Effects of treatment and drug resistance on the transmission dynamics of malaria in endemic areas

We present a mathematical model for malaria treatment and spread of drug resistance in an endemic population. The model considers treated humans that remain infectious for some time and partially immune humans who are also infectious to mosquitoes although their infectiousness is always less than their non immune counterparts. The model is formulated by considering delays in the latent periods in both mosquito and human populations and in the period within which partial immunity is lost. Qualitative analysis of the model including positivity and boundedness of solutions is performed. Analysis of the reproductive numbers shows that if the treated humans become immediately uninfectious to mosquitoes then treatment will always reduce the number of sensitive infections. If however treated humans are infectious then for treatment to effectively reduce the number of sensitive infections, the ratio of the infectious period of the treated humans to the infectious period of the untreated humans multiplied by the ratio of the transmission rate from a treated human to the transmission rate of an untreated human should be less than one. Our results show that the spread of drug resistance with treatment as a control strategy depends on the ratio of the infectious periods of treated and untreated humans and on the transmission rates from infectious humans with resistant and sensitive infections. Numerical analysis is performed to assess the effects of treatment on the spread of resistance and infection. The study provides insight into the possible intervention strategies to be employed in malaria endemic populations with resistant parasites by identifying important parameters.     

A sticky situation: the unexpected stability of malaria elimination

Malaria eradication involves eliminating malaria from every country where transmission occurs. Current theory suggests that the post-elimination challenges of remaining malaria-free by stopping transmission from imported malaria will have onerous operational and financial requirements. Although resurgent malaria has occurred in a majority of countries that tried but failed to eliminate malaria, a review of resurgence in countries that successfully eliminated finds only four such failures out of 50 successful programmes. Data documenting malaria importation and onwards transmission in these countries suggests malaria transmission potential has declined by more than 50-fold (i.e. more than 98%) since before elimination. These outcomes suggest that elimination is a surprisingly stable state. Elimination''s ‘stickiness’ must be explained either by eliminating countries starting off qualitatively different from non-eliminating countries or becoming different once elimination was achieved. Countries that successfully eliminated were wealthier and had lower baseline endemicity than those that were unsuccessful, but our analysis shows that those same variables were at best incomplete predictors of the patterns of resurgence. Stability is reinforced by the loss of immunity to disease and by the health system''s increasing capacity to control malaria transmission after elimination through routine treatment of cases with antimalarial drugs supplemented by malaria outbreak control. Human travel patterns reinforce these patterns; as malaria recedes, fewer people carry malaria from remote endemic areas to remote areas where transmission potential remains high. Establishment of an international resource with backup capacity to control large outbreaks can make elimination stickier, increase the incentives for countries to eliminate, and ensure steady progress towards global eradication. Although available evidence supports malaria elimination''s stickiness at moderate-to-low transmission in areas with well-developed health systems, it is not yet clear if such patterns will hold in all areas. The sticky endpoint changes the projected costs of maintaining elimination and makes it substantially more attractive for countries acting alone, and it makes spatially progressive elimination a sensible strategy for a malaria eradication endgame.     

Urinary metabolite markers characterizing tuberculosis treatment failure

Background

Considering that approximately 15% of the nine million new tuberculosis (TB) cases reported per annum are not treated successfully, new, distinctive and specific biomarkers are needed to better characterize the biological basis of a poor treatment outcome.

Methods

Urine samples from 41 active pulmonary TB patients were collected at baseline (time of diagnosis), during treatment (weeks 1, 2 and 4) and 2 weeks after treatment completion (week 26). These samples were divided into successful (cured) and unsuccessful (failed) treatment outcome groups and analyzed using a GCxGC-TOFMS metabolomics research approach.

Results

The metabolite data collected showed clear differentiation of the cured and failed treatment outcome groups using the samples collected at the time of diagnosis, i.e. before any treatment was administered.

Conclusions

The treatment failure group was characterized by an imbalanced gut microbiome, in addition to elevated levels of metabolites associated with abnormalities in the long-chain fatty acid β-oxidation pathway, accompanied by reduced l-carnitine and short-chain fatty acids, indicative of a mitochondrial trifunctional protein defect in particular. Furthermore, an altered amino acid metabolism was also observed in these patients, which confirms previous findings and associations to increased interferon gamma due to the host’s immune response to M. tuberculosis and a compromised insulin secretion.

     

Theoretical analysis of mixed Plasmodium malariae and Plasmodium falciparum infections with partial cross-immunity

A deterministic model for assessing the dynamics of mixed species malaria infections in a human population is presented to investigate the effects of dual infection with Plasmodium malariae and Plasmodium falciparum. Qualitative analysis of the model including positivity and boundedness is performed. In addition to the disease free equilibrium, we show that there exists a boundary equilibrium corresponding to each species. The isolation reproductive number of each species is computed as well as the reproductive number of the full model. Conditions for global stability of the disease free equilibrium as well as local stability of the boundary equilibria are derived. The model has an interior equilibrium which exists if at least one of the isolation reproductive numbers is greater than unity. Among the interesting dynamical behaviours of the model, the phenomenon of backward bifurcation where a stable boundary equilibrium coexists with a stable interior equilibrium, for a certain range of the associated invasion reproductive number less than unity is observed. Results from analysis of the model show that, when cross-immunity between the two species is weak, there is a high probability of coexistence of the two species and when cross-immunity is strong, competitive exclusion is high. Further, an increase in the reproductive number of species i increases the stability of its boundary equilibrium and its ability to invade an equilibrium of species j. Numerical simulations support our analytical conclusions and illustrate possible behaviour scenarios of the model.