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Fluoroquinolones for treating tuberculosis

  1. Lilia E Ziganshina1,*,
  2. Stephen B Squire2

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 21 JAN 2009

Assessed as up-to-date: 13 OCT 2007

DOI: 10.1002/14651858.CD004795.pub3

Database Title

Additional Information

How to Cite

Ziganshina LE, Squire SB. Fluoroquinolones for treating tuberculosis. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD004795. DOI: 10.1002/14651858.CD004795.pub3.

Author Information

  1. 1

    Kazan State Medical Academy, Department of Clinical Pharmacology and Pharmacotherapy, Kazan, Tatarstan, Russian Federation

  2. 2

    Liverpool School of Tropical Medicine, Clinical Group, Liverpool, Merseyside, UK

*Lilia E Ziganshina, Department of Clinical Pharmacology and Pharmacotherapy, Kazan State Medical Academy, 11 Mushtari Street, 420012, 14-15 Malaya Krasnaya Street, 420015, Kazan, Tatarstan, Russian Federation. lezign@mail.ru. lezign@gmail.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 21 JAN 2009

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Tuberculosis is caused by Mycobacterium tuberculosis. It may be fatal if untreated or treated inappropriately; it causes more adult deaths each year than any other single infectious disease (Kochi 1991). Pulmonary tuberculosis is the commonest clinical presentation of tuberculosis, and sputum-positive cases are the most important sources of infection in the community (Grzybowski 1975). Since 2005 the global tuberculosis epidemic has been on the threshold of decline, yet the global incidence of tuberculosis has been growing slowly, and much faster in sub-Saharan Africa, East Mediterranean and South-East Asia regions (WHO 2007a). There were an estimated 8.8 million people who became sick with the disease in 2005 and 1.6 million tuberculosis deaths (WHO 2007a).

Multiple-drug-resistant tuberculosis (MDR-TB), defined as in vitro resistance to at least isoniazid and rifampicin, is impairing the effectiveness of standard treatments and may contribute to increased mortality (Pablos-Mendez 2002). It is common in some countries and threatens tuberculosis control efforts ( Table 1), especially the former Soviet Union, where, for example, the rates of MDR-TB among 'newly enrolled' and 'non-responding' cases in prisons were 24.6% and 92.1%, respectively (Portaels 1999). In Mariinsk in the Russian Federation, the high rates of MDR-TB have been associated with failure rates of 23% to 50% among sputum smear-positive cases receiving fully supervised short-course treatment with first-line drugs (Portaels 1999). In the USA, 3.5% of strains were resistant to isoniazid and rifampicin at the time of the outbreak of tuberculosis in early 1990s (Reichman 1996).

The risk factors for MDR-TB are previous treatment or relapse, originating from MDR-TB areas, a history of imprisonment, homelessness, and HIV infection. Tuberculosis is a leading cause of death among HIV-positive people. In Africa, HIV is the single most important factor determining the increased incidence of tuberculosis since 1990 (WHO 2007b).

 

Treatment options

Effective pharmacological treatment of tuberculosis been available since the 1940s. The efficacy of regimens containing rifampicin and isoniazid is well established for treatment and prevention, even in HIV-positive people (Woldehanna 2004; WHO 2003). Cure rates with rifampicin-containing regimens for six to nine months can approach 100%, provided the disease is sensitive to the drugs, there is no additional co-morbidity (especially HIV infection), and the patients adhere to treatment (STS/BMRC 1981; Anon 1983; Kohno 1992). Cure of drug-sensitive tuberculosis is defined as sputum culture or smear negative, or both, at eight weeks and at the end of the treatment period. If the in vitro sensitivities are not known, then it is defined as at least two consecutive negative sputum smears or cultures with no subsequent positive sputum smears or cultures. For proven MDR-TB, it is defined as having a consistent negative sputum culture for the last 12 months of treatment with a minimum of three consecutive negative cultures taken at least 30 days apart.

The first-line (or essential) antituberculous drugs are the most active agents with proven clinical efficacy that form the core of initial standardized treatment regimens. These are isoniazid, rifampicin, pyrazinamide, and ethambutol (Blumberg 2003; WHO 2003; WHO 2006; WHO 2007c). Streptomycin, although used less commonly, is also a first-line drug on the World Health Organization's (WHO's) list of essential antituberculous drugs (WHO 2006; WHO 2007c). The WHO recommends second-line antituberculous drugs for those with MDR-TB or people intolerant of first-line drugs (WHO 2003; WHO 2006). The treatment of MDR-TB is difficult due to numerous adverse effects of second-line drugs and an expensive treatment regimen that usually lasts for around two years. Therefore, strategies for effective treatment and prevention of MDR-TB are urgently required. There is no single prescription for treating MDR-TB; appropriate use of second-line drug treatment is the key issue (Pablos-Mendez 2002; WHO 2006). It is difficult to estimate the performance of different antituberculous regimens in HIV-related tuberculosis (El-Sadr 2001). Recent research has highlighted the potential of including fluoroquinolones (sparfloxacin, ofloxacin, levofloxacin, moxifloxacin, and gatifloxacin) in treatment regimens for TB/MDR-TB (Telzak 1999; Wei 2000; Ginsburg 2003; WHO 2006). Guidelines suggest using fluoroquinolones as second-line drugs for treating drug-resistant tuberculosis or as a substitute for first-line drugs in cases of intolerance (Gillespie 1998; Blumberg 2003; WHO 2003; WHO 2006).

 

Fluoroquinolones

Fluoroquinolones are fluorine-containing nalidixic acid derivatives characterized by broad-spectrum antimicrobial activity. They have been included in antituberculous regimens (particularly for MDR-TB) since the late 1980s, but the role of fluoroquinolones in tuberculosis treatment still remains controversial. There are research data suggesting added efficacy of fluoroquinolones in managing MDR-TB when combined with well-established regimens (Huang 2000; WHO 2006), and there is evidence that levofloxacin and ofloxacin have a pivotal role in MDR-TB regimens (Yew 2000; Yew 2003). However, conflicting data have accumulated suggesting a lack of increased efficacy when fluoroquinolones are included in antituberculous regimens (Kohno 1992; Kennedy 1996; El-Sadr 1998; Burman 2006). One study suggested that substituting ofloxacin for ethambutol in an established first-line antituberculous regimen may make it possible to shorten tuberculosis chemotherapy from six months to five or even four months (TRC 2002), but this study contained no concurrent, recognized short-course chemotherapy as a control.

The favourable combination of pharmacodynamic and pharmacokinetic characteristics of fluoroquinolones (Ginsburg 2003) may give the following benefits when added to antituberculous regimens.

  • Add to the bactericidal and sterilizing effect of the combination therapy by inhibiting DNA-gyrase and increasing penetration into the infection loci.
  • Improve adherence to treatment due to the potentially better safety profile as compared with the first-line drugs and by allowing shorter courses of antituberculous treatment.

