July 2018 Newsletter

1. Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study.
Lancet Respir Med. 2018 Jul 9. pii: S2213-2600(18)30235-2. doi: 10.1016/S2213 2600(18)30235-2. [Epub ahead of print]
Schnippel K(1), Ndjeka N(2), Maartens G(3), Meintjes G(4), Master I(5), Ismail N(6), Hughes J(7), Ferreira H(8), Padanilam X(9), Romero R(10), Te Riele J(11), Conradie F(12).

BACKGROUND: Addition of bedaquiline to treatment for multidrug-resistant tuberculosis was associated with an increased risk of death in a phase 2b clinical trial, resulting in caution from WHO. Following a compassionate access programme and local regulatory approval, the South African National Tuberculosis  Programme began widespread use of bedaquiline in March, 2015, especially among patients with extensively drug resistant tuberculosis for whom no other effective treatment options were available. We aimed to compare mortality in patients on standard regimens with that of patients on regimens including bedaquiline.
METHODS: In this retrospective cohort study, we analysed patient data from the South African rifampicin-resistant tuberculosis case register (EDRweb), and identified additional mortality using the national vital statistics register. We  excluded patients who started treatment before July 1, 2014, or after March 31, 2016; patients younger than 15 years or older than 75 years; patients without documented rifampicin resistance, and patients with pre-extensively
drug-resistant tuberculosis (multidrug-resistant tuberculosis with further resistance to a second-line injectable or fluoroquinolone). We compared all-cause mortality between patients who received bedaquiline in treatment regimens and those who did not. Patients who did not receive bedaquiline had kanamycin or capreomycin and moxifloxacin as core medicines in their regimen. We estimated hazard ratios for mortality separately for multidrug-resistant or
rifampicin-resistant tuberculosis and extensively drug-resistant tuberculosis and adjusted using propensity score quintile strata for the potential confounders of  sex, age, HIV and antiretroviral therapy status, history of prior tuberculosis, valid identification number, and year and province of treatment.
FINDINGS: 24,014 tuberculosis cases were registered in the EDRweb between July 1, 2014, and March 31, 2016. Of these, 19 617 patients initiated treatment and met our analysis eligibility criteria. A bedaquiline-containing regimen was given to  743 (4·0%) of 18 542 patients with multidrug-resistant or rifampicin-resistant tuberculosis and 273 (25·4%) of 1075 patients with extensively drug-resistant tuberculosis. Among 1016 patients who received bedaquiline, 128 deaths (12·6%) were reported, and there were 4612 deaths (24·8%) among 18 601 patients on the standard regimens. Bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with multidrug-resistant or rifampicin-resistant tuberculosis (hazard ratio [HR] 0·35, 95% CI 0·28-0·46) and extensively drug-resistant tuberculosis (0·26, 0·18-0·38) compared with standard regimens.
INTERPRETATION: Our retrospective cohort analysis of routinely reported data in the context of high HIV and extensively drug-resistant tuberculosis prevalence showed that bedaquiline-based treatment regimens were associated with a large reduction in mortality in patients with drug-resistant tuberculosis, compared with the standard regimen.

Read abstract here.

2. Treatment and outcomes in children with multidrug-resistant tuberculosis: A systematic review and individual patient data meta-analysis.
PLoS Med. 2018 Jul 11;15(7):e1002591. doi: 10.1371/journal.pmed.1002591.eCollection 2018 Jul.
Harausz EP(1)(2), Garcia-Prats AJ(1), Law S(3), Schaaf HS(1), Kredo T(4), Seddon  JA(5), Menzies D(3), Turkova A(6), Achar J(7), Amanullah F(8), Barry P(9), Becerra M(10), Chan ED(11), Chan PC(12), Ioana Chiotan D(13), Crossa A(14), Drobac PC(10), Fairlie L(15), Falzon D(16), Flood J(9), Gegia M(17), Hicks RM(18), Isaakidis P(19), Kadri SM(20), Kampmann B(21)(22), Madhi SA(23), Marais E(24), Mariandyshev A(25), Méndez-Echevarría A(26), Moore BK(27), Nargiza P(28), Ozere I(29), Padayatchi N(30), Ur-Rehman S(31), Rybak N(32), Santiago-Garcia B(33), Shah NS(18), Sharma S(34), Shim TS(35), Skrahina A(36), Soriano-Arandes A(37), van den Boom M(38), van der Werf MJ(39), van der Werf TS(40), Williams B(41), Yablokova E(25), Yim JJ(42), Furin J(43), Hesseling AC(1); Collaborative Group for Meta-Analysis of Paediatric Individual Patient Data in MDR-TB.

BACKGROUND: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children.
METHODS AND FINDINGS: To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data  were from published or unpublished observational cohorts. We analyzed demographic, clinical, and treatment factors as predictors of treatment outcome.In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were infected with HIV. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p < 0.001 for all characteristics). Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of therapy: 548/731 (75%) of confirmed and 216/244 (89%) of clinically diagnosed children (absolute difference 14%, 95% confidence interval [CI] 8%-19%, p < 0.001). Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in children infected with HIV who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5%-48%, p = 0.006). In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15-20 mg/kg/day) were associated with treatment success (adjusted odds ratio [aOR] 2.9, 95% CI 1.0-8.3, p = 0.041 and aOR 5.9, 95% CI 1.7-20.5, p = 0.007, respectively). These findings for high-dose isoniazid may have been affected by site effect, as the majority of patients came from Cape Town. Limitations of this study include the difficulty of estimating the treatment effects of individual drugs within multidrug regimens, only observational cohort studies were available for inclusion, and treatment decisions were based on the clinician’s perception of illness, with resulting potential for bias.
CONCLUSIONS: This study suggests that children respond favorably to MDR-TB treatment. The low success rate in children infected with HIV who did not receive ART during their MDR-TB treatment highlights the need for ART in these children.  Our findings of individual drug effects on treatment outcome should be further evaluated.

Read full study here. 

3. Relative bioavailability of bedaquiline tablets suspended in water: implications for dosing in children.
Br J Clin Pharmacol. 2018 Jun 27. doi: 10.1111/bcp.13696. [Epub ahead of print]
Svensson EM(1)(2), du Bois J(3), Kitshoff R(3), de Jager VR(3), Wiesner L(4), Norman J(4), Nachman S(5), Smith B(6), Diacon A(3), Hesseling AC(7), Garcia-Prats AJ(7).

OBJECTIVES: Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared  to whole tablets.
METHODS: A randomized, open-label, two-period cross-over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48 hours was conducted at two occasions 14 days apart in each participant after administration of 400 mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed-effects modelling. A questionnaire was used to assess palatability and acceptability.
RESULTS: There was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94-108% of that of whole bedaquiline tablets; hence the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell.
CONCLUSIONS: The bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat MDR-TB in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.

Read full study here.

4. Increased Doses Lead to Higher Drug Exposures of Levofloxacin for the Treatment of Tuberculosis.
Antimicrob Agents Chemother. 2018 Jul 16. pii: AAC.00770-18. doi: 10.1128/AAC.00770-18. [Epub ahead of print]
Peloquin CA(1), Phillips PPJ(2)(3), Mitnick CD(4), Eisenach K(5), Patientia RF(6), Lecca L(7), Gotuzzo E(8), Gandhi NR(9), Butler D(10), Diacon AH(6), Martel B(7), Santillan J(8), Hunt KR(10), Vargas D(7), von Groote-Bidlingmaier F(6), Seas C(8), Dianis N(10), Moreno-Martinez A(11)(12), Kaur P(13), Horsburgh CR Jr(13)(14).

Patients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to weight-banded nominal doses of 11, 14, 17 or 20 mg/kg/day levofloxacin (minimum 750 mg) in combination with other second-line agents. 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median AUC0-24 were 109.49, 97.86, 145.33 and 207.04 h*mcg/ml. Median Cmax were 11.90, 12.02, 14.86, and 19.17 mcg/ml. Higher levofloxacin doses, up to 1500 mg daily, resulted in higher exposures. ClinicalTrials.gov Identifier: NCT01918397.

Read manuscript here.

5. Can patients afford the cost of treatment for multidrug-resistant tuberculosis in Ethiopia?
Int J Tuberc Lung Dis. 2018 Aug 1;22(8):905-911. doi: 10.5588/ijtld.17.0837.
Collins D(1), Beyene D(2), Tedla Y(3), Mesfin H(4), Diro E(5).

SETTING: Ethiopia has a high prevalence of tuberculosis (TB) and is one of the countries with the highest burden of multidrug-resistant TB (MDR-TB).
OBJECTIVE: To understand the costs that patients incur in obtaining diagnosis and treatment  for MDR-TB.
DESIGN: In March 2013, interviews were conducted with 169 MDR-TB patients at three hospitals in Ethiopia to identify the cost to patients and the impact on employment and family income.
RESULTS: The average MDR-TB patient incurred a total cost of US$1378, which represented 25 months of a mid-treatment household income of US$54. The impact on the patient’s employment and on overall patient and family income was generally catastrophic: 74% of all respondents reported losing their jobs, 66% of patients lost household income, and household income was reduced by 38%. To help cover the costs, 38% of patients sold some type of property, while 7% leased out property and 41% took out loans, any of which could jeopardize their future financial situation even further.
CONCLUSION: Despite services being officially free of charge, most patients incurred catastrophic costs and suffered significant income loss as a result of obtaining diagnosis and treatment for MDR-TB.

Read abstract here.

June 2018 Newsletter

1. Mortality and associated factors of patients with extensive drug-resistant tuberculosis: an emerging public health crisis in China.
BMC Infect Dis. 2018 Jun 7;18(1):261. doi: 10.1186/s12879-018-3169-7.
Bei C(1), Fu M(2), Zhang Y(3), Xie H(2), Yin K(2), Liu Y(2), Zhang L(4), Xie B(4), Li F(5), Huang H(6), Liu Y(7), Yang L(2), Zhou J(2).

