In vitro antimalarial therapeutic interventions using various combinations of antibiotics and standard antimalarials against multi drug resistant Indian field isolates of Plasmodium falciparum


  • Pooja Agarwal Assistant Professor, Department of Zoology, Maharaja Agarsen Mahavidhalaya, Bareilly, Uttar Pradesh



Antimalarial, Antibiotics, In vitro, Plasmodium falciparum, Combinations, Arteether tolerant phenotype.


Resistance to antimalarials is considered to be major cause of increased malaria morbidity and mortality. Present study was undertaken to explore an effective drug combination against selected mutant parasite various combinations using standard antimalarials {Chloroquine diphosphate (CQ), Quinine (QUIN), Mefloquine (MQ), Piperaquine (PPQ), Artemether (ARTM), Arteether (ARTE), Dihydro-artemisinin (DHA), Lumefantrine (LUME)and Atovaquone (ATQ)} belonging to three different classes and two antibiotics, Azithromycin (AZI) and Doxycycline (DOXY) have been tried against K1 (chloroquine-resistant) and 3D7 (chloroquine-sensitive) strains as well as selected arteether torelant parasite (MZRI-R) and field isolates (MZRI & MZRII)  of P. falciparum. SYBR Green I fluorescence (MSF) assay was used to determine IC50 values. Results of present studies highlighted that all the combinations used exhibited additive effect with varying intensity depending upon the drug ratios used. We also observed that combination of ARTM plus LUME was more advantageous than DOXY plus DHA/CQ and AZI plus CQ/ATQ for treatment of multidrug resistant parasites whereas combinations of LUME plus PPQ, ATQ plus DOXY/AZI can be used for treatment of CQ resistant parasite.


Andersen, S.L., Oloo, A.J., Gordon, D.M., Ragama, O.B., Aleman, G.M., Berman, J.D., Tang, D.B., Dunne, M.W., and Shanks, G.D., 1998. Successful double-blinded, randomized, placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya. Clin. Infect. Dis. 26, 146-150.

Borghini F.I., 2010. New once-a-day antimalarial combination therapy as effective as the twice-a-day gold standard regimen. Lancet.

Clyde, D.F., Miller R.M., Music S.I., McCarthy V.C., 1971. Prophylactic and porontocidal treatment of chloroquine-resistant Plasmodium falciparum from Vietnam. Am. J. Trop. Med. Hyg. 20, 1-5.

Delemarre B.J., van der Kaay H.J., 1979. Tropical malaria contracted the natural way in the

Netherlands. Ned Tijdschr Geneeskd. 123, 1981-1982.

Fivelman, Q. L., Walden J. C., Smith P. J., Folb P. I., Barnes K. I., 1999. The effect of artesunate combined with standard antimalarials against chloroquine- sensitive and chloroquine-resistant strains of Plasmodium falciparum in vitro. Trans. R. Soc. Tr. Med. Hyg. 93, 429–432.

Klein E.Y., 2013. Antimalarial drug resistance: a review of the biology and strategies to delay emergence and spread. Int. J. Antimicrob. Agents. 41, 311–317.

Korsinczky M., Chen N., Kotecka B., Saul A., Rieckmann K., Cheng Q., 2000. Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrob. Agents Chemother. 44, 2100–2108.

Looareesuwan S., Vanijanonta S., Viravan C., Wilairatana P., Charoenlarp P., Lasserre R., Canfield C., Kyle D.E., Webster H.K., 1994. Randomised trials of mefloquine-tetracycline and quinine-tetracycline for acute uncomplicated falciparum malaria. Acta Tropica. 57, 47-53.

Losert H., Schmid K., Wilfing A., Winkler S., Staudinger T., Kletzmayr J., Burgmann H., 2000. Experiences with severe Plasmodium falciparum malaria in the intensive care unit. Intensive Care Med. 26, 195-201.

Miller, R. S., Wongsrichanalai C., Buathong N., McDaniel P., Walsh D. S., Knirsch C., Ohrt C., 2006. Effective treatment of uncomplicated Plasmodium falciparum malaria with azithromycin-quinine combinations: a randomized, dose-ranging study. Am. J. Trop. Med. Hyg. 74, 401–406.

Nakornchai, S., Konthiang P., 2006. Activity of azithromycin or erythromycin in combination with antimalarial drugs against multidrug-resistant Plasmodium falciparum in vitro. Acta Trop. 100, 185-191.

Noedl H., Krudsood S., Chalermratana K., Silachamroon U., Leowattana W., Tangpukdee N., Looareesuwan S., Miller R.S., Fukuda M., Jongsakul K., Sriwichai S., Rowan J., Bhattacharyya H., Ohrt C., Knirsch C., 2006. Azithromycin combination therapy with artesunate or quinine for the treatment of uncomplicated Plasmodium falciparum malaria in adults: a randomized, phase 2 clinical trial in Thailand. Clin. Infect. Dis. 43, 1264–71.

Noedl H., Krudsood S., Leowattana W., Tangpukdee N., Thanachartwet W., Looareesuwan S., Miller R.S., Fukuda M., Jongsakul K., Yingyuen K., Sriwichai S., Ohrt C., Knirsch C., 2007. In vitro antimalarial activity of azithromycin, artesunate, and quinine in combination and correlation with clinical outcome. Antimicrob. Agents Chemother. 51, 651–656.

Noedl H., 2009. ABC-antibiotics-based combinations for the treatment of severe malaria? Trends Parasitol. 25, 540–544.

Nosten F., van Vugt M., Price R., Luxemburger C., Thway K.L., Brockman A., McGready R., ter Kuile F., Looareesuwan S. and White N.J., 2000. Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet. 356, 297-302.

