April eNewsletter

Care of the patient with XDR-TB who has failed treatment.

Jacobson KB, Tate M, Eksteen F, Moll A, Padayatchi N, Friedland G, Shenoi S.

Lancet Respir Med. 2015 Apr;3(4):269-70. doi: 10.1016/S2213-2600(15)00109-5.

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Primary capreomycin resistance is common, and associated with early mortality in extensively drug-resistant tuberculosis (XDR-TB) patients in KwaZulu-Natal, South Africa.

O’Donnell MR, Pillay M, Pillay M, Werner L, Master I, Wolf A, Mathema B, Coovadia YM, Mlisana K, Horsburgh CR, Padayatchi N.

J Acquir Immune Defic Syndr. 2015 Apr 13. [Epub ahead of print]

Abstract
BACKGROUND:
Capreomycin is a key antimycobacterial drug in treatment of extensively drug-resistant tuberculosis (XDR-TB). Drug susceptibility testing (DST) for capreomycin is not routinely performed in newly diagnosed XDR-TB in South Africa. We performed this study to assess the prevalence, clinical significance, and molecular epidemiology of capreomycin resistance in newly diagnosed XDR-TB patients in KwaZulu-Natal, South Africa.

METHODS:
Retrospective cohort study of consecutive XDR-TB patients admitted to a TB referral hospital without prior XDR-TBtreatment. A subset of isolates had extended DST (including capreomycin), mutational analysis and IS6110 restriction fragment length polymorphism (RFLP) assays.

RESULTS:
216 eligible XDR-TB patients were identified. The majority were treated with capreomycin (72%), were young (median age 35.5) and female (56%). 165 (76%) were HIV+, and 109 (66%) were on antiretroviral therapy. A subset of 52 patients had full DST. 47/52 (90.4%) XDR-TB patients were capreomycin resistant. Capreomycin-resistant patients experienced worse mortality and culture conversion than capreomycin susceptible though this difference was not statistically significant. The A1401G mutation in the rrs gene was associated with capreomycin resistance. The majority of capreomycin resistant strains were F15/LAM4/KZN lineage (80%), and clustering was common in these isolates (92.5%).

CONCLUSIONS:
Capreomycin resistance is common in patients with XDR-TB in KwaZulu-Natal, is predominantly due to ongoing province-wide transmission of a highly resistant strain, and is associated with high mortality. Capreomycin should be included in routine DST in all XDR-TB patients. New drug regimens that do not include injectable agents should be operationally tested as empiric treatment in XDR-TB.

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Variation and risk factors of drug resistant tuberculosis in sub-Saharan Africa: a systematic review and meta-analysis.

Lukoye D, Ssengooba W, Musisi K, Kasule GW, Cobelens FG, Joloba M, Gomez GB.

BMC Public Health. 2015 Mar 25;15(1):291. [Epub ahead of print]

Abstract
BACKGROUND:
Prevalence of multidrug resistant tuberculosis (MDR-TB), defined as in vitro resistance to both rifampicin and isoniazid with or without resistance to other TB drugs, in sub-Saharan Africa (SSA) is reportedly low compared to other regions. These estimates are based on data reported to the World Health Organization (WHO) on drug resistance surveys, which may suffer from a reporting bias. We set out to evaluate the variation in prevalence of drug resistant tuberculosis (DR-TB) and its determinants across SSA countries among new and previously treated TB patients.

METHODS:
The aim was to perform a systematic review and meta-analysis of DR-TB prevalence and associated risk factors in SSA. PubMed, EMBASE, Cochrane and bibliographies of DR-TB studies were searched. Surveys at national or sub-national level, with reported DR-TB prevalence (or sufficient data to calculate a prevalence) to isoniazid (INH), rifampicin (RMP), ethambutol (EMB), and streptomycin (SM) conducted in SSA excluding the Republic of South Africa, published between 2003 and 2013 with no language restriction were considered. Two authors searched and reviewed the studies for eligibility and extracted the data in pre-defined forms. Forest plots of all prevalence estimates by resistance outcome were performed. Summary estimates were calculated using random effects models, when appropriate. Associations between any DR-TB and MDR-TB with potential risk factors were examined through subgroup analyses stratified by new and previously treated patients.

