Ofloxacin

Objective: To analyze outcomes of patients with multidrug-resistant tuberculosis (MDR-TB) treated with ofloxacin/levofloxacin-containing regimens.

Materials and methods: From February 1990 through June 1997, 63 MDR-TB patients (with bacillary resistance to at least isoniazid and rifampin in vitro) were analyzed retrospectively. Twenty-two patients (34.9%) had had no previous antituberculosis chemotherapy. Each patient received either ofloxacin (53) or levofloxacin (10) even though 13 patients had bacilli resistant to ofloxacin in vitro. The other accompanying drugs mainly included aminoglycosides, cycloserine, ethionamide/prothionamide, and pyrazinamide. Sputum smear and culture examinations for acid-fast bacilli (AFB) were performed monthly for the initial 6 months and then at 2- to 3-month intervals until the end of treatment. Comparison was made between clinical successes and failures using univariate and multiple logistic regression analyses for the following variables: age, sex, presence of cavitation, extent of disease, sputum smear positivity, in vitro resistance to ofloxacin, in vitro resistance to streptomycin and/or ethambutol, treatment adherence, and the number of drugs per regimen.

Results: Fifty-one patients (81.0%) were cured, nine patients (14.3%) failed, and three patients (4.7%) died. For the entire group, the mean duration of treatment was 14.0 months, and the mean number of drugs was 4.7. Mean durations of chemotherapy in successful and failed patients were 14.5 and 14.2 months, respectively. Mean time for sputum smear and culture conversions were 1.7 and 2.1 months, respectively. Only cavitation, resistance to ofloxacin, and poor adherence were found to be variables independently associated with adverse outcomes (p [is less than] 0.05; odds ratios = 15.9, 13.5, 12.8, respectively). Negative sputum cultures after 2 and 3 months of therapy were 100% predictive of cure. Positive sputum cultures after 2 and 3 months were 52.3% and 84.6% predictive of failure, respectively. One patient (2.1%) relapsed after apparent cure. Twenty-five patients experienced adverse drug reactions, but only 12 of them needed drug modifications.

Conclusion: Most MDR-TB patients can be treated effectively with ofloxacin/levofloxacin-containing regimens. Presence of cavitation, resistance to ofloxacin in vitro, and poor adherence to therapy portend treatment failure. Monitoring monthly sputum culture for AFB in the initial months of chemotherapy helps predict clinical outcomes.

(CHEST 2000; 117:744-751)

Key words: multidrug resistance; ofloxacin/levofloxacin; tuberculosis

Abbreviations: AFB = acid-fast bacilli; MDR-TB = multidrug-resistant tuberculosis; MIC = minimum inhibitory concentration; TB = tuberculosis

The fluoroquinolones were found to have good in vitro activity against Mycobacterium tuberculosis in the 1980s.[1-5] Subsequent observations have suggested in vivo efficacy.[6-11] Thus, incorporation of fluoroquinolones in second-line regimens for the management of multidrug-resistant tuberculosis (MDR-TB) has been recommended by many authorities, including the World Health Organization.[12-14] Despite this, there is still a dearth of evidence on the role of fluoroquinolones in the management of MDR-TB.[13] Randomized, controlled clinical trials on MDR-TB are difficult to conduct and have additional ethical constraints. We therefore performed a retrospective analysis of a cohort of MDR-TB patients treated with fluoroquinolone-containing regimens in the 1990s. We hoped to evaluate the overall contribution of fluoroquinolones to the therapy of MDR-TB and the optimal duration of such treatment.

The fluoroquinolones studied were ofloxacin and levofloxacin. The former has been used by us for treatment of MDR-TB since the late 1980s.[7,9] More recent observations suggest in vitro activity of levofloxacin (active S-(-) enantiomer of ofloxacin) against M tuberculosis, although cross-resistance has also been demonstrated.[15,16] This superior in vitro activity, in addition to clinical data suggesting that levofloxacin causes less neurotoxicity,[17] resulted in a preference for levofloxacin in the later part of this study.

MATERIALS AND METHODS

Data Collection

The inpatient and outpatient medical records of 79 patients with MDR-TB were reviewed. These patients had been admitted to Grantham Hospital, a tertiary referral center for tuberculosis (TB), from chest clinics under the administration of the Department of Health in Hong Kong between February 1990 and June 1997. All 79 patients were seronegative for the HIV antibody by the enzyme-linked immunosorbent assay. M tuberculosis was identified by sputum culture or by both smear and culture. In vitro drug susceptibility indicated resistance to at least isoniazid and rifampin. Sixteen patients were excluded from the analysis for various reasons described below. Thus, 63 patients were available for evaluation. The details of demographic data, clinical characteristics, chemotherapy, adverse reactions to drugs, and follow-up assessment as well as regular sputum bacteriology and chest radiography results were recorded.

