Antibiotic treatment to reduce the duration and severity of travellers’ diarrhoea (Protocol)

Objectives
\nThis is a protocol for a Cochrane Review (intervention). The objectives are as follows:
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\nTo assess the effects of antibiotic treatment for travellers’ diarrhoea in relation to:
\nillness duration;
\nadverse effects;
\nacquisition of multidrug‐resistant organisms.
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\nBackground
\nDescription of the condition
\nThe passing of three or more watery or unformed stools in 24 hours by a person travelling from a high‐income country to a low‐ or middle‐income country is often described as travellers’ diarrhoea (TD) (CDC 2019). Loose bowel motions which are passed more frequently than usual are sometimes accompanied by nausea, vomiting, abdominal pain, or cramping (De Bruyn 2000). TD is typically acute and benign, and functional impact is used by the expert panel of the International Society of Travel Medicine to define its severity. The following definitions are used: mild (acute) diarrhoea is tolerable, not distressing, and does not interfere with planned activities; moderate (acute) diarrhoea is distressing or interferes with planned activities; severe (acute) diarrhoea is incapacitating or completely prevents planned activities (Riddle 2017).
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\nAlthough usually self‐limiting, with those affected normally recovering in five days or less (De Bruyn 2000), TD can lead to dehydration, and in severe cases, significant complications (Angelo 2018; Bae 2018; Ericsson 2018). In about 10% of cases, symptoms will persist beyond seven days (Farthing 1992; Kass 2005). When TD lasts 14 days or more, it is sometimes termed chronic or persistent diarrhoea and its management differs from usual TD (De Bruyn 2000). In a study evaluating risk factors associated with TD, the use of TD self‐treatment, and the risk of irritable bowel syndrome (IBS) during travel, 3.7% of TD cases developed dysentery (Lalani 2015), which is defined as febrile diarrhoea mixed with visible blood, indicating a potentially serious condition that warrants separate clinical investigation and management (De Bruyn 2000).
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\nTD causes vary by region, though the source is rarely identified in less severe cases. Viral and parasitic infections can cause symptoms, but the bacterial source enterotoxigenic Escherichia coli (ETEC) represents the most common pathogen, responsible for nearly 30% of cases. Other common bacterial species causing TD include Campylobacter jejuni, Shigella spp., and Salmonella spp. The most common parasitic source is Giardia intestinalis, while Entamoeba histolytica and Cryptosporidium spp. are other responsible pathogens (Connor 2018; Dunn 2020; Shirley 2018). Viral causes include norovirus, most common in adults, and rotavirus, which until the advent of global vaccination initiatives had been most common in children (Hall 2013; Kirk 2015; Phillips 2010). Around 20% to 30% of antibiotic‐associated diarrhoea is due to disruption of the usual gut flora which causes Clostridioides difficile infection (CDC 2019; NICE 2015).
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\nOne of the determinants of risk for TD is travel to low‐income countries, and causes depend on the season, destination, and setting (Connor 2012; Riddle 2006). A recent review on persistent or chronic diarrhoea in returning travellers found that TD is a leading syndromic diagnosis (condition characterized by a group of symptoms that collectively indicate the presence of the disorder) across all global regions. The review found 6% incidence (proportionate morbidity of 60) observed in over 300,000 global travellers, which is comparable to other previous estimates (Duplessis 2017).
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\nDescription of the intervention
\nAntibiotics treat and prevent bacterial infections by either killing or inhibiting the growth of bacteria and are classed as antimicrobial drugs (Waksman 1947). Antibiotic groups are based on the following criteria: (1) their class (e.g. quinolones, penicillins, macrolides, aminoglycosides, tetracyclines); (2) their mechanism of action (bacteriostatic or bactericidal); and (3) their bacterial spectrum (narrow or broad) (Bérdy 2005). Bacterial enteropathogens are the predominant risk, thought to account for ≥ 80% to 90% of TD cases (CDC 2019).
