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• W2124355658 abstract "New tuberculosis drug regimens are creating new priorities for drug susceptibility testing (DST) and surveillance. To minimise turnaround time, rapid DST will need to be prioritised, but developers of these assays will need better data about the molecular mechanisms of resistance. Efforts are underway to link mutations with drug resistance and to develop strain collections to enable assessment of new diagnostic assays. In resource-limited settings, DST might not be appropriate for all patients with tuberculosis. Surveillance data and modelling will help country stakeholders to design appropriate DST algorithms and to decide whether to change drug regimens. Finally, development of practical DST assays is needed so that, in countries where surveillance and modelling show that DST is advisable, these assays can be used to guide clinical decisions for individual patients. If combined judiciously during both development and implementation, new tuberculosis regimens and new DST assays have enormous potential to improve patient outcomes and reduce the burden of disease. New tuberculosis drug regimens are creating new priorities for drug susceptibility testing (DST) and surveillance. To minimise turnaround time, rapid DST will need to be prioritised, but developers of these assays will need better data about the molecular mechanisms of resistance. Efforts are underway to link mutations with drug resistance and to develop strain collections to enable assessment of new diagnostic assays. In resource-limited settings, DST might not be appropriate for all patients with tuberculosis. Surveillance data and modelling will help country stakeholders to design appropriate DST algorithms and to decide whether to change drug regimens. Finally, development of practical DST assays is needed so that, in countries where surveillance and modelling show that DST is advisable, these assays can be used to guide clinical decisions for individual patients. If combined judiciously during both development and implementation, new tuberculosis regimens and new DST assays have enormous potential to improve patient outcomes and reduce the burden of disease. This is the fourth in a Series of six papers about tuberculosisIntroductionPatient care algorithms can be improved in two main ways: by rethinking and reorganising existing methods and technologies, and by introducing new technologies. In recent decades, national tuberculosis programmes have used existing technologies more effectively than in previous decades, achieving substantial results.1Raviglione M Marais B Floyd K et al.Scaling up interventions to achieve global tuberculosis control: progress and new developments.Lancet. 2012; 379: 1902-1913Summary Full Text Full Text PDF PubMed Scopus (258) Google Scholar But further improvement is restricted by outdated and inadequate methods used to fight the epidemic: a vaccine with limited effectiveness; a drug regimen that is long and that places substantial demands on patients and health-care systems; and a diagnostic technique (smear microscopy) that detects only half of all cases and does not assess drug resistance of the infecting Mycobacterium tuberculosis strain.2Stop TB PartnershipIntroducing new approaches and tools for enhanced TB control (INAT) subgroup.http://www.stoptb.org/wg/dots_expansion/inatabout.aspGoogle ScholarAs efforts to improve these methods accelerate, investigators now have to consider how these various approaches will work together within a health system. Rapid development of resistance could occur if new drugs are added to failing regimens, or if combination regimens are used widely in populations that have substantial existing resistance to some of the drugs in those combinations. In some cases this resistance might leave only one effective drug in a regimen, increasing the chance of developing additional resistance and severely limiting the antimicrobial arsenal even further. Therefore, new tuberculosis regimens3Ma Z Lienhardt C McIlleron H Nunn AJ Wang X Global tuberculosis drug development pipeline: the need and the reality.Lancet. 