Antibiotic Therapy for Acute Watery Diarrhea and Dysentery

Abstract

Diarrheal disease affects a large proportion of military personnel deployed to developing countries, resulting in decreased job performance and operational readiness. Travelers’ diarrhea is self-limiting and generally resolves within five days; however, antibiotic treatment significantly reduces symptom severity and duration of illness. Presently, azithromycin is the preferred first-line antibiotic for the treatment of acute watery diarrhea (single dose 500 mg), as well as for febrile diarrhea and dysentery (single dose 1000 mg). Levofloxacin and ciprofloxacin are also options for acute watery diarrhea (single dose 500 mg and 750 mg, respectively) and febrile diarrhea/dysentery in areas with high rates of Shigella (500 mg once for three days [once daily with levofloxacin and twice daily with ciprofloxacin]), but are becoming less effective due to increasing fluoroquinolone resistance, particularly among Campylobacter spp. Another alternate for acute watery diarrhea is rifaximin (200 mg three times per day for three days); however, it should not be used with invasive illness. Use of loperamide in combination with antibiotic treatment is also beneficial as it has been shown to further reduce gastrointestinal symptoms and duration of illness. Due to regional differences in the predominance of pathogens and resistance levels, choice of antibiotic should take travel destination into consideration.

INTRODUCTION

Travelers visiting less developed nations are commonly affected by episodes of acute watery diarrhea or travelers’ diarrhea (TD), which is characterized per study definitions by having at least three unformed stools within 24 hours frequently associated with other clinical symptoms, including vomiting, abdominal pain or cramping, and nausea.^1,2 In general, TD is an acute syndrome commonly self-resolving within three to five days. Nonetheless, in a small number of cases, approximately 3% of patients may develop persistent TD with symptoms lasting for at least two weeks, while up to 20% are bedbound for 1–2 days and 40% experience decreased ability to complete planned activities during the 1–2 days of peak illness.^1–3 A more severe form of TD is dysentery, which is characterized by bloody diarrhea often accompanied by fever.^1,2 Bacterial enteropathogens, including diarrheagenic Escherichia coli (predominantly enterotoxigenic and enteroaggregative E. coli [ETEC and EAEC, respectively]), Campylobacter spp., Shigella spp., and non-typhoidal Salmonella spp. are the predominant etiologic agents associated with TD.² Although the circumstances of travel are different, deployed military personnel are also at risk for developing TD and/or dysentery.^4–10

Even with mild symptoms, diarrheal disease among deployed military personnel may impact operational readiness. In particular, job performance declines as the affected soldier misses patrols or other duties due to dehydration requiring IV fluids, having fecal incontinence, confined to bed, and/or hospitalization. Assessment of military personnel serving in support of operations in Iraq and Afghanistan found that 45% of individuals with diarrhea reported decreased job performance over a median of three days.⁸ Another survey of deployed military personnel found that 24%, 28%, and 32% had at least one diarrheal episode while serving in Kuwait, Iraq, and Afghanistan, respectively, with a mean duration of 2.7 days of illness. Among the personnel with diarrheal symptoms, 14% in Kuwait reported a decrease in job performance, while it was 21% for both Iraq and Afghanistan (median of 2 days with impacted job performance).¹¹

Empiric antibiotic therapy has been proven to be effective at managing the clinical symptoms and reducing the duration of diarrheal illness to approximately 1.5 days.^5,12,13 In a Cochrane meta-analysis of six randomized, double-blind, placebo-controlled trials several years ago, the efficacy of antibiotic treatment with TD were assessed. Antibiotics examined in the trials included trimethoprim/sulfamethoxazole, bicozamycin, norfloxacin, ciprofloxacin, and fleroxacin. The findings indicated a significantly greater number of patients with clinical cure (i.e., resolution of diarrheal illness and associated symptoms) at 72 hours in the antibiotics group compared to placebo (overall odds ratio: 5.9; 95% confidence interval: 4.1–8.6). In addition, the time to last unformed stool (TLUS) ranged from 25 to 39 hours with antibiotic use, while it was 54 to 64 hours with the placebo.¹²

Over the past two decades, recommendations related to antibiotic regimens have changed. Initially, treatment for TD involved a 3–5 day course of antibiotics;^2,13,14 however, findings from multiple randomized control trials supported the shift to single-dose regimens in recent guidelines.^15,16 Single-dose regimens were found to be as or more effective than a 3-day regimen in many trials.^10,17,18 The use of a single dose has a higher likelihood of compliance compared to multiple doses over 3–5 days.