RESULTS:
A total of 726 studies were identified, of which 27 articles fulfilled the inclusion criteria. Studies reported drug susceptibility testing (DST) results for a total of 13,465 new and 1,776 previously treated TB patients. Pooled estimate of any DR-TB prevalence among the new cases was 12.6% (95% CI 10.6-15.0) while for MDR-TB this was 1.5% (95% CI 1.0-2.3). Among previously treated patients, these were 27.2% (95% CI 21.4-33.8) and 10.3% (95% CI 5.8-17.4%), respectively. DR-TB (any and MDR-TB) did not vary significantly with respect to study characteristics.

CONCLUSIONS:
The reported prevalence of DR-TB in SSA is low compared to WHO estimates. MDR-TB in this region does not seem to be driven by the high HIV prevalence rates.

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Implementing rapid testing for tuberculosis in Mozambique.

Cowan J, Michel C, Manhiça I, Monivo C, Saize D, Creswell J, Gloyd S, Micek M.

Bull World Health Organ. 2015 Feb 1;93(2):125-30. doi: 10.2471/BLT.14.138560. Epub 2014 Nov 26.

Abstract
PROBLEM:
In Mozambique, pulmonary tuberculosis is primarily diagnosed with sputum smear microscopy. However this method has low sensitivity, especially in people infected with human immunodeficiency virus (HIV). Patients are seldom tested for drug-resistant tuberculosis.

APPROACH:
The national tuberculosis programme and Health Alliance International introduced rapid testing of smear-negative sputum samples. Samples were tested using a polymerase-chain-reaction-based assay that detects Mycobacterium tuberculosis deoxyribonucleic acid and a mutation indicating rifampicin resistance; Xpert® MTB/RIF (Xpert®). Four machines were deployed in four public hospitals along with a sputum transportation system to transfer samples from selected health centres. Laboratory technicians were trained to operate the machines and clinicians taught to interpret the results.

LOCAL SETTING:
In 2012, Mozambique had an estimated 140 000 new tuberculosis cases, only 34% of which were diagnosed and treated. Of tuberculosis patients, 58% are HIV-infected.

RELEVANT CHANGES:
From 2012-2013, 1558 people were newly diagnosed with tuberculosis using sputum smears at intervention sites. Xpert® detected M. tuberculosis in an additional 1081 sputum smear-negative individuals, an increase of 69%. Rifampicin resistance was detected in 58/1081 (5%) of the samples. However, treatment was started in only 82% of patients diagnosed by microscopy and 67% of patients diagnosed with the rapid test. Twelve of 16 Xpert® modules failed calibration within 15 months of implementation.

LESSONS LEARNT:
Using rapid tests to diagnose tuberculosis is promising but logistically challenging. More affordable and durable platforms are needed. All patients diagnosed with tuberculosis need to start and complete treatment, including those who have drug resistant strains.

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Has introduction of rapid drug susceptibility testing at diagnosis impacted treatment outcomes among previously treated tuberculosis patients in Gujarat, India?

Dave P, Vadera B, Kumar AM, Chinnakali P, Modi B, Solanki R, Patel P, Patel P, Pujara K, Nimavat P, Shah A, Bharaswadkar S,Rade K, Parmar M, Nair SA.

PLoS One. 2015 Apr 13;10(4):e0121996. doi: 10.1371/journal.pone.0121996. eCollection 2015.

Abstract
BACKGROUND:
Revised National TB Control Programme (RNTCP) in India recommends that all previously-treated TB (PT) patients are offered drug susceptibility testing (DST) at diagnosis, using rapid diagnostics and screened out for rifampicin resistance before being treated with standardized, eight-month, retreatment regimen. This is intended to improve the early diagnosis of rifampicin resistance and its appropriate management and improve the treatment outcomes among the rest of the patients. In this state-wide study from Gujarat, India, we assess proportion of PT patients underwent rapid DST at diagnosis and the impact of this intervention on their treatment outcomes.

METHODS:
This is a retrospective cohort study involving review of electronic patient-records maintained routinely under RNTCP. All PT patients registered for treatment in Gujarat during January-June 2013 were included. Information on DST and treatment outcomes were extracted from ‘presumptive DR-TB patient register’ and TB treatment register respectively. We performed a multivariate analysis to assess if getting tested is independently associated with unfavourable outcomes (death, loss-to-follow-up, failure, transfer out).

