Superior protection in a relapsing Plasmodium cynomolgi rhesus macaque model by a chemoprophylaxis with sporozoite immunization regimen with atovaquone-proguanil followed by primaquine.

BACKGROUND: To gain a deeper understanding of protective immunity against relapsing malaria, this study examined sporozoite-specific T cell responses induced by a chemoprophylaxis with sporozoite (CPS) immunization in a relapsing Plasmodium cynomolgi rhesus macaque model. METHODS: The animals received three CPS immunizations with P. cynomolgi sporozoites, administered by mosquito bite, while under two anti-malarial drug regimens. Group 1 (n = 6) received artesunate/chloroquine (AS/CQ) followed by a radical cure with CQ plus primaquine (PQ). Group 2 (n = 6) received atovaquone-proguanil (AP) followed by PQ. After the final immunization, the animals were challenged with intravenous injection of 104 P. cynomolgi sporozoites, the dose that induced reliable infection and relapse rate. These animals, along with control animals (n = 6), were monitored for primary infection and subsequent relapses. Immunogenicity blood draws were done after each of the three CPS session, before and after the challenge, with liver, spleen and bone marrow sampling and analysis done after the challenge. RESULTS: Group 2 animals demonstrated superior protection, with two achieving protection and two experiencing partial protection, while only one animal in group 1 had partial protection. These animals displayed high sporozoite-specific IFN-γ T cell responses in the liver, spleen, and bone marrow after the challenge with one protected animal having the highest frequency of IFN-γ+ CD8+, IFN-γ+ CD4+, and IFN-γ+ γδ T cells in the liver. Partially protected animals also demonstrated a relatively high frequency of IFN-γ+ CD8+, IFN-γ+ CD4+, and IFN-γ+ γδ T cells in the liver. It is important to highlight that the second animal in group 2, which experienced protection, exhibited deficient sporozoite-specific T cell responses in the liver while displaying average to high T cell responses in the spleen and bone marrow. CONCLUSIONS: This research supports the notion that local liver T cell immunity plays a crucial role in defending against liver-stage infection. Nevertheless, there is an instance where protection occurs independently of T cell responses in the liver, suggesting the involvement of the liver's innate immunity. The relapsing P. cynomolgi rhesus macaque model holds promise for informing the development of vaccines against relapsing P. vivax.

A Smartphone App for Real-Time Assessment of Malaria Prophylaxis Adverse Events.

Background: Growth of international travel to malarial areas over the last decades has contributed to more travelers taking malaria prophylaxis. Travel-related symptoms may be wrongly attributed to malaria prophylaxis and hinder compliance. Here, we aimed to assess the frequency of real-time reporting of symptoms by travelers following malaria prophylaxis using a smartphone app. Method: Adult international travelers included in this single-center study (Barcelona, Spain) used the smartphone Trip Doctor® app developed by our group for real-time tracking of symptoms and adherence to prophylaxis. Results: Six hundred four (n = 604) international travelers were included in the study; 74.3% (449) used the app daily, and for one-quarter of travelers, malaria prophylaxis was prescribed. Participants from the prophylaxis group traveled more to Africa (86.7% vs. 4.3%; p < 0.01) and to high travel medical risk countries (60.8% vs. 18%; p < 0.01) and reported more immunosuppression (30.8% vs. 23.1% p < 0.01). Regarding symptoms, no significant intergroup differences were observed, and no relationship was found between the total number of malarial pills taken and reported symptoms. Conclusions: In our cohort, the number of symptoms due to malaria prophylaxis was not significantly higher than in participants for whom prophylaxis was not prescribed, and the overall proportion of symptoms is higher compared with other studies.

Selection of Cytochrome b Mutants Is Rare among Plasmodium falciparum Patients Failing Treatment with Atovaquone-Proguanil in Cambodia.

