Malaria Prophylaxis Using Azithromycin: A Double‐Blind, Placebo‐Controlled Trial in Irian Jaya, Indonesia

Taylor, Walter; Richie, Thomas L.; Fryauff, David J.; Picarima, Helena; Ohrt, Colin; Tang, Douglas B.; Braitman, David J.; Murphy, Gerald S.; Widjaja, Hendra; Tjitra, Emiliana; Ganjar, Asep; Jones, Trevor R.; Basri, Hasan; Berman, Josh

doi:10.1086/515071

Cited by 131 publications

(67 citation statements)

References 26 publications

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“…This double-blind, placebo-controlled trial assessed the prophylactic efficacy and tolerability of azithromycin in men and women who had been radically cured (with concurrent quinine doxycycline and primaquine) of any preexisting malaria infection. Details of the study have been reported previously (21). Three hundred Indonesian adults (225 soldiers and 75 villagers) received either (i) azithromycin (750-mg loading dose followed by 250 mg/day) plus a doxycycline placebo (n ϭ 148) (arm A), (ii) doxycycline (100 mg/day) plus an azithromycin placebo (n ϭ 75) (arm D), or (iii) a double placebo (n ϭ 77) (arm P).…”

Section: Methodsmentioning

confidence: 99%

Tolerability of Azithromycin as Malaria Prophylaxis in Adults in Northeast Papua, Indonesia

Taylor

Richie

Fryauff

et al. 2003

Antimicrob Agents Chemother

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Drug tolerability affects compliance. We evaluated the tolerability levels of azithromycin (750-mg loading dose plus 250 mg/day; n ‫؍‬ 148 subjects), doxycycline (100 mg/day; n ‫؍‬ 75), and placebo (n ‫؍‬ 77) as prophylaxis against malaria in Indonesian adults over 20 weeks. Self-reported and elicited symptoms, health perception, hearing, hematology, and biochemistry were assessed. The loading dose was well tolerated. Prolonged drug use for disease prophylaxis, treatment, or suppression should be well tolerated. This is especially true for healthy recipients of prophylaxis, such as travelers and pregnant women, for whom the risk-to-benefit ratio requires both safe and easily tolerable regimens.Azithromycin has several clinical indications that include the treatment and prophylaxis of Mycobacterium avium-M. intracellulare complex (MAC) infection and the treatment of community-acquired pneumonia and genital or ocular Chlamydia trachomatis infection (25). The standard doses of azithromycin (30 mg/kg of body weight for children and 1.5 g total dose for adults) are well tolerated. Up to 12% of patients report any symptom, Ͻ10% report gastrointestinal symptoms, and 0.7 to 1.3% discontinue therapy. Such tolerability compares favorably to that of other antibiotics (7,11,12,22). High doses of azithromycin, 1 g/kg for adults and 20 mg/kg for children, are also well tolerated (2, 16). However, doses used for MAC infections (1.2 g/week or 300 to 600 mg/day) are less well tolerated (3, 9, 10, 17). Gastrointestinal symptoms are reported by a high proportion of patients (e.g., by 71 [78.9%] of 85 recipients of weekly azithromycin, resulting in six [7%] withdrawals [17]). Hearing loss in the speech frequency range has also been reported in 13 to 17% of patients with MAC infections. It is dose dependent and recovers within 2 to 11 weeks after discontinuation of the drug (3,9,23,24). Irreversible high-frequency-hearing loss has also been reported following treatment with 750 mg of oral azithromycin in a 37-year-old woman (19). Biochemical and hematological assessments in large clinical series have been unremarkable. Mild elevations of liver enzymes (0.3 to 1.7%) and transient neutropenia (1.5%) or neutrophilia (1.5%) have been documented (11). Significant hepatotoxicity (e.g., hypersensitivity hepatitis, cholestasis) is rare (4, 15), as are anaphylaxis, pseudomembranous colitis, erythema multiforme, and Churg-Strauss syndrome (12,13,22).One trial has previously assessed azithromycin as prophylaxis against malaria. Azithromycin was administered daily (250 mg) or weekly (1 g) for 13 weeks to Kenyan adults. The reported symptoms were similar to those of placebo recipients, and there was no evidence of toxicity on routine hematological or biochemical testing (1).We report the tolerability of daily-administered azithromycin as prophylaxis against malaria in Indonesian adults. MATERIALS AND METHODSSubjects and study conduct. This double-blind, placebo-controlled trial assessed the prophylactic efficacy and tolerability of azithromycin ...

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Section: Methodsmentioning

confidence: 99%

Tolerability of Azithromycin as Malaria Prophylaxis in Adults in Northeast Papua, Indonesia

Taylor

Richie

Fryauff

et al. 2003

Antimicrob Agents Chemother

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“…Blood blots were collected from participants in a clinical trial 30 assessing the prophylactic efficacy of azithromycin that was also conducted in Arso PIR V and surrounding villages from July 1996 to January 1997. After radical cure therapy (quinine, 10 mg/kg twice a day for 4 days, doxycycline, 100 mg twice a day for 10 days, primaquine base, 30 mg a day for 14 days) participants were randomized to receive azithromycin, doxycycline, or placebo.…”

Section: Methodsmentioning

confidence: 99%

Plasmodium falciparum mdr1 mutations and in vivo chloroquine resistance in Indonesia.

