Академический Документы
Профессиональный Документы
Культура Документы
1 Division of Mycobacterial and Respiratory Infections, National Jewish Address for correspondence Charles L. Daley, MD, Division of
Health, Denver, Colorado Mycobacterial and Respiratory Infections, National Jewish Health,
2 Division of Pulmonary Sciences and Critical Care, Department of 1400 Jackson Street, Denver, CO 80206 (e-mail: daleyc@njhealth.org).
Medicine, University of Colorado Denver, Aurora, Colorado
3 Division of Infectious Diseases, Department of Medicine,
University of Colorado Denver, Aurora, Colorado
4 Servicio de Neumologia, Hospital General de Gran Canaria,
Las Palmas, Canary Islands, Spain
5 International Union against Tuberculosis and Lung Disease
(The Union), Paris, France
Drug-resistant strains of Mycobacterium tuberculosis pose a TB strains that have acquired additional resistance to fluor-
major threat to global tuberculosis (TB) control. Despite the oquinolones and at least one second-line injectable. WHO
availability of curative anti-TB therapy, inappropriate and estimates that 6.2% of MDR-TB cases have XDR-TB.
inadequate treatment, as well as unchecked transmission, Management of drug-resistant TB begins with the identifi-
has allowed drug-resistant strains of M. tuberculosis to reach cation of cases. However, accurate diagnosis of drug-resistance
alarming levels. The World Health Organization (WHO) esti- remains a barrier to control. The END TB Strategy calls for
mates that there were 600,000 cases of multidrug-resistant TB universal access to drug susceptibility testing (DST) including
(MDR-TB)/rifampin-resistant TB (RR-TB) in 2016, with MDR- DST for at least RIF for all TB cases, plus DST for at least
TB, defined as strains that are resistant to at least isoniazid fluoroquinolones and second-line injectable agents among
(INH) and rifampicin (RIF), accounting for 82% of the total.1 The cases with RIF resistance.2 However, in 2016, only 41% of
WHO estimates that 4.1% of new TB cases and 19% of retreat- laboratory-confirmed TB patients notified globally were tested
ment cases have MDR-TB globally. The countries with the for RIF resistance, up from 11% in 2012. The development of
largest numbers of MDR/RR-TB, accounting for 47% of the new rapid molecular tests such as the Xpert MTB/RIF assay3
global total, are China, India, and the Russian Federation. By the and line probe assays4 allow for the diagnosis of INH and RIF
end of 2016, 123 countries had reported at least one case of resistance within a matter of hours, and these assays have
extensively drug-resistant strains (XDR-TB), which are MDR- accounted for some of the recent increases in testing.
Issue Theme Mycobacterial Diseases: Copyright © 2018 by Thieme Medical DOI https://doi.org/
Evolving Concepts; Guest Editors: Patrick Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0038-1661383.
A. Flume, MD, and Kevin L. Winthrop, New York, NY 10001, USA. ISSN 1069-3424.
MD, MPH Tel: +1(212) 584-4662.
Management of Multidrug-Resistant Tuberculosis Daley, Caminero 311
Among the 490,000 incident cases of MDR-TB in 2016, only Group A Drugs
153,000 (31%) were detected, and of these, 130,000 (85%) were Group A drugs include the later-generation fluoroquinolones
started on MDR-TB treatment.1 It is estimated that only 22% of (high-dose levofloxacin, moxifloxacin, and gatifloxacin), which
the 600,000 MDR/RR-TB cases started second-line treatment. are among the most important SLDs available to treat MDR-TB.