Antimotility agents (e.g., loperamide [Imodium®]) are frequently used in combination with antibiotic therapy. Used on its own, loperamide provides symptomatic relief over placebo, but does not result in clinical cure.^2,19–21 A separate meta-analysis of seven randomized, double-blind, placebo-controlled trials and two randomized, evaluator-blind clinical trials assessed the benefit of using loperamide in combination with antibiotic therapy (Figure 1). The studies involved different antibiotic regimens, including trimethoprim-sulfamethoxale, ciprofloxacin, ofloxacin, rifaximin, and azithromycin. When the 24-hour clinical cure rates were evaluated, use of combination therapy (antibiotics plus loperamide) showed a benefit compared to use of antibiotic alone (overall odds ratio: 2.6; 95% confidence interval: 1.8–3.6).²¹

Figure 1.

Forest plot of odds ratios for clinical cure at 24 hours comparing treatment with antibiotics alone to combination of antibiotics with loperamide. A pooled summary estimate is also included. This figure has been reprinted from Riddle et al.²¹ by permission of Oxford University Press.

When deployed personnel experience diarrheal symptoms, the main objective is to effectively treat the illness in order to allow the individual to expedite their return to full duty status. Due to geographic differences in the distribution of pathogens, the choice of antibiotic is often dependent upon the destination.^2,22 Furthermore, increased levels of resistance have reduced the effectiveness of previously preferred first-line antibiotics. Trimethoprim-sulfamethoxazole is one example of an antibiotic that is no longer commonly prescribed as a result of the increased resistance of ETEC and Salmonella spp., as well as inactivity against Campylobacter jejuni.² Antibiotic agents currently being prescribed are azithromycin, ciprofloxacin, levofloxacin, and rifaximin (Table 1). The following summarizes information related to antibiotic management of TD with a focus on efficacy, safety, and adjunct loperamide therapy of these agents.

Table 1.

Empiric Antibiotic Therapy for Acute Watery Diarrhea

Antibiotic	Dosage (adult)	Indication	Notes
Azithromycin1	500 mg (single dose) [1000 mg (single dose) or 500 mg (once daily for 3 days) for febrile diarrhea or dysentery]	Preferred agent in ALL regions of the world;	Antibiotic susceptibility across broad geographic range supports empiric use (particularly important in Southeast Asia with high rates of Campylobacter spp.)
		To be used when invasive pathogens (e.g., Campylobacter jejuni) are suspected as etiologic agent
Fluoroquinolones1
Levofloxacin	500 mg (single dose) [500 mg (once a day for up to 3 days) for febrile diarrhea or dysentery]	Re-evaluate 12–24 hours after single dose; continue for up to 3 days if diarrhea not resolved;	In cases of febrile diarrhea / dysentery in regions with high rates of Shigella, levofloxacin may be used
Ciprofloxacin	750 mg (single dose); 500 mg twice a day (up to 3 days)		Becoming less effective worldwide due to increasing antimicrobial resistance
Rifaximin	200 mg three times a day (3 days)	Effective when non-invasive Escherichia coli is etiologic agent;	Inactive against invasive causes of diarrhea.
		Should only be used with acute watery diarrhea

¹Single dose use is an off-label indication based on several randomized clinical trials and published practice guidance^15,16

AZITHROMYCIN

Efficacy

Azithromycin is an azalide antibiotic in the macrolide family (includes erythromycin) with activity against common enteropathogens.²³ Oral administration of azithromycin (500 mg dose) results in 37% bioavailability with a peak serum concentration of 0.4 mg/l. High intracellular levels of azithromycin are also found in the tissues 12 to 24 hours after oral dosing (mean >2 mg/l), which may persist for days (half-life of 2.3 days in prostate and 3.2 days in tonsillar tissue).²⁴