Drug Susceptibility Tests

The drug susceptibility tests were performed using the absolute minimum inhibitory concentration (MIC) method for isoniazid and the resistance-ratio method for all other drugs.[18] The inoculum size was standardized by suspending 2 mg of M tuberculosis organisms in 0.4 mL of sterile distilled water, followed by plating one loopful of organisms onto the Lowenstein-Jensen medium. Growth was defined as the presence of [is greater than or equal to] 20 colonies at the end of 4 to 6 weeks. The resistance ratio was defined as the minimum concentration inhibiting the growth of the test strain divided by the minimum concentration inhibiting the growth of the standard susceptible [H.sub.37]Rv strain in the same set of tests. A resistance ratio of [is less than or equal to] 2 was defined as susceptible and one of 4 to 8, as resistant. For streptomycin, rifampin, ethambutol, pyrazinamide, ethionamide, kanamycin, ofloxacin, cycloserine, and p-aminosalicylic acid, the usual MICs for [H.sub.37]Rv in different batches were 4 to 8 mg/L, 4 to 8 mg/L, 1 to 2 mg/L, 25 to 50 mg/L, 10 to 20 mg/L, 4 to 8 mg/L, 0.63 to 1.25 mg/L, 10 to 20 mg/L, and 0.25 to 0.5 mg/L, respectively. For isoniazid, an absolute MIC [is less than or equal to] 0.2 mg/L was used as the break point for susceptibility. Drug susceptibility studies were not performed for amikacin, amoxicillin-clavulanic acid, clofazimine, or levofloxacin.

Design of Chemotherapy Regimens and Drug Administration

All 63 patients in the main analysis received a fluoroquinolone, either ofloxacin or levofloxacin. The choice was based on the preference and experience of the physician initiating therapy. The other accompanying drugs included aminoglycosides (kanamycin, streptomycin, or amikacin), ethionamide/prothionamide, cycloserine, pyrazinamide, ethambutol, p-aminosalicylic acid, amoxicillin-clavulanic acid, and clofazimine; these were largely selected on the basis of results of in vitro susceptibility tests. After discharge from the hospital, patients continued to receive directly observed treatment, by clinic staff in most cases and by family members in a small number.

Monitoring of Sputum Bacteriology and Definitions of Outcomes

After the pretreatment sputum smear and culture, each patient had sputum evaluated monthly for 6 months. After that, the sputum was evaluated every 2 or 3 months, at the discretion of the attending physician. Success or cure was defined as sustained bacteriologic conversion of sputum culture of AFB from positive to negative for at least 6 consecutive months during therapy and after its cessation. Temporary conversion of sputum culture to negative not meeting the above was labeled as failure; so was the absence of sputum culture conversion to negative throughout treatment.

Statistical Analysis

Data were expressed in means [+ or -] SD and ranges. In identification of variables that might affect treatment outcomes, namely, age, male sex, presence of cavitation, extensive disease, sputum smear positivity, in vitro resistance to ofloxacin, in vitro resistance to streptomycin and/or ethambutol, poor adherence, and the number of drugs used, comparison of the success and failure or death groups was made using Student's independent samples t tests for numeric variables and [chi square] test for categoric variables. Where an expected value in a certain cell in a contingency table was [is less than] 5, the Fisher's Exact Test was used. A p value [is less than] 0.05 was considered significant. A multiple logistic regression analysis was then performed to identify the variables that were independently associated with adverse outcomes of chemotherapy.

RESULTS

Patients Excluded

Sixteen patients were excluded because they received treatment for [is less than] 6 months. Two patients left against medical advice and did not receive any chemotherapy. Another two patients succumbed before chemotherapy could be initiated; they had severe COPD and carcinomatosis. Three patients died of diseases other than TB: the first was a 72-year-old man who died of chronic renal failure after 5 months of drug treatment. Sputum smear and culture for AFB had converted from positive to negative after 1 month of treatment. The second was a 66-year-old man who died of acute myocardial infarction. Sputum smear and culture for AFB had become negative after 2 months of therapy. The third was a 61-year-old man who died suddenly of cerebrovascular accident after he had received 4 months of chemotherapy. Sputum smear and culture for AFB were still positive. Three more patients who did not receive fluoroquinolone-containing drug regimens were also excluded. Each of these three patients had bacilli resistant to ofloxacin. They received a mean of 4.3 [+ or -] 0.6 drugs (range, 4 to 5 drugs), and only one of them achieved treatment success. Finally, six more patients abandoned treatment after they had received chemotherapy for [is less than] 6 months (2.8 [+ or -] 1.6 months; range, 1 to 5 months).