On the other hand, fluoroquinolones also have the potential to do harm.

  • Increase liver and central nervous system (CNS) toxicity of antituberculous drugs (Yew 2001) and cause clinically significant drug interactions with antituberculous (Yew 2001), anti-HIV (Burman 1999), and other drugs, resulting in reduced efficacy and potential toxicity (WHO 2006).
  • Cause additional adverse drug reactions, such as musculoskeletal damage, gastrointestinal problems (pseudo-membranous colitis), cardiac arrhythmias, infections from fungi or bacteria, psychosis, and convulsions (Martindale 1996).
  • Induce resistance in M. tuberculosis (Alangaden 1997; Jacobs 1999; Wang 2006), which may become cross-resistant to all the representatives of the fluoroquinolone class (Ginsburg 2003).

The problem of resistance to fluoroquinolones is further complicated by the broad indications of this class of antimicrobials in treatment of various lower respiratory tract and other infections. This may at least be partially responsible for the rising resistance rates among M. tuberculosis strains to fluoroquinolones (Ginsburg 2003). Retrospective studies have shown that empiric antituberculous treatment with fluoroquinolones or fluoroquinolone use for misdiagnosed pneumonia delayed diagnosis of tuberculosis in an endemic area and impaired outcomes (Yoon 2005; Wang 2006). M. tuberculosis isolates acquired ofloxacin resistance within one week (Wang 2006).

In the light of the above uncertainties, we have conducted a systematic review of trials of fluoroquinolones in people with tuberculosis. These drugs are likely to be used as substitutes for existing drugs or as an addition to current treatment regimens. This review examines the benefits and harms of their use with these two approaches.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

To assess fluoroquinolones as additional or substitute components to antituberculous drug regimens for drug-sensitive and drug-resistant tuberculosis.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomized and quasi-randomized controlled trials.

 

Types of participants

People diagnosed with bacteriologically positive (sputum smear or culture) pulmonary tuberculosis. Both drug-sensitive and drug-resistant tuberculosis are included.

 

Types of interventions

 

Intervention

Antituberculous regimens containing fluoroquinolones.

 

Control

Other antituberculous regimens (not containing fluoroquinolones, or containing different fluoroquinolone doses or other fluoroquinolones).

 

Types of outcome measures

 

Primary

  • Cure. For drug-sensitive tuberculosis (or where in vitro sensitivities are not known): sputum culture and/or smear negative at eight weeks and at the end of treatment period (at least two consecutive negative smears or cultures with no subsequent positive smears or cultures). For participants with proven MDR-TB: consistent negative sputum culture for the last 12 months of treatment with a minimum of three consecutive negative cultures taken at least 30 days apart.
  • Treatment failure, defined as continued or recurrent positive sputum cultures after four months of treatment in participants in whom medication ingestion was assured. For proven MDR-TB participants: more than one positive culture in the last 12 months of treatment.

 

Secondary

  • Relapse, defined as becoming sputum smear or culture positive within a year of being culture negative while receiving or having completed therapy; or signs of clinical or radiographic deterioration consistent with active tuberculosis.
  • Time to cure, defined as a continuous outcome providing an estimate of time in weeks or months needed to achieve cure.
  • Time to sputum culture or smear conversion, defined as a continuous outcome providing an estimate of time in weeks or months needed to achieve the first negative sputum culture.
  • Clinical or radiological improvement at eight weeks and at the end of the treatment period.
  • Death (from any cause, tuberculosis-related).

 

Adverse events and effects

  • Serious adverse events, defined as fatal, life-threatening, requiring hospitalization, or change of treatment regimen.
  • Adverse effects specifically associated with fluoroquinolones (eg tendon rupture).
  • Total number of adverse events.

 

Search methods for identification of studies

We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).

 

Databases

We searched the following databases using the search terms and strategy described in Appendix 1: Cochrane Infectious Diseases Group's Specialized Register (July 2007); Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2007, Issue 3); MEDLINE (1966 to July 2007); EMBASE (1974 to July 2007); LILACS (1982 to July 2007); Science Citation Index (1940 to July 2007); and the Database of Russian Publications (1988 to July 2007). We also searched the metaRegister of Controlled Trials (July 2007) using the following search terms: tuberculosis AND (fluoroquinolones OR moxiflacin OR ofloxacin OR gatifloxacin OR levofloxacin OR ciprofloxacin).

 

Conference proceedings

We searched the following conference proceedings for relevant abstracts: 4th World Congress on TB, Washington, DC, USA, 3 to 5 June 2002 (published in Tubercle); International Union Against Tuberculosis Lung Disease (IUATLD) Annual Conference Proceedings (published in the International Journal of Tuberculosis and Lung Disease 1997 to 2007); American Thoracic Society Meetings Proceedings 2001 to 2007; and the British Society for Antimicrobial Therapy 2000 to 2007.

 

Researchers, organizations, and pharmaceutical companies

For the original review (Ziganshina 2005), we searched the current controlled trials website and contacted individual researchers working in the field, organizations (Centers for Disease Control and Prevention, the Clinical Trials Unit of the International Union against Tuberculosis and Lung Disease (IUATLD), and the UK Medical Research Council Clinical Trials Unit), and pharmaceutical companies (Bayer, Merck Sharp & Dohme, Hoechst Marion Roussel, and Aventis Pharma) for unpublished and ongoing trials.

 

Reference lists

We also checked the reference lists of all studies identified by the above methods.

 

Data collection and analysis

 

Selection of studies

We checked the citations and their abstracts to establish their relevance and obtained the full article if we agreed it was relevant and in cases of uncertainty. We independently applied the inclusion criteria using an eligibility form and resolved any disagreements by discussing them. Finally, where we were still unsure if the study should be included because further information was necessary, we allocated the study to the list of those awaiting assessment and then attempted to contact the study authors for clarification. We excluded studies that did not meet the inclusion criteria and gave the reason for exclusion in the 'Characteristics of excluded studies'.

 

Data extraction and management

We independently extracted data on trial methods, participants, interventions, and outcomes using a standardized data extraction form. We resolved any differences in the extracted data by referring to the original articles and through discussion. Where data were insufficient or missing we attempted to contact the trial authors for additional information.

For binary outcomes, we extracted the number of participants with the event in each group. For continuous outcomes, we used the arithmetic means and standard deviations for each group. If geometric means were used in the trial report, we would have extracted standard deviations on the log scale. Where possible, we extracted data to allow an intention-to-treat analysis (including all the participants in the groups to which they were originally randomly allocated). We calculated the percentage loss to follow up and presented it in the 'Characteristics of included studies' when the numbers randomized and the numbers analysed were inconsistent.

