• 1.

    Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, Sreng S, Anderson JM, Mao S, Sam B, Sopha C, Chuor CM, Nguon C, Sovannaroth S, Pukrittayakamee S, Jittamala P, Chotivanich K, Chutasmit K, Suchatsoonthorn C, Runcharoen R, Hien TT, Thuy-Nhien NT, Thanh NV, Phu NH, Htut Y, Han KT, Aye KH, Mokuolu OA, Olaosebikan RR, Folaranmi OO, Mayxay M, Khanthavong M, Hongvanthong B, Newton PN, Onyamboko MA, Fanello CI, Tshefu AK, Mishra N, Valecha N, Phyo AP, Nosten F, Yi P, Tripura R, Borrmann S, Bashraheil M, Peshu J, Faiz MA, Ghose A, Hossain MA, Samad R, Rahman MR, Hasan MM, Islam A, Miotto O, Amato R, MacInnis B, Stalker J, Kwiatkowski DP, Bozdech Z, Jeeyapant A, Cheah PY, Sakulthaew T, Chalk J, Intharabut B, Silamut K, Lee SJ, Vihokhern B, Kunasol C, Imwong M, Tarning J, Taylor WJ, Yeung S, Woodrow CJ, Flegg JA, Das D, Smith J, Venkatesan M, Plowe CV, Stepniewska K, Guerin PJ, Dondorp AM, Day NP, White NJ, Tracking Resistance to Artemisinin Collaboration, 2014. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 371: 411423.

    • Search Google Scholar
    • Export Citation
  • 2.

    Rosenthal PJ, 2013. The interplay between drug resistance and fitness in malaria parasites. Mol Microbiol 89: 10251038.

  • 3.

    Amaratunga C, Lim P, Suon S, Sreng S, Mao S, Sopha C, Sam B, Dek D, Try V, Amato R, Blessborn D, Song L, Tullo GS, Fay MP, Anderson JM, Tarning J, Fairhurst RM, 2016. Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect Dis 16: 357365.

    • Search Google Scholar
    • Export Citation
  • 4.

    Nankabirwa JI, Wandera B, Amuge P, Kiwanuka N, Dorsey G, Rosenthal PJ, Brooker SJ, Staedke SG, Kamya MR, 2014. Impact of intermittent preventive treatment with dihydroartemisinin-piperaquine on malaria in Ugandan schoolchildren: a randomized, placebo-controlled trial. Clin Infect Dis 58: 14041412.

    • Search Google Scholar
    • Export Citation
  • 5.

    Wells TN, Hooft van Huijsduijnen R, Van Voorhis WC, 2015. Malaria medicines: a glass half full? Nat Rev Drug Discov 14: 424442.

  • 6.

    Dahl EL, Rosenthal PJ, 2007. Multiple antibiotics exert delayed effects against the Plasmodium falciparum apicoplast. Antimicrob Agents Chemother 51: 34853490.

    • Search Google Scholar
    • Export Citation
  • 7.

    Sidhu AB, Sun Q, Nkrumah LJ, Dunne MW, Sacchettini JC, Fidock DA, 2007. In vitro efficacy, resistance selection, and structural modeling studies implicate the malarial parasite apicoplast as the target of azithromycin. J Biol Chem 282: 24942504.

    • Search Google Scholar
    • Export Citation
  • 8.

    Dahl EL, Rosenthal PJ, 2008. Apicoplast translation, transcription and genome replication: targets for antimalarial antibiotics. Trends Parasitol 24: 279284.

    • Search Google Scholar
    • Export Citation
  • 9.

    Krudsood S, Silachamroon U, Wilairatana P, Singhasivanon P, Phumratanaprapin W, Chalermrut K, Phophak N, Popa C, 2000. A randomized clinical trial of combinations of artesunate and azithromycin for treatment of uncomplicated Plasmodium falciparum malaria in Thailand. Southeast Asian J Trop Med Public Health 31: 801807.

    • Search Google Scholar
    • Export Citation
  • 10.

    Krudsood S, Buchachart K, Chalermrut K, Charusabha C, Treeprasertsuk S, Haoharn O, Duangdee C, Looareesuwan S, 2002. A comparative clinical trial of combinations of dihydroartemisinin plus azithromycin and dihydroartemisinin plus mefloquine for treatment of multidrug resistant falciparum malaria. Southeast Asian J Trop Med Public Health 33: 525531.

