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* From the Pulmonary Institute (Drs. D. Shitrit, Shlomi, Daniele, and Kramer), Rabin Medical Center, Beilinson Campus, Petah Tiqwa; Israel Lung Association (Dr. Baum), Tel Aviv; Macabbi Medical Service (Ms. Priess and Dr. Raz), Tuberculosis Center, Rehovot; Public Health Tel Aviv (Ms. Lavy), Israel Ministry of Health, Tel Aviv; and Department of Internal Medicine (Dr. A. B-G. Shitrit), Shaare-Zedek Medical Center, Jerusalem, Israel.
Correspondence to: Mordechai R. Kramer, MD, Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petah Tiqwa 49100, Israel; e-mail: davids3{at}clalit.org.il
Abstract
Background: Mycobacterium kansasii infection is one of the most common causes of nontuberculous mycobacterial lung disease in world. However, little is known about its background characteristics or drug sensitivity in nonendemic areas.
Design: We assessed the clinical features, radiologic findings, and drug sensitivity associated with M kansasii infection in Israel.
Methods: Patients with a culture-positive diagnosis of M kansasii infection between April 1999 and April 2004 were identified from a clinic database of tuberculosis centers. Mycobacterial cultures were performed with standard methods. Data on patient background and clinical features were collected from the medical files.
Results: Mean age (± SD) of the 56 patients was 58 ± 18 years, and 64% were men; 59% had associated lung disease. Fifteen percent were receiving immunosuppressive medications. None had HIV infection. Systemic comorbid diseases were noted in 27%. The most common clinical presentations were chest pain, cough, hemoptysis, fever, and night sweats. Cavitation was noted only in 54%. Older patients had more noncavitary disease than younger patients (p = 0.01, r = 0.35). Lower-lobe predominance was very rare (4%). None of the patients presented with pleural effusion or lymphadenopathy. Only seven patients (11%) underwent bronchoscopy for diagnosis. M kansasii isolates showed the highest sensitivity to rifampin, ethambutol, clarithromycin, and ofloxacin, and the highest resistance to ciprofloxacin and capreomycin. The mean duration of treatment was 21 ± 7.2 months. There were no disease-related deaths.
Conclusions: M kansasii disease in Israel has no association with HIV, more systemic comorbid diseases and associated lung disease, and fewer cavitations. Following appropriate treatment, patients with M kansasii disease have an excellent prognosis.
Key Words: cavitation • drug sensitivity • Mycobacterium kansasii
Mycobacterium kansasii has traditionally been considered the most virulent of the nontuberculous mycobacteria.12 It is the second most common nontuberculous mycobacterium after Mycobacterium avium complex3 and the most common cause of nontuberculous mycobacterial lung disease in the United Kingdom and Western Europe.245 Infection with M kansasii probably occurs via an aerosol route. Tap water is a major reservoir for M kansasii causing human infection. The incidence of M kansasii infection has a wide geographic variation, being highest in the central and southern United States, and England and Wales.678 Isolation of M kansasii from tap water can be intermittent, which may explain why some investigators9 have failed to recover it from that source. No other environmental (water or soil) source of M kansasii has been identified.9 Risk factors include chronic lung disease, previous mycobacterial disease, malignancy, and alcoholism.291011121314 In immunocompetent patients, pulmonary disease is the most frequent clinical manifestation,9 although approximately 40% have no associated illness.2 The prevalence of M kansasii infection may be very high in areas where HIV is common.9
According to the American Thoracic Society (ATS) guidelines, the current recommendation for treatment of pulmonary disease caused by M kansasii is the regimen of isoniazid, rifampin, and ethambutol administered daily for 18 months with an least 12 months of negative sputum culture results. In patients who are unable to tolerate one of these three drugs, clarithromycin would seem to be a reasonable alternative.15 M kansasii is also susceptible in vitro to sulfamethoxazole, amikacin, newer quinolones, and rifabutin.915 The incidence of Mycobacterium tuberculosis in Israel was six to eight cases per 100,000 from 2003 to 2004.16
However, because it is not a public health problem and not reportable, there are no data concerning the incidence of M kansasii in Israel. Moreover, little is known about patient demographics, clinical characteristics, association of the disease with HIV, or M kansasii drug sensitivity in nonendemic areas. The aim of the present study was to assess the clinical features, radiologic findings, and drug sensitivity in patients with M kansasii infection in Israel.
