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ABC - antibiotics-based combinations for the treatment of severe malaria?
Opinion
ABC - antibiotics-based combinations for the treatment of severe malaria? Harald Noedl Medical University of Vienna, Kinderspitalgasse 15, A-1090 Vienna, Austria
Almost one million people die of severe malaria every year. In recent years, artemisinin-based combination therapies have become the backbone of the treatment of uncomplicated falciparum malaria and have helped to reduce the burden of malaria in large parts of the malaria-endemic world. However, the treatment of severe malaria, the clinical syndrome responsible for most malaria-associated deaths, remains largely unaffected by this development. Invasive bacterial infections and misdiagnosis of bacterial infections as severe malaria are well recognized phenomena, but recent data indicate that their prevalence and clinical importance might be far greater than previously anticipated. Therefore, there could be good reasons to routinely combine antimalarials, such as artemisinins or quinine, with broad spectrum antibiotics with antimalarial activity in standardized combination therapies for the parenteral treatment of severe falciparum malaria. Why severe malaria? According to the WHO World Malaria report 2008, there were an estimated 247 million malaria cases among 3.3 billion people at risk in 2006, causing nearly one million deaths, mostly in Africa [1]. Severe malaria is almost exclusively caused by Plasmodium falciparum and, in endemic countries, most commonly encountered in children below the age of five years. Infection with P. falciparum can result in a wide variety of symptoms, ranging from none at all, through mild disease, to severe disease and death. Complications in severe malaria are largely age-dependent and include cerebral malaria, severe anemia, pulmonary edema, and acute renal failure. With the mortality of untreated severe malaria approaching 100%, it is essential to achieve therapeutic concentrations of a fast-acting parenterally administered antimalarial as soon as possible. Even with antimalarial treatment, the mortality might be as high as 15–20% overall, although within the broad definition of severe malaria, individual syndromes are associated with mortality rates that could vary considerably. Current treatment of severe malaria Quinine has been the treatment of choice for falciparum malaria for hundreds of years. In recent years, artemisinins derivatives from Artemisia annua, have evolved as a highly effective alternative to quinine. The current recommendation for treating severe malaria patients in highCorresponding authors: Noedl, H. ([email protected]) URL: http://www.marib.org
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transmission areas is either intravenous quinine or an artemisinin derivative, whereas parenteral artesunate is now recommended by WHO as the drug of choice for the treatment of severe malaria in low-transmission settings [2]. Intramuscular injections of artemisinin derivatives and suppositories have proven to be extremely useful in resource-limited settings. In a multicenter clinical trial conducted in South and Southeast Asia, patients receiving artesunate intravenously had a 35% lower mortality than those receiving intravenous quinine [3,4]. Why combination therapy? Within just a few years, artemisinin-based combination therapy (ACT) has become the backbone of the treatment of uncomplicated falciparum malaria. Between 2005 and 2006, the number of doses of ACTs increased from six million to 49 million, of which 45 million were for African countries [1,5]. Although the first cases of genuine artemisinin resistance have recently emerged in a relatively small region along the Cambodia–Thailand border [6–8], in most parts of the world ACTs remain the most potent and fast-acting therapy for the treatment of uncomplicated falciparum malaria [9]. In spite of rising numbers of failures in some regions, the importance of ACTs today is only comparable to that of chloroquine in the mid 20th century [10–12]. Most ACTs combine a fast-acting, short half-life artemisinin compound with a slower acting partner drug with longer half-life, ideally with a synergistic interaction profile. The main concept behind using ACTs in the treatment of uncomplicated falciparum malaria has been to delay or
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. Severe malaria-like syndrome: symptom complex clinically indistinguishable from severe malaria potentially caused by a variety of different organisms.