BACKGROUND: Limited treatment options of extensive drug-resistant tuberculosis (XDR-TB) have led to its high mortality worldwide. Relevant data about mortality  of XDR-TB patients in literature are limited and likely underestimate the real situation in China, since the majority of patients with XDR-TB are lost to follow-up after discharge from TB hospitals. In this study, we sought to investigate the mortality and associated risk factors of Human Immunodeficiency Virus (HIV)-negative patients with XDR-TB in China.
METHODS: All patients who were diagnosed with XDR-TB for the first time in four TB care centers across China between March 2013 and February 2015 were consecutively enrolled. Active tracking through contacting patients or family members by phone or home visit was conducted to obtain patients’ survival information by February 2017. Multivariable Cox regression models were used to evaluate factors associated with mortality.
RESULTS: Among 67 patients enrolled, the mean age was 48.7 (Standard Deviation [SD] = 16.7) years, and 51 (76%) were men. Fourteen patients (21%) were treatment naïve at diagnosis indicating primary transmission. 58 (86.8%) patients remained positive for sputum smear or culture when discharged. During a median follow-up period of 32 months, 20 deaths occurred, with an overall mortality of 128 per 1000 person-years. Among patients who were dead, the median survival was 5.4 months (interquartile range [IQR]: 2.2-17.8). Seventeen (85%) of them died at home, among whom the median interval from discharge to death was 8.4 months (IQR:
2.0-18.2). In Cox proportional hazards regression models, body mass index (BMI) < 18.5 kg/m2 (adjusted hazard ratio [aHR] = 4.5, 95% confidence interval [CI]: 1.3-15.7), smoking (aHR = 4.7, 95%CI:1.7-13.2), or a clinically significant comorbidity including heart, lung, liver, or renal disorders or auto-immune diseases (aHR = 3.5, 95%CI: 1.3-9.4), were factors independently associated with increased mortality.
CONCLUSION: Our study suggested an alarming situation of XDR-TB patients in China with a sizable proportion of newly transmitted cases, a high mortality rate, and a long period in community. This observation calls for urgent actions to improve XDR-TB case management in China, including providing regimens with high chances of cure and palliative care, and enhanced infection control measures.

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2. Drug Penetration Gradients Associated with Acquired Drug Resistance in Tuberculosis Patients.
Am J Respir Crit Care Med. 2018 Jun 7. doi: 10.1164/rccm.201711-2333OC. [Epub ahead of print]
Dheda K(1), Lenders L(1), Magombedze G(2), Srivastava S(2), Raj P(3), Arning E(2), Ashcraft P(4), Bottiglieri T(5), Wainwright H(1), Pennel T(1), Linegar A(1), Moodley L(1), Pooran A(6), Pasipanodya JG(7), Sirgel FA(8), van Helden PD(9), Wakeland E(3), Warren RM(10), Gumbo T(11).

RATIONALE: Acquired resistance is an important driver of multidrug-resistant tuberculosis, even with good treatment adherence. However, exactly what initiates the resistance, and how it arises remains poorly understood.
OBJECTIVES: To identify the relationship between drug concentrations and drug susceptibility readouts (MICs) in the tuberculosis cavity.
METHODS: We recruited patients with medically incurable tuberculosis who were undergoing therapeutic lung resection whilst on treatment with the cocktail of second line anti-tuberculosis drugs. On the day of surgery antibiotic concentrations were measured in the blood and at seven pre-specified biopsy sites within each cavity. Mycobacterium tuberculosis was grown from each biopsy site, MICs of each drug identified, and whole genome sequencing performed. Spearman correlation coefficients between drug concentration and MIC were calculated.
RESULTS: Fourteen patients treated for a median of 13 (range: 5-31) months were recruited. MICs and drug resistance-associated single nucleotide variants differed between the different geospatial locations within each cavity, and with  pretreatment and serial sputum isolates, consistent with ongoing acquisition of resistance. However, pre-treatment sputum MIC had an accuracy of only 49.48% in predicting cavitary MICs. There were large concentration-distance gradients for each antibiotic. The location-specific concentrations inversely correlated with
MICs (p<0.05), and therefore acquired resistance. Moreover, pharmacokinetic/ pharmacodynamic exposures known to amplify drug-resistant subpopulations were encountered in all positions.
CONCLUSIONS: These data inform interventional strategies relevant to drug delivery, dosing, and diagnostics to prevent the development of acquired resistance. The role of high intracavitary penetration as a biomarker of antibiotic efficacy, when assessing new regimens, requires clarification.

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3. Clinical and cardiac safety of long-term levofloxacin in children treated for multidrug-resistant tuberculosis.
Clin Infect Dis. 2018 May 16. doi: 10.1093/cid/ciy416. [Epub ahead of print]
Garcia-Prats AJ(1), Draper HR(1), Finlayson H(2), Winckler J(1), Burger A(3), Fourie B(2), Thee S(4), Hesseling AC(1), Schaaf HS(1).

Safety concerns persist for long-term pediatric fluoroquinolone use. Seventy children (median age 2.1 years) treated with levofloxacin 10-20 mg/kg once daily  for multidrug-resistant tuberculosis (median observation time 11.8 months) had few musculoskeletal events, no levofloxacin-attributed serious adverse events, and no QTcF >450 ms. Long-term levofloxacin was safe and well tolerated.

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4. Drug Penetration Gradients Associated with Acquired Drug Resistance in Tuberculosis Patients.
Am J Respir Crit Care Med. 2018 Jun 7. doi: 10.1164/rccm.201711-2333OC. [Epub ahead of print]
Dheda K(1), Lenders L(1), Magombedze G(2), Srivastava S(2), Raj P(3), Arning E(2), Ashcraft P(4), Bottiglieri T(5), Wainwright H(1), Pennel T(1), Linegar A(1), Moodley L(1), Pooran A(6), Pasipanodya JG(7), Sirgel FA(8), van Helden PD(9), Wakeland E(3), Warren RM(10), Gumbo T(11).

RATIONALE: Acquired resistance is an important driver of multidrug-resistant tuberculosis, even with good treatment adherence. However, exactly what initiates the resistance, and how it arises remains poorly understood.
OBJECTIVES: To identify the relationship between drug concentrations and drug susceptibility readouts (MICs) in the tuberculosis cavity.
METHODS: We recruited patients with medically incurable tuberculosis who were undergoing therapeutic lung resection whilst on treatment with the cocktail of second line anti-tuberculosis drugs. On the day of surgery antibiotic concentrations were measured in the blood and at seven pre-specified biopsy sites within each cavity. Mycobacterium tuberculosis was grown from each biopsy site, MICs of each drug identified, and whole genome sequencing performed. Spearman correlation coefficients between drug concentration and MIC were calculated.
RESULTS: Fourteen patients treated for a median of 13 (range: 5-31) months were recruited. MICs and drug resistance-associated single nucleotide variants differed between the different geospatial locations within each cavity, and with pretreatment and serial sputum isolates, consistent with ongoing acquisition of resistance. However, pre-treatment sputum MIC had an accuracy of only 49.48% in predicting cavitary MICs. There were large concentration-distance gradients for each antibiotic. The location-specific concentrations inversely correlated with
MICs (p<0.05), and therefore acquired resistance. Moreover, pharmacokinetic/pharmacodynamic exposures known to amplify drug-resistant subpopulations were encountered in all positions.
CONCLUSIONS: These data inform interventional strategies relevant to drug delivery, dosing, and diagnostics to prevent the development of acquired resistance. The role of high intracavitary penetration as a biomarker of antibiotic efficacy, when assessing new regimens, requires clarification.

Read full text here. 

5. Comparison of the validity of smear and culture conversion as a prognostic marker of treatment outcome in patients with multidrug-resistant tuberculosis.
PLoS One. 2018 May 23;13(5):e0197880. doi: 10.1371/journal.pone.0197880. eCollection 2018.
Alene KA(1)(2), Viney K(1)(3), Yi H(4), McBryde ES(5), Yang K(4), Bai L(6), Gray DJ(1), Xu Z(7), Clements ACA(1).

BACKGROUND: The World Health Organization (WHO) has conditionally recommended the use of sputum smear microscopy and culture examination for the monitoring of multidrug-resistant tuberculosis (MDR-TB) treatment. We aimed to assess and compare the validity of smear and culture conversion at different time points during treatment for MDR-TB, as a prognostic marker for end-of-treatment outcomes.
METHODS: We undertook a retrospective observational cohort study using data obtained from Hunan Chest Hospital, China and Gondar University Hospital, Ethiopia. The sensitivity and specificity of culture and sputum smear conversion for predicting treatment outcomes were analysed using a random-effects generalized linear mixed model.
RESULTS: A total of 429 bacteriologically confirmed MDR-TB patients with a culture and smear positive result were included. Overall, 345 (80%) patients had a successful treatment outcome, and 84 (20%) patients had poor treatment outcomes. The sensitivity of smear and culture conversion to predict a successful treatment outcome were: 77.9% and 68.9% at 2 months after starting treatment (difference between tests, p = 0.007); 95.9% and 92.7% at 4 months (p = 0.06); 97.4% and 96.2% at 6 months (p = 0.386); and 99.4% and 98.9% at 12 months (p = 0.412), respectively. The specificity of smear and culture non-conversion to predict a poor treatment outcome were: 41.6% and 60.7% at 2 months (p = 0.012); 23.8% and 48.8% at 4 months (p<0.001); and 20.2% and 42.8% at 6 months (p<0.001); and 15.4% and 32.1% (p<0.001) at 12 months, respectively. The sensitivity of culture and smear conversion increased as the month of conversion increased but at the cost of decreased specificity. The optimum time points after conversion to provide the best prognostic marker of a successful treatment outcome were between two and four months after treatment commencement for smear, and between four and six months for culture. The common optimum time point for smear and culture conversion was four months. At this time point, culture conversion (AUROC curve = 0.71) was significantly better than smear conversion (AUROC curve = 0.6) in predicting successful treatment outcomes (p < 0.001). However, the validity of smear conversion (AUROC curve = 0.7) was equivalent to culture conversion (AUROC curve = 0.71) in predicting treatment outcomes when demographic and clinical factors were included in the model. The positive and negative predictive values
for smear conversion were: 57.3% and 65.7% at two months, 55.7% and 85.4% at four months, and 55.0% and 88.6% at six months; and for culture conversions it was: 63.7% and 66.2% at two months, 64.4% and 87.1% at four months, and 62.7% and 91.9% at six months, respectively.
CONCLUSIONS: The validity of smear conversion is significantly lower than culture conversion in predicting MDR-TB treatment outcomes. We support the WHO recommendation of using both smear and culture examination rather than smear alone for the monitoring of MDR-TB patients for a better prediction of successful treatment outcomes. The optimum time points to predict a future successful treatment outcome were between two and four months after treatment commencement for sputum smear conversion and between four and six months for culture conversion. The common optimum times for culture and smear conversion together was four months.

