Ofloxacin

Objective: To compare levofloxacin and ofloxacin in the treatment of multidrug-resistant tuberculosis (MDR-TB).

Patients and methods: A retrospective analysis of 106 patients with MDR-TB (February 1990 through December 2000) receiving directly observed therapy with fluoroquinolone and accompanying drugs, which mainly included aminoglycosides, cycloserine, ethionamide/prothionamide, and pyrazinamide, was performed. Clinical data from 99 suitable patients were subjected to univariate analysis, stratification, and multiple logistic regression to compare the roles of levofloxacin and ofloxacin in multidrug regimens.

Results: Forty patients received 612.5 [+ or -] 79.0 mg qd levofloxacin (mean [+ or -] SD), and 59 patients received 628.8 [+ or -] 101.8 mg qd ofloxacin together with similar active second-line drugs for similar durations. The times to sputum smear (both 1.8 months) and culture conversion (both 2.1 months) were equivalent. Adverse reactions occurred at similar rates (10.0% vs 11.9%). The combined treatment success rate was 83.8%, being higher among ofloxacin-susceptible than ofloxacin-resistant cases (90.5% vs 64.0%, p < 0.01). The success rates for the levofloxacin group were 99.0% (overall), 96.2% (ofloxacin-susceptible cases), and 78.6% (ofloxacin-resistant cases) in comparison with 79.7%, 87.5%, and 45.5%, respectively, for the ofloxacin group (Mantel-Haenszel common odds ratio estimate, 4.0; p < 0.05). Bacillary susceptibility to ofloxacin, good adherence, radiographic extent of one lung or less, and use of levofloxacin were independent predictors of favorable outcome (odds ratios, 7.6 to 21.3). One patient each from both groups relapsed.

Conclusion: Levofloxacin was found to be more efficacious than ofloxacin when incorporated into multidrug regimens used for treatment of MDR-TB.

Key words: levofloxacin; multidrug; ofloxacin; resistance; tuberculosis

Abbreviations: MDR-TB = multidrug-resistant tuberculosis; MIC = minimum inhibitory concentration

In our previous study (1) on the use of ofloxacin/levofloxacin-containing regimens in multidrug-resistant tuberculosis (MDR-TB), bacillary resistance to ofloxacin in vitro was associated with a poorer outcome. A study (2) in Turkey also suggested that fluoroquinolones might play a significant role in the treatment of MDR-TB, as patient outcome was less favorable if there had been previous treatment with ofloxacin. Due to ethical constraints, it might not be feasible to conduct randomized controlled clinical trials to further delineate the exact contribution of the fluoroquinolones in the management of such a formidable disease. (3) Levofloxacin is the pharmacologically active S(-) enantiomer of ofloxacin, (4) whereas the latter fluoroquinolone is really a racemic mixture of the two stereoisomers. Studies (5,6) have shown levofloxacin to be approximately twice as active as ofloxacin against Mycobacterium tuberculosis in vitro. Clinical data pertinent to short-term administration have suggested that levofloxacin might be associated with a lower incidence of GI intolerance and neurotoxicity compared to ofloxacin. (4) This difference might, however, be somewhat confounded by variation in dosage of the fluoroquinolones used. (4) As only a few patients in our previous study were put on levofloxacin-containing regimens, we therefore would like to further explore the role of levofloxacin, in comparison with ofloxacin, in the treatment of MDR-TB, through extraction of information retrospectively from our accumulating database of patients with MDR-TB.

MATERIALS AND METHODS

Data Collection

Since our last analysis of 63 patients (February 1990 to June 1997), an additional 43 patients with MDR-TB (with bacillary resistance to at least isoniazid and rifampin in vitro) were managed in Grantham Hospital under the administration of the Hospital Authority, and chest clinics under the administration of the Department of Health in Hong Kong from July 1997 through December 2000. Seven patients received antituberculosis therapy for < 6 months prior to abscondment. They were excluded from the present analysis. Thus, a total of 99 patients were available for the present comparative study on the therapeutic roles of the two closely related fluoroquinolones. All patients were seronegative for HIV antibody by the enzyme-linked immunosorbent assay.

