Montezuma’s Revenge A journal club presentation on Travelers’ Diarrhea George B. McDonald, M.D.

1. Montezuma’s Revenge A journal club presentation on Travelers’ Diarrhea George B. McDonald, M.D. Division of Gastroenterolgy February 4, 2005

2. Themes of this journal club presentation Why would Montezuma want revenge? What new bugs should you be aware of? Why do some travelers get sick and others don’t? Are there new treatments for travelers diarrhea? What about prophylaxis?

3. Motecuhzoma Xocoyotzin (Montezuma II) (1467-1520)

4. Why would Montezuma want to exact revenge? •In 1502, Montezuma is elected Great Leader of Tenochtitlan and Lord of the Colhua by the Aztec imperial counsel. •Hernan Cortez et al arrive in the coastal waters off Mexico. •Montezuma, thinking that the Spanish were descendents of the god Quetzalcoatl, offers rich gifts to get them to leave. •Spanish stay, so Montezuma receives them in his court in 1519. •Cortez seizes Montezuma, Aztecs revolt, Montezuma is killed. •Tenochtitlan is destroyed and the Aztec Empire ends.

5. Themes of this journal club presentation Why would Montezuma want revenge? What new bugs should you be aware of? Why do some travelers get sick and others don’t? Are there new treatments for travelers diarrhea? What about prophylaxis?

6. Causes of Travelers’ Diarrhea, circa 2005 Bacteria Viruses Parasites ETEC Noravirus G. lamblia EAEC* Rotavirus Cryptosporidia Shigella Adenovirus E. histolytica Salmonella Microsporidia* Campylobacter* Cyclospora Helicobacter sp. Aeromonas* Plesiomonas Vibrios *to be discussed today

7. Prevalence of enteric pathogens among travelers with diarrhea acquired in Kenya, India, or Jamaica. JID 2002; 185: 497-502 Background: Geographic variation in acquired bugs-- ETEC  in Latin America,  in Asia Rotavirus  in Mexico Parasites  in Russia, Nepal Methods: Ads in tourist hotels in Mombasa, Goa, Montego Bay! Physicians attended welcome parties! Hotel staff collected stool samples from 1079 tourists! Stools were examined for parasites, Adenovirus, Rotavirus, ETEC, enteric bacteria galore

8. Prevalence of enteric pathogens among travelers with diarrhea acquired in Kenya, India, or Jamaica. JID 2002; 185: 497-502 Results: Goa Mombasa Jamaica (N=293) (N=464) (N= 322) ETEC+ 24% 35% 12% Shigella 10% 9% 0.3% Rotavirus 5% 6% 8% Multiple bugs 11% 6% 5% Negative 45% 47% 68% •Pathogen detection rates in patients with severe diarrhea: Goa = 60%, Mombasa = 57%, Montego Bay = 51%

9. Prevalence of enteric pathogens among travelers with diarrhea acquired in Kenya, India, or Jamaica. JID 2002; 185: 497-502 •Also: Non-ETEC bacterial pathogens in 25% Parasites in 3% •Antibiotic resistance (% of isolates resistant to antibiotics): Goa Mombasa Jamaica Ofloxacin 8% 1% 3% Bactrim 58% 42% 27% Doxycycline 54% 57% 48% Multiple drugs 68% 30% 69%

10. Rate of occurrence and pathogenic effect of enteraggregrative E coli virulence factors in travelers. J. Clin Microbiology 2002; 40: 4185-4190 Background: •Stool cultures are negative in 40-50% of travelers with severe diarrhea. •Enteroaggregrative E coli cause diarrhea--how frequently are they found in travelers? What is pathogenesis of diarrhea? Methods: •Stool samples from prior studies from Goa, Jamaica, and Guadalajara were re-examined for EAEC. •EAEC+ patients (N=86) compared to culture-negative patients (N=90).

11. Rate of occurrence and pathogenic effect of enteraggregrative E coli virulence factors in travelers. J. Clin Microbiology 2002; 40: 4185-4190 Results: •Plasmid-borne virulence factors found in 60/86 EAEC isolates vs. 7/90 non-pathogenic E. coli (p<.001) •EAEC with virulence factors had more IL-8 in stool samples (p=.007) Conclusions: •EAEC ~ ETEC as a cause of travelers’ diarrhea in many parts of the world. •Most EAEC carry plasmid-borne virulence factors. •EAEC with virulence factors cause acute intestinal inflammation with increased secretion of IL-8.

