SOGC CLINICAL PRACTICE GUIDELINE No. 269, November 2011 Advanced Reproductive Age and Fertility This clinical practice guideline has been prepared by the Reproductive Endocrinology and Infertility Committee, Objective: To improve awareness of the natural age-related reviewed by the Family Physicians Advisory Committee and
Take Clomid is contraindicated in the presence of cysts in the ovaries, liver and kidney failure, the presence of pituitary tumors or genital organs Problems with impregnation Before using the product you should consult with a specialist and to get acquainted with the instructions approved by the manufacturer.Cialis ne doit pas être prise à tous. Il est important que cialis en ligne est prescrit par un médecin, bien se familiariser avec les antécédents médicaux du patient. Ich habe Probleme mit schnellen Montage. Lesen Sie Testberichte Nahm wie cialis rezeptfrei 30 Minuten vor dem Sex, ohne Erfolg. Beginn der Arbeiten nach 4 Stunden, links ein Freund ein trauriges Ja, und Schwanz in sich selbst nicht ausstehen, wenn es keinen Wunsch ist.
MEDITERRANEAN JOURNAL OF HEMATOLOGY AND INFECTIOUS DISEASES www.mjhid.org ISSN 2035-3006 Review Articles
Prophylaxis of Malaria
The Center for Geographic Medicine and Tropical Diseases, The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel Correspondence to: Prof. Eli Schwartz MD, DTMH. The Center for Geographic Medicine and Tropical Diseases, The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. Tel: 972-3-5308456; Fax: 972-3-5308456. E-mail: firstname.lastname@example.org Competing interests: The authors have declared that no competing interests exist.
Published: June 29, 2012 Received: April 7, 2012 Accepted: May 19, 2012Citation: Mediterr J Hematol Infect Dis 2012, 4(1): e2012045, DOI: 10.4084/MJHID.2012.045 This article is available from: http://www.mjhid.org/article/view/10386This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract. Malaria prevention in travelers to endemic areas remains dependent principally on
chemoprophylaxis. Although malaria chemoprophylaxis refers to all malaria species, a distinction
should be drawn between falciparum malaria prophylaxis and the prophylaxis of the relapsing
malaria species (vivax & ovale). While the emergence of drug resistant strains, as well as the costs
and adverse reactions to medications, complicate falciparum prophylaxis use, there are virtually no
drugs available for vivax prophylaxis, beside of primaquine.
Based on traveler's malaria data, a revised recommendation for using chemoprophylaxis in low
risk areas should be considered.
Introduction. Every year, an estimated 50 million
chemoprophylaxis remains the principal means to travellers visit malaria endemic areas. Some 30,000 prevent malaria. malaria cases are reported annually in non-endemic, industrialised countries and imported malaria remains a Personal Protection. Personal protection refers to all
public health problem associated with high case fatality measures that can be taken to reduce the risk of the rates.1 The four European countries with the greatest anophline bites. Since the anophleles mosquito is a number of reported cases of imported malaria are the night feeder, protection is relatively easy when United Kingdom, France, Italy and Germany. P. compared for example to protection from dengue falciparum accounts for almost 70% of all the imports.2 mosquitoes, which are day feeders. Protective Theoretically malaria prevention could be based on strategies include wearing clothing after sunset that vaccine,
covers as much bare skin as possible, and using chemoprophylaxis. However, malaria vaccine is not
mosquito repellents on exposed skin containing about on the near horizon, especially not for travelers, despite some encouraging new data.3 Personal protection, formulations. The use of insecticide-impregnated albeit an important tool, is often not sufficient, thus clothing can also be helpful.4 While indoors, staying and sleeping in air-conditioned rooms, and sleeping Mediterr J Hematol Infect Dis 2012; 4; Open Journal System under mosquito nets provide good protection. For These results highlight the discrepancy between the expatriates who live in endemic areas, eradicating medical recommendations for malaria prophylaxis and mosquito breeding sites around the house is important. the travelers' perceptions. Strict adherence to these measures reduces the chances of acquiring malaria, but they cannot be relied upon to Principal of Chemoprophylaxis: Blood Stage vs.
prevent malaria in environments where anopheline Liver Stage Prophylaxis. The parasite's life cycle in
mosquitoes and infected humans are present in humans occurs in two stages (Figure 1). In the initial
liver stage, or exo-erythrocytic stage, parasites multiply Malaria in many areas of the world is seasonal and in the hepatocytes and eventually cause them to usually reaches its peak at the end of the rainy season, rupture. Two species, P. vivax and P. ovale, have thus avoiding travel during peak malaria seasons may persistent liver stages resulting in relapse months to reduce the risk. years later.
