I was under the impression that the WHO and other international health organizations laid down (non-mandatory) policy guidelines for the treatment of malaria and that endemic countries did not really care about those guidelines. After all, doctors prescribe the medication and are trained to tailor it to the needs of their patient, right ? As I read on the subject though, I quickly found that the Medical Association and Health Department of every malaria-endemic country has it's own mandatory policy based on the WHO's guidelines.
An overview of the chemotherapy policies for different regions are listed on the WHO's website here. (WHO, 2013)
Even as early as 1990, the WHO had some "General considerations for the development of a malaria treatment policy". I have briefly discussed some of them here, but the considerations are not restricted to the ones listed below.
The seasonality of the disease and the level of acquired immunity in the population are epidemiological factors that must be accounted for in Rx policies. Severity of illness is severely influenced by the species of Plasmodium that has infected the person. Drug resistance too depends on the species, with P.falciparum being the most prone to develop drug resistance. So, prevalance and drug sensitivity studies are essential before polices are drafted.
Availability of malaria services in a region heavily influences the success of chemotherapeutic intervention policies. Malaria services are best implemented in association with general health services, than as stand alone programs. Such an integration, if necessary, must be spelled out clearly.
It is also essential to identify and define high risk groups/individuals, who would need prophylaxis. This would help in triage in outbreak settings and also in delivering radical curative treatment in unstable malaria areas.
Treatment regimens are also usually available in the policies , for different age groups and physiological conditions (pregnancy etc). However, these must be tailored to suit each individual patient's needs as many of the regimens are based on clinical trials and are not validated for field conditions. Regimens must take into account the medical supervision available for the treatment, that is, different forms of the drugs can/must be used for outpatients and some other forms are better suited for in-hospital administration.
Sociological aspects such as self medication must be taken into account too.
Unit cost of the drug and number of doses needed form the basis of the economy of chemotherapy Subsidies play a huge role in adherence to therapy regimens, by giving a pseudo-increase in buying power. But, even with subsidies and free medication, adherence is not 100%, which on a side note is one of the driving forces for resistance development.
Here is an example , from India, of the national drug policy against malaria :
The chemotherapy recommendations are given by the National Vector Borne Disease Control Programme, operating under the Ministry of Health & Family Welfare, Govt of India. The policy statement, in the 2013 edition, declares that one of the aims is "to minimize the risk of spread of drug resistant parasites by use of effective drugs in appropriate doses for everyone". With that goal in mind, the drug policy is intended to be "Appropriate for today and safe for tomorrow".
The ultimate goals of these policies are to provide complete clinical and parasitological cure of all malaria cases, prevent the progression of uncomplicated malaria into severe malaria and thereby reduce mortality, prevent relapse by administration of chemotherapeutic agents, interrupt transmission by the use of gametocytocidal drugs and prevent the development of drug resistant malaria .
References:
Neave PE, Taylor S, Behrens RH. Does public subsidy of the cost of malaria chemoprophylaxis reduce imported malaria? A comparative policy analysis. Malar J 2013;12:238.
Country antimalarial drug policies: by region. (n.d.). WHO. Retrieved October 22, 2013, from http://www.who.int/malaria/am_drug_policies_by_region_afro/en/index.html
National Vector Borne Disease Control Programme (NVBDCP). (n.d.). National Vector Borne Disease Control Programme (NVBDCP). Retrieved October 22, 2013, from http://nvbdcp.gov.in/
Tuesday, October 22, 2013
Tuesday, October 15, 2013
Antimalarial drug resistance - Who is to blame?
