Malaria medical therapy: Difference between revisions

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__NOTOC__
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{{Malaria}}
{{Malaria}}
{{CMG}}
{{CMG}} '''Associate Editor-In-Chief:'''{{MD}};


==Overview==
==Overview==
Active malaria infection with ''P. falciparum'' is a [[medical emergency]] requiring [[hospital]]ization. Infection with ''P. vivax'', ''P. ovale'' or ''P. malariae'' can often be treated on an outpatient basis. Treatment of malaria involves supportive measures as well as specific antimalarial drugs. When properly treated, someone with malaria can expect a complete cure.<ref>[http://www.cdc.gov/malaria/faq.htm#treatment If I get malaria, will I have it for the rest of my life?] CDC publication, Accessed 14 Nov 2006</ref>
Malaria is an preventable and treatable disease. The primary objective of treatment is to ensure a rapid and complete elimination of the Plasmodium parasite from the patient’s blood in order to prevent progression of uncomplicated malaria to severe disease or death, and to chronic infection that leads to malaria-related anaemia.


==Medical Therapy==
==Medical Therapy==
===Antimicrobial Regimen===
:* 1. '''Plasmodium falciparum'''<ref>{{cite web | title = Guidelines for the treatment of malaria. Third edition April 2015 | url = http://apps.who.int/iris/bitstream/10665/162441/1/9789241549127_eng.pdf?ua=1&ua=1 }}</ref>
::* 1.1 '''Treatment of uncomplicated P. falciparum malaria'''
:::* 1.1.1 '''Treat children and adults with uncomplicated P. falciparum malaria (except pregnant women in their first trimester) with one of the following recommended ACT (artemisinin-based combination therapy)'''
::::* Preferred regimen (1):  [[Artemether]] 5–24 mg/kg/day PO bid {{and}} [[Lumefantrine]] 29–144 mg/kg/day PO bid for 3 days.
:::::* Note: The first two doses should, ideally, be given 8 h apart.
:::::* Dosage regimen based on Body weight (kg)
:::::* Body weight (kg)-5 to < 15-    [[Artemether]] 20 mg PO bid {{and}} [[Lumefantrine]] 120 mg PO bid  for 3 days
:::::* Body weight (kg)-15 to < 25-    [[Artemether]] 40 mg PO bid {{and}} [[Lumefantrine]] 240 mg PO bid  for 3 days
:::::* Body weight (kg)-25 to < 35-    [[Artemether]] 60 mg PO bid {{and}} [[Lumefantrine]] 360 mg PO bid  for 3 days
:::::* Body weight (kg)  ≥ 35-      [[Artemether]] 80 mg PO bid {{and}} [[Lumefantrine]] 480 mg PO bid  for 3 days
::::* Preferred regimen (2): [[Artesunate]] 2–10 mg/kg/day PO qd {{and}} [[Amodiaquine]] 7.5–15 mg/kg/day PO qd for 3 days
:::::* Note: A total therapeutic dose range of 6–30 mg/kg/day artesunate and 22.5–45 mg/kg/day per dose amodiaquine is recommended.
:::::* Dosage regimen based on Body weight (kg)
:::::* Body weight (kg)-4.5 to < 9-  [[Artesunate]] 25 mg PO qd {{and}} [[Amodiaquine]] 67.5 mg PO qd  for 3 days
:::::* Body weight (kg)-9 to < 18 -  [[Artesunate]] 50 mg PO qd {{and}} [[Amodiaquine]] 135 mg PO qd for 3 days
:::::* Body weight (kg)-18 to < 36-  [[Artesunate]] 100 mg PO qd {{and}} [[Amodiaquine]] 270 mg PO qd for 3 days
:::::* Body weight (kg)  ≥ 36 -        [[Artesunate]] 200 mg PO qd {{and}} [[Amodiaquine]] 540 mg PO qd for 3 days
::::* Preferred regimen (3): [[Artesunate]] 2–10 mg/kg/day PO qd {{and}} [[Mefloquine]] 2–10 mg/kg/day PO qd for 3 days
:::::* Dosage regimen based on Body weight (kg)
:::::* Body weight (kg)-5 to < 9-      [[Artesunate]] 25 mg PO qd {{and}} [[Mefloquine]] 55 mg PO qd  for 3 days
:::::* Body weight (kg)-9to < 18-      [[Artesunate]] 50 mg PO qd {{and}} [[Mefloquine]] 110 mg PO qd for 3 days
:::::* Body weight (kg)-18 to < 36-  [[Artesunate]] 100 mg PO qd {{and}} [[Mefloquine]] 220 mg PO qd for 3 days
:::::* Body weight (kg)- ≥ 36  -      [[Artesunate]] 200 mg PO qd {{and}} [[Mefloquine]] 440 mg PO qd for 3 days
::::* Preferred regimen (4): [[Artesunate]] 2–10 mg/kg/day PO qd for 3 days {{and}} [[Sulfadoxine]]-[[Pyrimethamine]]  1.25 (25–70 / 1.25–3.5) mg/kg/day  PO given as a single dose on day 1
:::::* Dosage regimen based on Body weight (kg)
:::::* Body weight (kg)-5 to < 10-      [[Artesunate]] 25 mg PO qd for 3 days {{and}} [[Sulfadoxine]]-[[Pyrimethamine]] 250/12 mg PO given as a single dose on day 1
:::::* Body weight (kg)-10 to < 25-    [[Artesunate]] 50 mg PO qd for 3 days {{and}} [[Sulfadoxine]]-[[Pyrimethamine]] 500/25 mg PO given as a single dose on day 1
:::::* Body weight (kg)-25 to < 50-      [[Artesunate]] 100 mg PO qd for 3 days {{and}} [[Sulfadoxine]]-[[Pyrimethamine]] 1000/50 mg PO given as a single dose on day 1
:::::* Body weight (kg)-    ≥50-        [[Artesunate]] 200 mg PO qd for 3 days {{and}} [[Sulfadoxine]]-[[Pyrimethamine]] 1500/75 mg PO given as a single dose on day 1
::::*  Preferred regimen (5): [[Dihydroartemisinin]] 2–10 mg/kg/day PO qd {{and}} [[Piperaquine]]16–27 mg/kg/day PO qd for 3 days
:::::* Dosage regimen based on Body weight (kg)
:::::* Body weight (kg)-5 to < 8-    [[Dihydroartemisinin]] 20 mg PO qd {{and}}  [[Piperaquine]] 160 mg PO qd for 3 days
:::::* Body weight (kg)-8 to < 11-      [[Dihydroartemisinin]] 30 mg PO qd {{and}}  [[Piperaquine]] 240 mg PO qd for 3 days
:::::* Body weight (kg)-11 to < 17 -      [[Dihydroartemisinin]] 40 mg PO qd {{and}}  [[Piperaquine]] 320 mg PO qd for 3 days
:::::* Body weight (kg)-17 to < 25-      [[Dihydroartemisinin]] 60 mg PO qd {{and}}  [[Piperaquine]] 480 mg PO qd for 3 days
:::::* Body weight (kg)-25 to < 36-      [[Dihydroartemisinin]] 80 mg PO qd {{and}}  [[Piperaquine]] 640 mg PO qd for 3 days
:::::* Body weight (kg)-36 to < 60-      [[Dihydroartemisinin]] 120 mg PO qd {{and}}  [[Piperaquine]] 960 mg PO qd for 3 days
:::::*  Body weight (kg)-60 < 80 -      [[Dihydroartemisinin]] 160 mg PO qd {{and}}  [[Piperaquine]] 1280 mg PO qd for 3 days
:::::* Body weight (kg)- >80-      Dose of [[Dihydroartemisinin]] 200 mg PO qd {{and}}  [[Piperaquine]] 1600 mg PO qd for 3 days
:::* 1.1.2 '''Reducing the transmissibility of treated P. falciparum infections In low-transmission areas in  patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months) '''
:::::* Preferred regimen: Single dose of 0.25 mg/kg [[Primaquine]] with ACT