Materials and Methods
The study sample included 56 patients with a diagnosis of M kansasii lung infection who attended the tuberculosis centers in Tel Aviv and Rehovot, Israel, from April 1999 to April 2004. The diagnosis was based on the guidelines of the ATS, namely appropriate symptomatology, compatible radiographic abnormalities, and multiple culture-positive respiratory specimens for M kansasii.15 Patients in whom there was a high clinical suspicion of tuberculosis but negative sputum smear results underwent bronchoscopy with BAL and transbronchial biopsy to confirm the diagnosis.
Mycobacterial cultures were performed with standard methods.917 Sputum smears were stained with auramine and examined using fluorescence microscopy, and the presence of acid-fast organisms was confirmed with Ziehl-Neelsen stain. Lowenstein-Jensen slopes were incubated for 12 weeks. All mycobacterial isolates were sent to the Public Health Laboratory Service, Mycobacterial Reference Unit in Tel Aviv for identification and sensitivity testing.
M kansasii strains were routinely tested for susceptibility to rifampicin, ethambutol, clarithromycin, ciprofloxacin, ofloxacin, capreomycin, ethionamide, and cycloserine. We did not test the M kansasii strains for susceptibility to isoniazid.
The resistance ratio method was used to test the susceptibility strains to all the drugs mentioned.17 This method is based on the growth of the tested strain relative to a standard sensitive (control) strain at five standard doubled drug concentrations. We calculated the resistance ratio of each test strain to each drug by dividing the minimum inhibitory concentration of the test by the model minimum inhibitory concentration. As doubling dilutions are used, the resistance ratio is 1 (or less), 2, 3, 4, or 8. Strains with a resistance ratio of 1 or 2 are reported as susceptible, those with a resistance ratio of 4 are resistant, and those with a resistance ratio of 8 are highly resistant.17
Molecular characterization was carried out on 20 isolates. For genotypic identification of M kansasii, we used the Accuprobe test (Gen-Probe; San Diego, CA), based on the hybridization of a DNA sequence, labeled with chemoluminescent substance, with the ribosomal RNA of a grown mycobacteria.1819 All our patients were treated with rifampicin (600 mg), ethambutol (25 mg/kg for the first 2 months, then 15 mg/kg), and clarithromycin (1,000 mg/d) administered daily for at least 12 months of negative sputum culture results.
Data on clinical features of the patients (including systemic comorbid disease and smoking status), radiologic findings, treatment, and outcome were obtained from the case notes and laboratory records by a single investigator. Chest radiographs obtained within 2 weeks of diagnosis of mycobacterial disease were read by an independent investigator who was blinded to the clinical findings. All the patients had been tested for HIV. The study was approved by the Ethics Committee of Rabin Medical Center.
Statistical Analysis
Results are shown as mean ± SD. To statistically analyze differences between categorical variables, a 
2 test or Fisher exact test were used, as appropriate. The Pearson correlation coefficient (r) and the significance for it (p value) were calculated between the variables; p 
0.05 was considered statistically significant.
Results
Background Characteristics
The background features of the patients are summarized in Table 1
. Mean age (± SD) was 58 ± 18 years; 24 patients (64%) were men, 22 patients (39%) were smokers, and 10 patients (18%) had environmental exposure to heavy air pollution or dusty environment. None had pneumoconiosis. Associated lung diseases included COPD in 19 patients (36%), previous tuberculosis in 7 patients (13%), and bronchiectasis in 7 patients (13%). Twenty-three patients (41%) had no underlying lung disease. Systemic comorbid nonpulmonary diseases included diabetes in seven patients (13%), nonpulmonary malignancy in three patients (5%), cardiac disease in four patients (7%), and a history of alcohol abuse (> 14 U/wk) in two patients (4%). Eight patients (14%) were receiving immunosuppressive agents, including steroids. None had HIV infection.