Due to the increasing resistance of enteropathogens to first-line antibiotics (e.g., fluoroquinolones and trimethoprim-sulfamethoxazole), azithromycin has become a preferred choice for the treatment of TD, particularly in regions of the world where prevalent Campylobacter spp. are largely resistant to fluoroquinolones, such as Southeast Asia.^10,17 In one randomized, double-blind trial in Mexico, patients received either a single dose of azithromycin (1000 mg) or levofloxacin (500 mg). Rate of treatment failure (9.5% versus 7.5%) and median TLUS (22.3 versus 21.5 hours) was not significantly different between the azithromycin and levofloxacin groups, respectively. It was noted that a significantly lower proportion of subjects in the azithromycin group had a TLUS of zero hours compared to levofloxacin (8% versus 21%, respectively; p=0.01), indicating that the levofloxacin patients had a more rapid clinical response. Overall, it was concluded that a single oral dose of azithromycin was as effective as levofloxacin for the treatment of TD.¹⁷

The effectiveness of azithromycin regimens (single-dose of 1000 mg or 500 mg/day for three days) with levofloxacin (500 mg/day for three days) was also assessed in a randomized, double-blind trial involving military personnel with TD in Thailand, with the outcome being clinical cure at 72 hours. Campylobacter spp. were the predominant etiologic agent (recovered from 64% of subjects, of which 95% was Campylobacter jejuni) followed by non-typhoidal Salmonella spp. (17%). The median TLUS was 35 and 45 hours for the single-dose and three-day azithromycin regimens, respectively, compared to 50 hours with levofloxacin (significantly different compared to single-dose azithromycin; p=0.03). The single dose of azithromycin resulted in the highest 72-hour cure rate (96%) followed by 85% with the three-day regimen and 71% with levofloxacin (p=0.001). Furthermore, the microbiological cure rates of Campylobacter spp. infections was 96% and 100% for the azithromycin single-dose and three-day regimen, respectively, compared to only 21% with levofloxacin (p=0.001). There was no significant difference in TLUS between the antibiotic regimen groups with non-Campylobacter spp. infections. These data indicate the effectiveness of azithromycin in treating TD in regions with increasing fluoroquinolone resistance.¹⁰ Prior studies have reported similar effectiveness of azithromycin at decreasing the duration of diarrhea when compared to ciprofloxacin.^25,26

Safety

Mild and self-limiting adverse events have been reported by patients prescribed azithromycin; however, they are not significantly different from adverse events reported with levofloxacin. The majority of complaints involve gastrointestinal symptoms (e.g., mild abdominal pain, fecal urgency, nausea, vomiting, constipation, and flatulence). Fatigue, insomnia, heartburn, chills, body ache, and headaches have also been reported and one subject had a transient skin rash along with anxiety.¹⁷ Nausea within 30 minutes of dosing has been reported among a higher proportion of patients taking a single dose of 1000 mg (with/without loperamide) compared to those prescribed levofloxacin.^10,27 A recent analysis also found an increased risk of ventricular arrhythmia (odds ratio: 4.32; 95% confidence interval: 2.95–6.33) and cardiovascular death (odds ratio: 2.62; 95% confidence interval: 1.69–4.06) associated with azithromycin use.²⁸ Further research is needed to determine whether the risk is directly related to azithromycin usage or the result of interactions with other medications and/or the comorbid illness.

Adjunct Therapy

As use of loperamide has been observed to reduce clinical symptoms associated with TD, a randomized, double-blind trial among travelers in Mexico with TD examined whether the combination of loperamide with azithromycin therapy provided an added benefit. Patients received a single dose of azithromycin alone (500 or 1000 mg) or in combination with loperamide (azithromycin: 500 mg; loperamide: 4 mg initially with 2 mg after each unformed stool; not exceeding 16 mg/day for two days). The average duration of diarrhea was significantly shorter in the azithromycin/loperamide combination group compared to both doses of azithromycin alone (11 versus 34 hours; p=0.0002). Within 24 hours of treatment, there were also significantly fewer loose unformed stools passed in the azithromycin/loperamide group (1.2 versus 3.4; p<0.0001). Furthermore, the proportion of subjects with treatment failure was significantly lower in the azithromycin/loperamide group (4%) compared to both doses of azithromycin alone (20–21%; p=0.01).²⁹

Another randomized, double-blind trial among military personnel with TD in Turkey was conducted to assess if the combination of loperamide with azithromycin therapy was as effective as the use of loperamide with levofloxacin. Patients received a single dose of either azithromycin (1000 mg) or levofloxacin (500 mg) with loperamide (4 mg initially with 2 mg after each unformed stool; not exceeding 16 mg/day). A higher proportion of subjects reported nausea within 30 minutes of dosing in the azithromycin group compared to levofloxacin (8% versus 1%; p=0.004). There was no significant difference regarding median TLUS (13 and 3 hours) and proportion of patients with clinical cure at 24 hours (33% and 39%) between the azithromycin and levofloxacin groups, indicating that azithromycin with loperamide was as effective as the combination of loperamide with levofloxacin.²⁷

