansasii have been reported to be the cause of bone and joint infections9.

(d) Cutaneous infections: M.szulgai4,3, M.marinum3,4,48-50 and M.vaccae66 have been reported to be a cause of skin infections. M.nntriniiin species has been recognized as a causative organism of swimming pool granuloma or fish tank granuloma.lt causes papular lesions in the extremities and may be confused with sporotrichosis3,4,48-560 M.\ulcerans is established cause of buruli ulcer61. M.vaccuehb has also been reported to be a cause of skin infections.

(e)Wound infection and sepsis: M. fortuitum causes pyogenic lesions in the soft tissue, joints, bursae and injection abscesses3,4,9,10. While M.chelonae abscessus is a well known cause of wound infections47, a new related species M.imimunogenum has been recently been recognized as a cause of sepsis46. M. mnarinum also causes infections of bones/joints/tendon sheaths specially in AIDS patients50. M.smegmatis62, M. wolinskvi and M. goodii 63 , M. thermoresistible64 and M. palustre67 have been reported to cause wound infections and also bacteraemia. Members of M.terrae complex (M. terrae, M. nonchromogenicum and M. triviale) may be associated with mycobacterial disease. Occasionally M.nonchrmogenicum and M.chelonae have been identified as causes of acupuncture induced infections70. M.seplicum a new rapidly growing species has been reported to be associated with catheter related bacteremia69.

(f) Crohn's disease'. Advances in molecular techniques have by and large established the aetiology of regional ileitis ( Crohn's disease) due to M. paratiibercnlosis , a species closely related to M. avium. Members of this species have been reported to be the causative agents of enteritis (.lohne's disease) in cattle, goats and sheep and can be characterized rapidly with the help of molecular techniques1435. By using gene probes and in situ hybridization strategy M.paratnherciilosia has been linked to the aetiology of Crohn's disease in man35,36 with reasonable certainty.

(g) Disseminated disease in immimocompromized individuals: Important NTM causing disseminated disease in immunocompromizcd cases including:

(i) MAC: Unlike tuberculosis, the strains of MAC are pathogens of very low virulence and despite being commonly found in the environment rarely cause disease11,26. In western countries, infections due to members of MAC have been frequently reported in AIDS patients27-30. Certain specific serotypes of M.avium9,24 plasmid containing M.avium29. and in some European and African countries certain restricted fragment length polymorphism (RFLP) types of M. avium have been found to be more commonly isolated from AIDS patients24,30. As compared to M. Intracellulare, M. avium appears to have greater predilection for causing disease in AIDS cases24. Further, these may cause mixed infections along with other NTM such as M.kansasii21 and M.simiae28 etc. MAC usually produce clinical disease only when the CD4 count is very low (<50 cells/ml) towards the end of natural history of disease, seen in 4 to 5 per cent of HIV infected patients. MAC strains isolated from AIDS cases in Africa have been shown to be different from those of western strain24. In AIDS patients, the portal of entry of MAC is thought to be mainly through the gut26. Persistent high grade fever, night sweats, anaemia and weight loss in addition to nonspecific symptoms of malaise, anorexia, diarrhoea, myalgia and occasional painful adenopathy are common signs and symptoms associated with MAC disease in AIDS cases.

(ii) Infections due to M.kansasii have become more important in AIDS cases and are common in individuals with severe immunodeficiency state27,31-33. While M.kansasii isolates are generally more resistant to antimicrobial agents than M. tuberculosis, therapeutic responses to multiple drug therapy have been usually found to be good6,33.

(iii) M. scrofulaceum (M. marianum) may cause adult pulmonary disease and disseminated infections in patients with AIDS9,37.

(iv) M. xenopi causes disease with clinical manifestations similar to those of MAC in advanced AIDS patients40. One instance of an outbreak of pulmonary disease due to this organism from hot water supply in a hospital has been reported9.

(v) M. simiae has been recognized as an agent of human pulmonary disease in AIDS as well as non-AIDS cases3,4,9,28.