    • Search Google Scholar
    • Export Citation
  • 11.

    Dunne MW, Singh N, Shukla M, Valecha N, Bhattacharyya PC, Dev V, Patel K, Mohapatra MK, Lakhani J, Benner R, Lele C, Patki K, 2005. A multicenter study of azithromycin, alone and in combination with chloroquine, for the treatment of acute uncomplicated Plasmodium falciparum malaria in India. J Infect Dis 191: 15821588.

    • Search Google Scholar
    • Export Citation
  • 12.

    Chandra R, Ansah P, Sagara I, Sie A, Tiono AB, Djimde AA, Zhao Q, Robbins J, Penali LK, Ogutu B, 2015. Comparison of azithromycin plus chloroquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in children in Africa: a randomized, open-label study. Malar J 14: 108.

    • Search Google Scholar
    • Export Citation
  • 13.

    Phong NC, Quang HH, Thanh NX, Trung TN, Dai B, Shanks GD, Chavchich M, Edstein M, 2016. In vivo efficacy and tolerability of artesunate plus azithromycin for the treatment of falciparum malaria in Vietnam. Am J Trop Med Hyg 95: 164167.

    • Search Google Scholar
    • Export Citation
  • 14.

    Andersen SL, Oloo AJ, Gordon DM, Ragama OB, Aleman GM, Berman JD, Tang DB, Dunne MW, Shanks GD, 1998. Successful double-blinded, randomized, placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya. Clin Infect Dis 26: 146150.

    • Search Google Scholar
    • Export Citation
  • 15.

    Taylor WR, Richie TL, Fryauff DJ, Picarima H, Ohrt C, Tang D, Braitman D, Murphy GS, Widjaja H, Tjitra E, Ganjar A, Jones TR, Basri H, Berman J, 1999. Malaria prophylaxis using azithromycin: a double-blind, placebo-controlled trial in Irian Jaya, Indonesia. Clin Infect Dis 28: 7481.

    • Search Google Scholar
    • Export Citation
  • 16.

    Gaynor BD, Amza A, Kadri B, Nassirou B, Lawan O, Maman L, Stoller NE, Yu SN, Chin SA, West SK, Bailey RL, Rosenthal PJ, Keenan JD, Porco TC, Lietman TM, 2014. Impact of mass azithromycin distribution on malaria parasitemia during the low-transmission season in Niger: a cluster-randomized trial. Am J Trop Med Hyg 90: 846851.

    • Search Google Scholar
    • Export Citation
  • 17.

    Moore BR, Benjamin JM, Auyeung SO, Salman S, Yadi G, Griffin S, Page-Sharp M, Batty KT, Siba PM, Mueller I, Rogerson SJ, Davis TM, 2016. Safety, tolerability and pharmacokinetic properties of co-administered azithromycin and piperaquine in pregnant Papua New Guinean women. Br J Clin Pharmacol doi:10.1111/bcp.12910.

    • Search Google Scholar
    • Export Citation
  • 18.

    Bhosai SJ, Bailey RL, Gaynor BD, Lietman TM, 2012. Trachoma: an update on prevention, diagnosis, and treatment. Curr Opin Ophthalmol 23: 288295.

    • Search Google Scholar
    • Export Citation
  • 19.

    Asiedu K, Fitzpatrick C, Jannin J, 2014. Eradication of yaws: historical efforts and achieving WHO's 2020 target. PLoS Negl Trop Dis 8: e3016.

  • 20.

    Gilliams EA, Jumare J, Claassen CW, Thesing PC, Nyirenda OM, Dzinjalamala FK, Taylor T, Plowe CV, Tracy LA, Laufer MK, 2014. Chloroquine-azithromycin combination antimalarial treatment decreases risk of respiratory- and gastrointestinal-tract infections in Malawian children. J Infect Dis 210: 585592.

    • Search Google Scholar
    • Export Citation
  • 21.

    Unger HW, Ome-Kaius M, Wangnapi RA, Umbers AJ, Hanieh S, Suen CS, Robinson LJ, Rosanas-Urgell A, Wapling J, Lufele E, Kongs C, Samol P, Sui D, Singirok D, Bardaji A, Schofield L, Menendez C, Betuela I, Siba P, Mueller I, Rogerson SJ, 2015. Sulphadoxine-pyrimethamine plus azithromycin for the prevention of low birthweight in Papua New Guinea: a randomised controlled trial. BMC Med 13: 9.

