Overuse of antibiotics in the management of acute diarrhea in children under five years in four provinces of Mozambique (2014-2019)

doi:10.21203/rs.3.rs-4720196/v1

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Overuse of antibiotics in the management of acute diarrhea in children under five years in four provinces of Mozambique (2014-2019)

https://doi.org/10.21203/rs.3.rs-4720196/v1

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Background

Even with great reduction in the last years, diarrhea continues as one of leading causes of hospital admission and mortality in children less than five years of age globally. The success of diarrheal disease management relies on the rapid recognition of the symptoms and adequate treatment, to which WHO guidelines, do not recommend antibiotic use for all cases of acute diarrhea in children under five years old, being reserved to specific conditions such as bloody diarrhea, co-infection, malnutrition and chronic associated conditions. Therefore, we aimed to evaluate the frequency of antibiotics use in diarrhea management in children aged 0–59 months admitted with acute diarrhea in four provinces of Mozambique, from 2014 to 2019.

Methods

A cross-sectional hospital-based surveillance was conducted from January 2015 to December 2019 in six sentinel sites located in four provinces. Socio-demographic, epidemiological and clinical data were obtained by interviewing the child’s caregivers and by accessing the child’s medical records and children’s vaccination card. Data collected through ViNaDia was double-entered in Epi Info^TM3.5.1. (Centers for Disease Control and Prevention, Atlanta 2008), followed by data comparison. IBM SPSS software was used to conduct the data analysis.

Results

During the study period 2382 children who presented at one of the study health facilities with diarrhea was enrolled through ViNaDia surveillance between 2015–2019 and a total of 85.1% (2028/2382) provided information about the use of ATB and were included in the present analysis. The majority was male. The most frequent age group was 0–11 months with 49.4%. Underweight was observed in 28.8% and wasting in 15.2%. The comorbidities observed was HIV (7.8%), malaria (7.0%), and pneumonia (2.1%). Bloody diarrhea and “rice-water” was reported in 1.5% (10/1664) and 2% (29/1664) respectively. Antibiotics use was 93.2% [95% CI: 92.0–94.2; 1890/2028]. Administration of multiple antibiotics was 49.1% [95% CI: 47.0–51.5; 930/1890]. The most prescribed antibiotics were Ampicillin (46.2%), Gentamicin (38.4%) and Cotrimoxazole (30.5%).

Conclusions

The results of our study indicate an overuse of antibiotics in the management of acute diarrhea in children attended in four provinces of Mozambique. The study suggests the drawing of a local guideline for the efficient management of acute diarrhea.

Acute diarrhea

Children under five

Antibiotics

Diarrhea management

Mozambique

Diarrheal diseases remain one of the skyrocketing causes of morbidity and mortality worldwide, notwithstanding its great reduction in the last years, diarrhea continues as an important cause of hospital admission and mortality in children less than five years of age globally (1). In 2019, 9,9% of childhood deaths due to diarrhea were reported in children under the age of five (2), and sub-Saharan African countries (including Mozambique) contributed with more than 80% of these deaths (3). In spite of the global decrease in the total number of deaths in children under five from 2009 to 2018, sub-Saharan Africa remains the major contributor to this morbidity rate(4).

In Mozambique, diarrhea has been reported as the 3rd leading cause of mortality (5) and considered to be responsible for 21% of deaths in children under 5 years old between 2019 and 2020 (5). Even with the implemented strategies in the last decades, the country still reports one of the higher prevalence of diarrhea in the region reports more than 7.340 deaths in children under five years annually, contributing with 13% of deaths in Sub-Saharan Africa (6, 7).

