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Antimicrobial Agents and Chemotherapy, May 2009, p. 1753-1759, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01723-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Reduced Efficacy of Intermittent Preventive Treatment of Malaria in Malnourished Children{triangledown}

Ina Danquah,1 Ekkehart Dietz,2 Philipp Zanger,3 Klaus Reither,4 Peter Ziniel,5 Ulrich Bienzle,1,{dagger} and Frank P. Mockenhaupt1*

Institute of Tropical Medicine and International Health, Charité University Medicine, Berlin, Germany,1 Institute of Biometry and Clinical Epidemiology, Charité University Medicine, Berlin, Germany,2 Institute of Tropical Medicine, University of Tuebingen, Tuebingen, Germany,3 Department of Infectious Diseases and Tropical Medicine, University of Munich, Munich, Germany,4 Northern Region Malaria Project, Tamale, Ghana5

Received 30 December 2008/ Returned for modification 25 January 2009/ Accepted 7 February 2009


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ABSTRACT
 
Intermittent preventive treatment in infants with sulfadoxine-pyrimethamine (IPTi-SP) reduces malaria episodes by 20 to 59% across Africa. This protective efficacy, however, may be affected by the high frequency of malnutrition in African infants. We analyzed the impact of malnutrition as defined by anthropometry on the incidence of malaria and on the protective efficacy of IPTi in a cohort of 1,200 children in northern Ghana, where malaria is hyperendemic. These children received IPTi-SP or placebo at 3, 9, and 15 months of age and were monitored until 24 months of age. Malnutrition was present in 32, 40, and 50% of children at ages 3, 9, and 15 months, respectively. It was associated with increased risks of severe anemia and death but not an increased risk of malaria. Although malaria slightly contributed to chronic malnutrition, IPTi did not substantially improve child growth. Importantly, the protective efficacies of IPTi in malnourished children were roughly half or even less of those observed in nonmalnourished children. In the first year of life, IPTi reduced the incidence of malaria to a significantly lesser extent in infants who received both doses in a malnourished condition (25%; 95% confidence interval [CI], –7 to 48%) compared to that of nonmalnourished children (46%; 95% CI, 30 to 58%; P = 0.049). Moreover, in contrast to nutritionally advantaged children, the rate of severe malaria appeared to be increased in malnourished children who took IPTi. IPTi might exhibit reduced efficacy in regions of abundant malnutrition. Concomitant nutrition programs may be needed in these places to achieve the desired impact.


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INTRODUCTION
 
Intermittent preventive treatment in infants (IPTi) with sulfadoxine-pyrimethamine (SP) appears to be a promising tool of malaria control in young children. The initial IPTi trial in Tanzania reported a protective efficacy (PE) against uncomplicated malaria in infancy of 59% and some degree of protection persisting into the second year of life (28, 29). In subsequent studies at sites of differing endemicity in sub-Saharan Africa, protection in infancy was confirmed; however, the PEs were lower, at 20 to 33% (5, 12, 15, 17, 23). We have reported previously that in Tamale, northern Ghana, IPTi reduced the incidence of asymptomatic parasitemia, uncomplicated malaria, and severe anemia from 3 to 24 months of age by 29, 17, and 15%, respectively. These effects were greatest in the first year of life and less pronounced in the second (23).

As in many regions of Africa, malnutrition is abundant in northern Ghana, reaching prevalences as high as 50% in preschool children, depending on seasonality and food availability (32 and http://www.who.int/nutgrowthdb/database/countries/nchs_reference/gha.pdf). Malnutrition causes relative immunosuppression, and repeated or chronic infections may contribute to poor nutritional status (27). However, the effect of malnutrition on malaria is less clear cut than would be expected: protein-energy malnutrition has been associated with greater malaria morbidity and mortality in some areas but not in others (4, 6, 8, 21, 24, 30). Moreover, the risk of antimalarial treatment failure appears to be increased in malnourished children (13, 14, 22, 39). Taken together, these findings suggest that malnutrition is one factor contributing to malaria-associated morbidity and that malaria control strategies without concomitant nutrition programs may not have the desired impact on childhood morbidity on a large scale (8). We hypothesized that malnutrition affects both malaria morbidity and IPTi efficacy. Alternatively, IPTi might improve children's growth and nutritional status. We reanalyzed data from a cohort from northern Ghana (23) regarding the effect of malnutrition on the PE of IPTi, and here we report the results of this secondary analysis.