The treatment approach in patients with suspected or confirmed malaria varies according to several factors namely travel history, species of Plasmodium, severity of presentation, and availability of certain therapeutic agents.
::* 1.2 '''Recurrent Falciparum Malaria'''
:::* 1.2.1 '''Failure within 28 days '''
::::* Note:The recommended second-line treatment is an alternative ACT known to be effective in the region. Adherence to 7-day treatment regimens (with artesunate or quinine both of which should be co-administered with + tetracycline, or doxycycline or clindamycin) is likely to be poor if treatment is not directly observed; these regimens are no longer generally recommended.
:::* 1.2.2 '''Failure after 28 days'''
::::* Note: all presumed treatment failures after 4 weeks of initial treatment should, from an operational standpoint, be considered new infections and be treated with the first-line ACT. However, reuse of mefloquine within 60 days of first treatment is associated with an increased risk for neuropsychiatric reactions, and an alternative ACT should be used.


===Initial Assessment & Severe Malaria===
::* 1.3 '''Reducing the transmissibility of treated P. falciparum infections In low-transmission areas in patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months) '''  
The first step in the management of patients with malaria is to conduct a clinical assessment of status and disease severity, as well as determination of the degree of parasitemia. Signs of severe malarial disease include any of the following: prostration, impaired consciousness/coma, respiratory distress, convulsions, shock, pulmonary edema, acute respiratory distress syndrome, abnormal bleeding, jaundice, severe anemia, acute kidney injury, disseminated intravascular coagulopathy, acidosis, hemoglobinuria, and parasitemia >5%. Patients with severe disease require rapid resuscitation and medical therapy. The most vital step in the management is immediate initiation of appropriate parenteral treatment. Unlike patients who appear stable clinically, patients with severe malaria do not require speciation prior to initiation of medical therapy. The therapeutic regimen in such patients consists of '''intravenous quinidine gluconate plus either tetracycline, doxycycline, or clindamycin'''.<ref name="pmid17519416">{{cite journal| author=Griffith KS, Lewis LS, Mali S, Parise ME| title=Treatment of malaria in the United States: a systematic review. | journal=JAMA | year= 2007 | volume= 297 | issue= 20 | pages= 2264-77 | pmid=17519416 | doi=10.1001/jama.297.20.2264 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17519416  }} </ref> Other supportive measures include admission to the intensive care unit, continuous monitoring of cardiac function, glycemia, parasitemia, hemoglobin and electrolytes. Exchange transfusions may also be considered in patients with a degree of parasitemia >10%.
:::* Note: Single dose of 0.25 mg/kg bw [[Primaquine]] with ACT


