May 2017 eNewsletter

1. Pharmacokinetics of Levofloxacin in Multidrug- and Extensively Drug Resistant Tuberculosis patients.
Antimicrob Agents Chemother. 2017 May 15. pii: AAC.00343-17. doi: 10.1128/AAC.00343-17. [Epub ahead of print]
Van’t Boveneind-Vrubleuskaya N(1,)(2), Seuruk T(3), van Hateren K(2), van der Laan T(4), Kosterink JGW(2), van der Werf TS(5), van Soolingen D(4,)(6), van den Hof S(2,)(7), Skrahina A(3), Alffenaar JC(8).

ABSTRACT: Pharmacodynamics are important in treatment of especially multidrug- and extensively resistant tuberculosis (M/XDR-TB). The free area under the concentration time curve in relation to minimal inhibitory concentration (fAUC/MIC) is the most relevant pharmacokinetic (PK)-pharmacodynamic (PD) parameter to predict the efficacy of levofloxacin (LFX). The objective of our study was to assess LFX PK variability in M/XDR-TB patients and its potential consequence for fAUC/MIC ratios. Patients with pulmonary M/XDR-TB received LFX as part of treatment regimen at a dose of 15 mg/kg once daily. Blood samples obtained at steady state before- and 1, 2, 3, 4, 7, and 12 hrs after drug administration were measured by validated a liquid chromatography-tandem mass spectrometry. MIC values of LFX were determined by the agar dilution method on Middlebrook 7H10 and the MGIT960 system. Twenty patients with a mean age of 31 (IQR; 27-35) years were enrolled in this study. The median AUC0-24h was 98.8 mg/h/L (IQR; 84.8-159.6). The MIC median value for LFX was 0,5 mg/L with a range of 0.25 to 2.0 mg/L and the median fAUC0-24/MIC ratio was 109.5 (IQR; 48.5-399.4). In four of the 20 patients the value was below the target value of ≥100. When a MIC of 0.25, 0.5, 1.0 and 2.0 mg/L were applicable, 19, 18, 3 and no patients, respectively, had a fAUC/MIC ratio that exceeded 100. We observed a large variability in AUC. A fAUC0-24/MIC of ≥ 100 was only observed in case MIC values for LFX were 0.25-0.5 mg/L. Dosages exceeding 15mg/kg should be considered for target attainment if exposures are assumed to be safe.

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2. Estimating the future burden of multidrug-resistant and extensively drug-resistant tuberculosis in India, the Philippines, Russia, and South Africa: a mathematical modelling study.
Lancet Infect Dis. 2017 May 9. pii: S1473-3099(17)30247-5. doi:10.1016/S1473-3099(17)30247-5. [Epub ahead of print]
Sharma A(1), Hill A(2), Kurbatova E(2), van der Walt M(3), Kvasnovsky C(4), Tupasi TE(5), Caoili JC(5), Gler MT(5), Volchenkov GV(6), Kazennyy BY(7), Demikhova OV(8), Bayona J(9), Contreras C(9), Yagui M(10), Leimane V(11), Cho SN(12), Kim HJ(13), Kliiman K(14), Akksilp S(15), Jou R(16), Ershova J(2), Dalton T(2), Cegielski P(2); Global Preserving Effective TB Treatment Study Investigators.

BACKGROUND: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are emerging worldwide. The Green Light Committee initiative supported programmatic management of drug-resistant tuberculosis in 90 countries.We used estimates from the Preserving Effective TB Treatment Study to predict MDR and XDR tuberculosis trends in four countries with a high burden of MDR tuberculosis: India, the Philippines, Russia, and South Africa.
METHODS: We calibrated a compartmental model to data from drug resistance surveys and WHO tuberculosis reports to forecast estimates of incident MDR and XDR tuberculosis and the percentage of incident MDR and XDR tuberculosis caused by acquired drug resistance, assuming no fitness cost of resistance from 2000 to 2040 in India, the Philippines, Russia, and South Africa.
FINDINGS: The model forecasted the percentage of MDR tuberculosis among incident cases of tuberculosis to increase, reaching 12·4% (95% prediction interval 9·4-16·2) in India, 8·9% (4·5-11·7) in the Philippines, 32·5% (27·0-35·8) in Russia, and 5·7% (3·0-7·6) in South Africa in 2040. It also predicted the percentage of XDR tuberculosis among incident MDR tuberculosis to increase, reaching 8·9% (95% prediction interval 5·1-12·9) in India, 9·0% (4·0-14·7) in the Philippines, 9·0% (4·8-14·2) in Russia, and 8·5% (2·5-14·7) in South Africa in 2040. Acquired drug resistance would cause less than 30% of incident MDR tuberculosis during 2000-40. Acquired drug resistance caused 80% of incident XDR tuberculosis in 2000, but this estimate would decrease to less than 50% by 2040.
INTERPRETATION: MDR and XDR tuberculosis were forecast to increase in all four countries despite improvements in acquired drug resistance shown by the Green Light Committee-supported programmatic management of drug-resistant tuberculosis. Additional control efforts beyond improving acquired drug resistance rates are needed to stop the spread of MDR and XDR tuberculosis in countries with a high burden of MDR tuberculosis.
FUNDING: US Agency for International Development and US Centers for Disease Control and Prevention, Division of Tuberculosis Elimination.

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3. A combination of baseline plasma immune markers can predict therapeutic response in multidrug resistant tuberculosis.
PLoS One. 2017 May 2;12(5):e0176660. doi: 10.1371/journal.pone.0176660. eCollection 2017.
Ferrian S(1), Manca C(2), Lubbe S(3), Conradie F(4), Ismail N(5), Kaplan G(6), Gray CM(1), Fallows D(2).

OBJECTIVE: To identify plasma markers predictive of therapeutic response in patients with multidrug resistant tuberculosis (MDR-TB).
METHODS: Fifty HIV-negative patients with active pulmonary MDR-TB were analysed for six soluble analytes in plasma at the time of initiating treatment (baseline) and over six months thereafter. Patients were identified as sputum culture positive or negative at baseline. Culture positive patients were further stratified by the median time to sputum culture conversion (SCC) as fast responders (< 76 days) or slow responders (≥ 76 days). Chest X-ray scores, body mass index, and sputum smear microscopy results were obtained at baseline.
RESULTS: Unsupervised hierarchical clustering revealed that baseline plasma levels of IP-10/CXCL10, VEGF-A, SAA and CRP could distinguish sputum culture and  cavitation status of patients. Among patients who were culture positive at baseline, there were significant positive correlations between plasma levels of CRP, SAA, VEGF-A, sIL-2Rα/CD40, and IP-10 and delayed SCC. Using linear discriminant analysis (LDA) and Receiver Operating Curves (ROC), we showed that a combination of MCP-1/CCL2, IP-10, sIL-2Rα, SAA, CRP and AFB smear could distinguish fast from slow responders and were predictive of delayed SCC with high sensitivity and specificity.
CONCLUSION: Plasma levels of specific chemokines and inflammatory markers measured before MDR-TB treatment are candidate predictive markers of delayed SCC. These findings require validation in a larger study.

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4. Population implications of the use of bedaquiline in people with extensively drug-resistant tuberculosis: are fears of resistance justified?
Lancet Infect Dis. 2017 May 19. pii: S1473-3099(17)30299-2. doi: 10.1016/S1473-3099(17)30299-2. [Epub ahead of print]
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 free TB Online article here