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Background: Relapsing babesiosis often occurs in highly immunocompromised patients and has been attributed to the acquisition of resistance against drugs commonly used for treatment such as atovaquone, azithromycin, and clindamycin. Tafenoquine, which is approved for malaria prophylaxis and presumptive antirelapse treatment of Plasmodium vivax malaria, has shown activity against Babesia microti in several animal models of acute infection and in a single human case of relapsing babesiosis. Here, we report 5 cases of relapsing babesiosis treated with tafenoquine, including the previous case, and begin to define the conditions for optimal use of tafenoquine in relapsing babesiosis., Methods: A definitive diagnosis of babesiosis was made by microscopic examination of Giemsa-stained thin blood smears or a real-time polymerase chain reaction (PCR) that targets the parasite 18S rRNA gene. Clearance of B. microti infection was ascertained by use of blood smear and real-time PCR., Results: Tafenoquine was initiated with a loading dose of 600 mg. A weekly maintenance dose consisted of 200 mg or 300 mg; the lower dose was associated with a delayed clearance of B. microti. In 2 cases, all antimicrobial agents but tafenoquine were discontinued prior to clearance of infection. In 2 other cases, clearance was achieved while tafenoquine was administered along with other antimicrobial agents. In 3 of these 4 cases, tafenoquine was used in combination with atovaquone-proguanil. Other agents included atovaquone, azithromycin, and/or clindamycin. In 1 case, tafenoquine was administered alone and failed to prevent relapse., Conclusions: Tafenoquine can be a useful adjunct for the treatment of highly immunocompromised patients experiencing relapsing babesiosis caused by B. microti., Competing Interests: Potential conflicts of interest . P. J. K. reports payments to the Yale School of Public Health from Gold Standard Diagnostics; payments made to self from UpToDate, Inc, for a chapter that addresses the modalities available for treatment of human babesiosis and that mentions tafenoquine as a promising therapeutic approach; and serving on the American Lyme Disease Foundation Board of Directors (no monetary compensation). E. V. reports payments made to Tufts Medical Center from Gold Standard Diagnostics; payments made to self from UpToDate, Inc, for a chapter that addresses the modalities available for treatment of human babesiosis and that mentions tafenoquine as a promising therapeutic approach; and patent application PCT/US2020/062315, Compositions and Methods for the Prophylaxis and Treatment of Babesiosis (pending). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Human babesiosis is a potentially fatal tick-borne disease caused by intraerythrocytic Babesia parasites. The emergence of resistance to recommended therapies highlights the need for new and more effective treatments. Here we demonstrate that the 8-aminoquinoline antimalarial drug tafenoquine inhibits the growth of different Babesia species in vitro, is highly effective against Babesia microti and Babesia duncani in mice and protects animals from lethal infection caused by atovaquone-sensitive and -resistant B. duncani strains. We further show that a combination of tafenoquine and atovaquone achieves cure with no recrudescence in both models of human babesiosis. Interestingly, elimination of B. duncani infection in animals following drug treatment also confers immunity to subsequent challenge. Altogether, the data demonstrate superior efficacy of tafenoquine plus atovaquone combination over current therapies for the treatment of human babesiosis and highlight its potential in providing protective immunity against Babesia following parasite clearance., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: The purpose of this study is to assess the in vitro antimicrobial and anti-biofilm effects of the anti-protozoal agent tafenoquine (TAF) on Enterococcus and elucidate its underlying mode of action., Methods and Results: The present work investigated the susceptibility of TAF on 3 type strains and 11 clinical isolates of enterococci. The results indicated that TAF exhibited powerful antimicrobial activity against both of Enterococcus faecalis and Enterococcus faecium with minimum inhibitory and bactericidal concentrations ranging from 8 to 16 µg ml-1. Meanwhile, biofilm inhibition and eradication assays showed that TAF exhibited potent anti-biofilm activity against E. faecalis ATCC 29212 and E. faecium ATCC 19434. Ultra-microscopic observations revealed significant changes in bacterial morphology and structure caused by TAF, particularly for the disruption of plasma membrane. Mechanistic investigations also revealed that TAF altered both membrane permeability and potential while also impacting adenosine triphosphate production as well as reactive oxygen species generation. In addition, no detectable cytotoxicity of TAF on human cells was observed at concentrations near the minimal inhibitory concentration., Conclusions: In summary, this study confirmed that TAF could effectively inhibit Enterococcus as well as its biofilm formation., (© The Author(s) 2024. Published by Oxford University Press on behalf of Applied Microbiology International.)