The second, or erythrocytic stage occurs when the Chemoprophylaxis. Malaria chemoprophylaxis in
parasites are released into the bloodstream, invade travelers to endemic areas is one of the most erythrocytes, and cause clinical illness. This stage complicated and challenging aspects of travel medicine occur usually after 12 + 3 days in P. falciparum and poses several significant problems. infection and after 14+ 3 days in P. vivax infection. A. Risk-benefit: the risk of malaria infection and It should be noted that: severe consequences of the disease should be The malaria parasite is different in its sensitivity weighed against the risk to the traveler of the to drugs in each form of its cycle. Thus a drug drug itself. Several drugs have had fatal which acts on the parasite during the intra- outcomes to consumers; others have caused erythrocytic stage will not necessarily act against significant adverse events and an interruption of it in its liver stage and vice versa. travel due to the adverse events. This side of the Chemoprophylaxis does not prevent the equation is not always weighed appropriately by infection (as in the case of vaccine preventable those who prescribe these drugs. diseases), but rather works as having a killing B. Cost-benefit: with the development of malaria- effect against the parasite, either within the resistant species, new drugs have been made erythrocytes or within the hepatocytes, thus available, usually at a higher cost. Thus for preventing the clinical disease. budget travelers, especially with long-term trips, Based on the parasite's life cycle, there are two use of these drugs becomes a burden. When the types of malaria chemoprophylaxis, based on the site of malaria risk is minimal, the benefit of such an expense is often felt unjustified. C. Inadequacy of the current chemoprophylaxis: Blood Stage (Suppressive) and Liver Stage
Although we use the term, "malaria Prophylaxis (Causal)(Figure 1).
prophylaxis," in reality we have "falciparum Blood stage prophylaxis refers to drugs that act only prophylaxis" and not a pan –malaria on parasites within the red blood cells. These are the commonly known antimalarial drugs that have been recommended prophylactic drugs may still used over the past 60 years or so. Among their present with late-onset vivax infection.5 disadvantages is that they must be continued for 4 Although vivax malaria in most cases does not weeks after travel to eliminate the parasites within the have a severe outcome, it remains a significant RBCs which may emerge from the liver as late as 2-4 disease, and one that the traveler would like to weeks after exposure. Another major disadvantage is prevent. Additionally, if a traveler contracts that since these drugs have no activity against the liver malaria despite taking prophylaxis, he or she stage and development of hypnozoites, they actually may deem it useless and skip taking it for prevent only primary vivax (and ovale) infection, and subsequent trips. they do not have the ability to prevent relapse. They are Adverse events, cost-benefit calculations and the therefore a complete prevention only in the case of P. inadequacy of preventing late-onset vivax malaria are falciparum infection. all probable reasons for low adherence to prophylaxis, Liver stage prophylaxis, refers to drugs that act on and well-known to those practicing travel medicine. A the parasite while invading the hepatocytes. Since these survey done in our institute of travelers presenting drugs kill the parasite early on during the infectious post-travel, seeking medical advice for any reason [n= process, there is no need to continue taking the drug 1207], demonstrated that only 15% adhered to malaria after leaving the endemic areas. For falciparum prophylaxis [E. Schwartz unpublished data]. infection, it has the advantage of shortening the Mediterr J Hematol Infect Dis 2012; 4: Open Journal System
Figure 1. Malaria Life cycle (partial illustration). Blood stage prophylaxis: Drugs which act on the malaria parasites only within the
erythrocytes. (such as: Mefloquine, Chloroquine, Amodiaquine). They have to be continued therefore for 1 month after leaving the malarious
area. As can be seen in the figure, late infections will not be prevented. Liver stage prophylaxis: Drugs which act on the malaria parasites
within the hepatocytes (such as Primaquine and Malarone). It is sufficient to continue the drug for a few days after leaving the endemic area.