RESULTS:
Of 5,829 PT patients, 5306(91%) were tested for drug susceptibility with rapid diagnostics. Overall, 71% (4,113) TB patients were successfully treated – 72% among tested versus 60% among non-tested. Patients who did not get tested at diagnosis had a 34% higher risk of unsuccessful outcomes as compared to those who got tested (aRR – 1.34; 95% CI 1.20-1.50) after adjusting for age, sex, HIV status and type of TB. Unfavourable outcomes (particularly failure and switched to category IV) were higher among INH-resistant patients (39%) as compared to INH-sensitive (29%).

CONCLUSION:
Offering DST at diagnosis improved the treatment outcomes among PT patients. However, even among tested, treatment outcomes remained suboptimal and were related to INH resistance and high loss-to-follow-up. These need to be addressed urgently for further progress.

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Limited Sampling Strategy and Target Attainment Analysis for Levofloxacin in Patients with Tuberculosis.

Alsultan A, An G, Peloquin CA.

Antimicrob Agents Chemother. 2015 Apr 13. pii: AAC.00341-15. [Epub ahead of print]

Abstract
There is an urgent need to improve and shorten the treatment of tuberculosis (TB) and multi-drug resistant tuberculosis (MDR-TB). Levofloxacin, a newer generation fluoroquinolone, has potent activity against TB both in vitro and in vivo. Levofloxacin dosing can be optimized to improve the treatment of both TB and MDR-TB. Levofloxacin efficacy is linked primarily to fAUC/MIC. Since obtaining a full time concentration profile is not feasible in the clinic, we developed a limited sampling strategy (LSS) to estimate the AUC. We also utilized Monte Carlo simulations to evaluate the dosing of levofloxacin. Pharmacokinetic data were obtained from ten Brazilian TB patients. The pharmacokinetic data were fit with a one compartment model. LSS were developed using two methods: linear regression and Bayesian approaches. Several LSS predicted levofloxacin AUC with good accuracy and precision. The most accurate were two samples collected at four and six hours (R2 = 0.91 using linear regression and 0.97 using Bayesian approaches), or at two and six hours (R2 = 0.90 using linear regression and 0.96 using Bayesian approaches). The two and six hour approach also provides a good estimate of Cmax. Our target attainment analysis showed that higher doses (17-20 mg/kg) of levofloxacin might be needed to improve its activity. Doses in the range of 17-20 mg/kg showed good target attainment for MIC values from 0.25-0.50. At an MIC of 2, poor target attainment was observed across all doses. This LSS for levofloxacin can be used for therapeutic drug monitoring, and for future pharmacokinetic/pharmacodynamic studies.

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Multidrug-resistant tuberculosis in the Amazonas State, Brazil, 2000-2011.

da S Garrido M, Bührer-Sékula S, Souza AB, de Oliveira GP, Antunes IA, Mendes JM, Saraceni V, Martinez-Espinosa FE, Ramasawmy R.

Int J Tuberc Lung Dis. 2015 May;19(5):531-6. doi: 10.5588/ijtld.14.0291.

Abstract
SETTINGS:
Amazonas is facing increasing challenges in tuberculosis (TB) control, with nearly 3000 cases per year, and multidrug-resistant TB (MDR-TB) may jeopardise the TB control programme.

OBJECTIVE:
To assess the number of MDR-TB cases in the Amazonas and to improve estimates of the burden of TB.

DESIGNS:
The Brazilian National Mandatory Disease Reporting System (SINAN) and the Brazilian Epidemiological Surveillance System of Multidrug Resistance (TBMR) were searched for MDR-TB cases in the State of Amazonas from 2000 to 2011.

RESULTS:
Eighty-one MDR-TB cases were notified. The rates of primary MDR-TB, initial MDR-TB during the first treatment regimen and acquired MDR-TB were respectively 3.8%, 13.7% and 82.7%; 26.9% of previously treated patients had ⩾4 treatment cycles. TheMDR-TB cases reported 263 contacts, only 35.0% of whom were examined. The cure and death rates among the 81 patients with MDR-TB were respectively 45.7% and 25.9%.

CONCLUSIONS:
The number of MDR-TB cases seems incompatible with the high TB prevalence in the Amazonas. Most patients were unaware of contact with TB patients. TB is endemic in the Amazonas. This highlights the need for improving resistance investigation among all TB cases.