Background: The long-acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood-stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD)-deficient individuals., Methods: Healthy adults with normal levels of G6PD were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48 ± 2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population., Results: Twelve participants were inoculated and administered 200 mg (n = 3), 300 mg (n = 4), 400 mg (n = 2), or 600 mg (n = 3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 hours and 4.2 hours, respectively) was faster than with 200 mg or 300 mg (11.8 hours and 9.6 hours, respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants) but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 106 and 109, respectively, in a 60-kg adult., Conclusions: Although a single dose of tafenoquine exhibits potent P. falciparum blood-stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency. Clinical Trials Registration. Australian and New Zealand Clinical Trials Registry (ACTRN12620000995976)., Competing Interests: Potential conflicts of interest. B. E. B. and J. S. M. declare receipt of funding from the Bill and Melinda Gates Foundation (BMGF) and Medicines for Malaria Venture (MMV) to perform the study. G. D. S. declares participation on an Expert Scientific Advisory Committee for MMV and participation on Data Safety Monitoring Boards for multiple MMV-sponsored clinical trials. J. J. M. is an employee of MMV. D. W. declares consultation for BMGF under contract. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

We describe a case of relapsing babesiosis in an immunocompromised patient. A point mutation in the Babesia microti 23S rRNA gene predicted resistance to azithromycin and clindamycin, whereas an amino acid change in the parasite cytochrome b predicted resistance to atovaquone. Following initiation of tafenoquine, symptoms and parasitemia resolved., Competing Interests: Potential conflicts of interest. P. J. K. reports payments to Yale School of Public Health from Gold Standard Diagnostics; payments made to self for a chapter that addresses the modalities available for treatment of human babesiosis and that mentions tafenoquine as a promising therapeutic approach from UpToDate, Inc; and serving on the board of directors for the American Lyme Disease Foundation (received no monetary compensation). E. V. reports payments made to Tufts Medical Center from the Global Lyme Alliance; payments for a chapter that addresses the modalities available for treatment of human babesiosis and that mentions tafenoquine as a promising therapeutic approach from UpToDate, Inc; and patent PCT/US2020/062315, Compositions and Methods for the Prophylaxis and Treatment of Babesiosis (pending). All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Blocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low-dose tafenoquine., Methods: Healthy adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Piperaquine was administered on days 9 and 11 to clear asexual parasitemia while allowing gametocyte development. A single 50-mg oral dose of tafenoquine was administered on day 25. Transmission was determined by enriched membrane feeding assays predose and at 1, 4, and 7 days postdose. Artemether-lumefantrine was administered following the final assay. Outcomes were the reduction in mosquito infection and gametocytemia after tafenoquine and safety parameters., Results: Six participants were enrolled, and all were infective to mosquitoes before tafenoquine, with a median 86% (range, 22-98) of mosquitoes positive for oocysts and 57% (range, 4-92) positive for sporozoites. By day 4 after tafenoquine, the oocyst and sporozoite positivity rate had reduced by a median 35% (interquartile range [IQR]: 16-46) and 52% (IQR: 40-62), respectively, and by day 7, 81% (IQR 36-92) and 77% (IQR 52-98), respectively. The decline in gametocyte density after tafenoquine was not significant. No significant participant safety concerns were identified., Conclusions: Low-dose tafenoquine (50 mg) reduces P. falciparum transmission to mosquitoes, with a delay in effect., Competing Interests: Potential conflicts of interest . B. E. B. declares receipt of funding support from the Bill and Melinda Gates Foundation and Medicines for Malaria Venture (MMV) and receipt of equipment (piperaquine) for clinical trial from Medicines for Malaria Venture. J. S. M. declares grant support from MMV to undertake this study. G. D. S. declares participation on an Expert Scientific Advisory Committee for MMV and participation on Data Safety Monitoring Boards for multiple MMV-sponsored clinical chemotherapy trials done at QIMR. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Plasmodium falciparum malaria (P.f. malaria) is frequently imported to non-endemic countries. Recommendations on outpatient treatment differ largely due to differences in country-level guidelines and even between tropical medicine referral centres within the same country., Methods: This survey among experts from TropNet or GeoSentinel referral centres for tropical medicine outside malaria endemic areas investigated common practices in P.f. malaria management, selection criteria for outpatient management and diagnostic procedures as a first step for developing a future common and evidence-based approach., Results: A total of 44 referral centres participated. Most of the centres are located in Europe (n = 37). Overall, 27 centres (61%) treat uncomplicated P.f. malaria patients as outpatients, of which eight centres (18%) reported treating ≥75% of patients on an outpatient basis. Seventeen centres (39%) reported treating patients only as inpatients. No single criterion stands out for the decision regarding outpatient treatment, but three groups of factors were identified: (i) clinical criteria including laboratory parameters, clinical condition and tolerance of oral medication; (ii) factors such as patient compliance, reachability by phone and support at home and (iii) patient origin and place of residence as a proxy for possible underlying semi-immunity. The threshold parasitaemia for outpatient treatment varied from 0.1 to 5% with a median of 2%. A median of 0.5% of outpatients were admitted during follow-up. During the last 10 years, 33 complications were reported by nine of the 27 centres and three deaths by one centre., Conclusion: This study gives insight into the heterogeneous management of P.f. malaria patients outside endemic regions. Although there is no consensus among experts, the majority of centres includes outpatient treatment in their clinical routine. However, the lack of evidence-based criteria and established safety for this approach shows the need for prospective studies to define and evaluate criteria and practices for safe outpatient management., (© International Society of Travel Medicine 2020. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

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., (Published by Oxford University Press on behalf of International Society of Travel Medicine 2020.)

Objectives: The World Health Organization recommends measurement of glucose-6-phosphate dehydrogenase (G6PD) activity before initiation of 8-aminoquinoline therapy. A new drug for malaria prophylaxis and treatment (tafenoquine) is contraindicated in patients with G6PD deficiency or unknown G6PD status given its prolonged half-life. Assessments of percentage of normal G6PD activity using laboratory-specific result distributions are not widely available, making tafenoquine-eligibility decisions potentially challenging., Methods: Using an institutional review board-exempt protocol, a data set of quantitative G6PD results was retrieved from a national reference laboratory. G6PD testing was previously performed at 37 °C using an automated enzymatic assay configured on a Roche cobas c501 chemistry analyzer., Results: Overall, 52,216 results from patients 18 years and older and 6,397 results from patients younger than 18 years were obtained. A modified adjusted male median of 12.7 U/g Hb was derived for adult males in this assay configuration. Result distributions showed higher G6PD activity in neonates., Conclusions: Retrospective data analysis can be used to determine laboratory-specific normal G6PD activity values in clinical populations and thus can assist in clinical-eligibility considerations for 8-aminoquinoline treatment., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© International Society of Travel Medicine 2019. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Primaquine was the only licenced antimalarial hypnozoiticidal drug available until recently. Now there is a newly approved alternative: tafenoquine. This review explores the efficacy of tafenoquine as a primary and terminal prophylactic agent in malaria. Multiple databases (Cochrane Central Register of Controlled Trials [CENTRAL], MEDLINE [PubMed], Embase [Ovid], Scopus, CINAHL [EBSCOhost] and LILACS) were searched for clinical randomised controlled trials that had used tafenoquine for prophylaxis without language or time restrictions. The last date of searching was 13 August 2018. For primary prophylaxis, tafenoquine reduced episodes of malaria compared with placebo, at a dose range from 50 mg weekly to 400 mg monthly in three trials conducted in Ghana, Kenya and Thailand. Two trials compared tafenoquine vs mefloquine, but malaria episodes were too few to reach a conclusion. For terminal prophylaxis, evidence from two trials suggest that tafenoquine may have equal or better efficacy compared with primaquine. All trials excluded pregnant participants or those with G6PD deficiency. Tafenoquine is effective for both primary and terminal prophylaxis. If used for primary prophylaxis it may continue to offer protection against vivax relapses after exposure has ended (as terminal prophylaxis)., (© The Author(s) 2019. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Tafenoquine was recently approved for chemoprophylaxis of malaria. Its specific activity against liver and blood stages of Plasmodium species has been separately characterized in animals but not in humans., Methods: In this randomized, double-blind, placebo-controlled study, 16 malaria-naive, glucose-6-phosphate dehydrogenase-normal participants aged 20-42 years received tafenoquine chemoprophylaxis prior to challenge with blood stage Plasmodium falciparum. Participants were randomly assigned to either tafenoquine (n = 12) or placebo (n = 4) and took blinded study medication (single 200-mg dose) on days 1, 2, 3, and 10, followed by intravenous inoculation with approximately 2800 P. falciparum parasitized erythrocytes on day 13. The primary endpoint was the number of participants requiring rescue treatment with artemether/lumefantrine due to the onset of parasitemia as determined by quantitative polymerase chain reaction., Results: None of the 12 participants who received tafenoquine developed parasitemia, whereas all placebo participants developed parasitemia (P = .0005). Two cases of mild hemoglobin decrease and a single case of mild hyperbilirubinemia occurred in the tafenoquine group., Conclusions: Tafenoquine chemoprophylaxis is safe and effective in preventing malaria in healthy nonimmune participants challenged with blood stage P. falciparum., Clinical Trials Registration: Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12617000102370., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Tafenoquine (TQ) was recently approved by the US Food and Drug Administration for prophylaxis of malaria and, in addition, for eradication of the hepatic phase of the relevant Plasmodium species. In this study, we evaluated the efficacy of TQ for treatment of Babesia microti infection in mice with severe combined immunodeficiency (SCID)., Methods: SCID mice were infected with 1.1-1.5 × 108 B. microti-infected red blood cells by intraperitoneal injection. On day 3 or 4 postinfection, when parasitemia levels typically exceeded 10%, mice were treated with TQ vs vehicle alone, both administered by oral gavage., Results: A single dose of TQ completely eliminated detectable parasites, with a >90% reduction in the level of parasitemia within just 4 days. Before elimination, a conspicuous phenotypic change in the parasite was observed. Although parasitologic cure was not achieved, there was no evidence for the development of drug resistance., Conclusions: This study suggests that TQ may be a highly useful drug to treat B. microti infection in patients. If further animal studies establish that a marked reduction in B. microti parasitemia can be reliably achieved with peak blood levels of TQ known to be well tolerated in humans, a clinical trial in patients should be considered., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Tafenoquine, an 8-aminoquinoline, is now indicated for causal prophylaxis against all human malarias and as radical curative (anti-relapse) treatment against Plasmodium vivax and Plasmodium ovale. As with other 8-aminoquinolines, tafenoquine causes hemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (hemizygous males and homozygous females) and is contraindicated in this population. Those with intermediate G6PD activity (heterozygous females) are also at risk for hemolysis. Awareness of how to prescribe tafenoquine in relation to G6PD status is needed so it can be used safely., Methods: A standard literature search was performed on varying combinations of the terms tafenoquine, Arakoda, Kodatef, Krintafel, Kozenis, primaquine, G6PD deficiency, malaria prophylaxis and radical cure. The data were gathered and interpreted to review how tafenoquine should be prescribed in consideration of the G6PD status of an individual and traveller., Results: Tafenoquine should only be given to those with G6PD activity >70% of the local population median. Qualitative G6PD tests are sufficient for diagnosing G6PD deficiency in males. However, in females quantitative G6PD testing is necessary to differentiate deficient, intermediate and normal G6PD statuses. Testing for G6PD deficiency is mandatory before tafenoquine prescription. Measures can be taken to avoid tafenoquine administration to ineligible individuals (i.e. due to G6PD status, age, pregnancy and lactation). Primaquine is still necessary for some of these cases. This review provides actions that can be taken to diagnose and manage hemolysis when tafenoquine is given inadvertently to ineligible individuals., Conclusion: Attention to G6PD status is required for safe prescription of tafenoquine. A high index of suspicion is needed if hemolysis occurs. Clinicians should seek evidence-based information for the management and treatment of iatrogenicy hemolysis caused by 8-aminoquinolines., (© International Society of Travel Medicine 2019. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Unlabelled: Prevention of relapse of Plasmodium vivax infection is a key treatment goal in malaria. Use of P. vivax genotyping in a multicenter, double-blind, randomized, placebo-controlled phase 2b study in Peru, India, Thailand, and Brazil allowed determination of genetically heterologous or homologous P. vivax infection recurrence following receipt of chloroquine plus one of 4 doses of tafenoquine (50, 100, 300, or 600 mg) or chloroquine plus primaquine, compared with receipt of chloroquine alone. The antihypnozoite efficacy of tafenoquine was evident as a reduction in homologous recurrences of P. vivax infection as drug doses were increased. No clear dose-response pattern was evident for heterologous recurrences of P. vivax infection. Rates of homologous recurrence of P. vivax infection appear to be clinically useful for comparing drug efficacy for the prevention of P. vivax infection relapse., Clinical Trials Registration: NCT01376167., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.)