However, only primaquine potentially may prevent all types of malaria including the late infection.
duration of the prophylaxis usage and instead of Eastern countries where the prevalence of P. continuing medication for 1 month post-travel there is falciparum is in any case very low.6 only a need to continue for several days, which may increase compliance with the full prophylaxis schedule. chemoprophylaxis since then includes trying to find In the case of vivax (and ovale) infection, liver stage new drugs that are both efficacious and well-tolerated. prophylaxis is imperative. Only drugs that act early on It should be remembered that a drug with even an the liver stage and prevent the hyponozoite formation infrequent severe adverse event, if used as prophylaxis offer complete prevention of this infection. There are for a very large volume of travelers, might quickly currently only 2 drugs which act on the liver stage: present as a harmful drug. Two drugs which were atovaquone-proguanil and primaquine, but only introduced after chloroquine, namely Amodiaquine and primaquine has cidal activity against the hyponozoites Sulfadoxin-Pyrimethamin (Fansidar), were excluded ( as discussed further in the vivax prophylaxis section). from use as prophylaxis due to severe adverse events, including fatal cases. With amodiaquine, fatalities were Falciparum prophylaxis. The introduction of
due to agranulocytosis, and with Fansidar they were chloroquine in the 1950's brought great hope that due to fatal toxic epidermal necrolysis. Risk-benefit falciparum prevention could be easily achieved with a calculations that were done at that time showed that in long acting drug, that was well-tolerated and taken on a some geographical areas, the risk of fatal outcomes weekly basis. However, within one decade drug from these drugs was higher than from the disease.7 resistance appeared, first in South East Asia and within The principal drugs currently in use are mefloquine, a few years this resistance spread throughout the doxycycline, atovaquone-proguanil (Malarone), and to endemic areas. Currently, the resistance of P. some extent Primaquine (Table 1)
falciparum to chloroquine is almost universal. It remains effective only in Central America, the Mefloquine. Mefloquine (Lariam, Mephaquin) was
Caribbean (mainly Haiti), and in some of the Middle Mediterr J Hematol Infect Dis 2012; 4: Open Journal System Table 1. Use of anti malarial drugs for P. falciparum prophylaxis.
End of prophylaxis (after
Atovaquone-proguanil * G6PD testing is mandatory [usually =2 tabs] before its use 300mg (base) =500 developed from a quinolone–methanol compound at The psychiatric disorders may include insomnia, the Walter Reed Institute. It was found to have potent strange dreams, restlessness, anxiety, depression, and anti-malaria activity, including against chloroquine- resistant P. falciparum strains and due to its long half- The incidence of any AE due to the drug is hard to life, it can be taken on a weekly basis. These assess since results varied and ranged from about 10%- characteristics of the drug created optimism, in the 90% depending on the study design and whether a mid-1980's when first introduced in Europe (and in the comparator was used.9 The rate of drug withdrawal US in 1990), that an ideal replacement for chloroquine also varied, from 0.9% to 5%.10,11 had been found. In addition, long-term prophylaxis The most concerning issue of chemoprophylaxis is usage among Peace Corps volunteers in Sub-Saharan the rate of serious AEs, resulting in a possible life Africa demonstrated its safety and good tolerability.8
threatening condition, or causing severe disability or However during the subsequent decades of its use, prolonged hospitalization. Well-designed prospective there arose several concerns. studies of mefloquine's adverse events may not identify a significantly higher number of events in comparison A. Mefloquine resistance: Resistance was occasionally to other anti-malaria drugs, because of the small reported first from the Thai-Cambodian border, number of participants, and also it is easy to miss the followed by reports from other parts of Asia and to relatively rare severe adverse events.10,11,12 Only post- lesser extent from Africa and the Amazon region. The marketing surveillance studies (with their limitations) level of mefloquine resistance in the area of Thai- have sample sizes large enough to capture the rare Cambodian and Thai-Burmese borders has reached serious adverse events, thereby drawing significant 50%, thus precluding it from use as prophylaxis in this specific region. While in all other regions, the Results of a study done by questionnaire among resistance level currently is more anecdotal and the mefloquine users in British soldiers showed a rate of drug can be used in these areas. severe AEs as 1:6000,13 while a questionnaire among However, the main concern for travelers regarding European travelers showed a rate of 1:10,000.13 the use of mefloquine is its safety and tolerability. Spontaneous reporting among Canadian travelers demonstrated a rate reaching 1:20,000.9 B. Mefloquine safety and tolerability: Mefloquine's Mefloquine AEs as reported in all studies are more