December 2018 Newsletter

NEWS AND ANNOUNCEMENTS

 

Upcoming Webinar

Managing Side Effects to Drug-resistant TB Treatment – Hosted by RESIST-TB and The Union’s NAPS
On January 16th at 08:30 EST (14:30 CET, 15:30 SAST), RESIST-TB and The Union’s Nurses and Allied Professionals Sub-Section (NAPS) will be hosting a webinar to discuss the ICN/CITC Nursing Guide for Management of Side Effects of DR-TB Treatment. Nurses are often the first to hear of a patient’s side effects during TB treatment, making them well positioned to intervene. The information presented in this guide, which will be the topic of this webinar, was developed to help nurses assess for and respond appropriately to side effects related to anti-TB medications.

For more information on how to join the webinar, continue to check our website.

 

PUBLICATIONS

1. Acceptability of a Novel Levofloxacin Dispersible Tablet Formulation in Young Children Exposed to Multidrug-Resistant Tuberculosis.
Pediatr Infect Dis J. 2018 Dec 13. doi: 10.1097/INF.0000000000002268. [Epub ahead of print]
Purchase SE, Garcia-Prats AJ, De Koker P, Draper HR, Osman M, Seddon JA, Schaaf HS, Hesseling AC.

ABSTRACT: Levofloxacin is used for the treatment and prevention of multidrug-resistant tuberculosis in children, but current adult formulations are poorly palatable. A questionnaire administered to caregivers of 27 children taking a novel 100 mg dispersible taste-masked levofloxacin tablet found the new formulation to be more palatable (69%) and easier to prepare (81%) than the adult formulation. This formulation may assist children to better adhere to anti-tuberculous therapy.

This article is can be found here.

2. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment.
Clin Infect Dis. 2018 Nov 28;67(suppl_3):S327-S335. doi: 10.1093/cid/ciy625
Bolhuis MS, Akkerman OW, Sturkenboom MGG,  Ghimire S, Srivastava S, Gumbo T, Alffenaar JC.

ABSTRACT: Linezolid has been successfully used for treatment of multidrug-resistant tuberculosis (MDR-TB). However, dose- and duration-related toxicity limit its use. Here, our aim was to search relevant pharmacokinetics (PK)/pharmacodynamics (PD) literature to identify the effective PK/PD index and to define the optimal daily dose and dosing frequency of linezolid in MDR-TB regimens. The systematic search resulted in 8 studies that met inclusion criteria. A significant PK variability was observed. Efficacy of linezolid seems to be driven by area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC). Literature is inconclusive about the preferred administration of a daily dose of 600 mg. To prevent development of drug resistance, an AUC/MIC ratio of 100 in the presence of a companion drug at relevant exposure is required. A daily dose of 600 mg seems appropriate to balance between efficacy and toxicity. Being a drug with a very narrow therapeutic window, linezolid treatment may benefit from a more personalized approach, that is, measuring actual MIC values and therapeutic drug monitoring.

This article is can be found here.

3. Minimum inhibitory concentrations of fluoroquinolones and pyrazinamide susceptibility correlate to clinical improvement in MDR-TB patients – a nationwide Swedish cohort study over two decades.
Clin Infect Dis. 2018 Dec 18. doi: 10.1093/cid/ciy1068. [Epub ahead of print]
Davies Forsman L, Jonsson J, Wagrell C, Werngren J, Mansjö
M, Wijkander M, Groenheit R, Hammar U, Giske CG, Schön T,
Bruchfeld J.

