Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Washington University Library on 12/29/14 For personal use only.
Review
Management of acute infectious diarrhea for children living in resource-limited settings Expert Rev. Anti Infect. Ther. 12(5), 621–632 (2014)
Miguel O’Ryan G*1, Liat AshkenaziHoffnung2,3, Miguel A O’Ryan-Soriano4 and Shai Ashkenazi3,5 1 Microbiology and Mycology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile 2 Department of Pediatrics C, Schneider Children Hospital, Petach Tikva, Israel 3 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 4 Roberto del Rı´o Hospital, Santiago, Chile 5 Department of Pediatrics A, The Pickel Chair for Pediatric Research, Schneider Children Hospital, Petach Tikva, Israel *Author for correspondence: Tel.: +56 229 789 506 [email protected]
informahealthcare.com
Acute infectious gastroenteritis continues to be a leading cause of morbidity and mortality in children below 5 years of age, with the majority of deaths concentrated in 35 ‘low income’ countries. In these countries the under five years of age mortality rates reach 100 per 1000 live births, of which a significant proportion are associated with acute diarrhea. Rotavirus, cryptosporidium, Shigella spp and enterotoxigenic Escherichia coli are the main pathogens causing disease in these settings, although other bacteria and parasites can cause moderate to severe disease in different regions and situations. Treatment of children in these setting should be focused on appropriate rehydration, early hospitalization of severely malnourished children, zinc supplementation, and in specific situations, antimicrobials should be considered. The rationale for antimicrobial use should be based on the potential benefits based on published literature and the opportunity for use. This review provides a pathogen-specific update on the potential benefits of antimicrobials and suggests an empirical management approach for children suffering an acute watery or bloody diarrhea in a resource-limited region. KEYWORDS: acute diarrhea • Africa • antimicrobials • developing world • gastroenteritis • management • resource-deprived • resource-limited • treatment
In a previous review, we discussed the clinical aspects of severe acute gastroenteritis in children including the diagnostic approach and the recommended antimicrobial and nonantimicrobial management without any population distinctions [1]. The focus of the current publication is the treatment of acute gastroenteritis occurring in children living in resource-limited locations. Our search strategy included a PubMed search for the last 5 years (2009–2013) with the key words ‘gastroenteritis, diarrhea, dysentery, resource poor, resource limited and specific enteric pathogens’. Some of the recommendations are unfortunately based on small-sized studies and case series. We will update the overall impact of acute infectious diarrhea in these settings and the most common etiologic agents based on the most recent publications, and provide the basis for antimicrobial treatment and treatment guidelines based on the clinical presentation of the acute gastroenteritis episode. This review is thus complementary to the 2010 publication, and we recommend reading 10.1586/14787210.2014.901168
them both in order to obtain a comprehensive and practical perspective aimed mainly for medical personnel treating children in the most vulnerable world regions. What do we mean by resource-limited settings & how does this impact in acute infectious gastroenteritis?
Defining this term is not only difficult but can also be obnoxious for those regions or countries/states included within this category. Nevertheless, it is needed in order to set priorities and highlight treatment and prevention strategies aimed to reduce mortality and morbidity which, in the areas meeting this definition, are disproportionally high [2]. In the WHO ‘low income group’, which currently includes 35 countries—the great majority in Africa (25), a few in Southeast Asia (4) and the rest in Europe (2), Eastern Mediterranean (2), Latin America and Western pacific (1 each)—childhood mortality is at its highest, surpassing an under-5-years-of-age mortality
2014 Informa UK Ltd
ISSN 1478-7210
621
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Washington University Library on 12/29/14 For personal use only.