Treatment success is estimated to be approximately 54%, with Fluoroquinolones have bactericidal and sterilizing activity and
16% of patients dying, 8% failing, and 21% lost to follow-up or not are very well tolerated, and resistance to these drugs is asso-
evaluated. Treatment success in XDR-TB patients is only 30%. ciated with higher rates of treatment failure and death.5,12
Inclusion of fluoroquinolones in the treatment regimen is
associated with improved outcomes.13,14 Resistance varies
Treatment of Multidrug-Resistant
depending on which fluoroquinolone and concentration are
Tuberculosis
used to define resistance. When ofloxacin (2 μg/mL) was used in
Treatment of MDR-TB is challenging because it requires the a WHO study, resistance ranged from 12.3% in Gauteng, South
administration of at least five anti-TB drugs, many associated Africa, to 30.7% in Minsk, Belarus.15 Levofloxacin has been
with significant adverse reactions, for at least 9 to 20 months. shown to be more effective than ofloxacin in both ofloxacin-
Selection of drugs to make up the regimen should be based susceptible and ofloxacin-resistant strains of M. tuberculosis.16
on the past treatment history, known patterns of resistance, Furthermore, early bactericidal studies have demonstrated that
and DST data, when available. At least two drugs should have levofloxacin, when given at high doses (1,000 mg/day), is asso-
good bactericidal activity, and one to two drugs should have ciated with early bactericidal activity (EBA) activity equivalent to
Abbreviations: EBA, early bactericidal activity; MDR-TB, multidrug-resistant tuberculosis; PD, pharmacodynamic; XDT-TB, extensively drug-resistant
tuberculosis.
studies,31–34 it appears that isolates acquiring resistance to patients who had been on treatment for median of 40 months
streptomycin usually remain susceptible to kanamycin, ami- prior to initiating linezolid. A study from Shanghai, China,
kacin, and capreomycin. Isolates acquiring resistance to which was not included in either review, reported that
capreomycin are usually susceptible to kanamycin and ami- culture conversion occurred in all 18 MDR-TB (including 15
kacin. Most isolates that acquire resistance to amikacin are XDR-TB) patients who received linezolid (900–1,200 mg
also resistant to both kanamycin and capreomycin, and intravenously) as part of their drug regimen.38 At the end
isolates acquiring resistance to kanamycin show different of the study, 9 of the 18 patients had achieved treatment
levels of cross-resistance to amikacin and capreomycin. The success.
WHO recommends that all adult patients with MDR/XDR-TB A randomized phase II clinical trial in patients with XDR-
receive an injectable agent as part of their initial therapy, TB demonstrated high rates of culture conversion.39,40
whether in a shorter course or conventional regimen.7 Subsequently, Tang et al41 published a prospective, multi-
As with the fluoroquinolones, GenoType MDRTBsl can center, randomized study to evaluate the efficacy, safety,
identify specific mutations, some of which do not confer and tolerability of linezolid in XDR-TB: 65 patients were
resistance to all the second-line injectables. For instance, randomly assigned to a 2-year individually based regimen
mutations in rrs1401 or 1484 usually confer high-level with or without linezolid. The linezolid therapy group was
resistance to all injectables; however, streptomycin may still given linezolid at a start dose of 1,200 mg/day for a period
be active if there is no rpSL mutation. On the contrary, of 4 to 6 weeks, and this was then followed by a dose of 300
mutations in rrs1402 can confer resistance to kanamycin to 600 mg/day. The proportion of sputum culture conver-
few treatment options, extending the duration of use beyond advantage that it can be given intramuscularly and just once
6 months is recommended in these settings.69 daily. Based on these studies, it appears that the carbapenems
have significant activity against drug-resistant M. tuberculosis;
however, the high costs, lack of availability of oral formula-
Group D3
tions, and variable market availability limit the usefulness
Para-Aminosalicyclic Acid globally.
PAS is a bacteriostatic agent that is highly specific for M.
tuberculosis. The drug is poorly tolerated, and, for this reason,
Conventional MDR-TB Regimen versus
it should be used only when there are no other options.5
Shorter Course Regimen
Resistant develops when mutations in thyA occur, but these
mutations account for only 6% of phenotypic resistance.43,88 In the 2016 WHO guidelines, a 9- to 12-month shorter course
Clinical trials demonstrated that monotherapy for 3 months regimen was recommended for the first time.7 The shorter
produced clinical improvement with efficacy similar to that course regimen can be used in children and adults who have
of streptomycin.89 The primary barrier to its use is the not previously been treated with SLDs and in whom resistance
frequency of gastrointestinal side effects as well as hyper- to fluoroquinolones and second-line injectable agents has
sensitivity reactions. Hypothyroidism is common particu- been excluded or is considered highly unlikely. If the patient
larly when combined with ethionamide. does not meet recommended criteria reviewed below for
PAS in the form of an enteric coated granule is widely used shorter course regimen, then an individualized regimen
relevance in the final outcome of these regimens, whereas patients, but as with the intensive phase, this duration can
confirmed resistance to either fluoroquinolones and/ be modified based on the patient’s response to therapy.26
or second-line injectables influences the outcomes of these Using the same analytical approach, the peak in cure occurred
regimens. Therefore, this exclusion criterion should be between 18.6 and 21.5 months for patients who had never
applied when fluoroquinolones and/or the second-line been treated for MDR-TB. In patients with a history of previous
injectables have been taken for a month or more, not for MDR-TB treatment, no clear trend could be identified.
the other drugs included in the shorter regimen.