INTRODUCTION: Minimum inhibitory concentration (MIC) testing, unlike routine drug susceptibility testing (DST) at a single critical concentration, quantifies drug resistance. The association of MICs and treatment outcome in multidrug-resistant
tuberculosis (MDR-TB) patients is unclear. Therefore, we correlated MICs of first-and second-line TB drugs with time to sputum culture conversion (tSCC) and treatment outcome in MDR-TB patients.
MATERIALS/METHODS: Clinical and demographic data of MDR-TB patients in Sweden 1992-2014 including DST results were retrieved from medical records. MIC determinations were performed retrospectively for the stored individual Mtb isolates using broth microdilution in Middlebrook 7H9. We fitted Cox proportional hazard models correlating MICs, DST results and clinical variables to tSCC and treatment outcome.                                                                                                                                                                                                                             RESULTS: Successful treatment outcome was observed in 83.5% (132/158) of MDR-TB patients. Increasing MICs of fluoroquinolones, diabetes and age > 40 years were significantly associated with unsuccessful treatment outcome. Patients treated with PZA had a significantly shorter tSCC compared to patients were not (median difference 27 days).
CONCLUSION: Increasing MICs of fluoroquinolones were correlated to unsuccessful treatment outcome in MDR-TB patients. Further studies, including MIC testing and clinical outcome data to define clinical Mtb breakpoints, are warranted. PZA treatmentwas associated with shorter tSCC, highlighting the importance of PZA DST.

This article can be found here.

4. Transmission of drug-resistant tuberculosis in HIV-endemic settings
Lancet Infect Dis. 2018 Dec 13. pii: S1473-3099(18)30537-1. doi: 10.1016/S1473-3099(18)30537-1. [Epub ahead of print]
Khan PY, Yates TA, Osman M, Warren RM, van der Heijden Y, Padayatchi N, Nardell EA, Moore D, Mathema B, Gandhi N, Eldholm V, Dheda K, Hesseling AC, Mizrahi V, Rustomjee R, Pym A.

ABSTRACT: The emergence and expansion of the multidrug-resistant tuberculosis epidemic is a threat to the global control of tuberculosis. Multidrug-resistant tuberculosis is the result of the selection of resistance-conferring mutations during inadequate antituberculosis treatment. However, HIV has a profound effect on the natural history of tuberculosis, manifesting in an increased rate of disease progression, leading to increased transmission and amplification of multidrug-resistant tuberculosis. Interventions specific to HIV-endemic areas are urgently needed to block tuberculosis transmission. These interventions should include a combination of rapid molecular diagnostics and improved chemotherapy to shorten the duration of infectiousness, implementation of infection control measures, and activescreening of multidrug-resistant tuberculosis contacts, with prophylactic regimens for individuals without evidence of disease. Development and improvement of the efficacy of interventions will require a greater understanding of the factors affecting the transmission of multidrug-resistant tuberculosis in HIV-endemic settings, including population-based molecular epidemiology studies. In this Series article, we review what we know about the transmission of multidrug-resistant tuberculosis in settings with high burdens of HIV and define the research priorities required to develop more effective interventions, to diminish ongoing transmission and the amplification of drug resistance.

This article can be accessed for free here. (With a registered Lancet account, also free)

Science-based Dosing of Second Line Antituberculosis Agents for TB Programs – IDSA Clinical Infectious Disease Volume 67, Supplement 3 

1.Pharmacokinetic/Pharmacodynamic Background and Methods and Scientific Evidence Base for Dosing of Second-line Tuberculosis Drugs

2. Gatifloxacin Pharmacokinetics/Pharmacodynamics–based Optimal Dosing for Pulmonary and Meningeal Multidrug-resistant Tuberculosis

3. Artificial intelligence–derived 3-Way Concentration-dependent Antagonism of Gatifloxacin, Pyrazinamide, and Rifampicin During Treatment of Pulmonary Tuberculosis

4. Levofloxacin Pharmacokinetics/Pharmacodynamics, Dosing, Susceptibility Breakpoints, and Artificial Intelligence in the Treatment of Multidrug-resistant Tuberculosis

5. Amikacin Dosing for MDR Tuberculosis: A Systematic Review to Establish or Revise the Current Recommended Dose for Tuberculosis Treatment

6. D-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal

7. Ethionamide Pharmacokinetics/Pharmacodynamics-derived Dose, the Role of MICs in Clinical Outcome, and the Resistance Arrow of Time in Multidrug-resistant Tuberculosis

8. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment

9.  The Sterilizing Effect of Intermittent Tedizolid for Pulmonary Tuberculosis

10. Multiparameter Responses to Tedizolid Monotherapy and Moxifloxacin Combination Therapy Models of Children With Intracellular Tuberculosis

11. Transformation Morphisms and Time-to-Extinction Analysis That Map Therapy Duration From Preclinical Models to Patients With Tuberculosis: Translating From Apples to Oranges

12.  Efficacy Versus Hepatotoxicity of High-dose Rifampin, Pyrazinamide, and Moxifloxacin to Shorten Tuberculosis Therapy Duration: There Is Still Fight in the Old Warriors Yet!

