1735CHAPTER 224 Malaria

Plasmodium species and the likelihood of acquiring malarial infection. Drugs effective against resistant P. falciparum should be used

(atovaquone-proguanil [Malarone], doxycycline, or mefloquine). Chemoprophylaxis is never entirely reliable, and malaria should always be

considered in the differential diagnosis of fever in patients who have

traveled to endemic areas, even if they are taking prophylactic antimalarial drugs.

Pregnant women planning to visit malarious areas should be warned

about the potential risks and advised to avoid all nonessential travel.

All pregnant women who live in endemic areas should be encouraged

to attend regular antenatal clinics. Mefloquine is the only drug advised

for pregnant women traveling to areas with drug-resistant malaria; this

drug is generally considered safe in the second and third trimesters of

pregnancy; the data on first-trimester exposure, although limited, are

reassuring. Chloroquine and proguanil are regarded as safe, but there

are now very few regions where these drugs can be recommended

for protection. The safety of other prophylactic antimalarial agents

in pregnancy has not been established. Antimalarial prophylaxis has

been shown to reduce mortality rates among children between the ages

of 3 months and 4 years in malaria-endemic areas; however, it is not

a logistically or economically feasible option in many countries. The

alternative—to give intermittent preventive treatment (IPT) to pregnant women, and in some areas to infants as well, or seasonal malaria

chemoprevention (SMC) to young children—is being implemented.

Other strategies are being evaluated, such as intermittent screening

and treatment.

IPT in pregnancy (IPTp) involves giving treatment doses of sulfadoxine-pyrimethamine at each antenatal visit (maximum, once

monthly) in the second and third trimesters of pregnancy. Women

with HIV infection who are taking trimethoprim-sulfamethoxazole as prophylaxis should not be given concomitant sulfadoxinepyrimethamine. Dihydroartemisinin-piperaquine is being evaluated as

an alternative. IPT in infancy (IPTi) involves giving treatment doses of

sulfadoxine-pyrimethamine along with the immunizations included in

the WHO’s Expanded Program on Immunization at 2, 3, and 9 months

of life. Seasonal malaria chemoprevention involves giving monthly

treatment doses of amodiaquine and sulfadoxine-pyrimethamine to

children aged between 3 and 59 months during the 3- to 4-month rainy

season across the Sahel region of Africa. Children born to nonimmune

mothers in malaria-endemic areas (usually expatriates moving to these

areas) should receive prophylaxis from birth.

Travelers to a malaria endemic region should start taking antimalarial drugs 2 days to 2 weeks before departure so that any untoward

reactions can be detected before travel and so that therapeutic antimalarial blood concentrations will be present if and when any infections

develop (Table 224-8). Antimalarial prophylaxis should continue for

4 weeks after the traveler has left the endemic area, except if atovaquoneproguanil or primaquine has been taken; these drugs have significant

activities against the liver stage of the infection (causal prophylaxis)

and can be discontinued 1 week after departure from the endemic area.

If suspected malaria develops while a traveler is abroad, obtaining a

reliable diagnosis and antimalarial treatment locally is a top priority.

Presumptive self-treatment for malaria with atovaquone-proguanil

(for 3 consecutive days) or one of the artemisinin-based combinations

can be considered under special circumstances; medical advice on

self-treatment should be sought before departure for malaria-endemic

areas and as soon as possible after illness begins. Every effort should be

made to confirm the diagnosis.

Atovaquone-proguanil (Malarone; 3.75/1.5 mg/kg or 250/100 mg,

daily adult dose) is a fixed-combination, once-daily prophylactic agent

that is very well tolerated by adults and children. This combination

is effective against all types of malaria, including multidrug-resistant

falciparum malaria. Atovaquone-proguanil is best taken with food or a

milky drink to optimize absorption. It is not recommended if the estimated glomerular filtration rate is <30 mL/min. There are insufficient

data on safety in pregnancy.

Mefloquine (250 mg of salt weekly, adult dose) has been widely

used for malarial prophylaxis because it is usually effective against

multidrug-resistant falciparum malaria and is reasonably well tolerated. Mefloquine has been associated with rare episodes of psychosis

and seizures at prophylactic doses; these reactions are more frequent

at the higher doses used for treatment. More common side effects

with prophylactic doses of mefloquine include mild nausea, dizziness,

fuzzy thinking, disturbed sleep patterns, vivid dreams, dysphoria, and

malaise. Mefloquine is contraindicated for use by travelers with known

hypersensitivity and by persons with active or recent depression,

anxiety disorder, psychosis, schizophrenia, another major psychiatric

disorder, or seizures; it is not recommended for persons with cardiac

conduction abnormalities, although the evidence that it is cardiotoxic

is very weak. Confidence is increasing with regard to the safety of

mefloquine prophylaxis during pregnancy; in studies in Africa, mefloquine prophylaxis was found to be effective and safe during pregnancy.

Daily administration of doxycycline (100 mg daily, adult dose) is an

effective alternative to atovaquone-proguanil or mefloquine. Doxycycline is generally well tolerated but may cause vulvovaginal thrush,

diarrhea, and photosensitivity and is not recommended for prophylaxis

in children <8 years old or pregnant women, although, evidence that it

is harmful is lacking.

Chloroquine can no longer be relied upon to prevent P. falciparum

infections in nearly all endemic areas but is still used to prevent and

treat malaria due to the other human Plasmodium species and for P.

falciparum malaria in Central American countries west and north of

the Panama Canal and in Caribbean countries. Chloroquine-resistant P.

vivax has been reported from parts of eastern Asia, Oceania, and Central

and South America. High-level resistance in P. vivax is prevalent in Oceania and Indonesia. Chloroquine is generally well tolerated, although

some patients cannot take it because of malaise, headache, visual

symptoms (due to reversible keratopathy), gastrointestinal intolerance,

alopecia, or pruritus. Chloroquine is considered safe in pregnancy.

With chronic administration for >5 years, a characteristic dose-related

retinopathy may develop, but this condition is rare at the doses used

for antimalarial prophylaxis. Idiosyncratic or allergic reactions are also

rare. Skeletal and/or cardiac myopathy is a potential problem with protracted prophylactic use, although it is more likely to occur at the high

doses used in the treatment of rheumatoid arthritis. Neuropsychiatric

reactions and skin rashes are unusual. Amodiaquine should not be used

for weekly prophylaxis because continuous weekly use is associated with

a high risk of agranulocytosis (~1 person in 2000) and hepatotoxicity

(~1 person in 16,000). Chloroquine, amodiaquine, and piperaquine all

cause moderate electrocardiograph QT prolongation but have not been

associated with ventricular arrhythmias at therapeutic doses.

