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Programmes and principles in treatment of multidrug-resistanttuberculosis Joia S Mukherjee, Michael L Rich, Adrienne R Socci, J Keith Joseph, Felix Alcántara Virú, Sonya S Shin, Jennifer J Furin, Mercedes C Becerra, Donna J Barry, Jim Yong Kim, Jaime Bayona, Paul Farmer, Mary C Smith Fawzi, Kwonjune J Seung Multidrug-resistant tuberculosis (MDR-TB) presents an increasing threat to global tuberculosis control. Many crucialmanagement issues in MDR-TB treatment remain unanswered. We reviewed the existing scientific research on MDR-TB treatment, which consists entirely of retrospective cohort studies. Although direct comparisons of these studiesare impossible, some insights can be gained: MDR-TB can and should be addressed therapeutically in resource-poorsettings; starting of treatment early is crucial; aggressive treatment regimens and high-end dosing are recommendedgiven the lower potency of second-line antituberculosis drugs; and strategies to improve treatment adherence, such asdirectly observed therapy, should be used. Opportunities to treat MDR-TB in developing countries are now possiblethrough the Global Fund to Fight AIDS, TB, and Malaria, and the Green Light Committee for Access to Second-line Anti-tuberculosis Drugs. As treatment of MDR-TB becomes increasingly available in resource-poor areas, where it is neededmost, further clinical and operational research is urgently needed to guide clinicians in the management of thisdisease.
Mycobacterium tuberculosis has re-emerged as a major strains. People who have primary drug resistance and who public-health threat. Instead of being eradicated, drug- are infected with a strain of tuberculosis that is already resistant strains have evolved and have been documented resistant frequently fail treatment with drug regimens in every country surveyed.1,2 Once a strain of M tuberculosis designed for use against drug sensitive disease and develops resistance to isoniazid and rifampicin, it is become progressively more resistant and difficult to cure.4 defined as multidrug-resistant tuberculosis (MDR-TB).
Some countries have already been labelled MDR-TB hot Without these two potent drugs, the treatment of MDR- spots, where a substantial proportion of incident TB becomes difficult since second-line drugs must be tuberculosis is MDR-TB.1 In areas with a concurrent used, which are less potent and not as well tolerated as rising incidence of HIV-1 infection, the prospect of a first-line agents. The improper management of MDR-TB so-called noxious synergy looms.5 Opportunities to treat can result in further drug resistance. Patients with MDR- MDR-TB in developing countries are now possible TB frequently have advanced disease associated with through the Global Fund to Fight AIDS, TB, and thick-walled cavities and chronic lung lesions that can be Malaria, and the Green Light Committee for Access to difficult for antibiotics to penetrate. Therefore they are Second-line Anti-tuberculosis Drugs.6,7 The development difficult to cure and pose a substantial threat to household of evidence-based guidelines for the treatment of MDR- contacts and to tuberculosis control efforts. Even in TB is necessary to guide clinicians and programmes countries with highly developed health-care systems, throughout the world, particularly in an era of the HIV outbreaks of MDR-TB have proven difficult to manage.