• Intolerance to more than one medicine in the shorter Shorter Course Regimens
MDR-TB regimen or risk of toxicity (e.g., drug-drug inter-
actions): as described previously, this exclusions criterion The WHO recently updated their position on the use of shorter
should relate to intolerance or a high risk of toxicity to course MDR-TB regimen following an expedited review of the
fluoroquinolones and/or second-line injectables only STREAM Stage 1 preliminary results and reiterated support of
(including drug–drug interactions). the shorter course regimen.11 The initial experience with the
• Pregnancy: this remains an appropriate exclusion criter- shorter course regimen was reported in 2010 from Bangla-
ion because these patients were not included in previous desh.50 In this study, patients with confirmed or suspected
studies of the shorter course regimen and because of the MDR-TB were assigned to one of six standardized treatment
possible teratogenic effect of the injectable drugs. regimens administered in a serial fashion. The last regimen to
• Extrapulmonary disease: This exclusion criterion was be studied, and the one with the best treatment outcomes,
shorter regimen than the conventional regimen, although it priate therapy for several months, with the goal of achieving
was not statistically significantly different (80.6 vs. 78.1%; smear and/or culture conversion preoperatively, if possible.
p ¼ 0.6). When adjusted for the site of study and HIV Prognosis appears to be better in those who underwent
infection, there was 2.1% favor of the control arm; however, partial resection after culture conversion.7,101
the study did not satisfy the noninferiority threshold of 10%.
There were no statistically significant differences in other
Special Situations
outcomes such as patient retention, time to culture conver-
sion, relapse or mortality. However, in the subgroup of Extrapulmonary Disease
patients with HIV infection, the number of observed deaths Current guidelines recommend that extrapulmonary TB is
was higher in the shorter course arm compared with the the same as pulmonary disease. The American Thoracic
control arm, but, again, the finding was not statistically Society, Infectious Diseases Society of America, and Centers
significant. for Disease Control and Prevention recommend extending
From a safety perspective, there were no statistical differ- the duration of therapy for patients with CNS TB
ences in the proportion of patients with AE of grade 3 to 5 (12 months).102 There are no specific recommendations for
severity; however, new onset prolongation of the QTc (Fri- the treatment of MDR-TB involving an extrapulmonary site.
dericia corrected) interval to 500 millisecond or longer was However, if there is CNS involvement, it is critical to select
seen more commonly.11 Importantly, the shorter regimen drugs that penetrate the blood–brain barrier. For example,
reduced the cost of treatment for the health system by an RIF, INH, PZA, prothionamide (ethionamide), cycloserine,
occurred in 39.1% of the children, the most common of which included age > 45 years, HIV infection, extrapulmonary dis-
were nausea and vomiting followed by hearing loss, psychia- ease, previous use of a fluoroquinolone, resistance to thioa-
tric effects, and hypothyroidism. mides, baseline positive smear, and no culture conversion by
The WHO recently published interim policy guidelines the third month. Predictors of failure included cavitary disease,
recommending that delamanid may be added to a WHO- resistance to any fluoroquinolone, resistance to any thioamide,
recommended longer treatment regimen in children and and no culture conversion by the third month. Default was
adolescents (6–17 years) with MDR/RR-TB who are not associated with unemployment, homelessness, imprisonment,
eligible for the shorter MDR-TB regimen.10 Data supporting alcohol abuse, and baseline positive smear.