From the different etiologies associated with diarrhea: virus, bacteria and parasites are the most common with Rotavirus A reported to be the most important etiology linked with severe acute diarrhea in children under five years (8). However, bacterial infections have an important role in the burden of bloody acute diarrhea. Different bacteria have been isolated, being Shigella the most common worldwide, contributing with over 60% of mortality, beyond Shigella, enterotoxigenic Escherichia coli (ETEC), Salmonella, Campylobacter, Entamoeba histolytica and Giardia are important bacteria equally attendant to bloody acute diarrhea in children under the age of five (8, 9). Along with the Global Enteric Multicenter Study (GEMS), others studies conducted in Mozambique reported enterotoxigenic Escherichia coli producing heatstable toxin (ST-ETEC; with or without co-expression of heat-labile enterotoxin) and Shigella as the main pathogens associated with diarrhea (7, 10). Fever is described as the first symptom, followed by headache, malaise, anorexia and vomiting, then, the bloody diarrhea; In severe illness, the number of stools can reach 20 per day (10). One of life threatening complication of bacterial infection in acute diarrhea is the hemolytic-uremic syndrome (HUS), characterized by hemolytic anemia, thrombocytopenia and acute kidney injury, directly related to the Shiga toxin produced by some bacterial strains as type 1 Shigella dysenteriae, entero-hemorrhagic Escherichia coli, Escherichia coli shiga producer, which are commonly associated with use of antibiotics as well (11, 12).

In the last decades, an increasing trend of multidrug resistant diarrheagenic bacteria has been reported worldwide (13–16). In Mozambique, studies have shown important rates of resistance in the most common diarrheagenic bacteria (E. coli, Shigella and Salmonella) (17, 18). Data from Manhiça district, Southern of Mozambique, showed a high frequency of resistance of Shigella to Trimethoprim-Sulfamethoxazole (92.5%), Chloramphenicol (53.7%) and Ampicillin (50.7%), multidrug resistance (MDR) was observed in 55.2% of shigella strains in children with diarrhea (17). Furthermore, an analysis of E. coli strains isolated from children with acute diarrhea in four Mozambican provinces, reported a high resistance to Ampicillin and Tetracycline, up to 97.0% and 68.0% respectively (19). Reassuring the indeed need of local antibiotic consumption optimization, including in diarrheal management recommendations (20).

The World Health Organization (WHO) and World Gastroenterology Organization Global Guidelines (WGOGG), admonishes an acute diarrhea treatment based on the clinical presentation, with a display of lower cost interventions such as oral rehydration solution, intravenous fluids, breastfeeding, probiotics, supplementation with zinc, vitamin A, and community-based management practices by parents or guardians, depending on severity level presented (21, 22). In fact, the WHO does not recommend the use of antibiotics for diarrhea management, even if the bacterial infection is confirmed (23). Withal, the antibiotic therapy can be considered in some specific clinical situations such as severe diarrhea with septic presentations, bloody stools or diarrhea associated with another acute infection (e.g. pneumonia, urinary tract infection); cholera, shigellosis, dysenteric presentation of campylobacteriosis and non-typhoidal salmonellosis in case of causing persistent diarrhea, when host immune status is compromised including severe acute malnutrition chronic disease, or lymph proliferative disorders; traveler’s diarrhea or diarrhea accompanied by fever (23–26).

Due to high burden of diarrhea in the country, the Instituto Nacional de Saúde implemented the National surveillance of Diarrhea (ViNaDia) since 2014, aiming to assess the etiology, the magnitude, and risk factors associated with diarrheal diseases in children in pediatric age (≤ 14-year-old) (27). Therefore, the present analysis aimed to evaluate the frequency of antibiotics use in diarrhea management in children aged 0–59 months admitted with acute diarrhea in four provinces of Mozambique, from 2014 to 2019 and the compliance with WHO guidelines.

Study design, site, population

A cross-sectional, hospital-based surveillance was conducted from January 2014 to December 2019 in six sentinel sites located in four provinces. Hospital Central de Maputo (HCM), Hospital Geral de Mavalane (HGM) and Hospital Geral José Macamo (HGJM) all located in Maputo Province; Hospital Central da Beira (HCB) located in Sofala Province; Hospital Geral de Quelimane (HGQ) located in Zambézia Province and Hospital Central de Nampula (HCN) located in Nampula Province. Children aged up to 59 months who presented to the pediatric services in six sentinel sites with diarrhea as cause of admission according to the WHO definition were recruited through ViNaDia (1, 26) and their care-givers signed informed consent. Children with nosocomial diarrhoea, without ATB information or those whose caregiver denied participating were excluded in the analysis.