Gómez-Saladín

Fryauff²,

Taylor³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. Mutations in the Pfmdr1 gene are reported to be associated with chloroquine resistance in some Plasmodium falciparum isolates. A polymerase chain reaction/restriction fragment length polymorphism method was used for the detection of Pfmdr1 mutations in chloroquine-resistant field isolates of P. falciparum collected in Irian Jaya. The frequency of Pfmdr1 mutations was significantly higher in chloroquine-resistant P. falciparum parasites than background frequencies observed in the same location. The 7G8 mutation was identified in some parasites although always in a mixed genotype status. Chloroquine-resistant P. falciparum specimens were characterized using the World Health Organization 28-day criteria, supplemented by demonstrating adequate chloroquine absorption and genetic analysis.Resistance of Plasmodium falciparum to chloroquine (CQ) and other antimalarial drugs is a widespread phenomenon that challenges current control efforts. Since early reports in the late 1950s, CQ resistance has been identified in most regions of the world where malaria is endemic. This problem has been investigated in several islands of the Indonesian archipelago such as Lombok, 1 Java, 2 and Irian Jaya, [3][4][5] where the first Indonesian case of CQ-resistant P. falciparum was described. 6 To understand the mechanism of CQ resistance in malaria parasites, a search for the responsible gene(s) has been launched. In 1989 two P. falciparum genes homologous to the mammalian multiple drug resistance (MDR) gene were identified, mapped to chromosome V, 7 and named Pfmdr1 and Pfmdr2. 8 This discovery, coupled with the fact that the calcium channel blocker verapamil reverses CQ resistance, 9 gave support to the theory that a mechanism similar to multiple drug resistance in mammalian tumor cells, in which over expression and amplification of the MDR gene confers drug resistance to tumor cells via an efflux mechanism, operates in P. falciparum. The product of the Pfmdr1 gene, Pglycoprotein homolog 1 (Pgh1) has been localized to the membrane of the digestive vacuole of mature blood stage parasites. 10 This model predicted that the Pfmdr1 gene would be amplified and/or over expressed in CQ-resistant isolates but several studies obtained mixed results. [11][12][13][14][15] Considerable controversy has been generated by conflicting reports that tested a second model: that mutations in the Pfmdr1 gene confer CQ resistance. DNA sequencing of the Pfmdr1 gene from reference strains and field isolates has revealed several point mutations that correlated with CQ resistance. 16 These mutations were classed into two genotypes: the K1 genotype, resulting in an asparagine (Asn) to tyrosine (Tyr) change at position 86 and the 7G8 genotype, with four point mutations resulting in amino acid substitutions at positions 184, 1034, 1042, and 1246. Shortly after a rapid polymerase chain reaction (PCR) and restriction digest method for the detection of these two genotypes in field isolates was developed;17 field studies applied this technique and confirmed ...

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“…Attack rates for malaria in the Arso region have typically ranged between 0 . 5 and 4 infections/person-year [32][33][34][35]. Cross-sectional studies in similar villages revealed relatively uniform prevalence of parasitemia across age groups during the first year of exposure [20].…”

Section: Study Sitementioning

confidence: 99%

Adult Javanese migrants to Indonesian Papua at high risk of severe disease caused by malaria

Baird¹,

Basri

Weina³

et al. 2003

Epidemiol. Infect.

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Migrants from Java arrive in hyperendemic Papua, Indonesia lacking exposure to endemic malaria. We evaluated records of evacuation to hospital with a diagnosis of severe malaria from a transmigration village in northeastern Papua. During the first 30 months, 198 residents with severe disease were evacuated (7·5 evacuations/100 person-years). During this period the risk of evacuation for adults (>15 years of age) was 2·8. (95% CI=2·1–3·8; P<0·0001) relative to children, despite apparently equal exposure to risk of infection. Relative risk (RR) for adults was greatest during the first 6 months (RR>16; 95% CI[ges ]2·0–129; P=0·0009), and diminished during the second 6 months (RR=9·4; 95% CI=2·7–32·8; P<0·0001) and the third 6 months (RR=3·7; 95% CI=1·7–7·9; P=0·0004). During the next two 6-month intervals, the RR for adults was 1·6 and 1·5 (95% CI range 0·8–2·6; P<0·18). Adults lacking chronic exposure were far more likely to progress to severe disease compared to children during initial exposure, but not after chronic exposure to infection.

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Malaria Prophylaxis Using Azithromycin: A Double‐Blind, Placebo‐Controlled Trial in Irian Jaya, Indonesia

Cited by 131 publications

References 26 publications

Tolerability of Azithromycin as Malaria Prophylaxis in Adults in Northeast Papua, Indonesia

Tolerability of Azithromycin as Malaria Prophylaxis in Adults in Northeast Papua, Indonesia

Plasmodium falciparum mdr1 mutations and in vivo chloroquine resistance in Indonesia.

Adult Javanese migrants to Indonesian Papua at high risk of severe disease caused by malaria

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