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October - December 2008: 
Volume 21, Issue 4

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The role of fluoroquinolones in the treatment of Tuberculosis
Abstract
SUMMARY. The need for new, more effective antituberculous drugs is pressing. The treatment of active disease needs to be shortened and simplified, the treatment given for latent tuberculosis (TB) also needs to be shortened and, most importantly, improved therapy for multi-drug resistant TB (MDR-TB) is needed. The fluoroquinolones are the first novel drugs since the rifamycins found to exert significant activity against M. tuberculosis. They are currently being used for the prophylactic treatment of individuals who have been exposed to MDR-TB, for the treatment of MDR-TB, for empirical treatment of TB in areas with high rates of MDR-TB and for patients who present severe adverse reactions to the conventional antituberculous regime. Conversely, their use is not recommended as a first-line drug for the routine treatment of TB. Fluoroquinolones are relatively safe antimicrobial compounds that bind to bacterial topoisomerases, resulting in cell death. They show strong bactericidal activity both in vitro and in vivo, and some, such as moxifloxacin, also exert sterilizing activity. Resistance to fluoroquinolones, associated with their previous use, is a significant issue. The emergence of resistance is far more likely when ciprofloxacin is included in the regime. In the case of community-acquired pneumonia the decision to administer a fluoroquinolone should be made with caution and the possibility of pulmonary TB should be considered. The appropriate use of fluoroquinolones both in the treatment of TB and for community-acquired pneumonia is of critical importance, since the emergence of resistance is becoming a significant problem. Pneumon 2008; 21(4):–
Full text

Introduction

Tuberculosis (TB) is a major public health issue world wide. One-third of the world's population has been infected with Mycobacterium tuberculosis and 2 million deaths are attributed to tuberculosis each year1,2. In Greece, 10 cases per 100,000 inhabitants are reported every year, although the real number may be twice as high3. The TB epidemic is fueled by the growing incidence of HIV infection and migration, and there appears to be an increase in multidrug-resistant TB (MDR-TB). MDR-TB is defined as TB resistant to at least isoniazid and rifampin, and extensively drug- resistant TB (XDR-TB) as disease caused by MDR strains that are also resistant to at least one fluoroquinolone and one or more injectable agents1,2,4. It is estimated that in 2004 half a million new MDR-TB cases were diagnosed world wide4. In these cases cure is rarely achieved in more than 85% of patients initiating therapy, even when all antituberculous agents are available4. Although TB treatment is successful in 98% of cases in the developed world, 5-20% of MDR-TB patients and 66% of MDR-TB and HIV co-infected patients die during treatment4.

The currently recommended treatment for active pulmonary TB is lengthy and cumbersome and associated with severe adverse effects. It consists of 4 drugs (isoniazid, rifampin, pyrazinamide and ethambutol) given for the first 2 months, followed by 2 drugs (isoniazid and rifampin) administered for 4 additional months5. The initial phase duration of 2 months applies so long as the M tuberculosis is proved to be susceptible, but it should be lengthened if susceptibility test results are not available. In the initial phase, combination treatment is given with the aim of killing the Mycobacteria in the exponentional-phase growth and to prevent emergence of drug resistance. Isoniazid in adequate concentrations is the main bactericidal drug. During the continuation phase the target is to kill non-replicating, persistent M. tuberculosis. Drugs with strong bactericidal activity, such as isoniazid, are necessary for the initial phase, whereas those with sterilizing activity are most effective during the continuation phase6,7. One additional difficulty with the currently available TB regime is the potential for drug interactions, primarily those between rifampin and the antiretroviral drugs used for the treatment of AIDS1.

The treatment of MDR-TB includes relatively less effective, poorly tolerated and more expensive drugs that need to be administered for 18-24 months1. Equally inadequate is the treatment of latent TB infection, which consists of isoniazid given for 6-9 months, for which the major problems are compliance and liver toxicity1.

Despite these problems, the development of new drugs has been almost nonexistent since the introduction of rifampin in 19708, and the need for new, more effective drugs that can achieve multiple goals in improving TB control is therefore urgent. The treatment of active disease needs to be shortened and simplified and the interactions of TB regimens with other drugs to be minimized. Treatment of latent TB also needs to be shortened. Most importantly, improved therapy for MDR-TB and XDR-TB is absolutely necessary1,4.