Primaquine (0.5 mg of base/kg or a daily adult dose of 30 mg taken

with food), an 8-aminoquinoline compound, has proved safe and effective in the prevention of drug-resistant falciparum and vivax malaria

in adults. Primaquine can be considered for adults (with the exception

of pregnant women) who are intolerant to other recommended drugs.

Abdominal pain can be prevented by taking primaquine with food.

G6PD deficiency must be excluded before primaquine is prescribed.

In the past, the dihydrofolate reductase inhibitors pyrimethamine and

proguanil (chloroguanide) were administered widely, but the rapid

selection of resistance in both P. falciparum and P. vivax has limited

their use. Whereas antimalarial quinolines such as chloroquine (a

4-aminoquinoline) act only on the erythrocyte stage of parasitic

development, the dihydrofolate reductase inhibitors (as well as atovaquone and primaquine) also inhibit preerythrocytic growth in the

liver (causal prophylaxis) and development in the mosquito (sporontocidal activity). Proguanil is safe and well tolerated, although mouth

ulceration occurs in ~8% of persons using this drug; it is considered

safe for antimalarial prophylaxis in pregnancy. Prophylactic use of the

combination of pyrimethamine and sulfadoxine is not recommended

for weekly administration because of an unacceptable incidence of

severe toxicity, principally exfoliative dermatitis and other skin rashes,

agranulocytosis, hepatitis, and pulmonary eosinophilia (incidence, 1 in

7000; fatal reactions, 1 in 18,000).

Because of the increasing spread and intensity of antimalarial drug

resistance (Fig. 224-10), the CDC recommends that travelers and

1736 PART 5 Infectious Diseases

Artemisinin and

Mefloquine

Resistance

Artemisinin and

Piperaquine

Resistance

Artemisinin

Resistance

FIGURE 224-10 Current geographic extent of artemisinin resistance and

artemisinin-based combination therapy partner drug resistance in Plasmodium

falciparum in the Greater Mekong subregion.

their providers consider their destination, type of travel, and current

medications and health risks when choosing antimalarial chemoprophylaxis. There is an increasingly appreciated problem of falsified and

substandard antimalarial drugs (and other medicines) on the shelves of

pharmacies in Southeast Asia and sub-Saharan Africa; hence, travelers

should purchase their preventive drugs from a reputable source before

going to a malarious country. Consultation for the evaluation of prophylaxis failures or treatment of malaria can be obtained from state and

local health departments and the CDC Malaria Hotline (770-488-7788)

or the CDC Emergency Operations Center (770-488-7100).

Acknowledgment

The authors gratefully acknowledge the substantial contributions of Joel

G. Breman to this chapter in previous editions.

■ FURTHER READING

Dondorp AM et al: Artesunate versus quinine in the treatment of

severe falciparum malaria in African children (AQUAMAT): An

open-label, randomised trial. Lancet 376:1647, 2010.

Van Der Pluijm RW et al: Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: A multicentre, open-label,

randomised clinical trial. Lancet 395:1345, 2020. Erratum in: Lancet

395:1344, 2020.

World Health Organization: Guidelines for the Treatment of

Malaria, 3rd ed. Geneva, World Health Organization, 2015. Available

at apps.who.int/iris/bitstream/10665/162441/1/9789241549127_eng.

pdf. Accessed December 8, 2017.

World Health Organization: Severe malaria. Trop Med Int Health

19(S1):i–vii, 2014. Available at dx.doi.org/10.1111/tmi.12313_1.

Accessed December 8, 2017.

Babesiosis is an emerging infectious disease caused by protozoan par

ion. Drugs effective against resistant P. falciparum should be used

(atovaquone-proguanil [Malarone], doxycycline, or mefloquine). Chemoprophylaxis is never entirely reliable, and malaria should always be

considered in the differential diagnosis of fever in patients who have

traveled to endemic areas, even if they are taking prophylactic antimalarial drugs.

Pregnant women planning to visit malarious areas should be warned

about the potential risks and advised to avoid all nonessential travel.

All pregnant women who live in endemic areas should be encouraged

to attend regular antenatal clinics. Mefloquine is the only drug advised

for pregnant women traveling to areas with drug-resistant malaria; this

drug is generally considered safe in the second and third trimesters of

pregnancy; the data on first-trimester exposure, although limited, are

reassuring. Chloroquine and proguanil are regarded as safe, but there

are now very few regions where these drugs can be recommended

for protection. The safety of other prophylactic antimalarial agents

in pregnancy has not been established. Antimalarial prophylaxis has

been shown to reduce mortality rates among children between the ages

of 3 months and 4 years in malaria-endemic areas; however, it is not

a logistically or economically feasible option in many countries. The

alternative—to give intermittent preventive treatment (IPT) to pregnant women, and in some areas to infants as well, or seasonal malaria

chemoprevention (SMC) to young children—is being implemented.

Other strategies are being evaluated, such as intermittent screening

and treatment.

IPT in pregnancy (IPTp) involves giving treatment doses of sulfadoxine-pyrimethamine at each antenatal visit (maximum, once

monthly) in the second and third trimesters of pregnancy. Women

with HIV infection who are taking trimethoprim-sulfamethoxazole as prophylaxis should not be given concomitant sulfadoxinepyrimethamine. Dihydroartemisinin-piperaquine is being evaluated as

an alternative. IPT in infancy (IPTi) involves giving treatment doses of

sulfadoxine-pyrimethamine along with the immunizations included in

the WHO’s Expanded Program on Immunization at 2, 3, and 9 months

of life. Seasonal malaria chemoprevention involves giving monthly

treatment doses of amodiaquine and sulfadoxine-pyrimethamine to

children aged between 3 and 59 months during the 3- to 4-month rainy

season across the Sahel region of Africa. Children born to nonimmune

mothers in malaria-endemic areas (usually expatriates moving to these

areas) should receive prophylaxis from birth.