(vi) M. fortuitum-M. chelonei complex: These rapidly growing organisms have been frequently isolated from soil in different countries including India, and are well known cause of soft tissue infections like injection abscesses and wound infections4-8,9,18- 20,44-17. These organisms can also cause generalized disease in immunocomprornized hosts and present as subcutaneous nodules; similar picture may be shared by other NTM like M. kansasii9,44.

(vii) M. genavense: These organisms initially isolated from AIDS patients with advanced disease, have been reported from many countries51-52. These organisms need enriched medium with mycobactin J and often grow after prolonged incubation periods. Weight loss, fever, abdominal pain and diarrhoea are the common presenting symptoms in infected individuals.

(viii) M. haemophihtm is a fastidious slow growing organism and requires enriched chocolate agar, haemin or ferric ammonium citrate for its growth. It grows well at a comparatively lower temperature of 37deg;0C. It has been recognized as a cause of life threatening infections in immunocompromised individuals like AIDS cases and bone marrow transplant recipients54-56.

(ix) Several other species of NTM namely M. celaium51, M. conspicuun58, and M. malmoense59,60 have been isolated from AIDS patients.

Diagnostic procedures

Due to ubiquitous presence of NTMs in the environment, establishing the causative relationship depends upon appropriate sampling and strict laboratory practices as contamination needs to be ruled out. These issues have been extensively debated and some broad guidelines are available9,10.

(a) Diagnosis of pulmonary disease: The clinical presentation of the pulmonary disease due to NTM may be like tuberculosis. Infection due to NTM should be suspected specially in cases in whom initial antitubercular treatment (ATT) has not produced the desired response. This should be corroborated by repeated isolation of the same NTM from sputum or bronchoalveolar lavage. Infection with NTM may be asymptomatic or subacute or chronic illness resembling pulmonary tuberculosis. While radiological appearances are usually like in tuberculosis with cavities and infiltrates, thin walled cavities with lesser parenchyma! infiltrates have been described as suggestive features 9,10, The changes may be uni- or bilateral and more than one lobes may be involved. High resolution computed tomography (CT) scanning may show clusters of small nodules associated with areas of bronchiectasis in the lower and middle zones. Pleural thickening and effusion is uncommon. Bronchoscopy is very useful to obtain lavage samples for culture and to obtain biopsy samples. Tissue biopsy showing granulomatous inflammation, which may or may not contain acid fast bacilli (AFB) and a positive culture, even if the sample was smear negative is considered as most appropriate strategy to establish the diagnosis.

(b) Other clinical forms: Infections with NTM should he considered in the differential diagnosis of any chronic infection, pyrcxia of unknown origin and localized clinical disease (abscess, ulcers, nodules, infiltrates etc.) not responding to antibiotics. Attempt lhcn should be made to repeatedly demonstrate and isolate the NTM from such lesions using most stringent criteria and precautions.

(c) Strategy to diagnose NTM infections

As many of the NTM are not amenable to routine antituberculosis therapy, it is important to correctly identify the causative mycobacteria and if required determine their sensitivity profile. Main strategic points are:

(i) Specimens: As far as possible the specimen should be directly from lesion/organ concerned9,10. For such purposes biopsies and procedures like bronchoalvcolar lavage have advantages. As NTM are more sensitive to agents like sodium hydroxide, the decontamination has to be gentler than M.tubeculosis. In case of the disseminated infections such as in AIDS patients with CD4 count less than 50 cells/mm isolation of mycobacteria from peripheral blood or hone marrow has been reported to be quite useful72-73

(ii) Histopathological examination: Histopathology has been described to be useful specially for demonstration of granuloma for specimens from such as aspirates/ biopsies from bone marrow, liver or lymph nodes19. Histopathology was reported to be rapid and useful approach to diagnose infections due to MAC74. It may be advisable to include some m situ methods (antigen detection/gene probes) to confirm the histological diagnosis and aetiology directly with perhaps good speed and specificity.