Review
O’Ryan, Ashkenazi-Hoffnung, O’Ryan-Soriano & Ashkenazi
rate of 100/1000 live births. In addition, 54 countries from all world regions belong to the ‘middle-low income group’, which share many of the critical problems associated with limited resources. These critical problems include limited access to clean drinking water and reasonable sanitation facilities (latrine, flush toilet or other improved sanitation facilities, the lack of which leads to substantial environmental contamination with fecal pathogens), lack of sufficient skilled health personnel, low family education level, high incidence of malnutrition and stunting, low compliance to relevant childhood vaccines, high HIV prevalence coupled with a lack of sufficient access to antiretroviral treatment, and disproportionately high slum dwelling in crowded urban areas [3]. In these settings, acute infectious gastroenteritis is significantly more common than in developed countries, with first episodes occurring earlier in life (mostly under 6 months of age) and with repeated severe cases occurring throughout childhood [4]. A recent longitudinal study demonstrated that children living in Bangladesh had on average an episode of clinically apparent diarrhea every 2.5 months, for a mean duration of 5.5 days per episode, so that these children actually had diarrhea for about 1 month of their first 12 months of life [5,6]. Importantly, using sensitive molecular techniques, one study documented that detecting multiple enteric pathogens in diarrheal stools of children in a resource-poor setting (Bangladesh) is the rule rather than the exception, with an average of 5.6 pathogens. Moreover, these authors also showed that an average of 4.3 enteropathogens were detected in asymptomatic Bangladeshi infants without diarrhea [6], which led to the term ‘intestinal pathobiome,’ which may prove to be relevant in these settings [5]. It is relatively simple to understand why the above-mentioned conditions occurring within resourcelimited settings and also within ghettos of poverty in more affluent countries lead to the vast majority of the estimated 700,000–800,000 annual deaths attributed to diarrheal diseases among children younger than 5 years of age worldwide [7–9]. The vicious cycle of poverty includes repeated and massive exposure to a variety of enteric pathogens beginning immediately after birth associated with environmental and water contamination and low maternal education; children with decreased capacity to respond to this infection due to malnutrition and stunting, and increased incidence of systemic bacterial and parasitic infections partly due to lack of appropriate vaccines and HIV; and lack of timely/appropriate treatments associated with low education levels and lack of medical resources. These conditions dictate distinct emphases and specific priorities in the management of acute gastroenteritis in resourcelimited settings, which will be highlighted in this review. Most common pathogens causing acute diarrhea in resource-limited settings
During the past 5 years, several studies, most of which have been performed in Africa, have intended to identify, among other objectives, the most relevant pathogens associated with acute diarrhea (TABLE 1) [10–14]. The considerable variability in 622
methodologies – including differences in definitions and severity of diarrhea, size of study populations, study duration, pathogens included and methods used for detection, use or not of a nondiarrhea control group, among other factors – complicate the interpretation and usefulness of several of these studies. Nevertheless, some general principles can be extrapolated from these studies and more precise etiological relations based on the most recent and robust Global Enteric Multicenter Study (GEMS) [14] can be advanced: in resource-limited settings, nearly all children will be harboring at least one potential pathogen throughout their childhood, difficulting the interpretation of a positive finding when diarrhea occurs; in diarrhea cases managed at the community level, current data do not allow to identify the most common etiological pathogens; it is likely that many cases are due to transitory imbalances of the diverse intestinal microbiota of children living in substandard conditions (which includes potentially pathogenic bacteria and parasites) and/or decreased periods of immunity associated with malnutrition, intercurrent diseases and HIV, among others; in moderate-to-severe acute diarrhea episodes, rotavirus is the leading cause of acute watery diarrhea in children below 24 months of age and the second cause in children 24–60 months of age, while other viruses such as astrovirus, adenovirus and sapovirus (possibly with the exception of norovirus as discussed further below) are less common; Shigella and Enterotoxigenic Escherichia coli (ETEC) are the leading bacterial causes in all age groups; Shigella is the most common cause of bloody diarrhea episodes; Cryptosporidium is the second most common cause of moderate–severe diarrhea (typically watery diarrhea) in children below 12 months of age and is the third in children 12– 24 months; later in life, it loses importance; Campylobacter can cause, in a lower proportion of children, acute moderate–severe diarrhea and in some areas, it is highly common in mild diarrhea cases, most probably reflecting significant human–animal contact; the role of Giardia as a cause of diarrhea is difficult to interpret because it is very common in children without diarrhea; it probably is a cause of acute diarrhea in young infants suffering a primary infection, who may become rapidly protected against recurrent symptomatic infections. Giardia is likely to cause prolonged diarrhea in a subset of children with specific susceptibilities such as severe malnutrition [15]; the role of norovirus as a cause of acute diarrhea remains unclear in these regions as data are conflicting; the high detection in nondiarrhea children will require studies focused on dissecting the role of early infection, prolonged shedding of this virus and possibly the role of viral load in occurrence of disease; Vibrio cholera needs to be considered in the differential diagnosis in endemic areas; and Entoamoeba causes bloody diarrhea, but it is not a common pathogen in most of the regions studied. Antimicrobial approach for bacterial gastroenteritis General principles
The potential goals of antimicrobial therapy of children with bacterial gastroenteritis are: to improve clinical symptoms (diarrhea, vomiting, fever and abdominal cramps); to shorten fecal Expert Rev. Anti Infect. Ther. 12(5), (2014)
informahealthcare.com
‡
Salmonella, Shigella, Vibrio, Campylobacter and Escherichia coli including pathotype differentiation by PCR (referenced but not described). MAC, SS, DCA agars (including Selenite F broth as pre-enrichment for Salmonella). DEC: Diarrheogenic E. coli; EAEC: Enteroaggregative E. Coli; STEC: Shiga toxin-producing E. coli.