 

Assessment of risk of bias in included studies

We independently evaluated the risk of bias in the trials by classifying the generation of allocation sequence and allocation concealment as adequate, inadequate, or unclear according to Jüni 2001, considering the inclusion of all randomized participants in the final analysis to be adequate if it was more than 90%, and stating whether the trial was open or who was blinded to the intervention. We presented the results of the risk of bias assessment in a table.

 

Data synthesis

We used Review Manager 5 to analyse the data, and grouped the trials to those that substituted or added fluoroquinolones to the basic antituberculous regimens. We used risk ratio (RR) as a measure of effect for binary outcomes, and mean difference (MD) for continuous data, and presented both with 95% confidence intervals (CI). We tested for homogeneity of effect sizes between the trials using the chi-squared test for heterogeneity. When heterogeneity was present (P < 0.1), and the number of trials permitted, we investigated it using HIV status (positive versus known HIV negative) in a subgroup analysis. Where we detected heterogeneity, and it was still appropriate to pool data, we used the random-effects model.

We were unable to use some methods described in the protocol because they were not possible with the available trials or because of variations in the outcome measures, but we intend to use these methods, described in Appendix 2, in future updates.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies.

 

Trial selection

We identified 42 potentially relevant articles of which 12 (reporting on 11 different trials) met our inclusion criteria (see 'Characteristics of included studies'). Two studies are awaiting assessment for inclusion in the review because we are attempting to obtain the data that were originally presented at a conference and remain unpublished (Abdullah 1997; Abdullah 1998). We have detailed the reasons for excluding the remaining 28 studies in the 'Characteristics of excluded studies'. There are eight ongoing studies (see 'Characteristics of ongoing studies').

 

Participants

The 11 trials included 1514 participants with a range of 20 to over 300 per trial. The participants were aged 13 years or older (mean age 39.54 years), and in one trial, Saigal 2001, ranged between eight and 63 years. Sixty-seven per cent were male with a range of 45% to 81% across trials.

Three trials included only individuals who had bacteriologically proven MDR-TB (Huang 2000; Sun 2000; Ji 2001), one trial involved only drug-sensitive participants (Kennedy 1996), and three trials included both drug-resistant and drug-sensitive individuals as one group (El-Sadr 1998; Lu 2000; Burman 2006). The remaining trials did not report on drug sensitivity.

Four trials included both HIV-positive and HIV-negative participants as one group (Kennedy 1993; Kennedy 1996; El-Sadr 1998; Burman 2006), although one also stratified the analysis by HIV status (Kennedy 1996). Four trials involved participants presumed to be HIV-negative according to local endemicity, reference data, and exclusion criteria (Mohanty 1993; Huang 2000; Lu 2000; Sun 2000). The remaining three trials did not report on HIV status.

 

Location and follow up

Trials were conducted in China (four trials), Japan (one trial), Tanzania (three trials), North America and Africa (one trial), and the USA (one trial). The mean duration of follow up ranged from eight weeks to 21 months.

 

Interventions

 

1. Fluoroquinolone (ciprofloxacin, ofloxacin, or moxifloxacin) substituted into regimen

Six trials compared ciprofloxacin, ofloxacin, or moxifloxacin substituted for first-line antituberculous drugs (rifampicin, ethambutol, or pyrazinamide plus ethambutol) in combination therapy with an established antituberculous drug regimen (Kohno 1992; Kennedy 1993; Mohanty 1993; Kennedy 1996; Saigal 2001; Burman 2006).

 

2. Fluoroquinolone (levofloxacin) added to regimen

One trial compared levofloxacin added to an established antituberculous regimen with that regimen (El-Sadr 1998).

 

3. Comparison of fluoroquinolones (levofloxacin versus ofloxacin) substituted into regimen

One trial compared levofloxacin with ofloxacin, each substituting for rifampicin in antituberculous first-line and second-line regimens (Lu 2000).

 

4. Comparison of fluoroquinolones (sparfloxacin versus ofloxacin) added to regimens

Three trials compared sparfloxacin with ofloxacin when they were each added to various isoniazid and rifampicin-containing antituberculous regimens (Huang 2000; Sun 2000; Ji 2001).

The trials used different daily oral doses of levofloxacin (300 mg or 500 mg) and ofloxacin (200 mg, 600 mg, or 800 mg (16 mg/kg)) but the same doses of sparfloxacin (400 mg) and ciprofloxacin (750 mg) for both the initiation and continuation phases. Burman 2006 used 400 mg of moxifloxacin for the initiation phase. The treatment doses of standard antituberculous drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, prothionamide, thioacetazone, and streptomycin) varied among the trials. All of the included trials ensured the adherence of participants by administering the drugs under direct observation with special nursing facilities in outpatient settings or in hospital settings.

 

Outcomes

None of the trials reported on all eight outcome measures chosen for this review. The reported outcomes included cure (seven trials), treatment failure (five trials), relapse (three trials), time to sputum culture or smear conversion (two trials), clinical or radiological improvement (seven trials), death (one trial), serious adverse events (four trials), and total adverse events (five trials). None of the trials reported on time to cure or fluoroquinolone-specific adverse effects.

 

Risk of bias in included studies

See  Table 2 for details of individual trials.

The methods used to generate the allocation sequence and to conceal allocation were adequate in one trial (Kennedy 1996), adequate only for the allocation sequence in three trials (El-Sadr 1998; Lu 2000; Saigal 2001), and unclear in the other trials. One trial blinded the providers, participants, and radiograph assessor (Mohanty 1993), two trials blinded the assessors (El-Sadr 1998; Kennedy 1996), and one trial blinded the participants (Lu 2000). Two trials used no blinding (Kennedy 1993; Saigal 2001), and blinding in the remaining five trials was unclear (one was described as "open"). All but Mohanty 1993 and Burman 2006 included more than 90% of the randomized participants in the final analysis (three had no losses to follow up), which we considered adequate.

 

Effects of interventions

 

1. Fluoroquinolone substituted into regimen (6 trials)

Five trials used one of the two older fluoroquinolones ciprofloxacin or ofloxacin (Kohno 1992; Mohanty 1993; Kennedy 1993; Kennedy 1996; Saigal 2001), and one trial used moxifloxacin in the initiation phase (Burman 2006). Saigal 2001 trial looked at the safety of ofloxacin substituting for rifampicin in participants with chronic liver disease.

 

1.1. Cure (sputum culture conversion at 8 weeks)

Fluoroquinolone substitution did not have an effect on cure (416 participants, 3 trials,  Analysis 1.1). The heterogeneity observed in the original version of the review (Ziganshina 2005) and tentatively attributed to the differences in drug substitutions (ciprofloxacin for ethambutol plus pyrazinamide in Kennedy 1996 and for rifampicin in Mohanty 1993) and differences in the basic antituberculous regimen, including streptomycin in the Mohanty 1993, disappeared with the addition of the results of the Burman 2006 trial (moxifloxacin for ethambutol).