12. Enteric pathogens in Mexican sauces of popular restaurants in Guadalajara and Houston. Ann Intern Med 2002; 136: 884-7. Background: Contaminated food is a major route of infection of bacterial causes of diarrhea in travelers. Methods: •Tabletop sauces (1 tbsp each of guacamole, pico de gallo, red sauces, green sauces) collected in sterile containers, homogenized, cultured •71 sauces from 36 Guadalajara restaurants •25 sauces from 12 Houston restaurants

13. Enteric pathogens in Mexican sauces of popular restaurants in Guadalajara and Houston. Ann Intern Med 2002; 136: 884-7. Results: Guadalajara Houston P E coli+ 47/71 (66%) 10/25 (40%) .03 Median colonies 1000 0 .007 ETEC+ 4/43 (9%) 0/10 .13 EAEC+ 14/32 (44%) 0/10 .002

14. Aeromonas spp. and traveler’s diarrhea: Clinical features and antimicrobial resistance. Emerging Infectious Dis 2003; 9, #5. Background: •Aeromonas cause GI, skin, wound, urinary, biliary infections. •How frequently do they cause travelers’ diarrhea? Methods: •863 patients in Barcelona with diarrhea after travel Results: •Aeromonas + in 2%--after travel to Africa, Latin America, Asia. •Diarrhea, fever, abdominal cramps--half with persistent symptoms. •Resistant to ampicillin, sensitive to ciprofloxacin

15. Detection of Microsporidia in travelers with diarrhea. J Clin Microbiology 2001; 39: 1630-1632. 148 German tourists returned from tropical climes with diarrhea •stools examined with Uvitex2B staining for Microsporidia •results compared with PCR for Microsporidia antigens Results: Microsporidia in 6% Microscopy-positive for Microsporidia Yes No Yes 5 4 PCR+ No 0 0

16. Themes of this journal club presentation Why would Montezuma want revenge? What new bugs should you be aware of? Why do some travelers get sick and others don’t? Are there new treatments for travelers diarrhea? What about prophylaxis?

17. Genetic susceptibility to enteroaggregrative E coli diarrhea: Polymorphism in the IL-8 promotor region. JID 2003;188:506-11 Background: •EAEC = E coli that adhere to Hep-2 cells with a characteristic stacked-brick aggregrative pattern. •EAEC flagellin  IL-8 from gut mucosa  recruitment of neutrophils  fluid secretion + epithelial damage. •EAEC infection causes diarrhea in some, not all. Hypothesis: SNPs in the IL-8 gene are associated with EAEC-related diarrhea.

18. Genetic susceptibility to enteroaggregrative E coli diarrhea: Polymorphism in the IL-8 promotor region. JID 2003;188:506-11 Methods: •White U.S. students in Mexico for short stays •Stools cultured for everything; EAEC+ students studied further: •Stool supernatants for IL-8 by ELISA •Student DNA isolated, analyzed for SNPs in IL-8 promotor, exons, introns

19. Results: IL-8 genotype AA AT TT P-value IL-8 phenotype    EAEC+/diarrhea+ (N=23) 87% 13% 0 EAEC+/diarrhea- (N=7) 29% 57% 14% .006 Genotype O.R. for EAEC+diarrhea Fecal IL-8 levels TT 1 3.8 pg/mL AT 14 (-2 to 106) 20.3 pg/mL AA 209 (-29 to 1526) 132.6 pg/mL* *p=.0053

20. Conclusions: •A polymorphism that causes increased IL-8 production is associated with enteroaggregrative E coli diarrhea and increased fecal IL-8. Comments: •Although the tyranny of small numbers makes this study less than definitive, it certainly suggests that one’s genetic makeup is a determinant of who gets EAEC+ diarrhea. •May not apply to intestinal infections with other organisms. •Did Montezuma and his descendents have the TT genotype? May explain why locales don’t get sick, but the turista does.

21. Themes of this journal club presentation Why would Montezuma want revenge? What new bugs should you be aware of? Why do some travelers get sick and others don’t? Are there new treatments for travelers diarrhea? What about prophylaxis?

