Mycobacterium kansasii

Authors: David E. Griffith DE, Richard J. Wallace, Jr., M.D.

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Microbiology

M. kansasii is a slowly growing species that is most closely related to M. marinum and M. szulgai. It produces rough buff-colored colonies that, after exposure to light, develop a yellowish pigmentation, because of the deposition of beta-carotene crystals. Isolates produce both catalase and nitrate reductase and hydrolyze Tween 80. Disease-producing strains are usually highly catalase-positive (23).

M. kansasii has long been considered morphologically homogeneous. Recent genetic studies have shown there is major genetic diversity among M. kansasii isolates recovered throughout the world (19, 20). Several DNA based studies have shown the presence of five subspecies among both environmental and human isolates of M. kansasii. One subtype, type I, appears to be the major pathogenic group while the other four are predominantly environmental isolates. Using DNA fingerprinting techniques that include pulsed field gel electrophoresis (PFGE) and major polymorphic tandem repeat (MPTR) probe sequence, most type I isolates in Europe and Japan have very closely related genotypes suggesting most or all clinical isolates of this subtype are clonal (4,19, 20,29). Zhang et al recently evaluated 51 clinical M. kansasii isolates recovered in the United States by PFGE and found that half of the isolates had the same genotype as the predominant pattern reported by Picardeau (19, 29). This clonal nature of most clinical isolates of M. kansasii would seem very unusual for an environmental species, and suggests their colonization of environmental sites of human disease acquisition is quite recent and involved only select genotypes. The close relationship of most clinical M. kansasii isolates by PFGE will complicate evaluation of M. kansasii strain relatedness in epidemiologic studies of suspected M. kansasii outbreaks. M. kansasii and M. marinum have traditionally been grouped together because they share in vitro growth and biochemical characteristics. Unfortunately, they have little in common clinically.

Epidemiology

Because it is not reportable, only estimates are available for the prevalence of M. kansasii disease. M. kansasii is generally the second most common cause of nontuberculous mycobacteria (NTM) lung disease in the U.S. and occurs most commonly in the southern and Central U.S. with the highest incidence of disease in the Southern states of Texas, Louisiana, and Florida and the Central states of Illinois, Kansas and Nebraska (27). Bittner et al. recently reported that M. kansasii was the most common mycobacterial pathogen isolated at a Veterans Affairs Hospital in Omaha Nebraska between 1971 and 1990 (7). It has also been reported that M. kansasii cases are more likely to come from urban than rural areas, which is consistent with our current understanding of reservoirs of M. kansasii (27). In geographic areas where HIV infection is common, the prevalence of M. kansasii disease may be very high. This increase is likely explained by the susceptibility of the population at risk for M. kansasii infection rather than factors related to presence of the organism in the environment or the virulence of the organism.

Clinical Manifestations

Pulmonary disease is the most frequent clinical manifestation of M. kansasii infection in immunocompetent patients. Of all NTM,M. kansasii lung disease most closely parallels the clinical course of M. tuberculosis. M. kansasii primarily affects middle aged men, but it can affect adult patients of any sex, race, or age. Until recently, symptoms and radiographic abnormalities with M. kansasii lung disease were felt to be essentially identical to those of patients with reactivation pulmonary tuberculosis. It is now apparent, and perhaps not surprising, that patients with M. kansasii lung disease can also present with non-cavitary (nodular/bronchiectatic) infiltrates similar toMycobacterium avium complex (MAC) lung disease (11).

As opposed to MAC, M. kansasii may produce pulmonary disease in AIDS patients unassociated with dissemination (8,27).M. kansasii pulmonary disease in HIV infected patients with relatively intact immune systems generally present with the same symptoms and radiographic findings as immunocompetent patients. Patients with more severe immune deficiency are more likely to present with non-cavitary pulmonary infiltrates, intrathoracic adenopathy and/or disseminated disease. Patients who present with disseminated M. kansasiidisease usually also have far advanced lung disease and profound immunosuppression.

Laboratory Diagnosis

Mycobacterium kansasii is isolated from respiratory specimens using standard mycobacteriology laboratory techniques. Currently, a highly sensitive and specific commercial DNA probe (Accuprobe; GenProbe, Inc.) is available for rapid identification of M. kansasii isolates. This method, along with high performance liquid chromatography (HPLC) analysis of mycolic acid esters, has increasingly replaced the slower traditional method of colony morphology, pigmentation and biochemicals (Runyon Classification System) providing rapid identification of the species in larger reference and state health laboratories.