1471-4922/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2009.09.001 Available online 12 October 2009
Opinion even prevent the development of drug resistance by combining two antimalarials with different modes of action, thereby drastically reducing the chances of selecting parasites simultaneously resistant to both drugs [13,14]. Why have ACTs not been used for the parenteral treatment of severe malaria? The main reason why combination therapies have never gained the attention in the treatment of severe malaria that they have gained in uncomplicated malaria is the fact that drug resistance development is not a major concern in the treatment of severe malaria. Why not? First, with most parenteral treatments taking place in a relatively wellcontrolled hospital or clinic environment, compliance and drug pressure are less of an issue. Second, the number of patients treated with intravenous drugs is considerably smaller. Third, the priority in treating severe malaria is to save the patient’s life and prevent sequelae and the development of drug resistance is therefore considered to be of secondary importance. Finally, relatively few of the new antimalarials used in ACTs are available as IV formulations. Why should antibiotics-based combination therapies be considered for severe malaria? Misdiagnosis Although, in theory, the diagnosis of malaria depends on microscopy or at least a positive rapid diagnostic test (RDT), in practice the most common means of diagnosing malaria remains presumptive diagnosis [15]. In resourcelimited health care systems, as typically encountered in malaria-endemic countries, adequate diagnosis can be a major challenge [16]. Also in high-prevalence regions, the presence of malaria parasites does not necessarily mean that the current clinical illness is because of malaria. Furthermore Malaria is commonly over-diagnosed and over-treated in people presenting with febrile illness, either because of clinical (mis)diagnosis or because of poor-quality microscopy [17,18]. This is associated with a failure to treat alternative causes of severe infection [19]. Quality laboratory testing would be crucial to confirm clinical diagnoses and to guide treatment policies [20], but the available laboratory and health care infrastructures are rarely sufficient to meet these needs. Frequently, even when available, adequate diagnostic facilities remain underused, and patients with negative test results get treated for malaria in the absence of an alternative diagnosis [21]. Unfortunately, the symptoms of malaria are notoriously nonspecific and a variety of febrile illnesses can mimic the clinical picture of severe malaria, most importantly septicemia, pneumonia, meningitis, typhoid fever, as well as numerous bacterial, parasitic, or viral diseases causing ‘severe malaria-like syndromes.’ In sub-Saharan Africa, malaria and pneumonia are the leading causes of child death and numerous authors conclude that community strategies need to address the malaria-pneumonia symptom overlap better by managing both conditions [22–24]. A prudently selected antibiotics-based combination (ABC) therapy for severe malaria cases could address many of the most common conditions that can be misdiagnosed as severe malaria, while at the same time treating malaria.
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Concomitant bacterial infections A situation commonly encountered by physicians treating confirmed falciparum malaria patients is that, in spite of adequate antimalarial treatment, the clinical condition of the patient might not improve and might even deteriorate. In parasitological terms, patients seem to respond well to the treatment, and even clear their parasites, although the clinical status of the patient might not improve. Another common finding is that the severity of disease in malaria is not correlated with the parasite burden, i.e. patients with low parasite densities can develop symptoms consistent with severe disease. A probable explanation for such scenarios is the presence of concomitant bacterial infections and, indeed, in such cases, many patients seem to respond well to empiric antibiotic therapy. Prospective studies have reported bacteremia because of a diversity of organisms in 4.6–12% of African children with severe malaria [25–28], and, to a similar extent, even in infants with uncomplicated malaria [29]. There is considerable evidence suggesting that concomitant bacterial infections might also play a significant role in mortality attributed to severe malaria, and that invasive bacterial infections could be an underappreciated cause of death, with an up to threefold increase in mortality [28]. Another major factor complicating therapy, particularly in sub-Saharan Africa, could be coinfection with HIV and HIVassociated infections. Other studies indicate that there could be a major overlap between meningitis and severe malaria in children with impaired consciousness and parasitemia [20]. The authors conclude that finding malaria parasites in an unconscious child in sub-Saharan Africa is not sufficient to establish a diagnosis of cerebral malaria, and that acute bacterial meningitis must be actively excluded. However, most health facilities in malaria-endemic countries lack the resources for microbiological studies. Concomitant infections in severe malaria are therefore easily missed even in relatively well-equipped laboratories mainly because of: (i) the common practice of self-treatment with subtherapeutic doses of antibiotics before seeking medical treatment; and (ii) the inherent challenges of conducting bacterial culture in malaria-endemic regions. Common causes of bacteremia in the tropics Community-acquired bacteremia is a major cause of death among