Data collection

Socio-demographic, epidemiological and clinical data, were obtained by interviewing the child’s caregivers and by accessing the child’s medical records and children vaccination card. Trained health professionals of the ViNaDia, filled all information in a semi-structured data collection form. Data regarding the use of ATB and the type were collected from the children medical record file.

Sample size

As far as we know, this is the first study in Mozambique reporting the use of ATB in children attended with diarrhea, so we considered the expected prevalence of 50% to estimate the maximum sample size. Considering a 95% Confidence Interval (CI) and assuming an acceptable error of 0.03, a minimum of 1068 children is required to respond the hypothesis of this analysis. We increased the sample size assuming a 20% of non-response compensation rate. Thus, at least 1282 children with diarrhea are required in the present analysis. The sample size was calculated using Epitools (29) (available from: http://epitools.ausvet.com.au).

Data management and statistical analysis

Data collected through ViNaDia was double entered in Epi Info^TM3.5.1. (Centers for Disease Control and Prevention, Atlanta, 2008), followed by data comparison. IBM SPSS (30) software was used to conduct the data analysis.

Descriptive statistics and chi-square comparison or Fisher’s Exact test for small sample sizes was used to identify socio-demographic and clinical factors related to antibiotics use in children aged up to 59 months.

Clinical factors related to antibiotic use were accessed by cross-tabulation followed by the chi-square test or Fisher’s Exact test if assumptions were not meet. All analysis were performed considering a 95% confidence interval and a p-value < 0.05 was considered statistically significant.

Ethical statement

The study protocol was approved by National Bioethics Committee for Health in Mozambique (IRB00002657, reference 348/CNBS/13). Parents or legal guardians of the children signed or put their fingerprint in the informed consent form, this document described the study objectives and clarified that participation in the study was voluntary.

During the study period, 2382 children who presented at one of the sentinel site with diarrhea were enrolled trough ViNaDia between 2014-2019 and a total of 85.1% (2028/2382) provided information about the use of ATB and were included in the present analysis.

Sociodemographics and clinical characteristic

The majority of children were male (59.3%). Forty-nine-point four percent of the children were aged from 0-11 months, 29.4%, were enrolled at HGM sentinel site and 31.8% were enrolled 2015 (Table 1).

Regarding the clinical chacteristics, in addition to the diarrhea, other concurrent symptoms as vomiting and fever was reported in 62.2% (1262/2028) and 17% (282/1678) children respectively. Three quarters (841/1129) of children presented with moderated dehydration and less than 1% (10/1129) with shock. Bloody diarrhea and “rice-water” were reported in 1.5% (10/1664) and 2% (29/1664) respectively.

In terms of children’s nutrition status, one third were underweight (28.8%), followed by stunting (16.8%) and wasting (15.2%). The comorbidities observed was HIV (7.8%), malaria (7.0%) and pneumonia (2.1%). Most of the children with diarrhea were discharged (63.9%) (Table 1).

Table 1: Sociodemographic and clinical characteristics of children with diarrhea, May 2014 to December 2019, Mozambique

Characteristics	Antibiotics use	Column1
	n/N	%
Sex
Male	4/6	66.7
Female	2/6	33.3
Sentinel site
HCM	2/6	33.3
HCB	3/6	50.0
HGQ	1/6	16.7
Year of admission
2015	2/6	33.3
2017	2/6	33.3
2018	2/6	33.3
Age categorized (in months)
0-11	5/6	83.3
24-59	1/6	16.7
Does the child has commorbities
No	5/6	83.3
Yes	1/6	16.7
Malaria
No	5/6	83.3
Yes	1/6	16.7
Pneumonia
No	6/6	100.0
Stunting
Yes	1/1	100.0
Wasting
No	1/2	50.0
Yes	1/2	50.0
Underweight
No	3/4	75.0
Yes	1/4	25.0
HIV
Negative	5/5	100.0
Fever
No	4/6	66.7
Yes	2/6	33.3
Vomit
No	4/6	66.7
Yes	2/6	33.3
Dehydration status
Moderate	3/3	100.0
Stool characteristics
Watery	4/6	66.7
Semi-pasty	1/6	16.7
Pasty	1/6	16.7
Bloody
Has the child received rotavirus vaccine?
No	2/6	33.3
Yes	4/6	66.7
Outcome
Discharge	5/5	100.0

(In annex).

