Fluoroquinolones for the treatment and prevention of multidrug-resistant tuberculosis

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1 INT J TUBERC LUNG DIS 20(12):S42 S47 Q 2016 The Union MDR-TB TRIALS LANDSCAPE SUPPLEMENT Fluoroquinolones for the treatment and prevention of multidrug-resistant tuberculosis T. R. Sterling Division of Infectious Diseases, Department of Medicine, and Vanderbilt Tuberculosis Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA SUMMARY Although fluoroquinolones (FQs) play an important role in the treatment of multidrug-resistant tuberculosis (MDR-TB), there are several issues that need to be addressed to optimize their effectiveness and minimize toxicity. This includes identification of the optimal dose of FQs such as levofloxacin (LVX) and moxifloxacin, and the optimal role of FQs in combination with other anti-tuberculosis drugs, particularly those with overlapping toxicity, such as QT prolongation. While the ability of FQs to penetrate into cavities and granulomas is likely beneficial, suboptimal sensitivity of genotypic tests to detect FQ resistance could negatively affect treatment outcomes of FQ-containing regimens. Several trials are underway to evaluate the safety and effectiveness of FQs as part of combination MDR-TB therapy; there are also two planned studies of LVX to prevent tuberculosis among close contacts of MDR-TB. KEY WORDS: tuberculosis; M. tuberculosis; fluoroquinolone resistance FLUOROQUINOLONES (FQS) HAVE excellent in vitro activity against rapidly dividing Mycobacterium tuberculosis organisms. 1 Newer 8-methoxy FQs, such as gatifloxacin (GFX) and moxifloxacin (MFX), have more potent activity than older agents such as ciprofloxacin (CFX) and ofloxacin (OFX), as demonstrated by the lower minimum inhibitory concentrations (MIC; the lowest concentration of drug that prevents visible growth in culture) of the newer agents. 2 7 FQs play a critical role in the successful treatment of multidrug resistant tuberculosis (MDR-TB; defined as resistance to at least isoniazid [INH] and rifampin [RMP]). GFX was a key component of the 9-month Bangladesh regimen, in which 84% of patients had a bacteriologically favorable outcome. 8,9 The risk of treatment failure and relapse was significantly increased among patients with high-level FQ resistance. 9 However, the toxicity profile of GFX includes dysglycemia, and it is no longer commercially available. MFX and levofloxacin (LVX) are also very effective against M. tuberculosis, and more widely available. In an openlabel randomized clinical trial among MDR-TB patients, the 3-month sputum culture conversion and treatment success rates were similar in persons who received MFX or LVX. 10,11 MFX and LVX are both under evaluation in several clinical trials of TB disease and treatment of latent tuberculous infection (Table 1). This includes regimens that could shorten the treatment duration for both MDR-TB and drugsusceptible disease, and prevent TB disease among household contacts of persons with MDR-TB. IMPORTANT ISSUES REGARDING FLUOROQUINOLONES FOR THE TREATMENT OF TUBERCULOSIS Two methods by which to evaluate the activity of anti-tuberculosis drugs are early bactericidal activity (EBA) and sterilizing activity. 14 EBA is quantified by the rate of decrease in the concentration of tubercle bacilli in the initial days of treatment. Sterilizing activity is the activity against tubercle bacilli that persist despite treatment, and is characterized by achieving negative mycobacterial cultures. FQs have excellent EBA against M. tuberculosis. MFX, the FQ with the most potent activity on a per gram basis against M. tuberculosis, has EBA similar to that of INH. 15,16 However, FQs do not have good sterilizing activity. To reduce treatment duration of either MDR-TB or drug-susceptible disease the FQ needs to be given with other drugs that have good sterilizing activity. This has been demonstrated by three recent Phase III clinical trials of FQs administered in combination with standard drugs for the treatment of drug-susceptible tuberculosis (DS-TB); all 4-month regimens were inferior to standard 6-month treatment of DS-TB in preventing the combined endpoint Correspondence to: Timothy R Sterling, A2209 Medical Center North, st Avenue South, Nashville, TN 37232, USA. Fax: (þ1) timothy.sterling@vanderbilt.edu Article submitted 9 February Final version accepted 1 July 2016.

