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World Health Organization Group 5 Drugs forthe Treatment of Drug-Resistant Tuberculosis:Unclear Efficacy or Untapped Potential? Kelly E. Dooley,1 Ekwaro A. Obuku,2 Nadza Durakovic,3 Vera Belitsky,3 Carole Mitnick,4 and Eric L. Nuermberger1on behalf of the Efficacy Subgroup, RESIST-TB1Johns Hopkins University School of Medicine, Baltimore, Maryland; 2Institute of Human Virology, University of Maryland School of Medicine, AIDSRelief Programme and Joint Clinical Research Centre, Kampala, Uganda; 3Partners In Health, Boston, Massachusetts; and 4Harvard Medical School,Boston, Massachusetts Background. Treatment of multidrug-resistant or extensively drug-resistant tuberculosis (DR-tuberculosis) is challenging because commonly used second-line drugs are poorly efficacious and highly toxic. Although WorldHealth Organization group 5 drugs are not recommended for routine use because of unclear activity, some mayhave untapped potential as more efficacious or better tolerated alternatives.
Methods. We conducted an exhaustive review of in vitro, animal, and clinical studies of group 5 drugs to identify critical research questions that may inform their use in current treatment of DR-tuberculosis and clinicaltrials of new DR-tuberculosis regimens.
Results. Clofazimine may contribute to new short-course DR-tuberculosis regimens. Beta-lactams merit further evaluation—specifically optimization of dose and schedule. Linezolid appears to be effective but is fre-quently discontinued due to toxicity. Thiacetazone is too toxic to warrant further evaluation. Mycobacterium tu- berculosis has intrinsic inducible resistance to clarithromycin.
Conclusions. Clofazimine and beta-lactams may have unrealized potential in the treatment of DR-tuberculosis and warrant further study. Serious toxicities or intrinsic resistance limit the utility of other group 5 drugs. For several group 5 compounds, better understanding of structure-toxicity relationships may lead to better-tolerated analogs.
Keywords. tuberculosis; second-line drugs; drug resistance; multidrug-resistant tuberculosis; clofazimine; line- zolid; amoxicillin/clavulanate; carbapenems; thiacetazone; clarithromycin; extensively drug-resistant tuberculosis.
The World Health Organization (WHO) estimates to treat drug-resistant (DR) tuberculosis have undesir- that more than 1.3 million people with multidrug- able toxicity profiles and/or lack potency, and current resistant (MDR) tuberculosis caused by Mycobacteri- MDR-tuberculosis treatment requires at least 18 months um tuberculosis resistant to isoniazid and rifampin of multidrug therapy. To improve treatment of DR- will require treatment in the 27 countries with the tuberculosis with existing drugs and identify optimized highest MDR-tuberculosis burden between 2010 and background regimens for trials with new compounds, the Drug Efficacy Subgroup of Research Excellence (XDR-tuberculosis; caused by M. tuberculosis resistant to Stop tuberculosis Resistance (RESIST-tuberculosis; to isoniazid, rifampin, fluoroquinolones, and at least one injectable agent), a more difficult-to-treat form of second-line tuberculosis drugs to ascertain the contribu- tuberculosis, is widespread ]. Second-line drugs used tion of individual agents to DR-tuberculosis treatment.
This review summarizes the evidence and gaps inknowledge for drugs that are classified by WHO as Received 17 January 2012; accepted 6 April 2012; electronically published 17 “group 5”—not recommended for routine use for treat- Correspondence: Kelly E. Dooley, Division of Clinical Pharmacology, 600 N ment of DR-tuberculosis because of unclear efficacy Wolfe St, Osler 527, Baltimore, MD 21287 (Table This group includes clofazimine, linezolid, amoxicillin-clavulanate, carbapenems, thiacetazone, and The Author 2012. Published by Oxford University Press on behalf of the InfectiousDiseases Society of America. All rights reserved. For Permissions, please e-mail: clarithromycin. We highlight and prioritize key research 1352 • JID 2013:207 (1 May) • Dooley et al Grouping of Drugs for Tuberculosis by the World adenosine triphosphate synthesis []. It is currently used at a dose of 50–100 mg daily for treatment of MDR-tuberculosis orXDR-tuberculosis when few treatment options are available.
