Correspondence
Multidrug-Resistant Tuberculosis
N Engl J Med 1996; 334:267-269January 25, 1996
- Article
To the Editor:
Telzak et al. (Oct. 5 issue)1 report on a series of persons in New York city who had multidrug-resistant tuberculosis but were not infected with the human immunodeficiency virus (HIV). The authors conclude that “contrary to previous reports, [such] patients can be expected to respond to appropriate chemotherapy.” This is good news, but a casual reading of the article may well be misleading.
Telzak et al. contrast their results with those of our study in Denver in 1993,2 but there are critical differences between these two series. Although both involve multidrug-resistant tuberculosis (i.e., disease resistant to isoniazid and rifampin), the patients in our series had more extensive drug resistance (resistance to a median of 6 drugs, vs. 3.5 in the New York series). There was resistance only to isoniazid and rifampin in 34.8 percent of the isolates in the New York study but in 3.7 percent of the isolates in the Denver study. All cases in the Denver study involved pulmonary disease, and in 84 percent of the patients it was bilateral with at least one cavity. Four of the 23 patients in New York had extrapulmonary disease (which is typically paucibacillary; bacteriologic follow-up data were not available on these patients). In addition, the nature of the pulmonary disease was not specified, a matter of considerable importance, since with multidrug-resistant tuberculosis, cavities are strongly associated with treatment failure and further acquired drug resistance. Moreover, 3 of the 19 patients with pulmonary disease in New York underwent resectional surgery, an intervention that may have contributed to the cure.3 Finally, the criteria for a response were more stringent in the Denver study, with a successful outcome defined as negative cultures for three consecutive months, typically with multiple specimens obtained each month. In contrast, the New York study defined a response as two or more negative cultures at least two weeks apart. In some cases such specimens were not available, and the response was defined according to clinical criteria.
A cautionary note is needed. Despite the favorable outcome in this small group of patients, clinicians should understand that patients with multidrug-resistant tuberculosis, particularly those with resistance to other first-line agents and with cavitary disease, are at substantial risk for treatment failure and even death. Great care is required in treating such patients.
3 ReferencesMichael D. Iseman, M.D.
Marian Goble, M.D.
National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 802061
Telzak EE ,Sepkowitz K ,Alpert P , et al. Multidrug-resistant tuberculosis in patients without HIV infection. N Engl J Med 1995;333:907-911
Full Text | Web of Science | Medline2
Goble M ,Iseman MD ,Madsen LA ,Waite D ,Ackerson L ,Horsburgh CR Jr . Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993;328:527-532
Full Text | Web of Science | Medline3
Iseman M ,Madsen L ,Iseman M ,Ackerson L . Impact of surgery on the management of MDR-TB. Am J Respir Crit Care Med 1995;151:Suppl:A336-A336 abstract.
To the Editor:
In comparing their data with those of Goble et al.,1 Telzak and coworkers comment that their results may “reflect the advantage of treating primary resistant disease, rather than disease in persons exposed intermittently to antituberculosis medication for years, resulting in secondary resistance and damaged lungs.” Our results are somewhat different.
In Rio Grande do Sul, a state of Brazil, we annually see about 25 new cases of tuberculosis resistant to first-line drugs (rifampin, isoniazid, and pyrazinamide) and second-line drugs (streptomycin, ethambutol, and ethionamide). Most of the patients do not have HIV infection; irregular treatment is the main cause of multidrug-resistant tuberculosis.
Thirty-five patients with multidrug-resistant tuberculosis who were negative for HIV were enrolled in a study up to December 1993 and have been followed since then. Thirty of these patients were described in a previous report.2 Treatment consisted of ofloxacin (600 mg per day for 12 months), amikacin (500 mg per day for 3 months), amithiazone (150 mg per day for 12 months), and isoniazid (400 mg per day). The patients were admitted to the hospital for 12 months. They had had tuberculosis for a median of 5.8 years and had previously received treatment with a median of six drugs. All the patients had bilateral pulmonary disease. Their median age was 38 years. Although these patients were similar in some respects to those described by Goble et al.,1 their response to treatment was different. Of the 35 patients, 23 had cures; treatment failed in 5 patients and was discontinued in 7 (6 patients abandoned treatment, and 1 had adverse effects requiring discontinuation). The five patients in whom treatment failed died during the first six months of treatment and had advanced illness (severe respiratory insufficiency, adrenal failure, and hemoptysis). We doubt that any antituberculous regimen would have been effective in these patients. The cured patients were followed, on average, for 20 months; the one patient with a relapse had diabetes mellitus. None of the patients underwent surgery. The seven patients who did not complete treatment had negative sputum samples after a median of three months of treatment. These patients would probably have been cured if they had completed the treatment.
The efficacy of a regimen of a quinolone plus amikacin and another appropriate drug would not be greatly influenced by the duration of disease or the number of drugs used previously. The severity of the sequelae of tuberculosis is related mainly to irregular treatment and premature abandonment of treatment.