infants and children admitted to rural hospitals in sub-Saharan Africa, reaching prevalences as high as 12.8% in some regions [30]. However, without adequate laboratory support severe malaria is virtually indistinguishable from septicemia [26]. Among the most commonly identified organisms causing invasive bacterial infections in African children are nontyphoidal Salmonella species, Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae B [25,26,31–33]. Moreover, the high prevalence rates of HIV in many African countries could greatly influence the spectrum of pathogens. Antibiotics-based combinations for the parenteral treatment of severe malaria? Antibiotics have been used empirically by many physicians to treat severe malaria patients with clinically evident or suspected bacterial coinfections [34]. So far, co-administration of antimalarial drugs with antibiotics in the 541
Opinion treatment of severe malaria remains controversial, mainly because the true prevalence and importance of coinfections for mortality in the malaria-endemic world remains unknown [26]. However, perhaps antibiotics should not be considered as a separate entity for treating coinfections, but rather as antimalarials that could improve antimalarial therapy while simultaneously covering numerous pathogens commonly encountered in coinfections or that cause syndromes which are clinically indistinguishable from severe malaria. Combination therapy has become the ‘gold standard’ for treating uncomplicated falciparum malaria. Should we not at least consider a standardized combination therapy for the much smaller number of severe malaria cases? Antibiotics with antimalarial activity Several classes of antibiotics are known to exert antimalarial activity [2]. Because many of these antibiotics are well characterized, well tolerated and approved for human use, they provide an attractive alternative for the treatment of uncomplicated falciparum malaria and have been incorporated into national treatment guidelines. The most commonly used combination therapy involving antibiotics is quinine combined with tetracycline or doxycycline, a combination that has been used extensively and (if compliance can be assured) with great success [6] as secondline therapy in several countries in Southeast Asia, an area with a high prevalence of multidrug resistance in falciparum malaria. Doxycycline has also been in use for prophylaxis as a single drug [35,36]. However, tetracyclines cannot be used in children and pregnancy, the populations most affected by severe malaria [37]. There is a limited armory of drugs in widespread use for falciparum malaria with relatively few new developments in the past three decades [38]. Antibiotics, particularly azithromycin, a relatively new macrolide antibiotic [39– 42], clindamycin, a lincosamide antibiotic [43], and members of the tetracycline group [6,44], have shown to be highly active and generally very well tolerated antimalarials (Box 1). However, owing to their slow clinical action
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resulting from a delayed death effect, most antibiotics should not be used alone in the treatment of falciparum malaria, and should be combined with faster-acting antimalarials such as artemisinins or quinine [45]. A major advantage of azithromycin and clindamycin over tetracyclines is the fact that there is extensive experience with their use in children and in pregnant women [46,2]. The WHO now recommends the use of oral quinine plus clindamycin in all trimesters of pregnancy and artesunate plus clindamycin during the second and third trimester. With its relatively long half-life of almost three days (68 h) oral azithromycin combinations were shown to be highly efficacious when given at adequate doses even using three-day regimens. Several newer antibiotics e.g. tigecycline are currently being evaluated for their antimalarial activity in vitro and could prove to be interesting additions to the list of antibiotics with antimalarial activity [47]. Parenteral formulations are available and registered and intravenous administration would therefore not only be possible, but could also overcome bioavailabilty issues in malaria. Benefits and caveats Although available data are limited, parenteral antibiotics with antimalarial activity (when used in combination with established intravenous antimalarials) might have several advantages. ABC therapies might enhance treatment efficacy while at the same time covering many organisms that potentially cause coinfections or infections that could be misdiagnosed as severe malaria. Currently, in most malaria-endemic countries, a typical treatment for moderately severe malaria will comprise an initial IV (intravenous) antimalarial therapy, followed by oral treatment, which is typically administered in an outpatient setting. With an IV (intravenous) combination therapy, including a longer half-life antibiotic, the treatment course could potentially be reduced to an observed intravenous therapy without (or at least with a shorter) oral follow-up treatment, thereby largely overcoming compliance issues commonly associated with outpatient treatment. Future
Box 1. Broad-spectrum antibiotics with clinically proven antimalarial activity 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 durations (more data needed from IV studies) Safe in children and extensive experience in pregnancy [37,46] Clindamycin
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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]