Demographic and Clinical Characteristics

Sixty-three patients were included in the final analysis. Sixty-two were Chinese and one was British. Forty-seven (74.6%) were male, and 16 (25.4%) were female. Mean age was 45.2 [+ or -] 16.0 years (range, 12 to 77 years). Mean body weight was 51.4 [+ or -] 8.8 kg (range, 29 to 73 kg). All had radiographic and bacteriologic evidence of pulmonary TB. Two patients had extrapulmonary involvement: meningitis and spondylitis. Concomitant medical diseases were present in 23 patients (36.5%). These included COPD, hypertension, diabetes mellitus, hyperlipidemia, and chronic viral or alcoholic liver diseases. Forty-one patients (65.1%) had previous therapy. The mean number of previous treatment courses was 2.0 [+ or -] 1.4 (range, 1 to 5). Each treatment course lasted [is greater than] 4 weeks. Thus, 34.9% of patients had initial resistance to isoniazid and rifampin (with or without associated resistance to streptomycin and/or ethambutol), whereas 65.1% of patients may have acquired resistance to the aforementioned drugs. A comparison of the various characteristics of the patients included in and those excluded from the final analysis is presented in Table 1. There are no significant differences, except that the excluded patients were older.

Table 1--Comparison of Demographic, Clinical, and Bacteriologic Characteristics Between Patients Included in and Excluded From Analysis(*)

(*) NS = not significant.

([dagger]) Total radiographic extent greater than one lung.

([double dagger]) With reference to (isoniazid and rifampin) [+ or -] (streptomycin and/or ethambutol).

Drug Regimens and Durations

As a group, all patients included in the final analysis received a mean of 4.7 [+ or -] 0.7 drugs (range, 3 to 6 drugs) on commencement of therapy. Ofloxacin was used in 53 patients and levofloxacin in 10 patients. The other common drugs in the regimens included aminoglycosides, ethionamide/prothionamide, cycloserine, pyrazinamide, and ethambutol (Table 2). The fluoroquinolone was administered until cessation of chemotherapy in all 63 patients. Aminoglycosides were usually administered for 3 to 6 months depending on tolerance. The duration of therapy with other agents was tailored to patient tolerance and individual physician judgment. The minimum duration of therapy for patients who responded microbiologically was 1 year. The variables considered at discontinuation of treatment included time of sputum smear and culture conversion, extent of radiographic disease and rapidity of improvement, rapidity and completeness of closure of cavities, extent of drug resistance in vitro, presence of diabetes mellitus or silicosis, and extrapulmonary disease. Presence of unfavorable variables prompted the decision to prolong therapy beyond 1 year. Patients who had not responded microbiologically after 9 to 12 months of chemotherapy would have treatment reviewed. Treatment was stopped then or continued for a few more months. The mean number of drugs received by patients at the seventh month was 3.6 [+ or -] 0.6 drugs (range, 3 to 5 drugs). Dosages of the second-line drugs are depicted in Table 3. The mean duration of chemotherapy in 63 patients was 14.0 [+ or -] 3.7 months (range, 0.5 to 24 months). Three patients died of TB after 0.5, 7, and 7 months of chemotherapy. Excluding those three patients, the mean duration of chemotherapy was 14.4 [+ or -] 3.1 months (range, 9 to 24 months).

Table 2--Profile of Susceptibility Patterns to Conventional Short-Course Chemotherapeutic Drugs and Treatment Regimens for 63 Patients With MDR-TB(*)

(*) A = amikacin; Aug = amoxicillin-clavulanic acid; Clo= clofazimine; Cyc = cycloserine; Et/Pt = ethionamide/prothionamide; H = isoniazid; K = kanamycin; L = levofloxacin; M = ethambutol; O =: ofloxacin; PAS = p-aminosalicylic acid; R = rifampin; S = streptomycin; Z = pyrazinamide.

([dagger]) 8 patients received 5 drugs; 4 patients received 4 drugs.

([double dagger]) 1 patients received 5 drugs; 7 patients received 4 drugs; 1 patient received 3 drugs.