2 S43 Table 1 Unpublished, ongoing or planned studies of DS-TB or drug-resistant TB or treatment of latent tuberculous infection that include a fluoroquinolone. Update based on RESIST-TB (Research Excellence to Stop TB Resistance), as of 21 June and Dr M Vjecha (personal communication, June 2016) Title Arms Phase DS-TB or MDR-TB Expected start date or publication date STREAM I* 4MfxCfzZEKmHPth/5MfxCfzZE vs. III MDR-TB Results 2018 standard WHO drug-resistant regimen STREAM II* Phase I plus: III MDR-TB Opened March LvxCfzZEBdqHPth/5LvxCfzZE vs. 6-month regimen with Bdq, and shorter Km NExT-5001 BdqLzdLvxEH H Z for 6 9 months III MDR-TB Results 2019 MAMS-TB-01 HR 35 ZE vs. HR 20 ZMfx 400 vs. HRZE II DS-TB Enrolling ACTG 5307 RMfx 400 ZE vs. RZE vs. HRZE 2-week EBA DS-TB Results 2016 Opti-Q Lvx (11 vs. 14 vs. 17 vs. 20 mg/kg/day) þ II MDR-TB Results 2018 STAND: NC-006/A5344 OBR vs. OBR Drug S: 4Pa 100 MfxZ vs. 4Pa 200 MfxZ vs. 6Pa 200 MfxZ MDR-TB: 6Pa 200 MfxZ Control: 2HRZE/4HR III 1200 DS-TB; 300 MDR-TB. All Mfx dosing 400 mg Trial on hold 13 NexGen EBA 1MfxRHZ 4-week EBA DS-TB Results 2018 TBTC 31/A5349 2HP 1200 ZE/2HP 1200 vs. 2HP 1200 ZMfx/ 2HP 1200 Mfx Control: 2HRZE/4HR III DS-TB Opened January 2016 MDR-END Lvx 750/1000 LzdZD vs. OBR II MDR-TB Opened January 2016 TB-PRACTECAL 2-stage: 6BdqPaMfxLzd vs. 6BdqPaLzdCfz II/III MDR-TB Opened February 2016 vs. 6BdqPaLzd vs. OBR XDR-TB endtb 9BdqLzdMfxZ vs. 9BdqLzdCfzLvxZ vs. III MDR-TB Opening DlmCfzMfxZ vs. OBR V-QUIN Lvx vs. placebo for TB prevention in adult and pediatric household contacts of MDR-TB III Contacts of MDR-TB Opening 2016 TB-CHAMP LVX vs. placebo for TB prevention in pediatric household contacts of MDR-TB III Contacts of MDR-TB Opening 2016 * Mfx dosing based on weight: 400, 600, or 800 mg. DS-TB¼drug-susceptible TB; TB¼tuberculosis; MDR-TB¼multidrug-resistant TB; Mfx¼moxifloxacin; Cfz¼clofazimine; Z¼pyrazinamide; E¼ethambutol; Km¼ kanamycin; H¼isoniazid; Pth¼prothionamide; WHO¼World Health Organization; Lvx¼levofloxacin; Bdq¼bedaquiline; XDR-TB¼extensively drug-resistant TB; Lzd ¼ linezolid; H H high-dose isoniazid; R ¼ rifampin; OBR ¼ optimal background regimen; Pa ¼ Pa-824; Dlm ¼ delamanid. of treatment failure, relapse, and death However, MFX-containing regimens have been associated with higher rates of sputum culture conversion to negative by month 2 than the standard anti-tuberculosis regimen of INH, RMP, pyrazinamide (PZA), and ethambutol (EMB). 17,20 Two recent studies of human TB have demonstrated excellent penetration of MFX and LVX into lung cavities, and a good correlation between serum and cavitary drug concentrations. 21,22 In the rabbit model of TB, MFX had excellent penetration into lung cavities and tissue granulomas. 23 High FQ tissue levels could account for their contribution to improved treatment outcomes of MDR-TB, but this has not been specifically evaluated. The toxicity profile of the drugs given in combination with the FQ also needs to be considered, particularly for the treatment of MDR-TB (Table 2). For example, FQs can prolong the QT interval MFX and GFX to perhaps a greater extent than LVX. 24 So, too, can other drugs used to treat MDR- TB, such as bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ). Any clinical trial of MFX or other FQs for the treatment of MDR-TB should include the other anti-tuberculosis drugs with which the FQ would be given in clinical practice, so that toxicity of the drug combination can be evaluated. Because cardiac events such as torsade de pointes have been rare to date in TB clinical trials, and given that monitoring for such cardiotoxicity (other than QT interval prolongation) can be difficult under field conditions, translational studies should be considered. This might include the use of induced pluripotent stem cell-derived cardiomyocytes in cardiac safety pharmacology assays. 25 FQ cross-resistance in M. tuberculosis isolates is frequent. 