2 ReferencesLuiz Carlos Corrêa da Silva, M.D.
Luciano Müller Corrêa da Silva, M.D.
University of Rio Grande do Sul, Porto Alegre 90049 RS, Brazil1
Goble M ,Iseman MD ,Madsen LA ,Waite D ,Ackerson L ,Horsburgh CR Jr . Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993;328:527-532
Full Text | Web of Science | Medline2
Correa da Silva LC ,Freitas TM ,Correa da Silva LM , et al. Treatment of chronic multiresistant tuberculosis with ofloxacin-amikacin-thiacetazone-isoniazid. Am J Respir Crit Care Med 1995;151:Suppl:A554-A554 abstract.
To the Editor:
Telzak and coworkers found that active tuberculosis involving multidrug-resistant strains may be successfully treated in immunocompetent patients without HIV infection. In their series, treatment with second-line drugs was effective, so the high rate of response is even more impressive.
It is possible that these multidrug-resistant strains of Mycobacterium tuberculosis were less virulent than drug-susceptible isolates. In earlier studies, isoniazid-resistant strains of M. tuberculosis were found to be less virulent than drug-susceptible isolates in animal models.1 Isolates of M. tuberculosis that are resistant to many antituberculous drugs are less able to cause infection than drug-susceptible strains or strains resistant to a smaller number of drugs.2 Is there an inverse relation between virulence and drug resistance? Although these data cannot be applied directly to human tuberculosis, the findings of Telzak et al. suggest that a lower degree of pathogenicity in the multidrug-resistant tuberculosis isolates may have contributed to the good outcomes in their immunocompetent patients. They even report spontaneous microbiologic clearance in one patient.
The resurgence of multidrug-resistant tuberculosis may pose less of a danger to the general population than many have claimed.
2 ReferencesGiovanni Di Perri, M.D., Ph.D.
Sandro Vento, M.D.
Ercole Concia, M.D.
Angelo Cazzadori, M.D.
University of Verona, 37126 Verona, ItalyAuthor/Editor Response
The authors reply:
To the Editor: We agree with Drs. Iseman and Goble that “great care is required” in treating patients with multidrug-resistant tuberculosis, and we hope our article did not suggest otherwise. We also agree that there are considerable differences between the series in Denver and ours in New York, and these differences probably contributed to the different success rates. In fact, in our report we noted that these clinical characteristics were dramatically different and elaborated on the differences in terms of primary disease as compared with reactivation, the susceptibility patterns of the isolates, the availability of the quinolones, the duration of previous tuberculosis, and the intensity of prior treatment. The Denver study, which continues to provide the foundation for the treatment of multidrug-resistant tuberculosis, included only referred patients with the most severe clinical manifestations in whom treatment had failed elsewhere.1 The patients we described are more likely to be representative of patients with multidrug-resistant tuberculosis in a nonreferral setting, since our patients received diagnoses and were treated at seven different hospitals. Finally, as we stated in the last paragraph of our article, the “long-term efficacy of this approach awaits several more years of patient follow-up.”
We appreciate the comments of Drs. da Silva and da Silva, which provide additional support for the view that quinolone therapy may make a substantial contribution to the treatment of multidrug-resistant therapy.
Since the introduction of streptomycin, there has been considerable interest in the relative virulence of drug-susceptible and drug-resistant strains of M. tuberculosis in both animals and humans.2,3 We are aware of no study that has conclusively demonstrated differences in pathogenicity, despite the suggestion by Di Perri et al. that such differences may have contributed to the high success rate. In addition, it should be noted that even if there are minor variations in virulence, drug-resistant tuberculosis has a long and ignoble history of causing substantial morbidity and mortality.
3 ReferencesEdward E. Telzak, M.D.
Bronx–Lebanon Hospital Center, Bronx, NY 10457Kent Sepkowitz, M.D.
Cornell University Medical Center, New York, NY 10021Glenn Turett, M.D.
Bronx–Lebanon Hospital Center, Bronx, NY 104571
Goble M ,Iseman MD ,Madsen LA ,Waite D ,Ackerson L ,Horsburgh CR Jr . Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993;328:527-532
Full Text | Web of Science | Medline2
Riley RL ,Mills CC ,O'Grady F ,Sultan LU ,Wittstadt F ,Shivpuri DN . Infectiousness of air from a tuberculosis ward: ultraviolet irradiation of infected air: comparative infectiousness of different patients. Am Rev Respir Dis 1962;85:511-525
Web of Science | Medline3
Snider DE Jr ,Kelly GD ,Cauthen GM ,Thompson NJ ,Kilburn JO . Infection and disease among contacts of tuberculosis cases with drug-resistant and drug-susceptible bacilli. Am Rev Respir Dis 1985;132:125-132
Web of Science | Medline
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