†
[13]
This study most probably reflects the high degree of intestinal contamination in children living in the poorest world regions. The role of these pathogens in acute diarrhea is obscured by the fact that cases were recruited in the field with a relatively broad definition of 3 or more unformed stools within 24 h irrespective of severity. Recruitment periods of 3 weeks also limit the overall generalization of these results Most common pathogens: Campylobacter including non-identified species (N = 209) and Campylobacter jejuni (161), G. lamblia (276), DEC (163), T. intestinales (136), rotavirus (112), remaining pathogens all less than 50 cases Comparing with controls only G. lamblia (crude OR; 95% CI: 1.7; 1.2–2.5), Trichomonas intestinales (3.2; 1.7–6.1) and Entamoeba histolytica (5.1; 1.2–20.9) were more common in diarrhea children
Stools were cultured for bacterial pathogens (except Vibrio apparently), and DEC was identified by multiplex PCR; rotavirus, adenovirus and astrovirus (not norovirus) were identified by EIA and parasites by microscopy A total of 2196 diarrhea cases and 496 controls were analyzed. Diarrhea characteristics were diverse (loose 65%, watery 25%, few bloody diarrhea cases). A total of 55% of cases and 46% of controls positive for >1 pathogen (~40% mixed infections)
14 sites in Madagascar Prospective cross-sectional survey performed during a 3-week period at each site within the peak diarrhea period (rainy season); children 8 years) or ciprofloxacin (>17 years)‡. Resistance is relatively common
Antibiotic therapy is important to reduce transmission. It is recommended mainly for the dysenteric form of Campylobacter gastroenteritis and most efficacious when started within 3 days after onset of the disease [33–35]
Campylobacter spp.
First-line treatment is metronidazole (30 mg/kg/day for 10 days). In unresponsive or relapsed cases – vancomycin p.o. (40 mg/kg/day)
Relatively uncommon in resource-poor settings. Stopping the offending antibiotic, when possible, is usually sufficient. Antibiotic therapy is recommended for moderate or severe cases [20]
Clostridium difficile
The clinical and bacteriological efficacies of antibiotic therapy have been documented in travelers infected with this organism. Recommended agents are azithromycin, ciprofloxacin (>17 years)‡ or rifaximin (>12 years)
A common cause of gastroenteritis among infants living in resource-poor settings, which can lead to persistent diarrhea with biofilm formation [20]
Enteroaggregative Escherichia coli
Antibiotic therapy is not recommended as it might increase the risk of hemolytic–uremic syndrome (albeit in uncontrolled studies and therefore controversial)
Called also Shiga toxin-producing E. coli. Usually causes self-limited diarrhea with low or no fever. The major problem is the development of hemolytic–uremic syndrome [38,39]
Enterohemorrhagic E. coli
Recommended agents are TMP/SMX, when susceptible, azithromycin or ciprofloxacin (>17 years)‡
Similar to Shigella spp. in terms of biology, clinical presentation and probably also in response to antibiotic therapy [20]
Enteroinvasive E. coli
First-line treatment is TMP/ (8 mg/kg/day of TMP), when susceptible. Alternatives are azithromycin (10 mg/kg/day for 3 days), ciprofloxacin‡ p.o. (20–30 mg/kg/day), cefixime (8 mg/kg/day for 5 days) or rifaximin (>12 years, 600 mg/day, for 3 days)
A common cause of gastroenteritis in resourcepoor locations and in travelers to these areas [36,40]
Enterotoxigenic E. coli
Recommended agents are oral neomycin (100 mg/kg/day for 5 days), gentamicin, TMP/SMX or ciprofloxacin‡
Can cause prolonged or chronic diarrhea Disease is usually self-limited; antibiotic therapy can reduce spread [20]
Enterotopathogenic E. coli
First-line agents are TMP/SMX (8 mg/kg/day of TMP) for a known susceptible strain or azithromycin (10 mg/kg/day) Alternative treatment – ciprofloxacin‡ p.o. (20–30 mg/kg/day). For severe cases – parenteral ceftriaxone (50–100 mg/kg/day) is recommended
Antibiotic therapy is indicated only in high-risk children (detailed in the text) to reduce the risk of bacteremia and extraintestinal focal infections Antibiotic resistance is increasing worldwide [30,32]
Salmonella spp. (nontyphoidal)
First-line agents are oral TMP/SMX (8 mg/kg/day of TMP) or ampicillin (100 mg/kg/day) for a known susceptible strain, or azithromycin (12 mg/kg on day 1, followed by 6 mg/kg for 4 days) Alternative agents are cefixime (8 mg/kg/day), ciprofloxacin‡ (20–30 mg/kg/day) or nalidixic acid (55 mg/kg/d) For severe cases: parenteral (intravenous or intramuscular) ceftriaxone (50 mg/kg for 2–5 days)