Atovaquone-proguanil remains effective against multidrug-resistant Plasmodium falciparum in Southeast Asia, but resistance is mediated by a single point mutation in cytochrome b (cytb) that can arise during treatment. Among 14 atovaquone-proguanil treatment failures in a clinical trial in Cambodia, only one recrudescence harbored the cytb mutation Y268C. Deep sequencing did not detect the mutation at baseline or in the first 3 days of treatment, suggesting that it arose de novo Further sequencing across cytb similarly found no low-frequency cytb mutations that were up-selected from baseline to recrudescence. Copy number amplification in dihydroorotate dehydrogenase (DHODH) and cytb as markers of atovaquone tolerance was also absent. Cytb mutation played a minor role in atovaquone-proguanil treatment failures in an active comparator clinical trial.

Plasmodium falciparum Clearance Is Pitting-Dependent With Artemisinin-Based Drugs but Pitting-Independent With Atovaquone-Proguanil or Mefloquine.

Pitting, the removal of dead parasites from their host erythrocyte, has been studied in patients with severe malaria treated parenterally with quinine or artesunate, and was recently shown to contribute to delayed hemolysis, a frequent adverse event of artesunate. We quantified pitting in 81 travelers treated with oral antimalarial therapy. Pitting rate was high (55.8%) with artemisinin-based combinations, but <10% with the nonartemisinin drugs quinine, mefloquine, and atovaquone-proguanil. This may, in part, explain the slower parasite clearance in patients treated with antimalarial drugs lacking an artemisinin component, as well as the absence of posttreatment hemolysis with these drugs.

A survey on outcomes of accidental atovaquone-proguanil exposure in pregnancy.

BACKGROUND: Malaria chemoprophylaxis options in pregnancy are limited, and atovaquone-proguanil (AP) is not recommended because of insufficient safety evidence. An anonymous, internet-based survey was disseminated to describe outcomes of pregnancies accidentally exposed to AP. Outcomes of interest included miscarriage (defined as pregnancy loss before 20 weeks), stillbirth (defined as pregnancy loss at or after 20 weeks), preterm birth or live birth prior to 37 weeks, and the presence of congenital anomalies. RESULTS: A total of 487 women responded and reported on 822 pregnancies. Of the 807 pregnancies with information available on exposure and outcomes, 10 (1.2%) had atovaquone-proguanil exposure, all in the first trimester, and all resulted in term births with no birth defects. CONCLUSIONS: Use of an anti-malarial not recommended in pregnancy is likely to occur before the woman knows of her pregnancy. This study adds to the limited evidence of the safety of AP in pregnancy. Further study on use of AP in pregnancy should be a high priority, as an alternative option for the prevention of malaria in pregnancy in non-immune travellers is urgently needed.

A randomized, open-label two-period crossover pilot study to evaluate the relative bioavailability in the fed state of atovaquone-proguanil (Atoguanil™) versus atovaquone-proguanil hydrochloride (Malarone®) in healthy adult participants.

Atoguanil™ is a novel complex of atovaquone (ATV) and proguanil (PG) with enhanced ATV bioavailability compared to Malarone®. This pilot study assessed whether the relative bioavailability (Frel) of ATV, PG, and the primary PG metabolite cycloguanil (CG) following a single oral dose in the fed state of Atoguanil was similar to Malarone despite a 50% lower ATV dose. This open-label, single-dose, randomized 2-period, 2-treatment, balanced crossover study was conducted between 17th November 2021 and 18th March 2022. Eligible participants (aged 18-55 years) were randomized (1:1) in period 1 to Atoguanil (ATV/PG 500/348 mg) or Malarone (ATV/PG hydrochloride 1000/400 mg) administered following a high-fat, high caloric meal. After a 24-day washout period, participants crossed treatment arms. For the doses tested, Frel was assumed similar if 90%CIs were between 80 and 125% for the geometric mean ratio of the least square mean differences for each exposure parameter. In 15 evaluable participants, Frel was similar for ATV Cmax (93.6% [90%CI 83.6, 104.9]) but not AUC0-inf (77.8% [67.4, 89.8]), for PG AUC0-inf (95.6% [92.1, 99.2]) but not Cmax (82.4% [75.8, 89.5]), and for both CG Cmax (100.8% [95.0, 107.0]) and AUC0-inf (102.9% [98.4, 107.7]). Nine adverse events occurred; all were of mild severity and not considered treatment related. At the doses tested, ATV Frel was lower following Atoguanil versus Malarone based on AUC0-inf, though when adjusted for dose Frel increased by 156%. Both drugs were well tolerated with no safety concerns. ClinicalTrials.gov: NCT04866602 (April 26th, 2021).