The MIC of clofazimine against M. tuberculosis ranges from 0.06 to 2.0 μg/mL, and 1 μg/mL is the suggested susceptibility breakpoint []. In one study, the minimum bactericidal concen- tration against M. tuberculosis ranged from 0.12 to 0.48 μg/mL, compared with 8–125 μg/mL for Mycobacterium avium complex (MAC) infection , providing evidence that the limited efficacy of clofazimine against MAC infection should not be extrapolated to tuberculosis. Similarly, potent activity cycloserine, terizidone, andpara-aminosalicylic acid against hypoxic, nonreplicating M. tuberculosis suggests clo- fazimine may have potential as a sterilizing drug. Mechanisms for resistance have not been reported.
thiacetazone, clarithromycin,and carbapenems Modified from Guidelines for the Programmatic Management of Drug- Resistant Tuberculosis 2008 (and 2011 update) from the World Health Clofazimine has substantial anti-tuberculosis activity in mouse models, but results are less impressive in guinea pigs and monkeys. In mice, a 20 mg/kg daily dose yields mean plasmaconcentrations of 0.55 μg/mL at steady state, but concentra- tions in tissues such as liver and lung are much higher , ].
At this dose, clofazimine monotherapy is bactericidal , ].
The onset of the bactericidal effect, however, is slow and maynot prevent death in heavily infected animals. Thus, short- In vitro studies were included if they used M. tuberculosis lab- term evaluations of clofazimine activity for acute infection oratory or clinical strains and reported minimum inhibitory may underestimate the drug’s expected activity.
concentration (MIC) or bactericidal activity as outcomes.
A challenge in the measurement of clofazimine activity in Animal studies involving mice or guinea pigs infected with animals is the “carryover” effect. The pronounced drug accu- laboratory or clinical M. tuberculosis strains describing phar- mulation in tissues with repeated dosing results in clofazimine macokinetic (PK), lung or spleen colony-forming units concentrations high enough to inhibit the growth of viable (CFUs), or mortality as outcomes were included. Clinical bacilli when organ homogenates are transferred onto culture studies were included if they had relevant PK, safety, and tol- media, leading to overestimation of clofazimine activity [].
erability endpoints; bacteriologic endpoints such as log de- Nonetheless, recent studies of multidrug combinations using crease in CFUs per day (early bactericidal activity [EBA]) or relapse as an outcome and activated charcoal in the culture sputum culture conversion; or clinical endpoints such as cure media to reduce carryover effects identified a strong combined without relapse, failure, 1-year favorable status, or death.
effect of clofazimine with pyrazinamide and the new diaryl- A search strategy using the MeSH terms “tuberculosis” and the drug being evaluated for the period January 2008 through Early results comparing clofazimine with isoniazid and September 2011 was employed in PubMed and Embase. Refer- streptomycin in guinea pigs were not as promising as those in ences at the end of included articles were hand-searched. Ref- mice, perhaps because of poor drug absorption or choice of erences in tuberculosis drug textbooks were hand-searched.
early mortality and pathology scores (rather than cure withoutrelapse) as endpoints , More damning at the time were results in rhesus macaques in which clofazimine was effectiveas prophylaxis but did not have sustained efficacy against es- tablished tuberculosis, despite adequate plasma concentrations Clofazimine is a riminophenazine initially synthesized in 1954 []. However, clofazimine resistance emerged in the majority for the treatment of tuberculosis Inconsistent results in of treatment failures and may have explained the poor out- animal models hindered its development for tuberculosis, but it was licensed for treatment of leprosy in 1969 ]. Its mechanismof action remains unclear, but existing evidence favors produc- tion of reactive oxygen species of M. tuberculosis, a mechanism Clofazimine is a component of multidrug therapy for lepro- which may lead to synergy with isoniazid, and inhibition of matous leprosy but is no longer recommended for treatment Research Agenda for Second-Line Tuberculosis Drugs • JID 2013:207 (1 May) • 1353 of AIDS-associated MAC infection because of its association salvage regimens for DR-tuberculosis. Linezolid inhibits bacteri- with excess mortality in this patient population [Among al protein synthesis by binding to 23S ribosomal RNA (rRNA).