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Introducing new tuberculosis diagnostics: the impact of Xpert(®) MTB/RIF testing on case notifications in Nepal.

Creswell J, Rai B, Wali R, Sudrungrot S, Adhikari LM, Pant R, Pyakurel S, Uranw D, Codlin AJ.

Int J Tuberc Lung Dis. 2015 May;19(5):545-51. doi: 10.5588/ijtld.14.0775.

Abstract
SETTING:
The Xpert(®) MTB/RIF assay is a highly sensitive molecular test with the potential to improve tuberculosis (TB) case detection. However, evidence supporting this potential at a programme level is minimal.

METHODS:
Xpert testing following smear microscopy and chest X-ray was implemented as part of routine case finding in 16 districts of Eastern Nepal. Changes in TB case notification were evaluated based on a pre/post analysis, as were expected notifications based on linear trend.

RESULTS:
A total of 9723 Xpert tests were performed, resulting in the identification of 1662 Mycobacterium tuberculosis-positive patients. Despite a previous declining trend in notifications, annual bacteriologically positive TB notifications increased by 15.2% during the intervention, from 3390 to 3906. However, annual notifications of pulmonary TB dropped by 8.5% overall, from 5123 to 4688. Both observations were significantly different from expected notifications based on historical trends. Treatment initiation for drug-resistant TBalmost doubled.

DISCUSSION:
Xpert testing significantly increased bacteriologically positive TB notifications, but large reductions in empiric treatment of smear-negative disease reduced the number of pulmonary TB notifications overall. While better diagnostics remain critical, focusing solely on superior test sensitivity may not increase TB case notifications. Additional interventions are required to reach the millions of people with TB who are missed by routine services.

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Changes in treatment outcomes of multidrug-resistant tuberculosis.

Kwak N, Kim HR, Yoo CG, Kim YW, Han SK, Yim JJ.

Int J Tuberc Lung Dis. 2015 May;19(5):525-30. doi: 10.5588/ijtld.14.0739.

Abstract
SETTING:
After several changes in treatment modalities, it is time to re-evaluate treatment outcomes of multidrug-resistant tuberculosis(MDR-TB).

OBJECTIVE:
To evaluate treatment outcomes, elucidate changes in outcomes over time and identify predictors of treatment success for MDR-TB.

DESIGN:
Patients diagnosed with MDR-TB at a tertiary referral centre in South Korea between January 2006 and December 2010 were included. Treatment modalities and outcomes were assessed. Predictors of treatment success were analysed using multiple logistic regression. The treatment modalities and outcomes of these patients were compared with those of MDR-TB patients between January 1996 and December 2005.

RESULTS:
Of the 123 MDR-TB patients diagnosed during the later study period, treatment was successful in 103 (83.7%). Extensive drug resistance (OR 0.31, P = 0.044) and additional resistance to fluoroquinolones (OR 0.23, P = 0.039) were inversely associated with treatment success. The treatment success rate improved from 53.5% in 1996-2000 to 68.8% in 2001-2005 and 83.7% in 2006-2010 (P < 0.001). Improved outcomes were accompanied with more frequent use of later-generation fluoroquinolones and linezolid and less frequent surgical resection.

CONCLUSION:
Treatment outcomes for MDR-TB improved at a tertiary referral centre in South Korea. The improvement was associated with more frequent use of later-generation fluoroquinolones and linezolid.

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High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon.

Kuaban C, Noeske J, Rieder HL, Aït-Khaled N, Abena Foe JL, Trébucq A.

Int J Tuberc Lung Dis. 2015 May;19(5):517-24. doi: 10.5588/ijtld.14.0535.

Abstract
SETTING:
Two specialised multidrug-resistant tuberculosis (MDR-TB) treatment units in Cameroon.

OBJECTIVE:
To assess outcome and adverse drug events with a standardised 12-month regimen for MDR-TB among second-line drug naïve patients.

DESIGN:
Prospective observational study of MDR-TB patients treated with a standardised 12-month regimen including gatifloxacin, clofazimine, prothionamide, ethambutol and pyrazinamide throughout, supplemented by kanamycin and isoniazid during an intensive phase of a minimum of 4 months. Progress was monitored monthly until treatment completion and twice over one year after treatment cessation.