epidemic, globalisation, and increasing air travel.8 During the early 1990s, several well-publicised outbreaks The existing data on MDR-TB treatment come entirely of MDR-TB in US cities were eventually controlled, but from retrospective cohort analyses. These analyses have at a cost estimated at millions of dollars.3 been cited in policy and modelling reports. However, the In resource-poor areas, inconsistent drug supply and non-standard methods of collection and analysis of weak tuberculosis-control infrastructure can lead to a outcome data do not allow easy comparison. We present a vicious cycle of inadequate treatment, the generation of critical overview of studies of MDR-TB treatment, with tuberculosis-drug resistance, and transmission of resistant an emphasis on differences in treatment settings, cohortselection criteria, patients’ characteristics, and treatmentprotocols. Although direct comparisons between these studies are impossible, we have been able to make insightsinto the treatment of MDR-TB. Most importantly, we Brigham and Women’s Hospital, Division of Social Medicine andHealth Inequalities, Boston, MA, USA (J S Mukherjee underscore the need for further clinical and operational MD, J K Joseph MD, S S Shin MD, J Y Kim MD, P Farmer MD, K J Seung MD); Partners In Health, Boston, MA, USA(J S Mukherjee, M L Rich, A R Socci BA, J K Joseph, S S Shin, J J Furin MD, M C Becerra ScD, D J Barry NP, J Y Kim, J Bayona MD, P Farmer, M C Smith Fawzi ScD, K J Seung); and Socios En Salud,Carabayllo, Lima, Perú (J S Mukherjee, M L Rich, J K Joseph, We searched MEDLINE from 1966 to 2001 and BIOSYS from F Alcántara Virú MD, S S Shin, J J Furin, M C Becerra, J Y Kim, 1970 to 2001, with use of the following key words: MDR-TB, multidrug-resistant tuberculosis, rifampin resistance, Correspondence to: Dr Joia S Mukherjee, Program in Infectious isoniazid resistance, tuberculosis, drug resistance, Disease and Social Change, Department of Social Medicine, Harvard treatment, DOTS, and outcomes. We also searched the Medical School, 641 Huntington Avenue, Boston, MA 02115, USA bibliographies of articles for relevant references.
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study and setting tuberculosis susceptibility BACTEC testing of Previous tuberculosis treatment in 88%. Mean 4·3 drugs used, mean 4·8 resistant. Mean duration 13 months, with 100% cure rate and Modified absolute Previous tuberculosis treatment in 34%. Mean 6 drugs used, mean 5 resistant. Mean 5% deaths, and 3/44 relapses.*† Resective second-line drugs, surgery used in 6 patientsincluding Z 2·5 (median) Varied by hospital; Previous tuberculosis treatment in 32%. Mean BACTEC and solid 4·1 drugs used, mean 3·4 resistant. Median duration 18 months, with 81% cure rate and 19% default rate. Relapses unknown. Resective of patients BACTEC testing of Previous tuberculosis treatment 6·6 resistant. Mean duration 18 months, with 79% cure rate, 3% default rate, and used. Resective surgery used in 5 patients Previous tuberculosis treatment in 78%. Mean 5·5 drugs used, mean 4·4 resistant. Mean (S, KM, AMK, CM) plus >2 oral negative for HIV-1 duration >18 months after last positive culture, agents; used in >80% of with 75% cure rate* 8% failure rate, 11% default rate, 5% death rate, and 1/88 relapses. Resective surgery used in 36 patientsNo outpatient DOT 24 months, with 75% cure rate, 3% failure and 4/24 relapses. Some DOT used. Resective surgery used in 6 patients 7: Mitnick, et al,15 3·7 (median) Proportion method Previous tuberculosis treatment in 100%. Median 6 drugs used, median 6 resistant. Median duration 23 months, with 73% cure rate, quinolone (OFX, CPX), CS, PAS; infection 1% failure rate, 7% default rate, 19% death rate, injectable continued until and 1/75 relapses. DOT used.*† Resective surgery used in 3 patientsNo outpatients DOT Previous tuberculosis treatment in 65%. *Mean 96% received quinolone (OFX, method on L-J; first- 4·7 drugs used, mean 3·5 resistant. Mean line and second-line duration 14·4 months, with 69% cure rate, 9% failure rate, 13% default rate, 8% death rate, and 1/47 relapses. DOT used. Resective surgery use unknown Proportion method Previous tuberculosis treatment in 100%. Mean General protocol: injectable on L-J; first-line and 5·1 drugs used, mean 4·2 resistant. Mean second-line drugs; duration >24 months after last positive culture, injectable administered for with 68% cure rate, 11% failure rate, 20% default rate, 0/52 relapses.*† Resective surgery 10: Goble, et al,18 6·0 (median) Proportion method Previous tuberculosis treatment in 100%. on 7H11; first- line Median 4 drugs used, median 6 resistant. Mean duration >24 months after last positive culture, with 49% cure rate, <32% failure rate, 14% default rate, >5% death rate, and 3/78 relapses.*† Resective surgery used in 7 patients usedNo outpatient DOT Previous tuberculosis treatment in 100%. on L-J; first-line and Mean 5·3 drugs used, mean 3·7 resistant. second-line drugs; Mean duration 23 months, with 48% cure rate, 5 oral drugs 8% failure rate, 39% default rate, 5% transfer out, 0·3% death rate, and 8/335 relapses. Resective surgery use unknownNo outpatient DOT THE LANCET • Vol 363 • February 7, 2004 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet.