Summary

Azithromycin is well-tolerated and has been shown to be effective using a single dose at reducing the duration of TD to less than one day for the majority of patients. It is also significantly more effective against Campylobacter spp. infections than levofloxacin, so it should be considered the preferred agent in regions where there is high fluoroquinolone resistance, which has been increasing worldwide. In addition, there is a benefit to use of adjunct therapy with loperamide as it does significantly further reduce both symptoms and duration of diarrheal illness.

FLUOROQUINOLONES

Efficacy

Ciprofloxacin

Ciprofloxacin is a fluoroquinolone antibiotic with a wide spectrum of antimicrobial activity and low cross resistance to non-quinolone antibiotic classes. Oral administration of ciprofloxacin results in rapid absorption through the gastrointestinal tract with approximately 70–80% bioavailability (~19% excreted in feces). A short half-life (3.5 to 5 hours) also allows for multiple doses per day.³⁰

Multiple studies have demonstrated the ability of ciprofloxacin to significantly reduce the time from diarrheal disease onset to clinical cure. In one randomized, blinded control study, patients with gastroenteritis received 500 mg ciprofloxacin or a placebo twice a day for five days. Campylobacter jejuni (predating emergence of fluoroquinolone resistance) and Salmonella enteritidis were the predominant etiologic agents. The duration of clinical illness was significantly shorter in the ciprofloxacin group compared to placebo (2.2 versus 4.6 days; p<0.0001) with 4% and 21% treatment failure (p<0.001), respectively.³¹ In another randomized trial, British marines stationed in Belize who developed TD were given a single 500 mg dose of ciprofloxacin or a placebo. The mean TLUS was significantly reduced in the ciprofloxacin group (25 versus 54 hours in placebo; p<0.001) with a mean 5.3 unformed stools compared to 11.7 in the placebo group (p<0.0001).¹⁸ Lastly, TD patients in Mexico, Guatemala, India, and Peru were randomized in parallel-group, double-blind study and received ciprofloxacin (500 mg twice per day and one placebo), rifaximin (200 mg three times per day), or a placebo for three days. The median TLUS for ciprofloxacin was significantly reduced compared to the placebo (29 versus 66 hours; p=0.0003). Ciprofloxacin also had a significantly lower proportion of treatment failure versus placebo (7% versus 27%; p<0.05).³²

Levofloxacin

Levofloxacin is another fluoroquinolone antibiotic with a similar spectrum of activity to ciprofloxacin. Oral administration of 500–1000 mg levofloxacin results in approximately 99% absolute bioavailability with high concentrations remaining in the tissues. The mean half-life of levofloxacin is approximately 6–9 hours, allowing for a single dose per day.³³

As with ciprofloxacin, levofloxacin is also frequently prescribed for the treatment of TD due to its ability to reduce the time to clinical cure as well as being well-tolerated by patients.¹³ A single dose of levofloxacin is frequently effective; however, a three-day regimen may be required with some etiologic agents (e.g., Campylobacter spp.) or suspicion of invasive disease.² In a randomized, double-blind trial in Mexico [see Azithromycin Efficacy section above], patients received either a single dose of levofloxacin (500 mg) or azithromycin (1000 mg). Patients in the levofloxacin group had a median TLUS of 21.5 hours and 21% of patients had rapid resolution of symptoms (i.e., zero loose unformed stools after treatment). Except for having a more rapid clinical response (p=0.01), there was no significant difference between the results with the levofloxacin and azithromycin groups.¹⁷

Military personnel stationed in Thailand with TD were also included in a randomized, double-blind trial comparing levofloxacin (500 mg for three days) to two different regimens of azithromycin (1000 mg single-dose or 500 mg for three days) [see Azithromycin Efficacy section above]. The significantly decreased rate of clinical and microbiological cure in the levofloxacin group, particularly when Campylobacter spp. was the etiologic agent (only 21% achieved microbiological cure) demonstrate the decreasing effectiveness of levofloxacin against Campylobacter spp. infections.¹⁰