2010; 375: 2100-2109Summary Full Text Full Text PDF PubMed Scopus (325) Google Scholar cannot be introduced without development of drug susceptibility testing (DST) assays suited to the new regimens. DST can be used to monitor patterns of emerging drug resistance and to direct patients towards appropriate therapy, but careful analysis is needed to establish the optimum DST strategy for each new drug regimen and each different epidemiological context.The primary backbone of tuberculosis treatment has not changed for decades; thus, susceptibility tests for additional drugs have not received much attention.4Wells WA Konduri N Chen C et al.TB regimen change in the high burden countries.Int J Tuberc Lung Dis. 2010; 14: 1538-1547PubMed Google Scholar But regimens with new tuberculosis drugs will change priorities for DST and drug resistance surveillance. Resistance against drugs in new first-line regimens will be particularly important to test for, especially since existing tuberculosis drugs are easily available in the private sector—in large volumes, and with little or no regulation—in many high tuberculosis burden countries.5Wells WA Ge CF Patel N Oh T Gardiner E Kimerling ME Size and usage patterns of private TB drug markets in the high burden countries.PLoS One. 2011; 6: e18964Crossref PubMed Scopus (88) Google ScholarKey messages•Advances in new drug regimens and diagnostics for tuberculosis, including drug susceptibility testing (DST), are exciting; however, strategies should be aligned to promote co-introduction for optimum results•Tuberculosis treatment should ideally be based on full information about drug susceptibility of the infecting strain; however, at least in the short term and in resource-limited settings, less comprehensive DST might be more feasible or advisable in some countries; potential gains from DST should be balanced against costs, complexity, and predicted loss to follow-up•DST and drug resistance surveillance are particularly important for existing and repurposed drugs, such as pyrazinamide and fluoroquinolones, that are being tested in first-line regimens and for which resistance already exists•DST should be rapid to maximise patient retention and ensure prompt treatment with effective regimens, thus minimising the generation and spread of resistance; a rapid DST assay will probably need to detect molecular, rather than phenotypic, correlates of resistance•To improve molecular tests, further research is needed to establish the genetic basis for resistance to existing and new drugs and to link each mutation with clinical effect; surveillance is needed to establish the background level of resistance•This information can be used by modellers to assess the potential effectiveness of different scenarios of drug and diagnostic introduction; by product developers to better define product specifications; and by country programmes and providers to better assess whether, and how, to adopt new productsThrough the Tuberculosis Diagnostics Research Forum, several partners are working to ensure that the necessary DST assays are developed in time for co-implementation with new tuberculosis drug regimens. The aim is to develop a framework for designing DST for new regimens. Such DST should meet at least the same performance criteria as DST for existing first-line therapy. The ultimate goal is to have sufficient information—including prevalence of existing resistance—so that all patients with tuberculosis can be confident that their regimen will be safe and effective.To reach these goals, translational science is needed to provide the basis for molecular diagnostics development. Furthermore, surveillance data and modelling are needed to design DST protocols and to guide decisions on regimen changes. And, in countries where the surveillance and modelling show that DST assays are necessary, development and use of these assays are needed to guide clinical decision making for individual patients. In this Series paper, we discuss alignment of new tuberculosis regimens and tuberculosis DST, and we outline the actions needed for the optimum, coordinated introduction of new technologies for tuberculosis control.Tuberculosis regimens: past, present, and futureFirst-line tuberculosis treatment has gradually evolved from monotherapy with streptomycin, to multidrug regimens of up to 24 months or more, and finally to the so-called short-course regimen now used in most high-burden countries.6Fox W Ellard GA Mitchison DA Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946–1986, with relevant subsequent publications.Int J Tuberc Lung Dis. 1999; 3: S231-S279PubMed Google Scholar This regimen is a 6 month course of treatment denoted as 2HRZE/4HR: a 2 month intensive phase of isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E) followed by a 4 month continuation phase of isoniazid and rifampicin. It has been the global standard first-line tuberculosis treatment for decades.The duration of the 6 month regimen puts substantial demands on health-care systems and patients.7Stop TB Partnership and WHOGlobal plan to stop TB 2006–2015. Report No.: WHO/HTM/STB/2006.35. World Health Organization, Geneva2006Google Scholar, 8TB AllianceNew TB regimens: what countries want. The value proposition of existing and new first-line regimens for drug-susceptible tuberculosis. Global Alliance for TB Drug Development, New York2009Google Scholar Meanwhile, second-line tuberculosis treatment, for patients with multidrug-resistant (MDR) tuberculosis (defined by resistance to both isoniazid and rifampicin), is based only on observational studies and expert