13. The Role of Novel Approaches and New Findings in the Pharmacology of Tuberculosis Medicines in Improving Treatment Outcomes

*The above links provide abstracts to the articles

New: MDR-TB Clinical Trials Landscape Supplement now online

The Pediatric Multidrug Resistant Tuberculosis Clinical Trials Landscape Supplement has been published in the International Journal of Tuberculosis and Lung Disease and is now available online! The supplement can be found in the December 2016 issue of the IJTDL – find a direct link to the issue and all included articles here.

A complete list of articles included in the Supplement is below:

Horsburgh, C. Robert; Rusen, I.D.; Mitnick, Carole D. 

Phillips, P.P.J.

Cellamare, M.; Milstein, M.; Ventz, S.; Baudin, E.; Trippa, L.; Mitnick, C.D.

Davies, G.R.; Wallis, R.S. 

Milstein, M.; Brzezinski, A.; Varaine, F.; Mitnick, C.D.

Dheda, K.; Esmail, A.; Limberis, J.; Maartens, G.

Gupta, R.; Wells, C.D.; Hittel, N.; Hafkin, J.; Geiter, L.J.

Murray, S.; Mendel, C.; Spigelman, M.

Sterling, T.R.

Nuermberger, E.

O’Donnell, M.R.; Padayatchi, N.; Metcalfe, J.Z.

 

Updated Research Agenda for the Programmatic Management of Drug-Resistant Tuberculosis

On May 25, PLoS One published an article by Dr. Carole Mitnick et al. on the updated research agenda for the programmatic management of drug-resistant tuberculosis (PMDT). The authors built upon previous PMDT publications by reviewing resources including guidelines, documents, websites and publications published between January 2008 and August 2013 that cited the last research agenda released in 2008. Resources reviewed spanned five main research categories: Laboratory Support, Epidemiology, Programmatically Relevant Research, Treatment Strategy, and Management of Contacts. Results showed that there was continuity around the priorities for research in PMDT that could help fill longstanding evidence gaps barring expanded treatment access.  Identified priorities specifically highlighted the importance of increased coordinated efforts to address questions regarding: shorter treatment regimens; knowledge of disease burden without representative data; and treatment for latent TB infection in household contacts of known drug-resistant (DR-TB) patients. Addressing such questions is essential to stem the epidemic of TB, including DR-TB.

Read the open-access article here.

Ambulatory multi-drug resistant tuberculosis treatment outcomes in a cohort of HIV-infected patients in a slum stting in Mumbai, India

Isaakidis P, Cox H, Varghese B, et al. PLoS One 2011; 6(12): e28066.

A study on the results of providing MDR-TB treatment to patients on an ambulatory basis and under directly observed therapy using a decentralized network of providers. Encouraging results were achieved, though authors warn that a rapid scale-up of both ART and second-line treatment for MDR-TB is needed to mitigate the growing epidemic.

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A Phase IIa Trial of the New Tuberculosis Vaccine, MVA85A, in HIV- and/or Mycobacterium tuberculosis-Infected Adults.

Scriba, T.J., Tameris, M., Smit, E., van der Merwe, L., et al. Am J Resp Crit Care Med 2012; 185(7): 769-78. Epub 2012 Jan 26. 