Because of the low infectious dose, shigellosis is easily transmitted from person to person and is common in resource-poor settings. Antibiotics are highly recommended for proven or suspected shigellosis to shorten the clinical course and to reduce transmission [22] Antibiotic resistance is increasing worldwide [23–26]
Shigella spp.
Recommended agents are TMP/SMX (when susceptible), doxycycline (>8 years), ciprofloxacin (>17 years)‡ or azithromycin (10 mg/kg/day for 3 days or a single 20 mg/kg dose)
Because of the high- volume diarrhea, rapid fluid and electrolyte replacement is crucial. Antibiotic therapy is recommended for confirmed or suspected case by local epidemiology or travel history [41]
Vibrio cholera
†
Depends on local antibiotic susceptibility profile which should be monitored. Can be used in children
Review
Management of acute infectious diarrhea for children living in resource-limited settings Expert Rev. Anti Infect. Ther. 12(5), 621–632 (2014)
Miguel O’Ryan G*1, Liat AshkenaziHoffnung2,3, Miguel A O’Ryan-Soriano4 and Shai Ashkenazi3,5 1 Microbiology and Mycology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile 2 Department of Pediatrics C, Schneider Children Hospital, Petach Tikva, Israel 3 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 4 Roberto del Rı´o Hospital, Santiago, Chile 5 Department of Pediatrics A, The Pickel Chair for Pediatric Research, Schneider Children Hospital, Petach Tikva, Israel *Author for correspondence: Tel.: +56 229 789 506 [email protected]
informahealthcare.com
Acute infectious gastroenteritis continues to be a leading cause of morbidity and mortality in children below 5 years of age, with the majority of deaths concentrated in 35 ‘low income’ countries. In these countries the under five years of age mortality rates reach 100 per 1000 live births, of which a significant proportion are associated with acute diarrhea. Rotavirus, cryptosporidium, Shigella spp and enterotoxigenic Escherichia coli are the main pathogens causing disease in these settings, although other bacteria and parasites can cause moderate to severe disease in different regions and situations. Treatment of children in these setting should be focused on appropriate rehydration, early hospitalization of severely malnourished children, zinc supplementation, and in specific situations, antimicrobials should be considered. The rationale for antimicrobial use should be based on the potential benefits based on published literature and the opportunity for use. This review provides a pathogen-specific update on the potential benefits of antimicrobials and suggests an empirical management approach for children suffering an acute watery or bloody diarrhea in a resource-limited region. KEYWORDS: acute diarrhea • Africa • antimicrobials • developing world • gastroenteritis • management • resource-deprived • resource-limited • treatment
In a previous review, we discussed the clinical aspects of severe acute gastroenteritis in children including the diagnostic approach and the recommended antimicrobial and nonantimicrobial management without any population distinctions [1]. The focus of the current publication is the treatment of acute gastroenteritis occurring in children living in resource-limited locations. Our search strategy included a PubMed search for the last 5 years (2009–2013) with the key words ‘gastroenteritis, diarrhea, dysentery, resource poor, resource limited and specific enteric pathogens’. Some of the recommendations are unfortunately based on small-sized studies and case series. We will update the overall impact of acute infectious diarrhea in these settings and the most common etiologic agents based on the most recent publications, and provide the basis for antimicrobial treatment and treatment guidelines based on the clinical presentation of the acute gastroenteritis episode. This review is thus complementary to the 2010 publication, and we recommend reading 10.1586/14787210.2014.901168
them both in order to obtain a comprehensive and practical perspective aimed mainly for medical personnel treating children in the most vulnerable world regions. What do we mean by resource-limited settings & how does this impact in acute infectious gastroenteritis?
