ABC - antibiotics-based combinationsfor the treatment of severe malaria?Harald Noedl

Medical University of Vienna, Kinderspitalgasse 15, A-1090 Vienna, Austria

Opinion

Glossary

ABC: Antibiotic-Based Combination Therapy for the treatment of severe

malaria. A standardized (possibly co-formulated) intravenous combination of

an antibiotic with antimalarial activity with a traditional antimalarial (such as

quinine or artesunate).

ACT: Artemisinin-Based Combination Therapy. Oral combination therapies

used in uncomplicated falciparum malaria combining an artemisinin derivative

with another antimalarial.

Co-formulation: drugs to be used in combination are distributed mixed as a

single entity (e.g. in a single vial or tablet).

Co-packaging: drugs used in combination are distributed in the same package

but not mixed (e.g. two different tablets or vials in a single package).

Delayed death effect: after drug exposure only the progeny of parasites

exposed to an antimalarial drug dies (rather than the first generation which is

actually exposed) generally resulting in a slow onset of action [45].

RDT: Rapid Diagnostic Test. Immunochromatographic tests usually based on

the detection of malaria-specific antigens, such as histidine-rich protein II,

parasite lactate dehydrogenase, or aldolase.

Almost one million people die of severe malaria everyyear. In recent years, artemisinin-based combinationtherapies have become the backbone of the treatmentof uncomplicated falciparum malaria and have helpedto reduce the burden of malaria in large parts of themalaria-endemic world. However, the treatment ofsevere malaria, the clinical syndrome responsible formost malaria-associated deaths, remains largely unaf-fected by this development. Invasive bacterial infectionsand misdiagnosis of bacterial infections as severemalaria are well recognized phenomena, but recent dataindicate that their prevalence and clinical importancemight be far greater than previously anticipated. There-fore, there could be good reasons to routinely combineantimalarials, such as artemisinins or quinine, withbroad spectrum antibiotics with antimalarial activity instandardized combination therapies for the parenteraltreatment of severe falciparum malaria.

Why severe malaria?According to the WHO World Malaria report 2008, therewere an estimated 247 million malaria cases among 3.3billion people at risk in 2006, causing nearly one milliondeaths, mostly in Africa [1]. Severe malaria is almostexclusively caused by Plasmodium falciparum and, inendemic countries, most commonly encountered in chil-dren below the age of five years. Infection with P. falci-parum can result in a wide variety of symptoms, rangingfrom none at all, through mild disease, to severe diseaseand death. Complications in severe malaria are largelyage-dependent and include cerebral malaria, severe ane-mia, pulmonary edema, and acute renal failure. With themortality of untreated severe malaria approaching 100%,it is essential to achieve therapeutic concentrations of afast-acting parenterally administered antimalarial as soonas possible. Even with antimalarial treatment, themortality might be as high as 15–20% overall, althoughwithin the broad definition of severe malaria, individualsyndromes are associated with mortality rates that couldvary considerably.

Current treatment of severe malariaQuinine has been the treatment of choice for falciparummalaria for hundreds of years. In recent years, artemisi-nins derivatives from Artemisia annua, have evolved as ahighly effective alternative to quinine. The current recom-mendation for treating severe malaria patients in high-

Corresponding authors: Noedl, H. (harald.noedl@meduniwien.ac.at)URL: http://www.marib.org

540 1471-4922/$ – see front matter � 2009 Elsev

transmission areas is either intravenous quinine or anartemisinin derivative, whereas parenteral artesunate isnow recommended by WHO as the drug of choice for thetreatment of severe malaria in low-transmission settings[2]. Intramuscular injections of artemisinin derivativesand suppositories have proven to be extremely useful inresource-limited settings. In a multicenter clinical trialconducted in South and Southeast Asia, patients receivingartesunate intravenously had a 35% lower mortality thanthose receiving intravenous quinine [3,4].

Why combination therapy?Within just a few years, artemisinin-based combinationtherapy (ACT) has become the backbone of the treatment ofuncomplicated falciparum malaria. Between 2005 and2006, the number of doses of ACTs increased from sixmillion to 49 million, of which 45 million were for Africancountries [1,5].

