Early Bactericidal Activity of Moxifloxacin in Treatment of Pulmonary Tuberculosis: a Prospective, Randomized Study

Moxifloxacin is the most active fluoroquinolone against Mycobacteriumtuberculosis in vitro. However, data about the efficacy in patientsare not available. We enrolled 17 patients with tuberculosisin a prospective, randomized study. After 5 days of monotherapywith either moxifloxacin or isoniazid, we detected significantdecreases in mean CFU per milliliter in sputum in both groups.The calculated early bactericidal activities for isoniazid andmoxifloxacin were 0.209 and 0.273 log₁₀ CFU per ml of sputumper day, respectively. According to the data from our study,moxifloxacin exhibits an early bactericidal activity that iscomparable to that of isoniazid.

INTRODUCTION

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Introduction

Tuberculosis remains one of the deadliest diseases in the world.The World Health Organization (WHO) estimates that more than8 million new cases of tuberculosis occur each year, and approximately3 million people die from the disease.

The emerging resistance of Mycobacterium tuberculosis to standardantituberculous drugs raises the need for the development ofnew agents. Fluoroquinolones are of particular interest, becausethere is no indication of cross-resistance to other antituberculousdrugs (9). The clinical efficacy of ciprofloxacin and ofloxacinhas already been proven in studies, and despite limited bactericidalactivity, these drugs are recommended as second-line therapyby WHO (1). To date, moxifloxacin and gatifloxacin have beenshown to be the most active fluoroquinolones against M. tuberculosisin vitro (2, 5), and moxifloxacin’s antimycobacterialactivity has been confirmed in animal studies (12, 14). However,data about the efficacy in patients are not available.

Early bactericidal activity (EBA) of antituberculosis drugsis the rate of decrease in the concentration of tubercle bacilliin sputum during the initial days of therapy and is used toassess the potency of new antituberculous drugs in clinicalstudies (6).

MATERIALS AND METHODS

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Materials and Methods

We performed a randomized, open, single-center study at theChest Hospital Heckeshorn, Berlin, Germany, to assess the clinicalefficacy of moxifloxacin in patients with pulmonary tuberculosis.The protocol was approved by the Ethical Committee of the FreieUniversität, Berlin, and written informed consent was obtainedfrom all subjects prior to enrollment. Seventeen adult, nonimmunocompromisedpatients with smear-positive pulmonary tuberculosis and radiologicalevidence of an infiltrate were orally treated with either 400mg of moxifloxacin (Bayer, Wuppertal, Germany) once daily (n= 8) or 6-mg/kg isoniazid (INH) (Fatol, Schiffsweiler, Germany)(n = 9) for 5 days. Patients who had received a previous antituberculouschemotherapy within the last 2 years, patients pretreated withany systemic antibacterial agent within 48 h prior to enrollment,and patients requiring concomitant systemic antibacterial therapywere excluded. The study treatment period was followed by astandard therapeutic regimen for 6 months. Sputum was collectedfrom 4:00 p.m. to 8:00 a.m. before treatment (baseline) andafter 2 and 5 days of study treatment. Hematological and biochemistryparameters were assessed simultaneously, and electrocardiogrammeasuring was performed. The count of CFU per milliliter wasdetermined as described previously (11). The EBA was calculatedfor each patient by the formula (log CFU/ml_day0 - log CFU/ml_day5)/5and is given as the mean ± standard deviation (SD). Asrecommended by several authors, we defined the EBA as the decreasein log₁₀ CFU per milliliter of sputum per day during the first5 days of treatment (3, 4).

The numbers of CFU per milliliter before therapy and after 2and 5 days of study treatment were compared by Wilcoxon's test.The EBAs of moxifloxacin and INH were compared by the Mann-WhitneyU test. Statistical analysis was performed with SPSS 11.0 forWindows.

RESULTS AND DISCUSSION

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Results and Discussion

Demographic data of enrolled patients are given in Table 1.Two patients in the moxifloxacin-treated group reported a previoustherapy against tuberculosis: One was treated 3 years priorto enrollment with a combination of INH, rifampin, pyrazinamide,and ethambutol. The other patient was treated 12 years priorto study enrollment. Further details about the specific treatmentof this patient were not available.

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TABLE 1. Patients' characteristics

All patients completed the study. Medication was well toleratedin both groups. No clinically relevant changes in laboratoryand ECG parameters (particularly no QT-interval extension) wererecorded. Antibiotic susceptibility testing revealed no evidenceof resistance to either moxifloxacin or the standard antituberculousdrugs (INH, rifampin, ethambutol, pyrazinamide, and streptomycin)in any patient. The INH MIC was $<=$ 0.125 mg/liter in all patients.The distribution of moxifloxacin MICs in both treatment groupsis given in Table 2.

