Person:

Kunkel, Amber

Tuberculosis (TB) recently surpassed HIV as the world’s leading infectious killer. Because antibiotic therapy forms the cornerstone of TB control, prevention, and treatment, it is important to apply TB drugs in a way that maximizes their potential benefits while minimizing the risks of resistance. Here, I present three modeling analyses intended to explore these tensions inherent in the use of TB drugs.

Preventive therapy involves the use of antimicrobials in asymptomatic and noninfectious individuals, and has been applied to diseases ranging from TB to HIV to malaria. In my first paper, I outline how population use of preventive therapy could increase, decrease, or have non-monotonic effects on the prevalence of drug resistance, depending on the relative contributions of resistance acquired as a result of preventive therapy, resistance acquired as a result of treatment for active disease, and transmitted resistance.

In my second paper, I consider the specific use of isoniazid preventive therapy (IPT) to prevent active TB among people living with HIV. Previous models have suggested that widespread IPT use could increase the prevalence of drug resistant TB by providing a selective pressure in favor of resistant strains. In this paper, I show that the impact of IPT on drug resistance is highly dependent on the projected TB/HIV epidemic trends, and that the risks of resistance are likely to remain low for even lifelong IPT durations as long as transmission is already declining.

Finally, in my third paper, I present a decision analytic model to determine the optimal targeting of the new TB drug bedaquiline for patients with pre-existing resistance to other available drugs. The optimal use strategy for this new drug depends on the outcome being considered; whereas more liberal strategies would likely decrease resistance to existing drugs as well as onward transmission, more restrictive strategies would decrease resistance to bedaquiline. More research is needed to confirm that more liberal bedaquiline use strategies would improve life expectancy.

Overall, these papers illustrate the complexity of the decisions surrounding optimal TB drug use. Thoughtful antibiotic policies, coupled with continued innovation, are needed to effectively combat the global burden of TB.

Background: Tuberculosis (TB) diagnosis continues to rely on sputum smear microscopy in many settings. We conducted a meta-analysis to estimate the percentage of children and adults with tuberculosis that are sputum smear positive. Methods: We searched PubMed, MEDLINE, Embase, and Global Health databases for studies that included both children and adults with all forms of active TB. The pooled percentages of children and adults with smear positive TB were estimated using the inverse variance heterogeneity model. This review was registered in the PROSPERO database under registration number CRD42015015331. Results: We identified 20 studies meeting our inclusion criteria that reported smear positivity for a total of 18,316 children and 162,574 adults from 14 countries. The pooled percentage of paediatric TB cases that were sputum smear positive was 6.8 % (95 % Confidence Interval (CI) 2.2–12.2 %), compared with 52.0 % (95 % CI 40.0–64.0 %) among adult cases. Eight studies reported data separately for children aged 0–4 and 5–14. The percentage of children aged 0–4 that were smear positive was 0.5 % (95 % CI 0.0–1.9 %), compared with 14.0 % (95 % CI 8.9–19.4 %) among children aged 5–14. Conclusions: Children, especially those aged 0–4, are much less likely to be sputum smear positive than adults. National TB programs relying on sputum smear for diagnosis are at risk of under-diagnosing and underestimating the burden of TB in children. Electronic supplementary material The online version of this article (doi:10.1186/s12879-016-1617-9) contains supplementary material, which is available to authorized users.