Although the first cases of genuine artemisinin resist-ance have recently emerged in a relatively small regionalong the Cambodia–Thailand border [6–8], in most partsof the world ACTs remain the most potent and fast-actingtherapy for the treatment of uncomplicated falciparummalaria [9]. In spite of rising numbers of failures in someregions, the importance of ACTs today is only comparableto that of chloroquine in the mid 20th century [10–12]. MostACTs combine a fast-acting, short half-life artemisinincompound with a slower acting partner drug with longerhalf-life, ideally with a synergistic interaction profile. Themain concept behind using ACTs in the treatment ofuncomplicated falciparum malaria has been to delay or

Severe malaria-like syndrome: symptom complex clinically indistinguishable

from severe malaria potentially caused by a variety of different organisms.

ier Ltd. All rights reserved. doi:10.1016/j.pt.2009.09.001 Available online 12 October 2009

Opinion Trends in Parasitology Vol.25 No.12

even prevent the development of drug resistance by com-bining two antimalarials with different modes of action,thereby drastically reducing the chances of selecting para-sites simultaneously resistant to both drugs [13,14].

Why have ACTs not been used for the parenteraltreatment of severe malaria?The main reason why combination therapies have nevergained the attention in the treatment of severemalaria thatthey have gained in uncomplicated malaria is the fact thatdrug resistance development is not a major concern in thetreatment of severe malaria. Why not? First, with mostparenteral treatments taking place in a relatively well-controlled hospital or clinic environment, compliance anddrug pressure are less of an issue. Second, the number ofpatients treated with intravenous drugs is considerablysmaller. Third, the priority in treating severe malaria isto save the patient’s life and prevent sequelae and the de-velopment of drug resistance is therefore considered to be ofsecondary importance. Finally, relatively few of the newantimalarialsusedinACTsareavailableasIVformulations.

Why should antibiotics-based combination therapies beconsidered for severe malaria?Misdiagnosis

Although, in theory, the diagnosis of malaria depends onmicroscopy or at least a positive rapid diagnostic test(RDT), in practice the most common means of diagnosingmalaria remains presumptive diagnosis [15]. In resource-limited health care systems, as typically encountered inmalaria-endemic countries, adequate diagnosis can be amajor challenge [16]. Also in high-prevalence regions, thepresence of malaria parasites does not necessarily meanthat the current clinical illness is because of malaria.Furthermore Malaria is commonly over-diagnosed andover-treated in people presenting with febrile illness,either because of clinical (mis)diagnosis or because ofpoor-quality microscopy [17,18]. This is associated witha failure to treat alternative causes of severe infection [19].Quality laboratory testing would be crucial to confirmclinical diagnoses and to guide treatment policies [20],but the available laboratory and health care infrastruc-tures are rarely sufficient to meet these needs. Frequently,even when available, adequate diagnostic facilities remainunderused, and patients with negative test results gettreated for malaria in the absence of an alternative diag-nosis [21].

Unfortunately, the symptoms of malaria are notoriouslynonspecific and a variety of febrile illnesses can mimic theclinical picture of severe malaria, most importantly septi-cemia, pneumonia, meningitis, typhoid fever, as well asnumerous bacterial, parasitic, or viral diseases causing‘severe malaria-like syndromes.’ In sub-Saharan Africa,malaria and pneumonia are the leading causes of childdeath and numerous authors conclude that communitystrategies need to address the malaria-pneumonia symp-tom overlap better by managing both conditions [22–24]. Aprudently selected antibiotics-based combination (ABC)therapy for severe malaria cases could address many ofthe most common conditions that can be misdiagnosed assevere malaria, while at the same time treating malaria.