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TABLE 2. Distribution of moxifloxacin MICs in both treatment groups

The baseline numbers of CFU per milliliter in sputum in themoxifloxacin-treated and INH-treated groups are shown in Table3. In both groups, a significant decrease in CFU per milliliterin sputum compared to baseline was detected after 5 days ofstudy treatment (Wilcoxon test P values for moxifloxacin andINH = 0.028 and 0.015, respectively). Whereas this was to beexpected for INH, this is the first evidence for the clinicalefficacy of moxifloxacin in patients. In contrast to moxifloxacin,INH treatment led to a faster reduction of the bacterial loadalready after 2 days of treatment. Nevertheless, the antimycobacterialeffect of moxifloxacin seems to be similar to that of INH after5 days of treatment. The reason for the delayed effect of moxifloxacincompared to that of INH might be due to the different mechanismof action: INH interferes with mycolic acid biosynthesis (13),whereas moxifloxacin mainly affects replicating bacteria bybinding to DNA gyrase and topoisomerase IV (8).

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TABLE 3. Change in CFU per milliliter of sputum and EBA in both treatment groups

The calculated mean EBAs (with 95% confidence intervals [CIs]in parentheses) for INH and moxifloxacin were 0.209 (0.009,0.394) and 0.273 (0.0001, 0.5462) log₁₀ CFU per ml of sputumper day, respectively. There were no significant differencesbetween the EBAs (P = 0.722, Mann-Whitney U test).

Despite the limited number of patients, these data suggest thatthe antimycobacterial activity of moxifloxacin is, with a delayof its onset, similar to that of INH. Different studies determineddifferent EBAs for the same drug and dosage. Therefore, it isimportant to relate the results of a new drug to a comparatordrug (mostly INH) tested in the same study. The EBA of INH (6mg/kg) has been described in other studies with results of between1.01 (11 patients) (11) and 0.21 (16 patients) log₁₀ CFU perml of sputum per day (4). This relative wide dispersion maybe caused by different methodologies—such as, for instance,duration of sputum collection (4)—and by the demographicparameters of the different study populations. Most of the studiesthat revealed a particularly high EBA for INH were conductedin countries with a high incidence of tuberculosis. The patientsenrolled in these studies were mainly younger, had a lighterbody weight, and presented a higher pretreatment count of CFUper milliliter than that in patients enrolled in studies inlow-incidence countries. This may lead to higher concentrationsof the drug in tissue, since the dose of orally administereddrugs was not adjusted for body weight (10), and higher pretreatmentcounts of CFU per milliliter might emphasize the decrease afterinitial therapy. A multicenter study performed by Sirgel etal. (11) supports the fact that the environment and study populationinfluence the EBA result. In this study, the pretreatment CFUcount in the patients in Hong Kong was markedly lower than thepretreatment counts in the patients in the other study centers(Cape Town, South Africa, Nairobi, Kenya, and Madras, India).In consequence, the EBA for INH (at 300 mg) was remarkably lowerin the Hong Kong patients (0.37 versus 0.64 to 1.01 log₁₀ CFUper ml of sputum per day) despite an identical methodology.

The EBA for INH in our study (0.209 log₁₀ CFU per ml of sputumper day) corresponds very well with the data from the U.S. studyby Hafner et al. mentioned above(4).

However, the EBA of moxifloxacin in our study was even greaterthan that of the comparator drug, whereas in other studies,INH was revealed to be the most powerful antimycobacterial drug(11). Due to the labor-intensive setting, most studies assessingthe EBA, including ours, enroll only a small number of patients,and studies with higher numbers of patients might be needed.Despite this situation, our data demonstrate the already presumedclinical efficacy of moxifloxacin in pulmonary tuberculosis.The calculation of the 95% CI of the difference between theEBA of moxifloxacin and INH (-0.337 to 0.210) revealed thatmoxifloxacin had at least 61.6% of the antimycobacterial activityof INH in our study. In fact, moxifloxacin is already used asa second-line drug for treatment of tuberculosis in particularcases. Moxifloxacin might be useful for the treatment of multidrug-resistanttuberculosis, because no cross-resistance to other classes ofantituberculous drugs is known. Other aspects to consider arethe possible side effects of moxifloxacin long-term treatment,which would be required for tuberculosis. Compared to the classicantituberculous drugs, fluoroquinolones can be considered tobe better tolerated. However, as yet, there are only limiteddata to support this issue, and therefore precautions shouldbe taken, particularly when combining fluoroquinolones withother antituberculous drugs (7).

ACKNOWLEDGMENTS

The study was supported by a grant from Bayer Vital GmbH, Germany.Mathias W. Pletz was supported by the German Research Foundation.

We thank Gisela Korfmann, Keith P. Klugman, Lesley McGee, andPeter Reimnitz for critical reading of the manuscript. The technicalassistance of Gudrun Bettermann, Birgit Howe, and Tessa Ziemssenis gratefully acknowledged.

FOOTNOTES

* Corresponding author. Present address: Department of International Health, Rollins School of Public Health, Emory University, 1518 Clifton Rd., Atlanta, GA 30322. Phone: (404) 727-3984. Fax: (404) 712-8419. E-mail: mpletz{at}sph.emory.edu.

REFERENCES

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