Ofloxacin is a new quinolone antimicrobial with a broad spectrum of activity for Gram-positive and Gram-negative bacteria, Legionella species, Mycoplasma pneumoniae, Chlamydia psittaci and Mycobacterium tuberculosis.[3-6] The excellent antimycobacterial activity of ofloxacin has encouraged one noncomparative clinical trial of ofloxacin for the treatment of pulmonary tuberculosis. The emergence of multi-drug-resistant M tuberculosis, especially in patients with human immunodeficiency virus infection, requires the use of new antituberculosis agents, one of which could be ofloxacin. We report the results of a well-controlled trial of ofloxacin or ethambutol, both combined with isoniazid and rifampicin, for the primary treatment of pulmonary tuberculosis.
Patient Enrollment and Treatment
Eligible study subjects were all patients with previously untreated, smear- or culture-positive pulmonary tuberculosis who were admitted to Nagasaki University Hospital and 11 affiliated hospitals during the period from January 1986 to May 1988. Study subjects were randomized into two treatment groups by a controller. The two treatments were either ofloxacin or ethambutol (1 g/day), plus rifampicin (0.45 g/day) and isoniazid (0.4 g/day). Ofloxacin was administered in a dosage of 0.6 g/day for the initial two months, then 0.3 g/day for the following seven months. All drugs were administered orally daily for nine months. Randomization of the two treatment groups was evaluated, comparing gender, age the presence of underlying immunosuppression or chronic lung diseases, the presence of cavities on chest roentgenogram and bacteriologic findings. Clinical efficacy was determined, based on the results of chest roentgenograms, sputum smears and cultures for mycobacteria and physical examinations, all of which were performed monthly. The improvement rates of the chest roentgenogram were classified into four categories, based on the reduction in size of shadows. Drug toxicity was evaluated, based on the results of hematologic and biochemical blood tests, urine analyses and physical examinations, all of which were performed monthly.
Antimicrobial Susceptibility Testing
Microbroth dilution was used to determine the minimum inhibitory concentrations of the antituberculosis drugs for patient isolates of M tuberculosis. Mycobacteria grown on Ogawa medium were suspended in Middlebrook 7H9 broth containing (0.1 percent) Tween 80 to approximate the optical density of a 0.5 McFarland barium sulfate standard. The bacterial suspensions (50 [Mu]g/l) were inoculated into microwells containing equal volumes of serially diluted antituberculosis drugs (0.05 to 100 [Mu]g/ml), and incubated for two weeks at 37 [degrees] C in 5 percent [CO.sub.2]. After the two-week incubation period, 0.33 M [NaNO.sub.3], in phosphate buffer (pH 7) was added (10 [Mu] 1) to the wells, and incubated at 37 [degrees] C for 2 h. Then a solution containing 1 percent each of N-(1-naphthyl)ethylenediamine, sulfanilamide and tartaric acid in distilled water was added (10 [Mu] 1), and incubated at 37 [degrees] C for 12 h. The minimum inhibitory concentration was defined as the lowest concentration at which complete inhibition of bacterial growth was seen, as determined by the optical density of the wells at 490 nm.
Chi square testing with correction for continuity was used to compare nonparametric frequencies; the Student's t test was used to compare ages. A p value >0.05 was classified as being not statistically significant.
Enrollment and Reasons for Study Exclusion
A total of 156 patients were enrolled into the study. Thirty-two enrolled patients were dropped from the study (Table 1), leaving 62 patients in each of the two treatment groups, or a total of 124 patients evaluable for clinical efficacy. In the analysis of side-effects, 14 patients excluded from analysis of efficacy because of drug side-effects were added, making 138 patients evaluable for this analysis. No significant differences were found for exclusion reasons between the two groups (p = 0.91).
Evaluation of Adequacy of Randomization
No significant differences (p>0.1) between the two treatment groups were found with respect to gender, age, the presence of underlying diseases, chest roentgenogram or bacteriologic findings (Table 2). [TABULAR DATA 2 OMITTED]
No differences in the rate of improvement of chest roentgenograms were observed for the different treatment groups (Fig 1). The frequencies of significant improvement of chest roentgenogram findings three months after starting treatment were 36 percent in the ofloxacin group and 50 percent in the ethambutol group (p = 0.15); six months postenrollment 66 percent of patients in the ofloxacin group had significant improvement of their chest roentgenogram findings vs 73 percent of patients in the ethambutol group (p = 0.56). Chest roentgenogram abnormality improvement rates were faster in the ethambutol group than in the offoxacin group, but the difference was statistically not significant (9 months p=0.50, 12 months p = 1.00). Conversion rates for mycobacterial smears and cultures are shown in Figure 2. All patient specimens were culture-negative six months after starting treatment, regardless of treatment group; no significant differences were observed for sputum smear or culture conversion rates between treatment groups. Neither radiologic aggravation nor bacteriologic relapse was seen in the 76 patients followed up for two years after the completion of treatment (Table 3).
In vitro Antimicrobial Sensitivity of Bacterial Isolates
Antimicrobial sensitivities of 11 randomly selected pretherapy M tuberculosis strains from each treatment group, or 22 total strains, is shown in Table 4. No resistance to any of the study drugs was demonstrated.
Nine of 70 (13 percent) in the ofloxacin group had abnormal laboratory tests vs 15 of 68 patients (22 percent) in the ethambutol group; abnormal liver function tests constituted the majority of abnormal results. Clinically detected adverse reactions, such as rash and fever, were seen in 10 of 70 (14 percent) patients in the ofloxacin group, in 5 of 68 (7 percent) patients in the ethambutol group. Adverse reactions necessitated chemotherapy changes in eight ofloxacintreated patients and six ethambutol-treated patients. No significant difference between the groups was seen in the frequencies of abnormal laboratory tests (p=0.23) or clinically observed adverse reactions (p=0.30).
Our study demonstrates that ofloxacin is as effective as ethambutol for the treatment of primary pulmonary tuberculosis when either drug is given with isoniazid and rifampicin. There were no significant differences between the study groups at study initiation, nor were any apparent during or after therapy. It is unknown whether the addition of either ethambutol or ofloxacin significantly altered the outcome of any patients in this study, and thus impossible to predict if ofloxacin would be effective in the face of multi-drug resistance of M tuberculosis. We treated 29 patients with persistent positive culture for multi-drug-resistant M tuberculosis by adding ofloxacin in a dosage of 0.8 g/day for the initial two months, then 0.6 g/day for the following four months to ongoing therapy, and culture conversion to negative was obtained in ten patients. In addition, Tsukamura et al showed that six to eight months of solitary ofloxacin therapy for the treatment of 19 cases of cavitary pulmonary tuberculosis, resistant to various antituberculosis drugs, resulted in decreased amounts of sputum mycobacteria in all cases and in culture conversion to negative in five cases. This suggests that ofloxacin may be useful for the treatment of chemoprophylaxis of multiresistant tuberculosis, although clinical trials are needed to study this further. Our patients were able to tolerate long-term administration of ofloxacin without significant adverse affects, despite the broad antibacterial spectrum of this drug. Since ofloxacin is more expensive than ethambutol, ofloxacin could be used as a substitute for ethambutol for patients who have adverse reactions to ethambutol or possibly for patients with M tuberculosis resistant to ethambutol.
ACKNOWLEDGMENT: We gratefully acknowledge the help of Tadao Shimao, M.D., for excellent advice on this study add Paul H. Edelstein, M. D., for editorial corrections.
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