Travelers to a malaria endemic region should start taking antimalarial drugs 2 days to 2 weeks before departure so that any untoward

reactions can be detected before travel and so that therapeutic antimalarial blood concentrations will be present if and when any infections

develop (Table 224-8). Antimalarial prophylaxis should continue for

4 weeks after the traveler has left the endemic area, except if atovaquoneproguanil or primaquine has been taken; these drugs have significant

activities against the liver stage of the infection (causal prophylaxis)

and can be discontinued 1 week after departure from the endemic area.

If suspected malaria develops while a traveler is abroad, obtaining a

reliable diagnosis and antimalarial treatment locally is a top priority.

Presumptive self-treatment for malaria with atovaquone-proguanil

(for 3 consecutive days) or one of the artemisinin-based combinations

can be considered under special circumstances; medical advice on

self-treatment should be sought before departure for malaria-endemic

areas and as soon as possible after illness begins. Every effort should be

made to confirm the diagnosis.

Atovaquone-proguanil (Malarone; 3.75/1.5 mg/kg or 250/100 mg,

daily adult dose) is a fixed-combination, once-daily prophylactic agent

that is very well tolerated by adults and children. This combination

is effective against all types of malaria, including multidrug-resistant

falciparum malaria. Atovaquone-proguanil is best taken with food or a

milky drink to optimize absorption. It is not recommended if the estimated glomerular filtration rate is <30 mL/min. There are insufficient

data on safety in pregnancy.

Mefloquine (250 mg of salt weekly, adult dose) has been widely

used for malarial prophylaxis because it is usually effective against

multidrug-resistant falciparum malaria and is reasonably well tolerated. Mefloquine has been associated with rare episodes of psychosis

and seizures at prophylactic doses; these reactions are more frequent

at the higher doses used for treatment. More common side effects

with prophylactic doses of mefloquine include mild nausea, dizziness,

fuzzy thinking, disturbed sleep patterns, vivid dreams, dysphoria, and

malaise. Mefloquine is contraindicated for use by travelers with known

hypersensitivity and by persons with active or recent depression,

anxiety disorder, psychosis, schizophrenia, another major psychiatric

disorder, or seizures; it is not recommended for persons with cardiac

conduction abnormalities, although the evidence that it is cardiotoxic

is very weak. Confidence is increasing with regard to the safety of

mefloquine prophylaxis during pregnancy; in studies in Africa, mefloquine prophylaxis was found to be effective and safe during pregnancy.

Daily administration of doxycycline (100 mg daily, adult dose) is an

effective alternative to atovaquone-proguanil or mefloquine. Doxycycline is generally well tolerated but may cause vulvovaginal thrush,

diarrhea, and photosensitivity and is not recommended for prophylaxis

in children <8 years old or pregnant women, although, evidence that it

is harmful is lacking.

Chloroquine can no longer be relied upon to prevent P. falciparum

infections in nearly all endemic areas but is still used to prevent and

treat malaria due to the other human Plasmodium species and for P.

falciparum malaria in Central American countries west and north of

the Panama Canal and in Caribbean countries. Chloroquine-resistant P.

vivax has been reported from parts of eastern Asia, Oceania, and Central

and South America. High-level resistance in P. vivax is prevalent in Oceania and Indonesia. Chloroquine is generally well tolerated, although

some patients cannot take it because of malaise, headache, visual

symptoms (due to reversible keratopathy), gastrointestinal intolerance,

alopecia, or pruritus. Chloroquine is considered safe in pregnancy.

With chronic administration for >5 years, a characteristic dose-related

retinopathy may develop, but this condition is rare at the doses used

for antimalarial prophylaxis. Idiosyncratic or allergic reactions are also

rare. Skeletal and/or cardiac myopathy is a potential problem with protracted prophylactic use, although it is more likely to occur at the high

doses used in the treatment of rheumatoid arthritis. Neuropsychiatric

reactions and skin rashes are unusual. Amodiaquine should not be used

for weekly prophylaxis because continuous weekly use is associated with

a high risk of agranulocytosis (~1 person in 2000) and hepatotoxicity

(~1 person in 16,000). Chloroquine, amodiaquine, and piperaquine all

cause moderate electrocardiograph QT prolongation but have not been

associated with ventricular arrhythmias at therapeutic doses.

Primaquine (0.5 mg of base/kg or a daily adult dose of 30 mg taken

with food), an 8-aminoquinoline compound, has proved safe and effective in the prevention of drug-resistant falciparum and vivax malaria

in adults. Primaquine can be considered for adults (with the exception

of pregnant women) who are intolerant to other recommended drugs.

Abdominal pain can be prevented by taking primaquine with food.

G6PD deficiency must be excluded before primaquine is prescribed.

In the past, the dihydrofolate reductase inhibitors pyrimethamine and

proguanil (chloroguanide) were administered widely, but the rapid

selection of resistance in both P. falciparum and P. vivax has limited

their use. Whereas antimalarial quinolines such as chloroquine (a

4-aminoquinoline) act only on the erythrocyte stage of parasitic

development, the dihydrofolate reductase inhibitors (as well as atovaquone and primaquine) also inhibit preerythrocytic growth in the

liver (causal prophylaxis) and development in the mosquito (sporontocidal activity). Proguanil is safe and well tolerated, although mouth

ulceration occurs in ~8% of persons using this drug; it is considered

safe for antimalarial prophylaxis in pregnancy. Prophylactic use of the

combination of pyrimethamine and sulfadoxine is not recommended

for weekly administration because of an unacceptable incidence of

severe toxicity, principally exfoliative dermatitis and other skin rashes,

agranulocytosis, hepatitis, and pulmonary eosinophilia (incidence, 1 in

7000; fatal reactions, 1 in 18,000).

Because of the increasing spread and intensity of antimalarial drug

resistance (Fig. 224-10), the CDC recommends that travelers and

1736 PART 5 Infectious Diseases

Artemisinin and

Mefloquine

Resistance

Artemisinin and

Piperaquine

Resistance

Artemisinin

Resistance

FIGURE 224-10 Current geographic extent of artemisinin resistance and

artemisinin-based combination therapy partner drug resistance in Plasmodium

falciparum in the Greater Mekong subregion.

their providers consider their destination, type of travel, and current

medications and health risks when choosing antimalarial chemoprophylaxis. There is an increasingly appreciated problem of falsified and

substandard antimalarial drugs (and other medicines) on the shelves of

pharmacies in Southeast Asia and sub-Saharan Africa; hence, travelers

should purchase their preventive drugs from a reputable source before

going to a malarious country. Consultation for the evaluation of prophylaxis failures or treatment of malaria can be obtained from state and

local health departments and the CDC Malaria Hotline (770-488-7788)

or the CDC Emergency Operations Center (770-488-7100).