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Radiologic Features
M kansasii infection was an incidental finding on chest radiography in only one patient. All others had symptoms of mycobacterial infection. Cavitary disease was noted radiologically in 30 patients (54%), and noncavitary disease was found in 26 patients (46%); one patient had normal chest radiograph findings. M kansasii disease was confined to the upper lobes in 46 patients (82%): the right lobe in 27 patients (48%) and the left lobe in 19 (34%); 6 patients (11%) had bilateral disease. None of the patients presented with pleural effusions or lymphadenopathy. Seven patients (13%) underwent bronchoscopy with BAL and transbronchial biopsy to confirm the diagnosis of tuberculosis after repeated negative sputum culture results.
Molecular Characterizations
Twenty M kansasii isolates underwent molecular characterization. Eighteen isolates were found to be M kansasii type I, and 2 isolates were M kansasii type II.
Drug Sensitivity
Table 2
summarizes the drug sensitivity of the M kansasii isolates. All isolates were sensitive to rifampicin, all but one isolate (borderline) were sensitive to ethambutol and ofloxacin, and all but two isolates (borderline) were sensitive to clarithromycin. Sensitivity rates to ethionamide and cycloserine were 91% and 94%, respectively, with one isolate resistant to each. A high rate of resistance was noted for ciprofloxacin (10 isolates, 29%) and capreomycin (26 isolates, 74%); 2 isolates (6%) were highly resistant to capreomycin.
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Outcome
All 56 patients survived the M kansasii infection. The mean duration of positive culture results after the start of treatment was 8.9 ± 10.3 months.
Correlations Between Clinical Variables
Older patients had more noncavitary disease than younger patients (p = 0.01, r = 0.35). Patients with bronchiectasis had a higher rate of hemoptysis than patients without bronchiectasis (p = 0.04, r = 0.30). Patients who had chronic underlying lung disease had more fever and night sweats than patients who did not (p = 0.0.3, r = 0.31).
Patients receiving immunosuppressive medication had cough as a presenting symptom less often than patients without a recognized immune defect, in addition to less cavitation and less upper-lobe predominance (p = 0.03, r = 0.31; p = 0.009, r = 0.49; and p = 0.03, r = 0.31, respectively). They also had lower sensitivity to ofloxacin (p = 0.006, r = 0.48).
Discussion
The characterization of the pulmonary infections caused by M kansasii in nonendemic areas may have important implications for the early introduction of appropriate treatment. So far, data remain sparse. Our study is one of the largest conducted on the clinical features of M kansasii infection in a nonendemic area, and the first one to come from Israel.
We noted several clinically significant findings. Series from the United States2021 and Spain22 suggested a higher-than-normal rate of isolation of M kansasii from HIV-positive patients, and a study23 done between 1981 and 1987 reported a 200-fold higher incidence of disseminated M kansasii infection in people with AIDS (138 per 100,000) than in the general population of the United States. However, in the present study, only a small number of patients received immunosuppressive medications, and none were HIV positive. This was also true for the series of Evans et al.24
Another important finding was the relatively low rate of cavitation in our study compared to that of Evans et al24 (54% vs 75%). In other series,911 rates of cavitary infiltrates were even higher (approximately 90%). This discrepancy might be explained by recent improvements in diagnosis and microbiological isolation of the organism.
The good outcome in our study compared to the earlier study24 (100% vs 79%) may be attributable to the fewer systemic comorbid diseases in our series compared to the reports of Evans et al.24 In addition, all deaths caused by mycobacterial disease in this study occurred either before or soon after treatment was started. These data provide support for the use of earlier treatment regimens in M kansasii infection.
Because the concentrations of antituberculous drugs used in susceptibility testing were chosen for their usefulness with M tuberculosis, and because M kansasii is less susceptible to these drugs, some isolates of the latter species may be reported resistant to isoniazid at 0.2 µg/mL or 1 µg/mL and to streptomycin at 2 µg/mL.15 These isolates are susceptible to 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 rifampicin is being used.15 Therefore, we did not test the M kansasii strains for susceptibility to isoniazid.