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May 2018 Newsletter

1. Linezolid-Containing Treatment Regimens for Tuberculosis in Children.
Pediatr Infect Dis J. 2018 May 10. doi: 10.1097/INF.0000000000002093. [Epub ahead of print]
Prieto LM, Santiago B(1), Del Rosal T(2), Carazo B(3), Jiménez AB(4), Pérez-Gorricho B(5), Rubio F(6), Tagarro A(7), Blázquez D(8), Moreno-Pérez D(3), Mellado MJ(2), Baquero-Artigao F(2); Spanish Paediatric TB Research Network (pTBred).

BACKGROUND: In recent years there is an increasing interest in the use of linezolid for the treatment of tuberculosis (TB).
METHODS: Patients under 18 years of age who received linezolid within the Spanish Pediatric TB Network (pTBred) from 2001 to 2016 were retrospectively included. Treatment characteristics, adverse events (AEs) and outcomes were analyzed.
RESULTS: Fifteen children were included (53% male) with a median age of 3.6 years (IQR: 1.6-6.2). Median follow up was 54 months (IQR: 38-76). The reasons for linezolid use were drug-resistant TB (DR-TB) in eight (53%) patients, drug-induced liver injury (DILI) in five (33%) patients and chronic liver disease (CLD) in two (13%) patients. Four children (26%) were on immunosuppressive therapy when TB was diagnosed. Five children (33%) were diagnosed with extrapulmonary TB. The median duration of linezolid treatment was 13 months (IQR: 7.5-17). Nine patients had 13 linezolid-related AEs. Hematologic toxicity was observed in eight patients (53%) and gastrointestinal intolerance in 3 patients (20%). In two patients linezolid dose was reduced and in two patients linezolid was discontinued because of AEs. A 2- year-old girl went back to her country of birth and was lost to follow-up. No relapses were observed among the other 14 patients (93%).
CONCLUSIONS: Linezolid may be considered when treating children with drug resistant TB but also in the cases of patients with chronic liver disease or drug induced liver injury. However, AEs should be closely monitored. Further studies are needed to determine the optimum dosage and the optimal duration of linezolid treatment in children.

Read abstract here.

2. Long Term Bedaquiline-Related Treatment Outcomes in Patients with Extensively Drug Resistant Tuberculosis from South Africa.
Eur Respir J. 2018 May 3. pii: 1800544. doi: 10.1183/13993003.00544-2018. [Epub ahead of print]
Olayanju O(1), Limberis J(1), Esmail A(1), Oelofse S(1), Gina P(1), Pietersen E(1), Fadul M(1), Warren R(2), Dheda K(1).

EXTRACT: The persistence of the multi-drug-resistant tuberculosis (MDR-TB) epidemic threatens to destabilise TB control [1, 2]. MDR-TB is defined as a TB strain with resistance to at least isoniazid and rifampicin. In 2016 ∼600 000 new cases of MDR- or rifampicin-resistant TB were estimated to have occurred globally. Detection rates have more than doubled in several countries such as China, India and Russia in the last several years, and almost 20% of Mycobacterium tuberculosisisolates globally are now resistant to at least one first or second line anti-TB drug [3]. Approximately 10% of global MDR-TB strains are thought to be extensively drug-resistant TB (XDR-TB), which is MDR-TB with additional resistance to a fluoroquinolone and a second line injectable drug.

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3. Prevalence of drug-resistant tuberculosis and imputed burden in South Africa: a
national and sub-national cross-sectional survey.
Lancet Infect Dis. 2018 Apr 20. pii: S1473-3099(18)30222-6. doi:
10.1016/S1473-3099(18)30222-6. [Epub ahead of print]
Ismail NA(1), Mvusi L(2), Nanoo A(3), Dreyer A(3), Omar SV(3), Babatunde S(4), Molebatsi T(2), van der Walt M(5), Adelekan A(6), Deyde V(6), Ihekweazu C(3), Madhi SA(7).

BACKGROUND: Globally, per-capita, South Africa reports a disproportionately high number of cases of multidrug-resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis. We sought to estimate the prevalence of resistance to tuberculosis drugs in newly diagnosed and retreated patients with tuberculosis provincially and nationally, and compared these with the 2001-02 estimates.
METHODS: A cross-sectional survey was done between June 15, 2012-June 14, 2014, using population proportionate randomised cluster sampling in the nine provinces in South Africa. 343 clusters were included, ranging between 31 and 48 per province. A patient was eligible for inclusion in the survey if he or she presented as a presumptive case during the intake period at a drug resistance survey enrolling facility. Consenting participants (≥18 years old) completed a questionnaire and had a sputum sample tested for resistance to first-line and second-line drugs. Analysis was by logistic regression with robust SEs, inverse probability weighted against routine data, and estimates were derived using a random effects model.
FINDINGS: 101 422 participants were tested in 2012-14. Nationally, the prevalence of MDR tuberculosis was 2·1% (95% CI 1·5-2·7) among new tuberculosis cases and 4·6% (3·2-6·0) among retreatment cases. The provincial point prevalence of MDR tuberculosis ranged between 1·6% (95% CI 0·9-2·9) and 5·1% (3·7-7·0). Overall, the prevalence of rifampicin-resistant tuberculosis (4·6%, 95% CI 3·5-5·7) was higher than the prevalence of MDR tuberculosis (2·8%, 2·0-3·6; p=0·01). Comparing the current survey with the previous (2001-02) survey, the overall MDR tuberculosis prevalence was 2·8% versus 2·9% and prevalance of rifampicin-resistant tuberculosis was 3·4% versus 1·8%, respectively. The prevalence of isoniazid mono-resistant tuberculosis was above 5% in all provinces. The prevalence of ethionamide and pyrazinamide resistance among MDR tuberculosis cases was 44·7% (95% CI 25·9-63·6) and 59·1% (49·0-69·1), respectively. The prevalence of XDR tuberculosis was 4·9% (95% CI 1·0-8·8). Nationally, the estimated numbers of cases of rifampicin-resistant tuberculosis, MDR tuberculosis, and isoniazid mono-resistant tuberculosis for 2014 were 13 551, 8249, and 17 970, respectively.
INTERPRETATION: The overall prevalence of MDR tuberculosis in South Africa in 2012-14 was similar to that in 2001-02; however, prevalence of rifampicin-resistant tuberculosis almost doubled among new cases. Furthermore, the high prevalence of isoniazid mono-resistant tuberculosis, not routinely screened for, and resistance to second-line drugs has implications for empirical management.
FUNDING: President’s Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention under the terms of 1U19GH000571.

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4. Pan-tuberculosis regimens: an argument for.
Lancet Respir Med. 2018 Apr;6(4):239-240. doi: 10.1016/S2213-2600(18)30096-1.
Wallis RS(1), Cohen T(2), Menzies NA(3), Churchyard G(4).

ABSTRACT: 600,000 cases of drug-resistant tuberculosis, causing 240 000 deaths, were estimated by WHO to have occurred worldwide in 2016.1 Cases are expected to increase over the next two decades, driven by the low likelihood that patients will initiate appropriate treatment and, in those who do, the low probability that treatment will succeed.2 Experience in Africa has highlighted the scope and complexity of this problem. In South Africa, where the Xpert MTB/RIF test has fully replaced sputum acid-fast bacilli smear for tuberculosis diagnosis, 59% of rifampicin-resistant patients have additional resistance to second-line drugs (eg, kanamycin, ethionamide, and ofloxacin).

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5. Pan-tuberculosis regimens: an argument against.
Lancet Respir Med. 2018 Apr;6(4):240-242. doi: 10.1016/S2213-2600(18)30097-3.
Dheda K(1), Gumbo T(2), Lange C(3), Horsburgh CR Jr(4), Furin J(5).

ABSTRACT: In 1986, after publication of a seminal paper about the use of short-course regimens for tuberculosis treatment, there was great optimism that a universal regimen for tuberculosis had been discovered.1Pierre Chaulet described the short-course regimens as “highly effective and reliable with the minimum of constraints either for patients or for health personnel.”2 Unfortunately, the emergence of rifampicin-resistant Mycobacterium tuberculosis strains soon rendered these short-course regimens ineffective for many individuals.

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1. MDR-TB patients in KwaZulu-Natal, South Africa: Cost-effectiveness of 5 models of care.

PLoS One. 2018 Apr 18;13(4):e0196003. doi: 10.1371/journal.pone.0196003. eCollection 2018.

Loveday M(1)(2), Wallengren K(3), Reddy T(4), Besada D(1), Brust JCM(5), Voce A(6), Desai H(7), Ngozo J(8), Radebe Z(8), Master I(9), Padayatchi N(2), Daviaud E(1).

BACKGROUND: South Africa has a high burden of MDR-TB, and to provide accessible treatment the government has introduced different models of care. We report the most cost-effective model after comparing cost per patient successfully treated across 5 models of care: centralized hospital, district hospitals (2), and community-based care through clinics or mobile injection teams.

METHODS: In an observational study five cohorts were followed prospectively. The cost analysis adopted a provider perspective and economic cost per patient successfully treated was calculated based on country protocols and length of treatment per patient per model of care. Logistic regression was used to calculate propensity score weights, to compare pairs of treatment groups, whilst adjusting for baseline imbalances between groups. Propensity score weighted costs and treatment success rates were used in the ICER analysis. Sensitivity analysis

focused on varying treatment success and length of hospitalization within each model.

RESULTS: In 1,038 MDR-TB patients 75% were HIV-infected and 56% were successfully treated. The cost per successfully treated patient was 3 to 4.5 times lower in the community-based models with no hospitalization. Overall, the Mobile model was the most cost-effective.

CONCLUSION: Reducing the length of hospitalization and following community-based models of care improves the affordability of MDR-TB treatment without compromising its effectiveness.

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2. Early experience with delamanid-containing regimens in the treatment of complicated multidrug-resistant tuberculosis in Hong Kong.

Eur Respir J. 2018 Apr 12. pii: 1800159. doi: 10.1183/13993003.00159-2018. [Epub  ahead of print]

Chang KC(1), Chung-Ching Leung E(2), Law WS(2), Leung WM(2), Tai LB(2), Lee SN(2), Lam FM(3), Chau CH(3), Yun-Wing Mok T(4), Yew WW(5), Leung CC(2).