Overall and yearly antibiotics use in four province

Antibiotics use was 93.2% [95% CI: 92.0 – 94.2; 1890/2028]. Administration of multiple antibiotics was 49.1% [95% CI: 47.0 – 51.5; 930/1890]. The most prescribed antibiotics were Ampicillin (46.2%), Gentamicin (38.4%), Cotrimoxazole (30.5%), Metronidazole (11.1%) and Ceftriaxone (8.8%) (Figure 1).

Between 2014 and 2019, antibiotics use has increased in all sentinel sites, being surprisingly administrated in 100% of children admitted in 2018 and 2019 (Table 2). Comparing the use of antibiotics per year, Ampicillin was the most prescribed antibiotic in 2014 (36.8% - 28/76), 2015 (34.2% - 364/1063), 2018 (36.3% - 165/455) and 2019 (28.4% - 63/222). While in 2016, Cotrimoxazole was the most prescribed antibiotic (30.5% - 181/594) and gentamicin in 2017 (33.0% - 199/603) (Table 3).

Table 2: Antibiotic use in children with diarrhea by site, in each year, May 2014- December 2019, Mozambique

Site	2014		2015		2016		2017		2018		2019
Site	n/N	%	n/N	%	n/N	%	n/N	%	n/N	%	n/N	%
HCM	-	-	0/46	0.0	43/46	93.5	48/49	98.0	28/28	100.0	31/31	100.0
HGM	50/91	54.9	175/181	96.7	59/59	100.0	85/85	100.0	121/121	100.0	60/60	100.0
HJM	-	-	140/142	98.6	21/21	100.0	102/102	100.0	74/74	100.0	5/5	100.0
HCB	-	-	11/18	61.1	32/32	100.0	27/27	100.0	26/26	100.0	-	-
HGQ	-	-	22/37	59.5	48/49	98.0	25/26	96.2	19/19	100.0	14/14	100.0
HCN	-	-	207/221	93.7	189/190	99.5	127/127	100.0	50/50	100.0	51/51	100.0
Total	50/91	54.9	555/645	86.0	392/397	98.7	414/416	99.5	318/318	100.0	161/161	100.0

Table 3: Antibiotic use by type within the years in children with diarrhea, May 2014-December 2019, Mozambique

(In annex).

Clinical and sociodemographic factors related with use of antibiotics

Antibiotic use was reported in the same proportion in male and female (93.2%). All age groups were prescribed antibiotics in more than 90%, being children aged 12-23 with the highest frequency (95.3%) and the lowest frequency in children under one year (91.2%). Two of the six sentinel sites had prescribed antibiotics in less than 90% of the children with diarrhea (HCM and HGQ), while HGJM presented the highest frequency ATB administration (99.45%) (Table 4).

In children with co-morbidities antibiotics were more prescribed in HIV positive (95.0% - 151/159) followed by Malaria (94.3% - 133/141), underweighted (93.8% - 549/585), stunted with 89.4% (305/341) and, pneumonia (85.7% - 36/42).

Fever (97.9% - 276/282) and vomiting (92.6% - 1169/1262) were the most common clinical characteristics related to ATB use (Table 4).

Children with bloody diarrhea received less antibiotics (86.7% - 26/30) compared with children without bloody diarrhea (98.7% - 376/381). Regardless the outcome, antibiotics prescription was more than 90%, being the highest frequency in those discharged (Table 4).

Table 4: Clinical and Sociodemographic factors related to Antibiotic use in children with diarrhea, May 2014-December 2019, Mozambique