 

1.2. Treatment failure at 12 months

We found no statistically significant difference between the regimens (388 participants, 3 trials,  Analysis 1.2).

 

1.3. Relapse

Substituting with ciprofloxacin or ofloxacin was associated with a higher incidence of relapse (RR 7.17, 95% CI 1.33 to 38.58; 384 participants, 3 trials,  Analysis 1.3). Kennedy 1996, which substituted ciprofloxacin for pyrazinamide plus ethambutol in participants with drug-sensitive tuberculosis, stratified the results according to HIV status. The risk ratio was not statistically significantly different for HIV-positive or HIV-negative participants ( Analysis 1.4).

 

1.4. Time to sputum culture conversion

Overall, time to sputum culture conversion was longer in the substitution group in Kennedy 1996 (MD 0.50 months, 95% CI 0.18 to 0.82; 168 participants, 1 trial,  Analysis 1.5).

We assessed the influence of HIV status on this outcome with the limited data stratified by HIV-status, as provided by the trial authors. The trial compared substitution with ciprofloxacin for pyrazinamide plus ethambutol in drug-sensitive areas and in participants with fully sensitive tuberculosis. For HIV-positive participants the mean difference was 1.20 months (95% CI 0.67 to 1.73; 55 participants, 1 trial,  Analysis 1.6) and for HIV-negative participants it was 0.20 months (95% CI -0.10 to 0.50; 101 participants, 1 trial,  Analysis 1.6).

 

1.5. Clinical or radiological improvement at 8 weeks

The trials did not demonstrate a statistically significant difference between the groups (216 participants, 2 trials,  Analysis 1.7). We could explain the statistically significant heterogeneity by the different drugs used in the substitution, the difference in the basic antituberculous regimens (Mohanty 1993 used streptomycin), or by the loss of more than 10% of the participants to follow up in Kohno 1992.

 

1.6. Serious adverse events

We found no demonstrable difference in the number of serious adverse events (743 participants, 5 trials,  Analysis 1.8). The events included nausea and vomiting, severe anaemia, conjunctivitis, pruritic rash, convulsions including one HIV-positive participant in the ciprofloxacin group in Kennedy 1993 who subsequently died, and hepatotoxicity in four participants with chronic liver disease that manifested with nausea, anorexia, malaise, and jaundice (Saigal 2001; rifampicin group). One participant died in the moxifloxacin group in Burman 2006; the authors attributed the death to pulmonary embolism unrelated to antituberculous treatment.

 

1.7. Total number of adverse events

We calculated the total number of adverse events in Burman 2006 by summing up the numbers of the listed adverse events for each group; we excluded death, hospitalization, and selected symptoms (any grade) from this calculation to avoid double summation of the same event. Overall we did not detect a statistically significant difference between the groups, or heterogeneity (712 participants, 4 trials,  Analysis 1.9). These adverse events included fever, rash, gastrointestinal disturbance, hepatotoxicity, arthralgia, vision change, giddiness, and serious adverse events. We subgrouped the results by fluoroquinolone substitutions for ethambutol and found that they − moxifloxacin in Burman 2006 and ofloxacin in Kohno 1992 − resulted in a greater number of adverse events (RR 1.34, 95% CI 1.05 to 1.72; 492 participants, 2 trials,  Analysis 1.10).

 

2. Fluoroquinolone added to regimen

El-Sadr 1998 compared levofloxacin (a newer fluoroquinolone) added to and compared with the standard combination of isoniazid, rifampicin, pyrazinamide, and ethambutol for two months of the induction phase in participants suspected to have HIV in drug-resistant areas. This trial, with 174 participants, provided data for six of the review outcomes. It did not demonstrate a difference in terms of cure (sputum culture conversion at eight weeks ( Analysis 2.1), treatment failure at 12 months ( Analysis 2.2), clinical or radiological improvement at eight weeks ( Analysis 2.3), death from any cause ( Analysis 2.4), tuberculosis-related death ( Analysis 2.5), or serious adverse events ( Analysis 2.6).

 

3. Comparison of fluoroquinolones (levofloxacin versus ofloxacin) substituted into regimen

Lu 2000, which included 144 participants with presumed MDR-TB, compared levofloxacin with ofloxacin, each substituting for rifampicin in both phases of antituberculous treatment as well as in the retreatment regimen for presumed drug-resistant tuberculosis. The basic regimen included isoniazid, ethambutol, pyrazinamide, and thioacetazone given daily. The trial did not detect a statistically significant difference in cure (sputum culture conversion within two to three weeks, Analysis 3.1), treatment failure at 12 months ( Analysis 3.2), clinical or radiological improvement at eight weeks ( Analysis 3.3), or the total number of adverse events ( Analysis 3.4).

 

4. Comparison of fluoroquinolones (sparfloxacin versus ofloxacin) added to regimens

The three trials that compared newer fluoroquinolones with older fluoroquinolones were all conducted in China and published in and after the year 2000 (Huang 2000; Sun 2000; Ji 2001). They compared sparfloxacin and ofloxacin added to basic regimens (containing isoniazid and rifampicin) in participants with proven or presumed MDR-TB.

 

4.1. Cure (sputum culture conversion within 2 to 3 weeks)

The trials showed quite different results, with higher cure rates with sparfloxacin in Huang 2000 but little difference in numbers cured in Sun 2000 (184 participants, 2 trials,  Analysis 4.1). The reason for the difference may be due to the difference in the basic drug regimens.

 

4.2. Treatment failure at 12 months

We detected no statistically significant difference, although there were fewer failures in the sparfloxacin group (149 participants, 2 trials,  Analysis 4.2).

 

4.3. Clinical or radiological improvement at 8 weeks

We found no statistically significant difference between the sparfloxacin and ofloxacin groups (333 participants, 3 trials,  Analysis 4.3).

 

4.4. Total number of adverse events

We found no statistically significant difference in the total number of adverse events (253 participants, 3 trials,  Analysis 4.4).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Despite inherent difficulties around methodology, drug regimens, and implementation in comparisons of fluoroquinolones for treating tuberculosis (Ginsburg 2003), methodologically sound randomized controlled trials are beginning to emerge. Current treatment guidelines have been formulated by expert opinion, and those on fluoroquinolone use have been guided by experimental and retrospective clinical studies (WHO 2006). We undertook this systematic review to provide quantified information and chose clinical outcome measures relevant to the overall healthcare burden of tuberculosis and avoided surrogate measures, such as early bactericidal activity (EBA).

Ten small trials and one large trial of moxifloxacin in the initiation phase (Burman 2006) with 1514 participants met the inclusion criteria. Only two of the trials were of high quality with adequate generation of allocation sequence and allocation concealment (Kennedy 1996; El-Sadr 1998). Most of the trials were conducted in low-income and middle-income countries, which means the results of this review are likely to be applicable to the situations where the burden of tuberculosis is high and new revised treatment strategies are most needed.