EXTRACT: Hong Kong is a tuberculosis (TB) intermediate-burden region with a disease notification rate of 60.5 per 100 000 population in 2015. With the use of supervised treatment since 1970s, and the use of drug susceptibility testing (DST) for guiding use of TB drugs for several decades, TB drug resistance rates in Hong Kong have declined and the multidrug-resistant (MDR) TB rate has been kept at around 1%. Successful control of MDR-TB was partly attributable to judicious use of ofloxacin and later levofloxacin in the 1990s, the introduction of linezolid in 2000s among patients with fluoroquinolone (FQ)-resistant MDR-TB or extensively drug-resistant (XDR) TB, with intermittent dosing to enable its prolonged use, and selective use of delamanid among patients with complicated MDR-TB since 2012. To echo our support for using delamanid in the treatment of MDR-TB, we would like to report our early experience in Hong Kong regarding the use of delamanid-containing regimens among patients with pre-XDR-TB (MDR-TB with bacillary resistance to either FQ or second-line injectable agents) or XDR-TB.

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3. Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis.

Lancet Respir Med. 2018 Apr;6(4):265-275. doi: 10.1016/S2213-2600(18)30078-X.

Fregonese F(1), Ahuja SD(2), Akkerman OW(3), Arakaki-Sanchez D(4), Ayakaka I(5), Baghaei P(6), Bang D(7), Bastos M(8), Benedetti A(9), Bonnet M(10), Cattamanchi A(11), Cegielski P(12), Chien JY(13), Cox H(14), Dedicoat M(15), Erkens C(16), Escalante P(17), Falzon D(18), Garcia-Prats AJ(19), Gegia M(18), Gillespie SH(20), Glynn JR(21), Goldberg S(22), Griffith D(23), Jacobson KR(24), Johnston JC(25), Jones-López EC(24), Khan A(22), Koh WJ(26), Kritski A(27), Lan ZY(9), Lee JH(28), Li PZ(1), Maciel EL(29), Galliez RM(30), Merle CSC(31), Munang M(15), Narendran G(32), Nguyen VN(33), Nunn A(21), Ohkado A(34), Park JS(28), Phillips PPJ(35), Ponnuraja C(36), Reves R(37), Romanowski K(38), Seung K(39), Schaaf HS(19), Skrahina A(40), Soolingen DV(41), Tabarsi P(6), Trajman A(42), Trieu L(2), Banurekha VV(32), Viiklepp P(43), Wang JY(13), Yoshiyama T(44), Menzies D(45).

BACKGROUND: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ.

METHODS: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months  or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1-3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology.

FINDINGS: Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8-9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95%  CI 1·1-7·3), but no significant effect on mortality (aOR 0·7, 0·4-1·1) or acquired rifampicin resistance (aOR 0·1, 0·0-1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2-0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates.

INTERPRETATION: In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen  for this important and common form of drug-resistant tuberculosis.

FUNDING: World Health Organization and Canadian Institutes of Health Research.

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lobal programmatic use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis.

Int J Tuberc Lung Dis. 2018 Apr 1;22(4):407-412. doi: 10.5588/ijtld.17.0706.

Cox V(1), Brigden G(2), Crespo RH(3), Lessem E(4), Lynch S(5), Rich ML(6), Waning B(3), Furin J(7).

SETTING: The World Health Organization recommended two new drugs, bedaquiline (BDQ) and delamanid (DLM), for the treatment of multidrug-resistant tuberculosis  (MDR-TB) in 2013 and 2014, respectively. An estimated one third of patients with MDR-TB would benefit from the inclusion of these drugs in their treatment regimens.

DESIGN: A convenience sample of 36 countries voluntarily reported monthly data on cumulative programmatic use of new drugs to the Drug-Resistant TB Scale-Up Treatment Action Team between 1 July 2015 and 31 June 2017. Programmatic use was defined as treatment for MDR-TB with newer drugs outside of clinical trials or compassionate use.

RESULTS: A total of 10 164 persons were started on BDQ and 688 started on DLM during the reporting period. Only 15.7% of the 69 213 persons estimated to need newer drugs over the study period were reported to have received them.

CONCLUSION: While there has been significant progress in some countries, uptake of the newer drugs has not kept pace with a conservative estimate of need; fewer than 20% of persons likely to benefit from either BDQ or DLM have received them. Concerted efforts are needed to ensure that the newer drugs are made available more widely for persons with MDR-TB in need of these therapeutic options.

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5. Treatment responses in multidrug-resistant tuberculosis in Germany.

Int J Tuberc Lung Dis. 2018 Apr 1;22(4):399-406. doi: 10.5588/ijtld.17.0741.

Heyckendorf J(1), van Leth F(2), Avsar K(3), Glattki G(4), Günther G(5), Kalsdorf B(1), Müller M(6), Olaru ID(7), Rolling T(8), Salzer HJF(1), Schuhmann M(9), Terhalle E(1), Lange C(10).

BACKGROUND: Excellent treatment outcomes have recently been reported for patients with multi/extensively drug-resistant tuberculosis (M/XDR-TB) in settings where optimal resources for individualised therapy are available.

OBJECTIVE: To ascertain whether differences remain in treatment responses between patients with M/XDR-TB and those with non-M/XDR-TB.

METHOD: Patients with TB were prospectively enrolled between March 2013 and March 2016 at five hospitals in Germany. Treatment was conducted following current guidelines and individualised on the basis of drug susceptibility testing. Two-month and 6-month sputum smear and sputum culture conversion rates were assessed. A clinical and radiological score were used to assess response to anti-tuberculosis treatment.

RESULTS: Non-M/XDR-TB (n = 29) and M/XDR-TB (n = 46) patients showed similar rates of microbiological conversion: 2-month smear conversion rate, 90% vs. 78%;  culture conversion rate, 67% vs. 61%; time to smear conversion, 19 days (IQR 10-32) vs. 31 days (IQR 14-56) (P = 0.066); time to culture conversion, 39 days (IQR 17-67) vs. 39 days (IQR 6-85) (P = 0.191). Both clinical and radiological scores decreased after the introduction of anti-tuberculosis treatment.

CONCLUSION: There were no significant differences in scores between the two groups until 6 months of treatment. Under optimal clinical conditions, with the availability of novel diagnostics and a wide range of therapeutic options for individualised treatment, patients with M/XDR-TB achieved 6-month culture conversion rates that were compatible with those in patients with non-M/XDR-TB.

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1. Precision medicine for drug-resistant tuberculosis in high-burden countries: is individualised treatment desirable and feasible?

Lancet Infect Dis. 2018 Mar 13. pii: S1473-3099(18)30104-X. doi:10.1016/S1473-3099(18)30104-X. [Epub ahead of print]

Cox H(1), Hughes J(2), Black J(3), Nicol MP(4).

ABSTRACT: Treatment for drug-resistant tuberculosis is largely delivered through standardised, empirical combination regimens in low-resource, high-burden settings. However, individualised treatment, guided by detailed drug susceptibility testing, probably results in improved individual outcomes and is the standard of care in well-resourced settings. Driven by the urgent need to scale up treatment provision, new tuberculosis drugs, incorporated into standardised regimens, are being tested. Although standardised regimens are expected to improve access to treatment in high-burden settings, they are also likely to contribute to the emergence of resistance, even with good clinical management. We argue that a balance is required between the need to improve treatment access and the imperative to minimise resistance amplification and provide the highest standard of care, through a precision medicine approach. In tuberculosis, as in other diseases, we should aim to reduce the entrenched inequalities that manifest as different standards of care in different settings.

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2. Bedaquiline and Delamanid for the Treatment of Multidrug-resistant Tuberculosis: A Multi-center Cohort Study in Korea.

Eur Respir J. 2018 Mar 15. pii: 1702467. doi: 10.1183/13993003.02467-2017. [Epub ahead of print]

Tae Kim C(1), Kim TO(2), Shin HJ(2), Chun Ko Y(3), Hun Choe Y(4), Kim HR(5), Kwon YS(2).

ABSTRACT: Relatively little is known about the efficacy and safety of the programmatic use of bedaquiline and delamanid in multidrug-resistant tuberculosis (MDR-TB) treatment. This study evaluated 61 patients with MDR-TB treated with bedaquiline (n=39), delamanid (n=11), or both, either sequentially (n=10) or in co-administration (n=1), for more than 1 month, combined with a World Health Organization-recommended regimen. Of these, 49 (80.3%) were men and 12 (19.7%) were women. The median age was 53 years (interquartile range [IQR]=38.5-61.0 years). Forty-two (68.9%) patients had fluoroquinolone-resistant MDR-TB and 16 (26.2%) had extensively drug-resistant TB. The median duration of treatment with bedaquiline and/or delamanid was 168 days (IQR 166.5-196.5 days), with 33 (54.1%) receiving linezolid for median 673 days (IQR 171-736 days). Of the 55 patients with positive sputum cultures at the start of bedaquiline and/or delamanid treatment, 39 (70.9%) achieved sputum culture conversion within a median of 119 days. Treatment was halted in four patients (6.6%) because of prolonged corrected QT interval. In conclusion, bedaquiline and delamanid were effective and safe for treating MDR-TB, with initial evidence of sequential administration of these two drugs as a viable treatment strategy for patients when an adequate treatment regimen cannot be constructed.

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3. Clinical Management of Multidrug-resistant Tuberculosis in 16 European Countries.

Am J Respir Crit Care Med. 2018 Mar 6. doi: 10.1164/rccm.201710-2141OC. [Epub ahead of print]

Günther G(1), van Leth F(2), Alexandru S(3), Altet N(4), Avsar K(5), Bang D(6), Barbuta R(7), Bothamley G(8), Ciobanu A(3), Crudu V(3), Danilovits M(9), Dedicoat M(10), Duarte R(11), Gualano G(12), Kunst H(13), de Lange W(14), Leimane V(15), McLaughlin AM(16), Magis-Escurra C(17), Muylle I(18), Polcová V(19), Popa C(20),  Rumetshofer R(21), Skrahina A(22), Solodovnikova V(23), Spinu V(24), Tiberi S(25), Viiklepp P(26), Lange C(27); for TBNET.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is a major burden to public health in Europe. Reported treatment success rates are around 50% or less and cure rates are even lower.

METHODS: We performed a prospective cohort study, analyzing management and treatment outcomes stratified by incidence of patients with MDR-TB in Europe. Treatment outcomes were compared by WHO and alternative simplified definitions.

RESULTS: 380 patients with MDR-TB were recruited and followed-up between 2010 and 2014 in 16 European countries. Patients in high-incidence countries compared with low-incidence countries were treated more frequently with standardized regimen (83.2% vs. 9.9%), had delayed treatment initiation (median 111 vs. 28 days), developed more additional drug resistance (23% vs. 5.8%), and had increased mortality (9.4% vs. 1.9%). Only 20.1% of patients using pyrazinamide had proven susceptibility to the drug. Applying WHO outcome definitions, frequency of cure (38.7% vs. 9.7%) was higher in high-incidence countries. Simplified outcome definitions that include one year of follow-up after the end of treatment showed similar frequency of relapse-free cure in low- (58.3%), intermediate- (55.8%) and high- incidence (57.1%) countries, but highest frequency of failure in high-incidence countries (24.1% vs. 14.6).