(iii) Cultivation: Most of NTM can be grown on ordinary media for mycobacteria like Lowenstein-Jensen, Middlebrook and Dubos Broth/ Agar9,76 While organisms like M. hemophilum may have special requirements like hemin which may be obtained from blood containing media -chocolate agar or supplement of ferric ammonium citrate, M.ganavense and M.paratuberculosis will need media enrichment with mycobactin J. Radiometrie systems such as BACTEC medium or an agar based isolator system have been reported to be highly sensitive for cultivation of MAC3,4,9,12,73-77. Different incubation temperatures such as 30 C for M.ulcerans and M.marinum, 37 C for most pathogens, 45 C for M.xenope etc., will have to be selected depending upon the suspected organisms.

(iv) Identification of isolates by phenotypic characteristics: Growth rates, colony pigmentation and biochemical tests such as niacin production, nitrate reduction, twcen-80 hydrolysis, arylsulphatase, urease. tellurite reduction, thiophen2-carboxylic acid hydrazide (TCII) sensitivity, catalase (qualitative and quantitative), growth on MaConkcy agar, sodium chloride tolerance etc., are adequate to identify majority of clinically relevant mycobacteria78,79. This strategy is, however, time consuming and not conclusive for many isolates with variable characters. Analysis of the lipids of mycobacteria by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) has been \recommended as an alternate approach. When used along with easy software programmes for rapid analysis, isolates from liquid/ solid medium can be rapidly identified79,80.

Serotyping methods using serotypc specific sera have been described for the members of mycobacterium avium intraccllulare scrolulacecm (MAIS) complex73,81 Some serotypes9,73 of M. avium have been shown to be preferentially associated with disease in AIDS patients. Isoenzyme and protein clectropherogram based schemes for rapid identification and characterization of strains of M tuberculosis and NTM have been developed which may be used in small laboratory settings82,83. Based on measurement of immunological divergences in the structure of certain enzyme molecules like catalase84 and Superoxide dismutase85, techniques have been described for identification of mycobacteria. All these techniques need some specialized infrastructure and expertise but are not difficult to set up.

(d) Identification and characterization of NTM by molecular methods

Based on new knowledge about the gene sequences of mycobacteria many gene probes for the identification of isolates as well as amplification of specific gene fragments from the lesions and mycobacteriai culture isolates have been developed:

(i) Gene probes: For the identification of important NTM several gene probes have been developed and some are also commercially available77,86'88. With the help of these probes, growth from solid slants/ liquid cultures (e.g., BACTEC) can be rapidly and reliably identified.

(ii) Gene amplification methods: Polymerase chain reaction (PCR) techniques for detection and rapid identification of various clinically relevant mycobacteria have been developed which include methods for concentration and detection of M. avium, M. intracellulare from the clinical specimens89-91, M. paratuberculosis from clinical specimens and milk34,92. PCR assays using genus/ group specific amplification followed by restriction analysis have been described for the analysis of gene regions like 65 kD93,94 and rRNA gene region which have been found to be useful for identification of different mycobacteria95-99. Besides the PCR-RFLP approach, PCR amplification followed by hybridization has been reported to be useful for M. avium, M. chelonae, M. scrofulaceum, M. ulcerons and other mycobacteria100-103. Most important and specific approach mainly applicable at reference level involves the amplification of 1 6S rRNA followed by sequencing and several species have been identified for the first time using this approach104,105. These PCR methods can be used for direct detection of mycobacterial pathogens89-'92 as well as for rapid identification of clinical isolates of NTM93-104. Keeping in view the diversity of these organisms present in different geographical locations, it is important to evaluate the usefulness of these techniques in different settings.