this recommendation are derived from phase I open-label
data and a subsequent open-label phase II extension study
Monitoring for Treatment Response
demonstrating the safe administration of delamanid in this
population. There are no WHO recommendations for the use The WHO recommends that treatment response be assessed
of bedaquiline in children, although 27 children and adoles- by monthly sputum smear and culture rather than smear
cents who received bedaquiline in programmatic settings did microscopy alone.26 This strategy is the best strategy for
well with no instance of drug withdrawal due to adverse identifying failures earlier. Alternative modeling strategies
reactions.106 were examined based on cohorts of MDR-TB from Estonia,
Latvia, Philippines, Russia, and Peru from 2000 to 2004.115
HIV-Infected Patients Less than monthly monitoring results in delays in identifying
Treatment Outcomes
Future Treatment Approaches
Several systematic reviews and meta-analyses have reported
the pooled estimate of treatment success in patients with The current anti-TB drug development pipeline has at least
MDR-TB and XDR-TB.110–113 The most recent review pub- eight drugs in phase 2 and 3 trials.118 New compounds under
lished by Bastos et al110 included 74 studies and 17,494 development include nitroimidazopyrans (pretomanid, for-
patients. Pooled treatment success was 60% in MDR-TB and merly called PA-824), oxazolidinones (sutezolid, AZD-5847),
26% in XDR-TB. The number of drugs, specific drug, and SQ109, benzothiazinones, and dinitrobenzamides.118,119
duration of use were not associated with improved outcome. Pretomanid (PA-824) is a nitroimidazo-oxazine with a very
MDR-TB patients receiving individualized treatments had similar mechanism of action as that of delamanid. The combi-
better outcome than those receiving standardized therapies nation of PA-824–moxifloxacin–PZA had the best mean 14-
(64 vs. 52%; p < 0.001). The adverse drug reactions were day EBA (0.233 [SD 0.128]), significantly higher than that of
from 0.5% for EMB to 12.2% for PAS. bedaquiline (0.061 [0.068]), bedaquiline-PZA (0.131 [0.102]),
Predictors of poor outcomes were reported from five DOTS- bedaquiline-PA-824 (0.114 [0.050]), but not PA-824-PZA
Plus projects in Estonia, Latvia, Philippines, Russia, and Peru (0.154 [0.040]), and comparable with that of standard treat-
between 2000 and 2004.114 Out of 1,768 patients with MDR-TB, ment (0·140 [0·094]).120 Preliminary data from a phase III trial
treatment was successful in 65%, with deaths in 11%, default in (NIX-TB) of an all-oral regimen (bedaquiline, pretomanid, and
14%, and failed therapy in 7%. Independent predictors of death linezolid) for the treatment of XDR-TB demonstrated that by
Source: Adapted from the World Health Organization Guidelines for the programmatic management of drug-resistant tuberculosis. Emergency update 2008.
Note: Drugs in bold type are more strongly associated with the adverse effect than drugs not in bold.
the end of 2016, 34 patients had completed 6 months of 19 Rustomjee R, Lienhardt C, Kanyok T, et al; Gatifloxacin for TB
therapy, and all culture converted with no relapses.121 Addi- (OFLOTUB) study team. A Phase II study of the sterilising
tional studies evaluating multiple different oral shorter course activities of ofloxacin, gatifloxacin and moxifloxacin in pulmon-
ary tuberculosis. Int J Tuberc Lung Dis 2008;12(02):128–138
regimens are currently underway.118 The STREAM study is
20 Lee J, Lee CH, Kim DK, et al. Retrospective comparison of levo-
evaluating a new arm in the shorter MDR-TB regimen without floxacin and moxifloxacin on multidrug-resistant tuberculosis
the injectable and with bedaquiline, levofloxacin, PZA, and treatment outcomes. Korean J Intern Med 2011;26(02):153–159
EMB for 9 months, and high-dose INH and prothionamide in 21 Kam KM, Yip CW, Cheung TL, Tang HS, Leung OC, Chan MY.
