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Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)
Medwave 2017;17(Suppl2):e6958 doi: 10.5867/medwave.2017.6958
Is it worth adding loperamide to antibiotic treatment of traveler’s diarrhea?
Yazmín Pinos, María Isabel Ruiz, Óscar Corsi, Gabriel Rada
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Abstract

Travelers' diarrhea is a frequent condition, especially in those traveling to high-risk areas. Although antibiotic treatment reduces the duration of diarrhea, it has been suggested adding loperamide could further reduce the symptoms. To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We identified two systematic reviews including 28 studies overall, of which 15 were randomized trials relevant for the question of interest. We extracted data from the systematic reviews, reanalysed data of primary studies and generated a summary of findings table using the GRADE approach. We concluded adding loperamide to antibiotic treatment might accelerate resolution of symptoms in traveler’s diarrhea with minimal or no adverse effects.


 
Problem

Travelers' diarrhea is a common condition affecting approximately 20-60% of those traveling to high-risk areas, usually low-income regions. Although it is not generally associated to serious complications, it entails morbidity, disability, and costs.

Antibiotic treatment is considered the standard treatment, but despite its use a substantial number of people persist with symptoms at 48 hours.

Loperamide is an antimotility agent that acts at the level of intestinal opioid receptors, reducing peristalsis. It has been suggested that adding it to antibiotic treatment could reduce the time of symptoms, as well as the duration of antimicrobial treatment, which would result in lower costs, adverse effects and antibiotic resistance.

Methods

To answer the question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies if data are suitable, a summary of findings table following the GRADE approach and a table of other considerations for decision-making. 

Key messages

  • Adding loperamide to antibiotic treatment might accelerate resolution of traveler’s diarrhea.
  • There are probably minimal or no adverse effects of loperamide when used in the treatment of traveler's diarrhea. 
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found two systematic reviews [1],[2] including 28 studies relevant for the question of interest [3],[4],[5], [6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17], [18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28], [29],[30], including 15 randomized controlled trials [3],
[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],
[17]. This table and the summary in general are based on the latter.

What types of patients were included*

Four trials included military personnel sent abroad for military operations [12],[13],[15],[16].The rest of the trials included regular people traveling.

The destinations were:

What types of interventions were included*

Loperamide was used in all trials, with a maximum dose of 16 mg per day.

Only two trials compared antibiotic treatment versus loperamide alone [4],[6], and one trial compared loperamide versus education, with co-interventions in both groups [16].

In the rest of the trials, antibiotic monotherapy was compaired to loperamide plus antibiotic, using the following antibiotic schemes:

  • Ciprofloxacin 500 mg bid for 3 days [15].
  • Ciprofloxacin 500 mg bid for 3 days, or 750 mg single dose [12].
  • Azithromycin single dose 500 mg [10]
  • Azithromycin single dose 1000 mg or levofloxacin 500 mg single dose [13].
  • Sulfamethoxazole-trimethoprim 800/160 mg for 3 days [6]
  • Sulfamethoxazole-trimethoprim at different doses (1600/320 mg single dose; 1600/320 mg single dose then 800/160 mg bid for 5 doses [8].
  • Ofloxacin 400 mg single dose [9].
  • Ofloxacin initial dose 400 mg followed by 200 mg bid for 3 days [11].
  • Rifaximin 200 mg tid for 3 days [4].

In some trials other cointerventions were used, such as the use of zaldaride [11],[14] or bismuth [16],[17].

What types of outcomes
were measured

The outcomes studied were:

  • Cure rate of diarrhea at 24 h after treatment initiation [4],[6],[9],[10],[12],[15].
  • Cure rate of diarrhea at 48 hours after treatment initiation [4],[6],[9],[10],[12],[15].
  • Cure rate of diarrhea at 72 hrs after treatment initiation [4],[6],[9],[10],[12].
  • TLUS: time until the last semiformated diarrheal deposition [4],[6],[9],[10],[12].
  • Adverse events were not reported in any of the trials.

* The information about primary studies is extracted from the systematic reviews identified, unless otherwise specified.

Summary of findings

Information on the effects of adding loperamide to the antibiotic treatment of traveler's diarrhea is based on 15 randomized trials involving 2527 patients. It was not possible to conduct meta-analysis from the data extracted from the different reviews, so the meta-analysis provided by an individual review was used [2].