Concomitant bacterial infections

A situation commonly encountered by physicians treatingconfirmed falciparum malaria patients is that, in spite ofadequate antimalarial treatment, the clinical condition ofthe patient might not improve and might even deteriorate.Inparasitological terms,patientsseemtorespondwell to thetreatment, and even clear their parasites, although theclinical status of the patient might not improve. Anothercommon finding is that the severity of disease in malaria isnot correlated with the parasite burden, i.e. patients withlowparasitedensitiescandevelopsymptomsconsistentwithsevere disease. A probable explanation for such scenarios isthepresenceof concomitantbacterial infectionsand, indeed,in such cases,manypatients seem to respondwell to empiricantibiotic therapy. Prospective studies have reported bac-teremia because of a diversity of organisms in 4.6–12% ofAfrican children with severe malaria [25–28], and, to asimilar extent, even in infants with uncomplicated malaria[29]. There is considerable evidence suggesting that conco-mitant bacterial infectionsmight also play a significant rolein mortality attributed to severe malaria, and that invasivebacterial infections could be an underappreciated cause ofdeath, with an up to threefold increase in mortality [28].Another major factor complicating therapy, particularly insub-SaharanAfrica, could be coinfectionwithHIV andHIV-associatedinfections.Otherstudies indicate that therecouldbeamajoroverlapbetweenmeningitisandseveremalaria inchildren with impaired consciousness and parasitemia [20].The authors conclude that finding malaria parasites in anunconscious child in sub-Saharan Africa is not sufficient toestablish a diagnosis of cerebral malaria, and that acutebacterial meningitis must be actively excluded. However,most health facilities inmalaria-endemic countries lack theresources for microbiological studies. Concomitant infec-tions in severe malaria are therefore easily missed even inrelatively well-equipped laboratories mainly because of: (i)the common practice of self-treatment with subtherapeuticdoses of antibiotics before seeking medical treatment; and(ii) the inherent challenges of conductingbacterial culture inmalaria-endemic regions.

Common causes of bacteremia in the tropics

Community-acquired bacteremia is a major cause of deathamong infants and children admitted to rural hospitals insub-Saharan Africa, reaching prevalences as high as 12.8%in some regions [30]. However, without adequate labora-tory support severe malaria is virtually indistinguishablefrom septicemia [26]. Among the most commonly identifiedorganisms causing invasive bacterial infections in Africanchildren are nontyphoidal Salmonella species, Staphylo-coccus aureus, Streptococcus pneumoniae, and Haemophi-lus influenzae B [25,26,31–33]. Moreover, the highprevalence rates of HIV in many African countries couldgreatly influence the spectrum of pathogens.

Antibiotics-based combinations for the parenteraltreatment of severe malaria?Antibiotics have been used empirically bymany physiciansto treat severe malaria patients with clinically evidentor suspected bacterial coinfections [34]. So far, co-admin-istration of antimalarial drugs with antibiotics in the

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treatment of severe malaria remains controversial, mainlybecause the true prevalence and importance of coinfectionsfor mortality in the malaria-endemic world remainsunknown [26]. However, perhaps antibiotics should notbe considered as a separate entity for treating coinfections,but rather as antimalarials that could improve antimalar-ial therapy while simultaneously covering numerouspathogens commonly encountered in coinfections or thatcause syndromes which are clinically indistinguishablefrom severe malaria. Combination therapy has becomethe ‘gold standard’ for treating uncomplicated falciparummalaria. Should we not at least consider a standardizedcombination therapy for the much smaller number ofsevere malaria cases?

Antibiotics with antimalarial activitySeveral classes of antibiotics are known to exert antima-larial activity [2]. Because many of these antibiotics arewell characterized, well tolerated and approved for humanuse, they provide an attractive alternative for the treat-ment of uncomplicated falciparum malaria and have beenincorporated into national treatment guidelines. The mostcommonly used combination therapy involving antibioticsis quinine combined with tetracycline or doxycycline, acombination that has been used extensively and (if com-pliance can be assured) with great success [6] as second-line therapy in several countries in Southeast Asia, an areawith a high prevalence of multidrug resistance in falci-parum malaria. Doxycycline has also been in use for pro-phylaxis as a single drug [35,36]. However, tetracyclinescannot be used in children and pregnancy, the populationsmost affected by severe malaria [37].