patients with leprosy taking the same dose (100 mg daily) that It also inhibits protein synthesis in mammalian mitochondria, was studied for AIDS-associated MAC infection, however, the giving rise to dose- and duration-dependent myelopoietic and drug has little serious toxicity. Encouraging results from 2 neuropathic toxicity. The standard dose for treatment of gram- recent studies sparked new interest in using clofazimine for positive infections is 600 mg twice daily, but daily doses of 300– DR-tuberculosis. One demonstrated cure of MDR-tuberculosis 600 mg once daily are commonly used for DR-tuberculosis in in nearly 90% of patients receiving a 9-month regimen includ- an effort to reduce or prevent toxicity associated with prolonged ing high-dose gatifloxacin, high-dose isoniazid, and clofazi- use []. The MIC for linezolid against M. tuberculosis is 0.5 μg/ mine in addition to standard second-line drugs ]. In mL ]. Mutations affecting the 23s rRNA gene confer high- another study, treatment of XDR-tuberculosis was successful level resistance (MIC, 16–32 μg/mL), whereas the mechanism in >60% of patients, and most received clofazimine [ for low-level resistance (MIC, 4–8 μg/mL) is unknown [].
PK studies demonstrate a prolonged lag time for absorption, high variability in bioavailability and clearance, and a terminal half-life of 70 days Mean steady state serum concentra- The activity of linezolid against gram-positive bacteria is most tions of approximately 0.24 μg/mL are achieved only after 1 closely linked to the area under the curve (AUC) and MIC.
month of 50 mg/day. Clofazimine is highly concentrated in Evidence from a mouse model suggests the same is true for fat, organs, skin, and bone with prolonged use. Despite such M. tuberculosis although time-dependent killing is sug- marked accumulation, clofazimine is relatively well-tolerated.
gested by a whole blood model Linezolid is bacteriostatic Slowly reversible red-black skin discoloration occurs in virtu- in mice at 50 mg/kg (AUC equivalent to 300 mg daily in ally all patients treated for more than a few months. Intriguing humans) and weakly bactericidal at doses corresponding to reports suggest that co-administration with isoniazid may reduce tissue accumulation while increasing clofazimine con-centrations in serum and urine ].
Clinical StudiesIn an EBA study, 600 mg of linezolid given once and twice daily reduced sputum CFU counts by 0.18 and 0.26 log10 CFUs/mL/ Clofazimine is a poorly understood drug. It has promising anti- day, respectively, over the first 2 days. The EBA over the next 3 tuberculosis activity in vitro and in mice, including strong com- days was minimal Multiple case series suggest that linezolid bined effects with new agents, but its activity in larger animal contributes to sputum culture conversion in patients with few models was discouraging. Given renewed interest in clofazimine treatment options, but there are no data from controlled clinical for DR-tuberculosis and ongoing efforts to develop more water- trials ]. Dose- and duration-limiting mitochondrial toxic- soluble analogs with reduced potential for skin deposition, clofa- ities such as peripheral neuropathy and bone marrow suppres- zimine warrants a more thorough evaluation in animal models sion limit the clinical utility of linezolid. Although adverse and clinically as part of new combinations for DR-tuberculosis.