Acknowledgment

The authors gratefully acknowledge the substantial contributions of Joel

G. Breman to this chapter in previous editions.

■ FURTHER READING

Dondorp AM et al: Artesunate versus quinine in the treatment of

severe falciparum malaria in African children (AQUAMAT): An

open-label, randomised trial. Lancet 376:1647, 2010.

Van Der Pluijm RW et al: Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: A multicentre, open-label,

randomised clinical trial. Lancet 395:1345, 2020. Erratum in: Lancet

395:1344, 2020.

World Health Organization: Guidelines for the Treatment of

Malaria, 3rd ed. Geneva, World Health Organization, 2015. Available

at apps.who.int/iris/bitstream/10665/162441/1/9789241549127_eng.

pdf. Accessed December 8, 2017.

World Health Organization: Severe malaria. Trop Med Int Health

19(S1):i–vii, 2014. Available at dx.doi.org/10.1111/tmi.12313_1.

Accessed December 8, 2017.

Babesiosis is an emerging infectious disease caused by protozoan parasites of the genus Babesia that invade and eventually lyse red blood

cells (RBCs). Most cases occur in the United States during the summer

months and are caused by Babesia microti, a species typically found

in small rodents and transmitted by the deer tick, Ixodes scapularis.

Symptoms are those of a flu-like illness. A single standard course

of atovaquone plus azithromycin often is sufficient to achieve cure.

Highly immunocompromised patients are at risk of persistent infection

and antibiotic resistance and should be treated for a longer duration

than immunocompetent patients. Adjunct exchange transfusion can

be useful for severe cases. In the absence of vaccine and prophylaxis,

persons at risk of severe babesiosis should minimize their exposure to

ticks and, if possible, avoid endemic areas.

■ ETIOLOGY, EPIDEMIOLOGY, AND

MODES OF TRANSMISSION

A few Babesia species have been implicated as etiologic agents of

human babesiosis. These species use wild or domesticated mammals

as reservoir hosts and are maintained in their enzootic cycle by ticks.

Humans are incidental, dead-end hosts. Most cases of human babesiosis are reported from across the Northern Hemisphere, but the predominant etiologic agent varies by continent.

United States • GEOGRAPHIC DISTRIBUTION B. microti is the

etiologic agent of nearly all cases in the United States. Most cases

(~95%) are reported from the Northeast and the upper Midwest, particularly from seven states: Massachusetts, Rhode Island, Connecticut,

New York, New Jersey, Minnesota, and Wisconsin (Fig. 225-1). Aside

from B. microti, other Babesia species seldom cause disease in the

United States. Symptomatic infection with Babesia duncani and B.

duncani–type organisms has been reported from Washington State,

Oregon and California. Symptomatic infection with Babesia divergens–

like organisms has been documented in Washington State but also in

the central states of Arkansas, Missouri, Michigan, and Kentucky.

Incidence Babesiosis has been a nationally notifiable disease since

January 2011. Cases are reported weekly by state health departments to

the Centers for Disease Control and Prevention (CDC) via the National

Notifiable Diseases Surveillance System. In 2018, a total of 2161 cases

were reported from 28 of the 40 states in which babesiosis was notifiable. In 2008, when reporting to the CDC was yet to be instituted,

624 cases were made known to health departments in the seven highly

endemic states; a decade earlier, this number was 230. The increase

in incidence over time is best explained by a greater density of ticks

in highly endemic areas as well as the steady expansion of the geographic range occupied by these ticks. Although B. microti and Borrelia

burgdorferi (the agent of Lyme disease; Chap. 186) are maintained in

their enzootic life cycle by the deer tick I. scapularis, the geographic

expansion of babesiosis has lagged behind that of Lyme disease. This

delay in geographic expansion likely reflects the poor ecologic fitness of

B. microti compared with that of B. burgdorferi and is consistent with the

observation that B. burgdorferi helps maintain B. microti in its enzootic

cycle. Other factors contributing to the rise in incidence include greater

exposure of residents to ticks due to forest fragmentation in suburban

areas and more time spent in leisure activities in grassy or wooded

areas. The seroprevalence of antibodies specific for B. microti has been

as high as 9% among residents of highly endemic states, particularly

in areas with the highest incidence of disease. Similar rates have been

noted among blood donors in these highly endemic states, indicating

that babesiosis is underreported and/or that asymptomatic infection is

more common than is recognized.

225 Babesiosis

Edouard Vannier, Jeffrey A. Gelfand

1737CHAPTER 225 Babesiosis

Modes of Transmission • TICK BITE B. microti is acquired

primarily during the blood meal of an I. scapularis tick. Only

one-half (~45%) of patients recall a tick bite within the 8 weeks

prior to symptom onset. Both nymphs and adult ticks can transmit

B. microti; tick larvae are not infected because B. microti is not

transmitted transovarially. Three-fourths of cases present from June

through August because nymphs—the primary vector—are active

from late spring to early summer. Patients who present in late summer

or early fall have likely acquired B. microti from an adult female tick.

B. duncani and B. divergens–like organisms are thought to be transmitted by Dermacentor albipictus and Ixodes dentatus ticks, respectively.

BLOOD TRANSFUSION More than 300 cases of transfusion-transmitted babesiosis due to B. microti have been reported. Most cases result

from the transfusion of packed RBCs; a few have been caused by

whole blood–derived platelets contaminated with RBCs. At the time

of transfusion, the age of the refrigerated RBC units has been 4–42

days, a range indicating that B. microti remains viable throughout the

RBC unit’s shelf life. Transfusion-transmitted babesiosis occurs yearround because B. microti infection can persist for more than a year in

untreated asymptomatic carriers. Given the seasonality of tick-borne

babesiosis, three-quarters of cases of transfusion-transmitted babesiosis are diagnosed from June through November. Like that of tick-borne

babesiosis, the incidence of transfusion-transmitted babesiosis has

sharply risen in the past 15 years. Most cases (>85%) occur in residents

of highly endemic areas, but transfusion-transmitted babesiosis does

occur in nonendemic areas when contaminated blood products are

imported from endemic areas or when asymptomatic B. microti carriers donate blood in nonendemic areas. B. microti is the pathogen most

often identified by investigations of transfusion-transmitted illnesses.