opinion.9WHOGuidelines for the programmatic management of drug-resistant tuberculosis—2011 update. World Health Organization, Geneva2011Google Scholar These multidrug regimens of 18–24 months are toxic, expensive, and of limited effectiveness.10WHOGlobal tuberculosis report 2012. World Health Organization, Geneva2012Google Scholar The inadequacy of these regimens, which has become increasingly evident as more people are diagnosed with MDR tuberculosis, has led to efforts to find and develop new tuberculosis drug regimens that would shorten first-line treatment, avoid drug–drug interactions with antiretroviral therapy, and improve second-line treatment.3Ma Z Lienhardt C McIlleron H Nunn AJ Wang X Global tuberculosis drug development pipeline: the need and the reality.Lancet. 2010; 375: 2100-2109Summary Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 11Grosset JH Singer TG Bishai WR New drugs for the treatment of tuberculosis: hope and reality.Int J Tuberc Lung Dis. 2012; 16: 1005-1014Crossref PubMed Scopus (102) Google ScholarTwo phase 3 trials of shorter duration first-line tuberculosis treatment have now completed patient enrolment and treatment. The OFLOTUB trial12A controlled trial of a 4-month quinolone-containing regimen for the treatment of pulmonary tuberculosis.http://clinicaltrials.gov/ct2/show/NCT00216385Google Scholar replaced ethambutol with the fluoroquinolone gatifloxacin in a 4 month regimen, although gatifloxacin has subsequently lost regulatory approval in many countries because of adverse events. The REMoxTB trial13Controlled comparison of two moxifloxacin containing treatment shortening regimens in pulmonary tuberculosis (REMoxTB).http://clinicaltrials.gov/ct2/show/NCT00864383Google Scholar replaced either isoniazid or ethambutol with the fluoroquinolone moxifloxacin (M) in two experimental, 4 month regimens (2HRZM/2HRM and 2MRZE/2MR). Results from REMoxTB are expected in late 2013; if positive, regulatory approval will be sought in 2014 and a national launch could start as early as 2015.Next-generation, first-line regimens are likely to include several new drugs.14Williams K Minkowski A Amoabeng O et al.Sterilizing activities of novel combinations lacking first- and second-line drugs in a murine model of tuberculosis.Antimicrob Agents Chemother. 2012; 56: 3114-3120Crossref PubMed Scopus (122) Google Scholar Clinically, the most advanced regimen15Diacon AH Dawson R von Groote-Bidlingmaier F et al.14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial.Lancet. 2012; 380: 986-993Summary Full Text Full Text PDF PubMed Scopus (352) Google Scholar, 16Evaluation of 8 weeks of treatment with the combination of moxifloxacin, PA-824 and pyrazinamide in patients with drug sensitive and multi drug-resistant pulmonary tuberculosis (TB).http://clinicaltrials.gov/ct2/show/NCT01498419?term=NCT01498419&rank=1Google Scholar in this category is known as PaMZ, a combination of the novel nitroimidazo-oxazine PA-824, moxifloxacin, and pyrazinamide. This regimen has the potential not only to shorten the duration of first-line treatment, but also to treat a proportion of patients who would previously have needed second-line treatment—ie, patients with MDR tuberculosis.17Diacon AH Donald PR Mendel CM Early bactericidal activity of new regimens for tuberculosis—authors' reply.Lancet. 2013; 381: 112-113Summary Full Text Full Text PDF PubMed Scopus (3) Google ScholarFinally, several tuberculosis drug candidates are in clinical development, but their optimised regimens have not yet been defined. Sutezolid (PNU-100480), an analogue of linezolid, is in phase 2a trials. More advanced are two new drugs that have been submitted for regulatory approval for treatment of MDR tuberculosis on the basis of phase 2b data. Bacterial burden was reduced more quickly when either bedaquiline (a diarylquinoline formerly known as TMC207)18Diacon AH Donald PR Pym A et al.Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance.Antimicrob Agents Chemother. 2012; 56: 3271-3276Crossref PubMed Scopus (302) Google Scholar or delamanid (a nitro-dihydro-imidazooxazole formerly known as OPC-67683)19Gler MT Skripconoka V Sanchez-Garavito E et al.Delamanid for multidrug-resistant pulmonary tuberculosis.N Engl J Med. 2012; 366: 2151-2160Crossref PubMed Scopus (578) Google Scholar was added, for 6 months, to an optimised background regimen for MDR tuberculosis.18Diacon AH Donald PR Pym A et al.Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance.Antimicrob Agents Chemother. 