adverse side effects may include neuropsychiatric, common in women. In most cases, susceptible gastrointestinal, and less commonly dermatological individuals have problems after the first 1-3 doses.15 The recommendation therefore is to start mefloquine The neuropsychiatric adverse events (AE) about 2 weeks prior to departure in order to assess any associated with mefloquine are the worrisome adverse effects which may necessitate the use of an complaints, and have received a vast amount of public alternative prophylaxis. attention, (probably more than any other malaria In a case control study among travelers with serious prophylactic drug). AEs due to mefloquine prophylaxis, no difference in The neurological disorders include headache, the level of mefloquine in the blood was found between dizziness, confusion, vertigo and seizures. Peripheral the patients and the control groups. Also, no significant neuropathies such as paresthesia, tremors and ataxia difference was found between mefloquine levels in the have also been reported. blood of men and women. These results suggest that blood levels of mefloquine do not correlate with its severe adverse events.15 Mediterr J Hematol Infect Dis 2012; 4: Open Journal System Pregnancy: One of the advantages of mefloquine is An important adverse effect of the drug among the fact that this is the only drug that can be taken female travelers is the risk for vaginal candidiasis, during pregnancy when traveling to chloroquine- which estimated to occur in 2.8%.18 resistant areas. It is officially recommended for the 2nd The requirement to take doxycycline daily and the and 3rdtrimesters of pregnancy. Limited data also fact that it must be continued for one month after suggest that its use during the first trimester is safe. leaving a malaria endemic area, are also drawbacks in Therefore, mefloquine should be recommended to a terms of its use. pregnant woman who cannot avoid traveling to An extra-benefit of using doxycycline for malaria endemic areas during her first trimester.16 prophylaxis might be its preventive measure against Contraindications: Due to the possible drug- leptospirosis, which is a common hazard in the tropics, neuropsychiatric and its potential protection against rickettsial diseases contraindicated in travelers who have seizure disorders. and traveler's diarrhea. In addition, it should not be given to travelers with Contraindications are for pregnant women, active psychiatric disorders such as depression, breastfeeding mothers, children under 8 years old, and anxiety, psychosis or any other major psychiatric those with a history of allergy to any of the tetracycline disorders. It is advisable not to prescribe this drug to patients with a history of the above-mentioned psychiatric disorders, even if they are currently Atovaquone-Proguanil. The spread of drug –resistant
falciparum malaria, and the widespread reluctance to Since the drug is related to quinine, it should not be use the known anti-malaria drugs due to their side given to persons with a known hypersensitivity to effects, led to the pursuit of new antimalaria drugs. mefloquine or to quinine compounds. It is also not Atovaquone-proguanil (Malarone) is the latest anti- recommended for travelers with cardiac conductions malarial drug to be developed. This drug is well-tolerated, and has good efficacy for resistant falciparum strains. Doxycycline. Doxycycline, a synthetically derived
An added advantage of this drug is the fact that it tetracycline, is a highly effective drug for the acts on the liver stage of the malaria parasite thus prevention of malaria. In studies conducted in non- shortening considerably the amount of time needed to immune populations, the dosage used was 100mg continue it post-travel (Figure 1). It is therefore the
daily, resulting in greater than 95% efficacy against first liver-stage drug since the introduction of malaria P.falciparum, indicating that it is as efficacious as the chemoprophylaxis, (with the exception of Primaquine, other drugs currently available, such as mefloquine and which will be discussed below). atovaquone–proguanil.17 Although it has some liver- The drug is a fixed combination of Atovaquone 250 stage activity, its main action is on the erythrocytic mg and of Proguanil 100mg. Pediatric tablet contain stage thus requiring 4 weeks of continuation of the the same combination with a quarter of the dose of drug after leaving an endemic area. each component (62.5/25 mg). Malaria resistance to doxycycline has not been Atovaquone alone was well-established drug against reported yet in any of the malaria endemic areas. Pneumocystitis carinii. Tolerability: The most common adverse events are Its mode of action against the plasmodia spp. is via gastrointestinal-related complaints such as abdominal inhibition of the mitochondrial electron transport pain, nausea, vomiting and diarrhea. A severe system, at the level of cytochrome-b complex. complication is esophageal ulceration, and therefore Proguanil is an old anti-malaria drug, which acts by the recommendation is to take it in an upright position, inhibiting the parasite's dehydrofolate reductase. with food or full glass of water and not before bedtime. Each