events, especially hematological toxicity, are less common with Efficacy studies should be performed in animal models which once-daily dosing of 300–600 mg, the impact of dose reduction exhibit more humanlike pathology than do mice, with careful at- on efficacy and the risk of neuropathy, which is often irrevers- tention to drug PK, outcome measures of sterilizing activity, and ible [], remains unclear. It is possible that alternative dosing methods to reduce drug carryover effects. The clinical evaluation schemes may provide sufficient exposures to inhibit M. tubercu- of clofazimine also presents challenges. Although EBA studies, losis while minimizing inhibition of mitochondrial protein syn- studies that quantitatively assess the reduction in sputum colony thesis An ongoing study of XDR-tuberculosis in Korea counts over time (generally 2–14 days), can assist with dose- is evaluating 600 mg daily followed by either continuation of finding and evaluation of PK-pharmacodynamic relationships 600 mg daily or de-escalation to 300 mg daily together with an for tuberculosis drugs, the long time to steady state and slow optimized background regimen. Preliminary results reveal onset of effect of clofazimine mean that 2-week EBA studies are culture negativity in liquid medium in 24% of patients at 2 unlikely to demonstrate the true potential of this drug. The lag in months, 57% of patients at 4 months, and 76% of patients at 6 absorption, low serum concentrations even in the setting of ade- months coupled with radiographic improvement Newer quate tissue concentrations, and long terminal half-life must be oxazolidinones in clinical development may be associated with considered in design of longer-term clinical trials.
reduced toxicity and greater efficacy [].
Linezolid is an oxazolidinone antibiotic developed to treat resis- Although experimental studies confirm the anti-tuberculosis ac- tant gram-positive bacterial infections. It is increasingly used in tivity of linezolid and promising clinical results have been 1354 • JID 2013:207 (1 May) • Dooley et al reported, its use is limited by toxicity. Better understanding of respectively, and reduced mortality despite achieving only the relationship of drug exposure with efficacy and toxicity 12% T>MIC [In contrast, administration of imipenem, could help optimize dosing strategies. An ongoing clinical trial meropenem, or ertapenem at 100 mg/kg with clavulanate once should shed light on whether or not a lower daily dose of 300 daily prevented mortality but permitted bacterial growth ].
mg will improve the risk-to-benefit ratio. However, becausenewer oxazolidinones in clinical development for tuberculosis are more potent than linezolid against M. tuberculosis in pre- The importance of achieving adequate T>MIC in humans may clinical models and may prove to be less toxic, more investment be evident in the results of 2 EBA studies. In a study using in linezolid for tuberculosis may not be prudent.
divided dosing of amoxicillin-clavulanate (1000 and 250 mgthrice daily), EBA0–2 was 0.34 log10 CFUs/mL/day ]. In a study using 3000 and 750 mg once daily, however, EBA0–2 Beta-lactams were initially developed to treat gram-positive in- was similar to that for no drug New formulations of fections in the 1940s. Beta-lactams inhibit cell wall synthesis amoxicillin-clavulanate (2000 and 125 mg) may be safely ad- by binding the transpeptidases which catalyze peptidoglycan ministered twice or thrice daily, achieving the 50% T>MIC cross-linking. A handful of beta-lactams, including amoxicillin target against isolates for which amoxicillin-clavulanate MICs (a penicillin) and the carbapenems (imipenem, ertapenem, and are 4 or 8 μg/mL, respectively. Anecdotal evidence suggests that meropenem), have been considered for tuberculosis treatment.
1 g of imipenem given twice daily contributes to sputum culture Although the broad-spectrum beta-lactamase of M. tuberculosis, conversion among patients with MDR-tuberculosis Twice- BlaC, limits the anti-tuberculosis potential of beta-lactams [], or thrice-daily dosing of imipenem or meropenem (but not it may be irreversibly inhibited by clavulanate, but not tazobac- ertapenem) with clavulanate also may be expected to achieve tam or sulbactam, to enhance beta-lactam activity Co-ad- the T>MIC values needed to treat patients infected with isolates ministration of clavulanate reduces the amoxicillin MIC against for which the MIC is as high as 4 μg/mL and the majority of M. tuberculosis from ≥16 μg/mL to 2–8 μg/mL Carba- those in which the MIC is 8 μg/mL, but this remains to be penems also are hydrolyzed by BlaC but at a slower rate than proven. Overall, beta-lactams are well-tolerated, but anaphy- for amoxicillin [Still, the addition of clavulanate to imipe- lactic reactions can occur in a minority (0.01%) of patients.