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MATERIALS AND METHODS
 
Study site and IPTi trial. The IPTi trial was conducted between March 2003 and July 2005 at Bulpeila Health Centre, located in a semiurban outskirt of Tamale, northern Ghana. Despite a population of 350,000, the town is of rural character and spread over a vast area. Subsistence farming and small-scale trade are the main income sources. Climate and vegetation are of the savanna type, with rains from May to October. Malaria in the region is hyperendemic, with modest seasonal variation; underweight and stunting each affect approximately one out of four children (8). At the time the study was carried out, bed net usage was low (3%), and malaria control basically consisted of chloroquine treatment, which achieved cure rates of <50% (22).

The study was a randomized, double-blind, placebo-controlled trial on the efficacy of SP given alongside the Expanded Program on Immunization (EPI) (http://clinicaltrials.gov; NCT00168948). Informed written consent was obtained from the participants' parent(s). The study protocol was approved by the Ethics Committee, University for Development Studies, Tamale, Ghana. Details have been described elsewhere (23). In brief, a total of 1,200 children received half a tablet of SP (dosage ratio, 125 mg S per kg of body weight/6.25 mg P per kg of body weight; Fansidar; Roche, Basel, Switzerland) or placebo at 3, 9, and 15 months of age and were monitored at 6, 12, 18, 21, and 24 months of age. For passive case detection, parents were instructed to bring their children to the health center in case of any health problem. A civil conflict involving changing curfews (until August 2004) occasionally impeded children from attending the health center or hospital in the late afternoon. At scheduled visits, children were clinically examined, a medical history was obtained, and a venous blood sample was collected. Blood samples also were collected at unscheduled visits in case of fever (axillary temperature, ≥37.5°C), a history of fever, or when requested by the clinician. Asexual malaria parasites were counted against 500 white blood cells on Giemsa-stained thick blood films, and hemoglobin (Hb) was measured (HemoCue, Ångelholm, Sweden). Malaria was defined as parasitemia of any density plus fever or a voluntarily reported history of fever within the preceding 48 h, severe anemia was defined as an Hb level of <7 g/dl (31), and severe malaria was defined according to WHO criteria (37). Malaria was treated under observation with artesunate (Plasmotrim; Mepha, Switzerland) at a dose of 4 mg/kg (with a double dose on first day) for 5 days. Other diseases were treated according to Ghana Health Service guidelines (10).

Measures of malnutrition. At each regular visit, weight and length/height were measured and related to age and sex. Malnutrition was defined by these anthropometric parameters according to the WHO 2006 standard reference data (WHO Anthro software, version 2.0.2.) (38). A weight-for-age z-score (waz) of ≤2 standard deviations (SD) characterized underweight, indicating general malnutrition. Likewise, for weight-for-height (whz) and height-for-age z-scores (haz), ≤2 SD denoted wasting (acute malnutrition) and stunting (chronic malnutrition), respectively. In this paper, the term overall malnutrition refers to children in at least one of these conditions. For the present analysis, the nutritional status was categorized using a static and a dynamic approach. Statically, the nutritional state was determined at baseline, at 1 year of age, and at each IPTi administration. Alternatively, and to account for the dynamic nature of the nutritional status, a nonparametric mixture model for longitudinal data (1) clustered the individual follow-up curves of anthropometrical z-scores from 3 to 24 months of age. Children whose scores belonged to a cluster of ≤2 SD were categorized as underweight, wasted, or stunted.