Novel TB vaccines should be safe and effective in populations infected with Mycobacterium tuberculosis (M.tb) and/or HIV for effective TB control. This study determined the safety and immunogenicity of MVA85A, a novel TB vaccine, among M.tb- and/or HIV-infected persons in a setting where TB and HIV are endemic. An open-label, phase IIa trial was conducted in 48 adults with M.tb and/or HIV infection. Safety and immunogenicity were analyzed up to 52 weeks after intradermal vaccination with 5 × 10(7) plaque-forming units of MVA85A. No significant effect of antiretroviral therapy on immunogenicity of MVA85A was observed. MVA85A was safe and immunogenic in persons with HIV and/or M.tb infection. These results support further evaluation of safety and efficacy of this vaccine for prevention of TB in these target populations.

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A systematic review of the cost and cost effectiveness of treatment for multidrug-resistant tuberculosis

Fitzpatrick C, Floyd K. Pharmacoeconomics 2012; 30(1): 63-80.

The authors conducted a systematic review of the cost and cost effectiveness of treatment for MDR-TB and synthesized the available data. They concluded that treatment for MDR-TB can be cost effective in low- and middle-income countries. Evidence of the cost effectiveness of outpatient vs inpatient models of care are limited and more data is needed from Africa and Asia – though unless there is strong evidence that hospitalization is necessary to achieve high rates of adherence to treatment, patients with MDR-TB should be treated using mainly ambulatory care.

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Daily 300 mg dose of linezolid for multidrug-resistant and extensively drug-resistant tuberculosis: updated analysis of 51 patients.

Koh WJ, Kang YR, Jeon K, Kwon OJ, Lyu J, Kim WS, Shim TS. J Antimicrob Chemother 2012;67(6):1503-7. Epub 2012 Mar 8.

The objective was to evaluate the efficacy, tolerability and adverse events of a 300 mg daily dose of linezolid in the treatment of MDR/XDR-TB. The study retrospectively reviewed the medical records of 51 MDR-TB patients, including 26 patients (51%) with XDR-TB, to evaluate the safety, tolerability and efficacy of therapy with 300 mg/day linezolid. All patients had failed previous treatments with second-line anti-TB drugs. The findings suggest that linezolid at a daily dose of 300 mg is effective against intractable MDR/XDR-TB, and may be associated with fewer neuropathic side effects than a daily dose of 600 or 1200 mg.

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Editorial: Encouraging News for multidrug-resistant tuberculosis treatment

Mitnick C and Horsburgh CR. Am J Respir Crit Med 2010; 182: 1337-43.

This editorial highlights a report of a short, highly effective standardized MDR-TB treatment regimen published in an earlier issue of the journal. The report, published by Van Deun and colleagues, describes a 9-month regimen containing 7 drugs in the intensive phase that achieved a cure in 88% of patients with MDR-TB in Bangladesh. Though the authors of the editorial point out some potential limitations, they maintain that if the regimen could assure similar results in heterogenous populations, it could represent a major advance in MDR-TB treatment. They encourage further randomized, controlled trials of multidrug regimens for MDR-TB in order to further tailor their efficacy and tolerability.

Frequency and type of microbiological monitoring of multidrug-resistant tuberculosis treatment

Kurbatova EV, Gammino VM, Bayona J, et al. IJTLD 2011; 15(11): 1553-5.

A retrospective analysis of three alternative monitoring strategies in a cohort of MDR-TB patients in Estonia, Latvia, Philippines, Russia and Peru (2000-2004), which illustrates that less frequent testing delays confirmation of bacteriological conversion. The delay prolongs intensive treatment, hospitalization, and respiratory isolation, increasing cost and toxicity. After conversion, less frequent testing could delay diagnosis of possible treatment failure.

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Household contact investigation of multidrug-resistant and extensively drug-resistant tuberculosis in a high HIV prevalence setting.

Vella V, Racalbuto V, Guerra R, et al. IJTLD 2011; 15(9): 1170-5.

A prospective, observational study evaluating adult household contacts for active TB in order to determine the incidence rates of MDR- and XDR-TB of index cases diagnosed between January 2005 and September 2008 in a high HIV prevalnece setting. The authors conclude that active case finding for drug-resistant TB is a high-yield public health activity and must be a priority, as early diagnosis may stem further disease spread and improve survival.

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