Malaria treatment failure can arise either due to true antimalarial drug resistance or due to failure to clear malarial parasites from the circulation. The latter is due to incorrect dosing, non-compliance with the duration of dosing, poor drug quality , drug interactions, poor or erratic absorption and misdiagnosis. (Sosa, 2010)
The problem of misdiagnosis is essentially one of overdiagnosis. In many endemic countries, many febrile cases are prescribed antimalarial medication. A prospective observational study conducted in Afghanistan noted that 99% of the bloodsmear-negative patients received antimalarial medication when the diagnosis was based solely on clinical diagnosis. But even when blood smears were used for diagnosis, 50% of smear-negative patients received the medication. (Leslie, 2012). Many patients were thus unnecessarily exposed to the drugs and if they had had low parasitemia, there would have been enough selection pressure to cause drug resistance development.
Unregulated dispensing of drugs is another common problem and is frequently associated with the self-medication. In many developing countries, prescription medication can commonly be purchased over the counter. These include antibiotics and antimalarial drugs. Although there are laws to prevent such practices, these are almost always ignored. The ethics of pharmaceutical personnel are also questionable in these cases and may arise out of sheer ignorance of both pharmaceutical ethics and sound science.
(Dernavich)
Poverty driven practices are explored in the paper by Planta, M. , titled "The role of poverty in Antimicrobial resistance" , published in the Journal of American Board of Family Medicine, in Nov 2007. The author compares the practices in developing and developed nations. Noncompliance takes different forms in these cohorts, with the factors in developing countries being inadequate access to effective drugs, unregulated manufacture and dispensation of antimicrobials and lack of money to pay for appropriate, high quality medication. In contrast, the practices in developed countries mainly are sharing of antimicrobials and self medication using leftovers from unfinished drug regimens . (Planta MB, 2007). This was also explored at length in the reading for the day (McNulty,2007). Although both the articles explored antibacterial resistance, the same principles apply to sociology of antimalarial resistance.
Other factors that affect drug compliance include age, sex, martial status,educational level, ability to read and household monthly income. A demographical study of arteminisin combination therapy compliance conducted in rural Kenya revealed that only upto 47% of all malaria patients adhered to therapy, in terms of duration and dosage. Of these, 58% were <13 years of age. Adherence was higher among females (55.7%) than males (50.3%). Underaged patients (children) were the most adherent (57.1%), when compared to the married (21.4%), widowed (7.9%), single (2.9%), and separated (0.7%). (Onyango EO,2012) . This was probably because of higher concern among parents when the children are affected. Busyness and forgetfulness may be contributing factors among the older age groups, because no one intentionally wants to die of malaria, when they have access to medicines.Curiously, adherence increased as household size increased , with households with >6 people being more compliant than others. Undoubtedly, the statistics from this study cannot be extrapolated to wide regions across the globe. But, it gives a glimpse of the various factors that ought to be addressed when policies are laid down to overcome antimalarial resistance.
Increasing the awareness of people everywhere to antimicrobial resistance is an essential next step. Targeted education, information and communication activities are the need of the hour to reduce the risk of contributing to antimalarial resistance. Extension strategies used for doctors and health care workers, pharmaceutical personnel, policy makers and ordinary people residing in endemic areas must be specially designed to adequately cater to each group. Together, we can achieve our goal of overcoming antimalarial resistance.
References :
Leslie T, Mikhail A, Mayan I, et al. Overdiagnosis and mistreatment of malaria among febrile patients at primary healthcare level in Afghanistan: observational study. BMJ 2012;345:e4389.
Sosa AbdJ. Antimicrobial resistance in developing countries. New York: Springer, 2010.
Planta MB. The role of poverty in antimicrobial resistance. J Am Board Fam Med 2007;20:533-539.
McNulty CA, Boyle P, Nichols T, et al. The public's attitudes to and compliance with antibiotics. J Antimicrob Chemother 2007;60 Suppl 1:i63-68
Onyango EO, Ayodo G, Watsierah CA, et al. Factors associated with non-adherence to Artemisinin-based combination therapy (ACT) to malaria in a rural population from holoendemic region of western Kenya.BMC Infect Dis 2012;12:143.