Data management and statistical analysis. In a first step, the effect of the nutritional status per se (static definition) on the main outcomes (asymptomatic parasitemia, uncomplicated malaria, severe malaria, severe anemia, and death) was analyzed by comparing incidence densities (ID; i.e., events per person years at risk [PYAR]) between malnourished and nonmalnourished children using negative binomial regression. Following an event, a child was considered not to be at the respective risk for 3 weeks, and the person time was reduced accordingly. Incidence rate ratios (IRRs; IDnonmalnourished/IDmalnourished) were adjusted for the intervention group. Vice versa, the impact of disease on the development of anthropometrical z-scores from 3 to 24 months of age was assessed by general estimating equation (GEE) accounting for repeated, correlated observations. The results are given as the means of differences in z-scores ({Delta} z-score) between children with at least one event and those with none, adjusted for the intervention. To further evaluate the effect of IPTi on anthropometrical development, time-dependent changes in weight, length, mid-upper arm circumference (MUAC), and z-scores were calculated, compared by Mann-Whitney U tests, and expressed as differences per month.

As the main analysis, we estimated the PEs of IPTi in strata of nutritional status. For that, the IDs of asymptomatic parasitemia, uncomplicated malaria, severe malaria, severe anemia, and death were calculated. As before, the person time was reduced for 3 weeks following an event. To account for repeated, dependent measures, the efficacies of IPTi (1 –IDSP/IDplacebo), 95% confidence intervals (CI), and P values were calculated by negative binomial regression and adjusted for the rainy season (http://www.fao.org/nr/water/aquastat/main/index.stm) and food availability (2 and http://documents.wfp.org/stellent/groups/public/documents/ena/wfp036439.htm). PEs of IPTi in malnourished and nonmalnourished children were estimated for various strata and observation periods. For the static classification of nutritional status, these were (i) from 3 to 24 months of age, grouping children into nonmalnourished (n = 809) and malnourished (n = 388) based on recruitment anthropometry; (ii) from 3 to 12 months of age, for which children were grouped according to whether they received both IPTi doses in a nonmalnourished (n = 527) or malnourished condition (n = 210); (iii) from >12 to 24 months of age, with the status at IPTi dose 3 defining the nutritional situation (nonmalnourished, n = 538; malnourished, n = 540); and (iv) each 6 months following an IPTi dose. The significance of differences in the PEs between nutritional strata was assessed by Wald tests. Calculations of PEs were repeated for the period of 3 to 24 months, applying nutritional strata derived from the nonparametric mixture model for longitudinal data (nonmalnourished, n = 200; malnourished, n = 999).

The software packages SPSS 14.0 (SPSS Inc., Chicago, IL) and STATA 9.0 (StataCorp LP, Chicago, IL) were used.


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RESULTS
 
Study population. Between March and September 2003, 1,200 infants were randomly assigned to receive SP or placebo. Baseline characteristics, drop-out rates, and mortality rates were similar in both study arms (23). Eighty-nine percent of the children received all three doses of IPTi, and 87% completed the follow-up until 24 months of age. The prevalences of overall malnutrition at 3, 9, and 15 months of age were 32, 40, and 50%, respectively (Table 1). Baseline characteristics of malnourished and nonmalnourished children were similar (data not shown).


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  		TABLE 1. Prevalence of malnutrition at application of intermittent preventive treatment at 3, 9, and 15 months of agea

Interaction between nutritional status and malaria. We assessed the incidences of asymptomatic parasitemia, uncomplicated malaria, severe anemia, and death during the complete follow-up period. These data were compared between children with and without malnutrition (including stunting, wasting, and being underweight) at recruitment. The nutritional status had no influence on asymptomatic parasitemia or on uncomplicated malaria; e.g., the latter occurred at a rate of 1.17/year and 1.11/year in malnourished and nonmalnourished children, respectively (P = 0.38). Two significant associations were observed: malnutrition increased the risk of dying by 89% (IRR, 1.89; 95% CI, 1.03 to 3.47; P = 0.04), and stunting increased the risk of severe anemia by 49% (IRR, 1.49; 95% CI, 1.07 to 2.07; P = 0.02).

The impact of the disease status on the development of nutritional indices was examined by GEE. Parasitemia and malaria were associated with measures indicating stunting: haz scores were aggravated in children who experienced at least one episode compared to those of unaffected children ({Delta} haz for parasitemia, –0.17 [P = 0.02]; {Delta} haz for malaria, –0.18 [P = 0.01]). Regarding severe anemia, this influence was more pronounced ({Delta} haz, –0.30; P < 0.0001) and also was discernible in terms of being underweight ({Delta} waz, –0.21; P = 0.001).