Of the new compounds being tested for their efficacy in TB treatment, the fluoroquinolones are the first novel drugs since the development of rifamycins to have been shown to have significant activity against M. tuberculosis9. Fluoroquinolones are fluorine-containing derivatives of older quinolones, such as nalidixic acid. As they have a broad-spectrum antimicrobial activity, they have been widely used for the treatment of bacterial infections of the respiratory, gastrointestinal and urinary tracts for the last 30 years2. Fluoroquinolones are the only antibiotics that directly inhibit DNA synthesis. They target bacterial topoisomerases II and IV, enzymes which control DNA topology2,10. Different fluoroquinolones appear to favour different enzyme; ciprofloxacin binds preferentially to topoisomerase IV, whereas moxifloxacin has a predilection for topoisomerase II. Fluoroquinolone binding to topoisomerases leads to bacterial death by mechanisms that have not been fully elucidated, although strand-breakage, autolysis, and blockade of replication by the topoisomerase-fluoroquinolone complex have all been proposed2,11. Fluoroquinolones have been shown to penetrate into macrophages where they also exert bactericidal activity2.

IN VITRO ACTIVITY

The newer fluoroquinolones sparfloxacin, gatifloxacin and moxifloxacin have lower minimum inhibitory concentrations (MIC) for M. tuberculosis than the older levofloxacin, ciprofloxacin and ofloxacin2 (Table 1). Of all the fluoroquinolones tested against rifampin-tolerant M. tuberculosis, gatifloxacin and moxifloxacin exert the greatest bactericidal activity2. When combined with various first-line antituberculous drugs, these compounds have been shown to cause greater reduction in colony forming units (CFU) of intramacrophage M. tuberculosis than the other drugs alone2. The in vitro activity of the various fluoroquinolones on M. tuberculosis is ranked in the order: lomefloxacin < ciprofloxacin < or = ofloxacin < sparfloxacin < moxifloxacin = gatifloxacin12. Gatifloxacin and moxifloxacin showed low MIC for both ofloxacin resistant and ofloxacin susceptible strains, although some cross resistances was observed12. Moxifloxacin appears to exert both bactericidal and sterilizing activity, maintained against persistent M. tuberculosis tolerant to high rifampin concentrations6. It has been shown that the number of viable counts for 100-day cultures of M. tuberculosis exposed to various concentrations of ciprofloxacin is significantly higher than that of those exposed to other fluoroquinolones, such as moxifloxacin and gatifloxacin; in other words, ciprofloxacin has a significantly lower bactericidal activity than the other fluoroquinolones6.

TABLE 1. Minimum inhibitory concentration (MIC) of fluoroquinolones against Mycobacterium tuberculosis2.

Fluoroquinolone

MIC (μg/mL)

Ciprofloxacin

0.5-4

Ofloxacin

1-2

Levofloxacin

1

Sparfloxacin

0.2-0.5

Gatifloxacin

0.2-0.25

Moxifloxacin

0.12-0.5

IN VIVO ACTIVITY

The in vivo activity of fluoroquinolones is concentration-dependent. One in vivo comparison found that gatifloxacin, moxifloxacin and isoniazid had similar activity against M. tuberculosis. According to several studies in mice, moxifloxacin is the most strongly bactericidal (possibly more than isoniazid) followed, in order of decreasing activity, by sparfloxacin, levofloxacin and ofloxacin. Moxifloxacin also appears to exert a degree of sterilizing activity that may enable achievement of the goals of a shortened therapy regime and improved treatment of latent TB2. In a mouse model the combination of rifampin, pyrazinamide, and moxifloxacin showed sterilizing activity that exceeded substantially not only that of the standard regime but also that of the standard regime with the addition of moxifloxacin13. Moxifloxacin has been demonstrated to be able to kill mycobacteria in the absence of ongoing protein synthesis, which might explain its efficacy against M. tuberculosis in a dormant state14.