study and setting tuberculosis susceptibility Previous tuberculosis treatment in 100%. Mean Standard empirical regimen 5 drugs used, mean resistant unknown. Mean duration 18 months, with 48% cure rate, 28% failure rate, 11% default rate, and 12% death rate. Relapses unknown. DOT used. Resective BACTEC testing of Previous tuberculosis treatment unknown. Mean 2·87 drugs used, mean 3·23 resistant. Mean duration unknown. 38% cure rate, 21% drugs; 7H11 media default rate, 41% death rate. Relapses unknown. Department and local private physicians; 48% HIV-1 positive Z=pyrazinamide. OFX=ofloxacin. CS=cycloserine. S=streptomycin. AMK=amikacin. PAS=paraminosalicylic. H=isoniazid. R=rifampicin. E=ethambutol. KM=kanamycin.
CPX=ciprofloxacin. CFZ=clofazamine. DOT=directly observed treatment. CM=capreomycin. PTH=prothionamide. LVX=levofloxacin. L-J=Lowestein-Jensen agar. VM=viomycin.
DST=drug sensitivity testing. ETH=ethionomide. *Personal communication. †Number of reported relapses per number of patients who received post-treatment follow-up.
Table 1: Treatment-outcome studies of MDR-TB excluded from analysis. Patients in cohort 12 were selected for treatment with a standard regimen for MDR- We included studies if patients were treated for MDR-TB TB on the basis of previous treatment failure on short- with second-line drugs; treatment regimens were course chemotherapy without confirmation of resistance documented; and, cure, death, default (treatment suspension), treatment failure, and relapse rates werereported or could be obtained by contacting the original researchers. Because we sought to assess the treatment of In all cohorts except cohort 12, treatment regimens were MDR-TB separately from the interaction between HIV-1 individually tailored to drug susceptibility testing (DST) and tuberculosis infection, we excluded studies if the results and previous treatment history. There was no HIV-1 prevalence in the cohort was higher than 50%. The standard method of choosing which drugs to use in the following information was extracted: length of illness due treatment regimens; however, an injectable agent (an to tuberculosis, history of previous tuberculosis treatment, aminoglycoside or capreomycin) and a quinolone formed antituberculosis drugs to which strains were resistant, the core of all regimens except for that in the earliest study, number of drugs used in treatment regimen, duration of cohort 10, which predated the routine use of quinolones treatment, HIV status, use of surgery, and demographic for the treatment of MDR-TB. Cohort 12 was the only data. We contacted the reports’ researchers to obtain cohort in which DST was not used to tailor regimens; every patient in the cohort received the same regimen of Table 1 shows the 13 retrospective cohort analyses from ethambutol, pyrazinamide, kanamycin, ciprofloxacin, and 12 studies we identified published from 1993 to 2003.9–20 ethionamide, irrespective of DST. Different methods were We know of no clinical trial in which any feature of MDR- used to calculate the mean or median numbers of drugs TB treatment has been assessed. The median number of reportedly taken. For example, in cohort 8 the mean patients who started MDR-TB treatment in each cohort number of drugs taken by patients at the beginning of the was 75 (range 8–1011). We excluded patients who died or treatment period was reported; in cohort 7 the median stopped treatment through non-adherence before an number of drugs taken for longer than 1 month at any time appropriate regimen was started. Only two cohorts (4 and during the entire treatment period was reported. In 13) had a notable number of HIV-1-positive patients; in addition, sensitivity documented by DST was not proven all other cohorts, HIV-1 co-infection was minimal or not for every drug used in a given regimen. The researchers for cohort 2 stated that they frequently used isoniazid even Most studies were done in developed countries: though all infecting strains had documented resistance to Denmark, Netherlands, USA, Canada, Hong Kong, and the drug. In cohorts 7 and 9, second-line drugs to which South Korea. Two were done in low-income or middle- strains had documented resistance were occasionally used income countries—Peru and Turkey. Nine cohorts were to treat highly resistant cases. Only in cohorts 5, 8, 9, 10, treated at tertiary referral hospitals, and four in outpatient 11, and 12 were the actual doses of the drugs used clinics. The most common method of retrospectively reported, and doses varied substantially between studies.