Defining this term is not only difficult but can also be obnoxious for those regions or countries/states included within this category. Nevertheless, it is needed in order to set priorities and highlight treatment and prevention strategies aimed to reduce mortality and morbidity which, in the areas meeting this definition, are disproportionally high [2]. In the WHO ‘low income group’, which currently includes 35 countries—the great majority in Africa (25), a few in Southeast Asia (4) and the rest in Europe (2), Eastern Mediterranean (2), Latin America and Western pacific (1 each)—childhood mortality is at its highest, surpassing an under-5-years-of-age mortality
2014 Informa UK Ltd
ISSN 1478-7210
621
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Washington University Library on 12/29/14 For personal use only.
Review
O’Ryan, Ashkenazi-Hoffnung, O’Ryan-Soriano & Ashkenazi
rate of 100/1000 live births. In addition, 54 countries from all world regions belong to the ‘middle-low income group’, which share many of the critical problems associated with limited resources. These critical problems include limited access to clean drinking water and reasonable sanitation facilities (latrine, flush toilet or other improved sanitation facilities, the lack of which leads to substantial environmental contamination with fecal pathogens), lack of sufficient skilled health personnel, low family education level, high incidence of malnutrition and stunting, low compliance to relevant childhood vaccines, high HIV prevalence coupled with a lack of sufficient access to antiretroviral treatment, and disproportionately high slum dwelling in crowded urban areas [3]. In these settings, acute infectious gastroenteritis is significantly more common than in developed countries, with first episodes occurring earlier in life (mostly under 6 months of age) and with repeated severe cases occurring throughout childhood [4]. A recent longitudinal study demonstrated that children living in Bangladesh had on average an episode of clinically apparent diarrhea every 2.5 months, for a mean duration of 5.5 days per episode, so that these children actually had diarrhea for about 1 month of their first 12 months of life [5,6]. Importantly, using sensitive molecular techniques, one study documented that detecting multiple enteric pathogens in diarrheal stools of children in a resource-poor setting (Bangladesh) is the rule rather than the exception, with an average of 5.6 pathogens. Moreover, these authors also showed that an average of 4.3 enteropathogens were detected in asymptomatic Bangladeshi infants without diarrhea [6], which led to the term ‘intestinal pathobiome,’ which may prove to be relevant in these settings [5]. It is relatively simple to understand why the above-mentioned conditions occurring within resourcelimited settings and also within ghettos of poverty in more affluent countries lead to the vast majority of the estimated 700,000–800,000 annual deaths attributed to diarrheal diseases among children younger than 5 years of age worldwide [7–9]. The vicious cycle of poverty includes repeated and massive exposure to a variety of enteric pathogens beginning immediately after birth associated with environmental and water contamination and low maternal education; children with decreased capacity to respond to this infection due to malnutrition and stunting, and increased incidence of systemic bacterial and parasitic infections partly due to lack of appropriate vaccines and HIV; and lack of timely/appropriate treatments associated with low education levels and lack of medical resources. These conditions dictate distinct emphases and specific priorities in the management of acute gastroenteritis in resourcelimited settings, which will be highlighted in this review. Most common pathogens causing acute diarrhea in resource-limited settings
During the past 5 years, several studies, most of which have been performed in Africa, have intended to identify, among other objectives, the most relevant pathogens associated with acute diarrhea (TABLE 1) [10–14]. The considerable variability in 622