There is a limited armory of drugs in widespread use forfalciparum malaria with relatively few new developmentsin the past three decades [38]. Antibiotics, particularlyazithromycin, a relatively new macrolide antibiotic [39–

42], clindamycin, a lincosamide antibiotic [43], and mem-bers of the tetracycline group [6,44], have shown to behighly active and generally very well tolerated antimalar-ials (Box 1). However, owing to their slow clinical action

Box 1. Broad-spectrum antibiotics with clinically proven antimal

Azithromycin

� A relatively new macrolide antibiotic derived from erythromycin

� Broad antibacterial spectrum

� Antimalarial activity (IC50) in the low micromolar range [41,45]

� Additive interaction profile with dihydroartemisinin and quinine [41]

� Highly efficacious in the treatment of uncomplicated falciparum

malaria in combination with quinine [42] and artesunate [40]

� Parenteral formulation available

� Long half-life potentially permitting for reduced treatment dura-

tions (more data needed from IV studies)

� Safe in children and extensive experience in pregnancy [37,46]

Clindamycin

� A lincosamide antibiotic derived from lincomycin

� More narrow antibacterial spectrum than azithromycin

� Antimalarial activity (IC50) in the low micromolar range [49,45]

� Additive interaction profile with dihydroartemisinin [49]

� Highly efficacious in the treatment of uncomplicated falciparum

malaria in combination with quinine and artesunate [43]

542

resulting from a delayed death effect, most antibioticsshould not be used alone in the treatment of falciparummalaria, and should be combined with faster-acting anti-malarials such as artemisinins or quinine [45]. A majoradvantage of azithromycin and clindamycin over tetra-cyclines is the fact that there is extensive experience withtheir use in children and in pregnant women [46,2]. TheWHO now recommends the use of oral quinine plus clin-damycin in all trimesters of pregnancy and artesunate plusclindamycin during the second and third trimester. Withits relatively long half-life of almost three days (68 h) oralazithromycin combinations were shown to be highly effi-cacious when given at adequate doses even using three-dayregimens. Several newer antibiotics e.g. tigecycline arecurrently being evaluated for their antimalarial activityin vitro and could prove to be interesting additions to thelist of antibiotics with antimalarial activity [47]. Parent-eral formulations are available and registered and intra-venous administration would therefore not only bepossible, but could also overcome bioavailabilty issues inmalaria.

Benefits and caveatsAlthough available data are limited, parenteral antibioticswith antimalarial activity (when used in combination withestablished intravenous antimalarials) might have severaladvantages. ABC therapies might enhance treatment ef-ficacy while at the same time covering many organismsthat potentially cause coinfections or infections that couldbe misdiagnosed as severe malaria. Currently, in mostmalaria-endemic countries, a typical treatment for moder-ately severe malaria will comprise an initial IV (intrave-nous) antimalarial therapy, followed by oral treatment,which is typically administered in an outpatient setting.With an IV (intravenous) combination therapy, including alonger half-life antibiotic, the treatment course couldpotentially be reduced to an observed intravenous therapywithout (or at least with a shorter) oral follow-up treat-ment, thereby largely overcoming compliance issues com-monly associated with outpatient treatment. Future

arial activity

� Parenteral formulation available

� Experience with parenteral administration in severe malaria [34,43]

� Short half-life

� Safe and recommended for use in children and pregnancy [2]

Doxycycline (tetracycline)

� Member of the tetracycline antibiotics group

� Broad antibacterial spectrum (but widespread resistance). Covers

many agents causing febrile illnesses in the tropics.

� Antimalarial activity (IC50) in the low micromolar range [45,50]

� Potentially synergistic interaction profile with artemisinin [51]

� Highly efficacious in the treatment of uncomplicated falciparum

malaria in combination with quinine when given for 7 days and

when compliance can be assured [2,6]

� Parenteral formulation available

� Short half-life, generally given for 7 days with quinine to treat

uncomplicated falciparum malaria [42]

� Not considered safe in children <8 years and pregnancy, thereby

prohibiting its use in these populations, and limiting its usefulness

in ABCs [2,37]

Opinion Trends in Parasitology Vol.25 No.12

studies will have to determine the optimal treatmentduration as well as provide a cost benefit analysis of suchstrategies.