 

Fluoroquinolones in drug-sensitive tuberculosis

The results provide clear evidence for the lack of equivalence in terms of relapse and time to sputum culture conversion when older fluoroquinolones (ciprofloxacin or ofloxacin) are substituted into and compared with first-line antituberculous regimens (rifampicin, ethambutol, or pyrazinamide plus ethambutol). These results are consistent with a note to the Editor of Chest of stressing that ciprofloxacin is not a component of first-line treatment of tuberculosis (O'Brien 1994). They also agree with the results of the trials that explored early bactericidal activity in the first two days of ciprofloxacin treatment and showed less activity of ciprofloxacin compared with rifampicin and isoniazid (Sirgel 1997; Sirgel 2000). At the same time we did not find evidence for a difference in cure rate (sputum culture conversion at eight weeks), clinical or radiological improvement, or the number of serious adverse events.

 

Fluoroquinolones in drug-resistant tuberculosis

Although retrospective clinical studies have shown effectiveness of fluoroquinolones (levofloxacin and ofloxacin) in MDR-TB (Yew 2000; Yew 2003; Chan 2004), the one randomized controlled trial in this review that evaluated a fluoroquinolone (levofloxacin) added to a first-line regimen in areas with drug resistance found no statistically significant difference in outcomes when compared with a standard antituberculous combination (El-Sadr 1998). This was a small trial, and more prospective randomized controlled trials that compare levofloxacin, ofloxacin, and other newer fluoroquinolones with second-line antituberculous drugs for treating MDR-TB are essential.

All other trials in drug-resistant tuberculosis compared different fluoroquinolones substituted into or added to regimens. One trial compared levofloxacin and ofloxacin substituted for rifampicin (Lu 2000). It included participants undergoing treatment or retreatment for drug-resistant or drug-sensitive tuberculosis and did not provide evidence for superiority in effect of levofloxacin over ofloxacin. Three trials compared sparfloxacin with ofloxacin added to regimens containing isoniazid and rifampicin in participants with proven or presumed MDR-TB. Overall there was no statistically significant difference in terms of cure and reduced treatment failure rate in the two trials reporting on these outcomes.

Levofloxacin, sparfloxacin, and moxifloxacin are new fluoroquinolones characterized by more favourable pharmacodynamic and pharmacokinetic profiles in terms of lower minimum inhibitory concentrations (MICs) against M. tuberculosis and a better value for the area under the inhibitory concentration time curve over 24 hours (AUC24/MIC) than ciprofloxacin and ofloxacin. These pharmacological advantages might be translated into improved clinical outcomes, but further trials need to investigate this.

 

HIV co-infection

HIV increases the risk of rapid progression of tuberculosis (Daley 1992; Shafer 1995), and tuberculosis is the most common cause of death in HIV-positive adults in low-income and middle-income countries (Corbett 2003). Only one trial stratified data by HIV status (Kennedy 1996). It tested ciprofloxacin substituted into first-line regimens for drug-sensitive tuberculosis and reported that the time to sputum culture conversion was longer in HIV-positive participants. There is an urgent need to determine the most appropriate antituberculous regimens for HIV-positive people and for further trials to explore the role of fluoroquinolones in these regimens.

 

Adverse events and effects

None of the trials reported on fluoroquinolone-specific adverse effects, such as tendon rupture, but they did report the number of adverse events, including those considered serious enough to discontinue or change treatment. The fluoroquinolones did not increase the incidence of serious adverse events. Substitutions for ethambutol in first-line basic regimens with ofloxacin or moxifloxacin resulted in higher total numbers of adverse events. When newer fluoroquinolones were compared with older ones, there seemed to be a favourable trend in favour of the newer drugs.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

Implications for practice

Five fluoroquinolones − ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin, and moxifloxacin − have been tested in randomized controlled trials for treating tuberculosis. In drug-sensitive tuberculosis, ciprofloxacin increased the relapse rate and time to cure when substituted into first-line regimens, but it showed no difference in terms of number of participants cured at the end of the treatment and number of adverse events. We cannot recommend it as an equivalent first-line drug substitute. No randomized controlled trials have looked at substituting newer fluoroquinolones for second-line drugs in drug-resistant tuberculosis. No difference has been demonstrated between sparfloxacin and ofloxacin in drug-resistant tuberculosis.

 
Implications for research

New trials looking at the effects and safety of fluoroquinolones that stratify results by drug resistance and HIV status are urgently needed. New trials evaluating the effects of fluoroquinolones substituted for second-line antituberculous drugs in drug-resistant tuberculosis are warranted. Further new trials comparing different dose regimens of fluoroquinolones substituted into or added to established antituberculous schedules could help in developing the optimal recommendations in treating tuberculosis. Future trials should include analyses of correlations between microbiological data, such as early bactericidal activity (EBA), and clinical outcomes.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

We acknowledge the following support provided for the original review (Ziganshina 2005): Alexander A Vizel for independently checking the Russian language contributing articles and the search results; and Paul Garner for advice. We finalized the original review (Ziganshina 2005) during the Fellowship Programme organized by the Cochrane Infectious Diseases Group in July 2004. The EQUI-TB Knowledge Programme (which receives funding from the UK Department for International Development) also provided support.

This document is an output from a project funded by the UK Department for International Development (DFID) for the benefit of developing countries. The views expressed are not necessarily those of DFID.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
Download statistical data