nem and meropenem reduces their MICs against M. tuberculo-sis by several dilutions. The ertapenem-clavulanate combination With greater appreciation of the time-dependent activity of Recent work shows that an alternative form of peptidoglycan beta-lactams and the potentiating effects of clavulanate, in vitro cross-linking (L,D-transpeptidation) predominates in M. tuber- and animal model studies should be performed to identify opti- culosis and may confer tolerance to penicillins, especially in the mized dosing strategies for amoxicillin-clavulanate as a relative- stationary phase of growth [Carbapenems, however, may ly well-tolerated and safe oral option for DR-tuberculosis.
still inhibit the L,D-transpeptidases involved in this process.
Because carbapenems inhibit newly discovered transpeptidases This may confer sterilizing activity on carbapenems, which have that may be important for mycobacterial persistence, merope- been shown to kill hypoxic, nonreplicating, persistent M. tuber- nem, which is less susceptible to hydrolysis by BlaC, may have culosis in vitro. Beta-lactams are added only occasionally to DR- sterilizing activity. Although meropenem must be given by tuberculosis regimens in individual cases in which fewer than intravenous infusion, which is highly impractical in most set- 4 drugs thought to be active against the organism are available.
tings, investigational carbapenems with oral prodrug formula- WHO guidelines suggest an amoxicillin-clavulanate dose of 500 tions could be evaluated. Dose-fractionation studies in hollow and 125 mg to 1000 and 250 mg orally 3 times per day and an fiber models and/or mice can determine the target T>MIC asso- imipenem dose of 500–1000 mg intravenously every 6 hours, ciated with optimal killing and evaluate sterilizing activity, en- but these recommendations are not supported by dose-finding abling prediction of the dose and schedule most likely to data from clinical trials. Of note, clavulanate is not commercially provide clinical benefit. However, divided dosing is almost cer- available in combination with carbapenems.
The pharmacodynamic parameter that correlates best with the Thiacetazone is a thiosemicarbazone initially evaluated in the bactericidal activity of beta-lactams against other pathogens is 1940s for tuberculosis ]. Its mechanism of action is unclear, time above MIC (T>MIC). Only 2 studies have examined the but recent work suggests that thiacetazone inhibits cyclopropa- efficacy of beta-lactams against tuberculosis in mice. An imi- nation during mycolic acid biosynthesis []. It is used in rare penem dose of 100 mg/kg twice daily reduced spleen and lung cases for the treatment of DR-tuberculosis when no other CFU counts by approximately 1.5 and 0.75 log10 CFUs/g, Research Agenda for Second-Line Tuberculosis Drugs • JID 2013:207 (1 May) • 1355 World Health Organization Group 5 Drugs: Research Priorities for Use in Treatment Regimens for Drug-Resistant tuberculosis or XDR-tuberculosis; followclosely as analogs move into clinicaldevelopment studies; evaluate optimized twice- orthrice-daily dosing in clinical trial optimized dosing likely to be twice-dailyor less populations (Asians and patients withHIV co-infection) makes it a poorcandidate for further clinical evaluations Intrinsic, inducible resistance precludes further evaluation of this drug fortuberculosis Cost, availability, and patent information that impact the use of these drugs for drug-resistant tuberculosis are summarized elsewhere and are not included in thistable [ Abbreviations: DR-tuberculosis, drug-resistant tuberculosis; EBA, early bactericidal activity; HIV, human immunodeficiency virus; MDR-tuberculosis, multidrug-resistant tuberculosis; PD, pharmacodynamic; PK, pharmacokinetic; XDR-tuberculosis, extensively drug-resistant tuberculosis.
uncommon in Africa [hence its disproportionate use in In mice and guinea pigs, thiacetazone has activity comparable Africa. However, among patients with human immunodefi- with that of streptomycin and superior to that of para- ciency virus (HIV) infection, thiacetazone can cause severe cu- aminosalicylic acid []. Even at high concentrations, thiaceta- taneous hypersensitivity reactions that can be life-threatening, zone is bacteriostatic and has poor sterilizing activity []. In so its usefulness in settings of high HIV infection prevalence a study to determine the utility of second-line drugs against MDR-tuberculosis, addition of thiacetazone did not enhanceactivity of low-dose moxifloxacin.