Safety

Approximately 5% of patients prescribed fluoroquinolones have reported mild and self-limiting adverse events, frequently involving gastrointestinal symptoms, such as nausea, vomiting, diarrhea, flatulence, and constipation.³⁴ Other less common complaints include central nervous effects (e.g., headache and dizziness), fever, rash, vaginitis, tenesmus, fatigue, insomnia, heartburn, chills, body ache, rash, and phototoxicity.^{17,30,32,33,35–37} In 2008, the U.S. Food and Drug Administration released a warning regarding the increased risk of tendinopathy (i.e., tendinitis and ruptured tendon) in patients receiving fluoroquinolones.³⁸ The risk was highest in patients over 60 years of age, transplant recipients, and individuals on steroid therapy. A recent analysis also found an increased risk of ventricular arrhythmia or cardiovascular death (odds ratio: 1.62; 95% confidence interval: 1.20–2.17) associated with levofloxacin use;²⁸ however, it is unknown whether the risk is directly linked to the antibiotic or the result of drug interactions or comorbid illness. Furthermore, use of fluoroquinolones has been shown to negatively impact the microbiome³⁹ and pose a significant risk for Clostridium difficile-associated diarrhea,⁴⁰ as well as community-associated infections or colonization with extended-spectrum β-lactamase-producing bacteria.^41–43

Adjunct Therapy

The benefit of adding loperamide to a fluoroquinolone treatment regimen has been examined in a number of studies. In one randomized, double-blind trial, dysentery patients in Thailand were given ciprofloxacin (500 mg twice daily for three days). Half of the patients received loperamide (4 mg initially followed by 2 mg after each unformed stool; not exceeding 16 mg/day) while the other half were given a placebo. Patients in the ciprofloxacin/loperamide combination group had a significantly reduced duration of diarrheal illness compared to ciprofloxacin alone (19 versus 42 hours; p=0.028). In addition, a significantly lower median number of total unformed stools was reported in the ciprofloxacin/loperamide group (2.0 versus 6.5; p=0.016).⁴⁴ Use of loperamide was also examined in a randomized, double-blind trial involving military personnel in Egypt with TD. All patients received 500 mg ciprofloxacin twice daily for three days with approximately half receiving loperamide (4 mg initially followed by 2 mg after each unformed stool; not exceeding 16 mg/day) and the other half a placebo. Clinical cure within 24 hours was reported for 84% of the patients in the ciprofloxacin/loperamide group compared to 67% in the ciprofloxacin alone group (p=0.08). No significant reduction was reported for the mean number of unformed stools between the groups. Although not statistically significant, 78% of patients with ETEC identified as the etiologic agent showed improvement within 24 hours in the ciprofloxacin/loperamide group compared to 69% with ciprofloxacin alone.⁴⁵

In a randomized, double-blind trial among military personnel with TD in Turkey, patients received a single dose of either levofloxacin (500 mg) or azithromycin (1000 mg) along with loperamide (4 mg initially with 2 mg after each unformed stool; not exceeding 16 mg/day) [see Azithromycin Adjunct Therapy section above]. Use of levofloxacin with loperamide resulted in a median TLUS of 3 hours with 39% of patients achieving clinical cure within 24 hours. In addition, the proportion of patients with nausea and vomiting prior to treatment (61% and 25%, respectively) decreased during the three-day observation period after treatment was initiated (54% and 15%).²⁷ Although patients did not receive levofloxacin without loperamide in the trial, a prior study reported a median TLUS of 21.5 hours with levofloxacin use,¹⁷ indicating the addition of loperamide was beneficial.

Summary

Fluoroquinolones are generally well-tolerated among the majority of patients with comparable efficacies between ciprofloxacin and levofloxacin. Mild and self-limiting adverse effects (e.g., nausea and vomiting) occur in approximately 5% of patients. Serious adverse effects, such as tendinopathy and C. difficile-associated diarrhea, are also associated with fluoroquinolone use, but are less frequent. Furthermore, increasing fluoroquinolone resistance worldwide has reduced the effectiveness of this antibiotic.^10,46–48 In particular, Campylobacter spp. have become increasingly resistant over the last two decades (most well-documented in Southeast Asia), so fluoroquinolones are not recommended for use in regions where Campylobacter is common. When fluoroquinolones are prescribed, loperamide should also be considered due to its added benefit of further reducing symptoms and duration of illness.