    • Search Google Scholar
    • Export Citation
  • 22.

    Porco TC, Gebre T, Ayele B, House J, Keenan J, Zhou Z, Hong KC, Stoller N, Ray KJ, Emerson P, Gaynor BD, Lietman TM, 2009. Effect of mass distribution of azithromycin for trachoma control on overall mortality in Ethiopian children: a randomized trial. JAMA 302: 962968.

    • Search Google Scholar
    • Export Citation
  • 23.

    Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM, 2012. Azithromycin and the risk of cardiovascular death. N Engl J Med 366: 18811890.

  • 24.

    Svanstrom H, Pasternak B, Hviid A, 2013. Use of azithromycin and death from cardiovascular causes. N Engl J Med 368: 17041712.

 
 
 
 

 

 
 
 

 

 

 

 

 

 

Azithromycin for Malaria?

View More View Less
  • 1 Department of Medicine, University of California, San Francisco, California.

Malaria continues to be one of the greatest infectious disease problems in the world. Antimalarial drugs play an essential role in the treatment and control of malaria. For treatment, older drugs are limited by resistance, but artemisinin-based combination therapy remains highly effective in most areas. However, artemisinin resistance has emerged in southeast Asia,1 and resistance to artemisinin partner drugs is already common in many areas.2 In Cambodia, where resistance to both artemisinins and piperaquine is prevalent, frequent failures after treatment with dihydroartemisinin–piperaquine have been seen.3 We can anticipate that artemisinin resistance will spread to other areas, and that resistance to artemisinins and partner drugs will seriously threaten our ability to treat malaria.

Chemoprevention is an important strategy for malaria control. Nonimmune travelers to malaria-endemic countries are typically prescribed atovaquone–proguanil (Malarone), mefloquine, or doxycycline to prevent malaria. This practice is highly effective, but impractical for endemic populations due to cost and toxicity concerns. In Africa, intermittent preventive therapy is advocated in high-risk populations, with intermittent administration of sulfadoxine–pyrimethamine (SP) to pregnant women, and seasonal administration of SP–amodiaquine to children in the Sahel subregion, where there is a relatively low level of resistance to these drugs. However, the utility of drugs to prevent malaria in endemic populations is limited by resistance to available agents. Monthly dihydroartemisinin–piperaquine has shown strong protective efficacy in African children in some trials,4 but is not standard practice yet.

For both treatment and chemoprevention, antimalarial drugs are increasingly limited by resistance. New drugs are greatly needed, and a quite robust pipeline of drugs is under development.5 However, development is challenging, typically with slow progress even after promising agents show excellent efficacy, and with the potential for lead compounds to fail in later stages of development. Indeed, no new classes of antimalarial drugs have been broadly approved in a few decades, and it remains unclear if the pipeline will satisfy upcoming needs.

With this background, it behooves us to consider repurposing of available antimicrobial drugs to treat malaria. One such drug is azithromycin, a macrolide antibiotic with broad-spectrum activity against gram-positive and atypical bacteria. As is the case with some other antibacterial protein synthesis inhibitors, including doxycycline, azithromycin exerts antimalarial activity by inhibiting function of the apicoplast.6,7 This action is necessarily slow. After treatment with doxycycline or azithromycin, parasites are killed by pharmacological concentrations of the drug only in the life cycle after treatment is initiated, presumably due to the ability of parasites to survive most of the life cycle without a functional apicoplast. Yet, doxycycline has a role in our antimalarial armamentarium, both for treatment in combination with quinine and for chemoprophylaxis. Azithromycin has advantages over doxycycline, namely a longer half-life, suggesting the possibility of weekly dosing for chemoprophylaxis, acceptability in young children, who should not be treated with doxycycline if possible, and generally better tolerability than doxycycline.