Current rapid diagnostic methods including the use of commercial broth media systems such as Bactec (Becton Dickinson), mycolic acid analysis, and nucleic acid probes.

Pathogenesis

Infection by M. kansasii probably occurs via an aerosol route. Although it is not known with certainty, tap water is likely a major reservoir for M. kansasii causing human infection (27). Isolation of M. kansasii from tap water can be intermittent, which may explain why some investigators have failed to recover it from that source. No other environmental (water or soil) source of M. kansasiihas been identified.

SUSCEPTIBILITY IN VITRO AND IN VIVO

Untreated strains of M. kansasii are inhibited by rifampin, rifabutin, isoniazid (INH), ethambutol, amikacin, streptomycin, clarithromycin and probably ciprofloxacin at concentrations readily achievable in the serum (and hence in tissues) with usual therapeutic doses (3,10,12,18,25). As with most nontuberculous mycobacteria (NTM), the MICs for most antituberculous drugs for M. kansasii are 10-100 times higher than those for M. tuberculosis, with the exception of rifampin, ethambutol, amikacin, and ciprofloxacin. All isolates are highly resistant to pyrazinamide (PZA). Untreated strains are highly susceptible to the rifamycins with rifampin MICs of 1.0 mg/ml or below and rifabutin MICs 0.5 mg/ml or below. Isolates of M. kansasii that have developed high level (>8.0 mg/ml) resistance to rifampin usually have comparably high rifabutin MIC’s, while isolates with low level rifampin resistance (MICs 2.0-8.0 mg/ml) exhibit MICs for rifabutin that are similar to untreated wild strains (< 0.5 mg/ml) (25). The genetic mechanism of rifampin resistance for M. kansasiiappears to involve multiple mutations in the RNA polymerase gene (rpo b) as it does with M. tuberculosis (21). MICs for untreated strains of M. kansasii to INH generally range from 1.0 to 4.0 mg/ml (25). These MICs are 10-50 times higher than for M. tuberculosis(< 0.1 mg/ml) and the value of this drug in routine treatment of clinical M. kansasii disease is in some question. MICs of M. kansasii for ethambutol are comparable to those of M. tuberculosis, and all susceptible MICs are 5.0 mg/ml or less. As with ethambutol resistance in tuberculosis, resistant MICs (>5.0 mg/ml) are associated with previous ethambutol therapy, resistance to other drugs, including rifampin, and treatment failure. The MICs of wild strains of M. kansasii for streptomycin are 2.0-8.0 mg/ml. Acquired resistance to rifampin, ethambutol, and INH (defined as significant changes in MICs associated with treatment failure or relapse) has been demonstrated in isolates from treatment failure cases, and resistance to the first two agents is reliably demonstrated by current M. tuberculosissusceptibility test methods (proportion method in agar) (3,18,25).

The concentrations of antituberculous drugs used for routine mycobacterial susceptibility testing, including M. kansasii, were chosen for their usefulness with M. tuberculosis. Because M. kansasii is less susceptible to these drugs in-vitro (but still susceptible to achievable blood/tissue levels of these drugs), all isolates will be reported resistant to INH at 0.2 mg/ml and many to 1.0 mg/ml and to streptomycin at 2.0 mg/ml. These isolates are susceptible to slightly higher drug concentrations and laboratory reports of resistance to the low concentrations of these two drugs have no clinical or therapeutic significance, as long as a rifampin containing regimen is being used. Thus, these drug concentrations would no longer be routinely used for susceptibility testing of M. kansasii. NCCLS (formerly the National Committee for Clinical Laboratory Standards) in 2000. and previously the 1997 American Thoracic society (ATS) statements on NTM recommend routine susceptibility testing of rifampin on all M. kansasii isolates to avoid this potential confusion (27,31). Additional drug testing is then performed if rifampin resistance is present.

The only drug for which resistance in-vitro to a defined drug concentration has been regularly associated with treatment failure for M. kansasii is rifampin. This is another reason that susceptibility testing of M. kansasii strains should initially include only rifampin (27,31). Since acquired rifampin resistance may develop during therapy and since the history of prior therapy may not be known, all initial isolates of M. kansasii as well as those from patients with known prior therapy should be tested to rifampin by the agar proportion method. Also, testing should be performed when the patient's sputum fails to convert from smear and/or culture positive or when a relapse occurs during therapy. For patients whose isolate is rifampin resistant, testing to all potentially useful agents, including rifabutin, ethambutol, and clarithromycin, should then be performed.