===Uncomplicated Malaria===
::* 1.4 '''Treating uncomplicated P. falciparum malaria in special risk groups'''
In patients with clinically and bacteriologically uncomplicated malaria, speciation is required to tailor medical therapy. For most non-falciparum species, chloroquine remains the first line therapeutic agent. It is important to add '''primaquine''' to the treatment regimen in patients with documented P. vivax and P. ovale infections to eradicate liver hypnozoites (dormant liver spores that are responsible for recurrence). Patients infected with P. malaria do not require primaquine as the species is not capable of forming hypnozoites.<ref name="pmid23953767">{{cite journal| author=White NJ, Pukrittayakamee S, Hien TT, Faiz MA, Mokuolu OA, Dondorp AM| title=Malaria. | journal=Lancet | year= 2014 | volume= 383 | issue= 9918 | pages= 723-35 | pmid=23953767 | doi=10.1016/S0140-6736(13)60024-0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23953767  }} </ref> Patients diagnosed with P. falciparum malaria require hospitalization given the risk of progression to severe malaria. These patients have to be monitored on daily basis with a blood film and a full physical exam. The choice of drug in these patients depends on two main factors: the area of acquisition of the parasite, and the center at which the patient is being treated.<ref name="pmid17519416">{{cite journal| author=Griffith KS, Lewis LS, Mali S, Parise ME| title=Treatment of malaria in the United States: a systematic review. | journal=JAMA | year= 2007 | volume= 297 | issue= 20 | pages= 2264-77 | pmid=17519416 | doi=10.1001/jama.297.20.2264 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17519416  }} </ref>
:::* 1.4.1 '''Pregnancy '''
::::* First trimester of pregnancy : [[Quinine]] {{and}} [[Clindamycin]] 10mg/kg/day PO bid for 7 days
::::* Second and third trimesters : [[Mefloquine]] is considered safe for the treatment of malaria during the second and third trimesters; however, it should be given only in combination with an artemisinin derivative.
::::* Note (1): Quinine is associated with an increased risk for hypoglycaemia in late pregnancy, and it should be used (with clindamycin) only if effective alternatives are not available.
::::* Note (2): Primaquine and tetracyclines should not be used in pregnancy.
:::* 1.4.2 '''Infants less than 5kg body weight''' :  with an ACT at the same mg/kg bw target dose as for children weighing 5 kg.
:::* 1.4.3 '''Patients co-infected with HIV''': should avoid [[Artesunate]] + SP if they are also receiving [[Co-trimoxazole]], and avoid [[Artesunate]] {{and}} [[Amodiaquine]] if they are also receiving efavirenz or zidovudine.
:::* 1.4.4 '''Large and Obese adults''': For obese patients, less drug is often distributed to fat than to other tissues; therefore, they should be dosed on the basis of an estimate of lean body weight, ideal body weight. Patients who are heavy but not obese require the same mg/kg bw doses as lighter patients.
:::* 1.4.5 '''Patients co-infected with TB''': Rifamycins, in particular rifampicin, are potent CYP3A4 inducers with weak antimalarial activity. Concomitant administration of rifampicin during quinine treatment of adults with malaria was associated with a significant decrease in exposure to quinine and a five-fold higher recrudescence rate
:::* 1.4.6 '''Non-immune travellers''' : Treat travellers with uncomplicated P. falciparum malaria returning to nonendemic settings with an ACT.
:::* 1.4.7 '''Uncomplicated hyperparasitaemia''': People with P. falciparum hyperparasitaemia are at increased risk of treatment failure, severe malaria and death so should be closely monitored, in addition to receiving an ACT.
:* 2. '''Treatment of uncomplicated malaria caused by P. vivax, P. ovale, P. malariae or P. knowlesi'''
::* 2.1  '''Blood Stage infection'''
:::* 2.1.1. '''Uncomplicated malaria caused by P. vivax'''
::::* 2.1.1.1 '''In areas with chloroquine-sensitive P. vivax'''
:::::* Preferred regimen: [[Chloroquine]] total dose of 25 mg/kg PO. [[Chloroquine]] is given at an initial dose of 10 mg/kg, followed by 10 mg/kg on the second day and 5 mg/kg on the third day.
::::* 2.1.1.2 '''In areas with chloroquine-resistant P. vivax'''
:::::* Note: ACTs containing [[Piperaquine]], [[Mefloquine]] {{or}} [[Lumefantrine]] are the recommended treatment, although [[Artesunate]] + [[Amodiaquine]] may also be effective in some areas. In the systematic review of ACTs for treating P. vivax malaria, [[Dihydroartemisinin]] + [[Piperaquine]] provided a longer prophylactic effect than ACTs with shorter half-lives ([[Artemether]] + [[Lumefantrine]], [[Artesunate]] + [[Amodiaquine]]), with significantly fewer recurrent parasitaemias during 9 weeks of follow-up.
:::* 2.1.2 '''Uncomplicated malaria caused by P. ovale, P. malariae or P. knowlesi malaria'''
::::* Note: Resistance of P. ovale, P. malariae and P. knowlesi to antimalarial drugs is not well characterized, and infections caused by these three species are generally considered to be sensitive to chloroquine. In only one study, conducted in Indonesia, was resistance to chloroquine reported in P. malariae. The blood stages of P. ovale, P. malariae and P. knowlesi should therefore be treated with the standard regimen of ACT or [[Chloroquine]], as for vivax malaria.
:::* 2.1.3 '''Mixed malaria infections '''
::::* Note: ACTs are effective against all malaria species and so are the treatment of choice for mixed infections.
::* 2.2 '''Liver stages (hypnozoites) of P. vivax and P. ovale'''
:::* Note: To prevent relapse, treat P. vivax or P. ovale malaria in children and adults (except pregnant women, infants aged < 6 months, women breastfeeding infants < 6 months, women breastfeeding older infants unless they are known not to be G6PD deficient and people with G6PD deficiency) with a 14-day course of primaquine in all transmission settings. Strong recommendation, high-quality evidence In people with G6PD deficiency, consider preventing relapse by giving primaquine base at 0.75 mg base/kg bw once a week for 8 weeks, with close medical supervision for potential primaquine-induced adverse haematological effects.]
::* 2.2.1 '''Primaquine for preventive relapse'''
:::* Preferred regimen: [[Primaquine]] 0.25–0.5 mg/kg/day PO qd for 14 days
::* 2.2.2 '''Primaquine and glucose-6-phosphate dehydrogenase deficiency'''
:::* Preferred regimen: [[Primaquine]] 0.75 mg base/kg/day PO once a week for 8 weeks.
:::* Note: The decision to give or withhold [[Primaquine]] should depend on the possibility of giving the treatment under close medical supervision, with ready access to health facilities with blood transfusion services.
::* 2.2.3 '''Prevention of relapse in pregnant or lacating women and infants'''
:::* Note: Primaquine is contraindicated in pregnant women, infants < 6 months of age and in lactating women (unless the infant is known not to be G6PD deficient).