of these drugs has weak anti-malarial activity but in combination there is a synergistic effect, with an photosensitivity, which is a concern for the travelers efficacy of 95-100%.19 Each of these drugs' exposed to the sun in tropical countries. The reported components was tested separately in human volunteers dermatological complications vary and may reach and found to be active at the liver stage.20,21 The fixed 21%,17 although in a four-arm multicenter randomized combination atovaquone-proguanil was also tested in controlled trial comparing doxycycline, mefloquine, human volunteer challenge trials where non-immune atovaquone-proguanil and chloroquine –proguanil, in subjects were given 1 tablet of this combination for 8 travelers to Africa, skin reactions with doxycycline days, starting 1 day before the mosquito challenge and were less common than with chloroquine–proguanil.12 continuing for 7 days after. None of the subjects (n=12) who took the active drug developed malaria, while all (n=4) who took placebo developed falciparum Mediterr J Hematol Infect Dis 2012; 4: Open Journal System malaria.22 This clearly demonstrated that the Primaquine. Primaquine, as viewed by many
combination of the drugs has good activity against the clinicians, has its only role in regard to its activity liver stage of P. falciparum. This study was the basis against P. vivax infection. However, since its for recommending the drug atovaquone-proguanil to be introduction in the early 1950's, primaquine has been continued for 7 days after leaving the endemic areas. found to be active against the early liver stages of both However, a very recent study done as the same method P. falciparum and P. vivax malaria. described above showed that even taking it at the last Primaquine is an 8-aminoquinoline and was day should be enough.23 developed in the 1940's. In a study conducted in 1954, healthy volunteers who were inoculated with P. Tolerability. Several studies of atovaquone-proguanil
falciparum malaria but were given primaquine, at a have been conducted among travelers to evaluate its daily dose of 30 mg before the sporozoite inoculation, safety and tolerability in comparison to other the infection was prevented.25 antimalrial drugs. In a four-armed multicenter Despite the fact that primaquine was highly randomized controlled trial comparing the 4 drugs effective against the early liver stages of the parasite commonly used in travelers, namely mefloquine, (P. falciparum and P. vivax), it never gained doxycycline, chloroquine-proguanil and atovaquone – widespread use as chemoprophylaxis. This was most proguanil, the latter had the lowest withdrawal rate due likely for two principal reasons. The first was the to adverse events (2%).12 Other studies where only one reporting of severe adverse effects, including drug was used as a comparator, either mefloquine or methemoglobinemia and hemolytic anemia occurring chloroquine-proguanil, the atovaquone-proguanil had a in glucose-6-phosphate dehydrogenase (G6PD)- better safety profile.11,24 deficient patients.26,27 The second reason was perhaps The drug has been in use for about a decade and due to the introduction of a new drug, chloroquine, seems to maintain a very good safety and tolerability which was relatively safe and highly potent. record. However, the main drawback for using it is the In recent years however, primaquine has made its higher cost in comparison to the other anti malarial comeback as prophylaxis and not just for the radical drugs, which obviously increases with increase the cure of vivax malaria. length of travel. The first study of primaquine used as prophylaxis was conducted in Kenya among a local population, in a Adverse events. The most common adverse events are
hyperendemic area, known to have a 90% incidence of related to gastrointestinal complaints, such as new cases of falciparum malaria and with an estimate abdominal pain, nausea or vomiting and therefore it is of nearly one infective mosquito bite per person per recommended that it be taken with a meal. night. The efficacy at the end of a 3-week follow-up Dermatological complaints such as rashes and period was 85% for primaquine, 84% for doxycycline, pruritus may occur, probably due to the proguanil Another study was conducted in Irian Jaya Indications. Atovaquone-proguanil is indicated for P.
(northeast Indonesia), an area endemic for both P. falciparum prohylaxis. In the US, it is indicated falciparum and P. vivax malaria, with a population of without a time limitation, meaning that long–term transmigrants who were most likely non immune. After travelers, expatriates and military personnel on long- 52 weeks, efficacy against P. falciparum relative to term missions can use it. In several countries in placebo was 94.5% for primaquine and 33.0% for Europe, its use is limited only to short-term travelers chloroquine, and efficacy against P. vivax was 90.4% (30-90 days), since data on its safety with prolonged for primaquine and 16.5% for chloroquine.29 use are lacking. A similar study was conducted in 1997 with It is indicated for children above 5 kg, but dose Colombian soldiers.30 In the primaquine group, the should be modified according to weight (Table 2).