M. kansasii is also susceptible in vitro to sulfamethoxazole, amikacin, the newer quinolones, and clarithromycin, although there is limited information on the clinical usefulness of these drugs (3,10,25). The usual MIC's for these agents include sulfamethoxazole 4.0mg/ml or less, amikacin 8.0 mg/ml or less, ciprofloxacin 0.5-2.0 mg/ml and clarithromycin 0.25 mg/ml or below. Isolates are usually resistant to high concentrations in vitro and therefore achievable levels of pyrazinamide, capreomycin and PAS.

Preliminary studies have shown that M. kansaii to susceptible to the new class of drugs the oxazolidinones, with the first available drug being linezolid (Pharmacia, Inc.) (7a). Preliminary studies also suggest the newer 8-methoxy quinolones gatifloxacin and moxifloxacin are several dilutions more active than ciprofloxacin and levofloxacin (7b). There is, as yet, no clinical data about the effectiveness of these drugs in vivo.

ANTIMICROBIAL THERAPY

Treatment of any M. kansasii infection except localized lymphadenitis (see below) requires multidrug therapy over a long period of time. There are currently no universally accepted intermittent or short-course treatment regimens for M. kansasii disease in the United States as there are for tuberculosis. The cornerstone of successful therapy for M. kansasii infections is inclusion of rifampin in a multidrug regimen that includes ethambutol, and (in the United States) INH. Monotherapy with rifampin (due either to patient noncompliance or inappropriate treatment recommendations) invariably leads to development of rifampin resistance, which in turn is invariably associated with treatment failure.

Special Situations

Pulmonary Disease in HIV Negative Patients

There have been no randomized comparative trials of treatment, comparing one drug regimen with another or with placebo, for pulmonary disease caused by M. kansasii. There have been, however, several retrospective and prospective studies of various treatment regimens that form a reasonable basis for drug therapy recommendations (1,2,5,18). The key to successful therapy of M. kansasii lung disease is inclusion of rifampin in a multidrug regimen. For antimycobacterial drug regimens without rifampin (and predating newer agents, such as clarithromycin), the sputum conversion rates at 6 months ranged from 52 to 81% (13,18). Relapse rates were approximately 10% even in patients with an initial response.

With the inclusion of rifampin in treatment regimens, response to therapy improved dramatically. Sputum conversion rates with rifampin-containing regimens at four months were 100% in 180 patients from three studies (1,2,18). The incidence of treatment failure in these studies was 1.1% and failure was invariably associated with the development of rifampin resistance. Long-term relapse rates from these three studies of rifampin containing regimens was also very low (0.8%).

The past and current American Thoracic Society (ATS) recommendation for treatment of lung disease caused by M. kansasii is the regimen of INH (300 mg/day), rifampin (600 mg/day), and ethambutol (25 mg/kg/day for the first 2 months, then 15 mg/kg/day) given daily for 18 months (24,27). Documentation of at least 12 months of negative sputum cultures is considered by us as well as other experts to be important for successful therapy. For patients with severe disease, especially patients with extensive cavitation and compromised respiratory reserve, consider adding streptomycin 0.5-1.0 gm IM three times per week (TIW) for the first 2-4 months of therapy or clarithromycin 500 mg BID.

In patients who are unable to tolerate one of the three primary drugs, clarithromycin appears to be a reasonable alternative based on its low MICs to M. kansasii and excellent activity in-vivo against other NTM, but has not been established by extensive clinical trials (see below). An additional concern is enhanced metabolism of clarithromycin by the cytochrome P-450 enzymes in the presence of rifampin (26). The knowledge that rifampin plus clarithromycin is effective for therapy of M. avium complex (MAC) lung disease and that MICs of M. kansasii are much lower to clarithromycin than MAC, suggest that rifampin/clarithromycin interaction is not a clinically significant issue. Azithromycin (which is not influenced by rifampin) and the newer 8-methoxy quinolones appear to be reasonable agents in this setting; however, there are no published reports of the efficacy of these drugs on which to base firm recommendations.

