Marked reduction in antibiotic usage following intensive malaria control in a cohort of Ugandan children

Intensive malaria control, including widespread distribution of long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) of insecticides, can significantly lower the burden of malaria in endemic settings [1]. Vector control interventions aimed at reducing transmission intensity can reduce malaria burden, but reducing malaria may have additional health benefits beyond those attributable to malaria alone [2, 3]. We hypothesized that intensive vector control in a previously high-transmission setting, resulting in the near elimination of malaria, would be associated with reduced antibiotic use among children.

Acute bacterial and viral infections are common in malaria-endemic settings, and malaria may affect the risk of co-infection with these other pathogens [4, 5]. Moreover, decisions about the use of antibiotics during clinical encounters are inextricably entwined with the burden of malaria in a community [6]. This interrelationship is most apparent during febrile clinical encounters, but even infection with malaria parasites in the absence of fever (i.e., asymptomatic parasitemia) may have an effect on the likelihood of clinical presentation resulting in the use of antibiotics. The widespread use of antibiotics to treat non-malarial infections and the concomitant use of antibiotics in patients treated with antimalarial drugs may be unnecessary and may contribute to the selection of antimicrobial resistance, which is a major public health threat [7‐9]. The effect of malaria control on malaria-specific outcomes and the interaction between malaria diagnoses and antibiotic use have been well-researched, but evidence on the use of antibiotics in the context of successful population-level malaria control is limited.

This observational study explores the temporal relationship between the implementation of highly effective malaria control interventions and antibiotic usage in two sequential cohorts of children aged 0.5 through 10 years in Tororo, Uganda. Potential mechanisms for observed trends are explored by stratifying analyses according to the history of fever and the presence or absence of malaria parasites on the day antibiotics were prescribed and summarizing categories of non-malaria diagnoses and antibiotics used.

In this highly malaria-endemic region of Uganda, successful malaria control with LLINs plus IRS was followed by almost complete elimination of symptomatic malaria and a substantial reduction in the incidence of antibiotic treatments among children 0.5 to 10 years of age. Indeed, in the 4–5 years following the implementation of IRS, children received nearly three fewer antibiotic treatments per year, a 70% reduction compared to the pre-IRS period. These results provide further evidence that in highly endemic settings, successful malaria control efforts can have substantial health benefits for children beyond those directly attributable to reducing the burden of symptomatic malaria.

In addition to the important health benefits to the children and the socioeconomic benefits to families, the magnitude of reduced antibiotic treatments demonstrated in this study has important implications for health systems in malaria-endemic settings. Countries like Uganda struggle with training and retaining staff to ensure quality care and meet patient needs [12]. Intensive malaria control with LLINs and IRS in this region was associated with 2.6 fewer treatments for malaria and nearly 2.88 fewer antibiotic treatments per child per year. At a health system level, this could result in a substantial reduction in patient volume, staffing needs, and costs associated with care. Furthermore, the high number of antibiotic treatments averted, mostly amoxicillin, could reduce selection pressure and help slow the spread of antimicrobial resistance which is a major public health threat in Uganda and elsewhere [13, 14].

There are multiple plausible mechanisms explaining the association between effective vector control leading to reduced malaria burden and an accompanying reduction in antibiotic use among children. As malaria burden decreased precipitously, the incidence of antibiotic treatments for all categories of children with parasitemia decreased compared to the period before IRS was implemented. This decrease was most marked among febrile children, such as those diagnosed with clinical malaria or were febrile with sub-microscopic parasitemia. There was a more modest decrease for children with parasitemia who were afebrile. This pattern of greater decreases in antibiotics prescribed for febrile versus afebrile children was observed across all categories of parasitemia. In general, patients diagnosed with malaria may also be prescribed antibiotics because of concern for other co-occurring illnesses. Indeed, in this study, 40% of children treated for malaria were also given antibiotics prior to the implementation of IRS, which decreased to 20% after the implementation of IRS. Thus, reducing the incidence of malaria may reduce susceptibility to concomitant illnesses and limit opportunities to prescribe concomitant antibiotics [5]. Sub-microscopic parasitemia may induce symptoms, including fever, triggering clinic visits that may result in an antibiotic prescription, particularly if the parasitemia is below the level of detection by standard laboratory tests and the clinician is unaware that the patient is infected with malaria. Other contributing factors that play into a clinician’s decision to prescribe an antibiotic may be independent of clinical symptoms. In cases where a clinician is unsure of the utility of antibiotics, clinicians often face an expectation to provide some form of intervention or treatment as a conservative measure or to meet patient demands [15]. Perceptions of risk for the progression to severe disease and trust within the clinician-patient relationship also play important roles [16].