Of course, all of this comes with limitations and caveats.Although oral antibiotics have been used extensively in thetreatment of uncomplicated malaria, drug interactions arestill not fully understood, and could be different withparenterally administered drugs. Another potential issuecould be the development of antibiotic resistance. How-ever, the fact that IV therapy generally takes place in arelatively well-controlled environment (in which compli-ance plays only a secondary role, and in which patients arelikely to receive the full course of treatment) makes this farless probable to happenwhen compared to the treatment ofuncomplicated malaria. Another limitation could be thecost of intravenous combination therapy and of changingnational treatment policies, as well as the availability ofantibiotics and the antibacterial resistance situation inmany malaria-endemic countries [48]. However, as thenumber of malaria patients receiving IV therapy is rela-tively small when compared to the vast numbers ofpatients receiving oral therapy, the economic impact onmalaria control programs is probably rather limited whencompared to the cost of switching from monotherapy toACTs for the treatment of uncomplicatedmalaria. Anotherlimitation, which applies to most strategies to treatingsevere malaria, remains the fact that most cases of sus-pected malaria are self-diagnosed and most treatmentsand deaths occur at home [15].

Could ABCs be for severe malaria what ACTs havebecome for uncomplicated malaria?The true importance of bacterial coinfections formortality insevere malaria still remains to be determined, but there isevery indication that this might be an underestimatedproblem. This similarly applies to bacterial infections caus-ing syndromes that are clinically indistinguishable fromsevere malaria, although here there is a general agreementthat this is a major problem that needs to be addressed.Undoubtedly, the rationale for introducing ABCs would bevery different from the underlying principle of ACTs, as themainmotivation for introducingsomething likeABCswouldbe to save lives rather than to slow down the development ofresistance, as is the case for ACTs.

Could ABCs reduce mortality due to ‘severe malaria’?Assuming that the role of bacterial infections causingcoinfections in malaria and ‘severe malaria-like syn-dromes’ is probably far greater than previously anticip-ated, the answer is likely to be ‘yes.’ In this case, aprudently selected antibiotics-based combination therapyfor severe malaria cases could cover many of the mostcommon conditions misdiagnosed as severe malaria orfound as concomitant infections in malaria patients whileat the same time improving malaria treatment, andthereby potentially saving many lives.

PerspectivesThere might be good reasons to quickly introduce standar-dized ABCs in hospital settings where intravenousmalariatherapy is already available. However, current data on

antibiotics in malaria therapy are largely limited to oraltherapy. More data from clinical studies are needed tobetter understand the potential risks and benefits in termsof mortality benefit, improved parasite clearance, and ef-ficacy of combining intravenous antimalarials with broadspectrum antibiotics with antimalarial activity. The de-velopment of standardized (possibly even coformulated)intravenous ABCs could significantly facilitate the intro-duction of such a new treatment paradigm.

Conflict of interest statementI declare that I have no conflict of interest.

References1 World Health Organisation (2008) World Malaria Report 2008. WHO/

HTM/GMP/2008.1 (http://apps.who.int/malaria/wmr2008/malaria2008.pdf)

2 World Health Organisation (2006) WHO guidelines for the treatmentof malaria. WHO/HTM/MAL/2006.1108 (http://apps.who.int/malaria/docs/TreatmentGuidelines2006.pdf)

3 Dondorp, A. et al. (2005) Artesunate versus quinine for treatment ofsevere falciparum malaria: a randomised trial. Lancet 366, 717–725