Influence of IPTi on child growth. The changes in weight, height, MUAC, and z-scores with increasing age are displayed in Table 2. IPTi improved weight gain exclusively in the first year of life and did so only to a small extent (14 g/month; P = 0.02). Moreover, this effect was restricted to children who were not malnourished when receiving IPTi doses 1 and 2 (nonmalnourished, 19 g/month [P = 0.08]; malnourished, 0.3 g/month [P = 0.73]). No beneficial impact of IPTi on nutritional indices was observed in the second year of life or for the complete follow-up period (Table 2).


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  		TABLE 2. Child growth according to age and use of intermittent preventive treatment

Efficacy of IPTi in malnourished children. Table 3 shows the PEs of IPTi against the main outcome parameters according to nutritional status and adjusted for the rainy season and food availability. Overall, the PEs of IPTi in malnourished children were roughly half or even less of those observed in nonmalnourished children. Also, in this analysis, significant risk reductions due to IPTi were observed only among nonmalnourished children. For instance, IPTi reduced the number of episodes of uncomplicated malaria by only 9.5% (P = 0.32) in malnourished children but by 18.4% (P = 0.006) among their nonmalnourished counterparts (Table 3). Generally, these differences in the impact of IPTi according to nutritional status did not yield statistical significance. Nonetheless, during infancy IPTi reduced malaria incidence to a significantly greater extent in nutritionally advantaged participants (46%) than in malnourished children (25%; P = 0.049). This was particularly pronounced following IPTi dose 1 (34% for nonmalnourished children, –14% for malnourished children; P = 0.02) (Table 4). A similar difference was observed with respect to severe anemia following IPTi dose 2 (P = 0.002) (Table 4) and in the second year of life (P = 0.047) (Table 3). The comparatively diminished efficacies of IPTi in malnourished children largely were confirmed not only for periods of 6 months following each treatment dose (Table 4) but also by a nonparametric mixture model (1) that categorizes nutritional status during the complete follow-up period (Fig. 1). However, in children who experienced malaria episodes during the 6 months after an IPTI administration, time periods until the respective first or only event were only slightly reduced in malnourished compared to those in nonmalnourished children and only following dose 2 (malnourished, 11.3 ± 8.5 weeks; nonmalnourished, 12.1 ± 8.6 weeks) and dose 3 (malnourished, 10.7 ± 6.8 weeks; nonmalnourished, 11.1 ± 6.8 weeks) but not so following dose 1 (malnourished, 14.1 ± 5.0 weeks; nonmalnourished, 13.3 ± 6.2 weeks) (for all comparisons, P > 0.5 by Mann-Whitney U tests).


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  		TABLE 3. PEs of intermittent preventive treatment separated by nutritional statusa


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  		TABLE 4. PEs of intermittent preventive treatment during 6 months following each dose stratified for nutritional status at time of dose administrationa


Figure 1
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  		FIG. 1. PEs and 95% CIs of intermittent preventive treatment from 3 to 24 months of age by nutritional status. Efficacies of IPTi were obtained by negative binomial regression and were adjusted for rainfall and food availability. Adjustment for possible socioeconomic confounders and differences in clinical parameters at baseline did not lead to meaningful differences. Footnote a indicates that a nonparametric mixture model for longitudinal data modified according to Aitkin (1) classified the individual follow-up curves of anthropometrical z-scores from 3 to 24 months of age.

A specific constellation was observed regarding IPTi, nutritional status, and severe malaria. Severe malaria occurred at similar rates in malnourished and nonmalnourished children (0.03/year for both groups). In the latter group, IPTi provided a nonsignificant degree of protection (PE, 14%; P = 0.67). Remarkably, however, the mere opposite was seen in children who were malnourished at recruitment: 14 episodes of severe malaria (0.046/year) occurred in children receiving SP, while only 5 episodes (0.016/year) occurred in the placebo group (PE, –169%; 95% CI, –670 to 6.3%; P = 0.07). This reversed impact of IPTi in malnourished children was significantly different from the protective effect in their nonmalnourished counterparts (P = 0.04). By repeating this analysis by applying the nonparametric mixture model as described above (1), the increased risk of severe malaria in malnourished children receiving SP appeared to be less pronounced but still was discernible (PE, –35%; 95% CI, –152 to 28%; P = 0.35; P = 0.16 by Wald test).