As malaria burden declined in the population following IRS, one might have expected an increase in the incidence of antibiotic treatments among the febrile children who tested negative for malaria by microscopy as has been found in other low transmission settings in Uganda [6]. However, we found that the incidence of antibiotic treatment decreased slightly for febrile children without parasitemia and increased for afebrile children without parasitemia following the implementation of IRS. It is possible that clinicians felt pressured to provide antibiotics for afebrile children, even for those with lower severity illnesses such as viral URIs for which antibiotics are typically not recommended, since they had nothing else to offer. On the other hand, febrile children received an urgent blood smear according to the study protocol. This diagnostic test may have fulfilled the expectation to provide some sort of intervention and allowed the clinician to forgo an antibiotic prescription. These results contrast, however, with multiple studies showing antibiotics are typically prescribed more frequently with negative malaria tests [6, 17‐19]. In this cohort study, repeated contact may have allowed clinicians to develop stronger relationships with families, making it easier to avoid antibiotics overall. It is also possible that the children may have become healthier over time solely due to the rigorous free health care provided as a part of the research study or that exposure to other bacterial or viral illnesses in the community, which we did not measure, may have also been declining. Future research is needed to explore antibiotic prescription practices relative to parasitemia status and fevers in more typical clinic settings.

Another potential mechanism underlying the reduced antibiotic treatments found here may be reduced susceptibility to co-infection with acute bacterial, viral, or other parasitic infections as a result of decreased parasitemia [20]. An association between malaria and serious bacterial infections has been documented among severely ill children in hospital settings [21]. While less well studied, malaria may also increase the risk of less severe infections seen in outpatient settings through indirect effects on the immune system [20], anemia [3], birth weight [22, 23], and nutrition/growth [24]. Indeed, malaria infections at any density have been associated with serious health outcomes [25]. Furthermore, malaria control may improve overall child health by mitigating the socioeconomic costs incurred by the household due to malaria-related illness [26]. Finally, malaria control targeting mosquitoes may decrease the risk of other vector-borne illnesses, such as arboviruses or other parasitic infections, though studies on these types of pathogens are limited. This could be one potential explanation for the decrease in the incidence of antibiotics among children who were febrile and non-parasitemic in our study, such that intensive malaria control (i.e., IRS) may have reduced the risk of other vector-borne illnesses and thus avoiding another opportunity to prescribe antibiotics for a febrile non-malarial illness.

This study had several limitations inherent with observational studies making “before and after” comparisons. First, we lacked a contemporary control group which did not receive intensive malaria control, thus limiting our ability to make causal inferences. Second, there are limitations with external validity given that our study participants were enrolled in a research study and provided more rigorous care than is typically available in resource-limited settings. However, the extended follow-up and the consistency inherent in clinical management by only a few providers using highly standardized procedures are benefits of the cohort study design. Third, our analyses did not adjust for secular trends in malaria and antibiotic treatments, as there is a complex relationship between these and seasonal variations making accurate modeling of these trends challenging. Though we are unaware of other significant changes in the district, it is possible that other health programs or other changes in the study area could explain the decrease in antibiotic use over time. Finally, the stratified analysis partially relied on estimates of daily parasite status interpolated from prior and subsequent lab results, potentially introducing bias.

Intensive malaria control in this previously high transmission setting was associated with a significant decline in the use of antibiotics, as well as malaria treatments, in a closely followed cohort of children. We found that investments in malaria control may have broader health benefits for children beyond malaria. Future studies should investigate the association between malaria control and antibiotic prescribing practices in other settings to further explore the impact on health systems and to inform strategies to mitigate the overuse of antibiotics and the threat of antimicrobial resistance in malaria-endemic settings.