Azithromycin has already been studied as a potential antimalarial agent. It exerts slow, but potent antimalarial activity via action against the apicoplast organelle.8 It is the most potent antimalarial macrolide, with mid-nanomolar activity against cultured Plasmodium falciparum after prolonged in vitro incubations.6 For the treatment of uncomplicated falciparum malaria, artesunate plus azithromycin offered improved efficacy over artesunate monotherapy, but this regimen was inferior to artesunate plus mefloquine.9 Similarly, dihydroartemisinin plus azithromycin had good efficacy, but was inferior to dihydroartemisinin plus mefloquine.10 Azithromycin plus chloroquine has been extensively studied against falciparum malaria after a trial in India showed the combination to offer excellent efficacy,11 but in Malian children azithromycin plus chloroquine was inferior compared with artemether–lumefantrine.12 In this issue of the American Journal of Tropical Medicine and Hygiene, Phong and colleagues report on a 3-day regimen of artesunate plus azithromycin for the treatment of falciparum malaria in a small number of children and adults in Vietnam; the regimen was well tolerated and had a corrected treatment efficacy of 96.7%.13

For the prevention of falciparum malaria, azithromycin had good preventive efficacy in Kenyan14 and Indonesian15 adults when administered daily, although the preventive efficacy was inferior to that of doxycycline in both trials (protective efficacy in Kenya was 83% for azithromycin versus 93% for doxycycline; in Indonesia 72% versus 96%). In Kenya, azithromycin preventive efficacy was fairly poor when administered weekly (64%). Mass distribution of azithromycin for the control of trachoma was associated with a reduction in malaria parasitemia compared with controls.16 Azithromycin plus piperaquine was well tolerated in pregnant Papua New Guinean women,17 although preventive efficacy data are not available.

Considering needs for new antimalarials for treatment and prevention and available data, should we consider azithromycin for this purpose? On the plus side, azithromycin is approved around the world and is generally considered safe in children and in pregnancy. Indeed, if used regularly, azithromycin may have benefits beyond malaria. Intermittent administration of azithromycin has played a major role in efforts to eliminate trachoma18 and yaws19; regular use of chloroquine plus azithromycin to treat malaria in Malawian children was associated with decreased respiratory and gastrointestinal infections compared with a group receiving only chloroquine20; azithromycin plus SP given to pregnant women was associated with increased birthweight21; and, remarkably, in a randomized trial in Ethiopia, infrequent (quarterly, biannual, or annual) dosing of azithromycin decreased child mortality by half.22 On the other hand, azithromycin efficacy for treatment and chemoprevention has typically been somewhat lower than that of comparator regimens. Also, wider use of azithromycin will probably select for drug-resistant bacterial infections. Lastly, use of the drug has been associated in some,23 but not other24 trials with increased risk of death from cardiovascular causes; this is probably a modest concern for use in malaria, particularly in children, but nonetheless is reason for caution. In a perfect world, azithromycin would probably not be considered further for the treatment or chemoprevention of malaria, as more efficacious and rapid-acting agents are available. However, limitations in efficacy or rate of action may be circumvented in combination regimens. With the continued threat of drug resistance and a sluggish pipeline for new agents, it seems appropriate to continue to study repurposing azithromycin, a tried-and-true antimicrobial drug for other indications, in combination regimens for the treatment and/or prevention of malaria.

ACKNOWLEDGMENTS

I thank Theodore Ruel for helpful discussions.

  • 1.

    Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, Sreng S, Anderson JM, Mao S, Sam B, Sopha C, Chuor CM, Nguon C, Sovannaroth S, Pukrittayakamee S, Jittamala P, Chotivanich K, Chutasmit K, Suchatsoonthorn C, Runcharoen R, Hien TT, Thuy-Nhien NT, Thanh NV, Phu NH, Htut Y, Han KT, Aye KH, Mokuolu OA, Olaosebikan RR, Folaranmi OO, Mayxay M, Khanthavong M, Hongvanthong B, Newton PN, Onyamboko MA, Fanello CI, Tshefu AK, Mishra N, Valecha N, Phyo AP, Nosten F, Yi P, Tripura R, Borrmann S, Bashraheil M, Peshu J, Faiz MA, Ghose A, Hossain MA, Samad R, Rahman MR, Hasan MM, Islam A, Miotto O, Amato R, MacInnis B, Stalker J, Kwiatkowski DP, Bozdech Z, Jeeyapant A, Cheah PY, Sakulthaew T, Chalk J, Intharabut B, Silamut K, Lee SJ, Vihokhern B, Kunasol C, Imwong M, Tarning J, Taylor WJ, Yeung S, Woodrow CJ, Flegg JA, Das D, Smith J, Venkatesan M, Plowe CV, Stepniewska K, Guerin PJ, Dondorp AM, Day NP, White NJ, Tracking Resistance to Artemisinin Collaboration, 2014. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 371: 411423.