 
Comparison 1. Fluoroquinolone substituted into regimen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Cure (sputum culture conversion) at 8 weeks3416Risk Ratio (M-H, Random, 95% CI)0.98 [0.82, 1.17]
    1.1 Ciprofloxacin vs rifampicin
160Risk Ratio (M-H, Random, 95% CI)1.08 [0.88, 1.32]
    1.2 Ciprofloxacin vs ethambutol plus pyrazinamide
120Risk Ratio (M-H, Random, 95% CI)0.68 [0.42, 1.09]
    1.3 Moxifloxacin vs ethambutol
1336Risk Ratio (M-H, Random, 95% CI)1.00 [0.83, 1.19]
 2 Treatment failure at 12 months3388Risk Ratio (M-H, Fixed, 95% CI)2.14 [0.71, 6.42]
    2.1 Ciprofloxacin vs rifampicin
160Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 70.83]
    2.2 Ciprofloxacin vs ethambutol plus pyrazinamide
2328Risk Ratio (M-H, Fixed, 95% CI)2.03 [0.63, 6.58]
 3 Relapse3384Risk Ratio (M-H, Fixed, 95% CI)7.17 [1.33, 38.58]
    3.1 Ciprofloxacin vs ethambutol plus pyrazinamide
1168Risk Ratio (M-H, Fixed, 95% CI)15.72 [0.91, 270.96]
    3.2 Ciprofloxacin vs rifampicin
160Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.33, 27.23]
    3.3 Ofloxacin vs ethambutol
1156Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 4 Relapse: by HIV status1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
    4.1 HIV-positive participants: ciprofloxacin vs ethambutol plus pyrazinamide
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.2 HIV-negative participants: ciprofloxacin vs ethambutol plus pyrazinamide
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 5 Time to sputum culture conversion (months)1Mean Difference (IV, Fixed, 95% CI)Totals not selected
    5.1 Ciprofloxacin vs ethambutol plus pyrazinamide
1Mean Difference (IV, Fixed, 95% CI)Not estimable
 6 Time to sputum culture conversion (months): by HIV status1Mean Difference (IV, Random, 95% CI)Totals not selected
    6.1 HIV-positive participants: ciprofloxacin vs ethambutol plus pyrazinamide
1Mean Difference (IV, Random, 95% CI)Not estimable
    6.2 HIV-negative participants: ciprofloxacin vs ethambutol plus pyrazinamide
1Mean Difference (IV, Random, 95% CI)Not estimable
 7 Clinical or radiological improvement at 8 weeks2216Risk Ratio (M-H, Random, 95% CI)0.89 [0.49, 1.59]
    7.1 Ciprofloxacin vs rifampicin
160Risk Ratio (M-H, Random, 95% CI)1.08 [0.88, 1.32]
    7.2 Ofloxacin vs ethambutol
1156Risk Ratio (M-H, Random, 95% CI)0.69 [0.44, 1.08]
 8 Serious adverse events5743Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.56, 1.72]
    8.1 Ciprofloxacin vs rifampicin
160Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 15.26]
    8.2 Ofloxacin vs ethambutol
1156Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.47, 3.57]
    8.3 Ciprofloxacin vs ethambutol plus pyrazinamide
1160Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.20, 4.69]
    8.4 Ofloxacin vs rifampicin
131Risk Ratio (M-H, Fixed, 95% CI)0.10 [0.01, 1.79]
    8.5 Moxifloxacin vs ethambutol
1336Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.50, 3.05]
 9 Total number of adverse events4712Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.96, 1.43]
    9.1 Ciprofloxacin vs rifampicin
160Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.22, 4.56]
    9.2 Ciprofloxacin vs ethambutol plus pyrazinamide
1160Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.60, 1.24]
    9.3 Ofloxacin vs ethambutol
1156Risk Ratio (M-H, Fixed, 95% CI)1.95 [0.70, 5.44]
    9.4 Moxifloxacin vs ethambutol
1336Risk Ratio (M-H, Fixed, 95% CI)1.29 [1.00, 1.66]
 10 Total number of adverse events, substitutions for ethambutol2492Risk Ratio (M-H, Fixed, 95% CI)1.34 [1.05, 1.72]

 
Comparison 2. Fluoroquinolone added to regimen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Cure (sputum culture conversion) at 8 weeks1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
    1.1 Levofloxacin vs no levofloxacin
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 2 Treatment failure at 12 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
    2.1 Levofloxacin vs no levofloxacin
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 3 Clinical or radiological improvement at 8 weeks1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
    3.1 Levofloxacin vs no levofloxacin
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 4 Death from any cause1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
    4.1 Levofloxacin vs no levofloxacin
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 5 Tuberculosis-related death1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
    5.1 Levofloxacin vs no levofloxacin
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 6 Serious adverse events1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
    6.1 Levofloxacin vs no levofloxacin
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 
Comparison 3. Comparison of fluoroquinolones (levofloxacin vs ofloxacin) substituted into regimen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Cure (sputum culture conversion) within 2 to 3 weeks1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 2 Treatment failure at 12 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 3 Clinical or radiological improvement at 8 weeks1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 4 Total number of adverse events1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 4. Comparison of fluoroquinolones (sparfloxacin vs ofloxacin) added to regimens
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Cure (sputum culture conversion within 2 to 3 weeks)2184Risk Ratio (M-H, Random, 95% CI)2.10 [0.77, 5.71]
 2 Treatment failure at 12 months2149Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.26, 1.47]
 3 Clinical or radiological improvement at 8 weeks3333Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.92, 1.24]
 4 Total number of adverse events3253Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.59, 1.64]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Appendix 1. Search methods: detailed search strategies

Search setCIDG SRaCENTRALMEDLINEbEMBASEbLILACSbSCIbRussian database
1tuberculosisTUBERCULOSISTUBERCULOSISTUBERCULOSIStuberculosistuberculosistuberculosis
2fluoroquinolonestuberculosistuberculosistuberculosisfluoroquinolonesfluoroquinolonesquinolones
3—fluoroquinolone1 or 21 or 2ciprofloxacinciprofloxacinfluoroquinolones
4—amifloxacinQUINOLINESQUINOLINE DERIVED ANTIINFECTIVE AGENTSenoxacinenoxacinciprofloxacin
5—balofloxacinQUINOLONESfluoroquinolonesfleroxacinfleroxacinclinafloxacin
6—cetefloxacinANTI-INFECTIVE AGENTS, QUINOLONEamifloxacinnorfloxacinnorfloxacinenoxacin
7—ciprofloxacinFLUOROQUINOLONESbalofloxacinpefloxacinpefloxacinfleroxacin
8—clinafloxacinamifloxacinCETEFLOXACIN2-7/or2-7/orgatifloxacin
9—enoxacinbalofloxacincetefloxacin1 and 81 and 8gemifloxacin
10—fleroxacincetefloxacinCIPROFLOXACIN——grepafloxacin
11—gatifloxacinCIPROFLOXACINciprofloxacin——levofloxacin
12—gemifloxacinciprofloxacinCLINAFLOXACIN——lomefloxacin
13—grepafloxacinclinafloxacinclinafloxacin——moxifloxacin
14—irloxacinENOXACINENOXACIN——norfleroxacin
15—levofloxacinenoxacinenoxacin——norfloxacin
16—lomefloxacinFLEROXACINFLEROXACIN——ofloxacin
17—moxifloxacinfleroxacinfleroxacin——pefloxacin
18—nordifloxacingatifloxacinGATIFLOXACIN——premafloxacin
19—norfleroxacingemifloxacingatifloxacin——rufloxacin
20—norfloxacingrepafloxacinGEMIFLOXACIN——sparfloxacin
21—ofloxacinirloxacingemifloxacin——temafloxacin
22—oxociprofloxacinlevofloxacinGREPAFLOXACIN——trovafloxacin
23—pefloxacinlomefloxacingrepafloxacin———
24—premafloxacinmoxifloxacinIRLOXACIN———
25—prulifloxacinnordifloxacinirloxacin———
26—rufloxacinnorfleroxacinLEVOFLOXACIN———
27—sitafloxacinNORFLOXACINlevofloxacin———
28—sparfloxacinnorfloxacinLOMEFLOXACIN———
29—temafloxacinofloxacinlomefloxacin———
30—tosufloxacinoxociprofloxacinMOXIFLOXACIN———
31—trovafloxacinPEFLOXACINmoxifloxacin———
32—2-31/ORpefloxacinNORDIFLOXACIN———
33—1 and 32premafloxacinnordifloxacin———
34——prulifloxacinNORFLEROXACIN———
35——rufloxacinnorfleroxacin———
36——sitafloxacinNORFLOXACIN———
37——sparfloxacinnorfloxacin———
38——temafloxacinOFLOXACIN———
39——tosufloxacinofloxacin———
40——trovafloxacinOXOCIPROFLOXACIN———
41——4-40/oroxociprofloxacin———
42——3 and 41PEFLOXACIN———
43——limit 42 to humanpefloxacin———
44———PREMAFLOXACIN———
45———premafloxacin———
46———PRULIFLOXACIN———
47———prulifloxacin———
48———RUFLOXACIN———
49———rufloxacin———
50———SITAFLOXACIN———
51———sitafloxacin———
52———SPARFLOXACIN———
53———sparfloxacin———
54———TEMAFLOXACIN———
55———temafloxacin———
56———tosufloxacin———
57———4-56/or———
58———3 and 57———
59———limit 58 to human———