4 Dondorp, A.M. and Day, N.P. (2007) The treatment of severe malaria.Trans. R. Soc. Trop. Med. 101, 633–634

5 Bloland, P.B. et al. (2000) Combination therapy for malaria in Africa:hype or hope? Bull. WHO 78, 1378–1388

6 Noedl, H. et al. (2008) Evidence of artemisinin-resistant malaria inwestern Cambodia. N. Engl. J. Med. 359, 2619–2620

7 Noedl, H. et al. (2009) Artemisinin-resistant malaria in Asia. N. Engl.J. Med. 361, 540–541

8 Noedl, H. (2005) Artemisinin resistance: how can we find it? TrendsParasitol. 21, 404–405

9 White, N.J. et al. (1999) Averting a malaria disaster. Lancet 353, 1965–

196710 International Artemisinin Study Group (2004) Artesunate

combinations for treatment of malaria: meta-analysis. Lancet 363,9–17

11 Carrara, V.I. et al. (2009) Changes in the treatment responses toartesunate-mefloquine on the northwestern border of Thailandduring 13 years of continuous deployment. PLoS One 4, e4551DOI:10.1371/journal.pone.0004551 (www.plosone.org)

12 Rogers, W.O. et al. (2009) Failure of artesunate-mefloquinecombination therapy for uncomplicated Plasmodium falciparummalaria in southern Cambodia. Malar. J. 8, 10

13 Peters, W. (1990) The prevention of antimalarial drug resistance.Pharmacol. Ther. 47, 499–508

14 White, N.J. (1998) Preventing antimalarial drug resistance throughcombinations. Drug Resist. Updat. 1, 3–9

15 Amexo, M. (2004) Malaria misdiagnosis: effects on the poor andvulnerable. Lancet 364, 1896–1898

16 Petti, C.A. et al. (2006) Laboratory medicine in Africa: a barrier toeffective health care. Clin. Infect. Dis.42 377–382

17 Reyburn, H. et al. (2004) Overdiagnosis of malaria in patients withsevere febrile illness in Tanzania: a prospective study. Br. Med. J. 329,1212

18 Gosling, R.D. et al. (2008) Presumptive treatment of fever cases asmalaria: help or hindrance for malaria control? Malar. J. 7, 132

19 Gwer, S. et al. (2007) Over-diagnosis and co-morbidity of severemalaria in African children: a guide for clinicians. Am. J. Trop.Med. Hyg. 77, 6–13

20 Berkley, J. et al. (1999) Cerebral malaria versus bacterial meningitis inchildren with impaired consciousness. QJM 92, 151–157

21 Hamer, D.H. et al. (2007) Improved diagnostic testing and malariatreatment practices in Zambia. JAMA 297, 2227–2231

22 Kallander, K. (2004) Symptom overlap for malaria and pneumonia–policy implications for home management strategies. Acta Trop. 90,211–214

23 O’Dempsey, T.J. (1993) Overlap in the clinical features of pneumoniaand malaria in African children. Trans. R. Soc. Trop. Med. Hyg. 87,662–665

543

Opinion Trends in Parasitology Vol.25 No.12

24 English, M. (1996) Clinical overlap between malaria and severepneumonia in Africa children in hospital. Trans. R. Soc. Trop. Med.Hyg. 90, 658–662

25 Evans, J.A. et al. (2004) High mortality of infant bacteraemia clinicallyindistinguishable from severe malaria. QJM. 97, 591–597

26 Bronzan, R.N. et al. (2007) Bacteremia in Malawian children withsevere malaria: prevalence, etiology, HIV coinfection, and outcome. J.Infect. Dis. 195, 895–904

27 Enwere, G. (1998) Bacteraemia in cerebral malaria. Ann. Trop.Paediatr. 18, 275–278

28 Berkley, J. et al. (1999) Bacteraemia complicating severe malaria inchildren. Trans. R. Soc. Trop. Med. Hyg. 93, 283–286

29 Ayoola, O.O. (2005) Concurrent bacteraemia and malaria in febrileNigerian infants. Trop. Doct. 35, 34–36

30 Berkley, J. et al. (2005) Bacteremia among children admitted to a ruralhospital in Kenya. N. Engl. J. Med. 352, 39–47

31 Kiratisin, P. (2008) Bacteraemia due to non-typhoidal Salmonella inThailand: clinical and microbiological analysis. Trans. R. Soc. Trop.Med. Hyg. 102, 384–388