The ATS recommends isoniazid, rifampicin, and ethambutol.15 In patients who cannot tolerate one of these drugs, clarithromycin appears to be a reasonable alternative.2526 The quinolones, especially the new generation, may also be useful for rifampicin-resistant M kansasii strains, although no efficacy trials have been conducted to date.27
In our study population,15 we preferred the clarithromycin-containing regimen without the isoniazid. Almost certainly, the key to successful therapy of M kansasii lung disease is inclusion of rifampicin in a multidrug regimen; whereas companion drugs may not enhance efficacy, they are essential to prevent the emergence of resistance to rifampicin. Both ethambutol and isoniazid appear to be effective for this latter role. Moreover, several studies1528 found that isoniazid does not contribute greatly to the treatment of M kansasii.
The present report supports M kansasii susceptibility to clarithromycin and ofloxacin.29 Ofloxacin was also superior to ciprofloxacin (Table 2). We believed that some isolates are susceptible to slightly higher ciprofloxacin concentrations; therefore, when clinically indicated, ciprofloxacin should be used regardless of the in vitro susceptibility results.2930
M kansasii infection affects middle-aged men more than women. The most common associated lung disease in the present series was COPD, although approximately 40% of the patients had no recognized immune defect. This has been reported in other studies2924 as well.
The chest radiograph findings in M kansasii infection are very similar to pulmonary tuberculosis, including cavitary infiltrates with an upper-lobe predilection (82% vs 4% for the lower lobe in the present study).9 However, noncavitary lung disease has also been recognized as part of the spectrum of M kansasii infection.49 Our study showed that cavitary disease occurred only in 54%. Like in the report of Evans et al,24 none of our patients had pleural effusion or lymphadenopathy. Lower rate of cough, cavitation, and upper-lobe predominance on chest radiograph were noted in patients receiving immunosuppressive medications in our study compared to the same patients in other studies.1321 However, the number of patients with recognized immune defect in our series was low (n = 8, 14%).
There were some differences in the clinical manifestation of M kansasii infection between our study population and that described by Evans et al24 (Table 1). We found fewer patients with weight loss and more patients with fever and night sweats. These differences may have been due to the short interval from symptom onset to diagnosis, so that most of our patients presented with symptoms of acute infection.
According to the ATS guidelines, the current duration for treatment of pulmonary disease caused by M kansasii is 18 months with an least 12 months of negative sputum culture results. The mean duration of positive culture results in our patients was long (8.9 to 10.3 months), and therefore the total duration of the treatment was longer (21 ± 7.2 months). The presence of more systemic comorbid diseases and associated lung disease could attribute to that. Following appropriate treatment, however, patients with M kansasii disease have an excellent prognosis.
Our study has several limitations. The first is the retrospective design with the use of medical records for data collection. The second is the absence of molecular characterization of the isolates. Every genotype described so far has a different clinical significance.3132 However, pilot tests of 20 of the M kansasii isolates in our series yielded M kansasii type I in 18 isolates and type II in 2 isolates, a relative incidence consistent with other published reports.2733 Third, we did not examine the drug susceptibility of the fluoroquinolones such as levofloxacin, gatifloxacin, and moxifloxacin.
In summary, M kansasii infections in Israel affect mainly middle-aged men without a recognized immune defect. The infection appears to be associated with a higher rate of COPD and a higher rate of fever and night sweats at presentation, and less weight loss than in other series, and with less cavitation on chest radiograph. It is also apparently not associated with HIV. Pleural effusion and lymphadenopathy are very uncommon. Clarithromycin and ofloxacin seem to be as effective for treatment as ethambutol.
Footnotes
Abbreviation: ATS = American Thoracic Society
Received for publication May 11, 2005. Accepted for publication July 11, 2005.
References
This article has been cited by other articles:
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  J. Glassroth Pulmonary Disease Due to Nontuberculous Mycobacteria Chest, January 1, 2008; 133(1): 243 - 251. [Abstract] [Full Text] [PDF]
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