methodologies – including differences in definitions and severity of diarrhea, size of study populations, study duration, pathogens included and methods used for detection, use or not of a nondiarrhea control group, among other factors – complicate the interpretation and usefulness of several of these studies. Nevertheless, some general principles can be extrapolated from these studies and more precise etiological relations based on the most recent and robust Global Enteric Multicenter Study (GEMS) [14] can be advanced: in resource-limited settings, nearly all children will be harboring at least one potential pathogen throughout their childhood, difficulting the interpretation of a positive finding when diarrhea occurs; in diarrhea cases managed at the community level, current data do not allow to identify the most common etiological pathogens; it is likely that many cases are due to transitory imbalances of the diverse intestinal microbiota of children living in substandard conditions (which includes potentially pathogenic bacteria and parasites) and/or decreased periods of immunity associated with malnutrition, intercurrent diseases and HIV, among others; in moderate-to-severe acute diarrhea episodes, rotavirus is the leading cause of acute watery diarrhea in children below 24 months of age and the second cause in children 24–60 months of age, while other viruses such as astrovirus, adenovirus and sapovirus (possibly with the exception of norovirus as discussed further below) are less common; Shigella and Enterotoxigenic Escherichia coli (ETEC) are the leading bacterial causes in all age groups; Shigella is the most common cause of bloody diarrhea episodes; Cryptosporidium is the second most common cause of moderate–severe diarrhea (typically watery diarrhea) in children below 12 months of age and is the third in children 12– 24 months; later in life, it loses importance; Campylobacter can cause, in a lower proportion of children, acute moderate–severe diarrhea and in some areas, it is highly common in mild diarrhea cases, most probably reflecting significant human–animal contact; the role of Giardia as a cause of diarrhea is difficult to interpret because it is very common in children without diarrhea; it probably is a cause of acute diarrhea in young infants suffering a primary infection, who may become rapidly protected against recurrent symptomatic infections. Giardia is likely to cause prolonged diarrhea in a subset of children with specific susceptibilities such as severe malnutrition [15]; the role of norovirus as a cause of acute diarrhea remains unclear in these regions as data are conflicting; the high detection in nondiarrhea children will require studies focused on dissecting the role of early infection, prolonged shedding of this virus and possibly the role of viral load in occurrence of disease; Vibrio cholera needs to be considered in the differential diagnosis in endemic areas; and Entoamoeba causes bloody diarrhea, but it is not a common pathogen in most of the regions studied. Antimicrobial approach for bacterial gastroenteritis General principles
The potential goals of antimicrobial therapy of children with bacterial gastroenteritis are: to improve clinical symptoms (diarrhea, vomiting, fever and abdominal cramps); to shorten fecal Expert Rev. Anti Infect. Ther. 12(5), (2014)
informahealthcare.com
‡
Salmonella, Shigella, Vibrio, Campylobacter and Escherichia coli including pathotype differentiation by PCR (referenced but not described). MAC, SS, DCA agars (including Selenite F broth as pre-enrichment for Salmonella). DEC: Diarrheogenic E. coli; EAEC: Enteroaggregative E. Coli; STEC: Shiga toxin-producing E. coli.
†
[13]
This study most probably reflects the high degree of intestinal contamination in children living in the poorest world regions. The role of these pathogens in acute diarrhea is obscured by the fact that cases were recruited in the field with a relatively broad definition of 3 or more unformed stools within 24 h irrespective of severity. Recruitment periods of 3 weeks also limit the overall generalization of these results Most common pathogens: Campylobacter including non-identified species (N = 209) and Campylobacter jejuni (161), G. lamblia (276), DEC (163), T. intestinales (136), rotavirus (112), remaining pathogens all less than 50 cases Comparing with controls only G. lamblia (crude OR; 95% CI: 1.7; 1.2–2.5), Trichomonas intestinales (3.2; 1.7–6.1) and Entamoeba histolytica (5.1; 1.2–20.9) were more common in diarrhea children
Stools were cultured for bacterial pathogens (except Vibrio apparently), and DEC was identified by multiplex PCR; rotavirus, adenovirus and astrovirus (not norovirus) were identified by EIA and parasites by microscopy A total of 2196 diarrhea cases and 496 controls were analyzed. Diarrhea characteristics were diverse (loose 65%, watery 25%, few bloody diarrhea cases). A total of 55% of cases and 46% of controls positive for >1 pathogen (~40% mixed infections)
14 sites in Madagascar Prospective cross-sectional survey performed during a 3-week period at each site within the peak diarrhea period (rainy season); children 8 years) or ciprofloxacin (>17 years)‡. Resistance is relatively common
Antibiotic therapy is important to reduce transmission. It is recommended mainly for the dysenteric form of Campylobacter gastroenteritis and most efficacious when started within 3 days after onset of the disease [33–35]
Campylobacter spp.