The summary of finding is as follows:

  • Adding loperamide to antibiotic treatment might accelerate resolution of traveler’s diarrhea, but the certainty of the evidence is low.
  • There are probably minimal or no adverse effects of loperamide when used in the treatment of traveler's diarrhea.The certainty of the evidence is moderate.

Other considerations for decision-making

To whom this evidence does and does not apply
  • This evidence applies to adult patients, both military and civilians, who travel to high-risk countries and develop non-dysenteric or febrile traveler's diarrhea.
  • Although there are multiple antibiotic schemes, it is clinically reasonable to extrapolate this evidence to any scheme.
About the outcomes included in this summary
  • The outcomes presented in the table are those considered critical for decision making by the authors of this summary.
  • The clinical cure at 48 hours was considered as the more important outcome for the patient who is traveling. Cure at a longer period was considered less relevant given the high probability of spontaneous resolution or in relation to the use of antibiotics.
Balance between benefits and risks, and certainty of the evidence
  • Adding loperamide to the treatment regimen is an intervention that probably has an effect on reducing the duration of symptoms, but the certainty of the evidence is low.
  • Considering that it is a probably safe strategy in these patients, the risk / benefit balance is favorable.
What would patients and their doctors think about this intervention
  • Adding loperamide to antibiotic treatment is a low-cost intervention, so it would not be a limitation for decision-making.
Resource considerations
  • With the evidence presented in this summary, most patients and clinicians should be inclined to add loperamide to antibiotic treatment for the treatment of traveler's diarrhea.
  • However, it will depend on how much value patients give to the duration of the symptoms - self-limiting and without serious complications in the vast majority of cases - and the uncertainty of the benefits.

Differences between this summary and other sources
  • The conclusions of this summary are consistent with those presented in the systematic reviews identified.
  • We did not identify international clinical guidelines, but the main non-systematic reviews also reached a similar conclusion [31],[32],[33].
Could this evidence change in the future?
  • The probability of the conclusions of this summary changing with future trials is high because of the existing uncertainty.
  • We did not identify ongoing trials in the International Clinical Trials Registry Platform of the World Health Organization aiming to answer the question of this summary.
How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Loperamide for traveler's diarrhea

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrices and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

La diarrea del viajero es una patología frecuente, en especial en quienes se dirigen a regiones de alto riesgo. Si bien el tratamiento antibiótico reduce la duración del cuadro, se ha planteado que la asociación de loperamida podría reducir aún más los síntomas. Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Identificamos dos revisiones sistemáticas que en conjunto incluyen 28 estudios primarios, de los cuales 15 corresponden a ensayos aleatorizados. Extrajimos los datos desde las revisiones identificadas y preparamos tablas de resumen de los resultados utilizando el método GRADE. Concluimos que agregar loperamida al tratamiento con antibióticos podría acelerar la resolución del cuadro, sin asociarse probablemente a efectos adversos importantes.

Authors: Yazmín Pinos[1,2], María Isabel Ruiz[2,3], Óscar Corsi[1,2], Gabriel Rada[1,2,4,5,6]

Affiliation:
[1] Departamento de Medicina Interna, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Proyecto Epistemonikos, Santiago, Chile
[3] Departamento de Psiquiatría, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[4] Centro Evidencia UC, Pontificia Universidad Católica de Chile, Santiago, Chile
[5] GRADE Working Group
[6] The Cochrane Collaboration

E-mail: radagabriel@epistemonikos.org

Author address:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Diagonal Paraguay 362
Santiago Centro
Chile

Citation: Pinos Y, Ruiz MI, Corsi , Rada G. Is it worth adding loperamide to antibiotic treatment of traveler’s diarrhea?. Medwave 2017;17(Suppl2):e6958 doi: 10.5867/medwave.2017.6958

