Abstract
Quinine remains an important anti-malarial drug almost 400 years after its effectiveness
was first documented. However, its continued use is challenged by its poor tolerability,
poor compliance with complex dosing regimens, and the availability of more efficacious
anti-malarial drugs. This article reviews the historical role of quinine, considers its
current usage and provides insight into its appropriate future use in the treatment of
malaria. In light of recent research findings intravenous artesunate should be the first-line
drug for severe malaria, with quinine as an alternative. The role of rectal quinine as prereferral treatment for severe malaria has not been fully explored, but it remains a
promising intervention. In pregnancy, quinine continues to play a critical role in the
management of malaria, especially in the first trimester, and it will remain a mainstay of
treatment until safer alternatives become available. For uncomplicated malaria,
artemisinin-based combination therapy (ACT) offers a better option than quinine though
the difficulty of maintaining a steady supply of ACT in resource-limited settings renders
the rapid withdrawal of quinine for uncomplicated malaria cases risky. The best approach
would be to identify solutions to ACT stock-outs, maintain quinine in case of ACT stockouts, and evaluate strategies for improving quinine treatment outcomes by combining it
with antibiotics. In HIV and TB infected populations, concerns about potential
interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and
these will need further research and pharmacovigilance.
Background and historical perspective
The discovery of quinine is considered the most serendipitous medical discovery of the
17th century [1] and malaria treatment with quinine marked the first successful use of a
chemical compound to treat an infectious disease[2]. Quinine, as a component of the bark
of the cinchona (quina-quina) tree, was used to treat malaria from as early as the 1600s,
when it was referred to as the "Jesuits' bark," "cardinal's bark," or "sacred bark." These
names stem from its use in 1630 by Jesuit missionaries in South America, though a
legend suggests earlier use by the native population[2]. According to this legend, an
Indian with a high fever was lost in an Andean jungle. Thirsty, he drank from a pool of
stagnant water and found that it tasted bitter. Realizing that the water had been
contaminated by the surrounding quina-quina trees he thought he was poisoned.
Surprisingly, his fever soon abated, and he shared this accidental discovery with fellow
villagers, who thereafter used extracts from the quina-quina bark to treat fever [3]. The
legend of quinine's discovery accepted in Europe differs though, and involves the Spanish
Countess of Chinchon who, while in Peru, contracted a fever that was cured by the bark
of a tree. Returning to Spain with the bark, she introduced quinine to Europe in 1638 and,
in 1742, botanist Carl Linnaeus called the tree "Cinchona" in her honour [4].
Before 1820, the bark of the cinchona tree was first dried, ground to a fine powder, and
then mixed into a liquid (commonly wine) before being drunk. In 1820, quinine was
extracted from the bark, isolated and named by Pierre Joseph Pelletier and Joseph
Caventou. Purified quinine then replaced the bark as the standard treatment for malaria
[5]. Quinine and other cinchona alkaloids including quinidine, cinchonine and
cinchonidine are all effective against malaria. The efficacies of these four alkaloids were
evaluated in one of the earliest clinical trials, conducted from 1866 to 1868 in 3600
patients using prepared sulfates of the alkaloids. With the main outcome measure of
"cessation of febrile paroxysms", all four alkaloids were found to be comparable, with
cure rates of >98%[6]. However, after 1890 quinine became the predominantly used
alkaloid, mainly due to a change in supply from South American to Javan cinchona bark,
which contained a higher proportion of quinine [7]. Quinine remained the mainstay of
malaria treatment until the 1920s, when more effective synthetic anti-malarials became
available. The most important of these drugs was chloroquine, which was extensively
used, especially beginning in the 1940s [6]. With heavy use, chloroquine resistance
developed slowly. Resistance of Plasmodium falciparum to chloroquine was seen in parts
of Southeast Asia and South America by the late 1950s, and was widespread in almost all
areas with falciparum malaria by the 1980s. With increasing resistance to chloroquine,
quinine again played a key role, particularly in the treatment of severe malaria [6]. Todate quinine continues to play a significant role in the management of malaria. This
review, discusses the historical role of quinine, considers its current usage, and provides
insight into the appropriate future use of quinine for the treatment of malaria. Information
was obtained by searching published literature in the National Library of Medicine via
Pub Med and MEDLINE search engines for research articles, reviews, books, and other
reports. Identification of published reports was done using key word searches such as
quinine and malaria treatment, quinine and drug resistance, quinine in pregnancy, quinine
and antibiotic combinations, and quinine and HIV/TB infected populations.
Overview of quinine use in the management of malaria
Quinine remains an important anti-malarial drug, almost 400 years after Jesuit priests first
documented its effectiveness. The 2010 World Health Organisation (WHO) guidelines
recommend a combination of quinine plus doxycycline, tetracycline or clindamycin as
second-line treatment for uncomplicated malaria (to be used when the first-line drug fails
or is not available) and quinine plus clindamycin for treatment of malaria in the first
trimester of pregnancy [23]. Based on recent trials, intravenous artesunate should be used
for the treatment of severe falciparum malaria in adults [20] and children[21], in
preference to quinine.
By 2009, 31 African countries recommended quinine as second-line treatment for
uncomplicated malaria, 38 as first-line treatment of severe malaria and 32 for treatment
of malaria in the first trimester of pregnancy [24]. In most of Africa, quinine is still used
as monotherapy, contrary to the WHO recommendations[23,24]; the reason for this
practice may be the higher costs of quinine-antibiotic combinations. Quinine continues to
play a significant role in the management of malaria in sub-Saharan Africa and other
malaria endemic areas, and its use in routine practice may not be restricted to the stated
WHO recommendations. In Cameroon, even one year after the introduction of ACT,
quinine continued to be used as first-line therapy, with 45% of adults receiving oral
quinine for uncomplicated malaria [25]. Recent surveillance data from sentinel sites in
Uganda showed that quinine was prescribed for up to 90% of children < 5 years with
uncomplicated malaria [26].
The use of quinine for uncomplicated malaria cases should have decreased due to
toxicities, poor compliance and the implementation of newer and better tolerated
therapies such as ACT. However, the limited availability of ACT and the increasing
resistance to chloroquine and antifolates have actually increased its use in recent times
[27]. Therefore, studies evaluating the role of quinine in the management of malaria have
been reviewed.