2012; 56: 3271-3276Crossref PubMed Scopus (302) Google Scholar, 19Gler MT Skripconoka V Sanchez-Garavito E et al.Delamanid for multidrug-resistant pulmonary tuberculosis.N Engl J Med. 2012; 366: 2151-2160Crossref PubMed Scopus (578) Google Scholar Bedaquiline was granted marketing approval by the US Food and Drug Administration on Dec 28, 2012. However, the extent to which these drugs can shorten and simplify MDR tuberculosis treatment will only be known after additional, multiyear phase 3 trials.Tuberculosis diagnostics and DST: past and present practiceFor decades, tuberculosis diagnosis in high-burden countries has relied almost entirely on smear microscopy, which is inexpensive but detects only half of all cases.10WHOGlobal tuberculosis report 2012. World Health Organization, Geneva2012Google Scholar Additionally, smear microscopy does not provide any information about drug resistance, so most patients are put directly onto a standardised first-line regimen without any knowledge of drug susceptibility. However, the increasing awareness of MDR tuberculosis20Zhao Y Xu S Wang L et al.National survey of drug-resistant tuberculosis in China.N Engl J Med. 2012; 366: 2161-2170Crossref PubMed Scopus (502) Google Scholar has drawn greater attention to the need for DST, with the initial focus on rifampicin DST for the diagnosis of MDR tuberculosis.DST results are more likely to reach patients in a timely fashion when the DST technology allows for implementation in simpler, more peripheral health-care settings that are closer to patients (table). The simplest health-care technologies might be suitable for the most peripheral settings (community level and health posts), but more complex technologies will be appropriate only for higher-level facilities—ie, health centres, subdistrict facilities, and larger district, provincial, and regional hospitals. The most technically demanding methods might be feasible only at the most centralised, national-level facilities (one or more of which typically operate as a reference laboratory for quality assurance).TableAdvantages and disadvantages of centralised and peripheral DSTDST in centralised laboratories (status quo for most high-burden countries)DST in peripheral settings (eg, microscopy centres or district laboratories)Technology requirementsAdvantage: centralised laboratories allow for deployment of high-throughput, sophisticated assays (eg, microarrays, DNA sequencing, beacons, real-time PCR); these methods might be better suited to assaying many mutations and more drugsDisadvantage: this setting might constrain technology to simpler platforms, which might not be ideal for new drugs or the addition of more drugs or mutations; the accompanying sample preparation technique should not need a laboratory with high levels of biocontainmentCostAdvantage: centralised DST can be used only for subpopulations of patients, reducing volume and costs; samples can be batched to further increase cost efficiencyDisadvantage: DST assays for peripheral settings might be more expensive and not cost efficient (lower test volume); the overall cost of tuberculosis diagnosis might increase and health systems could be unwilling to make such big investments, unless MDR tuberculosis prevalence is very highQualityAdvantage: quality testing and reliable results are easier to ensure in a small number of centralised laboratoriesDisadvantage: unless very simple or automated, DST in the periphery will need extensive quality assurance, training, and personnelTimeliness and use of resultsDisadvantage: turnaround times are too long and losses to follow-up are high, both with samples sent and patients who never come back for results; DST results are often not reviewed when they become available, and many results never get reported or usedAdvantage: if universal DST is needed at the time of tuberculosis diagnosis, then it has to be done in peripheral settings where most tuberculosis cases are diagnosed; rapid turnaround and lower losses to follow-up will mean doctors can actually act on the DST results and modify treatment decisions; they are likely to pick up MDR tuberculosis much earlier, before substantial transmission occursSample transport and reporting systemDisadvantage: needs good sample transport and a reporting system, which is not available in many settingsAdvantage: does not need an extensive sample transport and reporting systemDST=drug susceptibility testing. MDR=multidrug-resistant. Open table in a new tab New DST assays have been moving down this continuum; early assays were suitable only for centralised sites, but newer technologies are able to be used at more intermediate or peripheral sites. Development and field testing have led WHO to recommend automated liquid culture systems (in 2007), line-probe assays (in 2008), and the Xpert MTB/RIF test (in 2010). These systems offer benefits such as reduced time to detection of resistance (from effectively 106 days with conventional DST to 20 days with line-probe assay and less than 1 day with the Xpert MTB/RIF assay),21Boehme CC Nicol MP Nabeta P et al.Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study.Lancet. 