Efficacy of Artesunate-Amodiaquine and Quinine-Azithromycin Combination in Treatment of Uncomplicated Falciparum Malaria in Children
Karangan Asli
Efficacy of Artesunate-Amodiaquine
and Quinine-Azithromycin Combination in Treatment
of Uncomplicated Falciparum Malaria in Children
Ayodhia Pitaloka Pasaribu, Elvina Yulianti, Munar Lubis, Syahril Pasaribu, Chairuddin P. Lubis
Department of Child Health, Medical School - USU/H. Adam Malik Hospital, Medan
Abstract: Resistance of malaria treatment is a major problem. Because of the highly incidence of
malaria falciparum resistance in Indonesia, Department of Health, Republic of Indonesia since
end of 2004 change the treatment standard into artesunate - amodiaquine combination. The aim
of this study was to compare the efficacy of artesunate-amodiaquine with quinine-azithromycin
combination as treatment for uncomplicated malaria falciparum in children. We conducted a
randomized, open label, clinical trial since August 2006 until September 2006 in Panyabungan,
Kabupaten Mandailing Natal, North Sumatera Province, in school age children between 5 – 18
years. Group I received artesunate 4mg/bw/po combined with amodiaquine 10mg/bw for 3 days,
Group II received quinine oral for 7 days, 10mg/bw/divided in 3 doses for 4 days continued with
5mg/bw/divided in 3 doses for 3 days combined with azithromycin 10mg/bw/po for 3 days.
Parasitemia counted at the day of 0, 2, 7 and 28. Peripheral blood smear was done in 700
children with suspected malaria, 232 were positive for falciparum malaria. Then, randomly
separated into two groups, 116 received artesunate-amodiaquine and 116 received quinineazithromycin. End of study, we found 114 children in group I and 106 children in group II.
Peripheral blood smear at day 2, 7 and 28 showed 100% cure rate for both group (p = 0,001),
respectively. Tinnitus adverse event was found in 6 children in Group II (p = 0,042). Quinineazithromycin combination can be use as an alternative treatment for uncomplicated falciparum
malaria in children.
Keywords: artesunate-amodiaquine, quinine-azithromycin, falciparum malaria, parasitemia,
uncomplicated
Abstrak: Resistensi pada pengobatan malaria merupakan hal yang penting. Oleh karena tingginya
angka resistensi malaria falsiparum di Indonesia, Departemen Kesehatan Republik Indonesia sejak
akhir tahun 2004 mengubah standar pengobatan malaria falciparum dengan menggunakan
gabungan artesunat-amodiakuin. Tujuan dari penelitian ini untuk membandingkan efikasi
gabungan artesunat-amodiakuin dengan kinin- azitromisin sebagai pengobatan malaria falsiparum
pada anak. Suatu penelitian uji klinis, acak, terbuka dilakukan sejak bulan Agustus 2006 hingga
September 2006 di Penyabungan, Kab. Madina Propinsi Sumatera Utara, pada anak penderita
malaria antara usia 5 tahun sampai 18 tahun. Kelompok I mendapat pengobatan per oral
artesunat 4mg/kgbb digabung amodiakuin 10mg/kgbb selama 3 hari, Kelompok II mendapat
pengobatan kinin per oral selama 7 hari dengan dosis 10mg/kgbb/3dosis selama 4 hari dilanjutkan
5mg/kgbb/3dosis selama 3 hari digabung azitromisin per oral selama 3 hari dengan dosis
10mg/kgbb. Parasitemia dinilai pada hari ke-0, 2, 7 dan 28. Pemeriksaan darah tepi dilakukan
pada 500 anak yang diduga malaria,didapatkan 232 anak positif malaria falsiparum. Kemudian
secara acak dibagi menjadi dua kelompok, 116 anak mendapat artesunat-amodiakuin dan 116
anak mendapat kinin-azitromisin. Pada akhir penelitian didapatkan 114 anak pada kelompok I
dan 106 anak pada kelompok II. Dari hasil pemeriksaan darah tepi pada hari ke-2,7 dan 28 pada
kedua grup didapatkan angka kesembuhan 100% pada kedua kelompok (p = 0.0001), secara
berurutan. Efek samping telinga berdenging dijumpai pada 6 orang anak pada kelompok kedua (p
= 0.042). Gabungan kinin-azitromisin bisa digunakan sebagai alternatif pengobatan pada malaria
falsiparum tanpa komplikasi.
Kata kunci: Artesunat-amodiakuin, kinin-azitromisin, malaria falsiparum, parasitemia, tanpa
komplikasi
Majalah Kedokteran Nusantara Volume 41 y No. 4 y Desember 2008
228
Ayodhia Pitaloka Pasaribu dkk.
Efficacy of Artesunate-Amodiaquine...