The ratios of two pharmakokinetic parameters, the peak serum concentration (Cmax) and the 24-hour area-under-the-curve (AUC24), to the MIC are generally accepted as pharmacodynamic correlates of fluoroquinolone efficacy. The greatest bactericidal effect with a decreased probability of resistance to fluoroquinolones against various bacterial pathogens occurs at Cmax/MIC ratios of >8-10 and AUC24/MIC ratios of >100-125. It is evident that moxifloxacin at the recommended daily dose of 400mg would be the most active fluoroquinolone against tuberculosis, while ciprofloxacin is the least effective2 (Table 2).

TABLE 2. Pharmacokinetic and pharmacodynamic parameters of fluoroquinolones2.

Fluoroquinolone

Cmax (μg/mL/70kg)

AUC24 (μg*h/mL/70Kg)

Cmax/MIC

AUC24/MIC

Ciprofloxacin (250 mg)

1,5

5.75

1-2

10-20

Ofloxacin (400mg)

4

48

2

24

Levofloxacin (500mg)

6.21

44.8

5-7

40-50

Sparfloxacin (400mg)

1.18

33

2

40

Gatifloxacin (400mg)

3.42

30

8.4

68

Moxifloxacin (400mg)

4.34

39.3

9

96

Cmax : maximum concentration in serum, AUC: area under curve, MIC: minimum inhibitory concentration.

 

ACTIVITY AND SAFETY IN HUMANS

It has been shown in humans that fluoroquinolones are absorbed readily after oral administration and achieve effective tissue penetration and distribution into the lungs and alveolar macrophages (Table 2)2. The early bactericidal activity, i.e. the log fall in the CFU count in sputum during the first 48 hours of therapy, of ciprofloxacin and ofloxacin is lower than that of isoniazid. Apparently this is not the case with moxifloxacin, since two studies have demonstrated that its early bactericidal activity is superior to that of rifampin and perhaps comparable to that of isoniazid2,15,16.

Severe adverse effects of fluoroquinolones include tendonitis, photosensitivity, seizures, and QT interval prolongation. Gastrointestinal and central nervous system reactions, hepatitis, renal dysfunction and hypoglycaemia have also been reported. Fluoroquinolones are restricted for use in children due to the possibility of mutagenesis and cartilage abnormalities, and they are not recommended during pregnancy, except as second-line therapy for MDR-TB in that setting2.

Drug interactions between fluoroquinolones and other antituberculous drugs are infrequent, although a recent study has shown potentially serious interactions affecting gatifloxacin and rifampin concentrations. When these drugs are administered together gatifloxacin levels increase and rifampin levels decrease17. Fluoroquinolone absorption may be reduced when co-administered with antacids. Older fluoroquinolones have an excellent safety record in long-term therapy, as has also been suggested for moxifloxacin2.

CLINICAL TRIALS

Clinical trials on the use of fluoroquinolones in the treatment of TB have focused on shortening the first-line therapy regime and on improvement of MDR-TB treatment. In a clinical trial in India, which evaluated the possibility of treatment shortening, patients with TB were assigned to four treatment groups all of which received ofloxacin. As no standard therapy group was included in the study, the interpretation of the results was limited. However, the rate of sputum conversion at 2 months ranged from 92 to 98%, which is superior to that achieved by the classical regime. Even more impressive was the very low relapse rate. Patients who received daily isoniazid, rifampin, pyrazinamide, and ofloxacin for 3 months, followed by twice-weekly isoniazid and rifampin for 1 or 2 months, experienced a 2-4% relapse rate in the first 2 years after the completion of treatment. No increased incidence of adverse reactions was observed18.

Several clinical trials have been reported in the literature concerning the role of fluoroquinolones in the treatment of TB19-22. According to a recent meta-analysis of 11 randomized controlled trials comprising a total of 1,514 patients, no statistically significant difference was observed in relation to cure, treatment failure and clinical or radiological improvement when first-line drugs were replaced by a fluoroquinolone (ciprofloxacin, ofloxacin or moxifloxacin). The substitution of ciprofloxacin into first-line regimes was associated with a higher incidence of relapse and longer time to sputum conversion19,23. Addition of levofloxacin to the classic regime had no effect. Based on these findings, there is currently no justification for the substitution of a fluoroquinolone for first-line drugs or the addition of a fluoroquinolone to the standard regime19.

