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.

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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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