From 2010 to 2016, B. microti accounted for one-fourth of transfusion-related deaths caused by microbial infection. B. duncani has been

implicated in three cases of transfusion-transmitted babesiosis; none

ended in death. A fatal case of B. divergens–like infection in Arkansas

B. duncani

B. microti

I. scapularis

I. ricinus

I. ovatus

B. divergens

B. microti

B. venatorum

& B. crassa I. persulcatus

FIGURE 225-1 Geographic distribution of human babesiosis and associated tick vectors. Dark colors indicate areas where human babesiosis is endemic or sporadic

(defined by ≥5 cases). Light colors indicate areas where tick vectors are present but human babesiosis is rare (<5 cases), undocumented, or absent. Circles depict single

cases except in six locations (Colombia, Mexico, Montenegro, Poland, and the provinces of Gansu and Shandong in China) where all patients were diagnosed at one

hospital or identified via survey in one location. Colors distinguish the etiologic agents: red for Babesia microti, orange for B. duncani, blue for B. divergens, green for

B. venatorum, pink for B. crassa, brown for B. bovis and B. bigemina, black for B. motasi, and yellow for Babesia spp. XXB/Hang-Zhou. White circles depict cases caused

by uncharacterized Babesia species. Asymptomatic infections and cases of travel-associated babesiosis are omitted.

is suspected to have been caused by packed RBC units imported from

Missouri.

VERTICAL TRANSMISSION Passage of B. microti across the placenta

has been documented but is rare. Most cases of neonatal babesiosis are

acquired through blood transfusion or tick bite. Infants (<1 year of age)

account for <1% of the annual number of cases of babesiosis reported

to the CDC.

SOLID ORGAN TRANSPLANTATION This unusual mode of transmission has been highlighted in a single case report. Two patients received

a diagnosis of babesiosis 8 weeks after transplantation of a kidney

allograft obtained from a single donor who had received multiple

transfusions shortly before his death. Corneas from the deceased donor

were transplanted, but neither recipient was infected with B. microti;

this outcome suggests that RBCs that had remained in the vasculature

or fluids of the donated kidneys were the source of B. microti.

Risk Factors Most individuals (~80%) who present with symptoms of babesiosis are ≥50 years of age. Patients who are admitted to a

hospital (median age, 68 years) are a decade older than those who are

not (median age, 59 years). Although age >75 years is a risk factor for

hospital admission, it is not a risk factor for severe babesiosis. Major

risk factors for severe babesiosis include asplenia and immunosuppression. Asplenia can be congenital, functional (e.g., due to celiac disease

or hemoglobinopathies such as sickle cell disease and thalassemia), or

acquired (due to splenectomy). Immunosuppression often is iatrogenic

and associated with conditions such as autoimmune disorders, chronic

inflammatory disorders, malignancies, or transplantation. Immunosuppression can be inherent in comorbidities such as X-linked agammaglobulinemia, common variable hypogammaglobulinemia, and HIV/

AIDS. Risk factors for transfusion-transmitted babesiosis include conditions that require blood transfusion, such as hematologic disorders,

anemia of prematurity, bleeding during surgery, gastrointestinal disease,

and cardiovascular surgery or another cardiovascular procedure.

1738 PART 5 Infectious Diseases

Outside the United States Travel-associated babesiosis may

become more common if, as anticipated, Babesia species continue to

emerge worldwide (Fig. 225-1).

EUROPE More than 40 cases in Europe have been attributed to

B. divergens since the index case was reported from Croatia in 1957.

B. divergens is a parasite of cattle that is transmitted by the sheep tick

Ixodes ricinus. Most cases have occurred in Ireland and France and

have been more common in regions with cattle farms. Isolated cases

have been reported from Finland, Sweden, Norway, Spain, Portugal,

Turkey, Russia, and Georgia. The infection is rarely diagnosed in

immunocompetent individuals; most patients lack a spleen. The five

cases caused by Babesia venatorum have been reported from Italy,

Austria, Germany, and Sweden, and a single case of infection with

Babesia crassa–like organisms has been identified in Slovenia. All six

of these patients had been splenectomized. B. venatorum is found in

roe deer, whereas B. crassa is a parasite of sheep. In Europe, I. ricinus

is the suspected vector for B. venatorum; the tick species that transmits

B. crassa–like organisms may belong to the genus Haemaphysalis. A

German patient presumably acquired B. microti during the transfusion

of platelets prepared from the blood of an infected donor. Patients who

presented with mild babesiosis caused by B. microti in eastern Poland

were immunocompetent and normosplenic.

ASIA B. microti was recognized as a human pathogen in Taiwan in

the late 1990s. In the past decade, babesiosis has gained the status of

an emerging infectious disease in mainland China. In the northeastern

province of Heilongjiang, B. venatorum and B. crassa–like organisms

have caused mild disease in immunocompetent individuals, whereas

antibodies specific for B. microti have been detected in blood donors.

The taiga tick Ixodes persulcatus is a competent vector for B. microti

and the presumed vector for B. venatorum. In this province, B. crassa–

like organisms are found in I. persulcatus and Haemaphysalis concinna

ticks. Isolated cases due to B. divergens have been reported from the

eastern coastal province of Shandong and the north-central province of

Gansu. A case of B. venatorum infection was documented in the northwestern Xinjiang Autonomous Region. Several cases of B. microti infection have been reported from the southwestern province of Yunnan;

two of the patients involved were co-infected with Plasmodium species.

The single case of babesiosis in Japan was acquired through blood

transfusion and was caused by a B. microti organism that defines the

Kobe lineage. Two cases have been reported from South Korea; both

occurred in splenectomized individuals and were caused by Babesia

motasi–like organisms, which are parasites of sheep and goats. In one

case, Haemaphysalis longicornis was the presumed vector.

REMAINDER OF THE WORLD One case of B. microti infection

has been reported in New South Wales, Australia, and another in

Manitoba, Canada, but serosurveys indicate that babesiosis is not

endemic in these regions. Three cases of B. microti infection have

occurred in the state of Yucatan in Mexico. Definitive evidence that

Babesia bovis and Babesia bigemina can cause human illness has come

from Uraba, a region of Colombia where cattle ranching is important

and malaria is endemic. In Mozambique, B. bovis is presumed to have

caused disease and occasionally death. In South Africa, two patients

were diagnosed with babesiosis after visiting malaria-endemic areas in

Namibia and Zimbabwe.