Despite being the mainstay of therapy since its introduction, empiric treatment with chloroquine in patients with P. falciparum is no longer recommended due to a sharp increase in resistance. A detailed travel history is important to determine where the infection was acquired. Most malaria endemic countries have reported chloroquine resistant strains, with the exception of Central America west of Panama Canal, Mexico, Hispaniola, certain parts of China, and the Middle East (see figure below).  If acquired in any of the latter sites then treatment with chloroquine is adequate. Acquisition from all other endemic countries requires other therapeutic regimens such as '''oral quinine with either tetracycline, doxycycline, or clindamycin''' as a first line therapy in the United States, otherwise atovaquone-proguanil or mefloquine if the primary regimen is unavailable.
:* 3. '''Treatment of severe malaria'''
 
::* 3.1 Treatment of severe falciparum infection with Artesunate
Worldwide, the treatment of both complicated and uncomplicated P. falciparum malaria requires a combination therapy that includes  artemisinin derivatives. According to the 2010 WHO guidelines on the treatment of malaria, the following regimens are first line for the treatment of uncomplicated P. falciparum: '''artemether plus lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine, and artesunate plus sulfadoxine-pyrimethamin'''. For patients with severe P. falciparum malaria, '''artesunate IV or IM''' is first line followed by IV quinidine. The artemisinin derivatives clear parasites very rapidly have been shown to reduce mortality in severe malaria compared with parenteral quinine. Artemisins are not widely available in the United States and their use is not common practice. Only oral '''artemether plus lumefantrine''' is available, while IV atresunate can be obtained through the CDC part of an investigational drug protocol. <ref name="CDC2012artemisin">{{cite website| author=Centers for Disease Control and Prevention | title=Artesunate is available to treat severe malaria in the United States | url=http://www.cdc.gov/malaria/diagnosis_treatment/artesunate.html  }} </ref>
:::* 3.1.1 Adults and children with severe malaria (including infants, pregnant women in all trimesters and lactating women):-
{| border="1" style="border-collapse:collapse; text-align:center;" cellpadding="5" align="center"
::::* Preferred regimen: [[Artesunate]] IV/IM for at least 24 h and until they can tolerate oral medication. Once a patient has received at least 24 h of parenteral therapy and can tolerate oral therapy, complete treatment with 3 days of an ACT (add single dose [[Primaquine]] in areas of low transmission).
|+ '''''Recommended Indications and Doses of Common Anti-malarial Agents'''''
:::* 3.1.2 Young children weighing < 20 kg  
| bgcolor="#d9ff54"|'''Anti-malarial Agent''' || bgcolor="#d9ff54"|'''Indication''' || bgcolor="#d9ff54"|'''Dosing'''
::::* Preferred regimen:[[Artesunate]] 3 mg/kg per dose IV/IM q24h
|-
::::* Alternatives regimen: use [[Artemether]] in preference to quinine for treating children and adults with severe malaria
| bgcolor="#ececec"|'''Chloroquine phosphate''' || P. falciparum from chloroquine-sensitive areas<br>P. vivax from chloroquine-sensitive areas<br>All P ovale<br>All P. malariae || 1g oral load, followed by 500 mg orally at 6, 24, and 48 h
::* 3.2.'''Treating cases of suspected severe malaria pending transfer to a higher-level facility (pre-referral treatment)'''
|-
:::* 3.2.1 '''Adults and children '''
 
::::* Preferred regimen: [[Artesunate]] IM q24h
| bgcolor="#ececec"|'''Hydroxychloroquine''' || Same as chloroquine (second line agent) || 800 mg oral load, followed by 400 mg orally at 6, 24, and 48 h
::::* Alternative regimen: [[Artemether]] IM {{or}} [[Quinine]] IM
 
:::* 3.2.2 '''Children < 6 years'''
|-
::::* Preferred regimen: Where intramuscular injections of artesunate are not available, treat with a single rectal dose (10 mg/kg) of [[Artesunate]], and refer immediately to an appropriate facility for further care.
| bgcolor="#ececec"|'''Atovaquone-Proguanil''' || P. falciparum from chloroquine-resistant areas||  250 mg atovaquone/100 mg proguanil (1 tab) orally 4 times daily for 3 days
::::* Note: Do not use rectal artesunate in older children and adults.
 
::* 3.3 '''Pregancy'''
|-
:::* Note: Parenteral artesunate is the treatment of choice in all trimesters. Treatment must not be delayed.
| bgcolor="#ececec"|'''Primaquine phosphate''' || Cure  of P. vivax and P. ovale (to eliminate hypnozoites)|| 30 mg orally once daily for 14 days
::* 3.4 '''Treatment of severe P. Vivax infection'''
 
:::* Note: parenteral artesunate, treatment can be completed with a full treatment course of oral ACT or chloroquine (in countries where chloroquine is the treatment of choice). A full course of radical treatment with primaquine should be given after recovery.
|-
::* 3.5 '''Additional aspects of management in severe malaria'''
| bgcolor="#ececec"|'''Clindamycin'''* || P. falciparum or P. vivax from chloroquine-resistant areas || 20 mg/kg/day orally for 3 days<br>'''or'''<br>10 mg/kg IV load, followed by 5 mg/kg IV every 8 hours
:::* '''Fluid therapy''':  It is not possible to give general recommendations on fluid replacement; each patient must be assessed individually and fluid resuscitation based on the estimated deficit.
 