aCochrane Infectious Diseases Group Specialized Register.
bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2006); upper case: MeSH or EMTREE heading; lower case: free text term.

 

Appendix 2. Methods for future updates

MethodDetails
Continuous dataIf continuous data are reported with geometric means, we will combine the findings on a log scale and report them on the original one, and, where appropriate, calculate a summary statistic for each outcome
Stratifying trialsWe will stratify the trials by the route of drug administration, oral or intravenous
HeterogeneityWe will investigate heterogeneity using presence of drug resistance (between trials: areas with drug resistance versus those without; within trials where drug resistance is common: participants with confirmed multiple-drug-resistant tuberculosis (MDR-TB) versus those without), fluoroquinolone dose, age (< versus ≥ 15 years), and length of treatment
Sensitivity analysisWe will investigate the effect of methodological quality using a sensitivity analysis
Funnel plotsWe will use funnel plots to examine asymmetry, which may be caused by publication bias or heterogeneity


 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Last assessed as up-to-date: 13 October 2007.

DateEventDescription
18 August 2008AmendedConverted to new review format with minor editing.


 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Protocol first published: Issue 2, 2004
Review first published: Issue 3, 2005

DateEventDescription
13 November 2007New citation required but conclusions have not changed2008, Issue 1: We updated the search and included one new trial. Alexander Vizel stepped down as a co-author.


 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Lilia Ziganshina and Bertie Squire were authors of the original review and were jointly involved in this update.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Internal sources

  • Kazan State Medical Academy, Not specified.
  • Liverpool School of Tropical Medicine, UK.

 

External sources

  • Department for International Development (DFID), UK.

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

2005, Issue 3 (first review version): We did not search SIGLE because we searched for conference proceedings using alternative sources. We added "sputum smear positive" to the definition of the relapse outcome, and added "total number of adverse events" to the list of outcome measures.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
Burman 2006 {published data only}
  • Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW, et al. Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. American Journal of Respiratory & Critical Care Medicine 2006;174(3):331-8.
El-Sadr 1998 {published data only}
  • El-Sadr WM, Perlman DC, Matts JP, Nelson ET, Cohn DL, Salomon N, et al. Evaluation of an intensive intermittent-induction regimen and duration of short-course treatment for human immunodeficiency virus-related pulmonary tuberculosis. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG). Clinical Infectious Diseases 1998;26(5):1148-58.
Huang 2000 {published data only}
  • Huang CS, Wu CC. Observation of the clinical efficacy of sparfloxacin in the treatment of multiple drug resistance pneumonial tuberculosis. Chinese Journal of Antibiotics 2000;25(4):302-3.
Ji 2001 {published data only}
  • Ji YM, Dong LH, Wang Q, Yu WQ. Short-term observating of curative effects in treatment of multiple-drug resistance pulmonary tuberculosis with sparfloxacin and ofloxacin. Journal of Postgraduates of Medicines 2001;24(7):32-3.
Kennedy 1993 {published data only}
  • Kennedy N, Fox R, Uiso L, Ngowi FI, Gillespie SH. Safety profile of ciprofloxacin during long-term therapy for pulmonary tuberculosis. Journal of Antimicrobial Chemotherapy 1993;32(6):897-902.
Kennedy 1996 {published data only}
  • Kennedy N, Berger L, Curram J, Fox R, Gutmann J, Kisyombe GM, et al. Randomized controlled trial of a drug regimen that includes ciprofloxacin for the treatment of pulmonary tuberculosis. Clinical Infectious Diseases 1996;22(5):827-33.
  • Kennedy N, Fox R, Kisyombe GM, Saruni AO, Uiso LO, Ramsay AR, et al. Early bactericidal and sterilizing activities of ciprofloxacin in pulmonary tuberculosis. American Review of Respiratory Disease 1993;148(6 Pt 1):1547-51.
Kohno 1992 {published data only}
Lu 2000 {published data only}
  • Lu Y, Zhu L, Duan L. Antituberculosis effect of levofloxacin. Zhonghua Jiehe He Huxi Zazhi [Chinese Journal of Tuberculosis and Respiratory Diseases] 2000;23(1):50-4.
Mohanty 1993 {published data only}
Saigal 2001 {published data only}
  • Saigal S, Agarwal SR, Nandeesh HP, Sarin SK. Safety of an ofloxacin-based antitubercular regimen for the treatment of tuberculosis in patients with underlying chronic liver disease: a preliminary report. Journal of Gastroenterology and Hepatology 2001;16(9):1028-32.
    Direct Link:
Sun 2000 {published data only}
  • Sun W, Wenyi C, Cunzhi L, Yanhong Y, Yuzhen X, Zhaosheng S. A randomized controlled study of sparfloxacin and ofloxacin in the treatment of multiple drug resistant pulmonary tuberculosis. Chinese Journal of Antibiotics 2000;25(1):52-4.