the last 4 months. Stepwise decrease in moxifloxacin susceptibility amongst clin-
ical isolates of multidrug-resistant Mycobacterium tuberculosis:
correlation with ofloxacin susceptibility. Microb Drug Resist
References 2006;12(01):7–11
1 WHO. Global Tuberculosis Report 2017. Geneva: World Health 22 Cheng AF, Yew WW, Chan EW, Chin ML, Hui MM, Chan RC.
Organization; 2017 Multiplex PCR amplimer conformation analysis for rapid detec-
2 WHO. The End TB Strategy. Geneva: World Health Organization; tion of gyrA mutations in fluoroquinolone-resistant Mycobac-
2014 terium tuberculosis clinical isolates. Antimicrob Agents
3 Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detec- Chemother 2004;48(02):596–601
tion of tuberculosis and rifampin resistance. N Engl J Med 2010; 23 WHO. The Use of Molecular Line Probe Assays for the Detection
363(11):1005–1015 of Resistance to Second-Line Anti-Tuberculosis Drugs: Policy
4 Hillemann D, Rüsch-Gerdes S, Richter E. Evaluation of the Guidance. Geneva: World Health Organization; 2016
GenoType MTBDRplus assay for rifampin and isoniazid suscept- 24 Caminero JA, Sotgiu G, Zumla A, Migliori GB. Best drug treatment
38 Xu HB, Jiang RH, Li L, Xiao HP. Linezolid in the treatment of MDR- 58 Mitnick C, Bayona J, Palacios E, et al. Community-based therapy
TB: a retrospective clinical study. Int J Tuberc Lung Dis 2012;16 for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med
(03):358–363 2003;348(02):119–128
39 Lee M, Cho SN, Barry CE III, Song T, Kim Y, Jeong I. Linezolid for XDR- 59 Migliori GB, Besozzi G, Girardi E, et al; SMIRA/TBNET Study Group.
TB–final study outcomes. N Engl J Med 2015;373(03):290–291 Clinical and operational value of the extensively drug-resistant
40 Lee M, Lee J, Carroll MW, et al. Linezolid for treatment of chronic tuberculosis definition. Eur Respir J 2007;30(04):623–626
extensively drug-resistant tuberculosis. N Engl J Med 2012;367 60 WHO. Guidelines for the programmatic management of drug-
(16):1508–1518 resistant tuberculosis. Geneva: World Health Organization;
41 Tang S, Yao L, Hao X, et al. Clofazimine for the treatment of 2008
multidrug-resistant tuberculosis: prospective, multicenter, ran- 61 Gagneux S, Burgos MV, DeRiemer K, et al. Impact of bacterial
domized controlled study in China. Clin Infect Dis 2015;60(09): genetics on the transmission of isoniazid-resistant Mycobacter-
1361–1367 ium tuberculosis. PLoS Pathog 2006;2(06):e61
42 Migliori GB, Eker B, Richardson MD, et al; TBNET Study Group. 62 Cambau E, Viveiros M, Machado D, et al. Revisiting susceptibility
A retrospective TBNET assessment of linezolid safety, tolerability testing in MDR-TB by a standardized quantitative phenotypic
and efficacy in multidrug-resistant tuberculosis. Eur Respir J assessment in a European multicentre study. J Antimicrob Che-
2009;34(02):387–393 mother 2015;70(03):686–696
43 Dooley KE, Mitnick CD, Ann DeGroote M, et al; Efficacy Sub- 63 Morlock GP, Metchock B, Sikes D, Crawford JT, Cooksey RC. ethA,
group, RESIST-TB. Old drugs, new purpose: retooling existing inhA, and katG loci of ethionamide-resistant clinical Mycobac-
drugs for optimized treatment of resistant tuberculosis. Clin terium tuberculosis isolates. Antimicrob Agents Chemother
Infect Dis 2012;55(04):572–581 2003;47(12):3799–3805
44 Scardigli A, Caminero JA, Sotgiu G, Centis R, D’Ambrosio L, 64 Banerjee A, Dubnau E, Quemard A, et al. inhA, a gene encoding a
drug-resistant tuberculosis. Eur Respir J 2016;47(02): 95 Tiberi S, D’Ambrosio L, De Lorenzo S, et al. Ertapenem in the
564–574 treatment of multidrug-resistant tuberculosis: first clinical