protective efficacy was 94% against P. falciparum, and 85% against P. vivax. Another study, again with Contraindication. The drug is contraindicated in
transmigrants to Irian Jaya, showed similar results. patients with severe renal failure (creatinine clearance Participants received 20 weeks of primaquine or <30 mL/min), and in those with known allergies to one placebo. Primaquine showed an overall protective of the drug components. efficacy of 93%, with> 92% protective efficacy against The drug is contraindicated in pregnancy, since P. vivax and 88% against P. falciparum.31 there is not sufficient information about it safety in pregnancy. Tolerability. The most common adverse effects of
primaquine are gastrointestinal effects that are dose
Mediterr J Hematol Infect Dis 2012; 4: Open Journal System Table 2. Features of the main drugs used for P. falciparum prophylaxis
Reported Long term
Use in Pregnancy
Blood stage [resistance in S.E [mainly neuro- Yes, only >8 years Atovaquone-proguanil dependent. In studies done during the early 1950's, it for 1 month after departure from the malarious area was found that doses of up to 30 mg/day were (opposite to most of the other antimalarial drugs which associated with minimal gastrointestinal upset and only mentioned above, that act on the erythrocyte stage of doses of 45 mg/day or higher were associated with a the malaria parasite). Therefore, the traveler should significant rate of adverse effects.7 start taking it 1 day prior to entering the malarious area Recent studies also have shown minimal and to continue taking it daily for 3-7 days after adverse effects. In the Colombian study,25 two subjects departure from the malrious area. The recommended (2%) who were taking the drug withdrew from the dose is 30mg (2 tablets) per day for adults. Due to the study because of gastrointestinal complaints. In the short half-life of primaquine, it must be taken daily, Indonesian study,27 primaquine was taken daily for preferably with food to avoid gastrointestinal upset. about 1 year, with no withdrawals from significant The CDC recommends taking it for 7 days after adverse events. Complaints were similar in the placebo departure from the malarious area.33Other authorities and drug groups. recommend it for only 3 days after cessation of In the author's study among travelers,32 primaquine was well tolerated. There was only one The pediatric dose is 0.5 mg/kg/day. case of withdrawal, which was due to nausea and Pregnant women should not take it due mainly to vomiting (a rate of 1 per approximately 200 cases). the fear of G6PD deficiency in the fetus. Lactating Primaquine has gained more recognition in recent women can use it if the infant has been tested for years and was listed in Canada and the US as an option for malaria prophylaxis. Its role was reemphasized in a report from a CDC expert meeting on malaria Special Populations. Special populations who may
need particular attention are pregnant women, and children for whom not all drugs mentioned above can Toxicity. Primaquine can produce marked hemolysis
be recommended. (Table 2). Breast feeding mothers
when the drug is administered daily to individuals with should know that the amount of anti-malaria drugs G6PD deficiency; therefore, testing for G6PD before excreted in the milk is not sufficient to offer protection treatment is necessary. to the child, on the other hand it will not likely be Methemoglobinemia occurs in normal individuals, harmful even with drugs that are not approved for but without clinical significance. small children.35 Another special population are long-term travelers Dosage and Recommendation (Table 1). Since
(usually considered those travelling >6 mo.), or primaquine is a drug that acts on the liver stage of the expatriates who remain for several years in endemic malaria parasite, there is no need to continue taking it areas. Two questions arise; which drug is considered to Mediterr J Hematol Infect Dis 2012; 4: Open Journal System be safe for long-term use, and secondly, what is the have fewer relapses, and a longer period before relapse, best approach either taking chemoprophylaxis about 9 months.39 Thus, clinicians should be alert to the continuously, or use only personal protection measures possibility of vivax malaria attacks several months or and seek medical care in the case of a febrile illness.36 even a year or more following travel to an endemic Mefloquine, and chloroquine (which is of no value in most areas of the world ) are the only drugs that
have a good long-term follow-up record8 (Table 2).