Areas of Research InterestGiven its low potency and toxicity profile, especially among patients with HIV co-infection, further study of thiacetazone In the late 1940s, trials of thiacetazone efficacy were per- formed, but the results were limited by lack of controls andshort periods of observation. In East Africa, thiacetazone was as effective as para-aminosalicylic acid when given together Macrolides are important antibiotics for treatment of respiratory- with isoniazid in effecting sputum conversion and preventing tract infections. Macrolides inhibit protein synthesis by binding isoniazid resistance ]. In EBA studies, however, thiaceta- to the 50S ribosomal subunit. Although macrolides such as zone had poor activity ]. Thiacetazone was mostly used to azithromycin and clarithromycin have been used successfully to prevent resistance to co-administered agents, although its ca- treat nontuberculous mycobacterial infections, M. tuberculosis pacity to do so was relatively poor. Its primary benefit was displays intrinsic, rapidly inducible resistance due to methyla- that it was extraordinarily cheap for resource-limited settings.
tion of 23S rRNA by the erm37 gene product, which prevents When thiacetazone was first developed, severe toxicity, macrolide binding to the ribosome []. Values of MIC90 for notably rash, related to thiacetazone was common in Asia and clarithromycin against M. tuberculosis strains are typically 1356 • JID 2013:207 (1 May) • Dooley et al ≥16 μg/mL and may be ≥128 μg/mL especially after pre- incubation with clarithromycin ]. In vitro synergy has been We thank J. Peter Cegielski for sharing a clofazi- reported between clarithromycin and other drugs, including mine monograph and Hans L. Rieder for his input regarding thiacetazone.
isoniazid, rifampin, pyrazinamide, and ethambutol, but the We specially acknowledge the members of the RESIST-tuberculosis Drug clinical significance of these findings is unknown Macro- Efficacy Subgroup who participated in the teleconferences and contributedintellectually to this review: Mary Ann DeGroote, Carol D. Hamilton, Ma- lides also are known to have anti-inflammatory properties modikoe Makhene, Sarita Shah, and James Brust. Other members of the which could contribute to clinical benefit despite microbial group include Jason Andrews, Pepe Caminero, Scott Franzblau, Mark Harrington, Gary Horwith, Kayla Laserson, Sonal Munsiff, Alex Pym, Ra-jeswari Ramachandran, and Sonya Shin.
This work was supported by the National Insti- tutes of Health (grants K23AI080842 to K. E. D. and R24 TW007988 to E. A. O.); and the Bill and Melinda Gates Foundation (tuberculosis Drug Monotherapy with clarithromycin in mice has weak inhibitory Accelerator grant 42851 to E. L. N.).
effects on bacterial growth but may reduce mortality associat- Each author conducted the initial in-depth ed with overwhelming infection []. Addition of clari- review of the literature related to at least one study drug, including selec-tion, review, and critical interpretation of published studies. All authors thromycin did not improve upon isoniazid or streptomycin participated in the ultimate selection of included articles and the synthesis monotherapy in mice. No other macrolide-containing regi- and interpretation of data and crafting of the manuscript.
mens have been evaluated in animals.
Potential conflicts of interest. E. L. N. received a research grant from Pfizer within the past 3 years and is an inventor on a patent for combina-tion therapy of tuberculosis including PNU-100480. All other authors All authors have submitted the ICMJE Form for Disclosure of Potential No clinical studies evaluating the efficacy of clarithromycin Conflicts of Interest. Conflicts that the editors consider relevant to the for the treatment of tuberculosis have been reported to date.
content of the manuscript have been disclosed.
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