On the potential for discontinuing atovaquone-proguanil (AP) ad-hoc post-exposure and other abbreviated AP-regimens: Pharmacology, pharmacokinetics and perspectives.

According to current guidelines, atovaquone-proguanil (AP) malaria chemoprophylaxis should be taken once daily starting one day before travel and continued for seven days post-exposure. However, drug-sparing regimens, including discontinuing AP after leaving malaria-endemic areas are cost-saving and probably more attractive to travelers, and may thus enhance adherence. AP has causal prophylactic effects, killing malaria parasites during the hepatic stage. If early hepatic stages were already targeted by AP, AP could possibly be discontinued upon return. Pharmacokinetic data and studies on drug-sparing AP regimens suggest this to be the case. Nevertheless, the evidence is weak and considered insufficient to modify current recommendations. Field trials require large numbers of travelers and inherently suffer from the lack of a control group. Safely-designed controlled human malaria infection trials could significantly reduce study participant numbers and safely establish an effective AP abbreviated regimen which we propose as the optimal trial design to test this concept.

Artemether-lumefantrine, mefloquine and atovaquone-proguanil in the treatment of uncomplicated Plasmodium falciparum malaria in travellers: A retrospective comparative study of efficacy and treatment failures.

BACKGROUND: The aim of this study was to evaluate the rates of parasitaemia clearance and the prevalence of treatment failure in patients with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (AL), mefloquine (MQ), and atovaquone-proguanil (AP). METHOD: The retrospective descriptive study included adult patients with uncomplicated P. falciparum malaria treated at the University Hospital Bulovka in Prague from 2006 to 2019. Parasitaemia clearance was estimated using a linear regression model. RESULTS: The study included 72 patients with a median age of 33 years (IQR 27-45) and a male to female ratio of 3.2:1. Thirty-six patients (50.0%) were treated with AL, 27 (37.5%) with MQ and 9 (12.5%) with AP. The proportion of VFR and migrants was 22.2% with no significant differences among the three groups. The median time to the parasitaemia clearance was two days (IQR 2-3) in patients treated with AL versus four days in the MQ (IQR 3-4) and AP (IQR 3-4) groups, p < 0.001. The clearance rate constant was 3.3/hour (IQR 2.5-4.0) for AL, 1.6/hour (IQR 1.3-1.9) for MQ, and 1.9/hour (IQR 1.3-2.4) for AP, p < 0.001. Malaria recrudescence occurred in 5/36 (13.9%) patients treated with AL and in no patients treated with MQ or AP. CONCLUSIONS: The findings demonstrate the superior efficacy of AL compared to other oral antimalarials in early malaria treatment. However, we observed a higher rate of late treatment failure in patients treated with AL than previously reported. This issue warrants further investigation of possible dose adjustments, extended regimens, or alternative artemisinin-based combinations.

Discontinuing atovaquone/proguanil prophylaxis ad-hoc post-exposure and during-travel dose-sparing prophylactic regimens against P. falciparum malaria: An update with pointers for future research.