:::* '''Blood Transfusion ''':In high-transmission settings, blood transfusion is generally recommended for children with a haemoglobin level of < 5 g/100 mL(haematocrit < 15%). In low-transmission settings, a threshold of 20% (haemoglobin,7 g/100 mL) is recommended.
|-
:::* '''Exchange blood transfusion''': Exchange blood transfusion requires intensive nursing care and a relatively large volume of blood, and it carries significant risks. There is no consensus on the indications, benefits and dangers involved or on practical details such as the volume of blood that should be exchanged. It is, therefore, not possible to make any recommendation regarding the use of exchange blood transfusion.
| bgcolor="#ececec"|'''Doxycycline'''* || P. falciparum or P. vivax from chloroquine-resistant areas  || 100 mg orally twice daily for 7 days <br>'''or'''<br>100 mg IV every 12 hours for 7 days (can switch from
 
IV to PO)
 
|-
| bgcolor="#ececec"|'''Tertacycline'''* || P. falciparum or P. vivax from chloroquine-resistant areas  || 250 mg orally 4 times daily for 7 days <br>'''or'''<br>250 mg IV 4 times daily for 7 days (can switch from
 
IV to PO)
 
|-
| bgcolor="#ececec"|'''Mefloquine''' || P. falciparum or P. vivax from chloroquine-resistant areas except Thailand-Burmese and Thailand-Cambodian border regions  || 750 mg oral load, followed by 500 mg orally 6-12 hours after initial dose
 
|-
| bgcolor="#ececec"|'''Quinine sulfate''' || P. falciparum or P. vivax from chloroquine-resistant areas || 650 mg orally 3 times daily for 3 days or 7 days if acquired from Southeast Asia
 
|-
| bgcolor="#ececec"|'''Quinidine gluconate''' || Severe malaria (all species<br>Unable to tolerate oral agents<br>Parasitemia>10% || 10 mg/kg IV load over 1-2 hours, then 0.02 mg/kg/min continuous infusion for at least 24 hours
 
|-
| bgcolor="#ececec"|'''Artemether-lumefantrine''' || All P. falciparum (outside US) || 1.5 mg/kg - 9 mg/kg orally twice daily for 3 days
 
|-
| bgcolor="#ececec"|'''Dihydroartemisinin–piperaquine''' || All P. falciparum (outside US) || 2·5 mg/kg – 20 mg/kg orally once daily for 3 days
 
|-
| bgcolor="#ececec"|'''Artesunate''' || All P. falciparum (outside US)<br> First line IV agent for severe malaria(outside US) || '''In severe malaria:''' 2.4 mg/kg
IV or IM load,<br> followed by 2.4 mg/kg at 12 h and 24 h; continue injection once daily if necessary<br> '''In uncomplicated malaria: '''Monotherapy not recommended, 4mg/kg orally once daily for 3 days combined with a single oral dose of sulfadoxine–pyrimethamine 25/1.25 mg/kg or mefloquine 8 mg/kg orally daily for 3 days
 
|}
 
===Antimalarial Drugs===
{{further|[[Antimalarial drug]]s}}
There are several families of drugs used to treat malaria. [[Chloroquine]] is very cheap and, until recently, was very effective, which made it the antimalarial drug of choice for many years in most parts of the world. However, resistance of ''Plasmodium falciparum'' to chloroquine has spread recently from Asia to Africa, making the drug ineffective against the most dangerous Plasmodium strain in many affected regions of the world. In those areas where chloroquine is still effective it remains the first choice. Unfortunately, chloroquine-resistance is associated with reduced sensitivity to other drugs such as [[quinine]] and [[amodiaquine]].<ref>{{cite journal | author=Tinto H, Rwagacondo C, Karema C, ''et al.'' | title=In-vitro susceptibility of ''Plasmodium falciparum'' to monodesethylamodiaquine, dihydroartemsinin and quinine in an area of high chloroquine resistance in Rwanda | journal=Trans R Soc Trop Med Hyg | volume=100 | issue=6 | pages=509&ndash;14 | doi=10.1016/j.trstmh.2005.09.018 }}</ref>
 
There are several other substances which are used for treatment and, partially, for prevention (prophylaxis). Many drugs may be used for both purposes; larger doses are used to treat cases of malaria. Their deployment depends mainly on the frequency of resistant parasites in the area where the drug is used. One drug currently being investigated for possible use as an anti-malarial, especially for treatment of drug-resistant strains, is the [[beta blocker]] [[propranolol]]. Propranolol has been shown to block both ''Plasmodium'''s ability to enter red blood cell and establish an infection, as well as parasite replication. A December 2006 study by Northwestern University researchers suggested that propranolol may reduce the dosages required for existing drugs to be effective against ''P. falciparum'' by 5- to 10-fold, suggesting a role in combination therapies.<ref>{{cite journal |author=Murphy S, Harrison T, Hamm H, Lomasney J, Mohandas N, Haldar K |title=Erythrocyte G protein as a novel target for malarial chemotherapy |journal=PLoS Med |volume=3 |issue=12 |pages=e528 |year=2006 | month=Dec | id=PMID 17194200 | url=http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0030528}}</ref>
 