INTRODUCTION
Malaria has become a priority for the
international health community that affecting
deaths in children and pregnant women and
also reduce work productivity. Estimates of
annual mortality caused by malaria ranging
from 1,5 – 2,7 million people, especially
1-4
children and pregnant women. The spread of
chloroquine-resistant Plasmodium falciparum
has had a major impact on both the health of
residents in areas where the parasite is
endemic. Chloroquine treatment is now
ineffective in most areas of the world. The
usual
replacement,
pyrimethaminesulfadoxine, is rapidly losing efficacy in many
5,6
areas. New antimalarial regimens, urgently
needed
because
of
the
worldwide
development of multi drugs resistance, should
aim to cure patients no longer responding to
7
Artemisinin
based
standard
therapy.
Combination Therapy (ACT) is increasingly
being advocated to replace chloroquine as
standard treatment. The concept of ACT is
based on the use of two drugs with different
modes of action: an artemisinin-derivative that
causes rapid and effective reduction of
parasite biomass and gametocyte carriage and
a partner drug that has a longer duration of
action. The hypothesis is that these two drugs
together will achieve effective clinical and
parasitological cure, protect each other from
the development of resistance by P.
falciparum, and reduce the overall rate of
8
malaria transmission. Department of Health,
Republic of Indonesia since end of 2004 had
changed
the
standard
treatment
for
falciparum
malaria
with
artesunateamodiaquine as the first line drug replacing
1
chloroquine.
Artesunate is a water soluble derivative
of dihydroartemisinin that has ability to
reduce gametocyte carriage rate and used to
9
treat uncomplicated falciparum malaria.
Amodiaquine is a 4-aminoquinoline similar in
structure and activity to chloroquine in
10
preventing malaria. A study in Burkina Faso
revealed
combination
of
artesunateamodiaquine is very effective and can be used
as first-line treatment for uncomplicated
11
malaria. Effective quinine monotherapy for
malaria has been available for more than 350
years, quinine is also inexpensive and widely
available, but its side effects are not
229
insignificant, and, in many countries,
resistance has precluded its use as
6,7
Azithromycin, the most
monotherapy.
potent macrolide antimalarial with a long halflife (68 hours), demonstrates synergism with
quinine against P. falciparum in vitro,
suggesting clinical utility as a combination
12
therapy. In this study we compare the
efficacy
of
artesunate-amodiaquine
as
treatment for uncomplicated falciparum
malaria in children.
METHODS
Place and Time. This study was
conducted from August to September 2006 in
6 districts, Panyabungan Jae, Adian Jior,
Gunung Manaon, Pagarantonga, Gunung
Baringin and Purba, Kabupaten Mandailing
Natal, Sumatera Utara Province.
Study Design. This is a randomized,
open label clinical trial which done in primary
to high school children in those area. It has
been approved by Ethic Committee of
University of Sumatera Utara and it had got
the inform consent from the sample’s parents
before it was commenced.
Study Population. Seven hundred
children from primary to high school whose
5-18 years old which suspected positive
malaria were screen through thick and thin
blood smear examination. If falciparum
malaria was founding the blood smear, will be
put in inclusion criteria. After filling the
inform
consent,
anamnesis,
physical
examination and blood smear were taken.
Exclusion criteria include 1) cannot finish the
study completely, 2) severe malaria, 3) do not
take drugs properly. Participants who fulfill
the inclusion criteria randomly selected into
one of the two groups by using sample
random sampling, the first group is artesunate
plus amodiaquine and second group is quinine
plus azithromycin. Group I (A) recieved oral
treatment of artesunate 4mg/kgbw combine
with amodiaquine 10mg/kgbw for 3 days.
Group II (B) recieved oral quinine for 7 days
10 mg/kg/3 doses for 4 days then continued
with 5 mg/kg/3 doses for 3 days combine with
oral azithromycin for 3 days 10 mg/kgbw. All
antimalarial drugs given after meal.
Blood smear and clinical evaluation.
Routine recording of malaria symptoms,
history of consuming drugs and adverse events
Majalah Kedokteran Nusantara Volume 41 y No. 4 y Desember 2008
Karangan Asli
were done during study. Physical examination
and repeated blood smear examination were
done on day 2,7 and 28. The body weight was
measured with MIC scale (sensitivity 0,05 kg)
and height MIC scale (sensitivity 0,1 cm).
Nutritional status was measured with standard
anthropometry technic based on CDC
NCHS-WHO. Thick and thin blood smear
was prepared with giemsa based on procedure
and read by trained analyst. Sexual and
asexual parasites was counted in 200
leucocyte. Main result of the study was cure,
define as lost of parasites without
recrudescence in 28 days of observation.
Statistical Analysis. Data was processed
with SPSS for windows 14 (SPSS Inc,
Chicago). Data analysis to found out the
results before and after treatment in both
groups were test with Wilcoxon rank.