BACKGROUND: Atovaquone/proguanil (AP) is a highly effective malaria chemoprophylaxis combination. According to current guidelines, AP is taken once daily during, and continued for seven days post exposure. A systematic review by Savelkoel et al. summarised data up to 2017 on abbreviated AP regimens, and concluded that discontinuing AP upon return may be effective, although the available data was insufficient to modify current recommendations. The same applies to other studies evaluating during-travel dose-sparing regimens. METHODS: A literature search in Pubmed and Embase was performed including search terms related to AP prophylaxis and pharmacokinetics to search for recent studies on abbreviated AP regimens published since 2017. RESULTS: Since the 2017 review, no new studies assessing discontinuing AP ad-hoc post-exposure prophylaxis have been published. Two new studies were identified assessing other abbreviated AP regimens; one investigated a twice-weekly AP regimen in 32 travellers, and one a three-day AP course in therapeutic dose (1000/400 mg) prior to exposure in 215 travellers. No malaria cases were detected in the study participants adhering to these regimens. CONCLUSIONS: Further research would be needed if the research question is considered of sufficient importance to facilitate evidence-based decision-making to modify current guidelines, as efficacy studies in travellers are fraught with confounders. We recommend human challenge trials to study abbreviated AP regimens pertaining to malaria chemoprophylaxis as they allow for rational, subject number, time- and cost-saving trial designs.

Covid Media Misguidance: A Case Report Highlighting the Influence of Media on Patient Medication Decision Making.

PURPOSE: This case report details the influence of media on patients and the responsibility of health care providers to educate their patients on proper use of medications, and to be aware of potential misadventures based on messages in popular media. SUMMARY: The sudden rise of the COVID19 pandemic has led to media outlets reporting science without necessary peer review and has resulted in preliminary data presented as factual evidence. It is difficult for patients without an extensive medical background in science to fully understand the uncertainty of information shared in popular media. This was demonstrated when preliminary data showed potential promise of hydroxychloroquine for the treatment/prevention of COVID19. This led to patients requesting hydroxychloroquine prescriptions from their providers, as well as stockpiling medication, which led to a shortage. In addition, patients began taking chloroquine containing substances not intended for human consumption. Popular media created a belief in the general public that all antimalarial drugs may work to prevent COVID19. This case report presents an elderly patient that presented to clinic with shortness of breath and lightheadedness. Upon interviewing the patient, it was discovered that he had been taking an old supply of atovaquone and proguanil hydrochloride. Physical exam, and laboratory examination were evaluated to rule out any other etiology with all tests and exams being unremarkable. Two weeks after stopping atovaquone and proguanil hydrochloride, the patient's symptoms completely resolved. CONCLUSION: The media provides a significant portion of the information that patients receive regarding rapidly changing treatment information in a pandemic. It is crucial for health care providers to know what information patients are exposed to, and to educate patients with evidence-based information. Pharmacists are the most accessible health care providers and have a key role in medication review and management. Educating patients on evidence-based use of medications may help avoid harm caused by misinformation from unreliable media sources.

An update on prevention of malaria in travelers.

Malaria, a parasitic disease caused by protozoa belonging to the genus Plasmodium, continues to represent a formidable public health challenge. Despite being a preventable disease, cases reported among travelers have continued to increase in recent decades. Protection of travelers against malaria, a potentially life-threatening disease, is of paramount importance, and it is therefore necessary for healthcare professionals to be up to date with the most recent recommendations. The present review provides an update of the existent measures for malaria prevention among travelers.

Compliance with Primary Malaria Chemoprophylaxis: Is Weekly Prophylaxis Better Than Daily Prophylaxis?