CONCLUSIONS: Conventional standard MDR-TB treatment regimens resulted in a higher frequency of failure compared to individualized treatments. Overall, cure from MDR-TB is substantially more frequent than previously anticipated, and poorly reflected by WHO outcome definitions.

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4. Global programmatic use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis.

Int J Tuberc Lung Dis. 2018 Apr 1;22(4):407-412. doi: 10.5588/ijtld.17.0706.

Cox V(1), Brigden G(2), Crespo RH(3), Lessem E(4), Lynch S(5), Rich ML(6), Waning B(3), Furin J(7).

SETTING: The World Health Organization recommended two new drugs, bedaquiline (BDQ) and delamanid (DLM), for the treatment of multidrug-resistant tuberculosis (MDR-TB) in 2013 and 2014, respectively. An estimated one third of patients with MDR-TB would benefit from the inclusion of these drugs in their treatment regimens.

DESIGN: A convenience sample of 36 countries voluntarily reported monthly data on cumulative programmatic use of new drugs to the Drug-Resistant TB Scale-Up

Treatment Action Team between 1 July 2015 and 31 June 2017. Programmatic use was defined as treatment for MDR-TB with newer drugs outside of clinical trials or compassionate use.

RESULTS: A total of 10 164 persons were started on BDQ and 688 started on DLM during the reporting period. Only 15.7% of the 69 213 persons estimated to need newer drugs over the study period were reported to have received them.

CONCLUSION: While there has been significant progress in some countries, uptake of the newer drugs has not kept pace with a conservative estimate of need; fewer than 20% of persons likely to benefit from either BDQ or DLM have received them. Concerted efforts are needed to ensure that the newer drugs are made available more widely for persons with MDR-TB in need of these therapeutic options.

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1. Interim outcomes of delamanid for the treatment of MDR- and XDR-TB in South Korea.

J Antimicrob Chemother. 2018 Feb 1;73(2):503-508. doi: 10.1093/jac/dkx373.

Mok J(1), Kang H(2), Hwang SH(2), Park JS(2), Kang B(3), Lee T(4), Koh WJ(5), Yim JJ(6), Jeon D(7).

OBJECTIVES: Delamanid is a new anti-TB drug, but few data exist on its use outside clinical trials. The purpose of this study was to evaluate the efficacy as well as the safety and tolerability of a delamanid-containing regimen for 24 weeks in the treatment of MDR- and XDR-TB.

METHODS: We performed a retrospective cohort study among patients with MDR/XDR-TB who were treated with a delamanid-containing regimen in seven hospitals in South Korea.

RESULTS: A total of 32 patients with MDR-TB, of which 6 (18.8%) were XDR-TB, were included and all completed 24 weeks of delamanid treatment. Of 19 patients (59.4%) who had positive culture sputum at the initiation of delamanid treatment, the proportion of culture conversion at 8 weeks was 72.2% (13 of 18) in solid medium and 50.0% (7 of 14) in liquid medium. The proportion of culture conversion at 24 weeks was 94.4% (17 of 18) in solid medium and 92.9% (13 of 14) in liquid medium. The median time to culture conversion was 33 days (range = 5-81) using solid medium and 57 days (range = 8-96) using liquid medium. Of the 32 patients, there was no serious adverse event or death. Three patients developed a transient QTcF of > 500 ms.

CONCLUSIONS: The use of delamanid combined with optimized background regimens has the potential to achieve high culture conversion rates at 24 weeks with an acceptable safety and tolerability profile in patients with MDR/XDR-TB.

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2. Incremental Cost Effectiveness of Bedaquiline for the Treatment of Rifampicin-Resistant Tuberculosis in South Africa: Model-Based Analysis.

Appl Health Econ Health Policy. 2018 Feb;16(1):43-54. doi: 10.1007/s40258-017-0352-8.

Schnippel K(1), Firnhaber C(2)(3), Conradie F(2), Ndjeka N(4), Sinanovic E(5).

BACKGROUND: Nearly 20,000 people were diagnosed with multi-drug and rifampicin-resistant tuberculosis (MDR/RR-TB) in South Africa in 2015, yet only one-half of the patients who start treatment are expected to have a successful outcome. There is increasing evidence of the effectiveness and safety of new drug regimens containing bedaquiline for MDR/RR-TB; however, whether they are affordable for high-burden, limited-resource settings is uncertain.

OBJECTIVE: Our objective was to determine the incremental cost effectiveness of a bedaquiline-based regimen for MDR/RR-TB treatment in South Africa compared with the standard kanamycin-based regimen.

METHODS: We established a Markov model for ambulatory treatment of MDR/RR-TB in a high-HIV prevalence setting, parameterized using clinical outcomes from the South African National TB Programme (SA NTP) before (2012-2014) and after (2015-2016) bedaquiline roll-out. The effectiveness of treatment was evaluated in disability-adjusted life-years (DALYs). Ingredient costs from the provider’s perspective were collected in 2016 South African Rand and converted to $US, including bedaquiline at $US675.23 per 6-month treatment course. Culture conversion rates were derived from the phase IIb trial of bedaquiline, and disability adjustments were adapted from published literature. Costs and effectiveness were discounted at 3%.

RESULTS: For non-bedaquiline regimens, the total expected cost over the 10-year time horizon for a patient with MDR/RR-TB was $US4439 with disability-adjusted survival of 5.1 years. Replacing capreomycin with bedaquiline in patients who failed MDR/RR-TB treatment and required treatment for extensively drug-resistant (XDR-TB) resulted in cost savings ($US4356; 1.8% less) and similar effectiveness (0.02 DALYs averted). As a result, the standard regimen (no bedaquiline) was dominated. Replacing kanamycin with bedaquiline to provide all patients with MDR/RR-TB access to bedaquiline cost $US4647 (4.3% more) and averted 0.17 DALYs compared with the no bedaquiline regimen. The incremental cost-effectiveness ratio was $US1242/DALY averted.

CONCLUSION: Markov modelling indicates providing bedaquiline for all patients with MDR/RR-TB could increase the 24-month treatment success rate in South Africa from 56.3% using the current regimen to 60.6%, at a cost $US2.6 million over a 10-year horizon, less than 1% of the estimated $US425 million SA NTP annual budget.

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3. The Expanding Diversity of Mycobacterium tuberculosis Drug Targets.

ACS Infect Dis. 2018 Feb 15. doi: 10.1021/acsinfecdis.7b00255. [Epub ahead of print]

Wellington S(1)(2)(3), Hung DT(1)(2)(3).

ABSTRACT: After decades of relative inactivity, a large increase in efforts to discover

antitubercular therapeutics has brought insights into the biology of Mycobacterium tuberculosis (Mtb) and promising new drugs such as bedaquiline, which inhibits ATP synthase, and the nitroimidazoles delamanid and pretomanid, which inhibit both mycolic acid synthesis and energy production. Despite these advances, the drug discovery pipeline remains underpopulated. The field desperately needs compounds with novel mechanisms of action capable of inhibiting multi- and extensively drug -resistant Mtb (M/XDR-TB) and, potentially, non-replicating Mtb with the hope of shortening the duration of required therapy. New knowledge about Mtb, along with new methods and technologies, has driven exploration into novel target areas, such as energy production and central metabolism, that diverge from the classical targets in macromolecular synthesis. Here, we review new small molecule drug candidates that act on these novel targets to highlight the methods and perspectives advancing the field. These new targets bring with them the aspiration of shortening treatment duration as well as a pipeline of effective regimens against XDR-TB, positioning Mtb drug discovery to become a model for anti-infective discovery.

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4. Early safety and efficacy of the combination of bedaquiline and delamanid for the treatment of patients with drug-resistant tuberculosis in Armenia, India, and South Africa: a retrospective cohort study.

Lancet Infect Dis. 2018 Feb 13. pii: S1473-3099(18)30100-2. doi: 10.1016/S1473-3099(18)30100-2. [Epub ahead of print]

Ferlazzo G(1), Mohr E(2), Laxmeshwar C(3), Hewison C(4), Hughes J(2), Jonckheere S(3), Khachatryan N(5), De Avezedo V(6), Egazaryan L(7), Shroufi A(2), Kalon S(3), Cox H(8), Furin J(9), Isaakidis P(10).

BACKGROUND: Bedaquiline and delamanid have been approved for treatment of multidrug-resistant (MDR) tuberculosis in the past 5 years. Because of theoretical safety concerns, patients have been unable to access the two drugs in combination. Médecins Sans Frontières has supported the use of combination bedaquiline and delamanid for people with few treatment options since 2016. We describe early safety and efficacy of regimens containing the bedaquiline and delamanid combination in patients with drug-resistant tuberculosis in Yerevan, Armenia; Mumbai, India; and Khayelitsha, South Africa.

METHODS: We retrospectively analysed a cohort of all patients who received 6-12 months of oral bedaquiline and delamanid in combination (400 mg bedaquiline once per day for 2 weeks, then 200 mg bedaquiline three times per week and 100 mg delamanid twice per day) in MSF-supported projects. We report serious adverse events, QTc corrected using the Fridericia formula (QTcF) interval data, and culture conversion data during the first 6 months of treatment.

FINDINGS: Between Jan 1, 2016, and Aug 31, 2016, 28 patients (median age 32·5 years [IQR 28·5-40·5], 17 men) were included in the analysis. 11 (39%) of 28 patients were HIV-positive. 24 patients (86%) had isolates resistant to fluoroquinolones; 14 patients (50%) had extensively drug-resistant tuberculosis. No patient had an increase of more than 500 ms in their QTcF interval. Four patients (14%) had six instances of QTcF increase of more than 60 ms from baseline but none permanently discontinued the drugs. 16 serious adverse events were reported in seven patients. Of 23 individuals with positive baseline cultures, 17 (74%) converted to negative by month 6 of treatment.

INTERPRETATION: Use of the bedaquiline and delamanid combination appears to reveal no additive or synergistic QTcF-prolonging effects. Access to bedaquiline and delamanid in combination should be expanded for people with few treatment options while awaiting the results of formal clinical trials.

FUNDING: Médecins Sans Frontières (MSF).

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1. Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis.