Chemotherapy Regimens and Administration

Drug susceptibility testing of most conventional and second-line antituberculosis drugs were performed by the resistance ratio of proportion methods. (7,8) For isoniazid, the absolute concentration (7) method was used. For ofloxacin, susceptibility testing was performed by the absolute concentration (9) or resistance ratio (10) methods. For amoxicillin-clavulanic acid, rifabutin, and clofazimine, drug susceptibility testing was not performed. Ofloxacin-resistant isolates were defined as those with minimum inhibitory concentration (MIC) [greater than or equal to] 2 mg/L. Fifty-nine patients received ofloxacin, and 40 patients received levofloxacin. The patients reported earlier received ofloxacin or levofloxacin basing on the preference of the responsible physician. From July 1999 onwards, all new cases of MDR-TB were treated with levofloxacin. The other accompanying drugs included aminoglycosides (kanamycin, streptomycin, of amikacin), ethionamide/prothionamide, cycloserine, pyrazinamide, ethambutol, p-aminosalicylic, acid, amoxicillin-clavulanic acid, and clofazimine. The accompanying drugs were largely selected on the basis of results of drug susceptibility testing. All patients received directly observed therapy in the hospital of clinic settings. The latter also included a small number with supervision by family members. Poor adherence was defined as patient missing > 20% of the designated doses. Good adherence denoted the patient taking [greater than or equal to] 80% of the designated doses.

Monitoring of Sputum Bacteriology and Definitions of Outcome

After the pretreatment sputum smear and culture assessment, such evaluation would continue monthly for 6 months, and then every 2 to 3 months for the entire duration of treatment. Success was defined as sustained bacteriologic conversion of culture finding from positive to negative for at least 6 consecutive months during therapy and on cessation. Temporary conversion not meeting the above-mentioned criteria or absence of conversion to negative throughout treatment was labeled as failure.

Statistical Analysis

After retrieval of the necessary clinical and bacteriologic data, these were analyzed statistically using Student t test (for numeric variables) and [chi square] test/Fisher exact test (for categoric variables) as appropriate. Mantel-Haenszel common odds ratio estimate was used to test the significance of the overall difference, when comparison was made between two variables across multiple strata; p < 0.05 was considered significant. The demographic. clinical, bacteriologic, and treatment characteristics including age, sex, cavity, radiographic extent, sputum smear, susceptibility to ofloxacin in vitro, susceptibility to the number of first-line drugs, adherence, number of drugs used, and use of levofloxacin vs ofloxacin were then analyzed with multiple logistic regression to examine the impact of various factors on outcome. The efficacy of levofloxacin and ofloxacin was compared further by examining their respective success rates stratified according to the number of adverse factors present.

RESULTS

There was no significant difference in the demographic and other characteristics between the patients who received levofloxacin or ofloxacin (Table 1), apart from some suggestion of an excess of ofloxacin-resistant cases among the levofloxacin group. When the treatment details of the two groups of patients were compared (Table 2), there was no significant difference in the total number of drugs used and the number of active drugs administered (as gauged by antimicrobial susceptibility testing in vitro) between the patients in the levofloxacin group and the ofloxacin group. The accompanying drugs mainly included kanamycin, amikacin, cycloserine, ethionamide/prothionamide, pyrazinamide, ethambutol, and para-aminosalicylic acid. The duration of treatment did not differ between the two groups. Overall, similar dosages of levofloxacin and ofloxacin were employed. The dosage of ofloxacin was slightly higher than that of levofloxacin only for those patients who harbored bacilli resistant to ofloxacin in vitro. This was most likely related to our previous practice of using ofloxacin at a dosage of 800 mg qd in such patients if the drug proved tolerable.