Currently available anti-malarial drugs include:<ref>[http://www.cdc.gov/travel/malariadrugs.htm Prescription drugs for malaria] Retrieved [[February 27]], [[2007]].</ref>
* [[Artemether]]-[[lumefantrine]] (Therapy only, commercial names ''Coartem''® and ''Riamet''®)
* [[Artesunate]]-[[amodiaquine]] (Therapy only)
* [[Artesunate]]-[[mefloquine]] (Therapy only)
* [[Artesunate]]-[[sulfonamide (medicine)|Sulfadoxine]]/[[pyrimethamine]] (Therapy only)
* [[Atovaquone]]-[[proguanil]], trade name [[Malarone]] (Therapy and prophylaxis)
* [[Quinine]] (Therapy only)
* [[Chloroquine]] (Therapy and prophylaxis; usefulness now reduced due to resistance)
* [[Cotrifazid]] (Therapy and prophylaxis)
* [[Doxycycline]] (Therapy and prophylaxis)
* [[Mefloquine]], trade name Lariam (Therapy and prophylaxis)
* [[Primaquine]] (Therapy in ''P. vivax'' and ''P. ovale'' only; not for prophylaxis)
* [[Proguanil]] (Prophylaxis only)
* [[Sulfonamide (medicine)|Sulfadoxine]]-[[pyrimethamine]] (Therapy; prophylaxis for semi-immune pregnant women in endemic countries as "Intermittent Preventive Treatment" - IPT)
*[[Hydroxychloroquine]], trade name Plaquenil (Therapy and prophylaxis)
 
The development of drugs was facilitated when ''Plasmodium falciparum'' was successfully [[Malaria culture|cultured]].<ref name="Trager1976">{{cite journal | author= Trager W, Jensen JB.| title=Human malaria parasites in continuous culture | journal=Science| year=1976| volume=193(4254)| pages=673&ndash;5  | id=PMID 781840}}</ref> This allowed in vitro testing of new drug candidates.
 
Extracts of the plant ''Artemisia annua'', containing the compound [[artemisinin]] or semi-synthetic derivatives (a substance unrelated to quinine), offer over 90% efficacy rates, but their supply is not meeting demand.<ref>{{cite journal | author = Senior K | title = Shortfall in front-line antimalarial drug likely in 2005 | journal = Lancet Infect Dis | volume = 5 | issue = 2 | pages = 75 | year = 2005 | id = PMID 15702504}}</ref> One study in Rwanda showed that children with uncomplicated P. falciparum malaria demonstrated fewer clinical and parasitological failures on post-treatment day 28 when amodiaquine was combined with [[artesunate]], rather than administered alone (OR = 0.34).  However, increased resistance to amodiaquine during this study period was also noted.  <ref>{{cite journal |author=Rwagacondo C, Karema C, Mugisha V, Erhart A, Dujardin J, Van Overmeir C, Ringwald P, D'Alessandro U |title=Is amodiaquine failing in Rwanda? Efficacy of amodiaquine alone and combined with artesunate in children with uncomplicated malaria |journal=Trop Med Int Health |volume=9 |issue=10 |pages=1091-8 |year=2004 |pmid=15482401}}.</ref>
Since 2001 the [[World Health Organization]] has recommended using [[artemisinin]]-based combination therapy (ACT) as first-line treatment for uncomplicated malaria in areas experiencing resistance to older medications. The most recent [[WHO]] [http://www.who.int/malaria/docs/TreatmentGuidelines2006.pdf treatment guidelines for malaria] recommend four different ACTs. While numerous countries, including most African nations, have adopted the change in their official malaria treatment policies, cost remains a major barrier to ACT implementation. Because ACTs cost up to twenty times as much as older medications, they remain unaffordable in many malaria-endemic countries. The molecular target of artemisinin is controversial, although recent studies suggest that [[SERCA]], a calcium pump in the [[endoplasmic reticulum]] may be associated with artemisinin resistance.<ref>{{cite journal | author = Eckstein-Ludwig U, Webb R, Van Goethem I, East J, Lee A, Kimura M, O'Neill P, Bray P, Ward S, Krishna S | title = Artemisinins target the SERCA of Plasmodium falciparum. | journal = Nature | volume = 424 | issue = 6951 | pages = 957-61 | year = 2003 | id = PMID 12931192}}</ref> Malaria parasites can develop resistance to artemisinin and resistance can be produced by mutation of SERCA.<ref>{{cite journal | author = Uhlemann A, Cameron A, Eckstein-Ludwig U, Fischbarg J, Iserovich P, Zuniga F, East M, Lee A, Brady L, Haynes R, Krishna S | title = A single amino acid residue may determine the sensitivity of SER`CAs to artemisinins. | journal = Nat Struct Mol Biol | volume = 12 | issue = 7 | pages = 628-9 | year = 2005 | id = PMID 15937493}}</ref> However, other studies suggest the mitochondrion is the major target for artemisinin and its analogs.<ref>{{cite journal | author = Li W, Mo W, Shen D, Sun L, Wang J, Lu S, Gitschier J, Zhou B | title = Yeast model uncovers dual roles of mitochondria in action of artemisinin. | journal = PLoS Genet | volume = 1 | issue = 3 | pages = e36 | year = 2005 | id = PMID 16170412}}</ref>
 
===Counterfeit Drugs===
Sophisticated [[counterfeit drugs|counterfeits]] have been found in Thailand, Vietnam, Cambodia<ref>{{cite journal | author=Lon CT, Tsuyuoka R, Phanouvong S, ''et al.'' | title=Counterfeit and substandard antimalarial drugs in Cambodia | year=2006 | journal=Trans R Soc Trop Med Hyg | volume=100 | issue=11 | pages=1019&ndash;24 | doi=10.1016/j.trstmh.2006.01.003 }}</ref> and China,<ref>{{cite web | author=U. S. Pharmacopeia | title=Fake antimalarials found in Yunan province, China | url=http://www.uspdqi.org/pubs/other/FakeAntimalarialsinChina.pdf | accessdate=2006-10-06 | year=2004 }}</ref> and are an important cause of avoidable death in these countries.<ref>{{cite journal | author=Newton PN, Green MD, Fernández FM, Day NPJ, White NJ. | title=Counterfeit anti-infective drugs | journal=Lancet Infect Dis | year=2006 | volume=6 | issue=9 | pages=602&ndash;13 | id=PMID 16931411 }}</ref>  There is no reliable way for doctors or lay people to detect counterfeit drugs without help from a laboratory.  Companies are attempting to combat the persistence of counterfeit drugs by using new technology to provide security from source to distribution.