(iii) DNA fingerprinting techniques: DNA fingerprinting techniques are of interest for identifying the subtypes/strains which would be more commonly associated with disease and also to investigate hospital acquired infections. Several DNA fingerprinting techniques have been tried to investigate the diversity in NTM106. Techniques like pulsed field gel electrophoresis107, random amplified polymorphic DNA (RAPD) - arbitrary PCR108, rRNA gene polymorphism109'111, typing using different insertion/repeat elements53,112,113, plasmid typing114 and single gene polymorphism115 have been successfully used for molecular typing of NTM. Insertion sequence based RFLP methods have been described to be useful for characterization of M. hemophilum55, M. avium112 as well as M. kansasii113. Using these methods certain RFLP types of M. avhim have been shown to be closely linked with disease in Europe and Africa2430. In India, such information about molecular types of NTM is very scanty.

(e) Determination of sensitivity profiles

The drug susceptibility profile of NTM is usually quite different from M.tuberculosis. Firstly, these organisms are usually sensitive at high concentrations of antitubercular drugs9,10, thus higher cut off values for deciding sensitivity/resistance are recommended. secondly, rapid growing mycobacteria are usually resistant to rifampicin and isoniazid (INH) whereas these are sensitive to drugs like new generation macrolides, cephalosporins and sulphones. The media usually recommended for the sensitivity screening of M. tuberculosis are used for NTM also. Other media like chocolate agar/ supplemcnted with ferric ammonium salts/mycobactins etc., will be needed for the sensitivity screening of fastidious species. Newer techniques like BACTEC and E test have been also found to be quite useful for sensitivity determination of rapid as well as slow growing NTM116-118. A new technique using recombinant strain of M.avium expressing beta- galactosidase to evaluate the activities of antimycobacterial agents inside macrophages lias been recently described119.

Management of NTM infections

Prophylaxis, medical and surgical treatment are (hrce important aspects of management of infections due to NTM9,10.

(a) Prophylaxis: Chemoprophylaxis with antimycobacterial drugs such as rifabutin has been recommended as primary prophylaxis by US Kood and Drug Administration to prevent and delay the onset of bacteraemia in AIDS patients120. There is a need to undertake studies in India to gain experience as profile of NTM causing infection in AIDS cases may be quite different from west and these infections may not be very important in our country.

(b) Surgical treatment: Surgical intervention has been recommended for the management of cervical lymphadenitis121 and also as a last resort in the management of localized infections due to drug resistant organisms122,123. Additional antimycobacterial treatment is also considered to be beneficial by some investigators whereas others disagree''. Surgical debridement is required in cases with accumulation of pus, dead tissue and is indicated in infections due to M.fortuitu-chelonae9 and in some cases of M.marinum49 as an adjunct to antimycobacterial treatment.

(c) Medical treatment: Medical treatment for NTM infections should be based on background information about sensitivity profiles9,10 which is very limited for NTM in India10. In United States, trends about the type of NTM isolates and their sensitivity profile have been studied over a long period of time and some broad principles of management have already been suggested by American Thoracic Society (ATS)9. An initial trial of 2 wk with ATT and repeated isolation of NTM is suggested as starting point. After that drug combinations and their dosage for treatment of various NTM infections differ significantly from tuberculosis. In general, dosage higher than recommended for the treatment of tuberculosis is recommended and requires intense monitoring of side effects of these drugs and combinations.

(i) Treatment of M. avium complex: A variety of compounds and their combinations have been reported to be effective against MAC strains124-140 The compounds showing activity against MAC include rifampicin, rifabutin, clofazimine, ciprofloxacin, amikacin, ethambutol, azithromycin, clarithromycin, telithromycin, and INH. While the experience about many of the above compounds is still experimental124,125,134-136, others have been tested in patients as well. Important regimens tried for the treatment of MAC infections include combinations of rifampin, isoniazid, ethambutol streptomycin9,126; ansamycins, clofazimine, ethambutol and isoniazid127; and amikacin, ethambutol, rifampin and ciprofloxacin128; rifabutin, clofazimine, INH, ethambutol129; rifampin, ethambutol, clofazimine and ciprofloxacin130. Clarithromycin and azithromycin have been considered two promising drugs for treatment of MAC infections131-134. Telithromycin has been observed to be active against M.avium in mice despite lacking significant activity in vitro and within macrophages135. Liposomized encapsulated clofazimine has been reported to be more effective than clofazimine alone in the experimental studies in mice136. A combination of clofazimine, rifampin, ethionamide, streptomycin and ethamutol has been observed to be effective against M. intracellulare infections139. Combination of amikacin and rifampicin which has been reported to be active against M.avium in mice, holds promise in management of infections in humans as well141. Except for ATS regimen9 the duration of other regimens is not certain and more trials need to be carried out.