32 Graham, S.M. (2000) Clinical presentation of non-typhoidalSalmonella bacteraemia in Malawian children. Trans. R. Soc. Trop.Med. Hyg. 94, 310–314

33 Kankwatira, A.M. (2004) Non-typhoidal salmonella bacteraemia – anunder-recognized feature of AIDS in African adults. Trop. Doct. 34,198–200

34 Losert, H. (2000) Experiences with severe P. falciparummalaria in theintensive care unit. Intensive Care Med. 26, 195–201

35 Petersen, P.E. (2004) Malaria chemoprophylaxis: when should we useit and what are the options? Expert Rev. Anti. Infect. Ther. 2, 119–132

36 Checkley, A.M. and Hill, D.R. (2007) Prevention of malaria in long-term travellers. Trends Parasitol. 23, 462–465

37 Lalloo, D.G. et al. (2007) UKmalaria treatment guidelines. J. Infect. 54,111–121

38 Winstanley, P.A. (2000) Chemotherapy for Falciparum Malaria: TheArmoury, the Problems and the Prospects. Parasitol. Today 16,146–153

39 Bunnag, D. et al. (1996) Quinine-tetracycline for multi-drug resistantfalciparum malaria. Southeast Asian J. Trop. Med. Public Health 27,15–18

544

40 Noedl, H. et al. (2006) Azithromycin combination therapy withartesunate or quinine for the treatment of uncomplicatedPlasmodium falciparum malaria in adults: a randomized, phase 2clinical trial in Thailand. Clin. Infect. Dis. 43, 1264–1271

41 Noedl, H. et al. (2007) In vitro antimalarial activity of azithromycin,artesunate, and quinine in combination and correlation with clinicaloutcome. Antimicrob. Agents Chemother. 51, 651–656

42 Miller, R.S. et al. (2006) Effective treatment of uncomplicatedPlasmodium falciparum malaria with azithromycin-quininecombinations: a randomized, dose-ranging study. Am. J. Trop. Med.Hyg. 74, 401–406

43 Lell, B. and Kremsner, P.G. (2002) Clindamycin as an antimalarialdrug: review of clinical trials.Antimicrob. Agents Chemother. 46, 2315–

232044 Taylor, W.R. et al. (2001) Chloroquine/doxycycline combination versus

chloroquine alone, and doxycycline alone for the treatment ofPlasmodium falciparum and Plasmodium vivax malaria innortheastern Irian Jaya, Indonesia.Am. J. Trop. Med. Hyg. 64, 223–228

45 Dahl, E.L. and Rosenthal, P.J. (2007) Multiple antibiotics exertdelayed effects against the Plasmodium falciparum apicoplast.Antimicrob. Agents Chemother. 51, 3485–3490

46 Sarkar, M. et al. (2006) Pregnancy outcome following gestationalexposure to azithromycin. BMC Pregnancy Childbirth 6, 18

47 Starzengruber P. et al. (2009) Antimalarial activity of tigecycline, anovel glycylcycline antibiotic. Antimicrob. Agents Chemother.DOI:10.1128/AAC.00312-09 (http://aac.asm.org/)

48 Mulligan, J.A. et al. (2006) The costs of changing national policy:lessons from malaria treatment policy guidelines in Tanzania. Trop.Med. Int. Health. 11, 452–461

49 Ramharter, M. (2003) In vitro activity and interaction of clindamycincombined with dihydroartemisinin against Plasmodium falciparum.Antimicrob. Agents Chemother. 47, 3494–3499

50 Pradines, B. (2006) Prevalence of in vitro resistance to eleven standardor new antimalarial drugs among Plasmodium falciparum isolatesfrom Pointe-Noire, Republic of the Congo. J. Clin. Microbiol. 44, 2404–

240851 Sponer, U. (2002) Pharmacodynamic interaction of doxycycline

and artemisinin in Plasmodium falciparum. Antimicrob. AgentsChemother. 46, 262–264