■ CLINICAL MANIFESTATIONS

United States • B. MICROTI INFECTION Symptoms typically

appear 1–4 weeks after the bite of an infected tick but appear later—at

3–7 weeks (median, 37 days; range, 11–176 days)—after transfusion

of contaminated blood products. Patients experience a gradual onset

of fatigue and/or malaise that is followed within days by fever and one

or more of the following: chills, sweats, headache, and myalgia. Fever

is persistent or intermittent and has reached 40.9°C (105.6°F). Less

common symptoms include anorexia, arthralgia, nausea, dry cough,

neck stiffness, sore throat, emotional lability, and vomiting. Diarrhea,

crampy abdominal pain, and joint swelling are rare. Dark urine and

jaundice raise the suspicion of severe hemolytic anemia and may be

accompanied by shortness of breath.

On physical examination, fever is the salient feature. The skin may

be pale or yellowish. A focal red rash may reveal the site of the tick

bite; an erythema migrans rash (Fig. A1-8) signifies intercurrent Lyme

disease (Chap. 186) or southern tick-associated rash illness (STARI)

(Chap. 186). Scleral icterus is consistent with severe hemolytic anemia.

Retinopathy with splinter hemorrhages and retinal infarcts are rare.

Tenderness of the abdominal upper left quadrant suggests splenomegaly, which may be accompanied by hepatomegaly. Abdominal pain

or unexplained hypotension accompanied by tachycardia raises the

possibility of splenic rupture and hemoperitoneum. Splenic infarction

and subcapsular hematoma can occur in the absence of splenic rupture.

Splenic infarction and splenic rupture are confirmed by CT.

Severe babesiosis requires hospital admission. Of the patients with

cases reported to the CDC in 2011–2015, one-half were admitted to

the hospital for at least 1 day. Of those for whom the length of stay

was documented, the median was 4 days (range, 1–63 days). Severe

babesiosis can be accompanied by one or several complications. The

most common complications are severe anemia, acute respiratory distress syndrome, renal insufficiency or failure, hepatic compromise, and

congestive heart failure. Less common complications include disseminated intravascular coagulation, shock, and splenic rupture. Patients

who receive a diagnosis of babesiosis >7 days after symptom onset are

predisposed to severe disease, which is defined as an illness requiring

admission to an intensive care unit (ICU); an illness complicated by

heart failure, shock, or splenic rupture; or an illness requiring intubation

or RBC exchange transfusion. Among clinical features, diarrhea and

nausea or vomiting are strong predictors of severe babesiosis as just

defined. Asplenia and autoimmune disorders predispose to severe

disease, but underlying cardiac conditions do not. Intercurrent Lyme

disease does not increase the risk of severe disease but rather decreases

the number and duration of symptoms evoked by babesiosis; the

implication is that babesiosis may be overlooked if it is accompanied

by intercurrent Lyme disease.

Despite therapy, babesiosis can be fatal. A review of 10,305 Medicare

recipients who received a diagnosis of babesiosis between 2006 and

2013 revealed that 1% died within 30 days. Among inpatients, the fatality rate was 3%. Of the 7612 cases of babesiosis reported to the CDC

in 2011–2015, 46 (0.6%) were fatal. Death rates are particularly high

among immunocompromised patients (~20%) but are also elevated

among patients who acquire B. microti through blood transfusion. In a

series of 159 transfusion-transmitted cases reported from 1979 through

2009, the fatality rate was 17%. In a series of 77 cases identified by

the American Red Cross Hemoviligance Program from 2010 through

2017, the fatality rate was 5%.

OTHER BABESIA INFECTIONS The eight documented cases of B. duncani infection reported in the United States were moderate to severe;

one patient died. Symptoms were similar to those evoked by B. microti.

All six patients infected with B. divergens–like organisms had severe

illness and required hospitalization; three died.

Global Considerations Most cases of B. divergens infection in

Europe have occurred in splenectomized individuals and have been

severe. Symptoms develop suddenly and consist of fever (>41°C

[>105.8°F]), shaking chills, drenching sweats, headache, myalgia, and

lumbar and abdominal pain. Jaundice and hemoglobinuria are common. Without immediate therapy, patients often develop pulmonary

edema and renal failure. All five patients infected with B. venatorum

in Europe had been splenectomized; their illness ranged from mild to

severe, and none died. The 32 cases of B. venatorum infection reported

from northeastern China occurred in spleen-intact residents. The symptoms were similar to those evoked by B. microti, although chills were

rare. Seven of the 32 patients were hospitalized for irregular fever (as

high as 40°C). Only four patients were treated with clindamycin (without quinine), but all 32 patients recovered. Cases of B. crassa–like infection reported from northeastern China also occurred in spleen-intact

residents. Fever, fatigue, and myalgia were less common than among

1739CHAPTER 225 Babesiosis

patients infected with B. microti, but headache was as common and

nausea or vomiting more common. No patient was admitted to the

hospital. Only 3 of 31 patients were given clindamycin (without quinine), but in most cases, symptoms resolved. Cases of B. motasi–like

infection in South Korea were severe; one patient died but the other

recovered following clindamycin monotherapy.

■ PATHOGENESIS

Anemia Hemolytic anemia generates cell debris that may accumulate in the kidney and cause renal failure. Hemoglobin forms a complex

with haptoglobin, but minute amounts of free hemoglobin are sufficient to promote systemic inflammation. Exposed to oxidative stress,

RBCs are poorly deformable and filtered out by splenic macrophages

as they attempt to pass through the red pulp. Erythrophagocytosis

contributes to splenomegaly and splenic rupture and has led to hemophagocytic lymphohistiocytosis, a fatal condition. Anemia also results

from erythropoiesis suppression by inflammatory cytokines such as

interferon γ (IFN-γ) and interleukin (IL) 6. Persistent anemia, despite

resolution of infection, has been attributed to autoantibodies that tag

RBCs for clearance and may activate the complement system.