Characteristic data and adverse events was
analysed with Pearson chi square. Tests were
significant if p
Efficacy of Artesunate-Amodiaquine
and Quinine-Azithromycin Combination in Treatment
of Uncomplicated Falciparum Malaria in Children
Ayodhia Pitaloka Pasaribu, Elvina Yulianti, Munar Lubis, Syahril Pasaribu, Chairuddin P. Lubis
Department of Child Health, Medical School - USU/H. Adam Malik Hospital, Medan
Abstract: Resistance of malaria treatment is a major problem. Because of the highly incidence of
malaria falciparum resistance in Indonesia, Department of Health, Republic of Indonesia since
end of 2004 change the treatment standard into artesunate - amodiaquine combination. The aim
of this study was to compare the efficacy of artesunate-amodiaquine with quinine-azithromycin
combination as treatment for uncomplicated malaria falciparum in children. We conducted a
randomized, open label, clinical trial since August 2006 until September 2006 in Panyabungan,
Kabupaten Mandailing Natal, North Sumatera Province, in school age children between 5 – 18
years. Group I received artesunate 4mg/bw/po combined with amodiaquine 10mg/bw for 3 days,
Group II received quinine oral for 7 days, 10mg/bw/divided in 3 doses for 4 days continued with
5mg/bw/divided in 3 doses for 3 days combined with azithromycin 10mg/bw/po for 3 days.
Parasitemia counted at the day of 0, 2, 7 and 28. Peripheral blood smear was done in 700
children with suspected malaria, 232 were positive for falciparum malaria. Then, randomly
separated into two groups, 116 received artesunate-amodiaquine and 116 received quinineazithromycin. End of study, we found 114 children in group I and 106 children in group II.
Peripheral blood smear at day 2, 7 and 28 showed 100% cure rate for both group (p = 0,001),
respectively. Tinnitus adverse event was found in 6 children in Group II (p = 0,042). Quinineazithromycin combination can be use as an alternative treatment for uncomplicated falciparum
malaria in children.
Keywords: artesunate-amodiaquine, quinine-azithromycin, falciparum malaria, parasitemia,
uncomplicated
Abstrak: Resistensi pada pengobatan malaria merupakan hal yang penting. Oleh karena tingginya
angka resistensi malaria falsiparum di Indonesia, Departemen Kesehatan Republik Indonesia sejak
akhir tahun 2004 mengubah standar pengobatan malaria falciparum dengan menggunakan
gabungan artesunat-amodiakuin. Tujuan dari penelitian ini untuk membandingkan efikasi
gabungan artesunat-amodiakuin dengan kinin- azitromisin sebagai pengobatan malaria falsiparum
pada anak. Suatu penelitian uji klinis, acak, terbuka dilakukan sejak bulan Agustus 2006 hingga
September 2006 di Penyabungan, Kab. Madina Propinsi Sumatera Utara, pada anak penderita
malaria antara usia 5 tahun sampai 18 tahun. Kelompok I mendapat pengobatan per oral
artesunat 4mg/kgbb digabung amodiakuin 10mg/kgbb selama 3 hari, Kelompok II mendapat
pengobatan kinin per oral selama 7 hari dengan dosis 10mg/kgbb/3dosis selama 4 hari dilanjutkan
5mg/kgbb/3dosis selama 3 hari digabung azitromisin per oral selama 3 hari dengan dosis
10mg/kgbb. Parasitemia dinilai pada hari ke-0, 2, 7 dan 28. Pemeriksaan darah tepi dilakukan
pada 500 anak yang diduga malaria,didapatkan 232 anak positif malaria falsiparum. Kemudian
secara acak dibagi menjadi dua kelompok, 116 anak mendapat artesunat-amodiakuin dan 116
anak mendapat kinin-azitromisin. Pada akhir penelitian didapatkan 114 anak pada kelompok I
dan 106 anak pada kelompok II. Dari hasil pemeriksaan darah tepi pada hari ke-2,7 dan 28 pada
kedua grup didapatkan angka kesembuhan 100% pada kedua kelompok (p = 0.0001), secara
berurutan. Efek samping telinga berdenging dijumpai pada 6 orang anak pada kelompok kedua (p
= 0.042). Gabungan kinin-azitromisin bisa digunakan sebagai alternatif pengobatan pada malaria
falsiparum tanpa komplikasi.
Kata kunci: Artesunat-amodiakuin, kinin-azitromisin, malaria falsiparum, parasitemia, tanpa
komplikasi
Majalah Kedokteran Nusantara Volume 41 y No. 4 y Desember 2008
228
Ayodhia Pitaloka Pasaribu dkk.
Efficacy of Artesunate-Amodiaquine...