RIFAXIMIN

Efficacy

Rifaximin is a rifamycin-based antibiotic with broad-spectrum activity against aerobic and anaerobic bacteria. Oral administration of rifaximin results in poor absorption (<0.4% bioavailability) with ~97% being excreted unchanged in the feces.^49,50 Although rifaximin has been shown to be effective against many enteropathogens, it is largely inactive against invasive pathogens, including Campylobacter spp.^50,51

In a randomized, parallel-group, double-blind, multicenter study in Guatemala, Mexico, and Kenya, patients with TD received one of two rifaximin regimens for three days (200 mg and 400 mg three times daily) or a placebo. The predominant etiologic agent identified was ETEC. Median TLUS was significantly decreased in both the rifaximin groups (33 hours for both) compared to placebo (60 hours; p=0.0001). When locations were compared, Kenya had the longest TLUS (30 and 43 hours for low and high-dose rifaximin groups, respectively; 74 hours for placebo) and Guatemala had the shortest (23 and 29 hours for rifaximin groups, respectively; 49 hours for placebo). A significantly higher rate of clinical cure at 120 hours was reported in the rifaximin groups (79% and 81%, respectively, versus 61%; p=0.001). In addition, treatment failure occurred in 16–17% of the rifaximin groups, respectively, compared to 35% in the placebo group (p=0.001).⁵²

The effectiveness of rifaximin has also been compared with other antibiotics. In a randomized, parallel-group, double-blind study in Mexico, Guatemala, India, and Peru, TD patients received rifaximin (200 mg three times per day), ciprofloxacin (500 mg twice per day and one placebo), or a placebo for three days. The median TLUS for rifaximin was significantly reduced compared to the placebo (32 versus 66 hours; p=0.001). In addition, among patients with non-invasive E. coli, the median TLUS was 24 hours compared to 38 hours in the placebo group (p=0.045). When the rifaximin and ciprofloxacin groups were compared, there was no significant difference related to median TLUS (32 versus 29 hours; p=0.35). Nonetheless, ciprofloxacin had a significantly lower proportion of treatment failure than rifaximin (7% versus 15%; p=0.05). When patients with invasive pathogens (i.e., Shigella, C. jejuni, and Salmonella) were assessed, the median TLUS could not be calculated for the rifaximin group because over half of the patients did not achieve clinical wellness within 24 hours (i.e., lack of watery stools and no more than two soft tools without other clinical symptoms except for mild flatulence in 24-hour period). When patients from the Goa site were excluded (>50% lost to follow-up), there was no statistically significant difference in TLUS between the rifaximin and placebo groups among patients with invasive pathogens (44 versus 48 hours; p=0.5). Furthermore, the proportion of clinical wellness among patients with invasive pathogens was 68% in the rifaximin group compared to 56% and 86% in the placebo and ciprofloxaxin groups, respectively.³²

In another randomized, double-blind, clinical study, patients with TD in Mexico and Jamaica received either rifaximin (400 mg twice per day) or ciprofloxacin (500 mg twice per day) for three days. There was no significant difference in median TLUS (26 versus 25 hours) or treatment failure (10% versus 6%) between the rifaximin and ciprofloxacin groups.³⁶ Similar findings were reported in a randomized, double-blind study in Korea with no significant differences in rifaximin and ciprofloxacin group median TLUS (34 and 35 hours) and treatment failure rates (9% and 12%).⁵³

Safety

Patients prescribed rifaximin have reported adverse events such as nausea, excess flatulence, abdominal pain or cramps, fecal urgency, vomiting, headache, constipation, and fatigue at rates similar to placebo recipients,^32,36,52,53 indicating that oral rifaximin is safe for use in treating TD. Although diarrheagenic E. coli minimum inhibitory concentrations (MICs) for rifaximin have shown mild increases among patients with persistent infections, there has been no impact on clinical treatment efficacy.^32,54

Adjunct Therapy

The use of loperamide in combination with rifaximin was examined in a randomized, double-blinded study. Patients received rifaximin alone (200 mg three times per day for three days), loperamide alone (4 mg initially with 2 mg after each unformed stool; not exceeding 8 mg/day), or rifaximin with loperamide (same dosing as when given alone). Median TLUS was significantly decreased in the rifaximin alone and combination groups (median 33 and 27 hours, respectively) compared to the loperamide alone group (69 hours; p=0.0019). Although the proportion of clinical cure within 120 hours (longer period than typically assessed) was similar between the patients who received rifaximin alone and in combination with loperamide (77% and 75%, respectively), the mean number of total unformed stools during the study was significantly lower in the rifaximin/loperamide combination group (3.99 versus 6.23; p=0.004).⁵⁵