constructing cohorts of MDR-TB patients was to uselaboratory records to identify strains with resistance to Number of resistant drugs and drug susceptibility isoniazid and rifampicin. In some cohorts, however, other sampling techniques were reported. Cohort 3 was made The reported mean or median number of drugs to which up of patients identified through a specific referral isolates were resistant ranged from 3·2 to 6·6. Studies did network of hospital physicians. In cohort 9, cases of not test susceptibility to the same number of drugs. In MDR-TB were identified by reviewing clinic records, cohorts 5 and 12, only DST to first-line antituberculosis even though most patients had previously been admitted to the hospital for several months to start treatment with ethambutol) was done. Patients in cohort 12 where second-line drugs. In cohort 11, MDR-TB patients who treated with an empirical MDR-TB regimen and not all had previously been treated with second-line drugs were patients received DST. Of the 72% of patients who THE LANCET • Vol 363 • February 7, 2004 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet.
received DST, 87% had documented resistance to obtained from the researchers to reflect four consistent and mutually exclusive outcomes: cure, failure, death, and Studies reported a range of DST methods, with use of default.21 Reported cure rates were revised in many studies solid and liquid media; some non-standard methods were reported. In cohorts 1, 4, 6, and 13, the proprietary liquid recalculation of treatment outcomes, although helpful in media system BACTEC (Becton, Dickinson, and the comparison of these studies, does not correct for more Company of Franklin Lakes, NJ, USA) was used to test first-line and second-line drugs. Pyrazinamide testing, produced by the differences in practices for referral of when available, was mainly done with the Wayne method; patients and cohort selection criteria.
in later studies, BACTEC testing became more common. The most common definition of cure was the completion of a prescribed course of treatment with 12 or more months of negative cultures (cohorts 3, 4, 5, 6, 7, 9, The mean or median duration of treatment was reported 10, and 13). In cohort 8, cure was defined as 6 months of for cohorts 1, 2, 3, 4, 6, 7, 8, and 11, and ranged from 13 consistently negative cultures. In cohort 11, cure was to 24 months. The shortest lengths of treatment were defined as two or more negative cultures at the end of reported in Denmark (cohort 1) and Hong Kong treatment. In cohort 12, cure was defined as two negative (cohort 8). When criteria for successful treatment were smears or two negative cultures at the end of the reported, these criteria generally stipulated 18–24 months 18-month treatment period. In cohorts 1 and 2, the of chemotherapy after the last positive culture. definition of cure was not stated. Failure was defined as the In cohorts 4, 6, 7, 8, 12, and 13, directly observed occurrence of persistently positive sputum despite treatment was used, but in only four (4, 7, 8, and 12) was treatment. Death was defined as all causes of death during it for the entire duration of treatment. An additional six treatment. We defined default as treatment suspension for cohorts (1, 2, 3, 5, 9, and 10) were treated as inpatients at any reason. Relapse was only reported in a few studies but the beginning of treatment, at which time treatment was we included it after obtaining information from the original observed or closely monitored; after discharge, treatment researchers. Relapse was defined as a positive culture during the follow-up period after documented cure. We made every effort to assess treatment outcomes Treatment outcomes for each cohort are listed in across studies in a standard way. Since treatment table 1. Cure rates ranged from 38% (cohort 13) to 100% outcomes were reported according to various definitions (cohort 1). Default rates ranged from 0% (cohorts 1 and in the original studies, we recalculated the published 2) to 44% (cohort 11), although the latter included a treatment outcome data with additional information Efficacy against M tuberculosis