Submission date: 14/5/2017

Acceptance date: 22/5/2017

Publication date: 23/5/2017

PubMed record

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  1. Riddle MS, Arnold S, Tribble DR. Effect of adjunctive loperamide in combination with antibiotics on treatment outcomes in traveler's diarrhea: a systematic review and meta-analysis. Clin Infect Dis. 2008 Oct 15;47(8):1007-14 | CrossRef | PubMed |
  2. Lääveri T, Sterne J, Rombo L, Kantele A. Systematic review of loperamide: No proof of antibiotics being superior to loperamide in treatment of mild/moderate travellers' diarrhoea. Travel Med Infect Dis. 2016 Jul-Aug;14(4):299-312 | CrossRef | PubMed |
  3. Caeiro JP, DuPont HL, Albrecht H, Ericsson CD. Oral rehydration therapy plus loperamide versus loperamide alone in the treatment of traveler's diarrhea. Clin Infect Dis. 1999 Jun;28(6):1286-9 | PubMed |
  4. Dupont HL, Jiang ZD, Belkind-Gerson J, Okhuysen PC, Ericsson CD, Ke S, et al. Treatment of travelers' diarrhea: randomized trial comparing rifaximin, rifaximin plus loperamide, and loperamide alone. Clin Gastroenterol Hepatol. 2007 Apr;5(4):451-6 | PubMed |
  5. DuPont HL, Flores Sanchez J, Ericsson CD, Mendiola Gomez J, DuPont MW, Cruz Luna A, et al. Comparative efficacy of loperamide hydrochloride and bismuth subsalicylate in the management of acute diarrhea. Am J Med. 1990 Jun 20;88(6A):15S-19S | PubMed |
  6. Ericsson CD, DuPont HL, Mathewson JJ, West MS, Johnson PC, Bitsura JA. Treatment of traveler's diarrhea with sulfamethoxazole and trimethoprim and loperamide. JAMA. 1990 Jan 12;263(2):257-61 | PubMed |
  7. Ericsson CD, DuPont HL, Mathewson JJ. Optimal dosing of ofloxacin with loperamide in the treatment of non-dysenteric travelers' diarrhea. J Travel Med. 2001 Jul-Aug;8(4):207-9 | PubMed |
  8. Ericsson CD, Nicholls-Vasquez I, DuPont HL, Mathewson JJ. Optimal dosing of trimethoprim-sulfamethoxazole when used with loperamide to treat traveler's diarrhea. Antimicrob Agents Chemother. 1992 Dec;36(12):2821-4 | PubMed |
  9. Ericsson CD, DuPont HL, Mathewson JJ. Single Dose Ofloxacin plus Loperamide Compared with Single Dose or Three Days of Ofloxacin in the Treatment of Traveler's Diarrhea. J Travel Med. 1997 Mar 1;4(1):3-7 | PubMed |
  10. Ericsson CD, DuPont HL, Okhuysen PC, Jiang ZD, DuPont MW. Loperamide plus azithromycin more effectively treats travelers' diarrhea in Mexico than azithromycin alone. J Travel Med. 2007 Sep-Oct;14(5):312-9 | PubMed |
  11. Okhuysen PC, DuPont HL, Ericsson CD, Marani S, Martinez-Sandoval FG, Olesen MA, et al. Zaldaride maleate (a new calmodulin antagonist) versus loperamide in the treatment of traveler's diarrhea: randomized, placebo-controlled trial. Clin Infect Dis. 1995 Aug;21(2):341-4 | PubMed |
  12. Petruccelli BP, Murphy GS, Sanchez JL, Walz S, DeFraites R, Gelnett J, et al. Treatment of traveler's diarrhea with ciprofloxacin and loperamide. J Infect Dis. 1992 Mar;165(3):557-60 | PubMed |
  13. Sanders JW, Frenck RW, Putnam SD, Riddle MS, Johnston JR, Ulukan S, et al. Azithromycin and loperamide are comparable to levofloxacin and loperamide for the treatment of traveler's diarrhea in United States military personnel in Turkey. Clin Infect Dis. 2007 Aug;45(3):294-301 | CrossRef | PubMed |
  14. Silberschmidt G, Schick MT, Steffen R, Kilpatrick ME, Murphy JR, Oyofo BA, et al. Treatment of travellers' diarrhoea: zaldaride compared with loperamide and placebo. Eur J Gastroenterol Hepatol. 1995 Sep;7(9):871-5 | PubMed |
  15. Taylor DN, Sanchez JL, Candler W, Thornton S, McQueen C, Echeverria P. Treatment of travelers' diarrhea: ciprofloxacin plus loperamide compared with ciprofloxacin alone. A placebo-controlled, randomized trial. Ann Intern Med. 1991 May 1;114(9):731-4 | PubMed |