INTRODUCTION
Malaria has become a priority for the
international health community that affecting
deaths in children and pregnant women and
also reduce work productivity. Estimates of
annual mortality caused by malaria ranging
from 1,5 – 2,7 million people, especially
1-4
children and pregnant women. The spread of
chloroquine-resistant Plasmodium falciparum
has had a major impact on both the health of
residents in areas where the parasite is
endemic. Chloroquine treatment is now
ineffective in most areas of the world. The
usual
replacement,
pyrimethaminesulfadoxine, is rapidly losing efficacy in many
5,6
areas. New antimalarial regimens, urgently
needed
because
of
the
worldwide
development of multi drugs resistance, should
aim to cure patients no longer responding to
7
Artemisinin
based
standard
therapy.
Combination Therapy (ACT) is increasingly
being advocated to replace chloroquine as
standard treatment. The concept of ACT is
based on the use of two drugs with different
modes of action: an artemisinin-derivative that
causes rapid and effective reduction of
parasite biomass and gametocyte carriage and
a partner drug that has a longer duration of
action. The hypothesis is that these two drugs
together will achieve effective clinical and
parasitological cure, protect each other from
the development of resistance by P.
falciparum, and reduce the overall rate of
8
malaria transmission. Department of Health,
Republic of Indonesia since end of 2004 had
changed
the
standard
treatment
for
falciparum
malaria
with
artesunateamodiaquine as the first line drug replacing
1
chloroquine.
Artesunate is a water soluble derivative
of dihydroartemisinin that has ability to
reduce gametocyte carriage rate and used to
9
treat uncomplicated falciparum malaria.
Amodiaquine is a 4-aminoquinoline similar in
structure and activity to chloroquine in
10
preventing malaria. A study in Burkina Faso
revealed
combination
of
artesunateamodiaquine is very effective and can be used
as first-line treatment for uncomplicated
11
malaria. Effective quinine monotherapy for
malaria has been available for more than 350
years, quinine is also inexpensive and widely
available, but its side effects are not
229
insignificant, and, in many countries,
resistance has precluded its use as
6,7
Azithromycin, the most
monotherapy.
potent macrolide antimalarial with a long halflife (68 hours), demonstrates synergism with
quinine against P. falciparum in vitro,
suggesting clinical utility as a combination
12
therapy. In this study we compare the
efficacy
of
artesunate-amodiaquine
as
treatment for uncomplicated falciparum
malaria in children.
METHODS
Place and Time. This study was
conducted from August to September 2006 in
6 districts, Panyabungan Jae, Adian Jior,
Gunung Manaon, Pagarantonga, Gunung
Baringin and Purba, Kabupaten Mandailing
Natal, Sumatera Utara Province.
Study Design. This is a randomized,
open label clinical trial which done in primary
to high school children in those area. It has
been approved by Ethic Committee of
University of Sumatera Utara and it had got
the inform consent from the sample’s parents
before it was commenced.
Study Population. Seven hundred
children from primary to high school whose
5-18 years old which suspected positive
malaria were screen through thick and thin
blood smear examination. If falciparum
malaria was founding the blood smear, will be
put in inclusion criteria. After filling the
inform
consent,
anamnesis,
physical
examination and blood smear were taken.
Exclusion criteria include 1) cannot finish the
study completely, 2) severe malaria, 3) do not
take drugs properly. Participants who fulfill
the inclusion criteria randomly selected into
one of the two groups by using sample
random sampling, the first group is artesunate
plus amodiaquine and second group is quinine
plus azithromycin. Group I (A) recieved oral
treatment of artesunate 4mg/kgbw combine
with amodiaquine 10mg/kgbw for 3 days.
Group II (B) recieved oral quinine for 7 days
10 mg/kg/3 doses for 4 days then continued
with 5 mg/kg/3 doses for 3 days combine with
oral azithromycin for 3 days 10 mg/kgbw. All
antimalarial drugs given after meal.
Blood smear and clinical evaluation.
Routine recording of malaria symptoms,
history of consuming drugs and adverse events
Majalah Kedokteran Nusantara Volume 41 y No. 4 y Desember 2008
Karangan Asli
were done during study. Physical examination
and repeated blood smear examination were
done on day 2,7 and 28. The body weight was
measured with MIC scale (sensitivity 0,05 kg)
and height MIC scale (sensitivity 0,1 cm).
Nutritional status was measured with standard
anthropometry technic based on CDC
NCHS-WHO. Thick and thin blood smear
was prepared with giemsa based on procedure
and read by trained analyst. Sexual and
asexual parasites was counted in 200
leucocyte. Main result of the study was cure,
define as lost of parasites without
recrudescence in 28 days of observation.
Statistical Analysis. Data was processed
with SPSS for windows 14 (SPSS Inc,
Chicago). Data analysis to found out the
results before and after treatment in both
groups were test with Wilcoxon rank.
Characteristic data and adverse events was
analysed with Pearson chi square. Tests were
significant if p