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 studies will have to determine the optimal treatment duration as well as provide a cost benefit analysis of such strategies. Of course, all of this comes with limitations and caveats. Although oral antibiotics have been used extensively in the treatment of uncomplicated malaria, drug interactions are still not fully understood, and could be different with parenterally administered drugs. Another potential issue could be the development of antibiotic resistance. However, the fact that IV therapy generally takes place in a relatively well-controlled environment (in which compliance plays only a secondary role, and in which patients are likely to receive the full course of treatment) makes this far less probable to happen when compared to the treatment of uncomplicated malaria. Another limitation could be the cost of intravenous combination therapy and of changing national treatment policies, as well as the availability of antibiotics and the antibacterial resistance situation in many malaria-endemic countries [48]. However, as the number of malaria patients receiving IV therapy is relatively small when compared to the vast numbers of patients receiving oral therapy, the economic impact on malaria control programs is probably rather limited when compared to the cost of switching from monotherapy to ACTs for the treatment of uncomplicated malaria. Another limitation, which applies to most strategies to treating severe malaria, remains the fact that most cases of suspected malaria are self-diagnosed and most treatments and deaths occur at home [15]. Could ABCs be for severe malaria what ACTs have become for uncomplicated malaria? The true importance of bacterial coinfections for mortality in severe malaria still remains to be determined, but there is every indication that this might be an underestimated problem. This similarly applies to bacterial infections causing syndromes that are clinically indistinguishable from severe malaria, although here there is a general agreement that this is a major problem that needs to be addressed. Undoubtedly, the rationale for introducing ABCs would be very different from the underlying principle of ACTs, as the main motivation for introducing something like ABCs would be to save lives rather than to slow down the development of resistance, as is the case for ACTs. Could ABCs reduce mortality due to ‘severe malaria’? Assuming that the role of bacterial infections causing coinfections in malaria and ‘severe malaria-like syndromes’ is probably far greater than previously anticipated, the answer is likely to be ‘yes.’ In this case, a prudently selected antibiotics-based combination therapy for severe malaria cases could cover many of the most common conditions misdiagnosed as severe malaria or found as concomitant infections in malaria patients while at the same time improving malaria treatment, and thereby potentially saving many lives. Perspectives There might be good reasons to quickly introduce standardized ABCs in hospital settings where intravenous malaria therapy is already available. However, current data on
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antibiotics in malaria therapy are largely limited to oral therapy. More data from clinical studies are needed to better understand the potential risks and benefits in terms of mortality benefit, improved parasite clearance, and efficacy of combining intravenous antimalarials with broad spectrum antibiotics with antimalarial activity. The development of standardized (possibly even coformulated) intravenous ABCs could significantly facilitate the introduction of such a new treatment paradigm. Conflict of interest statement I declare that I have no conflict of interest. References 1 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 treatment of 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 of severe 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 in western 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? Trends Parasitol. 21, 404–405 9 White, N.J. et al. (1999) Averting a malaria disaster. Lancet 353, 1965– 1967 10 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 to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment. PLoS One 4, e4551 DOI:10.1371/journal.pone.0004551 (www.plosone.org) 12 Rogers, W.O. et al. (2009) Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria 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 through combinations. Drug Resist. Updat. 1, 3–9 15 Amexo, M. (2004) Malaria misdiagnosis: effects on the poor and vulnerable. Lancet 364, 1896–1898 16 Petti, C.A. et al. (2006) Laboratory medicine in Africa: a barrier to effective health care. Clin. Infect. Dis.42 377–382 17 Reyburn, H. et al. (2004) Overdiagnosis of malaria in patients with severe febrile illness in Tanzania: a prospective study. Br. Med. J. 329, 1212 18 Gosling, R.D. et al. (2008) Presumptive treatment of fever cases as malaria: help or hindrance for malaria control? Malar. J. 7, 132 19 Gwer, S. et al. (2007) Over-diagnosis and co-morbidity of severe malaria 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 in children with impaired consciousness. QJM 92, 151–157 21 Hamer, D.H. et al. (2007) Improved diagnostic testing and malaria treatment practices in Zambia. JAMA 297, 2227–2231 22 Ka¨llander, 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 pneumonia and malaria in African children. Trans. R. Soc. Trop. Med. Hyg. 87, 662–665 543