  16. Letizia A, Riddle MS, Tribble D, Mostafa M, Monteville M, Armstrong A, et al. Effects of pre-deployment loperamide provision on use and travelers' diarrhea outcomes among U.S. military personnel deployed to Turkey. Travel Med Infect Dis. 2014 Jul-Aug;12(4):360-3 | CrossRef | PubMed |
  17. Johnson PC, Ericsson CD, DuPont HL, Morgan DR, Bitsura JA, Wood LV. Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers' diarrhea. JAMA. 1986 Feb 14;255(6):757-60 | PubMed |
  18. Belderok SM, van den Hoek A, Kint JA, Schim van der Loeff MF, Sonder GJ. Incidence, risk factors and treatment of diarrhoea among Dutch travellers: reasons not to routinely prescribe antibiotics. BMC Infect Dis. 2011 Oct 29;11:295 | CrossRef | PubMed |
  19. Brown JA, Riddle MS, Putnam SD, Schlett CD, Armstrong AW, Jones JJ, et al. Outcomes of diarrhea management in operations Iraqi Freedom and Enduring Freedom. Travel Med Infect Dis. 2009 Nov;7(6):337-43 | CrossRef | PubMed |
  20. Hill DR. Occurrence and self-treatment of diarrhea in a large cohort of Americans traveling to developing countries. Am J Trop Med Hyg. 2000 May;62(5):585-9 | PubMed |
  21. Kantele A, Mero S, Kirveskari J, Lääveri T. Increased Risk for ESBL-Producing Bacteria from Co-administration of Loperamide and Antimicrobial Drugs for Travelers' Diarrhea. Emerg Infect Dis. 2016 Jan;22(1):117-20 | CrossRef | PubMed |
  22. Lalani T, Maguire JD, Grant EM, Fraser J, Ganesan A, Johnson MD, et al. Epidemiology and self-treatment of travelers' diarrhea in a large, prospective cohort of department of defense beneficiaries. J Travel Med. 2015 May-Jun;22(3):152-60 | CrossRef | PubMed |
  23. Meuris B. Observational Study of Travelers' Diarrhea. J Travel Med. 1995 Mar 1;2(1):11-15 | PubMed |
  24. Peetermans WE, Van Wijngaerden E. Implementation of pretravel advice: good for malaria, bad for diarrhoea. Acta Clin Belg. 2001 Sep-Oct;56(5):284-8 | PubMed |
  25. Pitzurra R, Steffen R, Tschopp A, Mutsch M. Diarrhoea in a large prospective cohort of European travellers to resource-limited destinations. BMC Infect Dis. 2010 Aug 4;10:231 | CrossRef | PubMed |
  26. Porter CK, Riddle MS, Tribble DR, Putnam SD, Rockabrand DM, Frenck RW, et al. The epidemiology of travelers' diarrhea in Incirlik, Turkey: a region with a predominance of heat-stabile toxin producing enterotoxigenic Escherichia coli. Diagn Microbiol Infect Dis. 2010 Mar;66(3):241-7 | CrossRef | PubMed |
  27. Putnam SD, Sanders JW, Frenck RW, Monteville M, Riddle MS, Rockabrand DM, et al. Self-reported description of diarrhea among military populations in operations Iraqi Freedom and Enduring Freedom. J Travel Med. 2006 Mar-Apr;13(2):92-9 | PubMed |
  28. Reinthaler FF, Feierl G, Beubler E, Kollaritsch H, Ruckenbauer G, Klem G, et al. Treatment of travelers' diarrhea among Austrian tourists. J Travel Med. 2004 Jan-Feb;11(1):66-8 | PubMed |
  29. Sanders JW, Putnam SD, Gould P, Kolisnyk J, Merced N, Barthel V, et al. Diarrheal illness among deployed U.S. military personnel during Operation Bright Star 2001--Egypt. Diagn Microbiol Infect Dis. 2005 Jun;52(2):85-90 | PubMed |
  30. Soonawala D, Vlot JA, Visser LG. Inconvenience due to travelers' diarrhea: a prospective follow-up study. BMC Infect Dis. 2011 Nov 20;11:322 | CrossRef | PubMed |
  31. Steffen R, Hill DR, DuPont HL. Traveler's diarrhea: a clinical review. JAMA. 2015 Jan 6;313(1):71-80 | CrossRef | PubMed |
  32. Barrett J, Brown M. Travellers' diarrhoea. BMJ. 2016 Apr 19;353:i1937 | CrossRef | PubMed |
  33. Giddings SL, Stevens AM, Leung DT. Traveler's Diarrhea. Med Clin North Am. 2016 Mar;100(2):317-30 | CrossRef | PubMed |
Riddle MS, Arnold S, Tribble DR. Effect of adjunctive loperamide in combination with antibiotics on treatment outcomes in traveler's diarrhea: a systematic review and meta-analysis. Clin Infect Dis. 2008 Oct 15;47(8):1007-14 | CrossRef | PubMed |