Group 1: Oral first-line agentsIsoniazid, rifampicin, In-vitro and in-vivo clinical data support use. Historical and clinical evidence suggests that these agents are most potent oral antituberculosis medications. Ethambutol is generally bacteriostatic, but at high doses (25 mg/kg) can be bactericidal.24 In-vitro and in-vivo clinical data support use Group 2: InjectablesStreptomycin, kanamycin, Bactericidal. In-vitro and in-vivo clinical data support use25–28,29 Group 3: FluoroquinolonesCiprofloxacin, ofloxacin, Bactericidal. In-vitro and in-vivo clinical data support use.30–32 Newer agents (moxifloxacin, gatifloxacin, sparfloxacin) have lower minimum inhibitory concentrations,33,34 but clinical importance of this feature unknown Group 4: Bacteriostatic second-line drugs Ethionamide, cycloserine, Bacteriostatic. In-vitro and in-vivo clinical data support use26–29,35–39 Group 5: Other drugs (potentiallyuseful agents with conflicting animal or clinical evidence or agents with unclear efficacy because of possible cross-resistance)Clofazimine Bacteriostatic in vitro.40 Conflicting animal model data. MIC90 <1·0 mg in vitro. Concentrations attainable in vivo, particularly in macrophages.41,42 Activity in murine and guinea pig models, but no activity in rhesus monkey model43 (between-speciesdifferences may be explained by peak serum differences)44 ␤ lactams in combination with b lactamase inhibitors bactericidal in vitro.45 Conflicting clinical data of early bactericidal activity. One report showed significant decrease in colony-forming units when used alone for 7 days46 and suggests possible role,47 whereas another showed no effect48 Although in-vitro antimycobacterial properties reported,49,50 including increase in ability when used in combination with standard antituberculosis drugs against multidrug-resistant strains, data from animal and in vivo studies conflicting.28,51–53Clinical usefulness remains to be determined May be useful against some isolates of MDR-TB (resistant to rifampicin in vitro but sensitive to rifabutin). Clinical experiencesuggests no role in routine use in treatment of MDR-TB because of cross-resistance with rifampicin32,54–56 In-vivo and in-vitro evidence of bacteriostatic activity. Cross-resistance frequently seen between thiacetazone and both isoniazid and ethionamide. High rate of side-effects in HIV-1 patients; use not recommended in patients with suspected HIV-1 infection57–59 Animal model supports use. Conflicting clinical data. Cessation of INH generally recommended in confirmed MDR-TB, however high doses (16–20 mg/kg twice weekly) might have a role.60,61 In one study, regular doses of no benefit.61 Supporting data in a mouse model62 Potency of drugs decreases from top to bottom of table.
Table 2: Hierarchy of classes of antituberculosis drugs and evidence for use THE LANCET • Vol 363 • February 7, 2004 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet.
In the studies we reviewed, drug regimens were The proportion of patients who had a history of treatment frequently individually tailored to DST results. Although for tuberculosis ranged from 32–100%. In several studies the use of empirical regimens, in which patients are given patients were reported as being referred for treatment only a standard combination of second line drugs based on after failing to respond to other treatment regimens.
their likely pattern of resistance, has been suggested if Cohorts 2 and 3 had the lowest proportion of re-treatment DST is unavailable or unreliable, the practical usefulness cases at 34% and 32%, respectively. Among patients with of this approach has not been validated in controlled history of tuberculosis, the length of time with trials. Only cohort 12 used a fully empirical approach to tuberculosis ranged from 2·5 to 6·7 years. MDR-TB treatment, although the cure rate was poor.