    • Search Google Scholar
    • Export Citation
  • 2.

    Rosenthal PJ, 2013. The interplay between drug resistance and fitness in malaria parasites. Mol Microbiol 89: 10251038.

  • 3.

    Amaratunga C, Lim P, Suon S, Sreng S, Mao S, Sopha C, Sam B, Dek D, Try V, Amato R, Blessborn D, Song L, Tullo GS, Fay MP, Anderson JM, Tarning J, Fairhurst RM, 2016. Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect Dis 16: 357365.

    • Search Google Scholar
    • Export Citation
  • 4.

    Nankabirwa JI, Wandera B, Amuge P, Kiwanuka N, Dorsey G, Rosenthal PJ, Brooker SJ, Staedke SG, Kamya MR, 2014. Impact of intermittent preventive treatment with dihydroartemisinin-piperaquine on malaria in Ugandan schoolchildren: a randomized, placebo-controlled trial. Clin Infect Dis 58: 14041412.

    • Search Google Scholar
    • Export Citation
  • 5.

    Wells TN, Hooft van Huijsduijnen R, Van Voorhis WC, 2015. Malaria medicines: a glass half full? Nat Rev Drug Discov 14: 424442.

  • 6.

    Dahl EL, Rosenthal PJ, 2007. Multiple antibiotics exert delayed effects against the Plasmodium falciparum apicoplast. Antimicrob Agents Chemother 51: 34853490.

    • Search Google Scholar
    • Export Citation
  • 7.

    Sidhu AB, Sun Q, Nkrumah LJ, Dunne MW, Sacchettini JC, Fidock DA, 2007. In vitro efficacy, resistance selection, and structural modeling studies implicate the malarial parasite apicoplast as the target of azithromycin. J Biol Chem 282: 24942504.

    • Search Google Scholar
    • Export Citation
  • 8.

    Dahl EL, Rosenthal PJ, 2008. Apicoplast translation, transcription and genome replication: targets for antimalarial antibiotics. Trends Parasitol 24: 279284.

    • Search Google Scholar
    • Export Citation
  • 9.

    Krudsood S, Silachamroon U, Wilairatana P, Singhasivanon P, Phumratanaprapin W, Chalermrut K, Phophak N, Popa C, 2000. A randomized clinical trial of combinations of artesunate and azithromycin for treatment of uncomplicated Plasmodium falciparum malaria in Thailand. Southeast Asian J Trop Med Public Health 31: 801807.

    • Search Google Scholar
    • Export Citation
  • 10.

    Krudsood S, Buchachart K, Chalermrut K, Charusabha C, Treeprasertsuk S, Haoharn O, Duangdee C, Looareesuwan S, 2002. A comparative clinical trial of combinations of dihydroartemisinin plus azithromycin and dihydroartemisinin plus mefloquine for treatment of multidrug resistant falciparum malaria. Southeast Asian J Trop Med Public Health 33: 525531.

    • Search Google Scholar
    • Export Citation
  • 11.

    Dunne MW, Singh N, Shukla M, Valecha N, Bhattacharyya PC, Dev V, Patel K, Mohapatra MK, Lakhani J, Benner R, Lele C, Patki K, 2005. A multicenter study of azithromycin, alone and in combination with chloroquine, for the treatment of acute uncomplicated Plasmodium falciparum malaria in India. J Infect Dis 191: 15821588.

    • Search Google Scholar
    • Export Citation
  • 12.

    Chandra R, Ansah P, Sagara I, Sie A, Tiono AB, Djimde AA, Zhao Q, Robbins J, Penali LK, Ogutu B, 2015. Comparison of azithromycin plus chloroquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in children in Africa: a randomized, open-label study. Malar J 14: 108.

    • Search Google Scholar
    • Export Citation
  • 13.

    Phong NC, Quang HH, Thanh NX, Trung TN, Dai B, Shanks GD, Chavchich M, Edstein M, 2016. In vivo efficacy and tolerability of artesunate plus azithromycin for the treatment of falciparum malaria in Vietnam. Am J Trop Med Hyg 95: 164167.

    • Search Google Scholar
    • Export Citation
  • 14.