RESULTS:
Eighty-seven potentially eligible patients were lost and never treated due to delayed availability of test results. Among the 150/236 eligible and treated patients, 134 (89%) successfully completed treatment, 10 died, 5 were lost, 1 failed and none relapsed. The patients’ mean age was 33.7 years (range 17-68), 73 (49%) were females, 120 (80%) had failed on previous treatment, 30 (20%) were human immunodeficiency virus seropositive, 62 (43%) had a body mass index <18.5 kg/m(2) and 41 (27%) had radiographic involvement of five or six of the six lung zones. The most important adverse drug event was hearing impairment, which occurred in 46 of 106 (43%) patients.

CONCLUSIONS:
These results add further evidence for the usefulness of shorter, standardised regimens among patients without second-line drug resistance.

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Expanding the evidence base supporting shorter treatment durations for multidrug-resistant tuberculosis.

Nuermberger E, Yew WW.

Int J Tuberc Lung Dis. 2015 May;19(5):497-8. doi: 10.5588/ijtld.15.0110.

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Cost effectiveness of treating multi-drug resistant tuberculosis by adding Deltyba™ to background regimens in Germany.

Diel R, Hittel N, Schaberg T.

Respir Med. 2015 Feb 4. pii: S0954-6111(15)00020-7. doi: 10.1016/j.rmed.2015.01.017. [Epub ahead of print]

Abstract
OBJECTIVE:
To assess the cost-effectiveness of adding delamanid (Deltyba™) to a background regimen (BR) for treating multidrug-resistant tuberculosis (MDR-TB) in Germany.

METHODS:
The incremental cost-effectiveness of treating a cohort of MDR-TB patients, 38-years old on average, with Deltyba™ plus BR versus a five drug- BR regimen alone was compared in a Markov model over a period of 10 years. Cost per quality-adjusted life year (QALY) and disability-adjusted life years (DALY) were determined from a societal perspective. Recent data from a German cost calculation on MDR-TB were applied to the 24-month outcome results of patients participating in the placebo-controlled, phase II Otsuka’s Trial 204. Costs and effectiveness were discounted at a rate of 3% and subjected to deterministic as well as probabilistic sensitivity analysis in a Monte Carlo simulation.

RESULTS:
Based on the current market prices the total discounted cost per patient on BR plus Deltyba™ was €142,732 compared to €150,909 for BR alone. The total discounted QALYs per patient were 8.47 for Deltyba™ versus 6.13 for BR alone. Accordingly, the addition of Deltyba™ proved to be dominant over the BR alone-strategy by simultaneously saving €8177 and gaining 2.34 QALYs. Deltyba™ was cost saving in 73% of probabilistic sensitivity analyses compared to BR alone and 100% cost effective at a willingness-to-pay (WTP) threshold of €10,000.

CONCLUSIONS:
Under conditions prevalent in Germany, Deltyba™ added to a five drug BR regimen is likely to be cost-saving compared to BR alone under a wide range of assumptions. Adding delamanid remained cost-effective when costs due to loss of productivity were excluded as the QALYs gained by lower lethality and a higher proportion of successfully treated patients outweighed the delamanid drug costs. These results strongly support the application of Deltyba™ in treating MDR-TB patients.

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Multidrug-resistant tuberculosis in Ukraine at a time of military conflict.

Dudnyk A, Rzhepishevska O, Rogach K, Kutsyna G, Lange C. Int J Tuberc Lung Dis. 2015 Apr;19(4):492-3. doi: 10.5588/ijtld.14.0940.

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Genetic mutations associated with rifampicin and isoniazid resistance in MDR-TB patients in North-West India.

Kumar P, Kumar P, Balooni V, Singh S.

Int J Tuberc Lung Dis. 2015 Apr;19(4):434-9. doi: 10.5588/ijtld.14.0596.

Abstract
BACKGROUND:
Effective tuberculosis (TB) control has been hindered by the emergence of multidrug-resistant TB (MDR-TB).

OBJECTIVE:
To analyse the frequency of drug resistance among presumed cases of drug-resistant TB in the state of Punjab, India, and to determine the frequency of various genetic mutations detected using the line-probe assay (LPA).