2011; 377: 1495-1505Summary Full Text Full Text PDF PubMed Scopus (781) Google Scholar thus allowing for more rapid initiation of MDR tuberculosis treatment.22Shin SS Asencios L Yagui M et al.Impact of rapid drug susceptibility testing for tuberculosis: program experience in Lima, Peru.Int J Tuberc Lung Dis. 2012; 16: 1538-1543Crossref PubMed Scopus (12) Google Scholar, 23Jacobson KR Theron D Kendall EA et al.Implementation of GenoType MTBDRplus reduces time to multidrug-resistant tuberculosis therapy initiation in South Africa.Clin Infect Dis. 2013; 56: 503-508Crossref PubMed Scopus (73) Google Scholar, 24Barnard M Warren R Van Pittius NG et al.GenoType MTBDRsl line probe assay shortens time to diagnosis of XDR-TB in a high-throughput diagnostic laboratory.Am J Respir Crit Care Med. 2012; 186: 1298-1305Crossref PubMed Scopus (50) Google Scholar Liquid culture and line-probe assays can be implemented in national and regional reference laboratories, and the Xpert MTB/RIF assay (an automated, cartridge-based, real-time PCR assay) in more peripheral sites such as subdistrict laboratories.Before more recent developments, the primary method for tuberculosis DST involved the culturing of M tuberculosis; these phenotypic growth assays are slow and need sophisticated facilities with high biocontainment. For some MDR tuberculosis drugs, even phenotypic DST is not well established, and will need to be further researched because data are insufficient to calculate clinically relevant threshold concentrations.25WHOPolicy guidance on drug-susceptibility testing (DST) of second-line antituberculosis drugs. World Health Organization, Geneva2008Google Scholar Other phenotypic (growth-based) diagnostics, such as the microscopic observation drug-susceptibility assay and the nitrate reductase assay, might be an interim solution for resource-limited settings.26Drobniewski F Nikolayevskyy V Balabanova Y Bang D Papaventsis D Diagnosis of tuberculosis and drug resistance: what can new tools bring us?.Int J Tuberc Lung Dis. 2012; 16: 860-870Crossref PubMed Scopus (70) Google Scholar However, due to the very slow growth of M tuberculosis in phenotypic assays, truly rapid testing needs a molecular approach that avoids the need to grow M tuberculosis and instead uses molecular biology methods to detect resistance-associated mutations in DNA. Such molecular assays are the primary focus of this Series paper.Line-probe assays, though molecular, also present challenges. As with liquid culture, they need laboratory infrastructure that is not available at the periphery of the health-care system (eg, at health centres, district hospitals, or even most provincial hospitals), so they are not practical for routine testing of all individuals with confirmed or suspected tuberculosis in most high-burden countries.27Van Deun A Martin A Palomino JC Diagnosis of drug-resistant tuberculosis: reliability and rapidity of detection.Int J Tuberc Lung Dis. 2010; 14: 131-140PubMed Google Scholar Such a step would need a massive sputum sample referral and transport system that typically does not exist. Instead, cultures and line-probe assays are used largely for patients at high risk of resistance—eg, those with persistent symptoms.The Xpert MTB/RIF test, however, has great potential because it can be used at the district or subdistrict level.28Lawn SD Mwaba P Bates M et al.Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test.Lancet Infect Dis. 2013; (published online March 24.)http://dx.doi.org/10.1016/S1473-3099(13)70008-2Google Scholar It not only detects rifampicin resistance, but also detects far more tuberculosis cases than does smear microscopy, particularly in regions where many people are co-infected with HIV and tuberculosis.21Boehme CC Nicol MP Nabeta P et al.Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study.Lancet. 2011; 377: 1495-1505Summary Full Text Full Text PDF PubMed Scopus (781) Google Scholar As a result, the Xpert MTB/RIF assay has been scaled up rapidly in South Africa, where it is used as the first diagnostic for all individuals with suspected tuberculosis. In other countries, such as Kenya, it is used for all HIV-infected individuals with suspected tuberculosis. Other resource-limited countries, however, still struggle with the cost,29Meyer-Rath G Schnippel K Long L et al.The impact and cost of scaling up GeneXpert MTB/RIF in South Africa.PLoS One. 2012; 7: e36966Crossref PubMed Scopus (127) Google Scholar electricity, and maintenance requirements of this assay.30Evans CA GeneXpert—a game-changer for tuberculosis control?.PLoS Med. 2011; 8: e1001064Crossref PubMed Scopus (118) Google Scholar Although the price of the Xpert technology has been reduced to under US$10 per cartridge, this negotiated price is not available to the large number5Wells WA Ge CF Patel N Oh T Gardiner E Kimerling ME Size and usage patterns of private TB drug markets in the high burden countries.PLoS One. 2011; 6: e18964Crossref PubMed Scopus (88) Google Scholar of patients