Opinion 24 English, M. (1996) Clinical overlap between malaria and severe pneumonia 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 clinically indistinguishable from severe malaria. QJM. 97, 591–597 26 Bronzan, R.N. et al. (2007) Bacteremia in Malawian children with severe 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 in children. Trans. R. Soc. Trop. Med. Hyg. 93, 283–286 29 Ayoola, O.O. (2005) Concurrent bacteraemia and malaria in febrile Nigerian infants. Trop. Doct. 35, 34–36 30 Berkley, J. et al. (2005) Bacteremia among children admitted to a rural hospital in Kenya. N. Engl. J. Med. 352, 39–47 31 Kiratisin, P. (2008) Bacteraemia due to non-typhoidal Salmonella in Thailand: clinical and microbiological analysis. Trans. R. Soc. Trop. Med. Hyg. 102, 384–388 32 Graham, S.M. (2000) Clinical presentation of non-typhoidal Salmonella bacteraemia in Malawian children. Trans. R. Soc. Trop. Med. Hyg. 94, 310–314 33 Kankwatira, A.M. (2004) Non-typhoidal salmonella bacteraemia – an under-recognized feature of AIDS in African adults. Trop. Doct. 34, 198–200 34 Losert, H. (2000) Experiences with severe P. falciparum malaria in the intensive care unit. Intensive Care Med. 26, 195–201 35 Petersen, P.E. (2004) Malaria chemoprophylaxis: when should we use it 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 longterm travellers. Trends Parasitol. 23, 462–465 37 Lalloo, D.G. et al. (2007) UK malaria treatment guidelines. J. Infect. 54, 111–121 38 Winstanley, P.A. (2000) Chemotherapy for Falciparum Malaria: The Armoury, the Problems and the Prospects. Parasitol. Today 16, 146–153 39 Bunnag, D. et al. (1996) Quinine-tetracycline for multi-drug resistant falciparum malaria. Southeast Asian J. Trop. Med. Public Health 27, 15–18
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ABC - antibiotics-based combinations for the treatment of severe malaria? Harald Noedl Medical University of Vienna, Kinderspitalgasse 15, A-1090 Vienna, Austria
Almost one million people die of severe malaria every year. In recent years, artemisinin-based combination therapies have become the backbone of the treatment of uncomplicated falciparum malaria and have helped to reduce the burden of malaria in large parts of the malaria-endemic world. However, the treatment of severe malaria, the clinical syndrome responsible for most malaria-associated deaths, remains largely unaffected by this development. Invasive bacterial infections and misdiagnosis of bacterial infections as severe malaria are well recognized phenomena, but recent data indicate that their prevalence and clinical importance might be far greater than previously anticipated. Therefore, there could be good reasons to routinely combine antimalarials, such as artemisinins or quinine, with broad spectrum antibiotics with antimalarial activity in standardized combination therapies for the parenteral treatment of severe falciparum malaria. Why severe malaria? According to the WHO World Malaria report 2008, there were an estimated 247 million malaria cases among 3.3 billion people at risk in 2006, causing nearly one million deaths, mostly in Africa [1]. Severe malaria is almost exclusively caused by Plasmodium falciparum and, in endemic countries, most commonly encountered in children below the age of five years. Infection with P. falciparum can result in a wide variety of symptoms, ranging from none at all, through mild disease, to severe disease and death. Complications in severe malaria are largely age-dependent and include cerebral malaria, severe anemia, pulmonary edema, and acute renal failure. With the mortality of untreated severe malaria approaching 100%, it is essential to achieve therapeutic concentrations of a fast-acting parenterally administered antimalarial as soon as possible. Even with antimalarial treatment, the mortality might be as high as 15–20% overall, although within the broad definition of severe malaria, individual syndromes are associated with mortality rates that could vary considerably. Current treatment of severe malaria Quinine has been the treatment of choice for falciparum malaria for hundreds of years. In recent years, artemisinins derivatives from Artemisia annua, have evolved as a highly effective alternative to quinine. The current recommendation for treating severe malaria patients in highCorresponding authors: Noedl, H. ([email protected]) URL: http://www.marib.org
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transmission areas is either intravenous quinine or an artemisinin derivative, whereas parenteral artesunate is now recommended by WHO as the drug of choice for the treatment of severe malaria in low-transmission settings [2]. Intramuscular injections of artemisinin derivatives and suppositories have proven to be extremely useful in resource-limited settings. In a multicenter clinical trial conducted in South and Southeast Asia, patients receiving artesunate intravenously had a 35% lower mortality than those receiving intravenous quinine [3,4]. Why combination therapy? Within just a few years, artemisinin-based combination therapy (ACT) has become the backbone of the treatment of uncomplicated falciparum malaria. Between 2005 and 2006, the number of doses of ACTs increased from six million to 49 million, of which 45 million were for African countries [1,5]. Although the first cases of genuine artemisinin resistance have recently emerged in a relatively small region along the Cambodia–Thailand border [6–8], in most parts of the world ACTs remain the most potent and fast-acting therapy for the treatment of uncomplicated falciparum malaria [9]. In spite of rising numbers of failures in some regions, the importance of ACTs today is only comparable to that of chloroquine in the mid 20th century [10–12]. Most ACTs combine a fast-acting, short half-life artemisinin compound with a slower acting partner drug with longer half-life, ideally with a synergistic interaction profile. The main concept behind using ACTs in the treatment of uncomplicated falciparum malaria has been to delay or
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. Severe malaria-like syndrome: symptom complex clinically indistinguishable from severe malaria potentially caused by a variety of different organisms.