Cartoons :
Dernavich, D. http://www.condenaststore.com/-sp/Woman-looking-at-pharmacy-shelves-labelled-Classics-Best-Sellers-and-New-Yorker-Cartoon-Prints_i8479870_.htm
Glasbergen, R. http://www.glasbergen.com/pharmacy-cartoons/
The problem of misdiagnosis is essentially one of overdiagnosis. In many endemic countries, many febrile cases are prescribed antimalarial medication. A prospective observational study conducted in Afghanistan noted that 99% of the bloodsmear-negative patients received antimalarial medication when the diagnosis was based solely on clinical diagnosis. But even when blood smears were used for diagnosis, 50% of smear-negative patients received the medication. (Leslie, 2012). Many patients were thus unnecessarily exposed to the drugs and if they had had low parasitemia, there would have been enough selection pressure to cause drug resistance development.
(Dernavich)Poverty driven practices are explored in the paper by Planta, M. , titled "The role of poverty in Antimicrobial resistance" , published in the Journal of American Board of Family Medicine, in Nov 2007. The author compares the practices in developing and developed nations. Noncompliance takes different forms in these cohorts, with the factors in developing countries being inadequate access to effective drugs, unregulated manufacture and dispensation of antimicrobials and lack of money to pay for appropriate, high quality medication. In contrast, the practices in developed countries mainly are sharing of antimicrobials and self medication using leftovers from unfinished drug regimens . (Planta MB, 2007). This was also explored at length in the reading for the day (McNulty,2007). Although both the articles explored antibacterial resistance, the same principles apply to sociology of antimalarial resistance.
Other factors that affect drug compliance include age, sex, martial status,educational level, ability to read and household monthly income. A demographical study of arteminisin combination therapy compliance conducted in rural Kenya revealed that only upto 47% of all malaria patients adhered to therapy, in terms of duration and dosage. Of these, 58% were <13 years of age. Adherence was higher among females (55.7%) than males (50.3%). Underaged patients (children) were the most adherent (57.1%), when compared to the married (21.4%), widowed (7.9%), single (2.9%), and separated (0.7%). (Onyango EO,2012) . This was probably because of higher concern among parents when the children are affected. Busyness and forgetfulness may be contributing factors among the older age groups, because no one intentionally wants to die of malaria, when they have access to medicines.Curiously, adherence increased as household size increased , with households with >6 people being more compliant than others. Undoubtedly, the statistics from this study cannot be extrapolated to wide regions across the globe. But, it gives a glimpse of the various factors that ought to be addressed when policies are laid down to overcome antimalarial resistance.
Increasing the awareness of people everywhere to antimicrobial resistance is an essential next step. Targeted education, information and communication activities are the need of the hour to reduce the risk of contributing to antimalarial resistance. Extension strategies used for doctors and health care workers, pharmaceutical personnel, policy makers and ordinary people residing in endemic areas must be specially designed to adequately cater to each group. Together, we can achieve our goal of overcoming antimalarial resistance.
References :
Leslie T, Mikhail A, Mayan I, et al. Overdiagnosis and mistreatment of malaria among febrile patients at primary healthcare level in Afghanistan: observational study. BMJ 2012;345:e4389.
Sosa AbdJ. Antimicrobial resistance in developing countries. New York: Springer, 2010.
Planta MB. The role of poverty in antimicrobial resistance. J Am Board Fam Med 2007;20:533-539.
McNulty CA, Boyle P, Nichols T, et al. The public's attitudes to and compliance with antibiotics. J Antimicrob Chemother 2007;60 Suppl 1:i63-68
Onyango EO, Ayodo G, Watsierah CA, et al. Factors associated with non-adherence to Artemisinin-based combination therapy (ACT) to malaria in a rural population from holoendemic region of western Kenya.BMC Infect Dis 2012;12:143.