77 Borisov SE, Dheda K, Enwerem M, et al. Effectiveness and safety experience. Eur Respir J 2016;47(01):333–336
of bedaquiline-containing regimens in the treatment of MDR- 96 Trébucq A, Schwoebel V, Kashongwe Z, et al. Treatment outcome
and XDR-TB: a multicentre study. Eur Respir J 2017;49(05):49 with a short multidrug-resistant tuberculosis regimen in nine
78 Cox V, Brigden G, Crespo RH, et al. Global programmatic use of African countries. Int J Tuberc Lung Dis 2018;22(01):17–25
bedaquiline and delamanid for the treatment of multidrug- 97 Ahmad Khan F, Salim MAH, du Cros P, et al. Effectiveness and
resistant tuberculosis. Int J Tuberc Lung Dis 2018;22(04): safety of standardised shorter regimens for multidrug-resistant
407–412 tuberculosis: individual patient data and aggregate data meta-
79 Gler MT, Skripconoka V, Sanchez-Garavito E, et al. Delamanid for analyses. Eur Respir J 2017;50(01):1700061
multidrug-resistant pulmonary tuberculosis. N Engl J Med 2012; 98 Xu HB, Jiang RH, Li L. Pulmonary resection for patients with
366(23):2151–2160 multidrug-resistant tuberculosis: systematic review and meta-
80 Chang KC, Chung-Ching Leung E, Law WS, et al. Early experience analysis. J Antimicrob Chemother 2011;66(08):1687–1695
with delamanid-containing regimens in the treatment of com- 99 Kempker RR, Vashakidze S, Solomonia N, Dzidzikashvili N,
plicated multidrug-resistant tuberculosis in Hong Kong. Eur Blumberg HM. Surgical treatment of drug-resistant tuberculosis.
Respir J 2018:1800159 Lancet Infect Dis 2012;12(02):157–166
81 Kuksa L, Barkane L, Hittel N, Gupta R. Final treatment outcomes 100 Pomerantz BJ, Cleveland JC Jr, Olson HK, Pomerantz M. Pulmon-
of multidrug- and extensively drug-resistant tuberculosis ary resection for multi-drug resistant tuberculosis. J Thorac
patients in Latvia receiving delamanid-containing regimens. Cardiovasc Surg 2001;121(03):448–453
Eur Respir J 2017;50(05):50 101 Fox GJ, Mitnick CD, Benedetti A, et al; Collaborative Group for
82 Hewison C, Ferlazzo G, Avaliani Z, et al. Six-month response to Meta-Analysis of Individual Patient Data in MDR-TB. Surgery as
114 Kurbatova EV, Taylor A, Gammino VM, et al. Predictors of poor 118 Tiberi S, Muñoz-Torrico M, Duarte R, Dalcolmo M, D’Ambrosio L,
outcomes among patients treated for multidrug-resistant tuber- Migliori GB. New drugs and perspectives for new anti-tubercu-
culosis at DOTS-plus projects. Tuberculosis (Edinb) 2012;92(05): losis regimens. Pulmonology 2018;24(02):86–98
397–403 119 Grosset JH, Singer TG, Bishai WR. New drugs for the treatment of
115 Kurbatova EV, Gammino VM, Bayona J, et al. Frequency and tuberculosis: hope and reality. Int J Tuberc Lung Dis 2012;16
type of microbiological monitoring of multidrug-resistant (08):1005–1014
tuberculosis treatment. Int J Tuberc Lung Dis 2011;15(11): 120 Diacon AH, Dawson R, von Groote-Bidlingmaier F, et al. 14-day
1553–1555, ii. bactericidal activity of PA-824, bedaquiline, pyrazinamide, and
116 Nathanson E, Gupta R, Huamani P, et al. Adverse events in the moxifloxacin combinations: a randomised trial. Lancet 2012;
treatment of multidrug-resistant tuberculosis: results from 380(9846):986–993
the DOTS-Plus initiative. Int J Tuberc Lung Dis 2004;8(11): 121 Conradie F, Diacon AH, Everitt D, et al. Interim results of nix-TB
1382–1384 clinical study of pretomanid, bedaquiline, and linezolid for
117 Bloss E, Kuksa L, Holtz TH, et al. Adverse events related to treatment of XDR and treatment intolerant/failed MDR-TB.
multidrug-resistant tuberculosis treatment, Latvia, 2000-2004. Abstract OA-3117. Presented at the 47th Union World Confer-
Int J Tuberc Lung Dis 2010;14(03):275–281 ence on Lung Health, 2016