==References==
==References==
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[[Category:Disease]]
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Latest revision as of 18:00, 18 September 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor-In-Chief:Monalisa Dmello, M.B,B.S., M.D. [2];

Overview

Malaria is an preventable and treatable disease. The primary objective of treatment is to ensure a rapid and complete elimination of the Plasmodium parasite from the patient’s blood in order to prevent progression of uncomplicated malaria to severe disease or death, and to chronic infection that leads to malaria-related anaemia.

Medical Therapy

Antimicrobial Regimen

  • 1. Plasmodium falciparum[1]
  • 1.1 Treatment of uncomplicated P. falciparum malaria
  • 1.1.1 Treat children and adults with uncomplicated P. falciparum malaria (except pregnant women in their first trimester) with one of the following recommended ACT (artemisinin-based combination therapy)
  • Preferred regimen (1): Artemether 5–24 mg/kg/day PO bid AND Lumefantrine 29–144 mg/kg/day PO bid for 3 days.
  • Note: The first two doses should, ideally, be given 8 h apart.
  • Dosage regimen based on Body weight (kg)
  • Body weight (kg)-5 to < 15- Artemether 20 mg PO bid AND Lumefantrine 120 mg PO bid for 3 days
  • Body weight (kg)-15 to < 25- Artemether 40 mg PO bid AND Lumefantrine 240 mg PO bid for 3 days
  • Body weight (kg)-25 to < 35- Artemether 60 mg PO bid AND Lumefantrine 360 mg PO bid for 3 days
  • Body weight (kg) ≥ 35- Artemether 80 mg PO bid AND Lumefantrine 480 mg PO bid for 3 days
  • Preferred regimen (2): Artesunate 2–10 mg/kg/day PO qd AND Amodiaquine 7.5–15 mg/kg/day PO qd for 3 days
  • Note: A total therapeutic dose range of 6–30 mg/kg/day artesunate and 22.5–45 mg/kg/day per dose amodiaquine is recommended.
  • Dosage regimen based on Body weight (kg)
  • Body weight (kg)-4.5 to < 9- Artesunate 25 mg PO qd AND Amodiaquine 67.5 mg PO qd for 3 days
  • Body weight (kg)-9 to < 18 - Artesunate 50 mg PO qd AND Amodiaquine 135 mg PO qd for 3 days
  • Body weight (kg)-18 to < 36- Artesunate 100 mg PO qd AND Amodiaquine 270 mg PO qd for 3 days
  • Body weight (kg) ≥ 36 - Artesunate 200 mg PO qd AND Amodiaquine 540 mg PO qd for 3 days
  • Preferred regimen (3): Artesunate 2–10 mg/kg/day PO qd AND Mefloquine 2–10 mg/kg/day PO qd for 3 days
  • Preferred regimen (4): Artesunate 2–10 mg/kg/day PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1.25 (25–70 / 1.25–3.5) mg/kg/day PO given as a single dose on day 1
  • 1.1.2 Reducing the transmissibility of treated P. falciparum infections In low-transmission areas in patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)
  • Preferred regimen: Single dose of 0.25 mg/kg Primaquine with ACT
  • 1.2 Recurrent Falciparum Malaria
  • 1.2.1 Failure within 28 days
  • Note:The recommended second-line treatment is an alternative ACT known to be effective in the region. Adherence to 7-day treatment regimens (with artesunate or quinine both of which should be co-administered with + tetracycline, or doxycycline or clindamycin) is likely to be poor if treatment is not directly observed; these regimens are no longer generally recommended.
  • 1.2.2 Failure after 28 days
  • Note: all presumed treatment failures after 4 weeks of initial treatment should, from an operational standpoint, be considered new infections and be treated with the first-line ACT. However, reuse of mefloquine within 60 days of first treatment is associated with an increased risk for neuropsychiatric reactions, and an alternative ACT should be used.
  • 1.3 Reducing the transmissibility of treated P. falciparum infections In low-transmission areas in patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)
  • Note: Single dose of 0.25 mg/kg bw Primaquine with ACT
  • 1.4 Treating uncomplicated P. falciparum malaria in special risk groups
  • 1.4.1 Pregnancy
  • First trimester of pregnancy : Quinine AND Clindamycin 10mg/kg/day PO bid for 7 days
  • Second and third trimesters : Mefloquine is considered safe for the treatment of malaria during the second and third trimesters; however, it should be given only in combination with an artemisinin derivative.
  • Note (1): Quinine is associated with an increased risk for hypoglycaemia in late pregnancy, and it should be used (with clindamycin) only if effective alternatives are not available.
  • Note (2): Primaquine and tetracyclines should not be used in pregnancy.
  • 1.4.2 Infants less than 5kg body weight : with an ACT at the same mg/kg bw target dose as for children weighing 5 kg.
  • 1.4.3 Patients co-infected with HIV: should avoid Artesunate + SP if they are also receiving Co-trimoxazole, and avoid Artesunate AND Amodiaquine if they are also receiving efavirenz or zidovudine.
  • 1.4.4 Large and Obese adults: For obese patients, less drug is often distributed to fat than to other tissues; therefore, they should be dosed on the basis of an estimate of lean body weight, ideal body weight. Patients who are heavy but not obese require the same mg/kg bw doses as lighter patients.
  • 1.4.5 Patients co-infected with TB: Rifamycins, in particular rifampicin, are potent CYP3A4 inducers with weak antimalarial activity. Concomitant administration of rifampicin during quinine treatment of adults with malaria was associated with a significant decrease in exposure to quinine and a five-fold higher recrudescence rate
  • 1.4.6 Non-immune travellers : Treat travellers with uncomplicated P. falciparum malaria returning to nonendemic settings with an ACT.