Four short-course treatment trials for M. kansasii lung disease has provided some provocative results, but have not yet clearly demonstrated equivalence to the 18-24 months daily treatment regimens. Ahn et al. studied 40 patients and found that adding streptomycin (1 gm twice weekly) for the first 3 months to daily INH, rifampin and ethambutol at standard doses for 12 months resulted in apparent cure of all but 1 patient (2). A second trial sponsored by the British Medical Research Council featured ethambutol (15 mg/kg) and rifampin (450-600) mg given for 9 months; 154 patients from this trial were available for analysis (14). Most patients received multiple drugs for presumed tuberculosis initially; some, however, received only INH and rifampin at the start of therapy. INH was discontinued in all patients when M. kansasii was identified. All isolates were susceptible in-vitro to rifampin and ethambutol; all were judged to be resistant in-vitro to INH. Sputum conversion was achieved in 99% of patients; a 12% relapse rate was noted through 5 years follow-up. For most of these patients, relapse was attributed to medication noncompliance or severe underlying disease. Unfortunately, DNA fingerprinting of these isolates was not performed, so the possibility of reinfection rather than relapse in some of these patients cannot be excluded. This study suggests that INH does not contribute greatly to the treatment of M. kansasii, and that 9 months may not be a long enough treatment period for this two drug regimen.

The third study described 28 patients from France with M. kansasii lung disease (21). The patients were randomized to 12 or 18 month regimens. Fourteen patients received rifampin 600 mg/day, INH 300 mg/day, and ethambutol 25 mg/kg daily for the first 6 months then rifampin and INH to complete a total of 12 months. The second group was treated with the same regimen (including the initial 6 months of ethambutol) for 18 months. All patients converted their sputum to negative. After 12-30 months of follow-up, only one patient (7%) in the 12 month and none in the 18 month group had relapsed. The results of this study are encouraging, but it was not large enough and did not have sufficient long-term follow-up to establish 12 months of chemotherapy as the standard for treatment. Use of high dose (25 mg/kg/day) ethambutol is not without risk, and may not be readily accepted in the United States. This study also appears to contradict the findings of the study by Jenkins et al with respect to the importance of INH in the treatment regimen. Almost certainly, rifampin is the critical agent for efficacy, and while companion drugs may not enhance efficacy, they are essential to prevent emergence of resistance to rifampin. Both ethambutol and INH appear to be effective for this latter role. None of these studies included a macrolide which may prove to be as active as rifampin and may provide the basis for effective short course regimens.

Griffith et al evaluated a three times weekly (TIW) regimen including clarithromycin, rifampin and ethambutol in 15 patients withM. kansasii lung disease (11). The primary treatment end-point was 12 months of sputum AFB culture negativity. Three patients were lost to follow-up (two had converted their sputum cultures to negative). The remaining 12 patients successfully completed therapy with a mean duration of therapy of 12.9 months. All patients who successfully completed therapy remain AFB culture negative after a mean of 30 months of follow-up.

It would be extremely desirable to have a reliable short course treatment regimen for M. kansasii disease from many perspectives. The availability of several drug classes with excellent in vitro activity against M. kansasii including rifamycins, macrolides and 8-methoxy quinolones suggests that a very effective short course treatment regimen for M. kansasii disease could be constructed. All that remains are clinical trials to evaluate such regimens.

For patients whose organisms have developed mutational resistance to rifampin as a result of previous therapy, a regimen of oral and injectable agents has been shown effective (3,25). This regimen consists of high-dose daily INH (900 mg), high dose ethambutol (25mg/kg/day), and sulfamethoxazole (1.0 gm three times per day) combined with daily or five times per week streptomycin or amikacinfor the initial 2 to 3 months. The initial regimen is followed by intermittent streptomycin or amikacin for a total of 6 months of parenteral therapy. (3,25). The oral drugs are given for 12-15 months after sputum cultures become negative. Results with this regimen include sputum conversion in 18 of 20 patients (90%) after a mean of 11 weeks, with only one relapse (8%) among patients culture negative for at least 12 months while on therapy.

The above trial antedated the introduction of clarithromycin and the 8-methoxy quinolones which, as noted above, have excellent in-vitro activity against M. kansasii. As also noted from preliminary data clarithromycin appears to have utility in the treatment of M. kansasii pulmonary disease. Clarithromycin with or without one of the 8-methoxy quinolones will very likely be useful in retreatment regimens for rifampin resistant strains, perhaps allowing for omission of the aminoglycoside, as a substitute for patients intolerant to one of the first line drugs, and in the treatment regimen for patients with M. kansasii infection (pulmonary and/or disseminated) and AIDS. Given the success of medical regimens with rifampin-resistant M. kansasii, few patients require surgical resection.