Inflammation The spleen not only clears parasitized RBCs but also

provides protective immunity; thus, asplenia is a major risk factor for

severe babesiosis. Protective immunity involves CD4+ T cells, particularly Th1 cells, as revealed by high-grade persistent parasitemia in mice

that are depleted of CD4+ T cells or treated with an IFN-γ-neutralizing

antibody. The importance of CD4+ T cells is corroborated by the severity

of babesiosis in patients with AIDS and in allograft recipients. Flulike

symptoms such as fever, chills, and sweats likely result from an inflammatory response that has become systemic. Inflammatory cytokines

such as tumor necrosis factor α (TNF-α) and IL-6 have been detected

in the blood of a patient infected with B. microti. Excessive inflammation promotes pathology. In a mouse model of B. duncani infection,

TNF-α was detected in the alveolar septa, and blockade of TNF-α

rescued the animals from death caused by pulmonary edema. Even in

the absence of pulmonary edema, as in mice infected with B. microti,

TNF-α is detrimental to host defense, as indicated by faster parasite

clearance in the absence of TNF receptor type 1. Although nearly every

immunocompetent patient has antibody to B. microti detectable at the

time of diagnosis, a role for humoral immunity is uncertain. Administration of rituximab for cancer or an autoimmune disorder predisposes

to persistent or relapsing babesiosis; this observation indicates that

B cells and presumably antibodies are critical for parasite clearance in

some individuals.

■ DIAGNOSIS

Babesiosis should be considered for any patient who presents with

symptoms compatible with babesiosis and who resides in an endemic

area between late spring and early fall or has received transfused blood

components, particularly packed RBCs, in the past 6 months. Given

that one-tenth of patients with Lyme disease are infected with B.

microti, and because co-infected patients usually experience an illness

that lasts longer and is more severe than that caused by Lyme disease

alone, babesiosis should be considered for any patient diagnosed

with Lyme disease, particularly if symptoms worsen or do not abate

within days or weeks of initiation of appropriate antibiotic therapy.

Conversely, because one-half of patients diagnosed with babesiosis are

infected with B. burgdorferi, a diagnosis of babesiosis should prompt a

diagnostic evaluation for Lyme disease. Other tick-borne diseases, such

as human granulocytotropic anaplasmosis and ehrlichiosis (Chap.

187), should also be considered.

Routine Laboratory Testing The complete blood count often

is remarkable for anemia. An elevated reticulocyte count signifies

stress-induced erythropoiesis. Low levels of haptoglobin or elevated

levels of lactate dehydrogenase are consistent with hemolytic anemia.

Severe anemia often is preceded by severe thrombocytopenia. The

white blood cell (WBC) count is reduced, unchanged, or elevated.

Elevated levels of alkaline phosphatase, aspartate aminotransferase,

and alanine aminotransferase signify hepatocyte injury. Elevated total

bilirubin levels result from hemolytic anemia but may denote hepatic

compromise. Elevated levels of blood urea nitrogen and serum creatinine indicate renal compromise. Urinalysis may reveal excess urobilinogen, hemoglobinuria, and/or proteinuria. Given that babesiosis is an

imitator of HELLP (hemolysis, elevated liver enzymes, and low platelet

count) syndrome, a diagnosis of babesiosis should be considered for

pregnant women who are at risk of tick exposure and have laboratory

abnormalities that define this syndrome.

There is no consensus on the use of a particular laboratory parameter as a predictor of severe babesiosis. In a study of severe disease as

defined above (see “Clinical Manifestations”), a total bilirubin level

of >1.9 mg/dL was highly predictive of severe disease, whereas WBC

counts of <5 × 103

/μL were associated with a better prognosis. Parameters associated with severe disease also included parasitemia of >10%

at diagnosis, WBC counts of >10 × 103

/μL, and creatinine levels of

>1.2 mg/dL. An earlier study identified alkaline phosphatase levels

of >125 IU/L and WBC counts of >5 × 103

/μL as strong predictors

of severe disease, in this case defined as a hospital stay of >2 weeks,

an ICU stay of >2 days, or death. In that study, parasitemia of >4% at

admission was associated with severe disease.

Specific Testing A definitive diagnosis of babesiosis is made

by microscopic examination of Giemsa-stained thin blood smears

(Fig. 225-2) or amplification of Babesia DNA in blood. Babesia trophozoites appear round, oval, or ameboid. The ring form is most

common and lacks the central brownish (hemozoin) deposit typical of

Plasmodium falciparum late-stage trophozoites (see Fig. A2-1). For travelers who have returned from P. falciparum–endemic areas and reside

in a Babesia-endemic area, a negative result in the BinaxNOW malaria

test readily rules out falciparum malaria when microscopy cannot. The

presence of extracellular merozoites, particularly when parasitemia is

high, and the absence of gametocytes and schizonts also distinguish

A B

C D

FIGURE 225-2 Giemsa-stained thin blood films showing Babesia microti parasites.

B. microti is an obligate parasite of erythrocytes. Trophozoites may appear as ring

forms (A) or as ameboid forms (B). C. Merozoites can be arranged in tetrads that

are pathognomonic. D. Extracellular parasites can be noted, particularly when

parasitemia is high. (Reproduced with permission from E Vannier, PJ Krause: Human

babesiosis. N Engl J Med 366:2397, 2012.)

1740 PART 5 Infectious Diseases

babesiosis from malaria. Merozoites are arranged in pairs and occasionally in tetrads (the “Maltese cross”). Tetrads are pathognomonic of babesiosis and can be seen in human erythrocytes infected with B. microti,

B. duncani, B. venatorum, or B. divergens–like organisms. Parasitemia

typically ranges from 0.1 to 10% in immunocompetent patients but has

reached 30–40% in immunocompromised patients. If parasites cannot

be identified by microscopy and babesiosis is still suspected, amplification of Babesia DNA is recommended. Most assays target the 18S rRNA

gene, and the most sensitive use a fluorescent probe. Real-time polymerase chain reaction (PCR) assays detect as few as 1–10 parasites/μL

of blood and are well suited for speciation of the causative agent.

A single positive serologic result is not sufficient to establish a diagnosis of babesiosis because antibodies can persist for >1 year after the

illness has resolved and the parasite has been cleared. An indirect fluorescent antibody test is most commonly used. For B. microti, IgM titers

of ≥1:64 and IgG titers of ≥1:1024 suggest active or recent infection.

Antibodies to B. microti do not react with B. duncani or B. divergens

antigen. Sera from patients infected with B. venatorum or B. crassa–like

organisms react with B. divergens antigen.

TREATMENT

Babesiosis

MILD TO MODERATE B. MICROTI ILLNESS

Mild to moderate babesiosis caused by B. microti should be treated

with atovaquone plus azithromycin administered orally for 7–10

days. Dosages for adults and children are provided in Table 225-1.