26 So, although the MFX MIC is lower than the LVX MIC, if there is resistance to CFX, OFX, or LVX, there will usually be resistance to MFX. However, a recent study of MDR-TB isolates found a low level of concordance of phenotypic FQ resistance test results, driven in part by high rates of CFX and OFX resistance in isolates that were intermediate or susceptible to MFX. 27 A recent study noted that some of the discrepancy can be associated with the resistance testing method used, and MICs near the resistance cut-off. 28 FQ resistance in M. tuberculosis is conferred primarily by mutations in the DNA gyrase, particularly at codons 90, 91, and 94 in the A subunit (gyra). Current genotypic tests focus primarily on mutations in these codons. However, a systematic literature

3 S44 The International Journal of Tuberculosis and Lung Disease Table 2 Comparison of the fluoroquinolones in the treatment of tuberculosis Drug Relative activity against M. tuberculosis* Characteristic adverse events Relative cost Comments Ciprofloxacin Low Rash, GI upset Low Widely available, widely used Ofloxacin Low Rash, GI upset Low Gatifloxacin High Dysglycemia Limited availability Levofloxacin High QT prolongation Low Moxifloxacin Highest QT prolongation High Lowest M. tuberculosis MIC; PK/PD has not been evaluated; 400 mg may not be optimal * As determined by MIC. Additional adverse events can occur with all fluoroquinolones, including GI upset, headache, dizziness, insomnia, alterations in mood, rash, arthropathy, tendinitis, tendon rupture, nephrotoxicity, hepatotoxicity. GI ¼ gastrointestinal; PK/PD ¼ pharmacokinetic/pharmacodynamics; MIC ¼ minimum inhibitory concentration. review found that 45% of FQ-resistant isolates did not have mutations at these codons. 29 This suggests that current genotypic tests may have reduced sensitivity for detecting FQ resistance. A recent Cochrane review found that as the GenoType w MTBDRsl (Hain Lifescience, Nehren, Germany) assay was 83% sensitive, it would not detect ~1 in 5 FQ-resistant TB cases. 30 Heteroresistance is the coexistence of populations with differing nucleotides at a drug resistance locus within a sample of organisms. Heteroresistance in gyra and gyrb occurred in 38% of phenotypically FQ-resistant M. tuberculosis clinical isolates in one recent study. 31 The presence of heteroresistance can make the detection of genotypic resistance difficult, particularly with less-sensitive genotypic tests. AREAS THAT HAVE NOT BEEN EVALUATED REGARDING FLUOROQUINOLONES FOR THE TREATMENT OF TUBERCULOSIS The optimal dose of LVX or MFX for the treatment of TB is unknown. There is an ongoing LVX doseranging study for the treatment of MDR-TB (Opti-Q; Tuberculosis Trials Consortium Study 32; NCT ); this study will intensively evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of LVX. I am not aware of ongoing dose-ranging studies of MFX for the treatment of TB, although the STREAM trial is dosing MFX according to the participant s weight: 400 mg (,33 kg), 600 mg (33 50 kg), or 800 mg (.50 kg). A recent PK study in children aged 7 15 years with MDR-TB who received MFX 10 mg/kg/day found low serum concentrations compared to adults receiving 400 mg daily. 32 As mentioned above, the optimal FQ dose may depend at least in part on the companion drugs in the regimen, given the potentially overlapping toxicity (e.g., QT prolongation). Drugs that reduce the absorption of FQs, such as divalent and trivalent cations (e.g., aluminum, magnesium, or calcium-containing antacids), could also affect drug activity and dosing. It is unclear whether the method used to detect FQ resistance prior to the initiation of treatment for MDR-TB affects treatment outcome. For example, it has not been evaluated whether diagnostic tests with low sensitivity for detecting DNA gyrase mutations (or persons infected with a FQ-resistant M. tuberculosis strain that lacks DNA gyrase mutations) are associated with worse treatment outcomes. The ability to detect FQ heteroresistance (which is also related to assay sensitivity), could also affect antituberculosis treatment outcomes. In addition, among M. tuberculosis isolates from MDR-TB patients, different gyra and gyrb mutations confer different levels of resistance to MFX and OFX, and this can affect treatment outcomes For example, mutations at codon 94 in gyra (except D94A) are associated with higher MICs, and worse treatment outcomes. 