Lymphadenitis

In the treatment of lymph node disease in children, all accessible nodes should be excised at the time of the initial biopsy, since the probabilities are that the etiologic agent is MAC (or occasionally NTM other than M. kansasii) for which excision is the indicated treatment (22,27). In some patients, complete surgical excision of involved lymph nodes may be impossible. There is, unfortunately, little published information addressing this scenario. Experience with lymphadenitis due to MAC suggests that chemotherapy with a macrolide containing regimen following incomplete surgical excision of involved nodes is associated with a high rate of success. Additionally, antibiotic therapy may only be required for 6 months (6).

Disseminated Infection in Non-AIDS Patients

For treatment of disseminated disease due to M. kansasii in non-HIV infected patients, the regimen of antimycobacterial drugs should be the same as for lung disease. It is unknown at present if drugs should be prescribed differently or for a longer period of time than for patients with lung disease. Since these patients are invariably immunocompromised and/or immunosuppressed, the duration of therapy may depend on the reversibility of the immune deficiency. The major group with this problem are patients who have received organ transplants which introduces a potential significant drug interaction between rifampin and cyclosporine. For patients who receive rifampin based regimens cyclosporine levels should be monitored and cyclosporine dosages increased if necessary. Rifabutin, which is a less potent inducer of the cytochrome P-450 enzymes, could also be substituted for rifampin although cyclosporine levels would still need to be monitored.

HIV Disease

For patients with advanced HIV disease and AIDS with pulmonary and/or disseminated M. kansasii infection, the treatment regimen may be the same as for immunocompetent patients with M. kansasii pulmonary disease (Table 1). Untreated M. kansasii infection in these patients is essentially always fatal (8). The choice of drugs and the duration of therapy in HIV infected patients remains problematic. For patients with relatively intact and stable immune function (or who recover immune function), the duration of therapy could be comparable to that for immunocompetent patients. These patients require very close clinical follow-up and monitoring, however. For patients with advanced HIV disease and AIDS with poor immune function, the duration of treatment probably should be longer than standard therapy and perhaps lifelong for some patients who do not recover immune function.

The antiretroviral drugs, especially the protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI), have complicated the treatment of pulmonary and disseminated M. kansasii disease in patients with HIV disease. Rifamycins (rifampinmore than rifabutin) accelerate the metabolism of PI’s and NNRTI’s through induction of the hepatic cytochrome P-450 enzymes, resulting in subtherapeutic levels of these drugs. Low levels of these drugs facilitate or enhance rapid mutational resistance in HIV strains to the protease inhibitors. Currently, it is recommended that indinavir, nelfinavir and amprenavir not be used with rifampin. It is also recommended that delavirdine and probably nevirapine not be used with rifampin (30). Efavirenz can be used with rifampin at 800 mg/day (30). To complicate the situation even more, PI’s retard the metabolism of rifamycins, resulting in increased serum levels of rifamycins and the potential for drug toxicity (rifabutin more than rifampin).

There are several options for treating patients with M. kansasii disease who are also undergoing therapy for HIV infection (30). A current popular strategy for patients with a low HIV viral load is the use of nucleoside reverse transcriptase inhibitors (NRTI’s) as initial therapy for HIV disease which would allow use of the standard (rifampin-containing) regimen for M. kansasii disease. As noted above, efavirenz with the appropriate dosage adjustment can also be added to a multi-drug HIV treatment regimen containing NRTI’s and the patient could still receive a rifampin-containing regimen for M. kansasii disease. For patients receiving the PI’s indinavir, nelfinavir and amprenavir or the NNRTI’s nevirapine or evafirenz, rifabutin could be substituted for rifampin in the M. kansasii regimen. Some dosage adjustment for the rifabutin may be necessary depending on which drugs are chosen in the HIV treatment regimen. Recently a strategy for boosting PI levels by giving ritonavir has been developed which might also allow concomitant administration of rifampin with the PI’s. Addition of clarithromycin to these three drugs would also likely improve the efficacy of the regimen, although the risk of rifabutin-related toxicity would be augmented further. The role of potentially useful agents such as the newer quinolones is unknown in this setting.

Clearly, the treatment of M. kansasii disease in HIV infected patients can be very complicated. Treatment regimens for HIV infection are rapidly changing with the introduction of new agents associated with important drug-drug interactions. Inappropriate combinations of drugs may result in treatment failure of one or both infections as well as significant drug-related toxicity. Physicians who do not routinely treat HIV infected patients or who are not familiar with the drugs involved should seek expert consultation for the management of these patients.