Blood Stage Prophylaxis In Vivax Malaria. Blood
Atovaquone-proguanil, although recommended by the stage prophylaxis is the most common type of CDC for long-term use, has never been assessed in prophylaxis in use. Chloroquine, was the first drug in large numbers, and maximal period of observation was this group to be extensively used. It was introduced in the early 1950's for the prevention of both falciparum The safety of doxycycline has been demonstrated in and vivax malaria. While chloroquine-resistant P. patients taking it for long periods for acne, for malaria falciparum appeared quite quickly, in the late 1950's, prophylaxis there are reports of long-term use among chloroquine-resistant P. vivax presented only in the late soldiers taking it for up to 1 year.38 1980's. It is a significant problem in eastern Indonesia The safety of long term primaquine use was tested where more than half of infections with P. vivax in Indonesia where it was given for52 weeks.29 appears to be resistant. Resistance has been It is evident that expatriates who live for long occasionally reported from other areas in Southeast periods of time even in Sub-Saharan Africa typically Asia, South Asia, and in South America.40 do not take malaria chemoprophylaxis continuously, Mefloquine and doxycycline, are also common but rather rely on identifying symptoms and seeking blood stage drugs for prophylaxis and are effective medical care (usually available and known to them) against p. falciparum and found to be effective against when needed. However, even in these cases it is vivax malaria as well. During the 1990's, well- advisable to use chemoprophylaxis, at least at their first controlled trials of all of these drugs were conducted in few months of their stay. northeastern Indonesian New Guinea, where vivax Long term travelers who are traveling in endemic malaria is heavily endemic and notoriously resistant to areas and moving from one place to the other including chloroquine. They demonstrated 100% protective remote areas, should be encouraged to take efficacy.41 Since these drugs have no activity against chemoprophylaxis continuously throughout their trip liver stages and development of hypnozoites, they especially when it is done in Sub Saharan Africa. actually prevent only primary infection and not late relapses. In fact in recent years, with the increase of travel to the tropics, it has become more evident that P. Vivax ( it relates to P. ovale as well) has a more using recommended prophylaxis, which is almost complicated life cycle than P. falciparum due to the exclusively blood stage prophylaxis, only postpones formation of liver hypnozoites, which can result in a the first clinical attack of malaria to several months clinical relapse several months after the primary after return. This was clearly demonstrated in a study infection. Therefore, complete prevention of this among US and Israeli travelers where the majority of infection is much more challenging and can be achieved all imported vivax cases [60-80%] were late infections only if both primary and late infections are prevented. (more than 2 months after return) in travelers who took The life cycle of P.vivax has a bimodal incubation recommended prophylaxis. This clearly illustrates the deficiency of the currently recommended prophylaxis A. The primary attack, which follows exposure to in fully preventing vivax infection.5 infectious sporozoites, occurs about 14+ 3 days The common recommendation of chloroquine use after the mosquito bite ( for P. falciparum this for vivax prevention is based on the sensitivity of vivax incubation time is of 12+ 3 days). spp. to chloroquine, but it ignores the fact that B. The late infection is a relapse following chloroquine can not prevent the hypnozoite formation activation and maturation of the dormant liver and therefore can not prevent late infection. stage hypnozoite (Figure 1).
Thus, the role of chloroquine or other blood stage The chance of, and incubation time for relapse prophylaxis in complete prevention of vivax is very largely depends upon the geographic origin of the limited (it might have some value only in areas where infection. The tropical P. vivax strains tend to have a the relapse rate is very low), and should not be regard
higher probability of relapse (>30%), a shorter period as vivax prophylaxis. between primary attack and relapse (17-45d), and a To overcome this problem there are 2 options higher incidence of multiple relapses (>2), while the (Figure 2); one is by adding Terminal prophylaxis,
temperate strains (such as the Korean strain) tend to meaning presumptive standard treatment with Mediterr J Hematol Infect Dis 2012; 4: Open Journal System Figure 2. Vivax prophylaxis Strategy
primaquine upon leaving an endemic area. The term efficacy of the drug for vivax malaria, found it to be "presumptive anti-relapse therapy" (PART) has been 82% efficacious in Indonesia and 100% in proposed to better describe this treatment strategy.33 It Colombia.42,43 However both studies evaluated its is intended to kill latent liver stages of P. vivax and efficacy only for primary infection (a follow- up of 1 thus prevent relapse. The dose of primaquine for this month after exposure). Recent evidence from Israeli purpose is under re-evaluation. The common travelers to Ethiopia (Omo region) has shown the knowledge of dosing with 15mg daily for 14 days, is inefficacy of this drug to prevent late infection. probably insufficient, especially for the high body Although during the first month post travel the efficacy weight of typical travelers from industrialized of the atovaquone-proguanil was 100%, the relapse rate countries. The current preferred recommendation is a among the users was 56% during 1 year of follow up, single 30mg dose of primaquine (base) taken daily for similar to blood stage drugs [E. Schwartz, submitted 2 weeks after leaving the endemic area. for publication]. There remains with this approach a grey area On the other hand, primaquine studies of the last 10 regarding which travelers would benefit. Should years show effective protection against primary attacks everyone who was in a malaria endemic area where in transmigrants in Indonesia and in travelers.44In there is p. vivax take it, or should it be reserved for travelers, long-term follow up demonstrated its efficacy high risk populations, such as long term travelers or also in preventing relapse.32 Our above mentioned those who have been to highly endemic vivax area study showed that in the highly endemic area of (such as in our experience the Omo region in Ethiopia). Ethiopia, while the malaria attack rate among non- The second approach and more convenient one is by primaquine users (mefloquine, doxycycline and
using Liver stage Prophylaxis. This prophylaxis can
atovaquone-proguanil) was about 50%, in primaquine eliminate both primary attacks and relapses of P. vivax users it was 1.4% [E. Schwartz, submitted for and can be effective for P. falciparum prevention as publication ].