34 There are limited data on FQs for the prevention of TB among close contacts of MDR-TB. 36,37 Two studies are planned (Table 1). Previous studies have demonstrated poor tolerability of regimens such as an FQ plus PZA, although this may be due in large part to PZA. 38 Other companion drugs, such as EMB, may be better tolerated. 39 Inclusion of any newer drug in studies on MDR-TB prevention (e.g., BDQ) is unlikely because to date there are limited safety data, and safety is a primary objective in the treatment of asymptomatic LTBI. However, the PHOENIx study plans to compare DLM vs. INH in such close contacts. 40 I am not aware of ongoing studies of FQs in combination with other drugs for the prevention of MDR-TB. The optimal FQ dose for the prevention of TB is unknown. POTENTIAL FUTURE STUDIES It is important to determine the optimal combination and dosing of FQs for MDR-TB treatment. In particular, should FQs be given or avoided when other drugs that prolong the QT interval are included in the regimen? How should the key components of MDR-TB treatment be combined? This might include an assessment of regimens that contain or exclude key drugs, such as FQs, BDQ, DLM and injectable agents. But given the improved treatment outcomes when an FQ is included in regimens for the treatment of MDR-TB, 41,42 a trial that excludes FQs may be

4 S45 difficult to design and conduct. One would probably select key drugs to include as the backbone of a MDR-TB regimen, then study them in a trial to optimize their dosing. Potential components of a backbone might include MFX, CFZ, BDQ, DLM, PZA, pretomanid, and/or an injectable agent. One might also want to evaluate regimens with fewer than five drugs (depending on the potency of the drugs used), or regimens that spare certain classes, such as injectable agents. The optimal duration and timing of the FQs and the other drugs need to be evaluated. This may be particularly important given the overlapping toxicities to maximize drug exposure at the most important time during the treatment course, and minimize toxicity. A recent study demonstrated that an MFX derivative, 8-methyl-moxifloxacin, was more potent than MFX against wild-type M. tuberculosis. This derivative also displayed greater activity against DNA gyrase with the A90V and D94G gyra mutations than did MFX against wild-type M. tuberculosis. 43 Such potent FQ derivatives merit further investigation. The optimal regimen for the prevention of TB in close contacts of MDR-TB needs to be evaluated. Questions include the optimal duration, the evaluation of FQs alone vs. in combination with other drugs, and the optimal FQ dose for LTBI treatment. Two trials of LVX include V-QUIN, which will study adults and children in Viet Nam, and TB-CHAMP (by The International Maternal Pediatric Adolescent AIDS Clinical Trials network), which will study pediatric household contacts in South Africa (Table 1). LTBI treatment has not been associated with an increased risk of drug resistance among persons who subsequently develop TB. 44,45 STUDIES THAT MAY NOT BE WORTH PURSUING It may not be necessary to perform a clinical trial to assess treatment of FQ-resistant TB with regimens that include late-generation FQs, such as MFX, to assess their contribution to activity. MFX does appear to have activity against some OFX-resistant strains of M. tuberculosis, but the activity varies according to the underlying mutation in DNA gyrase and the resultant MFX MIC. 46 A recent observational study found that MFX use was associated with earlier culture conversion among persons with OFX-resistant MDR-TB. 47 For a clinical trial, it would be difficult to achieve a sufficient sample size of FQresistant MDR-TB cases with isolates that had a relatively low MFX MIC, and any effect of MFX alone would be very difficult to tease out, as other drugs would also be given in the