It is evident that new, well planned clinical trials are needed to assess the role of fluoroquinolones in the treatment of TB. Gatifloxacin and moxifloxacin are being studied in phase II and/or III trials on the shortening of treatment duration for active, drug-susceptible pulmonary TB. These compounds are being examined more closely than any other drug in the treatment of TB and are being tested in combination regimes in which they replace ethambutol or isoniazid1. In a completed phase II study the sputum of patients who received gatifloxacin or moxifloxacin instead of ethambutol cleared more quickly than that of patients receiving conventional therapy or a regime that included ofloxacin, although the overall rate of sputum conversion at 2 months was not improved21. These results were confirmed by another study with moxifloxacin22. The ability of gatifloxacin or moxifloxacin to substitute ethambutol, or to shorten the duration of treatment to 4 months is now being tested in phase III trials1. It has been shown that substitution of moxifloxacin for isoniazid shortens the duration of therapy much more effectively than does substitution of moxifloxacin for ethambutol13. Moreover the combination of moxifloxacin and isoniazid is not antagonistic and there is even a suggestion that moxifloxacin might increase the activity of isoniazid20.

Concerning MDR-TB, in a retrospective study improvement of the cure rate (75% vs 56%) and reduction of the mortality rate (12% vs 22%) were observed in the period 1984-1998 in comparison with the period 1973-1983. This improvement was attributed to the implementation of surgical methods and the use of fluoroquinolones in the treatment of MDR-TB, especially in older patients24. Fluoroquinolone use was associated with significant improvement in survival24. In a comparative study between ofloxacin and its active S(-) enantiomer, levofloxacin, the latter was found to be more efficacious than the former when incorporated into MDR-TB regimes25. It is evident that the role of fluoroquinolones is much better established in MDR-TB than for susceptible TB. According to the ATS/CDC guidelines of 20035 fluoroquinolones should be used for:

  • Prophylactic treatment of individuals who have been exposed to MDR-TB
  • Treatment of MDR-TB
  • Empirical treatment of TB in areas with high rates of MDR-TB, and
  • Patients receiving the conventional regime who present severe adverse reactions2,19.

FLUOROQUINOLONE RESISTANCE

As mentioned above, fluoroquinolones target bacterial topoisomerases II and IV. Unlike most other bacterial species, M. tuberculosis includes only topoisomerase II and lacks topoisomerase IV. Moxifloxacin has a predilection for topoisomerase II, which may explain, at least in part, the stronger bactericidal activity of moxifloxacin compared with ciprofloxacin, which binds preferentially to topoisomerase IV2,26. Topoisomerase II or gyrase is a tetramer that consists of two A and two B subunits which include areas of interaction with the fluoroquinolones. These areas are encoded by the DNA regions QRDR. Mutations within the QRDR have been identified that are associated with fluoroquinolone resistance. The most common mutation is a substitution at codon 94 of the subunit A gene. Many mutations have been reported and it appears that different substitutions cause different levels of resistance2. Resistance level appears to be related to the number of mutations since single mutations are associated with low-level fluoroquinolone resistance whereas bacteria with high-level resistance generally have two mutations2,27. Thus, high-level resistance to fluoroquinolones appears to be generated in a stepwise process of additive mutations2,11. Mutations in the same area have also been associated with hypersusceptibility to fluoroquinolones27.

It is apparent that M. tuberculosis resistance to fluoroquinolones occurs primarily due to mutations in the QRDR of gyrase A gene. However such mutations are not found in all patients with fluoroquinolone resistance. In fact only 42-85% of resistant M. tuberculosis isolates have mutations in gyrase A QRDR and to date, no isolates have been associated with gyrase B QRDR mutations. Other mechanisms that may account for fluoroquinolone resistance include mutations in areas other than QRDR, decreased cell wall permeability to the drug, drug inactivation, or an active drug efflux pump2,28.