METHODS:
Eight hundred patients with presumptive drug-resistant TB were enrolled under the programmatic management of drug-resistant TB under India’s Revised National Tuberculosis Control Programme. Sputum samples from these patients were subjected to smear microscopy and LPA. Clinicodemographic details along with drug resistance patterns and genetic mutations were studied.

RESULTS:
After excluding non-eligible samples, 545 samples were analysed, of which 290 (53.2%) showed resistance. Isoniazid and rifampicin (RMP) monoresistance were detected in respectively 9.3% (51/545) and 18% (98/545) of samples, while MDR was present in 25.8% (141/545) of samples. Of the MDR-TB cases, 2.1% (3/141) were treatment-naïve, while 90.8% (128/141) were on retreatment. The most common mutation conferring RMP resistance was S531L.

CONCLUSION:
All patients undergoing retreatment for TB should be tested for drug susceptibility at the initial evaluation. Factors responsible for high MDR-TB and heteroresistance in Punjab need further studies.

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Mycobacterium tuberculosis genotypic drug resistance patterns and clustering in Jayapura, Papua, Indonesia.

Chaidir L, Sengstake S, de Beer J, Krismawati H, Lestari FD, Ayawaila S, van Soolingen D, Anthony R, van Crevel R, Alisjahbana B.

Int J Tuberc Lung Dis. 2015 Apr;19(4):428-33. doi: 10.5588/ijtld.14.0350.

Abstract
BACKGROUND:
Little is known about drug-resistant tuberculosis (TB) and its transmission in Papua, which has one of the highest rates of TB in Indonesia.

DESIGN:
We examined genotypic drug resistance patterns using multiplex ligation-dependent probe amplification and the degree of molecular clustering using 24-locus mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) among 199 consecutive pulmonary TB patients in Jayapura, Papua.

RESULTS:
Drug resistance mutations were present in 30/198 (15.2%) patients: 16/144 (11.1%) primary cases and 14/51 (27.5%) retreatment cases. Genotypic resistance to rifampicin was found in 15 (7.6%) patients, to isoniazid in 19 (9.6%), to ethambutol in 7 (3.5%), and to streptomycin and second-line injectable drugs in 5 (2.5%) patients. Eight (4.0%) patients had multidrug-resistant TB, while no mutations were found for fluoroquinolones. The most common lineage found among all isolates was East-African Indian (n = 66, 33.7%), followed by Euro-American (n = 38, 19.4%). Drug resistance mutations were more common among Beijing strains than other lineages. Of the 30 drug-resistant isolates, 12 (40.0%) fell into four clusters that were separate from drug-susceptible clusters as determined using MIRU-VNTR.

CONCLUSIONS:
These are the first genotypic drug resistance data from Jayapura, Papua, showing moderate rates of resistance to first-line drugs and likely transmission of drug-resistant TB.

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Treatment interruption and directly observed treatment of multidrug-resistant tuberculosis patients in China.

Wei XL, Yin J, Zou GY, Zhang ZT, Walley J, Harwell J, Li HT, Sun Q, Li RZ, Wang LX, Zhang XL.

Int J Tuberc Lung Dis. 2015 Apr;19(4):413-9. doi: 10.5588/ijtld.14.0485.

Abstract
BACKGROUND:
China has nearly one fifth of global multidrug-resistant tuberculosis (MDR-TB) cases, and follows the 24-month World Health Organization (WHO) standardised regimens.

OBJECTIVE:
To assess treatment interruption among MDR-TB patients and its association with the provision of directly observed treatment (DOT).

METHODS:
We reviewed clinical charts and conducted a questionnaire survey among all confirmed MDR-TB patients who had been treated for at least 6 months from 1 January 2009 to 30 April 2012 in Shandong Province. Treatment interruption was defined as missing a dose for at least 1 day but for <8 consecutive weeks; the subset ‘severe interruption’ was defined as missing doses for 2-8 consecutive weeks.

RESULTS:
Of 110 patients, 75 (68%) interrupted treatment; 19 (17%) reported severe interruption, with a median duration of 30 days. Of the 110 patients, 26 (24%) received injections from family members and 55 (50%) received DOT, 7 (13%) from village doctors and 48 (87%) from family members. Patients who underwent DOT with a family member had less severe interruptions (OR 0.25, 95%CI 0.05-0.98) than those who were given DOT by a village doctor or who did not undergo DOT.