BACKGROUND: Chemoprophylaxis is an effective tool for individuals to minimize their risk of contracting malaria and serves an important public health role in preventing imported malaria. Yet, it is only effective if the traveller is fully compliant with the prescribed regimen. For many destinations, a choice of prophylactic agents is available, so historical compliance data can be helpful for both physicians and travellers to make an informed decision. METHODS: We analyzed the historical self-reported compliance data for six chemoprophylactic agents currently recommended by CDC for primary malaria chemoprophylaxis by searching PubMed, Embase, CINAHL, Web of Science, and Scopus for observational studies reporting on travelers within the last 25 years. The quality of data was graded as "good" or "poor" using the NIH quality assessment tool for cohort and cross-sectional studies. Cumulative compliance data were compiled for all studies (gross compliance) and the subgroup of studies with "good" quality evidence (refined compliance). Subgroup analyses were performed for weekly vs daily administered regimens, between military and civilian travelers, and across each prophylactic agent. RESULTS: Twenty-four eligible studies assessed compliance for mefloquine (n=20), atovaquone-proguanil (n=11), doxycycline (n=13), and chloroquine (n=3). No studies were found for primaquine or tafenoquine. Both gross and refined compliance were significantly better for weekly regimens than daily regimens (P<0.0001). Stopping chemoprophylaxis due to adverse events was significantly more for doxycycline (P<0.0001) compared to other drugs. Compliance was significantly worse in military travelers, but they were also more likely to be prescribed doxycycline. CONCLUSION: Malaria chemoprophylaxis for a traveler should depend on prevailing resistance patterns at destination, current national guidelines, and patient preferences. However, when there is a choice, historical compliance data are useful to select a regimen that the traveler is more likely to comply with.

Malaria in the pregnant traveler.

Pregnant travelers face numerous risks, notably increased susceptibility to or severity of multiple infections, including malaria. Because pregnant women residing in areas non-endemic for malaria are unlikely to have protective immunity, travel to endemic areas poses risk of severe illness and pregnancy complications, such as low birthweight and fetal loss. If travel to malaria-endemic areas cannot be avoided, preventive measures are critical. However, malaria chemoprophylaxis in pregnancy can be challenging, since commonly used regimens have varying levels of safety data and national guidelines differ. Furthermore, although chloroquine and mefloquine have wide acceptance for use in pregnancy, regional malaria resistance and non-pregnancy contraindications limit their use. Mosquito repellents, including N,N-diethyl-m-toluamide (DEET) and permethrin treatment of clothing, are considered safe in pregnancy and important to prevent malaria as well as other arthropod-borne infections such as Zika virus infection. Pregnant travelers at risk for malaria exposure should be advised to seek medical attention immediately if any symptoms of illness, particularly fever, develop.

Drug interactions with antimalarial medications in older travelers: a clinical guide.

Increasingly older adults are traveling to international destinations with malaria as a present risk. Surveillance systems indicate that older adults are more likely to suffer severe complications from malaria. The role of health care providers in selecting an appropriate medication for chemoprophylaxis or treatment of malaria in adults becomes more difficult as older adults undergo physiologic changes that alter the pharmacokinetic and pharmacodynamic nature of medications potentially causing increased drug interactions, adverse events and altered drug action. A comprehensive literature search from 1970 to present, with a focus on the past 10 years, was conducted on drug interactions, pharmacokinetic and pharmacodynamic effects on antimalarials in adults. It was determined that due to pharmacodynamic and pharmacokinetic changes in older adults, especially renal and cardiovascular, special attention should be given to this population of travelers in order to minimize the likelihood of adverse events or altered drug efficacy. Antimalarial drug-disease interactions in older adults can occur more often due to QT prolongation, exacerbation of hypoglycemia, decreased renal elimination and decreased hepatic metabolism. Older antimalarials have well-documented drug-drug interactions. Tafenoquine, a new antimalarial, requires glucose-6-phosphate dehydrogenase screening like primaquine and monitoring of new potential drug interaction with MATE1 and OCT2 substrates. While drug-drug interactions in older travelers may occur more often as a result of polypharmacy, data did not indicate adverse reactions or decreased drug efficacy is greater compared with younger adults. Overall, with the exception of recently approved tafenoquine, much is known about antimalarial drug and disease interactions, but new drugs are always being approved, requiring travel health providers to understand the pharmacokinetics and pharmacodynamics of antimalarial drugs to predict the impact on safety and efficacy in travelers. This guide provides travel health providers with valuable insights on potential outcomes associated with drug interactions in adults and recommended monitoring or drug regimen modification.