combination. It also may not be necessary to assess treatment outcome according to the method used to detect FQ resistance (e.g., Xpert w MTB/RIF Ultra, Cepheid, Sunnyvale, CA, USA; MTBDRsl v2.0, Hain Life- Sciences, Nehren, Germany; or DNA gyrase sequencing). As the sensitivity of these later-generation tests is greater than that of earlier versions (e.g., MTBDRsl v2.0 vs. v1.0), 48,49 the sample size required to demonstrate a difference in treatment outcome would likely be prohibitively large. In addition, it can be difficult to demonstrate an improvement in treatment outcome associated with a more sensitive diagnostic test due to the many factors involved in accurate diagnosis and timely, appropriate treatment. 50 CONCLUSION FQs play an important role in MDR-TB treatment, but there are several key issues that should be addressed to optimize their effectiveness and minimize their toxicity. This includes identification of the optimal dose of FQs such as LVX and MFX, and the optimal role of FQs in combination with other antituberculosis drugs, particularly those with overlapping toxicity, such as QT prolongation. Acknowledgement I would like to thank the editor and the anonymous peer reviewers for their very helpful comments regarding this manuscript. Conflicts of interest: TS has been on a Data Safety Monitoring Board for Otsuka for an MDR-TB clinical trial of delamanid. References 1 Garcia-Rodriguez J A, Gomez Garcia A C. In vitro activities of quinolones against mycobacteria. J Antimicrob Chemother 1993; 32: Clinical and Laboratory Standards Institute, The National Committee for Clinical Laboratory Standards. Susceptibility testing of mycobacteria, nocardiae, and other aerobic actinomycetes: approved Standard. NCCLS Document 2003; M24-A. Wayne, PA, USA: NCCLS, Tomioka H, Sato K, Akaki T, et al. 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7 i Les fluoroquinolones (FQ) jouent un rôle important dans le traitement de la tuberculose multirésistante (TB- MDR), mais il reste plusieurs questions à examiner afin d optimiser leur efficacité et de minimiser leur toxicité. Ces questions comprennent l identification de la dose optimale des FQ comme la lévofloxacine (LVX) et la moxifloxacine ainsi que le rôle optimal des FQ en combinaison avec d autres médicaments antituberculeux, particulièrement ceux qui ont une toxicité commune, comme l allongement de QT. Si la RESUME capacité des FQ à pénétrer dans les cavernes et les granulomes est probablement bénéfique, la sensibilité sousoptimale des tests génotypiques à détecter la résistance aux FQ pourrait affecter négativement le résultat du traitement par des protocoles contenant de la FQ. Plusieurs essais sont en cours afin d évaluer la sécurité et l efficacité des FQ sous forme de traitement combiné de la TB-MDR ; il y a également deux études planifiées de la LVX dans la prévention de la TB parmi les contacts rapprochés de TB-MDR. Las fluoroquinolonas (FQs) cumplen una función primordial en el tratamiento de la tuberculosis multirresistente (TB-MDR), pero es importante abordar determinados aspectos con el fin de optimizar su eficacia y aminorar su toxicidad. Estos aspectos incluyen la determinación de la dosis óptima de FQ como la levofloxacina (LVX) y la moxifloxacina (MFX) y la función central de las FQ en asociación con otros medicamentos antituberculosos, sobre todo con los cuales existe una superposición de la toxicidad, como la prolongación del segmento QT. Aunque la capacidad de las FQ para penetrar en las cavernas y los granulomas RESUMEN puede ser útil, la escasa sensibilidad de las pruebas genotípicas de resistencia a estos medicamentos podría producir un efecto negativo en los desenlaces terapéuticos de los esquemas que los contienen. En la actualidad, están en curso varios ensayos clínicos destinados a evaluar la seguridad toxicológica y la eficacia de las FQ como parte de una polifarmacoterapia contra la TB-MDR; se han planeado además dos nuevos estudios sobre la utilización de la LVX en la prevención de la TB de los contactos directos de pacientes con TB- MDR.