  • 1.4.7 Uncomplicated hyperparasitaemia: People with P. falciparum hyperparasitaemia are at increased risk of treatment failure, severe malaria and death so should be closely monitored, in addition to receiving an ACT.
  • 2. Treatment of uncomplicated malaria caused by P. vivax, P. ovale, P. malariae or P. knowlesi
  • 2.1 Blood Stage infection
  • 2.1.1. Uncomplicated malaria caused by P. vivax
  • 2.1.1.1 In areas with chloroquine-sensitive P. vivax
  • Preferred regimen: Chloroquine total dose of 25 mg/kg PO. Chloroquine is given at an initial dose of 10 mg/kg, followed by 10 mg/kg on the second day and 5 mg/kg on the third day.
  • 2.1.1.2 In areas with chloroquine-resistant P. vivax
  • 2.1.2 Uncomplicated malaria caused by P. ovale, P. malariae or P. knowlesi malaria
  • Note: Resistance of P. ovale, P. malariae and P. knowlesi to antimalarial drugs is not well characterized, and infections caused by these three species are generally considered to be sensitive to chloroquine. In only one study, conducted in Indonesia, was resistance to chloroquine reported in P. malariae. The blood stages of P. ovale, P. malariae and P. knowlesi should therefore be treated with the standard regimen of ACT or Chloroquine, as for vivax malaria.
  • 2.1.3 Mixed malaria infections
  • Note: ACTs are effective against all malaria species and so are the treatment of choice for mixed infections.
  • 2.2 Liver stages (hypnozoites) of P. vivax and P. ovale
  • Note: To prevent relapse, treat P. vivax or P. ovale malaria in children and adults (except pregnant women, infants aged < 6 months, women breastfeeding infants < 6 months, women breastfeeding older infants unless they are known not to be G6PD deficient and people with G6PD deficiency) with a 14-day course of primaquine in all transmission settings. Strong recommendation, high-quality evidence In people with G6PD deficiency, consider preventing relapse by giving primaquine base at 0.75 mg base/kg bw once a week for 8 weeks, with close medical supervision for potential primaquine-induced adverse haematological effects.]
  • 2.2.1 Primaquine for preventive relapse
  • Preferred regimen: Primaquine 0.25–0.5 mg/kg/day PO qd for 14 days
  • 2.2.2 Primaquine and glucose-6-phosphate dehydrogenase deficiency
  • Preferred regimen: Primaquine 0.75 mg base/kg/day PO once a week for 8 weeks.
  • Note: The decision to give or withhold Primaquine should depend on the possibility of giving the treatment under close medical supervision, with ready access to health facilities with blood transfusion services.
  • 2.2.3 Prevention of relapse in pregnant or lacating women and infants
  • Note: Primaquine is contraindicated in pregnant women, infants < 6 months of age and in lactating women (unless the infant is known not to be G6PD deficient).
  • 3. Treatment of severe malaria
  • 3.1 Treatment of severe falciparum infection with Artesunate
  • 3.1.1 Adults and children with severe malaria (including infants, pregnant women in all trimesters and lactating women):-
  • Preferred regimen: Artesunate IV/IM for at least 24 h and until they can tolerate oral medication. Once a patient has received at least 24 h of parenteral therapy and can tolerate oral therapy, complete treatment with 3 days of an ACT (add single dose Primaquine in areas of low transmission).
  • 3.1.2 Young children weighing < 20 kg
  • Preferred regimen:Artesunate 3 mg/kg per dose IV/IM q24h
  • Alternatives regimen: use Artemether in preference to quinine for treating children and adults with severe malaria
  • 3.2.Treating cases of suspected severe malaria pending transfer to a higher-level facility (pre-referral treatment)
  • 3.2.1 Adults and children
  • 3.2.2 Children < 6 years
  • Preferred regimen: Where intramuscular injections of artesunate are not available, treat with a single rectal dose (10 mg/kg) of Artesunate, and refer immediately to an appropriate facility for further care.
  • Note: Do not use rectal artesunate in older children and adults.
  • 3.3 Pregancy
  • Note: Parenteral artesunate is the treatment of choice in all trimesters. Treatment must not be delayed.
  • 3.4 Treatment of severe P. Vivax infection
  • Note: parenteral artesunate, treatment can be completed with a full treatment course of oral ACT or chloroquine (in countries where chloroquine is the treatment of choice). A full course of radical treatment with primaquine should be given after recovery.
  • 3.5 Additional aspects of management in severe malaria
  • Fluid therapy: It is not possible to give general recommendations on fluid replacement; each patient must be assessed individually and fluid resuscitation based on the estimated deficit.
  • Blood Transfusion :In high-transmission settings, blood transfusion is generally recommended for children with a haemoglobin level of < 5 g/100 mL(haematocrit < 15%). In low-transmission settings, a threshold of 20% (haemoglobin,7 g/100 mL) is recommended.
  • Exchange blood transfusion: Exchange blood transfusion requires intensive nursing care and a relatively large volume of blood, and it carries significant risks. There is no consensus on the indications, benefits and dangers involved or on practical details such as the volume of blood that should be exchanged. It is, therefore, not possible to make any recommendation regarding the use of exchange blood transfusion.

References

  1. ↑ "Guidelines for the treatment of malaria. Third edition April 2015" (PDF).

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