1471-4922/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2009.09.001 Available online 12 October 2009
Opinion even prevent the development of drug resistance by combining two antimalarials with different modes of action, thereby drastically reducing the chances of selecting parasites simultaneously resistant to both drugs [13,14]. Why have ACTs not been used for the parenteral treatment of severe malaria? The main reason why combination therapies have never gained the attention in the treatment of severe malaria that they have gained in uncomplicated malaria is the fact that drug resistance development is not a major concern in the treatment of severe malaria. Why not? First, with most parenteral treatments taking place in a relatively wellcontrolled hospital or clinic environment, compliance and drug pressure are less of an issue. Second, the number of patients treated with intravenous drugs is considerably smaller. Third, the priority in treating severe malaria is to save the patient’s life and prevent sequelae and the development of drug resistance is therefore considered to be of secondary importance. Finally, relatively few of the new antimalarials used in ACTs are available as IV formulations. Why should antibiotics-based combination therapies be considered for severe malaria? Misdiagnosis Although, in theory, the diagnosis of malaria depends on microscopy or at least a positive rapid diagnostic test (RDT), in practice the most common means of diagnosing malaria remains presumptive diagnosis [15]. In resourcelimited health care systems, as typically encountered in malaria-endemic countries, adequate diagnosis can be a major challenge [16]. Also in high-prevalence regions, the presence of malaria parasites does not necessarily mean that the current clinical illness is because of malaria. Furthermore Malaria is commonly over-diagnosed and over-treated in people presenting with febrile illness, either because of clinical (mis)diagnosis or because of poor-quality microscopy [17,18]. This is associated with a failure to treat alternative causes of severe infection [19]. Quality laboratory testing would be crucial to confirm clinical diagnoses and to guide treatment policies [20], but the available laboratory and health care infrastructures are rarely sufficient to meet these needs. Frequently, even when available, adequate diagnostic facilities remain underused, and patients with negative test results get treated for malaria in the absence of an alternative diagnosis [21]. Unfortunately, the symptoms of malaria are notoriously nonspecific and a variety of febrile illnesses can mimic the clinical picture of severe malaria, most importantly septicemia, pneumonia, meningitis, typhoid fever, as well as numerous bacterial, parasitic, or viral diseases causing ‘severe malaria-like syndromes.’ In sub-Saharan Africa, malaria and pneumonia are the leading causes of child death and numerous authors conclude that community strategies need to address the malaria-pneumonia symptom overlap better by managing both conditions [22–24]. A prudently selected antibiotics-based combination (ABC) therapy for severe malaria cases could address many of the most common conditions that can be misdiagnosed as severe malaria, while at the same time treating malaria.
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Concomitant bacterial infections A situation commonly encountered by physicians treating confirmed falciparum malaria patients is that, in spite of adequate antimalarial treatment, the clinical condition of the patient might not improve and might even deteriorate. In parasitological terms, patients seem to respond well to the treatment, and even clear their parasites, although the clinical status of the patient might not improve. Another common finding is that the severity of disease in malaria is not correlated with the parasite burden, i.e. patients with low parasite densities can develop symptoms consistent with severe disease. A probable explanation for such scenarios is the presence of concomitant bacterial infections and, indeed, in such cases, many patients seem to respond well to empiric antibiotic therapy. Prospective studies have reported bacteremia because of a diversity of organisms in 4.6–12% of African children with severe malaria [25–28], and, to a similar extent, even in infants with uncomplicated malaria [29]. There is considerable evidence suggesting that concomitant bacterial infections might also play a significant role in mortality attributed to severe malaria, and that invasive bacterial infections could be an underappreciated cause of death, with an up to threefold increase in mortality [28]. Another major factor complicating therapy, particularly in sub-Saharan Africa, could be coinfection with HIV and HIVassociated infections. Other studies indicate that there could be a major overlap between meningitis and severe malaria in children with impaired consciousness and parasitemia [20]. The authors conclude that finding malaria parasites in an unconscious child in sub-Saharan Africa is not sufficient to establish a diagnosis of cerebral malaria, and that acute bacterial meningitis must be actively excluded. However, most health facilities in malaria-endemic countries lack the resources for microbiological studies. Concomitant infections in severe malaria are therefore easily missed even in relatively well-equipped laboratories mainly because of: (i) the common practice of self-treatment with subtherapeutic doses of antibiotics before seeking medical treatment; and (ii) the inherent challenges of conducting bacterial