well. Primaquine is the only available drug known to Since the early clinical trials of primaquine have this prophylactic activity against vivax malaria. demonstrated its activity against falciparum malaria as Atovaquone-proguanil, despite being a known liver well,25 it can be used as a single agent for all malaria stage prophylaxis against falciparum malaria (as mentioned above), does not prevent late vivax The dose and contraindications are mentioned infection. Although studies, which looked at the above (Table 1).
Mediterr J Hematol Infect Dis 2012; 4: Open Journal System In conclusion, for travelers to vivax-predominant recommended policy is personal protection only areas; short-term travelers, a daily dose of primaquine [named: type 1 prophylaxis].16 (only if G6PD is normal) seems to be the most The real challenge in travel medicine is making convenient option. recommendations for low risk malaria areas such as For long-term travelers, a weekly dose of Central and South America, and several parts of East chloroquine (depends on the area), or of mefloquine (if Asia. In these regions the risk of malaria definitely there are no contraindications) followed by terminal exists and there are cases of imported malaria from prophylaxis with primaquine, would be the most those areas, however the overall risk for travelers is convenient and efficacious (Figure 2).
low. A study from Europe suggests that the risk of adverse events from hemoprophylaxis is likely to be significantly higher than the risk of acquiring malaria The Threshold for Malaria Chemoprophylaxis Use.
in the most popular tourist destinations in Central and Malaria chemoprophylaxis should not be used in areas where there is no malaria., therefore, the practitioner A similar conclusion came from an analysis of who sees the traveler prior to his departure should be malaria imported into eight European countries from familiar with the non-endemic areas. It should be the Indian sub-continent (ISC) (India, Pakistan, remembered that even within endemic countries, there Bangladesh and Sri Lanka).46 The proportion of cases are often areas free of malaria. For example, travelers from the ISC ranged from 1.4%–4.6% of total imported who trek in Nepal are not at risk due to the high cases, and again P. falciparum cases accounted for altitude. The same holds true for travelers to high only 13% of all cases from the region. Thus, the altitude areas even within Sub-Saharan Africa such as calculated risk of malaria in UK residents visiting the Addis Ababa and the Ethiopian plateau which are region was > 1 case per 1,000 years exposed.46 highland areas above 2000 m., etc. Therefore, the TropNet group recommends that the In the endemic areas, the risk for travelers varies non-selective prescribing chemoprophylaxis for significantly. The higher risk for falciparum malaria is visitors to the India subcontinent, should be dropped.46 in West Africa, estimated to be 2.4% per month of stay, An alternate strategy adopted by a number of while in East Africa is 1.5% per month of stay, risk is European countries, for example Switzerland,47 is to also high in travelers to the Pacific islands (Solomons and Papua New Guinea), but is 10-20 times less in treatment" to be used in case malaria symptoms occur
travelers to Asia, and 30-40 times less in travelers to during travel. This assures treatment of a life threatening attack of falciparum malaria, and avoids Thus, the more complicated issue is the decision about malaria chemoprophylaxis in those who travel to chemoprophylaxis low risk areas, and what should be decided as the There is no consensus about the use of stand by threshold(if any) for using chemoprophylaxis. There is therapy. However the strategy of bite prevention no consensus yet about this issue. According to the measures remains important, as these are effective, safe policy of the US CDC, the world is divided to "All or and have the added benefit of reducing other vector None" in regard to recommending chemoprophylaxis; borne diseases. In addition, travelers have to be one should either take it or not.35 The WHO introduced educated to seek medical advice in the case of a febrile another category for certain areas of the world and the References:
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Mediterr J Hematol Infect Dis 2012; 4: Open Journal System
Kno c he nmarke rkrankung e n Priv.-Do z. Dr. Ro land Re pp Me dizinis c he Klinik V Klinikum Bambe rg Was will ic h Ihne n e rzähle n … • Funktion des Knochenmarks • Welche Symptome werden durch ein gestörtes Knochenmark verursacht? • Was sind die häufigsten Erkrankungen des Knochenmarks? • Wie werden diese Erkrankungen