([sections]) 3 patients received 6 drugs; 12 patients received 5 drugs; 2 patients received 4 drugs.

([parallel]) 2 patients received 6 drugs; 19 patients received 5 drugs; 4 patients received 4 drugs.

Table 3--Dosages of Second-Line Antituberculosis Drugs Used in 63 Patients With MDR-TB(*)

(*) Dosage is reported as mean [+ or -] SD, with range in parentheses.

Adherence to Therapy

Fourteen patients (22.2%) had poor adherence to chemotherapy, which was defined as missing [is greater than] 20% of the designated number of drug doses. The rest received [is greater than or equal to] 80% of the designated treatment doses.

Outcomes

Fifty-one patients were cured. These included the two patients with extrapulmonary disease. Their sputum smear for AFB converted from positive to negative at a mean of 1.7 [+ or -] 1.0 months (range, 1 to 5 months) after chemotherapy commencement. Their sputum culture converted from positive to negative at a mean of 2.1 [+ or -] 1.2 months (range, 1 to 5 months) after starting chemotherapy. The bacteriologic conversion of the successful patients was sustained. Nine patients failed and three died of TB. The mean duration of chemotherapy in the 51 successful patients was 14.5 [+ or -] 3.0 months (range, 9 to 24 months). Four patients in this group discontinued chemotherapy at their own will after receiving 9 to 11 months of drug treatment. However, all of them had sputum culture converted to negative at a mean of 2.3 [+ or -] 1.3 months (range, 1 to 4 months) after initiation of chemotherapy. One patient with extensive drug resistance received 24 months of treatment. The mean duration of chemotherapy in the nine living patients with treatment failure was 14.2 [+ or -] 3.4 months (range, 10 to 18 months). Thus, there was no difference in the durations of chemotherapy between the treatment success and failure groups (p [is greater than] 0.05).

Of the variables that might be associated with the treatment outcome, only the presence of cavitation, resistance to ofloxacin in vitro, and poor adherence emerged as variables significantly associated with adverse outcomes (Table 4). When the total number of drugs used, as well as the number of active drugs at different junctures of treatment, namely, at commencement, seventh month, and cessation of treatment, was compared by univariate analysis between the success and failure or death groups, no significant difference was noted. Active drugs referred to those drugs with activity demonstrated by susceptibility tests in vitro. Further analysis was made after stratification of patients receiving fluoroquinolones into those who received ofloxacin (n = 53) and levofloxacin (n = 10). Forty-three of 53 patients in the ofloxacin group had bacilli susceptible to ofloxacin, and 37 achieved treatment success. Among the remaining 10 patients with bacillary resistance to ofloxacin, only 5 were cured. In the levofloxacin group, 7 of 10 patients had bacilli susceptible to ofloxacin, and all had treatment success with levofloxacin-containing regimens. Of the remaining three patients with bacillary resistance to ofloxacin, two were successfully treated with levofloxacin-containing regimens. The three variables independently associated with adverse outcomes persisted when multiple logistic regression analysis was applied to the 53 patients given ofloxacin only (p = 0.01 [cavity], p = 0.004 [resistance to ofloxacin], p = 0.01 [poor adherence]; odds ratios, 17.5, 18.2, and 10.8, respectively).

Table 4--Demographic, Clinical, Bacteriologic, and Treatment Characteristics in 63 MDR-TB Patients With Different Outcomes and Their Comparison by Univariate and Multiple Logistic Regression Analyses(*)

(*) See footnote of Table 1 for abbreviation.

Adverse Drug Reactions

Twenty-five of the treated patients (39.7%) experienced adverse drug reactions of varying severity. The most common ones were related to the otovestibular and gastrointestinal systems and the CNS. Some patients had multiple adverse reactions (Table 5). However, modification of drug regimens was needed in only 12 patients. Nine of them required termination of aminoglycoside treatment after a mean of 3.0 [+ or -] 1.6 months (range, 1 to 5 months) because of otovestibular toxicity or nephrotoxicity. Five patients had CNS dysfunction, namely, depression (n = 3) and seizures (n = 2), which necessitated withdrawal of cycloserine at a mean of 4.0 [+ or -] 3.6 months (range, 1 to 9 months). Four patients had intolerable bloating, nausea, and vomiting that required withdrawal of ethionamide/prothionamide from the regimen after a mean of 4.0 [+ or -] 3.6 months (range, 1 to 9 months). Two patients had pyrazinamide withdrawn after 3 months of therapy because of severe clinical gout and drug-induced hepatitis. Two patients had ethambutol withdrawn because of blurring of vision after 4 months of treatment. Finally, one patient had persistent dizziness despite withdrawal of cycloserine. This necessitated change of the fluoroquinolone from ofloxacin 600 mg daily to levofloxacin 300 mg daily 4 months from commencement of therapy. There was no significant difference in the incidence of adverse effects from the drugs between the success and failure groups (p [is greater than] 0.05).