Adjunctive resective surgery was reportedly used in On the other hand, cohort 5 was treated with a partly cohorts 2, 3, 4, 5, 6, 7, 9, and 10. The proportion of empirical approach—first-line drugs were selected on the patients that received surgery in these cohorts ranged basis of DST, but second-line drugs were selected on the basis of previous treatment history. In this study the curerate was good (75%), which suggests that at least partly empirical approaches may be effective in some settings.
In areas with poor socioeconomic conditions where access Second-line antituberculosis drugs should be selected to tertiary care is limited, it would be hard to treat cases of based on efficacy. Table 2 presents the known antituber- MDR-TB only in specialised centres. Our review shows culosis drugs grouped hierarchically based on the that, importantly, MDR-TB treatment is feasible in a wide evidence of their efficacy against Mycobacterium variety of settings. In several studies MDR-TB treatment tuberculosis.25–68 An injectable agent and a quinolone was provided to large numbers of MDR-TB patients in should be included in any MDR-TB treatment regimen.
outpatient treatment centres in resource-poor areas. Treatment regimens in the reviewed cohort studies In the past, MDR-TB has been deemed too expensive varied enormously, but all included an injectable to treat patients in low-income countries. The price aminoglycoside or capreomycin. Quinolones have reduction of second-line drugs, however, has made become indispensable in the treatment of MDR-TB treatment more affordable. In cohort 12, a cost- because of their bactericidal activity and excellent oral effectiveness analysis was done. Although this study had a bioavailability, and were used in all studies except the low cure rate (48%), the researchers concluded that earliest before quinolones were considered standard of treating MDR-TB with second-line drugs is feasible and cost effective. The cost per disability-adjusted life year The use of multidrug regimens in the treatment of saved was US$211, and the average total treatment cost tuberculosis helps to prevent drug resistance. Poor drug per patient was $2381. The cost per disability-adjusted availability, the lack of controlled trials, and provider life year saved is lower than the per-person gross domestic inexperience, have led to regimens commonly being product of many countries, a general benchmark for incorrect or inadequate.69 The exact number of second- assessing whether or not an intervention is cost effective.22 line drugs in an MDR-TB treatment regimen needed to Such values are low enough to be judged by the World prevent the creation of further drug resistance is Bank as reasonable investments even in low-income unknown. Most studies used regimens of four to six drugs, a prudent approach given the high bacillary With new funding opportunities for MDR-TB, burden and chronic lesions among patients and the poor treatment from the Global Fund to Fight AIDS, TB, and potency and penetration of second-line drugs. If a partly Malaria, and further reductions in the prices of second- or fully empirical treatment approach is taken, the use of line tuberculosis drugs, increased variation in treatment many second-line drugs might be advisable to cover the settings and numbers of MDR-TB patients can be possibility of pre-existing resistance. The importance of expected in the future. Evidence-based clinical guidelines using a sufficient number of drugs in an MDR-TB for MDR-TB treatment are urgently needed, for specialty treatment regimen is highlighted by a subgroup analysis centres and for resource-poor outpatient treatment of cohorts 4 and 13 by Narita and colleagues,12 who centres that will treat the largest number of patients with argued that patients treated by subspecialists at a tertiary MDR-TB. The studies we reviewed do not answer many referral centre in Florida, USA, had significantly better crucial questions about how best to treat MDR-TB since treatment outcomes than did those treated in the differences in baseline cohort characteristics and community, partly because of a significant difference in treatment settings make direct comparison impossible.