culture in malaria-endemic regions. Common causes of bacteremia in the tropics Community-acquired bacteremia is a major cause of death among infants and children admitted to rural hospitals in sub-Saharan Africa, reaching prevalences as high as 12.8% in some regions [30]. However, without adequate laboratory support severe malaria is virtually indistinguishable from septicemia [26]. Among the most commonly identified organisms causing invasive bacterial infections in African children are nontyphoidal Salmonella species, Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae B [25,26,31–33]. Moreover, the high prevalence rates of HIV in many African countries could greatly influence the spectrum of pathogens. Antibiotics-based combinations for the parenteral treatment of severe malaria? Antibiotics have been used empirically by many physicians to treat severe malaria patients with clinically evident or suspected bacterial coinfections [34]. So far, co-administration of antimalarial drugs with antibiotics in the 541
Opinion treatment of severe malaria remains controversial, mainly because the true prevalence and importance of coinfections for mortality in the malaria-endemic world remains unknown [26]. However, perhaps antibiotics should not be considered as a separate entity for treating coinfections, but rather as antimalarials that could improve antimalarial therapy while simultaneously covering numerous pathogens commonly encountered in coinfections or that cause syndromes which are clinically indistinguishable from severe malaria. Combination therapy has become the ‘gold standard’ for treating uncomplicated falciparum malaria. Should we not at least consider a standardized combination therapy for the much smaller number of severe malaria cases? Antibiotics with antimalarial activity Several classes of antibiotics are known to exert antimalarial activity [2]. Because many of these antibiotics are well characterized, well tolerated and approved for human use, they provide an attractive alternative for the treatment of uncomplicated falciparum malaria and have been incorporated into national treatment guidelines. The most commonly used combination therapy involving antibiotics is quinine combined with tetracycline or doxycycline, a combination that has been used extensively and (if compliance can be assured) with great success [6] as secondline therapy in several countries in Southeast Asia, an area with a high prevalence of multidrug resistance in falciparum malaria. Doxycycline has also been in use for prophylaxis as a single drug [35,36]. However, tetracyclines cannot be used in children and pregnancy, the populations most affected by severe malaria [37]. There is a limited armory of drugs in widespread use for falciparum malaria with relatively few new developments in the past three decades [38]. Antibiotics, particularly azithromycin, a relatively new macrolide antibiotic [39– 42], clindamycin, a lincosamide antibiotic [43], and members of the tetracycline group [6,44], have shown to be highly active and generally very well tolerated antimalarials (Box 1). However, owing to their slow clinical action
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resulting from a delayed death effect, most antibiotics should not be used alone in the treatment of falciparum malaria, and should be combined with faster-acting antimalarials such as artemisinins or quinine [45]. A major advantage of azithromycin and clindamycin over tetracyclines is the fact that there is extensive experience with their use in children and in pregnant women [46,2]. The WHO now recommends the use of oral quinine plus clindamycin in all trimesters of pregnancy and artesunate plus clindamycin during the second and third trimester. With its relatively long half-life of almost three days (68 h) oral azithromycin combinations were shown to be highly efficacious when given at adequate doses even using three-day regimens. Several newer antibiotics e.g. tigecycline are currently being evaluated for their antimalarial activity in vitro and could prove to be interesting additions to the list of antibiotics with antimalarial activity [47]. Parenteral formulations are available and registered and intravenous administration would therefore not only be possible, but could also overcome bioavailabilty issues in malaria. Benefits and caveats Although available data are limited, parenteral antibiotics with antimalarial activity (when used in combination with established intravenous antimalarials) might have several advantages. ABC therapies might enhance treatment efficacy while at the same time covering many organisms that potentially cause coinfections or infections that could be misdiagnosed as severe malaria. Currently, in most malaria-endemic countries, a typical treatment for moderately severe malaria will comprise an initial IV (intravenous) antimalarial therapy, followed by oral treatment, which is typically administered in an outpatient setting. With an IV (intravenous) combination therapy, including a longer half-life antibiotic, the treatment course could potentially be reduced to an observed intravenous therapy without (or at least with a shorter) oral follow-up treatment, thereby largely overcoming compliance issues commonly associated with outpatient treatment. Future
Box 1. Broad-spectrum antibiotics with clinically proven antimalarial activity 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 durations (more data needed from IV studies) Safe in children and extensive experience in pregnancy [37,46] Clindamycin