ENDPOINTS FOR MONITORING THERAPY

Serial sputum surveillance is the most important element of monitoring treatment of M. kansasii lung disease. Sputum bacteriology is an indication of medication efficacy; rendering the patient sputum-culture negative is the primary marker of success, and the time to sputum conversion may help determine the length of therapy in some patients. Sputum cultures identify relapse of disease in patients who had previously converted and provides material for in-vitro susceptibility testing in patients who have relapsed. Some patients cease sputum production during therapy, making sputum analysis impossible; however, diligent effort should be made to collect sputum throughout the course of treatment. Patients failing therapy may not be recognized until therapy is discontinued, unless there is careful sputum surveillance during therapy.

Periodic chest radiographs are also helpful in this setting. The chest radiograph is likely to improve slowly; thus, frequent radiographs are not necessary, if the patient appears to be responding well to therapy (i.e. weight gain, improvement in cough and sputum production). Because of the potential for drug-related adverse events, patients initially require at least monthly contact with health care workers. Specific drug toxicities and monitoring recommendations have been outlined in detail (27). The inclusion of ethambutol at a dose of 25 mg/kg /day in the routine treatment regimen dictates that visual symptoms and simple visual acuity and color vision testing should be checked at least monthly. With decrease in the ethambutol dose to 15 mg/kg/day, visual acuity and red green color discrimination need be assessed at baseline and then only with symptomatic changes in the patient's vision (27). The necessity for frequent patient contact to evaluate possible drug toxicity also facilitates frequent evaluation of disease symptom status.

CONTROVERSIES, CAVEATS, OR COMMENTS

The recommendation that all patients with suspected tuberculosis with a significant risk of drug resistance receive four drugs, including INH, rifampin, pyrazinamide, and ethambutol, has an additional benefit in that patients who prove to have M. kansasii lung disease will receive adequate (i.e. three active drug) therapy from the outset, since pyrazinamide has little or no activity against M. kansasii. This treatment approach may be most important in areas with a high incidence of M. kansasii, such as reported by Bittner et al. (7).

M. kansasii lung disease patients would benefit from the same treatment approach as that currently used for pulmonary tuberculosis, namely, directly observed therapy to avoid emergence of acquired rifampin resistance through noncompliance. Unfortunately, in the face of competing monetary demands for control of tuberculosis, it is not likely that state departments of health will treat M. kansasiiin this manner. Certainly, this process would be facilitated if there were a short course and/or intermittent regimen that was effective for treatment of M. kansasii. It is reasonable to hope that clinical trials, perhaps with drug combinations that include a rifamycin and a macrolide, will address this problem in the future.

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Table 1. Recommended Regimens for Treatment of M. kansasii Infection [Download PDF]

1) Pulmonary or disseminated disease in the immunocompetent host or for HIV infected patients not on protease inhibitors or non-nucleoside reverse transcriptase inhibitors*.

Rifampin 600 mg/day
Isoniazid 300 mg/day
Ethambutol 25 mg/kg/day for 2 mos then 15 mg/kg/day
Oral medicines for 18 mos and 12 mos of sputum culture negativity
For severe disease consider adding Streptomycin 0.5-1.0 gm IM TIW for the first 2-4 mos of therapy or clarithromycin 500 mg BID

2) Pulmonary or disseminated disease in the immunocompetent host that is Rifampin resistant or in patients who are Rifampin intolerant.

Clarithromycin 500 mg BID
Isoniazid 900 mg/day (plus pyridoxine 50 mg/day)
Ethambutol 25 mg/kg/day
Sulfamethoxazole 1.0 gm/TID or TMP/SMX one DS tablet TID
For severe disease consider adding Streptomycin 0.5-1.0 gm IM TIW for the first 2-4 mos of therapy.
Duration of therapy as above.

3) Pulmonary or Disseminated infection in HIV positive patients on selected protease inhibitors and non-nucleoside reverse transcriptase inhibitors**.

Clarithromycin 500 mg BID
Rifabutin 150 mg/day
Ethambutol 25 mg/kg/day for 2 mos then 15 mg/kg/day
Isoniazid 300 mg/day
For severe disease consider Streptomycin 0.5-1.0 gm IM TIWfor the first 2-4 mos of therapy.
Duration of therapy as above or as appropriate for level of immune function.

4) Lymph node disease