Symptoms usually abate within 48 h after initiation of therapy and

resolve within 1–2 weeks. If symptoms persist despite therapy, testing for Lyme disease or other tick-borne diseases such as human

granulocytotropic anaplasmosis is essential. Fatigue may persist for

weeks to months but does not warrant, on its own, that treatment be

extended or resumed. Parasite DNA can be detected for as long as

3 months, but follow-up PCR testing is not recommended because

relapse of infection in immunocompetent individuals is unlikely.

SEVERE B. MICROTI ILLNESS

First-Line Antimicrobial Therapy The preferred regimen for the

treatment of severe babesiosis caused by B. microti is oral atovaquone plus IV azithromycin (Table 225-1). Use of this combination

is supported by a retrospective study of 40 patients who were

admitted for severe babesiosis, including 11 who were admitted

to the ICU. In all but one of the 40 patients, infection resolved

during treatment with atovaquone plus azithromycin. Clindamycin

plus quinine has long been recommended for severe babesiosis.

Quinine, however, carries a risk for QTc prolongation and other

adverse events (e.g., cinchonism). A prospective, nonblinded,

randomized clinical trial established that atovaquone plus azithromycin is as effective as clindamycin plus quinine in clearing

B. microti parasites and resolving symptoms of non-life-threatening

babesiosis. No trial has compared the two regimens in severe babesiosis. Given that quinine often must be discontinued, atovaquone

plus azithromycin has become the mainstay for the treatment of

severe babesiosis. Some experienced clinicians add IV clindamycin

to the recommended two-drug regimen (Table 225-1, footnote d);

this approach, however, has not been subjected to clinical trial. For

patients at risk of QTc prolongation, clindamycin can be substituted

for azithromycin.

Intravenous azithromycin should be initiated at a dosage of

500 mg/d, along with atovaquone. Laboratory parameters should be

monitored daily until symptoms abate and parasitemia is reduced to

<4%. Thereafter, if the patient has a functional spleen and is immunocompetent, azithromycin can be administered orally and the

dosage reduced to 250–500 mg/d. The regimen is administered for

7–10 days, but the duration should be extended if symptoms persist.

If the patient is asplenic or immunocompromised, a higher dose

of azithromycin (500 mg/d) should be considered. Given the risk

of persistent or relapsing babesiosis in such patients, the regimen

should be administered until symptoms have resolved and parasites

are no longer seen on blood smear for 2 weeks.

Adjunct Exchange Transfusion Partial or complete RBC exchange

(RCE) is recommended for patients with high-grade parasitemia

(≥10%) or moderate- to high-grade parasitemia and any of the

following: severe hemolytic anemia and/or pulmonary, renal, or

hepatic compromise. Therapeutic apheresis should be performed in

close consultation with a transfusion medicine specialist. The main

purpose of RCE is to rapidly decrease parasitemia; it also corrects

anemia and removes toxic by-products of hemolysis, particularly

free hemoglobin and free heme. The criteria for RCE are not strictly

defined and are based on single case reports and a few small case

series. In one such study that was performed at a single institution

and in which RCE reduced parasitemia by ~75%, age and pre-RCE

parasitemia were predictors of post-RCE length of hospital stay.

Post-RCE parasitemia, however, was not associated with post-RCE

length of stay or mortality; this finding advocates against the use of

repeat RCE to reduce parasitemia to an arbitrary level. Given that

pre-RCE parasitemia did not predict mortality, the decision to use

TABLE 225-1 Treatment of Human Babesiosis

ADULTS CHILDREN

Mild to Moderate B. microti Infectiona

Atovaquone (750 mg q12h PO)

plus

Azithromycin (500 mg/d PO on day 1,

250 mg/d PO thereafter)

Atovaquone (20 mg/kg q12h PO;

maximum, 750 mg/dose)

plus

Azithromycin (10 mg/kg qd PO on day

1 [maximum, 500 mg], 5 mg/kg qd PO

thereafter [maximum, 250 mg])

Severe B. microti Infectionb,c

Preferredd

Atovaquone (750 mg q12h PO)

plus

Azithromycin (500 mg qd IV followed by

250–500 mg qd PO)

Alternativee,f

Clindamycin (600 mg q6h IV followed by

600 mg q8h PO)

plus

Quinine (650 mg q6–8h PO)

Consider exchange transfusion

Preferred

Atovaquone (20 mg/kg q12h PO;

maximum, 750 mg/dose)

plus

Azithromycin (10 mg/kg qd IV followed

by 10 mg/kg qd PO [maximum, 500 mg])

Alternative

Clindamycin (7–10 mg/kg q6–8h IV

followed by 7–10 mg/kg q6–8h PO

[maximum, 600 mg/dose])

plus

Quinine (8 mg/kg q8h PO; maximum,

650 mg/dose)

Consider exchange transfusion

B. divergens Infectiong

Immediate complete exchange

transfusion

plus

Clindamycin (600 mg q6–8h IV)

plus

Quinine (650 mg q8h PO)

Immediate complete exchange

transfusion

plus

Clindamycin (7–10 mg/kg q6–8h IV;

maximum, 600 mg/dose)

plus

Quinine (8 mg/kg q8h PO; maximum,

650 mg/dose)

a

Treat for 7–10 days. b

Treat for 7–10 days, but extend duration if symptoms persist. c

For severely immunocompromised patients, antimicrobial therapy should be given

for at least 6 consecutive weeks, including 2 final weeks during which parasites

are no longer detected on blood smear. d

If the risk of QTc prolongation or allergy

associated with use of azithromycin is a concern, clindamycin can be substituted

for azithromycin. For severely immunocompromised patients, IV clindamycin can be

added to atovaquone plus azithromycin at initiation of treatment. e

Clindamycin plus

quinine is no longer the preferred regimen because quinine often is discontinued

due to QTc prolongation or other side effects, including tinnitus. This regimen can

be considered for cases that respond poorly to atovaquone plus azithromycin.

f

Other alternative regimens have been used successfully, as documented in a

limited number of case reports. If quinine toxicity is a concern, atovaquone can

be substituted for quinine. For cases that respond poorly to atovaquone plus

azithromycin, atovaquone-proguanil can be added to the two-drug regimen or can

be substituted for atovaquone. g

A few cases of B. divergens infection in Europe

have been treated successfully with atovaquone plus azithromycin or atovaquoneproguanil plus azithromycin.