Cartoons :
Dernavich, D. http://www.condenaststore.com/-sp/Woman-looking-at-pharmacy-shelves-labelled-Classics-Best-Sellers-and-New-Yorker-Cartoon-Prints_i8479870_.htm
Glasbergen, R. http://www.glasbergen.com/pharmacy-cartoons/
Tuesday, October 8, 2013
The pharmacological basis of anti-malarial therapeutics
As we move into module 2 , "Chemotherapy and Resistance", we shift our focus from prophylaxis (prevention) to therapeutics (treatment). Chemotherapy, which is the use of chemical substances for therapy, against malaria is primarily available in the form of antiprotozoal drugs and anti-vector drugs (insecticides). This post will primarily focus on the drugs available and on resistance mechanisms.
There are three major classes of drugs that are clinically useful. Class I agents are used to treat or prevent clinically symptomatic malaria, but are not reliable against primary or latent liver stages or P.falciparum gametocytes.
Class II agents can target the asexual erythrocytic and the primary liver stages.
Class III agent can kill primary and latent liver stages as well as gametocytes.
The drugs are summarized below :
The timeline of drugs used against malaria, their introduction and establishment of resistance have been summarized (click to enlarge):
Current status :
Congeners of Chloroquine have been developed , which seem to be effective against chloroquine-resistant Plasmodium species. The antifolate drug combination (sulfadoxine and pyrimethamine) are still used in preventative therapy. Atovaquone and proguanil have recently also been used for prevention. Artemisinin and its derivatives form the core therapy primarily because of their speed of action, their efficacy against chloroquine-resistant Plasmodium and the additional effect of reducing transmission.
Drugs efficacious against P.falciparum is assumed to be effective against all the other Plasmodium species. However, the hypnozoite form of P.vivax can only be killed by treatment with primaquine.
Many other drugs and combinations are in clinical development. Example : NITD609, which is a spiroindolone that attacks the Na-ATPase PfATP4 is in Phase II trial.
Resistance mechanisms of Plamodium sps :
These have been summarized :
Abbreviations: PfCRT: P. falciparum chloroquine resistance transporter; PfMDR1: P. falciparum multidrug resistance transporter 1; PfMRP: P. falciparum multidrug resistance protein; CQ: chloroquine; AQ: amodiaquine; MQ: mefloquine; LM: lumefantrine; ART: artemisinin (and derivatives); KO: knock-out; RBC: red blood cell; P: parasite; DV: digestive vacuole.
References :
There are three major classes of drugs that are clinically useful. Class I agents are used to treat or prevent clinically symptomatic malaria, but are not reliable against primary or latent liver stages or P.falciparum gametocytes.
Class II agents can target the asexual erythrocytic and the primary liver stages.
Class III agent can kill primary and latent liver stages as well as gametocytes.
The drugs are summarized below :
The timeline of drugs used against malaria, their introduction and establishment of resistance have been summarized (click to enlarge):
Current status :
Congeners of Chloroquine have been developed , which seem to be effective against chloroquine-resistant Plasmodium species. The antifolate drug combination (sulfadoxine and pyrimethamine) are still used in preventative therapy. Atovaquone and proguanil have recently also been used for prevention. Artemisinin and its derivatives form the core therapy primarily because of their speed of action, their efficacy against chloroquine-resistant Plasmodium and the additional effect of reducing transmission.
Drugs efficacious against P.falciparum is assumed to be effective against all the other Plasmodium species. However, the hypnozoite form of P.vivax can only be killed by treatment with primaquine.
Many other drugs and combinations are in clinical development. Example : NITD609, which is a spiroindolone that attacks the Na-ATPase PfATP4 is in Phase II trial.
Resistance mechanisms of Plamodium sps :
These have been summarized :
References :
Ines Petersen, Richard Eastman, Michael Lanzer, Drug-resistant malaria: Molecular mechanisms and implications for public health, FEBS Letters, Volume 585, Issue 11, 6 June 2011, Pages 1551-1562
Subscribe to:
Posts (Atom)