Characteristics	Antibiotics use	Column1	p-value
	n/N	%
Sex			0.976
Male	1120/1202	93.2
Female	769/825	93.2
Age categorized (in months)			0.002
0-11	914/1002	91.2
12-23	696/730	95.3
24-59	280/296	94.6
Does the child has comorbidities			<0.001
No	1270/1339	94.8
Yes	618/686	90.1
Malaria			0.052
No	1672/1715	97.5
Yes	133/141	94.3
Pneumonia			0.001
No	1767/1812	97.5
Yes	36/42	85.7
Stunting			0.496
No	504/573	88.0
Yes	305/341	89.4
Wasting			0.393
No	572/650	88.0
Yes	265/308	86.0
Underweight			0.347
No	1185/1279	92.7
Yes	549/585	93.8
HIV			0.418
Positive	151/159	95.0
Negative	1251/1341	93.3
Fever			0.356
No	1352/1396	96.8
Yes	276/282	97.9
Vomit			0.338
No	677/722	93.8
Yes	1169/1262	92.6
Dehydration status			NA
None	21/21	100.0
Moderate	841/841	100.0
Severe	256/257	99.6
Shock	10/10	100.0
Stool characteristics			0.102
Watery	591/639	92.5
Semi-pasty	359/359	100
Pasty	592/627	94.4
Bloody	10/10	100.0
Rice water	25/29	86.2
Mucuous	4/4	100.0
Has the child bloody diarrhoea?			0.002
No	376/381	98.7
Yes	26/30	86.7
Has the child received rotavirus vaccine?			<0.001
No	1108/1238	89.5
Yes	782/790	99.0
Outcome			0.030
Discharge	1267/1296	97.8
Died	17/18	94.4
Transferred/Abondened	46/50	92.0

In this present analysis, we provided evidence on the extent of antibiotic use in children with acute diarrhea admitted in six hospitals from four provinces of Mozambique. Our results demonstrated that the majority of children were treated with at least one antibiotic regardless of their clinical presentation or laboratorial evidence of bacterial infection.

The overuse of antibiotics in children under 5 years with diarrhea reported in this study (93%) is higher than those from previous studies in other African countries (85% in Nigeria and 68.9% in Tanzania), thus the fact that these studies were conducted in outpatients may explain the differences on antibiotics administration percentages (31,32). However, similar studies conducted in outpatients with acute diarrhea of different Low and Middle Income countries (LMIC), have shown lower rates of antibiotics prescription to the management of children with acute diarrhea, being accounted to Shigella and rotavirus, specific enteric pathogens considered to be the leading causes of diarrhea in these settings (32). Moreover, the rate of inappropriate antibiotic prescription have thriven over the years in these six sentinel sites, and consequently increasing the treatment costs and contributing to the emergence of resistant bacterial strains over these years, as reported previously in several countries, demonstrating a direct impact in children mortality rate (34,35).

The empirical antibiotics overuse by clinicians may be driven by the limitations faced in microbiology facilities at the hospitals, considering that similar studies have reported inappropriate antibiotic prescription for childhood diarrhea management in rural and urban sites of LMIC (17,36). Although ViNaDia is based in all hospitals collecting and testing samples, it does not provide real-time results for the clinician to make decisions. Since the objective is to produce scientific evidence for research purposes, and contributing to the country’s health policy changes by providing data about acute diarrhea burden in children from 0-14 years and the etiology associated to four provinces of Mozambique (6,37–39).

According to the WHO management guidelines on acute diarrhea in children, antibiotics are not indicated routinely, being recommended in specific situations as bloody diarrhea, co-infections, the presence of malnutrition, and other special conditions. The first choice of recommended antibiotic is Ciprofloxacin specially in bloody diarrhea and Ceftriaxone as an alternative (21,40). These WHO guidelines were designed based on the clinical presentation, feces characteristics and considering laboratory diagnosis limitations of LMIC (21).

The magnitude of antibiotics over-prescription is unjustifiable, given that the present analysis reported a low number of children with bloody diarrhea (less than 10 children), as observed in co-infection and co-morbidities, conditions which indicate the use of antibiotics for its treatment, underlying the inappropriate prescription and use of antibiotics in acute watery diarrhea (41), suggesting that clinicians perceive acute diarrheal illness as an indication for antibiotic use, despite the WHO recommendations.

Taking into account the diarrheal etiologic aspects, previous studies described high rates of viral and parasitic infections on the children included in the present analysis showcasing that not all diarrhea manifestations are caused by bacterial infection, instilling the need of careful usage of ATB in Mozambique (37,39,42).