Lääveri T, Sterne J, Rombo L, Kantele A. Systematic review of loperamide: No proof of antibiotics being superior to loperamide in treatment of mild/moderate travellers' diarrhoea. Travel Med Infect Dis. 2016 Jul-Aug;14(4):299-312 | CrossRef | PubMed |

Caeiro JP, DuPont HL, Albrecht H, Ericsson CD. Oral rehydration therapy plus loperamide versus loperamide alone in the treatment of traveler's diarrhea. Clin Infect Dis. 1999 Jun;28(6):1286-9 | PubMed |

Dupont HL, Jiang ZD, Belkind-Gerson J, Okhuysen PC, Ericsson CD, Ke S, et al. Treatment of travelers' diarrhea: randomized trial comparing rifaximin, rifaximin plus loperamide, and loperamide alone. Clin Gastroenterol Hepatol. 2007 Apr;5(4):451-6 | PubMed |

DuPont HL, Flores Sanchez J, Ericsson CD, Mendiola Gomez J, DuPont MW, Cruz Luna A, et al. Comparative efficacy of loperamide hydrochloride and bismuth subsalicylate in the management of acute diarrhea. Am J Med. 1990 Jun 20;88(6A):15S-19S | PubMed |

Ericsson CD, DuPont HL, Mathewson JJ, West MS, Johnson PC, Bitsura JA. Treatment of traveler's diarrhea with sulfamethoxazole and trimethoprim and loperamide. JAMA. 1990 Jan 12;263(2):257-61 | PubMed |

Ericsson CD, DuPont HL, Mathewson JJ. Optimal dosing of ofloxacin with loperamide in the treatment of non-dysenteric travelers' diarrhea. J Travel Med. 2001 Jul-Aug;8(4):207-9 | PubMed |

Ericsson CD, Nicholls-Vasquez I, DuPont HL, Mathewson JJ. Optimal dosing of trimethoprim-sulfamethoxazole when used with loperamide to treat traveler's diarrhea. Antimicrob Agents Chemother. 1992 Dec;36(12):2821-4 | PubMed |

Ericsson CD, DuPont HL, Mathewson JJ. Single Dose Ofloxacin plus Loperamide Compared with Single Dose or Three Days of Ofloxacin in the Treatment of Traveler's Diarrhea. J Travel Med. 1997 Mar 1;4(1):3-7 | PubMed |

Ericsson CD, DuPont HL, Okhuysen PC, Jiang ZD, DuPont MW. Loperamide plus azithromycin more effectively treats travelers' diarrhea in Mexico than azithromycin alone. J Travel Med. 2007 Sep-Oct;14(5):312-9 | PubMed |

Okhuysen PC, DuPont HL, Ericsson CD, Marani S, Martinez-Sandoval FG, Olesen MA, et al. Zaldaride maleate (a new calmodulin antagonist) versus loperamide in the treatment of traveler's diarrhea: randomized, placebo-controlled trial. Clin Infect Dis. 1995 Aug;21(2):341-4 | PubMed |

Petruccelli BP, Murphy GS, Sanchez JL, Walz S, DeFraites R, Gelnett J, et al. Treatment of traveler's diarrhea with ciprofloxacin and loperamide. J Infect Dis. 1992 Mar;165(3):557-60 | PubMed |

Sanders JW, Frenck RW, Putnam SD, Riddle MS, Johnston JR, Ulukan S, et al. Azithromycin and loperamide are comparable to levofloxacin and loperamide for the treatment of traveler's diarrhea in United States military personnel in Turkey. Clin Infect Dis. 2007 Aug;45(3):294-301 | CrossRef | PubMed |

Silberschmidt G, Schick MT, Steffen R, Kilpatrick ME, Murphy JR, Oyofo BA, et al. Treatment of travellers' diarrhoea: zaldaride compared with loperamide and placebo. Eur J Gastroenterol Hepatol. 1995 Sep;7(9):871-5 | PubMed |

Taylor DN, Sanchez JL, Candler W, Thornton S, McQueen C, Echeverria P. Treatment of travelers' diarrhea: ciprofloxacin plus loperamide compared with ciprofloxacin alone. A placebo-controlled, randomized trial. Ann Intern Med. 1991 May 1;114(9):731-4 | PubMed |