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
Andries 2005 {published data only}
Anonymous 1997 {published data only}
  • Anonymous. A controlled study of rifabutin and an uncontrolled study of ofloxacin in the retreatment of patients with pulmonary tuberculosis resistant to isoniazid, streptomycin and rifampicin. Hong Kong Chest Service/British Medical Research Council. Tubercle and Lung Disease 1997;73(1):59-67.
Chambers 1998 {published data only}
Chen 2003 {published data only}
  • Chen QL, Chen L, Yin JJ. A study on the clinical efficacy of a combination regimen with levofloxacin and capreomycin in the treatment of multi-drug resistant pulmonary tuberculosis. Zhonghua Jiehe He Huxi Zazhi [Chinese Journal of Tuberculosis and Respiratory Diseases] 2003;26(8):454-7.
Chukanov 2006 {published data only}
  • Chukanov VI, Komissarova OG, Maishin VI, Abdullaev RI, Kononets AS. Efficiency of a new standard chemotherapy regimen in the treatment of patients with recurrent pulmonary tuberculosis. Problemy Tuberculeza I Boleznej Legkih 2006, (8):9-13.
Estebanez 1992 {published data only}
  • Estebanez Zarranz MJ, Martinez-Sagarra JM, Alberte A, Amon Sesmero J, Rodriguez Toves A. Treatment of urogenital tuberculosis with ofloxacin. Preliminary study. Actas Urologicas Espanolas 1992;16(1):64-8.
Gosling 2003 {published data only}
  • Gosling RD, Uiso LO, Sam NE, Bongard E, Kanduma EG, Nyindo M, et al. The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis. American Journal of Respiratory and Critical Care Medicine 2003;168(11):1342-5.
Grishin 1998 {published data only}
  • Grishin VK, Polunina TE. Lomefloxacin in phthisiatric practice. Antibiotiki i Khimioterapiia 1998;43(10):17-8.
Johnson 2006 {published data only}
  • Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, et al. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. International Journal of Tuberculosis & Lung Disease 2006;10(6):605-12.
Kawahara 1992 {published data only}
  • Kawahara S, Eirei J. Evaluation of new antitubercular agents--new quinolone agents. Kekkaku 1992;67(10):679-82.
Kumar 2004 {published data only}
  • Kumar AK, Gurumurthy P. Disposition of uric acid upon administration of ofloxacin alone and in combination with other anti-tuberculosis drugs. Indian Journal of Experimental Biology 2004;42(3):323-5.
Marra 2005 {published data only}
O'Brien 1994 {published data only}
Pletz 2004 {published data only}
  • Pletz MW, De Roux A, Roth A, Neumann KH, Mauch H, Lode H. Early bactericidal activity of moxifloxacin in treatment of pulmonary tuberculosis: a prospective, randomized study. Antimicrobial Agents and Chemotherapy 2004;48(3):780-2.
Sirgel 1997 {published data only}
  • Sirgel FA, Botha FJ, Parkin DP, Van de Wal BW, Schall R, Donald PR, et al. The early bactericidal activity of ciprofloxacin in patients with pulmonary tuberculosis. American Journal of Respiratory and Critical Care Medicine 1997;156(3 Pt 1):901-5.
Sirgel 2000 {published data only}
  • Sirgel FA, Donald PR, Odhiambo J, Githui W, Umapathy KC, Paramasivan CN, et al. A multicentre study of the early bactericidal activity of anti-tuberculosis drugs. Journal of Antimicrobial Chemotherapy 2000;45(6):859-70.
Sokolova 1998 {published data only}
  • Sokolova GB, Kunichan AD, Koriakin VA, Lazareva IaV. Lomefloxacin in complex treatment of acute progressive form of pulmonary tuberculosis. Antibiotiki i Khimioterapiia 1998;43(10):10-2.
Suo 1996 {published data only}
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Valerio 2003 {published data only}
  • Valerio G, Bracciale P, Manisco V, Quitadamo M, Legari G, Bellanova S. Long-term tolerance and effectiveness of moxifloxacin therapy for tuberculosis: preliminary results. Journal of Chemotherapy 2003;15(1):66-70.
Venter 2006 {published data only}
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Wang 2006 {published data only}
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Yoon 2005 {published data only}
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Zhang 1997 {published data only}
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Zhang 2006 {published data only}
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Zhao 2003 {published data only}
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Zheng 2004 {published data only}
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References to studies awaiting assessment

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
Abdullah 1997 {published data only}
  • Abdullah A, Abu-Hussein AH, Al-Akshar M, Abdel R, Ads CH, El Taieb S. Ofloxacin in the treatment of primary drug resistant pulmonary tuberculosis (PDR-TB). European Respiratory Journal 1997;10 Suppl:25214.
Abdullah 1998 {published data only}
  • Abdullah A, Hussein A, Al-Akshar M, Ads CH, El-Taieb S. Ofloxacin dosage in the treatment of multidrug resistant pulmonary tuberculosis (MDR-TB). European Respiratory Journal 1998;12 Suppl:28367.

References to ongoing studies

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
ISRCTN07062956 {published data only}
  • ISRCTN 07062956. A randomised comparison of ciprofloxacin, levofloxacin and gatifloxacin for the treatment of adults with tuberculous meningitis. www.controlled-trials.com/ISRCTN07062956/07062956 (accessed 27 July 2007).
ISRCTN13670619 {published data only}
  • ISRCTN13670619. A comparative study of the bactericidal and sterilizing activity of three fluoroquinolones: gatifloxacin, moxifloxacin and ofloxacin substituted for ethambutol in the 2 month initial phase of the standard anti-tuberculosis treatment regimen also containing rifampicin, isoniazid and pyrazinamide (South Africa). www.controlled-trials.com/ISRCTN13670619/ISRCTN13670619 (accessed 27 July 2007).
ISRCTN44153044 {published data only}
  • ISRCTN44153044. An international multicentre controlled clinical trial to evaluate high dose RIFApentine and a QUINolone in the treatment of pulmonary tuberculosis. www.controlled-trials.com/ISRCTN44153044/ISRCTN44153044 (accessed 27 July 2007).
ISRCTN85595810 {published data only}
  • ISRCTN85595810. Controlled comparison of two moxifloxacin containing treatment shortening regimens in pulmonary tuberculosis. www.controlled-trials.com/mrct/trial/260713/REMoxTB (accessed 27 July 2007).
NCT00144417 {published data only}
  • NCT00144417. Evaluation of a moxifloxacin-based, isoniazid-sparing regimen for tuberculosis treatment. www.clinicaltrials.gov/show/NCT00144417 (accessed 23 July 2007).
NCT00216385 {published data only}
  • NCT00216385. A controlled trial of a 4-month quinolone-containing regimen for the treatment of pulmonary tuberculosis. clinicaltrials-nccs.nlm.nih.gov/ct2/show/NCT00216385 (accessed 23 July 2007).
NCT00396084 {published data only}
  • NCT00396084. Randomized, open label, multiple dose Phase I study of the early bactericidal activity of linezolid, gatifloxacin, levofloxacin, and moxifloxacin in HIV-non-infected adults with Initial episodes of sputum smear-positive pulmonary tuberculosis (DMID 01-553). clinicaltrials.gov/ct/show/NCT00396084?order=11 (accessed 27 July 2007).

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
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