Ohrt, C., Willingmyre G. D., Lee P., Knirsch C., Milhous W., 2002. Assessment of azithromycin in combination with other antimalarial drugs against Plasmodium falciparum in vitro. Antimicrob. Agents Chemother. 46, 2518–2524

Pradel G., Schlitzer M., 2010. Antibiotics in malaria therapy and their effect on the parasite apicoplast. Curr. Mol. Med. 10, 335–349.

Ramharter M., Noedl H., Winkler H., Graninger W., Wernsdorfer W. H., Kremsner P. G., Winkler S., 2003. In Vitro Activity and Interaction of Clindamycin Combined with Dihydroartemisinin against Plasmodium falciparum. Antimicrob. Agents Chemother. 47, 3494–3499.

Rieckmann K.H., Powell R.D., McNamara J.V., Willerson D. Jr., Lass L., Frischer H., Carson P.E., 1971. Effects of tetracycline against chloroquine-resistant and chloroquine-sensitive Plasmodium falciparum. Am J Trop Med Hyg. 20: 811–815.

Rosenthal P. J., 2013. The interplay between drug resistance and fitness in malaria parasites. Mol. Microbiol. 89, 1025–1038.

Sagara I., Abraham R. O., Modest Mulenga , Yemou D. , Bernhards O., Alfred B. T. , Peter M., Ali S., Monique W., Kevin C. K., Abdoulaye A. D., Shirsendu S., Chandra R., Jeffery R., Michael W. D., 2014. Efficacy and safety of a combination of azithromycin and chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria in two multi-country randomised clinical trials in African adults. Malaria Journal. 13, 458.

Sanchez J.L., DeFraites R.F., Sharp T.W., Hanson R.K., 1993. Mefloquine or doxycycline prophylaxis in US troops in Somalia. Lancet. 341, 1021-1022.

Singh S., Srivastava R.K, Srivastava M., Puri S.K., Srivastava K., 2011. In-vitro culture of Plasmodium falciparum: Utility of Modified (RPNI) Medium for drug sensitivity studies using SYBR Green I assay. Exp. Parasitol. 127, 318-321.

Srivastava K., Puri S.K., 2004. Plasmodium falciparum: modified medium composition supports continuous with foetal bovine serum, Exp. Parasitol. 108, 74-75.

Tan K.R., Magill A.J., Parise M.E., Arguin P.M., 2011. Doxycycline for malaria chemoprophylaxis and treatment: Report from the CDC Expert meeting on malaria chemoprophylaxis. Am. J. Trop. Med. Hyg. 84, 517–531.

Taylor W.R., Widjaja H.,. Richie T.L., Basri H., Ohrt C., Tjitra E., Taufik E.,. Jones T.R, Kain K.C., Hoffman S.L., 2001, Chloroquine/doxycycline combination versus chloroquine alone, and doxycycline alone for the treatment of Plasmodium falciparum and Plasmodium vivax malaria in northeastern Irian Jaya, Indonesia. Am. J. Trop. Med. Hyg. 64, 223–228

Tun K.M., Imwong M., Lwin K.M., Win A.A., Hlaing T.M., Hlaing T., Lin K., Kyaw M.P., Plewes K., Faiz M.A., Dhorda M., Cheah P.Y., Pukrittayakamee S., Ashley E.A., Anderson T.J., Nair S., McDew-White M., Flegg J.A., Grist E.P., Guerin P., Maude R.J., Smithuis F., Dondorp A.M., Day N.P., Nosten F., White N.J., Woodrow C.J., 2015. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. Lancet Infect. Dis. 15 , 415-21.

Van Eijk A.M., Terlouw D.J., 2011. Azithromycin for treating uncomplicated malaria.

Cochrane Database Syst Rev, CD006688.

Watt, G., Loesuttivibool, L., Shanks, G.D., Boudreau, E.F., Brown, A.E., Pavanand, K., Webster, H.K., Wechgritaya, S., 1992 Quinine with tetracycline for the treatment of drug-resistant falciparum malaria in Thailand. Am. J. Trop. Med. Hyg. 47, 108–111.

Willerson, D., Jr., Rieckmann, K.H., Carson, P.E., and Frischer, H., 1972. Effects of minocycline against chloroquine-resistant falciparum malaria. Am. J. Trop. Med. Hyg. 21, 857-862.

Wongsrichanalai C., Sibley C.H., 2013. Fighting drug-resistant Plasmodium falciparum: the challenge of artemisinin resistance. Clin. Microbiol. Infect. 19, 908–916.

World Health Organization., 2001. Antimalarial Drug Combination Therapy. Report of a WHO Technical Consultation. In: World Health Organization, Geneva. WHO/CDS/RBM/2001.35.

World Health Organization., 2006. Guidelines for the treatment of malaria. World Health Organization, Geneva, Switzerland.

World Health Organization., 2010. Guidelines for the Treatment of Malaria, (2nd edn), World Health Organization. malaria/publications/atoz/ 9789241547925/en/index.html.

World Health Organization., 2012. World malaria report. World Health Organization. Geneva, Switzerland. /publications/world malaria report 2012/en/.

Yeo, A.E., Rieckmann, K.H., Christopherson, R.I., 1998. Indirect inhibition by antibiotics of nucleotide and deoxynucleotide biosynthesis in Plasmodium falciparum. Southeast Asian J. Trop. Med. Public Health. 29, 24-26.




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In vitro antimalarial therapeutic interventions using various combinations of antibiotics and standard antimalarials against multi drug resistant Indian field isolates of Plasmodium falciparum . (2024). Knowledgeable Research: A Multidisciplinary Journal, 2(10), 12-25.