First-line treatment is metronidazole (30 mg/kg/day for 10 days). In unresponsive or relapsed cases – vancomycin p.o. (40 mg/kg/day)
Relatively uncommon in resource-poor settings. Stopping the offending antibiotic, when possible, is usually sufficient. Antibiotic therapy is recommended for moderate or severe cases [20]
Clostridium difficile
The clinical and bacteriological efficacies of antibiotic therapy have been documented in travelers infected with this organism. Recommended agents are azithromycin, ciprofloxacin (>17 years)‡ or rifaximin (>12 years)
A common cause of gastroenteritis among infants living in resource-poor settings, which can lead to persistent diarrhea with biofilm formation [20]
Enteroaggregative Escherichia coli
Antibiotic therapy is not recommended as it might increase the risk of hemolytic–uremic syndrome (albeit in uncontrolled studies and therefore controversial)
Called also Shiga toxin-producing E. coli. Usually causes self-limited diarrhea with low or no fever. The major problem is the development of hemolytic–uremic syndrome [38,39]
Enterohemorrhagic E. coli
Recommended agents are TMP/SMX, when susceptible, azithromycin or ciprofloxacin (>17 years)‡
Similar to Shigella spp. in terms of biology, clinical presentation and probably also in response to antibiotic therapy [20]
Enteroinvasive E. coli
First-line treatment is TMP/ (8 mg/kg/day of TMP), when susceptible. Alternatives are azithromycin (10 mg/kg/day for 3 days), ciprofloxacin‡ p.o. (20–30 mg/kg/day), cefixime (8 mg/kg/day for 5 days) or rifaximin (>12 years, 600 mg/day, for 3 days)
A common cause of gastroenteritis in resourcepoor locations and in travelers to these areas [36,40]
Enterotoxigenic E. coli
Recommended agents are oral neomycin (100 mg/kg/day for 5 days), gentamicin, TMP/SMX or ciprofloxacin‡
Can cause prolonged or chronic diarrhea Disease is usually self-limited; antibiotic therapy can reduce spread [20]
Enterotopathogenic E. coli
First-line agents are TMP/SMX (8 mg/kg/day of TMP) for a known susceptible strain or azithromycin (10 mg/kg/day) Alternative treatment – ciprofloxacin‡ p.o. (20–30 mg/kg/day). For severe cases – parenteral ceftriaxone (50–100 mg/kg/day) is recommended
Antibiotic therapy is indicated only in high-risk children (detailed in the text) to reduce the risk of bacteremia and extraintestinal focal infections Antibiotic resistance is increasing worldwide [30,32]
Salmonella spp. (nontyphoidal)
First-line agents are oral TMP/SMX (8 mg/kg/day of TMP) or ampicillin (100 mg/kg/day) for a known susceptible strain, or azithromycin (12 mg/kg on day 1, followed by 6 mg/kg for 4 days) Alternative agents are cefixime (8 mg/kg/day), ciprofloxacin‡ (20–30 mg/kg/day) or nalidixic acid (55 mg/kg/d) For severe cases: parenteral (intravenous or intramuscular) ceftriaxone (50 mg/kg for 2–5 days)
Because of the low infectious dose, shigellosis is easily transmitted from person to person and is common in resource-poor settings. Antibiotics are highly recommended for proven or suspected shigellosis to shorten the clinical course and to reduce transmission [22] Antibiotic resistance is increasing worldwide [23–26]
Shigella spp.
Recommended agents are TMP/SMX (when susceptible), doxycycline (>8 years), ciprofloxacin (>17 years)‡ or azithromycin (10 mg/kg/day for 3 days or a single 20 mg/kg dose)
Because of the high- volume diarrhea, rapid fluid and electrolyte replacement is crucial. Antibiotic therapy is recommended for confirmed or suspected case by local epidemiology or travel history [41]
Vibrio cholera
†
Depends on local antibiotic susceptibility profile which should be monitored. Can be used in children