Regarding the commonly prescribed ATBs, it was observed that Ampicillin is the first choice, making it the most used with a rate between 28 - 36.6% over the five years of analysis. The consumption of cephalosporin increased from less than 3% in 2014 to 18% in 2019, possibly due to the antibiotic availability at the moment of the treatment (43). The barrier to access antibiotics remains global, especially in LMIC, where some settings have to endure with less than 60% of essential listed medicines available. The most significant challenges are associated with the low availability of essential medicines, weak health systems, poor quality control and inadequate government funding (43).

In 2016, Cotrimoxazole was rated as the third most used antibiotic reaching 30.5%, although it is no longer used routinely to treat patients with acute diarrhea in Mozambique, however, it is used for the prevention of opportunistic infections in HIV-positive and exposed children, suggesting that the high rate of consumption is due to the high prevalence of HIV infections in Mozambique (44).

Previous studies in Mozambique found that clinical condition (severity) and age under 5 years were the main determinants for antibiotic prescription in children with different pathologies including diarrhea, and beta-lactams being the most used antibiotic class (45).

The findings shows a strong evidence of high levels of over-prescription of antibiotics and a weak adherence of antibiotic guidelines in children with acute diarrhea, resulting in a urgent need of education on antibiotic use, development of local guidelines and antibiotic stewardship implementation programs (46,47).

Our findings had some limitations such as the missing data for some clinical variables, which disables the overall screen of the study settings. All the hospitals are quaternary and located in urban areas, which does not allow having the whole scenario of populations living in rural areas as well as, patients assisted on health centers or other type of health services that provides primary care. Despite the limitations, we were able to produce important information about ATB use in children with diarrhea in four provinces of Mozambique.

The results of our study indicate an overuse of antibiotics in management of acute diarrhea in children attended in four provinces of Mozambique. Clinicians should consider more the epidemiology, the etiology and the clinical presentation of acute diarrhea, as well as consulting the approved guidelines on management of acute diarrhea and empirical antibiotic therapy. Mozambique has produced sufficient epidemiologic data to draw a local guideline on management of acute diarrhea in order to improve the care given to children with diarrhea, likewise to define policies that will reduce the overuse of antibiotics, as a preventable measure for antibiotic resistance emergence.

Ethics approval and consent to participate

The ViNaDia Protocol was approved by the National Health Bioethics Committee of Mozambique (CNBS) under number (IRB00002657, reference Nr: 348 / CNBS / 13). The participant’s documents were stored in a secure and access-restricted location in the National Institute of Health. Parents or legal guardians of the children signed the informed consent form this document described the study objectives and clarified that participation in the study was voluntary and that refusal participation would not result in any penalty or loss of medical care.

Consent for publication

Not applicable.

Availability of data and material

The raw data are available upon reasonable request from the corresponding author.

Competing interests

The authors have no conflicts of interest to declare.

Funding

This study was supported by a Senior Fellowship awarded to Nilsa de Deus by the European Foundation Initiative for African Research into Neglected Tropical Diseases (EFINTD) and World Health Organization (WHO).

Authors' contributions –: J.S.F., A.C., and N.dD - Designed the study. NdD - principal investigator supervised the research and funding acquisition, J.S.F., and A.C – analyzed data. J.S.F., and A.C – wrote the manuscript first draft. J.S.F., A.C., M.C., N.dD – Methodology. J.S.F., A.C., A.K., L.M. and N.dD – Writing review and editing. N.dD – funding acquisition. All authors reviewed and approved the final manuscript.

Acknowledgements

The authors would like to thank the caregivers who consented for their children participation in the ViNaDia. Adilson Bauhofer, Elda Anapakala, Júlia Assiat Monteiro Sambo, Diocreciano Matias Bero, Idalecia Cossa-Moiane, Esperança Guimarães and Jerónimo Langa for their contribution to the surveillance activities. The pediatrics professional from all sentinel sites for their dedication and effort with the children enrollment, data collection and shipment of the samples. Marta Cassocera passed away before the submission of the final version of this manuscript. Judite Salência-Ferrão accepts responsibility for the integrity and validity of the data collected and analyzed.

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Overuse of antibiotics in the management of acute diarrhea in children under five years in four provinces of Mozambique (2014-2019)

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