Forty-one of the 99 treated patients (41.4%) had adverse drug reactions of varying severity. Twenty-two patients reported CNS adverse effects, including depression (n = 6), unstable emotions (n = 2), insomnia (n = 6), bizarre behavior/psychotic features (n = 2), dizziness (n = 3), seizures (n = 2), muscle twitching (n = 1), and paraesthesia (n = 1). Nineteen patients reported GI reactions manifesting as nausea, vomiting, or epigastric discomfort. Twelve patients had otovestibular disturbances in form of vertigo, tinnitus, or impaired hearing. Other reported adverse reactions included arthralgia/gout (n = 8), liver function impairment (n = 6), skin rash (n = 3), renal function impairment (n = 2), and blurring of vision (n = 2).

Twenty of those 22 patients reporting CNS adverse effects were also receiving cycloserine. Eight patients improved with withdrawal (n = 7) or reduction in dosage (n = 1) of cycloserine. One patient had underlying depressive disorder, and his symptoms improved with antidepressant treatment. The depressive symptoms of two other patients were mild and responded to counseling. The CNS adverse effects of these 11 patients were considered more likely attributable to cycloserine. The remaining 11 patients reported insomnia (n = 6), dizziness (n = 2), dizziness plus seizure (n = 1), paraesthesia (n = 1), and muscle twitching (n = 1). Their CNS adverse effects were considered by the attending physicians to be attributable to fluoroquinolones.

Most patients tolerated the fluoroquinolones well, as adverse reactions to this class of drug only accounted for 14.9% of the overall adverse drug reaction rate in the multidrug regimens employed. Adverse reactions to levofloxacin occurred at a similar rate as those of ofloxacin (10.0% and 11.9%, respectively; p > 0.05). Adverse drug reactions that required modification of antimicrobials occurred in 22 of all 99 patients (22.2%). Reduction of dosage of levofloxacin was required in only one patient with moderate dizziness, while dosage modification or substitution of ofloxacin was required in four patients with moderate dizziness (n = 2), moderate dizziness and seizure (n = 1), and moderate insomnia (n = 1). This difference in tolerance between the two fluoroquinolones (2.5% vs 6.8%), while encouraging, failed to reach statistical significance (p > 0.0.5). Among the latter four patients, two had substitution of ofloxacin by levofloxacin that eventually resulted in better drug tolerance.

Figure 1 depicts the treatment outcomes of all patients, further stratified into those with bacillary susceptibility and resistance to ofloxacin, respectively. The overall treatment success rate was 83 of 99 patients (83.8%), with a higher success rate among ofloxacin-susceptible cases than ofloxacin-resistant cases (90.5% vs 64.0%, p = 0.005). These findings corroborate our previous published results. (1) The success rates for the levofloxacin group were 90.0% overall, 96.2% for ofloxacin-susceptible cases, and 78.6% for ofloxacin-resistant cases. The corresponding figures for the ofloxacin group were 79.7%, 87.5%, and 45.5%, respectively. After stratification by ofloxacin resistance, the difference in overall success rates between the two groups was statistically significant (Mantel-Haenszel common odds ratio estimate, 4.00; p = 0.049). Among successfully treated patients, there was no difference in the times required for sputum smear and culture finding conversion to negative between two groups (1.8 [+ or -] 0.8 months vs 1.8 [+ or -] 1.0 months for smear conversion, and 2.1 [+ or -] 0.9 months vs 2.1 [+ or -] 1.2 months for culture conversion; both p > 0.05). Thirty-two successfully treated patients from the levofloxacin group and 45 similar patients from the ofloxacin group were available for follow-up of 18.3 [+ or -] 16.2 months and 45.7 [+ or] 23.6 months, respectively (mean [+ or -] SD). Only one patient from each group had bacteriologic relapse at 6 months after treatment cessation. Both patients had extensive bacillary resistance to antimicrobials including ofloxacin. There was no significant difference in relapse rates between the successfully treated patients in the two groups. When the demographic, clinical, bacteriologic, and treatment characteristics were examined by multiple logistic regression, four variables independently associated with a favorable outcome emerged (Table 3). A beneficial effect was found associated with the use of levofloxacin rather than ofloxacin, thus implicating a greater in vivo efficacy of the former fluoroquinolone than the latter in multidrug regimens for MDR-TB.