    Andersen SL, Oloo AJ, Gordon DM, Ragama OB, Aleman GM, Berman JD, Tang DB, Dunne MW, Shanks GD, 1998. Successful double-blinded, randomized, placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya. Clin Infect Dis 26: 146150.

    • Search Google Scholar
    • Export Citation
  • 15.

    Taylor WR, Richie TL, Fryauff DJ, Picarima H, Ohrt C, Tang D, Braitman D, Murphy GS, Widjaja H, Tjitra E, Ganjar A, Jones TR, Basri H, Berman J, 1999. Malaria prophylaxis using azithromycin: a double-blind, placebo-controlled trial in Irian Jaya, Indonesia. Clin Infect Dis 28: 7481.

    • Search Google Scholar
    • Export Citation
  • 16.

    Gaynor BD, Amza A, Kadri B, Nassirou B, Lawan O, Maman L, Stoller NE, Yu SN, Chin SA, West SK, Bailey RL, Rosenthal PJ, Keenan JD, Porco TC, Lietman TM, 2014. Impact of mass azithromycin distribution on malaria parasitemia during the low-transmission season in Niger: a cluster-randomized trial. Am J Trop Med Hyg 90: 846851.

    • Search Google Scholar
    • Export Citation
  • 17.

    Moore BR, Benjamin JM, Auyeung SO, Salman S, Yadi G, Griffin S, Page-Sharp M, Batty KT, Siba PM, Mueller I, Rogerson SJ, Davis TM, 2016. Safety, tolerability and pharmacokinetic properties of co-administered azithromycin and piperaquine in pregnant Papua New Guinean women. Br J Clin Pharmacol doi:10.1111/bcp.12910.

    • Search Google Scholar
    • Export Citation
  • 18.

    Bhosai SJ, Bailey RL, Gaynor BD, Lietman TM, 2012. Trachoma: an update on prevention, diagnosis, and treatment. Curr Opin Ophthalmol 23: 288295.

    • Search Google Scholar
    • Export Citation
  • 19.

    Asiedu K, Fitzpatrick C, Jannin J, 2014. Eradication of yaws: historical efforts and achieving WHO's 2020 target. PLoS Negl Trop Dis 8: e3016.

  • 20.

    Gilliams EA, Jumare J, Claassen CW, Thesing PC, Nyirenda OM, Dzinjalamala FK, Taylor T, Plowe CV, Tracy LA, Laufer MK, 2014. Chloroquine-azithromycin combination antimalarial treatment decreases risk of respiratory- and gastrointestinal-tract infections in Malawian children. J Infect Dis 210: 585592.

    • Search Google Scholar
    • Export Citation
  • 21.

    Unger HW, Ome-Kaius M, Wangnapi RA, Umbers AJ, Hanieh S, Suen CS, Robinson LJ, Rosanas-Urgell A, Wapling J, Lufele E, Kongs C, Samol P, Sui D, Singirok D, Bardaji A, Schofield L, Menendez C, Betuela I, Siba P, Mueller I, Rogerson SJ, 2015. Sulphadoxine-pyrimethamine plus azithromycin for the prevention of low birthweight in Papua New Guinea: a randomised controlled trial. BMC Med 13: 9.

    • Search Google Scholar
    • Export Citation
  • 22.

    Porco TC, Gebre T, Ayele B, House J, Keenan J, Zhou Z, Hong KC, Stoller N, Ray KJ, Emerson P, Gaynor BD, Lietman TM, 2009. Effect of mass distribution of azithromycin for trachoma control on overall mortality in Ethiopian children: a randomized trial. JAMA 302: 962968.

    • Search Google Scholar
    • Export Citation
  • 23.

    Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM, 2012. Azithromycin and the risk of cardiovascular death. N Engl J Med 366: 18811890.

  • 24.

    Svanstrom H, Pasternak B, Hviid A, 2013. Use of azithromycin and death from cardiovascular causes. N Engl J Med 368: 17041712.

Author Notes

* Address correspondence to Philip J. Rosenthal, Department of Medicine, University of California, Box 0811, San Francisco, CA 94946. E-mail: philip.rosenthal@ucsf.edu

Financial support: This work was supported by the National Institutes of Health and Medicines for Malaria Venture.

Author's address: Philip J. Rosenthal, Department of Medicine, University of California, San Francisco, CA, E-mail: philip.rosenthal@ucsf.edu.

Save