Table 5--Adverse Reactions to Second-Line Drugs Experienced by 25 Patients With MDR-TB

Follow-up Assessment

Four of the 51 patients cured were lost to follow-up. The remaining 47 were followed up for a mean of 24.5 [+ or -] 16.5 months (range, 3 to 75 months). Only one patient (2.1%) was found to have radiographic and bacteriologic relapse 6 months after treatment cessation. This patient had 24 months of treatment and initial bacillary resistance to ofloxacin in vitro. She eventually had a right upper lobectomy performed 6 months after retreatment with drugs. Three of the nine patients with treatment failure were lost to follow-up on completion of chemotherapy. The remaining six patients with treatment failure were followed up for a mean of 28.0 [+ or -] 21.9 months (range, 3 to 66 months). Two subsequently died of TB 48 and 52 months after discontinuation of chemotherapy. None of the failed patients was suitable for surgical treatment, largely because of the presence of bilateral disease.

Monitoring of Sputum Bacteriology

The relationship between sputum culture after 2 and 3 months of chemotherapy and final outcomes was also assessed. Information was available in all patients except one who died of TB within the first month of chemotherapy. All 41 patients with negative sputum cultures after 2 months of chemotherapy and all 49 patients with negative sputum cultures after 3 months of chemotherapy eventually achieved success. Thus, the predictive values of negative sputum cultures after 2 and 3 months of treatment for success were both 100%. Eleven of 21 patients with positive sputum cultures after 2 months of chemotherapy and 11 of 13 patients with positive sputum cultures after 3 months of chemotherapy eventually failed or died. Thus, the predictive values of positive sputum cultures after 2 and 3 months of treatment for failure were 52.4% and 84.6%, respectively.

DISCUSSION

In this community, the initial MDR-TB prevalence rates ranged from 0.4 to 0.7%, and the combined MDR-TB prevalence rates ranged from 0.9 to 1.0% in the study period (unpublished data, Department of Health, Hong Kong). The demographic and clinical characteristics of MDR-TB patients in our analyzed cohort were similar to other series, with a predominance of male patients.[19-24] Approximately 40% of our patients did not receive any previous antituberculosis drugs. Our high initial MDR-TB proportion concurred with data from some series[20-22] but not others.[19,24] The overall success rate of approximately 80% corroborates the best results of published studies or analyses.[14,20,24]

Among the three variables that were found to be independently associated with adverse outcomes of patients, the presence of cavitation might impede drug penetration and thus attenuate the therapeutic efficacy of antimicrobial agents. In a study on retreatment cases, it was found that cavitary disease per se, irrespective of drug-resistance status, was associated with poor treatment outcomes.[25] Poor adherence linked with adverse treatment outcomes is not unexpected and emphasizes the importance of directly observed therapy in the treatment of TB, which should be mandatory for all patients with MDR-TB.[26] Contrary to one important study undertaken in the United States, male sex was not found to be an important determinant for adverse outcomes.[19] This might be related to particular factors linked to the male population in that study but not in ours. As the details of previous history of chemotherapy were generally incomplete for our patients, we could not study the relationship between the number of previously used drugs and the likelihood of adverse treatment outcomes. Some investigators have found this relationship significant.[19]