Nat Genet. 2018 Jan 22. doi: 10.1038/s41588-017-0029-0. [Epub ahead of print]

Coll F(1), Phelan J(1), Hill-Cawthorne GA(2)(3), Nair MB(2), Mallard K(1), Ali S(2), Abdallah AM(2), Alghamdi S(4), Alsomali M(2), Ahmed AO(5), Portelli S(1)(6), Oppong Y(1), Alves A(7), Bessa TB(8), Campino S(1), Caws M(9)(10), Chatterjee A(11), Crampin AC(12)(13), Dheda K(14), Furnham N(1), Glynn JR(12)(13), Grandjean L(15), Minh Ha D(10), Hasan R(16), Hasan Z(16), Hibberd ML(1), Joloba M(17), Jones-López EC(18), Matsumoto T(19), Miranda A(7), Moore DJ(1)(15), Mocillo N(20), Panaiotov S(21), Parkhill J(22), Penha C(23), Perdigão J(24), Portugal I(24), Rchiad Z(2), Robledo J(25), Sheen P(14), Shesha NT(26), Sirgel FA(27), Sola C(28), Oliveira Sousa E(8)(29), Streicher EM(27), Helden PV(27), Viveiros M(30), Warren RM(27), McNerney R(31)(32), Pain A(33)(34), Clark TG(35)(36).

ABSTRACT: To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 Mycobacterium tuberculosis clinical isolates from more than 30 countries. A GWAS approach within a mixed-regression framework was followed by a phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes, novel mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to ethionamide, pyrazinamide, capreomycin, cycloserine and para-aminosalicylic acid was enhanced by inclusion of insertions and deletions. Odds ratios for mutations within candidate genes were found to reflect levels of resistance. New epistatic relationships between candidate drug-resistance-associated genes were identified. Findings also suggest the involvement of efflux pumps (drrA and Rv2688c) in the emergence of resistance. This study will inform the design of new diagnostic tests and expedite the investigation of resistance and compensatory epistatic mechanisms.

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2. Defining Bedaquiline Susceptibility, Resistance, Cross-Resistance and Associated Genetic Determinants: A Retrospective Cohort Study.

EBioMedicine. 2018 Jan 9. pii: S2352-3964(18)30005-7. doi: 10.1016/j.ebiom.2018.01.005. [Epub ahead of print]

Ismail NA(1), Omar SV(2), Joseph L(2), Govender N(2), Blows L(2), Ismail F(3), Koornhof H(2), Dreyer AW(2), Kaniga K(4), Ndjeka N(5).

BACKGROUND: Bedaquiline (BDQ) is a novel agent approved for use in combination treatment of multi-drug resistant tuberculosis (MDR-TB). We sought to determine BDQ epidemiological cut-off values (ECVs), define and assess interpretive criteria against putative resistance associated variants (RAVs), microbiological outcomes and cross resistance with clofazimine (CFZ).

METHODS: A retrospective cohort study was conducted. Minimal inhibitory concentrations (MIC) to BDQ were determined using 7H9 broth microdilution (BMD) and MGIT960. RAVs were genetically characterised using whole genome sequencing. BDQ ECVs were determined using ECOFFinder and compared with 6-month culture conversion status and CFZ MICs.

FINDINGS: A total of 391 isolates were analysed. Susceptible and intermediate categories were determined to have MICs of ≤0.125μg/ml and 0.25μg/ml using BMD and ≤1μg/ml and 2μg/ml using MGIT960 respectively. Microbiological failures occurred among BDQ exposed patients with a non-susceptible BDQ MIC, an Rv0678 mutation and ≤2 active drug classes. The Rv0678 RAVs were not the dominant mechanism of CFZ resistance and cross resistance was limited to isolates with an Rv0678 mutation.

INTERPRETATION: Criteria for BDQ susceptibility are defined and will facilitate improved early detection of resistance. Cross- resistance between BDQ and CFZ is an emerging concern but in this study was primarily among those with an Rv0678 mutation.

Read free ScienceDirect article here. 


3. Catastrophic total costs in tuberculosis-affected households and their determinants since Indonesia’s implementation of universal health coverage.

Infect Dis Poverty. 2018 Jan 12;7(1):3. doi: 10.1186/s40249-017-0382-3.

Fuady A(1)(2), Houweling TAJ(3), Mansyur M(4), Richardus JH(3).

BACKGROUND: As well as imposing an economic burden on affected households, the high costs related to tuberculosis (TB) can create access and adherence barriers. This highlights the particular urgency of achieving one of the End TB Strategy’s targets: that no TB-affected households have to face catastrophic costs by 2020. In Indonesia, as elsewhere, there is also an emerging need to provide social protection by implementing universal health coverage (UHC). We therefore assessed the incidence of catastrophic total costs due to TB, and their determinants since the implementation of UHC.

METHODS: We interviewed adult TB and multidrug-resistant TB (MDR-TB) patients in urban, suburban and rural areas of Indonesia who had been treated for at least one month or had finished treatment no more than one month earlier. Following the WHO recommendation, we assessed the incidence of catastrophic total costs due to TB. We also analyzed the sensitivity of incidence relative to several thresholds, and measured differences between poor and non-poor households in the incidence of catastrophic costs. Generalized linear mixed-model analysis was used to identify determinants of the catastrophic total costs.

RESULTS: We analyzed 282 TB and 64 MDR-TB patients. For TB-related services, the median (interquartile range) of total costs incurred by households was 133 USD (55-576); for MDR-TB-related services, it was 2804 USD (1008-4325). The incidence of catastrophic total costs in all TB-affected households was 36% (43% in poor households and 25% in non-poor households). For MDR-TB-affected households, the incidence was 83% (83% and 83%). In TB-affected households, the determinants of catastrophic total costs were poor households (adjusted odds ratio [aOR] = 3.7, 95% confidence interval [CI]: 1.7-7.8); being a breadwinner (aOR = 2.9, 95% CI: 1.3-6.6); job loss (aOR = 21.2; 95% CI: 8.3-53.9); and previous TB treatment (aOR = 2.9; 95% CI: 1.4-6.1). In MDR-TB-affected households, having an income-earning job before diagnosis was the only determinant of catastrophic total costs (aOR = 8.7; 95% CI: 1.8-41.7).

CONCLUSIONS: Despite the implementation of UHC, TB-affected households still risk catastrophic total costs and further impoverishment. As well as ensuring access to healthcare, a cost-mitigation policy and additional financial protection should be provided to protect the poor and relieve income losses.

Read free PMC article here.


4. Meropenem-clavulanate for drug-resistant tuberculosis: a follow-up of relapse-free cases.

Int J Tuberc Lung Dis. 2018 Jan 1;22(1):34-39. doi: 10.5588/ijtld.17.0352.

Payen MC(1), Muylle I(2), Vandenberg O(3), Mathys V(4), Delforge M(1), Van den Wijngaert S(3), Clumeck N(1), De Wit S(1)

BACKGROUND: Extensively drug-resistant tuberculosis (XDR-TB), defined as TB caused by a Mycobacterium strain resistant to at least rifampicin, isoniazid, any fluoroquinolone and one of the injectable anti-tuberculosis drugs, remains a worldwide public health threat. Among repurposed drugs empirically used for XDR-TB cases, carbapenems have been studied in vitro and in animal models, with encouraging results. However, only short-term follow-up data from clinical studies are currently available.

OBJECTIVES: To study the long-term follow-up of XDR-TB cases treated with a regimen containing meropenem-clavulanate (M/Clav).

DESIGN: Retrospective observational case series study at a single hospital.

METHODS: All hospitalised drug-resistant TB patients who received M/Clav as part of their treatment from 2009 to 2016 were included. Demographic and clinical data were extracted from medical records.

RESULTS: Eighteen XDR-TB patients were included in the analysis. The successful outcome and mortality rates were respectively 83.3% and 11.1%. No relapses were observed in cured patients after a median follow-up of 4 years. No specific adverse events were attributed to treatment with M/Clav.

CONCLUSION: The rate of sustained successful treatment outcome observed here is far higher than the 26% observed in the 2014 World Health Organization XDR-TB cohort, suggesting that carbapenems may be beneficial for the treatment of difficult-to-treat TB cases.

Read abstract here. 


1. Treatment outcomes of rifabutin-containing regimens for rifabutin-sensitive multidrug-resistant pulmonary tuberculosis.

Int J Infect Dis. 2017 Dec;65:135-141. doi: 10.1016/j.ijid.2017.10.013.

Lee H(1), Ahn S(2), Hwang NY(2), Jeon K(1), Kwon OJ(1), Huh HJ(3), Lee NY(3), Koh WJ(4).

OBJECTIVES: The aim of this study was to evaluate whether rifabutin can improve treatment outcomes in patients with rifabutin-sensitive MDR-TB.

METHODS: A retrospective cohort study was performed on 76 patients with rifabutin-sensitive MDR-TB who were treated with or without rifabutin between 2006 and 2011.

RESULTS: Overall, 75% (57/76) of patients achieved favorable outcomes, including cure (53/76, 70%) and treatment completion (4/76, 5%). In contrast, 25% (19/76) had unfavorable treatment outcomes, which included treatment failure (6/76, 8%), death (2/76, 3%), loss to follow-up (4/76. 5%), and no evaluation due to transfer to other institutions (7/76, 9%). Rifabutin was given to 52 (68%) of the 76 patients with rifabutin-sensitive MDR-TB. Although favorable treatment outcomes were more frequent in patients who received rifabutin [81% (42/52)] than in those who did not receive rifabutin [63% (15/24)], this difference was not statistically significant (P=0.154). However, in multivariable regression logistic analysis, use of rifabutin was significantly associated with favorable treatment outcomes in patients with rifabutin-sensitive MDR-TB (adjusted odds ratio=9.80, 95% confidence interval=1.65-58.37, P=0.012).

CONCLUSIONS: These results suggest that the use of rifabutin can improve treatment outcomes in patients with rifabutin-sensitive MDR-TB.

Read free IJID article here.


2. Rapid Microarray-based Detection of Rifampicin-, Isoniazid- and Fluoroquinolone Resistance in Mycobacterium tuberculosis using a Single Cartridge.

J Clin Microbiol. 2017 Dec 6. pii: JCM.01249-17. doi: 10.1128/JCM.01249-17.

Havlicek J(1), Dachsel B(1), Slickers P(1), Andres S(2), Beckert P(3)(4), Feuerriegel S(3)(4), Niemann S(3)(4), Merker M(5)(4), Labugger I(1).