(ii) Treatment of M. kanasasii infections: A regimen comprising of isoniazid, rifampin and ethambutol for a duration of 18-24 months has been recommended by ATS for the treatment of M. kansasii infections9. Sulphonamidcs and short course regimens for the treatment of rifampin resistant M. kansasii have been also been suggested142,143.

(iii) Treatment of other NTM infections: Regimens used for MAC infections have been generally reported to be good for the management of infections due to M.malmoense, M.simiae, M.szulgai and M.xenopi as well9. Rifampicin and ethambutol has been recommended for the management of M. xenopi, M. kansasii, M. fortiiitum. For infections due to M.marinum and M.szulgai a combination of trimethoprim- sulfamethoxazole and doxycycline has been suggested4,49. There is extensive information which suggests that commonly used antitubercular drugs like rifampin and INH have no role to play in the treatment of infections due to M. fortiiitum chelonei complex. Clarithromycin144 and combination of amikacin and doxycycline have been observed to be effective against M.fortnitum- chelonei infections145. For the treatmentof severe infections caused by these organisms cefoxitin, sulpha drugs and amikacin have been recommended9. For the treatment of M haemphilum infections, a regimen comprising of rifampin, clofazimine and clarithromycin has been de\scribed to be effective146. For the treatment of infections due to other NTM, no specific recommendations are available. Antimicrobial drug screening results should guide the management of such infections.

Recent developments relevant in improving the therapy of NTM infections

There are several new developments which may have long-term effect on improving the therapy of NTM infections . Moxifloxacin, telithromycin and quinupristin and dalfopristin have been reported to be more effective against M.marinum than other macrolides and antibiotics147. It has also been reported that mycothiol deficient mutants ofM.smegmatis are inhibited better by antibiotics'48. Further C-8 halogen and methoxy moeties have been shown to enhance fluoroquinolone activity even in gyrase resistant mutants140. A new protein involved in intrinsic resistance to quinolone has been identified150. Further studies need to be done to reach at some meaningful conclusions.

It may be unrealistic to imagine common mechanisms of susceptibility/resistance in these diverse organisms. Several studies have shown that the mechanisms of drug susceptibility in NTM are quite distinct from M.tuberculosis . While mutations in gene targets like rpoB have been found be responsible for resistance to rifampicin in most isolates of M.tuberculosis, these are much less important in case of NTM. Other mutations seen in drug-resistant isolates of M.tuberculosis are not frequently found in drug resistant NTM151-155. In general, mechanisms like alterations in the permeability at cell wall140 and efflux pumps appear to be far more important than mutations in the targets151"153. It would be appropriate to conclude that these mechanisms are by and large not well understood in NTM. More in depth studies for gaining better understanding of these mechanisms are required which may help in developing better diagnostics and therapeutics for the treatment of NTM infections.

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V.M. Katoch

Central JALMA Institute for Leprosy and Other Mycobacterial Diseases (ICMR), Agra, India

Received July 16, 2003

Reprint requests: Dr V.M. Katoch, Director. Central JALMA Institute for Leprosy & Other Myeohaeterial Diseases (ICMR), lajganj, Agra 280002, India

e-mail: jalma@sancharnct.in

rohinik@sancharnet.in

Copyright Indian Council of Medical Research Oct 2004

Source: Indian Journal of Medical Research

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