with tuberculosis in the private health sector in some high-burden countries.31Pai M Palamountain KM New tuberculosis technologies: challenges for retooling and scale-up.Int J Tuberc Lung Dis. 2012; 16: 1281-1290Crossref PubMed Scopus (21) Google ScholarThe roll-out of the Xpert MTB/RIF assay has been associated with difficulties that will probably also be applicable to DST development for new tuberculosis regimens. One major issue is positive predictive value.32WHORapid implementation of the Xpert MTB/RIF diagnostic test: technical and operational ‘how-to’—practical considerations. World Health Organization, Geneva2011Google Scholar, 33Trebucq A Enarson DA Chiang CY et al.Xpert(R) MTB/RIF for national tuberculosis programmes in low-income countries: when, where and how?.Int J Tuberc Lung Dis. 2011; 15: 1567-1572Crossref PubMed Scopus (111) Google Scholar Even with a pooled sensitivity for rifampicin resistance of 94% and a pooled specificity of 98%,34Steingart KR Sohn H Schiller I et al.Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults.Cochrane Database Syst Rev. 2013; 1 (CD009593)PubMed Google Scholar the latest iteration of the Xpert MTB/RIF assay has a positive predictive value for MDR tuberculosis of only about 50% or 67% when rifampicin resistance prevalence is 1% or 2%, respectively.32WHORapid implementation of the Xpert MTB/RIF diagnostic test: technical and operational ‘how-to’—practical considerations. World Health Organization, Geneva2011Google Scholar Such resistance values are typical in new patients with tuberculosis, and the low positive predictive value results in many false positives and a substantial demand for confirmatory DST.35WHOThe use of molecular line probe assay for the detection of resistance to second-line anti-tuberculosis drugs. World Health Organization, Geneva2013Google Scholar (Of note, however, even smear culture is not 100% accurate, so the true specificity of the Xpert assay for rifampicin resistance might be higher than the initially reported 98%.) In many countries with low HIV or MDR tuberculosis prevalence, the issues of positive predictive value and costs have restricted the uptake of the Xpert MTB/RIF assay.Future needs: alignment of new drug regimens and new diagnosticsSelecting drugs to test and ways to test themWhich of the new drugs are the most important targets for future DST? Typically, DST has focused on drugs for which resistance has one or more of three consequences: it undermines treatment effectiveness, it increases the risk of resistance amplification, or it strongly predicts resistance to other drugs (ie, acts as a triage assay). At present, rifampicin DST has been prioritised to diagnose MDR tuberculosis.36Moore DA Shah NS Alternative methods of diagnosing drug resistance—what can they do for me?.J Infect Dis. 2011; 204: S1110-S1119Crossref PubMed Scopus (21) Google Scholar Evidence suggests isoniazid DST should also be done: substantial numbers of patients harbour isoniazid-resistant, rifampicin-susceptible strains, and patients with such strains have reduced treatment success.37Gegia M Cohen T Kalandadze I Vashakidze L Furin J Outcomes among tuberculosis patients with isoniazid resistance in Georgia, 2007–2009.Int J Tuberc Lung Dis. 2012; 16: 812-816PubMed Google Scholar, 38Menzies D Benedetti A Paydar A et al.Effect of duration and intermittency of rifampin on tuberculosis treatment outcomes: a systematic review and meta-analysis.PLoS Med. 2009; 6: e1000146Crossref PubMed Scopus (162) Google Scholar For implementation of the 4 month regimens, DST to detect susceptibility to rifampicin and fluoroquinolones will be of interest, especially in countries that already do DST for rifampicin. For the PaMZ regimen, a rapid test for moxifloxacin and pyrazinamide would probably be the first priority, because clinically significant resistance to PA-824 has not yet been shown. Development of DST for PA-824 and other new drugs will be prioritised—initially for use in surveillance—as resistance to them develops and their use becomes more widespread.After deciding which drugs to test, additional information is needed. To be rapid and clinically useful, a DST assay will probably need to be molecular. Therefore, information about resistance mutations—and the correlation of those mutations with clinical outcomes—is needed to form the basis for such a test.The Xpert MTB/RIF assay's 94% sensitivity for detection of rifampicin resistance is only possible because almost every mutation contributing to rifampicin resistance is known and present in a short, defined DNA region. For fluoroquinolones, however, incomplete knowledge o" @default.
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• W2124355658 title "Alignment of new tuberculosis drug regimens and drug susceptibility testing: a framework for action" @default.
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