Summary

Rifaximin is a safe, well-tolerated, non-absorbable antibiotic effective against diarrheagenic E. coli. Due to its reduced efficacy in treating TD caused by invasive pathogens, such as Campylobacter, Salmonella, and Shigella spp., caution should be applied in regions where these etiologies are common. Importantly, rifaximin is specifically not recommended for use in patients with invasive illness, which includes diarrhea with fever or dysentery.³² Data indicate that there is an added benefit to use of loperamide with rifaximin therapy.

DISCUSSION

The development of TD among deployed military personnel impacts both the individual and operational readiness as job performance declines with the onset of diarrheal symptoms. The morbidity is also further intensified in hot environments, such as Iraq where the daytime temperatures are approximately 100°F. In particular, a soldier may lose two liters of sweat per hour with exercise⁵⁶ and this increased loss of fluid and/or electrolytes may lead to earlier clinical symptoms associated with dehydration during an episode of TD.

Early antibiotic treatment is recommended to reduce the duration of diarrheal illness and mitigate the impact on job performance. Nevertheless, deployed military personnel experiencing TD symptoms do not always seek immediate medical treatment. Instead, personnel may wait days and only request medical attention if symptoms persist or worsen.⁵ Standardized guidance recommending medical treatment for personnel experiencing watery diarrhea or bloody stools at the first onset of symptoms is needed.

Although further data are needed, there is also the potential that the use of early antibiotic therapy may help prevent long-term complications, resulting from post-infectious sequelae. One such sequelae is irritable bowel syndrome (IBS), which is characterized by relapsing gastrointestinal symptoms. In an analysis of military personnel, the occurrence of IBS was associated with antecedent infectious gastroenteritis (odds ratio: 2.05; 95% confidence interval: 1.53–2.75).⁵⁷ Another cohort study found 3% of travelers developed post-infectious IBS six months after their travel with risk factors including pre-travel diarrhea (odds ratio: 2.5; 95% confidence interval: 1.2–5.2) and TD (odds ratio: 3.6; 95% confidence interval: 1.7–7.5).⁵⁸ Campylobacter spp. infections have also been associated with the development of Guillain-Barré Syndrome.^59,60 In particular, C. jejuni infections have been significantly associated with a Guillain-Barré Syndrome outbreak in Mexico (odds ratio: 8.1; 95% confidence interval: 1.5 to infinity).⁶¹ Furthermore, rheumatoid disorders (e.g., reactive arthritis) have been observed to develop following episodes of diarrheal disease (odds ratio: 2.7; 95% confidence interval: 1.1–6.5).⁶²

The choice of antibiotic is dependent upon the predominant etiologic agents in the travel destination, as well as regional antimicrobial resistance rates.²² It is important to remember that antibiotics are ineffective when the cause of TD is viral (i.e., norovirus, rotavirus, or astrovirus) or protozoan (e.g., Giardia spp.).¹ Moreover, the preference of the traveler may impact the choice of antibiotic. Specifically, travelers may prefer not to use an antibiotic if they had adverse effects with it during a prior course of treatment. The cost of antibiotics (per civilian pharmacy estimates) is another factor. Ciprofloxacin is the least expensive at approximately $19, followed by azithromycin which averages approximately $25–47. Presently, rifaximin is the most expensive at approximately $160 for a three-day regimen.⁶³

Another factor to consider is that use of empiric antibiotics to treat self-limiting illnesses may result in increased antimicrobial resistance, emphasizing the importance of limiting use to moderate to severe illness. Antibiotics that were previously effective at treating TD (e.g., trimethoprim-sulfamethoxale) are no longer active against enteropathogens. Presently, the preferred first-line antibiotic is azithromycin with fluoroquinolones (i.e., ciprofloxacin and levofloxacin) as alternative first-line agents (Table 1). In cases with non-invasive diarrheagenic E. coli, rifaximin is also an option. Single-dose regimens of these azithromycin and fluoroquinolones are highly effective, particularly when use with adjunct therapy, and are recommended in recently published guidance.^15,16