the mean number of drugs used in the two cohorts (5·51 However, some insights about MDR-TB treatment may be learned from a careful review of the existing scientific We recommend a systematic algorithm for the design of MDR-TB treatment regimens. Based on table 2, afive-drug regimen can be designed (panel) by adding drugs from each of the five groups, to which patient’s The starting of treatment early is crucial to the effective isolate is sensitive. First-line drugs should be used treatment of MDR-TB. In many studies, 100% of whenever possible, all regimens should contain an patients had previously failed to respond to treatment for injectable and a quinolone, and the remainder of the five- tuberculosis. Cohorts 2 and 3 had the greatest proportion drug regimen can be comprised of bacteriostatic second- of treatment-naive patients and were among the studies line agents.70 Given the severity of disease and poor with the highest cure rates. Delay in the diagnosis of potency of the second-line antituberculosis drugs, high- MDR-TB results in patients presenting with chronic end dosing of these medications should be used disease, progressive parenchymal destruction, higher bacillary loads, and continuing transmission.23,24 Although Aggressive treatment regimens, using four to six drugs rapid diagnostic tools such as BACTEC might not be to which isolates had documented sensitivity, were available in resource-poor settings, every effort should be frequently used in the cohort studies. The dominant made to quickly identify patients with MDR-TB and start resistance pattern was not to isoniazid and rifampicin alone. The mean or median number of resistant drugs in THE LANCET • Vol 363 • February 7, 2004 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet.
most studies was four or more, including ethambutol and pyrazinamide in addition to isoniazid and rifampicin. These Despite the many challenges in the diagnosis and highly resistant MDR-TB strains have been documented in treatment of MDR-TB, many of the studies we reviewed resource-poor settings where resistance has developed to show that successful treatment is possible in various four or five drugs because of repeated use of empirical settings, that aggressive regimens with four to six drugs, short-course chemotherapy with first-line antituberculosis attention to adherence, and management of side-effects drugs, a phenomenon termed the amplifier effect.4,71 Such are important in achieving high cure rates. However, highly resistant patterns of drug resistance also argue for many crucial management issues remain unresolved and early initiation of aggressive treatment protocols for MDR- cannot be answered through the existing data. The evidence-based treatment recommendations we present, In the studies we reviewed, default from treatment was based on the reviewed papers, provide only general an important cause of poor cure rates, particularly in some guidance to clinicians. Controlled clinical trials are of the outpatient centre studies. Directly observed needed to answer more complex questions concerning treatment and other strategies to support adherence are best treatment regimens and optimum treatment highly recommended. Adherence is a major problem in the protocols for MDR-TB. In addition, further operational treatment of MDR-TB because of the long duration of research in resource-poor areas is needed to address treatment and adverse effects of second-line drugs. Chaulk common programme issues, such as high treatment and Kazandjian72 assessed adherence principles in a review default rates. As treatment becomes increasingly available of tuberculosis programmes and showed that treatment in these settings, where it is needed most, clinical and completion rates for pulmonary tuberculosis exceeded 90% operational research is urgently needed to guide clinicians when treatment included directly observed therapy with worldwide in the management of MDR-TB.
multiple incentives to improve adherence to treatment,such as transportation vouchers (enablers) or food Conflict of interest statementNone declared.
supplements (enhancers). DOT also allows for the dailymonitoring of adverse effects, the timely management of We thank Marian Goble, Masahiro Narita, Monica Avendaño, treatment will probably become more common for MDR- Seung-kyu Park, Wya Geerligs, Tjip van der Werf, Michael Iademarco, TB, since it is a standard requirement in WHO’s guidelines Kemal Tahao´glu, Tülay Törün, K Viskum, and Wing Wai Yew, theresearchers of the studies used for this review, for their collaboration and on the treatment of this disorder.73 Additional strategies to help in providing data in addition to that which was published in their improve adherence include support groups for patients, education for patients and family, nutritional support, caseworkers, transportation, and housing assistance.
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