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Column: How might the antibiotics challenge relate to malaria? - by Jenni Lawton

September 4, 2014 - 18:14 -- Ingeborg van Schayk
The column below was contributed by Jenni Lawton.
 
£10 million Longitude prize for antibiotics: opening up the search for rapid detection methods
 
Less than a century after the discovery of penicillin, antibiotics have transformed medicine, adding an estimated 20 years onto our lives. Yet the rapid acquisition and spread of resistance have left us vulnerable to the threat of regressing back to the pre-antibiotic era. Similarly for anti-malarials, resistance to chloroquine began to develop within less than 20 years of widespread use [1] and artemisinin now seems to be following the same trend [2][3].
 
So how can we avoid the worrying fate posed by these predictions? Of course, drug discovery remains vital, but the careful use of our existing arsenal could drastically increase their remaining useful ‘shelf lives’. The malaria community has demonstrated this by restricting chloroquine use, resulting in sensitivity increases in the absence of continued selection [4][5]. Crucial to such management strategies are accurate means to detect which drugs will be effective for treatment.
 

Improving naval navigation

In 1714, the original Longitude prize was launched to help mariners have a more accurate means to determine their position at sea. Until then, most navigation relied on astronomy to determine longitude: the east-west position. John Harrison produced a clock that could keep time accurately at sea, making it possible to navigate by calculating the time distance from Greenwich Mean Time & hence longitude. His ‘marine chronometer’ made navigation safer and thereby also helped expand trade across the globe.

This summer, a prize has been launched as an incentive to encourage new ideas in the search for better detection of antibiotic resistance. This is based on a historic challenge, which aimed to find an accurate method of determining longitude at sea, as poor navigation and shipwrecks were costing thousands of lives (outlined in box). Renewing this idea for the 21st century, the 2014 Longitude prize was announced earlier this year http://www.longitudeprize.org, to encourage everyone to participate in solving this problem.

What does the antibiotics challenge ask?

“The focus of the £10m award will go to the best idea for a cheap, fast and accurate detector for bacteria and their associated antibiotic resistance mechanisms that could help better guide treatment.” The successful design will enable clinicians to use the most appropriate antibiotics for each patient, making the best use of our arsenal of drugs; extending their useful life, whilst preventing the spread and / or development of resistance.

If you’re interested, sign up now! The competition is open to everyone to register (Register your interest), and then entries can be made from this autumn onwards, according to the timeline below:

How might the antibiotics challenge relate to malaria?

  • Similar strategies could be used to help rationalise our use of antimalarials
  • Some antibiotics are effective against Plasmodium spp (eg doxycycline) so increased development and easier screening of compounds could also identify novel antimalarials
  • Rapid methods to assess drug efficacy may aid detection of fake drugs, which often contain less active compound than their licenced counterparts, facilitating development of resistance
  • Developing novel rapid diagnostics for bacteria may help design better malaria detection methods too, improving the utility of the rapid diagnostic tests that are already available.
This last point is a particular challenge because detection of malaria parasites may not reflect an individual’s risk of illness.
 
From our research collaborations with colleagues at MLW, Blantyre, Malawi, I’ve been surprised to learn how basic the needs for diagnosis still are. For example, it is difficult to predict how many children with detectable asymptomatic parasitaemia will go on to develop illness and severe complications. When presented with a sick child, this is an enormous decision for clinical officers to make with very limited resources, especially as some complications such as cerebral malaria can develop very rapidly! Should they send the child to hospital just in case, potentially costing the family a month’s wages? Or send the child home with oral therapy, knowing that they could deteriorate overnight?
 
In this scenario, detecting the presence or absence of parasites isn’t enough, but if the total parasite burden could influence disease outcome, then a quantitative measure would be invaluable [6]. One potential biomarker is Plasmodium falciparum histidine-rich protein 2 (PfHRP2), a protein released during schizont rupture so plasma concentrations reflect the total parasite burden. High PfHRP2 concentrations have been associated with severe disease in African children [7], although not all P. falciparum strains contain this antigen so an ideal test would combine several biomarkers, including detection of other Plasmodium spp.
 
If these strategies could be improved, made stable and easy to use in resource poor settings, they could revolutionize our ability to treat malaria complications. In conjunction with rapid measures of drug sensitivity, it might even be possible to do all this without immediate use of novel drugs. Although we have several rapid diagnostic tests (RDTs) available, these remain limited and further improvements could help to identify patients at risk of complications for preventative therapy. The more we understand about parasite and host biology, the better we can find appropriate biomarkers; and perhaps the Longitude antibiotics challenge will provide some unexpected help either in terms of biomarker discovery or RDT design and supply. You can keep up with developments by following @longitude_prize on Twitter or visiting http://www.longitudeprize.org/blog.

References:
[1] Wellems TE & Plowe CV (2001). Chloroquine-Resistant Malaria. The Journal of Infectious Diseases. 184:770-776.
[2] Dondorp AM, Nosten F, Yi P, et al. (2009). Artemisinin Resistance in Plasmodium falciparum Malaria. New England Journal of Medicine. 361:455-467.
[3] Phyo AP, Nkhoma S, Stepniewska K, et al. (2012). Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. The Lancet. 379: 1960-1966.
[4] Kublin JG, Cortese JF, Njunju EM, et al. (2003). Re-emergence of Chloroquine-Sensitive Plasmodium falciparum Malaria after Cessation of Chloroquine Use in Malawi. The Journal of Infectious Diseases. 187: 1870-1875.
[5] Kebede S, Medhin G, Berhe N, et al. (2014). Return of chloroquine-sensitive Plasmodium falciparum parasites and emergence of chloroquine-resistant Plasmodium vivax in Ethiopia. Malaria Journal. 13:244.
[6] Manning L & Davis TME. (2013). The mechanistic, diagnostic and prognostic utility of biomarkers in severe malaria. Biomarkers in Medicine.  7: 363-380.
[7] Hendriksen ICE, Mwanga-Amumpaire J, von Seidlein L, et al. (2012). Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement. PLoS Medicine. DOI: 10.1371/journal.pmed.1001297
 

Jenni Lawton is a post-doctoral researcher at the University of Glasgow, UK. Her research interests focus on the interactions between Plasmodium infected red blood cells (iRBCs) and the host; dynamic processes which are still incompletely understood. The behaviour of iRBCs may have important implications both in generating effective immune responses and in the escalation of some malaria infections towards severe complications. This will be her first foray into communications and she hopes to provide some interesting perspectives from the lab to the Malaria World community!