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DISCUSSION
 
IPTi is a simple means of malaria control in young children, particularly when administered alongside the well-established EPI schedule. This approach has the potential to overcome one of the predominant problems in disease control in sub-Saharan Africa, i.e., limited access to health structures providing accurate treatment or prevention. Due to the advantages of low cost, single-dose treatment, and a favorable safety profile, most IPTi trials so far have used SP (5, 12, 15, 17, 23, 28), although the use of other drugs also is conceivable. The mode of action of IPTi with SP is not fully understood, but it comprises properties of both treatment and chemoprophylaxis, the latter appearing to predominate (23). The protective effect also may result from an attenuation or containment of parasites exposed to SP, consequently preventing clinical disease but providing an enhanced opportunity to develop protective immunity (11, 29). If that is true, some degree of SP resistance might be tolerable, but its exact level is unknown. In fact, SP-resistant Plasmodium falciparum parasites have spread throughout Africa in recent years, a development that also is discernible in Ghana (18, 20).

Malnutrition among infants is shamefully frequent in many parts of Africa and has been shown to affect antimalarial treatment responses, drug absorption, and immune responses, among others (13, 14, 22, 27, 33, 35, 39). Thus, it is appropriate to hypothesize that nutritional status influences the effect of IPTi. In fact, in the present study, the PEs of IPTi were roughly halved in malnourished children, and as regards malaria, this was significant in the first year of life, when this intervention usually achieves its highest impact (15, 23). Not astonishingly, therefore, IPTi did not improve the growth of children who were malnourished.

A general problem in prospectively relating the nutritional status to morbidity or IPTi efficacy is the dynamic nature of the former. Not only did the prevalence of malnutrition increase during follow-up but anthropometric measures also exhibited various longitudinal patterns, e.g., poor or good initial values that subsequently declined, persisted, or increased. Our post hoc analysis is simplified in that these dynamic changes largely are not accounted for. We nevertheless consider our results valid, because stratified analyses of shorter time periods following various starting points produced basically the same results (Table 4). We consider the static classification of nutrition comprehensible and tangible, and, in terms of potential nutritional intervention, the status of a child beginning with IPTi appears to be practically relevant. Reassuringly, the nonparametric mixture model (1), which categorized nutritional status during the complete follow-up period, essentially confirmed the findings produced by the static approach. Nevertheless, this limitation should be kept in mind when construing our data.

How could malnutrition abate the PE of IPTi? An increased incidence of malaria in malnourished infants could lead to the impression that IPTi is less effective in these children. However, such increased morbidity was not observed in the present study, contrasting with previous findings (4, 6, 30) but corresponding with others (24). Malnutrition did increase all-cause mortality. Due to the civil conflict during the study, many deaths occurred at home, and a reliable diagnosis was not available for all children. Most deaths, however, presumably resulted from gastroenteritis, respiratory infections, and malaria. In accordance with current concepts (27, 30), this indicates that malnutrition compromised antipathogen immunity. Considering the hypothesis that (possibly enhanced) immune responses to parasites attenuated or contained by SP treatment are part of the mode of action of IPTi (11, 29), immune suppression caused by poor nutritional status may translate into a reduced PE. Such could be reflected by efficacy differences between malnourished and nonmalnourished children increasing with age. However, in the present study this was not observed. Also, malnutrition may influence the efficacy of SP by reducing the contribution of immunity to parasite clearance (9). In fact, in malnourished children the risk of the failure of antimalarial treatment (16, 24), including SP (13, 39), appears to be increased, although not uniformly so (16, 19). Altered pharmacokinetics of SP in malnourished children also could play a role by causing, e.g., increased clearance, reduced drug concentrations, and reduced half-life, as has been shown for quinine (33). Likewise, oral chloroquine treatment has been reported to be associated with reduced peak and overall drug concentrations in children with kwashiorkor, suggesting decreased bioavailability (35). If the pharmacokinetic properties of SP were altered in malnourished children (and related to the reduced efficacy of IPTi), such influence would be expected to be pronounced. This is because undernourished infants in the present study received a fixed and, thus, comparatively higher dose of SP than well-nourished children. Regrettably, no pharmacokinetic data of SP in malnourished children, let alone in IPTi per se, are available. This gap urgently needs to be closed, and the selection of alternative or future drugs for IPTi also should allow for pharmacokinetic properties.