The first report of atovaquone/proguanil-induced vanishing bile duct syndrome: Case report and mini-review.

The combination of Atovaquone and Proguanil (Malarone™) has been widely used for treatment and prevention of Plasmodium falciparum malaria. Transient elevation of liver enzymes is a recognized side effect of the medication. The association of Vanishing bile duct syndrome (VBDS) with the use of Atovaqoune/Proguanil was not previously reported. We describe a case of a 62-year-old male with no history of liver disease who presented with painless jaundice after receiving malaria prophylaxis with Atovaquone-proguanil for 25 days. The patient developed severe hepatitis with Vanishing bile duct syndrome. This case highlights a serious side effect of a usually well-tolerated medication.

Atovaquone-Proguanil in Combination With Artesunate to Treat Multidrug-Resistant P. falciparum Malaria in Cambodia: An Open-Label Randomized Trial.

BACKGROUND: Recent artemisinin-combination therapy failures in Cambodia prompted a search for alternatives. Atovaquone-proguanil (AP), a safe, effective treatment for multidrug-resistant Plasmodium falciparum (P.f.), previously demonstrated additive effects in combination with artesunate (AS). METHODS: Patients with P.f. or mixed-species infection (n = 205) in Anlong Veng (AV; n = 157) and Kratie (KT; n = 48), Cambodia, were randomized open-label 1:1 to a fixed-dose 3-day AP regimen +/-3 days of co-administered artesunate (ASAP). Single low-dose primaquine (PQ, 15 mg) was given on day 1 to prevent gametocyte-mediated transmission. RESULTS: Polymerase chain reaction-adjusted adequate clinical and parasitological response at 42 days was 90% for AP (95% confidence interval [CI], 82%-95%) and 92% for ASAP (95% CI, 83%-96%; P = .73). The median parasite clearance time was 72 hours for ASAP in AV vs 56 hours in KT (P < .001) and was no different than AP alone. At 1 week postprimaquine, 7% of the ASAP group carried microscopic gametocytes vs 29% for AP alone (P = .0001). Nearly all P.f. isolates had C580Y K13 propeller artemisinin resistance mutations (AV 99%; KT 88%). Only 1 of 14 treatment failures carried the cytochrome bc1 (Pfcytb) atovaquone resistance mutation, which was not present at baseline. P.f. isolates remained atovaquone sensitive in vitro but cycloguanil resistant, with a triple P.f. dihydrofolate reductase mutation. CONCLUSIONS: Atovaquone-proguanil remained marginally effective in Cambodia (≥90%) with minimal Pfcytb mutations observed. Treatment failures in the presence of ex vivo atovaquone sensitivity and adequate plasma levels may be attributable to cycloguanil and/or artemisinin resistance. Artesunate co-administration provided little additional blood-stage efficacy but reduced post-treatment gametocyte carriage in combination with AP beyond single low-dose primaquine.

Atovaquone-proguanil exposure in pregnancy and risk for adverse fetal and infant outcomes: A retrospective analysis.