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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]
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 studies will have to determine the optimal treatment duration as well as provide a cost benefit analysis of such strategies. Of course, all of this comes with limitations and caveats. Although oral antibiotics have been used extensively in the treatment of uncomplicated malaria, drug interactions are still not fully understood, and could be different with parenterally administered drugs. Another potential issue could be the development of antibiotic resistance. However, the fact that IV therapy generally takes place in a relatively well-controlled environment (in which compliance plays only a secondary role, and in which patients are likely to receive the full course of treatment) makes this far less probable to happen when compared to the treatment of uncomplicated malaria. Another limitation could be the cost of intravenous combination therapy and of changing national treatment policies, as well as the availability of antibiotics and the antibacterial resistance situation in many malaria-endemic countries [48]. However, as the number of malaria patients receiving IV therapy is relatively small when compared to the vast numbers of patients receiving oral therapy, the economic impact on malaria control programs is probably rather limited when compared to the cost of switching from monotherapy to ACTs for the treatment of uncomplicated malaria. Another limitation, which applies to most strategies to treating severe malaria, remains the fact that most cases of suspected malaria are self-diagnosed and most treatments and deaths occur at home [15]. Could ABCs be for severe malaria what ACTs have become for uncomplicated malaria? The true importance of bacterial coinfections for mortality in severe malaria still remains to be determined, but there is every indication that this might be an underestimated problem. This similarly applies to bacterial infections causing syndromes that are clinically indistinguishable from severe malaria, although here there is a general agreement that this is a major problem that needs to be addressed. Undoubtedly, the rationale for introducing ABCs would be very different from the underlying principle of ACTs, as the main motivation for introducing something like ABCs would be to save lives rather than to slow down the development of resistance, as is the case for ACTs. Could ABCs reduce mortality due to ‘severe malaria’? Assuming that the role of bacterial infections causing coinfections in malaria and ‘severe malaria-like syndromes’ is probably far greater than previously anticipated, the answer is likely to be ‘yes.’ In this case, a prudently selected antibiotics-based combination therapy for severe malaria cases could cover many of the most common conditions misdiagnosed as severe malaria or found as concomitant infections in malaria patients while at the same time improving malaria treatment, and thereby potentially saving many lives. Perspectives There might be good reasons to quickly introduce standardized ABCs in hospital settings where intravenous malaria therapy is already available. However, current data on
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antibiotics in malaria therapy are largely limited to oral therapy. More data from clinical studies are needed to better understand the potential risks and benefits in terms of mortality benefit, improved parasite clearance, and efficacy of combining intravenous antimalarials with broad spectrum antibiotics with antimalarial activity. The development of standardized (possibly even coformulated) intravenous ABCs could significantly facilitate the introduction of such a new treatment paradigm. Conflict of interest statement I declare that I have no conflict of interest. References 1 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 treatment of 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 of severe 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 in western 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? Trends Parasitol. 21, 404–405 9 White, N.J. et al. (1999) Averting a malaria disaster. Lancet 353, 1965– 1967 10 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 to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment. PLoS One 4, e4551 DOI:10.1371/journal.pone.0004551 (www.plosone.org) 12 Rogers, W.O. et al. (2009) Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria 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 through combinations. Drug Resist. Updat. 1, 3–9 15 Amexo, M. (2004) Malaria misdiagnosis: effects on the poor and vulnerable. Lancet 364, 1896–1898 16 Petti, C.A. et al. (2006) Laboratory medicine in Africa: a barrier to effective health care. Clin. Infect. Dis.42 377–382 17 Reyburn, H. et al. (2004) Overdiagnosis of malaria in patients with severe febrile illness in Tanzania: a prospective study. Br. Med. J. 329, 1212 18 Gosling, R.D. et al. (2008) Presumptive treatment of fever cases as malaria: help or hindrance for malaria control? Malar. J. 7, 132 19 Gwer, S. et al. (2007) Over-diagnosis and co-morbidity of severe malaria 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 in children with impaired consciousness. QJM 92, 151–157 21 Hamer, D.H. et al. (2007) Improved diagnostic testing and malaria treatment practices in Zambia. JAMA 297, 2227–2231 22 Ka¨llander, 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 pneumonia and malaria in African children. Trans. R. Soc. Trop. Med. Hyg. 87, 662–665 543
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