ABSTRACT: Rapid and robust identification of mutations in Mycobacterium tuberculosis complex (MTBC) strains mediating multidrug and extensively drug-resistant (M/XDR) phenotypes is crucial to combat the MDR tuberculosis (TB) epidemic. Currently available molecular TB drug susceptibility tests are either restricted to single targets/drugs (i.e. Xpert MTB/RIF) or aid the risk of cross-contaminations due to the design limitations of the open platform (i.e. line probe assays).With a good understanding of the technical and commercial boundaries we designed a test cartridge with an introduction of dried reagents, based on an oligonucleotide array, which has the ability to identify MTBC strains resistant to isoniazid, rifampicin and the fluoroquinolones. The melting curve assay interrogates in a closed cartridge system within 90 minutes 43 different mutations in the rifampicin resistance determining region (RRDR) of rpoB, rpoB codon 572, katG codon 315, the inhA promoter region, and the quinolone resistance determining region (QRDR) of gyrA The assay performance was evaluated with 265 clinical MTBC isolates from Swaziland including MDR/XDR, non-MDR, and fully susceptible isolates from a drug resistance survey performed in 2009/2010. In 99.5% of the cases, the results were consistent with the previously acquired data utilizing Sanger sequencing. By means of the closed cartridge system in combination with the battery-powered Alere™ q analyzer and with the potential to extent the current gene target panel the assay could serve as a rapid and robust point-of-care test in settings lacking comprehensive molecular laboratory infrastructure to differentiate MDR and non-MDR TB-patients and to assist clinicians in early treatment decisions.

Read free ASM article here.


3. Limited Effect of Later-generation Fluoroquinolones in the Treatment of Ofloxacin-resistant and Moxifloxacin-susceptible Multidrug-resistant Tuberculosis.

Antimicrob Agents Chemother. 2017 Dec 4. pii: AAC.01784-17. doi: 10.1128/AAC.01784-17. [Epub ahead of print]

Lee H(1), Ahn S(2), Hwang NY(2), Jeon K(1), Kwon OJ(1), Huh HJ(3), Lee NY(3), Kim CK(4), Koh WJ(5).

ABSTRACT: Recent data conflict on the clinical efficacy of later-generation fluoroquinolones, such as moxifloxacin or levofloxacin, for the treatment of multidrug-resistant tuberculosis (MDR-TB) that is resistant to ofloxacin but susceptible to moxifloxacin. The purpose of the present study was to evaluate whether later-generation fluoroquinolones can improve treatment outcomes in patients with ofloxacin-resistant/moxifloxacin-susceptible MDR-TB. A retrospective cohort study was performed on 208 patients with moxifloxacin-susceptible MDR-TB who were treated between 2006 and 2011. Later-generation fluoroquinolones were used in all patients. Overall, 171 patients (82%) had ofloxacin-susceptible/moxifloxacin-susceptible MDR-TB (ofloxacin-susceptible group) and 37 (18%) had ofloxacin-resistant/moxifloxacin-susceptible MDR-TB (ofloxacin-resistant group). Compared to the ofloxacin-susceptible group, the ofloxacin-resistant group was more likely to have a previous history of MDR-TB treatment (P < 0.001) and cavitary lesions on chest radiography (P < 0.001). In addition, the ofloxacin-resistant group was more likely than the ofloxacin-susceptible group to have drug resistance to pyrazinamide (P = 0.003), streptomycin (P = 0.015), prothionamide (P < 0.001), and para-aminosalicylic acid (P < 0.001). Favorable outcomes were more frequently achieved in the ofloxacin-susceptible group than in the ofloxacin-resistant group [91% (156/171) vs. 57% (21/37), respectively; P < 0.001]. In multivariable regression logistic analysis, the ofloxacin-susceptible group was about 5.36 (95% confidence interval = 1.55-18.53) times more likely than the ofloxacin-resistant group (P < 0.001) to have favorable outcomes. Despite in vitro moxifloxacin susceptibility, favorable treatment outcomes for ofloxacin-resistant MDR-TB were significantly lower than for ofloxacin-susceptible MDR-TB, even when later-generation fluoroquinolones were used, indicating that more aggressive therapies may be needed for ofloxacin-resistant MDR-TB.

Read abstract here.


4. Population implications of the use of bedaquiline in people with extensively drug-resistant tuberculosis: are fears of resistance justified?

Lancet Infect Dis. 2017 Dec;17(12):e429-e433. doi: 10.1016/S1473-3099(17)30299-2. Epub 2017 May 19.

Kunkel A(1), Furin J(2), Cohen T(3).

ABSTRACT: Global rollout of the new antituberculosis drug bedaquiline has been slow, in part reflecting concerns about spread of bedaquiline resistance. Acquired resistance to bedaquiline is especially likely in patients with extensively

drug-resistant (XDR) tuberculosis. However, the very high mortality rates of patients with XDR not receiving bedaquiline, and promising cohort study results, suggest these patients also have greatest need for the drug. In this Personal View, we argue that resistance concerns should not forestall use of bedaquiline

in patients with XDR tuberculosis. Our position in favour of increased access to bedaquiline for these patients is based on three arguments. First, the use of drug combinations that include bedaquiline might prevent spread of XDR disease to others in the community. Second, until new combination regimens of novel drugs for XDR tuberculosis become available, patients with XDR disease and their infected contacts will face equivalent outcomes if bedaquiline is either not provided because of policy, or not effective because of resistance. Finally, because resistance to bedaquiline and other antituberculosis drugs is caused by mutations within a single bacterial chromosome, use of bedaquiline in patients with XDR tuberculosis will not substantially increase the risk of bedaquiline resistance in patients with drug-susceptible or multidrug-resistant (non‑XDR) tuberculosis strains.

Read abstract here.


1. Pharmacokinetic interaction between bedaquiline and clofazimine in patients with drug-resistant tuberculosis.

Int J Tuberc Lung Dis. 2017 Nov 16. doi: 10.5588/ijtld.17.0615. [Epub ahead of print]

Maartens G(1), Brill MJE(2), Pandie M(1), Svensson EM(2).

BACKGROUND: Bedaquiline (BDQ) and clofazimine (CFZ) are both recommended for treating drug-resistant tuberculosis(DR-TB). As CFZ is an inhibitor of the cytochrome P450 isoenzyme 3A4 (CYP3A4) in vitro, and BDQ a substrate of CYP3A4, there is a potential for pharmacokinetic (PK) drug-drug interaction that may result in increased BDQ exposure when co-administered with CFZ, which could increase the toxicity of BDQ.

METHODS: We assessed the effect of co-administered CFZ on BDQ bioavailability, or on clearance of BDQ and its N-monodesmethyl metabolite (M2), in patients with DR-TB using a population PK model developed from data of patients with DR-TB. This was a secondary analysis of a study designed to explore drug-drug interactions between BDQ and antiretrovirals.

RESULTS: Of 46 participants, 30 were on concomitant CFZ when intensive PK sampling of BDQ was done. CFZ did not have a statistically significant effect on BDQ bioavailability (&minus;9.1&percnt;, 90&percnt;CI &minus;22.8 to &plus;7.1; P&equals; 0.19) or on BDQ and M2 clearance (&plus;12.2&percnt;, 90&percnt;CI &minus;13.7 to &plus;38; P &equals; 0.32).

CONCLUSION: We did not find a statistically significant PK drug-drug interaction between BDQ and CFZ, but cannot exclude a potentially clinically relevant interaction due to the wide confidence intervals of the estimated interaction effects.

Read abstract here.

2. Levofloxacin population pharmacokinetics in South African children treated for multidrug-resistant tuberculosis.

Antimicrob Agents Chemother. 2017 Nov 13. pii: AAC.01521-17. doi: 10.1128/AAC.01521-17. [Epub ahead of print]

Denti P(1), Garcia-Prats AJ(2), Draper HR(2), Wiesner L(3), Winckler J(2), Thee S(4), Dooley KE(5), Savic RM(6), McIlleron HM(3), Schaaf HS(2), Hesseling AC(2).

BACKGROUND: Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited paediatric pharmacokinetic data to inform dose selection for children.

METHODS: Children routinely receiving levofloxacin (250 mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following a 15 or 20 mg/kg dose, given as whole tablet(s) or crushed, orally, or by nasogastric tube. Pharmacokinetic parameters were estimated using non-linear mixed effects modelling. Model-based simulations were performed to estimate doses across weight bands that would achieve adult exposures with 750mg once-daily dosing.

RESULTS: 109 children were included, median age 2.1 years (range 0.3-8.7); median weight 12 kg (range 6-22). Levofloxacin followed 2-compartment kinetics with 1st-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterised age-driven maturation of clearance (CL) with an effect reaching 50% around 2 months after birth and 100% by 2 years of age.. CL in a typical child (12 kg, 2-year-old) was 4.7 L/h. HIV infection reduced CL by 16%. Using the adult 250 mg formulation, Levofloxacin exposures were substantially lower than those reported in adults receiving a similar mg/kg dose. To achieve adult-equivalent exposures at a 750 mg daily dose, higher levofloxacin paediatric doses may be required -from 18 mg/kg/day for younger children with weights 3-4 kg (due to immature clearance) to 40 mg/kg/day for older children.

CONCLUSIONS: Currently recommended doses of levofloxacin for MDR-TB in children result in exposures considerably lower than in adults. The effect of different formulations and formulation manipulation require further investigation.We recommend age- and weight-banded doses of 250 mg tablets adult-formulation most likely to achieve target concentrations for prospective evaluation.

Read abstract here.

3. What is resistance? Impact of phenotypic versus molecular drug resistance testing on multi- and extensively drug-resistant tuberculosis therapy.

Antimicrob Agents Chemother. 2017 Nov 13. pii: AAC.01550-17. doi: 10.1128/AAC.01550-17. [Epub ahead of print] 

Heyckendorf J(1)(2)(3), Andres S(4), Köser CU(5), Olaru ID(1)(2), Schön T(6)(7), Sturegård E(8), Beckert P(2)(9), Schleusener V(9), Kohl TA(2)(9), Hillemann D(4), Moradigaravand D(10), Parkhill J(10), Peacock SJ(5)(10)(11), Niemann S(12)(9), Lange C(13)(2)(3)(14)(15), Merker M(2)(9).