BACKGROUND: Malaria in pregnancy can cause severe maternal and fetal complications. Chloroquine (CQ) and mefloquine (MQ) are recommended for chemoprophylaxis in pregnancy, but are not always suitable. Atovaquone-proguanil (AP) might be a viable option for malaria prevention in pregnancy, but more safety data are needed. METHODS: Data for pregnancies and live births among active duty military women, 2003-2014, from the Department of Defense Birth and Infant Health Research program were linked with pharmacy data to determine antimalarial exposure. Multivariable Cox and logistic regression models were used to assess the relationship of antimalarial exposure with fetal and infant outcomes, respectively. RESULTS: Among 198,164 pregnancies, 50 were exposed to AP, 156 to MQ, and 131 to CQ. Overall, 17.6% of unexposed pregnancies and 28.0%, 16.0%, and 6.1% of pregnancies exposed to AP, MQ, and CQ, respectively, ended in fetal loss (spontaneous abortion or stillbirth) (adjusted hazard ratios [aHR] = 1.46, 95% confidence interval [CI] 0.87-2.46; aHR = 1.06, 95% CI 0.72-1.57; and aHR = 0.47, 95% CI 0.24-0.94, respectively). CONCLUSIONS: The small number of AP exposed pregnancies highlights the difficulty in assessing safety. While definitive conclusions are not possible, these data suggest further research of AP exposure in pregnancy and fetal loss is warranted. TWITTER LINE: More research on fetal loss following atovaquone-proguanil exposure in pregnancy is warranted.

Abbreviated atovaquone-proguanil prophylaxis regimens in travellers after leaving malaria-endemic areas: A systematic review.

BACKGROUND: We evaluated existing data on the prophylactic efficacy of atovaquone-proguanil (AP) in order to determine whether prophylaxis in travellers can be discontinued on the day of return from a malaria-endemic area instead of seven days after return as per currently recommended post-travel schedule. METHODS: PubMed and Embase databases were searched to identify relevant studies. This PROSPERO-registered systematic review followed PRISMA guidelines. The search strategy included terms or synonyms relevant to AP combined with terms to identify articles relating to prophylactic use of AP and inhibitory and half-life properties of AP. Studies considered for inclusion were: randomized controlled trials, cohort studies, quasi-experimental studies, open-label trials, patient-control studies, cross-sectional studies; as well as case-series and non-clinical studies. Data on study design, characteristics of participants, interventions, and outcomes were extracted. Primary outcomes considered relevant were prophylactic efficacy and prolonged inhibitory activity and half-life properties of AP. RESULTS: The initial search identified 1,482 publications, of which 40 were selected based on screening. Following full text review, 32 studies were included and categorized into two groups, namely studies in support of the current post-travel regimen (with a total of 2,866 subjects) and studies in support of an alternative regimen (with a total of 533 subjects). CONCLUSION: There is limited direct and indirect evidence to suggest that an abbreviated post-travel regimen for AP may be effective. Proguanil, however, has a short half-life and is essential for the synergistic effect of the combination. Stopping AP early may result in mono-prophylaxis with atovaquone and possibly select for atovaquone-resistant parasites. Furthermore, the quality of the studies in support of the current post-travel regimen outweighs the quality of the studies in support of an alternative short, post-travel regimen, and the total sample size of the studies to support stopping AP early comprises a small percentage of the total sample size of the studies performed to establish the efficacy of the current AP regimen. Additional research is required - especially from studies evaluating impact on malaria parasitaemia and clinical illness and conducted among travellers in high malaria risk settings - before an abbreviated regimen can be recommended in current practice. PROSPERO REGISTRATION NUMBER: CRD42017055244.

Recrudescing Plasmodium malariae infection despite appropriate treatment in an immigrant toddler.

Compared with other plasmodium species which cause human malaria, Plasmodium malariae is considered to be relatively infrequent and milder, although recent reports indicate that its prevalence and impact have been under-estimated. A 23-month-old boy, born and previously living in a refugee camp in Liberia who presented with P. malariae 6 weeks after arrival in the USA, is reported. Despite ostensibly effective anti-malarial treatment with artemether/lumefantrine and two courses of hydrochloroquine, he experienced recurrent parasitaemia, refractory anaemia and splenomegaly over a 6-month period; the symptoms resolved after he received atovaquone/proguanil. It is hypothesised that the recrudescing clinical malaria in this case was related to the long pre-erythrocytic phase unique to P. malariae, and potentially also to a proportion of the parasites being drug-resistant.