What is the relevance of a reduced efficacy of IPTi in malnourished children? Affirmatively, the potential of IPTi appears to be higher than thought (23), considering the 46% PE against malaria in well-nourished children during the first year of life. Contrarily, the abundance of malnutrition in African infants may impair the value of one of the few available malaria control measures. The worsening international food crisis primarily affects the poor and vulnerable, and malnutrition in African children consequently can be expected to increase. Already, the average Ghanaian family spends some 70% of its budget on food (http://www.irinnews.org/Report.aspx?ReportId=78389). At present, it is unknown whether, and after which time period, malnourished children would benefit from refeeding in terms of IPTi. Moreover, individual nutritional assessments preceding IPTi would question the concept of a simple and affordable tool piggybacked onto the EPI system. Such operational difficulties are key issues in implementing IPTi and, overall, in reducing morbidity and mortality among African children. However, as stated previously (8) and confirmed here, malaria control programs will have limited effects without targeting the underlying causes, including malnutrition. On a large scale, training to detect poor nutritional status, nutritional counseling, and the education of caretakers and feeding programs are needed. Specifically, operational trials assessing the potential impact of refeeding on the efficacy of IPTi are warranted.

In malnourished children, the protective effect of IPTi against severe malaria appeared to be reversed, i.e., malnourished children receiving SP experienced an excess of episodes. Because of small numbers and borderline statistical significance, this finding needs to be interpreted with caution. As reported previously (23), most of these cases emerged during 16 to 24 months of age and were due to severe malarial anemia (Hb < 5 g/dl). Folate deficiency complicating overall malnutrition could partially explain our findings: in the 1970s, folate deficiency was seen in 70% of young Ghanaian children (25), and no major improvement was observed recently in neighboring Togo (3). Deficient children will experience a decrease in plasma tetrahydrofolate concentrations after 3 to 4 months of insufficient folate intake, which will result in increasing megaloblastic anemia (36). SP inhibits the P. falciparum dihydropteroate synthase and dihydrofolate reductase, causing a disturbed folate metabolism in the parasite (26). In Wistar rats, SP induced folate deficiency (34), probably by the parasite's ability to assimilate external folate reservoirs, as observed in Malawian children (7). The administration of SP in malnourished and concomitantly folate-deficient children eventually may contribute to the development of severe anemia. Unfortunately, concentrations could not be assessed in the present study. Further investigations are needed to rule out the above hypothesis.

In conclusion, in northern Ghana, IPTi in malnourished children achieved only roughly half the PE attainable under normal nutritional conditions. Moreover, malnourished children did not benefit from IPTi in terms of weight gain or growth and, possibly, bear the risk of rare but severe adverse events. This latter aspect should be looked at carefully in ongoing IPTi trials and during potential implementation. Further investigations of the interaction between malnutrition and IPTi and of the potential impact of nutritional programs in this regard are warranted. In regions where malnutrition is frequent, IPTi might not achieve its maximum effect.


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ACKNOWLEDGMENTS
 
This work was supported by the German Ministry of Education and Research (grant 01KA0202), the German Academic Exchange Service (DAAD), and Charité University Medicine Berlin (grant 2005-543).

We thank all of the children and their families for participation in this study as well as all members of the Northern Region Malaria Project (NORMAP). We thank Andrew Seidu-Korkor and Elias Sory, Regional Health Administration, Tamale, Ghana, for general and infrastructural support.

We do not have a commercial or other association that might pose a conflict of interest.


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FOOTNOTES
 
* Corresponding author. Mailing address: Institute of Tropical Medicine and International Health, Spandauer Damm 130, 14050 Berlin, Germany. Phone: 49 30 30116 815. Fax: 49 30 30116 888. E-mail: frank.mockenhaupt{at}charite.de Back

{triangledown} Published ahead of print on 17 February 2009. Back

{dagger} Deceased. Back


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Antimicrobial Agents and Chemotherapy, May 2009, p. 1753-1759, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01723-08
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