CONCLUSIONS:
Family members may act as treatment supporters for MDR-TB patients to reduce treatment interruptions, but require orientation on their role.

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Phenotypic and genotypic diversity in a multinational sample of drug-resistant Mycobacterium tuberculosis isolates.

Garfein RS, Catanzaro DG, Rodwell TC, Avalos E, Jackson RL, Kaping J, Evasco H, Rodrigues C, Crudu V, Lin SY, Groessel E, Hillery N, Trollip A, Ganiats T, Victor TC, Eisenach K, Valafar F, Channick J, Qian L, Catanzaro A.

Int J Tuberc Lung Dis. 2015 Apr;19(4):420-7. doi: 10.5588/ijtld.14.0488.

Abstract
OBJECTIVE:
To develop and evaluate rapid, molecular-based drug susceptibility testing (DST) for extensively drug-resistant tuberculosis (XDR-TB), we assembled a phenotypically and genotypically diverse collection of Mycobacterium tuberculosis isolates from patients evaluated for drug resistance in four high-burden countries.

METHODS:
M. tuberculosis isolates from India (n = 111), Moldova (n = 90), the Philippines (n = 96), and South Africa (n = 103) were selected from existing regional and national repositories to maximize phenotypic diversity for resistance to isoniazid, rifampin (RMP), moxifloxacin, ofloxacin, amikacin, kanamycin, and capreomycin. MGIT™ 960 was performed on viable isolates in one laboratory using standardized procedures and drug concentrations. Genetic diversity within drug resistance phenotypes was assessed.

RESULTS:
Nineteen distinct phenotypes were observed among 400 isolates with complete DST results. Diversity was greatest in the Philippines (14 phenotypes), and least in South Africa (9 phenotypes). Nearly all phenotypes included multiple genotypes. All sites provided isolates resistant to injectables but susceptible to fluoroquinolones. Many patients were taking drugs to which their disease was resistant.

DISCUSSION:
Diverse phenotypes for XDR-TB-defining drugs, including resistance to fluoroquinolones and/or injectable drugs in RMP-susceptible isolates, indicate that RMP susceptibility does not ensure effectiveness of a standard four-drug regimen. Rapid, low-cost DST assays for first- and second-line drugs are thus needed.

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Highly successful treatment outcome of multidrug-resistant tuberculosis in the Netherlands, 2000-2009.

van Altena R, de Vries G, Haar CH, de Lange WC, Magis-Escurra C, van den Hof S, van Soolingen D, Boeree MJ, van der Werf TS.

Int J Tuberc Lung Dis. 2015 Apr;19(4):406-12. doi: 10.5588/ijtld.14.0838.

Abstract
SETTING:
Resistance to the two key anti-tuberculosis drugs isoniazid and rifampicin is a characteristic of multidrug-resistant tuberculosis (MDR-TB). MDR-TB is a scourge requiring toxic, prolonged treatment and is associated with poor outcomes. The Netherlands is a country with a long-standing, integrated, well-resourced TB service where all patients are offered culture-confirmed diagnosis by a central reference laboratory.

OBJECTIVE:
To assess the treatment outcomes of MDR-TB patients over a period of 10 years in The Netherlands.

DESIGN:
Demographic, clinical and microbiological features of all patients with MDR-TB who started treatment in 2000-2009 in the Netherlands were analysed from national registry and patient records.

RESULTS:
Characteristics of the 113 MDR-TB patients were as follows: male/female ratio 1.57, 96% foreign born, median age 29 years, 96 (85%) pulmonary TB, 56 (50%) smear-positive, 14 (12%) human immunodeficiency virus (HIV) co-infected. Of the 104 (92%) patients who started MDR-TB treatment, 86% had a successful outcome using a median of six active drugs; eight underwent pulmonary surgery. HIV negativity was associated with successful outcome (adjusted OR 2.1, 95%CI 1.1-3.8).

CONCLUSION:
High success rates for MDR-TB treatment were achieved with close collaboration of all stakeholders, reaching the targets set for drug-susceptible TB. HIV remained an independent risk factor for unsuccessful treatment outcome.

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Low rates of recurrence after successful treatment of multidrug-resistant tuberculosis in Tomsk, Russia.

Gelmanova IY, Ahmad Khan F, Becerra MC, Zemlyanaya NA, Unakova IA, Andreev YG, Berezina VI, Pavlova VE, Shin S, Yedilbayev AB, Krasnov VA, Keshavjee S.