[FIGURE 1 OMITTED]

The relationship between treatment success rate and the number of adverse factors is depicted in Table 4. The adverse factors referred to bacillary resistance to ofloxacin in vitro, radiographic extent of disease greater than one lung, and poor adherence to treatment. Levofloxacin- and ofloxacin-containing regimens were equally effective when no adverse factor was present. There was a trend toward better efficacy in the levofloxacin group when one or two factors were present. Both groups did not fare well when all three adverse factors were present. The overall difference between the two groups was statistically significant (Mantel-Haenszel common odds ratio estimate, 6.80; p = 0.045).

DISCUSSION

Levofloxacin has been found to be more active than ofloxacin in vitro (5,6); however, there is still a dearth of clinical data concerning the comparative efficacy of the two closely related fluoroquinolones in the treatment of MDR-TB. In the present report, we have demonstrated that levofloxacin is more efficacious than ofloxacin when the fluoroquinolone is incorporated into multidrug regimens comprising similar accompanying agents.

As stated earlier, since July 1999 all new cases of MDR-TB have been treated with levofloxacin. For those harboring bacilli susceptible to ofloxacin, levofloxacin was used at a dose of 500 to 600 mg qd, with the latter dose reserved for patients weighing [greater than or equal to] 50 kg. For those harboring bacilli resistant to ofloxacin, levofloxacin was used at a dose of 600 to 800 mg qd, with the latter dose administered to patients weighing [greater than or equal to] 50 kg. The recommendation concerning ofloxacin-resistant disease is based on the premise that the achievable peak serum levofloxacin concentration (7.31 [+ or -] 2.11 mg/L) and consequential lung tissue concentration might be able to surmount the escalated MIC of some ofloxacin-resistant M tuberculosis strains with low-or moderate-resistance phenotype (MIC of levofloxacin [less than or equal to] 4 mg/L, MIC of ofloxacin [less than or equal to] 8 mg/L). (5,11) Such theoretical consideration appears to be somewhat supported by our current data showing a very reasonable treatment success rate with multidrug regimens containing levofloxacin even in the presence of ofloxacin resistance in vitro, as well as better efficacy of levofloxacin over oflaxacin. The superiority of levofloxacin to ofloxacin correlates with the better pharmacodynamics of the former (peak serum drug concentration, MIC) and higher lung tissue penetration.

We cannot be absolutely certain that a dosage of ofloxacin higher than 600 to 800 mg qd would not produce similar efficacy as levofloxacin; however, this hypothesized strategy is likely to be limited by drug intolerance of patients and perhaps also undesirable cost. We feel strongly for the need to delineate the most efficacious fluoroquinolone with the best tolerance profile in the cost-effective management of MDR-TB. It is hoped that the present report may promote further research in this direction. It is of interest to note that levofloxacin at a dosage of 500 to 1,000 mg/d has been recently recommended for treatment of MDB-TB in the United States. (12) Furthermore, fluoroquinolones with [C.sub.8]-methoxy substitution such as moxifloxacin (13) and gatifloxacin (14) have been found to possess good activities in vitro against M tuberculosis, although there are no pertinent clinical data at present.

REFERENCES

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

Manuscript received October 22, 2002; revision accepted February 28, 2003.

Correspondence to: Wing Wai Yew, MB, FCCP, Tuberculosis & Chest Unit, Grantham Hospital, 125 Wong Chuk Hang Rd, Aberdeen, Hong Kong, China; e-mail: wwyew@ha.org.hk

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