ABSTRACT: Rapid and accurate drug-susceptibility testing (DST) is essential for the treatment of multi- and extensively drug-resistant tuberculosis(M/XDR-TB). We compared the utility of genotypic DST assays with phenotypic DST (pDST) using BACTEC 960 MGIT or Löwenstein-Jensen to construct M/XDR-TB treatment regimens for a cohort of 25 consecutive M/XDR-TB patients and 15 possible anti-TBdrugs.Genotypic DST results from Cepheid GeneXpert MTB/RIF (Xpert) and line probe assays (LPAs: Hain GenoType MTBDRplus 2.0 and MTBDRsl 2.0)] and whole genome sequencing (WGS) were translated into individual algorithm-derived treatment regimens for each patient. We further analysed if discrepancies between the various methods were due to flaws in the genotypic or phenotypic test using MIC results.Compared with pDST, the average agreement in the number of drugs prescribed in ‘genotypic’ regimens ranged from just 49% (95% CI 39-59%) for Xpert and 63% (95% CI 56-70%) for LPAs to 93% (95% CI 88-98%) for WGS. Only the WGS regimens did not comprise any drugs to which pDST showed resistance. Importantly, MIC testing revealed that pDST likely underestimated the true rate of resistance for key drugs (rifampicin, levofloxacin, moxifloxacin, and kanamycin) because critical concentrations (CCs) were too high.WGS can be used to rule-in resistance even in M/XDR strains with complex resistance patterns, but pDST for some drugs is still needed to confirm susceptibility and construct the final regimens. Some CCs for pDST need to be re-examined to avoid systematic false-susceptible results in low-level resistant isolates.

Read abstract here. 

4. Polyclonal Pulmonary Tuberculosis Infections and Risk for Multidrug Resistance, Lima, Peru.

Emerg Infect Dis. 2017 Nov;23(11):1887-1890. doi: 10.3201/eid2311.170077.

Nathavitharana RR, Shi CX, Chindelevitch L, Calderon R, Zhang Z, Galea JT, Contreras C, Yataco R, Lecca L, Becerra MC, Murray MB, Cohen T.

ABSTRACT: Because within-host Mycobacterium tuberculosis diversity complicates diagnosis and treatment of tuberculosis (TB), we measured diversity prevalence and associated factors among 3,098 pulmonary TB patients in Lima, Peru. The 161 patients with polyclonal infection were more likely than the 115 with clonal or the 2,822 with simple infections to have multidrug-resistant TB.

Read free PMC article here.

October 2017 Newsletter

1. The Physicochemical Basis of Clofazimine-Induced Skin Pigmentation.
J Invest Dermatol. 2017 Oct 14. pii: S0022-202X(17)33040-3. doi: 10.1016/j.jid.2017.09.031. [Epub ahead of print]
Murashov MD(1), LaLone V(1), Rzeczycki PM(1), Keswani RK(1), Yoon GS(1), Sud S(1), Rajeswaran W(2), Larsen S(2), Stringer KA(3), Rosania GR(4).

ABSTRACT: Clofazimine is a weakly basic, FDA-approved antibiotic recommended by the World Health Organization to treat leprosy and multi-drug-resistant tuberculosis. Upon prolonged treatment, clofazimine extensively bioaccumulates and precipitates throughout the organism, forming crystal-like drug inclusions (CLDIs). Because of the drug’s red color, it is widely believed that clofazimine bioaccumulation results in skin pigmentation, its most common side effect. To test whether clofazimine-induced skin pigmentation is due to CLDI formation, we synthesized a closely related clofazimine analog that does not precipitate under physiological pH and chloride conditions that are required for CLDI formation. Despite the absence of detectable CLDIs in mice, administration of this analog still led to significant skin pigmentation. In clofazimine treated mice, skin cryosections revealed no evidence of CLDIs when analyzed with a microscopic imaging system specifically designed for detecting clofazimine aggregates. Rather, the reflectance spectra of the skin revealed a signal corresponding to the soluble, free base form of the drug. Consistent with the low concentrations of clofazimine in the skin, these results suggest that clofazimine-induced skin pigmentation is not due to clofazimine precipitation and CLDI formation, but rather to the partitioning of the circulating, free base form of the drug into subcutaneous fat.

Read abstract here

2. Bilateral cavitary multidrug- or extensively drug-resistant tuberculosis: role of surgery.
Eur J Cardiothorac Surg. 2017 Oct 10. doi:10.1093/ejcts/ezx350.
Marfina GY(1), Vladimirov KB(2), Avetisian AO(1), Starshinova AA(1), Kudriashov GG(1), Sokolovich EG(1), Yablonskii PK(1)(3).

OBJECTIVES: Cavitary disease and bilateral lesions are among the risk factors for poor outcome of pulmonary tuberculosis (TB). Our aim was to explore the value and limits of surgery in patients with advanced TB.
METHODS: A retrospective study of 57 consecutive patients who underwent thoracic surgery for culture-positive bilateral cavitary pulmonary TB was performed. Forty-four (77.2%) patients were men and 13 (22.8%) patients were women; their ages were in the range of 18-61 years. Twenty-two (38.6%) patients had multidrug-resistant (MDR) TB and 35 (61.4%) patients had extensively drug-resistant (XDR) TB confirmed with cultures. On admission, 49 (86.0%) patients had sputum smear microscopy positive for acid-fast bacilli. The main indication for surgery was treatment failure manifested as contagious persisting cavities despite best available therapy. The surgical procedures included combinations of pulmonary resections of different levels, selective thoracoplasties and/or endobronchial valve treatment. The operations were performed consecutively, starting with the most affected side. TB therapy preceded the operation for a minimum of 6 months and was continued after the operation on the basis of the patient’s susceptibility to drugs for Mycobacterium tuberculosis.
RESULTS: We performed 121 operations: 42 in 22 patients with MDR TB (1.9 operations per patient) and 79 procedures in 35 patients with XDR TB (2.3 operations per patient). No deaths occurred in the 1st year. Two late deaths followed, 1 unrelated to and 1 due to TB progression. Ten major complications (1 complication per patient) developed: main bronchus stump fistula (n = 4), prolonged air leak (n = 3), respiratory failure (n = 2) and wound seroma (n = 1). At the 1-month follow-up visit, sputum smear conversion was observed in 11(68.8%) patients with MDR and in 15 (45.5%) patients with XDR TB. At the late (20-36 months) follow-up visit, culture negativity was achieved in 21 (95.5%) patients with MDR TB and in 23 (65.7%) patients with XDR TB (P = 0.015).
CONCLUSIONS: Thoracic surgery may significantly improve patients’ outcomes and even result in a cure in a good portion of patients with bilateral cavitary MDR and XDR TB and should be considered as the essential element of multimodality treatment for MDR and XDR TB, even in patients with bilateral cavitary disease and borderline respiratory reserves.

Read abstract here

3. A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance.
BMC Genomics. 2017 Oct 11;18(1):769. doi: 10.1186/s12864-017-4146-z.
Sheen P(1), Requena D(1), Gushiken E(1), Gilman RH(2), Antiparra R(1), Lucero B(1), Lizárraga P(1), Cieza B(1), Roncal E(1), Grandjean L(3), Pain A(4), McNerney R(5), Clark TG(5)(6), Moore D(5), Zimic M(7).

BACKGROUND: Tuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear.
RESULTS: We genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping. We analyzed the association between PZA resistance with non-synonymous mutations and specific genes. We found mutations in pncA and novel genes significantly associated with PZA resistance in strains without pncA mutations. These included genes related to transportation of metal ions, pH regulation and immune system evasion.
CONCLUSIONS: These results suggest potential alternate mechanisms of PZA resistance that have not been found in other populations, supporting that the antibacterial activity of PZA may hit multiple targets.

Read free PMC article here 

4. Fluoroquinolone Resistance Mutation Detection Is Equivalent to Culture-Based Drug Sensitivity Testing for Predicting Multidrug-Resistant Tuberculosis Treatment Outcome: A Retrospective Cohort Study.
Clin Infect Dis. 2017 Oct 15;65(8):1364-1370. doi: 10.1093/cid/cix556.
Farhat MR(1)(2), Jacobson KR(3), Franke MF(4), Kaur D(5), Murray M(4)(6), Mitnick CD(4)(7).

BACKGROUND: Molecular diagnostics that rapidly and accurately predict fluoroquinolone (FQ) resistance promise to improve treatment outcomes for individuals with multidrug-resistant (MDR) tuberculosis (TB). Mutations in the gyr genes, though, can cause variable levels of in vitro FQ resistance, and some in vitro resistance remains unexplained by gyr mutations alone, but the implications of these discrepancies for treatment outcome are unknown.
METHODS: We performed a retrospective cohort study of 172 subjects with MDR/extensively drug-resistant TB subjects and sequenced the full gyrA and gyrB open reading frames in their respective sputum TB isolates. The gyr mutations were classified into 2 categories: a set of mutations that encode high-level FQ resistance and a second set that encodes intermediate resistance levels. We constructed a Cox proportional model to assess the effect of the gyr mutation type on the time to death or treatment failure and compared this with in vitro FQ resistance, controlling for host and treatment factors.
RESULTS: Controlling for other host and treatment factors and compared with patients with isolates without gyr resistance mutations, “high-level” gyr mutations significantly predict poor treatment outcomes with a hazard ratio of 2.6 (1.2-5.6). We observed a hazard of death and treatment failure with “intermediate-level” gyr mutations of 1.3 (0.6-3.1), which did not reach statistical significance. The gyr mutations were not different than culture-based FQ drug susceptibility testing in predicting the hazard of death or treatment failure and may be superior.
CONCLUSIONS: FQ molecular-based diagnostic tests may better predict treatment response than traditional drug susceptibility testing and open avenues for personalizing TB therapy.

Read abstract here

5. The devil we know: is the use of injectable agents for the treatment of MDR-TB justified?
Int J Tuberc Lung Dis. 2017 Nov 1;21(11):1114-1126. doi: 10.5588/ijtld.17.0468.
Reuter A(1), Tisile P(2), von Delft D(2), Cox H(3), Cox V(4), Ditiu L(5), Garcia-Prats A(6), Koenig S(7), Lessem E(8), Nathavitharana R(9), Seddon JA(10), Stillo J(11), von Delft A(12), Furin J(7).

ABSTRACT: For decades, second-line injectable agents (IAs) have been the cornerstone of treatment for multidrug-resistant tuberculosis (MDR-TB). Although evidence on the efficacy of IAs is limited, there is an expanding body of evidence on the serious adverse events caused by these drugs. Here, we present the results of a structured literature review of the safety and efficacy of IAs. We review the continued widespread use of these agents in the context of therapeutic alternatives-most notably the newer TB drugs, bedaquiline and delamanid-and from the context of human rights, ethics and patient-centered care. We conclude that there is limited evidence of the efficacy of IAs, clear evidence of the risks of these drugs, and that persons living with MDR-TB should be informed about these risks and provided with access to alternative therapeutic options.

Read full IJTLD article here