Letizia A, Riddle MS, Tribble D, Mostafa M, Monteville M, Armstrong A, et al. Effects of pre-deployment loperamide provision on use and travelers' diarrhea outcomes among U.S. military personnel deployed to Turkey. Travel Med Infect Dis. 2014 Jul-Aug;12(4):360-3 | CrossRef | PubMed |

Johnson PC, Ericsson CD, DuPont HL, Morgan DR, Bitsura JA, Wood LV. Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers' diarrhea. JAMA. 1986 Feb 14;255(6):757-60 | PubMed |

Belderok SM, van den Hoek A, Kint JA, Schim van der Loeff MF, Sonder GJ. Incidence, risk factors and treatment of diarrhoea among Dutch travellers: reasons not to routinely prescribe antibiotics. BMC Infect Dis. 2011 Oct 29;11:295 | CrossRef | PubMed |

Brown JA, Riddle MS, Putnam SD, Schlett CD, Armstrong AW, Jones JJ, et al. Outcomes of diarrhea management in operations Iraqi Freedom and Enduring Freedom. Travel Med Infect Dis. 2009 Nov;7(6):337-43 | CrossRef | PubMed |

Hill DR. Occurrence and self-treatment of diarrhea in a large cohort of Americans traveling to developing countries. Am J Trop Med Hyg. 2000 May;62(5):585-9 | PubMed |

Kantele A, Mero S, Kirveskari J, Lääveri T. Increased Risk for ESBL-Producing Bacteria from Co-administration of Loperamide and Antimicrobial Drugs for Travelers' Diarrhea. Emerg Infect Dis. 2016 Jan;22(1):117-20 | CrossRef | PubMed |

Lalani T, Maguire JD, Grant EM, Fraser J, Ganesan A, Johnson MD, et al. Epidemiology and self-treatment of travelers' diarrhea in a large, prospective cohort of department of defense beneficiaries. J Travel Med. 2015 May-Jun;22(3):152-60 | CrossRef | PubMed |

Meuris B. Observational Study of Travelers' Diarrhea. J Travel Med. 1995 Mar 1;2(1):11-15 | PubMed |

Peetermans WE, Van Wijngaerden E. Implementation of pretravel advice: good for malaria, bad for diarrhoea. Acta Clin Belg. 2001 Sep-Oct;56(5):284-8 | PubMed |

Pitzurra R, Steffen R, Tschopp A, Mutsch M. Diarrhoea in a large prospective cohort of European travellers to resource-limited destinations. BMC Infect Dis. 2010 Aug 4;10:231 | CrossRef | PubMed |

Porter CK, Riddle MS, Tribble DR, Putnam SD, Rockabrand DM, Frenck RW, et al. The epidemiology of travelers' diarrhea in Incirlik, Turkey: a region with a predominance of heat-stabile toxin producing enterotoxigenic Escherichia coli. Diagn Microbiol Infect Dis. 2010 Mar;66(3):241-7 | CrossRef | PubMed |

Putnam SD, Sanders JW, Frenck RW, Monteville M, Riddle MS, Rockabrand DM, et al. Self-reported description of diarrhea among military populations in operations Iraqi Freedom and Enduring Freedom. J Travel Med. 2006 Mar-Apr;13(2):92-9 | PubMed |

Reinthaler FF, Feierl G, Beubler E, Kollaritsch H, Ruckenbauer G, Klem G, et al. Treatment of travelers' diarrhea among Austrian tourists. J Travel Med. 2004 Jan-Feb;11(1):66-8 | PubMed |

Sanders JW, Putnam SD, Gould P, Kolisnyk J, Merced N, Barthel V, et al. Diarrheal illness among deployed U.S. military personnel during Operation Bright Star 2001--Egypt. Diagn Microbiol Infect Dis. 2005 Jun;52(2):85-90 | PubMed |

Soonawala D, Vlot JA, Visser LG. Inconvenience due to travelers' diarrhea: a prospective follow-up study. BMC Infect Dis. 2011 Nov 20;11:322 | CrossRef | PubMed |

Steffen R, Hill DR, DuPont HL. Traveler's diarrhea: a clinical review. JAMA. 2015 Jan 6;313(1):71-80 | CrossRef | PubMed |

Barrett J, Brown M. Travellers' diarrhoea. BMJ. 2016 Apr 19;353:i1937 | CrossRef | PubMed |

Giddings SL, Stevens AM, Leung DT. Traveler's Diarrhea. Med Clin North Am. 2016 Mar;100(2):317-30 | CrossRef | PubMed |

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