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\nThere is increasing resistance to trimethoprim‐sulfamethoxazole and ampicillin. Therefore, these are less suitable for blind therapy. Fluoroquinolone antibiotics were once the treatment of choice, with standard doses for three to five days reducing the severity and duration of illness by at least 50% (Ericsson 1987; Mattila 1993). However, there is a growing resistance to fluoroquinolones among Campylobacter spp. in some Southeast Asian countries, which poses a significant challenge to its usefulness for TD treatment (Ericsson 2017). A prospective, multisite cross‐sectional study evaluating antibiotic prescriptions for the self‐treatment of TD among adult international travellers between 2009 and 2018 found that fluoroquinolone prescribing has declined dramatically, especially among travellers to Southeast Asia, while azithromycin is now the most frequently prescribed antibiotic for TD (Gandhi 2020). Since the last Cochrane Review on antibiotics for treatment of TD in 2000, there has been a notable decrease of fluoroquinolone use. This is not just due to the emergence of resistance, but also to 'black box' warnings in the USA, which has limited their use not only in children, but in adults too (Kuula 2019).
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\nAlthough fluoroquinolone antibiotics are generally well‐tolerated, concerns remain about fluoroquinolone‐induced articular toxicity in immature animals and the fact that the quality of evidence supporting clinical use in children is less robust. This has limited their use in children in some areas. However, clinicians still prescribe them, even as antimicrobial‐resistant pathogens continue to emerge (Patel 2016).
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\nHow the intervention might work
\nThe efficacy of antibiotics has been shown in the treatment of TD in many randomized placebo‐controlled and comparative trials (De Bruyn 2000). While acknowledging the importance of reducing the use of unnecessary antibiotics, there are circumstances in which these drugs are needed and are potentially life‐saving, particularly in severely sick children, those who have chronic conditions or specific risk factors, or in particular settings (Bruzzese 2018). As shown by several trials, antibiotics taken as a single dose or for up to three days will improve the condition within 20 to 36 hours, shortening the duration of diarrhoea by one to two days, when compared with controls taking placebos (Hill 2008). A graded position statement from Canadian health authorities endorsed the use of antibiotics for treatment of some cases of TD in 2015 (CATMAT 2015).
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\nIn 2017, a guideline on the prevention and treatment of TD was published, in which an expert panel used adapted GRADE methodology to make recommendations based on the available evidence. This guideline suggests that there is high‐certainty evidence supporting the effectiveness of antimicrobial therapy in most cases of moderate to severe TD. For management of most cases of mild diarrhoea, either increasing fluid intake only or loperamide or bismuth subsalicylate may suffice (Riddle 2017). Where indicated, a single‐dose regimen of azithromycin, a broad‐spectrum macrolide antibiotic with a long half‐life and excellent tissue penetration, is listed as a treatment choice for enteric infections (McMullan 2015).
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\nTravellers from low‐ and middle‐income countries apparently develop some partial protective immunity for a few months during subsequent travel, and those from countries with an intermediate or high risk of TD have a far lower incidence rate compared with those from low‐risk countries (Angelo 2017; Dupont 1977; Kuenzli 2017; Steffen 2003).
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\nTD is potentially serious in the elderly and very young, those with an impaired immune response, reduced gastric acidity as well as those with underlying health issues such as heart disease (De Bruyn 2000). TD can also result in other comorbid conditions and complications such as cardiovascular symptoms (Martins 2016), and other triggers such as IBS, lactose intolerance, and reduced effectiveness of some medications (Diemert 2006).
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\nWhy it is important to do this review
\nIncreased globalized trade and travel are risk factors for infectious disease emergence (IOM 2010), including TD. Although TD is unlikely to result in death, it can disrupt travel plans and lead to severe or incapacitating symptoms (De Bruyn 2000). TD remains a very relevant cause of death, mainly among infants and children (Steffen 2015; WHO 2022), and despite a significant decline from 2.5 million deaths in 2000, diarrhoeal infections are among the world’s top 10 causes of mortality, particularly in low‐income countries, where they rank fifth. They accounted for more than 1.5 million global deaths in 2019 (WHO 2020).
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\nDays lost to illness can be unexpectedly disruptive to international travellers, who are often on restricted schedules, in addition to other factors that might limit their accessibility to TD treatment. These include unfamiliar health systems, language barriers, remoteness, and time constraints, thereby creating a demand for prompt relief. There is a risk of significant impact on travel plans due to TD, with up to 52% of travellers reporting partial or complete incapacitation for a day (Lalani 2015). In up to 30% of travellers, significant or complete disablement has been reported (Riddle 2017). Despite an abundance of information on food and drink safety prior to overseas travel, travellers may not always comply with guidance for various reasons, such as the desire to sample local foods (Kass 2005). A multicentre study of 67,000 people travelling to India, Jamaica, Kenya, and Brazil found that more than 96% of travellers did not follow recommended safe food a

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