Int J Tuberc Lung Dis. 2015 Apr;19(4):399-405. doi: 10.5588/ijtld.14.0415.Abstract
SETTING:
Tomsk, Russia, where multidrug-resistant tuberculosis (MDR-TB) is prevalent.

OBJECTIVES:
To report rates of recurrence following successful treatment of MDR-TB in a program providing individualized treatment regimens designed according to the current global standard of care.

DESIGN:
A retrospective cohort study of 408 adults successfully treated for pulmonary MDR-TB from 10 September 2000 to 1 November 2004, and followed for up to 6 years post-treatment. We used Poisson regression with generalized estimating equations to assess whether recurrence rates changed significantly with time.

RESULTS:
We analyzed 399 (97.5%) patients with at least one follow-up visit (15 850 person-months of observation [PMO]). Baseline resistance to second-line drugs was common (65.2%); 398 patients (99.7%) were human immunodeficiency virus (HIV) negative. In the first year of post-treatment follow-up, there were six episodes of recurrence (1.4/1000 PMO, 95%CI 0.5-3.0). After the first post-treatment year, there were 21 episodes of recurrence (1.8/1000 PMO, 95%CI 1.1-2.8). The rate did not change significantly with time.

CONCLUSION:
Individualized regimens designed according to the current global standard of care achieved low rates of MDR-TBrecurrence among non-HIV-infected persons treated in a programmatic setting.

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QTc prolongation and treatment of multidrug-resistant tuberculosis.

Harausz E, Cox H, Rich M, Mitnick CD, Zimetbaum P, Furin J.

Int J Tuberc Lung Dis. 2015 Apr;19(4):385-91. doi: 10.5588/ijtld.14.0335.

Abstract
Electrocardiographic (ECG) monitoring is recommended for some of the new and re-purposed drugs used in the treatment of multidrug-resistant tuberculosis (MDR-TB), as these drugs have been shown to prolong the QTc interval. ECG monitoring is relatively new in the management of TB patients, and has several implications for programs and providers. This review discusses what is known about QTc prolongation and the medications currently being studied or used to treat MDR-TB, and discusses strategies for managing QTc prolongation in the context of treating such a serious infectious disease. It also reviews some major implications of ECG monitoring in the field, including interpretation of ECGs and QTc intervals, management of patients with prolonged QTc intervals, and contextualizing the risk of QTc prolongation for patients being treated for MDR-TB.

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Drug Resistance in Mycobacterium tuberculosis: Molecular Mechanisms Challenging Fluoroquinolones and Pyrazinamide Effectiveness.

Miotto P, Cirillo DM, Migliori GB.

Chest. 2015 Apr 1;147(4):1135-43. doi: 10.1378/chest.14-1286.

Abstract
Physicians are more and more often challenged by difficult-to-treat cases of TB. They include patients infected by strains of Mycobacterium tuberculosis that are resistant to at least isoniazid and rifampicin (multidrug-resistant TB) or to at least one fluoroquinolone (FQ) and one injectable, second-line anti-TB drug in addition to isoniazid and rifampicin (extensively drug-resistant TB). The drug treatment of these cases is very long, toxic, and expensive, and, unfortunately, the proportion of unsatisfactory outcomes is still considerably high. Although FQs and pyrazinamide (PZA) are backbone drugs in the available anti-TB regimens, several uncertainties remain about their mechanisms of action and even more remain about the mechanisms leading to drug resistance. From a clinical point of view, a better understanding of the genetic basis of drug resistance will aid (1) clinicians to provide quality clinical management to both drug-susceptible and drug-resistant TB cases (while preventing emergence of further resistance), and (2) developers of new molecular-based diagnostic assays to better direct their research efforts toward a new generation of sensitive, specific, cheap, and easy-to-use point-of-care diagnostics. In this review we provide an update on the molecular mechanisms leading to FQ- and PZA-resistance in M tuberculosis.

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Linezolid for multidrug-resistant tuberculosis in HIV-infected and -uninfected patients.

Hughes J, Isaakidis P, Andries A, Mansoor H, Cox V, Meintjes G, Cox H. Eur Respir J. 2015 Apr 2. pii: ERJ-01881-2014. [Epub ahead of print]

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