Previous studies on the outcomes of chemotherapy in patients with MDR-TB have stressed the negative impact of extensiveness of drug resistance and the positive impact of the number of appropriate drugs ([is greater than or equal to] 2) administered in accordance to drug susceptibility tests.[19,22,24] However, it has also been shown that some patients who received drugs to which their organisms were susceptible in vitro did not respond microbiologically.[19,24] At least one possible explanation for this discrepancy between in vitro activity and in vivo efficacy is that susceptibility testing for second-line agents needs greater standardization. For practical purposes, it would be useful to find a single drug resistance that could help predict the outcome of therapy. We focused our attention on ofloxacin resistance as such a potential marker for several reasons. First, the MICs of ofloxacin against strains of M tuberculosis have been consistent irrespective of the methodology or culture medium used, with MICs against 90% of ofloxacin susceptible strains [is less than or equal to] 1.25 mg/L.[1-5,7] Many other fluoroquinolones behave similarly.[l-5] Second, ofloxacin or other fluoroquinolones are very commonly included in second-line drug regimens for MDR-TB.[12,13] Third, preliminary data have suggested a good correlation between activity in vitro and efficacy in vivo for ofloxacin.[6,7] In our analysis, bacillary resistance to ofloxacin was indeed found to be an important variable significantly associated with adverse treatment outcomes. This finding implicates the likely pivotal role of ofloxacin/levofloxacin in multidrug regimens used for treatment of patients with MDR-TB. The six patients with bacillary resistance to ofloxacin in vitro who failed ofloxacin/ levofloxacin-containing regimens still received a mean of 2.7 active drugs (range, 2 to 3 drugs).

Aside from in vivo efficacy, ofloxacin/levofloxacin has the favorable therapeutic characteristics of high peak serum drug concentration: MIC ratio,[7] good tissue penetration, particularly into lungs,[27] and good tolerance by patients on long-term administration.[28,29] Our patients tolerated the fluoroquinolones even at high doses, corroborating the experience of others. Fluoroquinolones must be used carefully to prevent the emergence of cross-resistance among other members of this class of drugs.[15] This has been experienced in certain communities.[30-32] In our present cohort of patients, only one of the six failed patients who had ofloxacin-susceptible M tuberculosis strains developed acquired resistance to ofloxacin with treatment. This patient also had poor adherence to therapy. Further, our data suggest that levofloxacin, when used at a dose of 600 to 800 mg daily, is more effective than ofloxacin at a similar dose. However, the difference in efficacy of the two fluoroquinolones for patients with ofloxacin-susceptible and ofloxacin-resistant bacilli did not reach statistical significance (p [is greater than] 0.05). Evaluation with a larger sample size might allow a more definitive conclusion.

The optimal duration of therapy for patients with MDR-TB is unknown. A number of authorities including the World Health Organization have recommended a total duration of [is greater than or equal to] 18 months after culture conversion, even for non-HIV-infected subjects.[12,13] However, our data suggest that at least some non-HIV-infected patients who managed to achieve sustained sputum culture conversion to negative status could be adequately treated with 12 months of fluoroquinolone-containing second-line chemotherapy regimens. In our patients, only those at risk because of diabetes mellitus, silicosis, extensive radiographic disease with or without cavities, extensive drug resistance in vitro, delayed sputum culture conversion (ie, after [is greater than] 3 months of chemotherapy), and extrapulmonary involvement were treated for [is greater than] 12 months, often for 15 to 18 months in toto. Although our relapse rate of 2.1% is gratifying, it is important to note that approximately 50% of our patients were followed up for [is less than] 24 months; some of these may have relapsed subsequently. We believe that in formulating the optimal duration of therapy for MDR-TB, multiple factors must be considered, particularly the bactericidal capacity and dosage of the drugs used, cost, and drug toxicity as well as anticipated patient adherence.

In this retrospective analysis of MDR-TB patients, those who responded achieved sputum culture negativity during the early months of treatment, usually within 3 months. This concurs with a study of HIV-negative subjects with MDR-TB.[20] Negative sputum culture at 2 and 3 months was predictive of eventual cure in 100% of patients. The predictive value for failure of positive sputum cultures at 2 and 3 months was 52.4% and 84.6%, respectively. The predictive values of negative and positive sputum cultures for failure or success both reached 100% after 6 months. Thus, monitoring monthly sputum culture for AFB in the initial 6 months of treatment helps greatly in predicting outcome. Such monitoring has been our practice since 1990 and currently is recommended by the World Health Organization.[13]

ACKNOWLEDGMENT: The authors thank Professor David Schlossberg for reviewing the manuscript.

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(*) From the Tuberculosis and Chest Unit, Grantham Hospital (Drs. Yew, Chau, Wong, and Lee), and the Tuberculosis Service, Department of Health, Wanchai Chest Clinic (Drs. Chan, Tam, and Leung), Hong Kong, China.

Presented in abstract form at the 1999 Annual Congress of the European Respiratory Society at Madrid, Spain.

Manuscript received May 11, 1999; revision accepted October 5, 1999.

Correspondence to: Wing Wai Yew, MB, FCCP, Tuberculosis and Chest Unit, Grantham Hospital, 125 Wong Chuk Hang Rd, Hong Kong, China

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