When M. tuberculosis is sequentially challenged with increasing concentrations of fluoroquinolones, stepwise resistance occurs and these mutations appear to map the gyrase gene. However, eventually a concentration is reached at which no mutant is recovered. The term "mutant prevention concentration" (MPC) has been proposed as a new measure of antibiotic activity that is indicative of the drug concentration above which resistant colonies are no longer recoverable when over 1010 cell are plated2. Of the first-line antituberculosis agents, none achieves human Cmax levels that exceed the MPC, in contrast to moxifloxacin and gatifloxacin. According to MPC, ciprofloxacin is the least active fluoroquinolone with a very low AUC/MPC ratio (Table 3)29, which is clinically significant as the emergence of resistance is far more likely when ciprofloxacin is included in the regimen rather than the other fluoroquinolones.

As fluoroquinolone susceptibility is not assessed routinely, the prevalence of fluoroquinolone resistance in M. tuberculosis is unknown, but several recent studies are concerned with the emergence of resistant clinical isolates2,30,31. The significance of M. tuberculosis resistance to fluoroquinolones is underlined by the fact that ciprofloxacin failure does not appear to be due to poor bactericidal activity but to rapid emergence of resistance at the doses used clinically 32. In the Philippines, ciprofloxacin resistance increased from 13.3% in 1989 to 1994 to 51.4% in 1995 to 2000, mainly because ciprofloxacin was often the only effective drug in the regimen used for the treatment of MDR-TB33. Emergence of fluoroquinolone resistance in MDR M. tuberculosis strains is possible, and decisions concerning the treatment regime in these cases should be made with caution2,31,33. Concerning moxifloxacin, the currently recommended dose of 400mg is likely to suppress the emergence of resistance in 60% of patients, whereas a much higher percentage (86-93%) would achieve this goal with 600-800mg/day. Whether these doses are well tolerated remains to be seen7.

TABLE 3. Area under the curve (AUC)/mutant prevention concentration (MPC) ratio of fluoroquinolones against Mycobacterium tuberculosis29.

Fluoroquinolone

AUCtot/MPC50

AUCtot/MPC90

Ciprofloxacin

6-38.5

2.4-15.4

Levofloxacin

74.7

29.9

Gatifloxacin

75

30

Moxifloxacin

98.2

32.7

AUCtot: total area under the curve, MPC50: mutant prevention concentration when 50% of the strains were considered, MPC 90: mutant prevention concentration when 90% of the strains were considered.

 

While there have been no reports of cross-resistance between fluoroquinolones and other classes of antituberculous agents, cross-resistance is observed within the fluoroquinolone class. Fluoroquinolone resistance is primarily seen as a result of in vivo selection of a fluoroquinolone-resistant mutant subpopulation, and therefore emergence of resistance is associated with their previous use. The time needed for acquisition of resistance varies, but it has been suggested the resistant strains can develop after courses of treatment shorter than 2 weeks2,34. Because of this, the decision to administer a fluoroquinolone for community-acquired pneumonia when there is a possibility of TB is critical. Recent studies have demonstrated that initial empirical therapy with a fluoroquinolone in presumed bacterial pneumonia which was finally diagnosed as TB was associated with delay in the diagnosis and a worse outcome of the TB35,36. After empirical use of fluoroquinolones (mainly ciprofloxacin) for 1-3 weeks, 11% of M. tuberculosis isolates became resistant35. In areas with high TB incidence, therefore, when fluoroquinolones are to be used, pulmonary TB should be considered and careful microbiological evaluation for M. tuberculosis should be performed37.

CONCLUSIONS

Fluoroquinolones are a new and important alternative drug category for the treatment of TB. In order for them to be used appropriately the following points should be kept in mind:

Currently fluoroquinolones are used as antituberculous agents in MDR-TB and, to a lesser extent, in the case of severe adverse reactions to the conventional antituberculous regime.

In the majority of cases of TB the current conventional treatment regime is successful. Fluoroquinolones are not included at present in the first-line treatment of TB, although that might change in the future, in order to shorten treatment duration.

The newer fluoroquinolones moxifloxacin and gatifloxacin have been shown to exert better activity and are associated with a lower probability of emergence of resistance.

Ciprofloxacin should not be included in the treatment of TB because emergence of resistance is probable, due to pharmacokinetic and pharmacodynamic parameters.

The appropriate use of fluoroquinolones in the treatment of TB and for community-acquired pneumonia is of critical significance, since with uncontrolled use the emergence of resistance might render this important group of antimicrobial compounds useless.

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References