22. Montezuma’s Revenge Recipe* Ingredients 12 oz. Corona beer 1 oz. Jose Cuervo Especial Gold Tequila Directions Fill shot glass with tequila. Fill large glass with beer. Drop tequila-filled shot glass into the glass of beer. Imbibe. Disclaimer: It is not clear whether this recipe is intended to be curative for Travelers’ Diarrhea or a human model of the illness. If it to be used as therapy, be advised that any recommendation is not evidence-based. *http://www.drinksmaster.com/drink7847.html

23. Rifaximin vs. Ciprofloxacin for treatment of traveler’s diarrhea: A randomized, double-blind clinical trial. CID 2001: 33: 1807-15. Rationale: •In ~85% of travelers’ diarrhea cases, bacteria are the culprit. •Rifaximin is active vs. GP and GN bacteria, including anaerobes, and is not absorbed from the gut. Methods: •U.S. students in Guadalajara and tourists in Jamaica with diarrhea. •{Rifaximin 200 mg BID + Cipro placebo} vs. {Cipro 500 mg BID + Rifaximin placebo}, each for 3 days. •Primary end point = rapidity of resolution of diarrhea.

24. Rifaximin vs. Ciprofloxacin for treatment of traveler’s diarrhea: A randomized, double-blind clinical trial. CID 2001: 33: 1807-15. Results: Rifaximin Ciprofloxacin Time to last diarrhea 25.7 h. 25 h. No further diarrhea 7/93 (8%) 19/94 (20%) Wellness within 3 d. 81/93 (87%) 83/94 (88%) Failure of Rx 9/93 (10%) 5/94 (6%) Conclusions: Rifaximin is a safe and effective alternative to ciprofloxacin in the treatment of travelers diarrhea in Mexico or Jamaica.

25. An observational study of diarrheal illness in U.S. military personnel in Thailand: presentation and outcome of Campyloacter infection. Am J Trop Med Hyg 2002: 67: 533-8. Background: In Thailand, Campylobacter accounts for ~50% of bacterial isolates in travelers diarrhea and may be worse than other causes. Methods: •Stool cultures from 169 diarrheal and 77 healthy military people. •Prospective diaries after presenting with diarrhea. •Sensitivities of bacterial isolates to ciprofloxacin, azithromycin •Course with Campylobacter compared to course with other pathogens.

26. An observational study of diarrheal illness in U.S. military personnel in Thailand: presentation and outcome of Campyloacter infection. Am J Trop Med Hyg 2002: 67: 533-8. Results: Cases ControlsO.R. (N=169) (N=77) Campylobacter1,2 13.6% 2.6% 5.91 Salmonella 18.3% 11.7% 1.7 ETEC 14.2% 2.6% 6.21 1 more likely to have fever, myalgias, arthralgias, more diarrhea, and stay sicker, longer, than patients with other causes of diarrhea (each p<.05). 2 Campylobacter were resistant to ciprofloxacin in 96% of isolates and resistant to azithromycin in none of isolates.

27. Azithromycin found to be comparable to levofloxacin for treatment of US travelers with acute diarrhea acquired in Mexico. CID 2003; 37: 1165-1171. Background: Increased quinolone resistance world-wide; is azithromycin a reasonable substitute? Methods: •217 U.S. students in Guadalajara with acute diarrhea •Randomized to receive azithromycin 1000 mg (one dose) vs. levofloxacin 500 mg. (one dose) •Followed for 4 days. •Primary end point = time to resolution of diarrhea

28. Azithromycin found to be comparable to levofloxacin for treatment of US travelers with acute diarrhea acquired in Mexico. CID 2003; 37: 1165-1171. Results: Azithromycin Levofloxacin (N=105) (N=106) Time to last diarrhea 22.3 h. 21.5 h. No further diarrhea 8% 21% Failure of Rx 9.5% 7.5% Conclusions: Azithromycin is a safe and effective for treatment of acute diarrhea in travelers to Mexico--especially for pregnant women and children for whom quinolones are contraindicated.

29. Themes of this journal club presentation Why would Montezuma want revenge? What new bugs should you be aware of? Why do some travelers get sick and others don’t? Are there new treatments for travelers diarrhea? What about prophylaxis?

30. Rendi-Wagner P, Kollaritsch H. Drug prophylaxis for traveler’s diarrhea. Clinical Infectious Diseases 2002; 34: 628-633 Effective Ineffective low-dose quinolones doxycycline bismuth subsalicylate TMP/SMX ampicillin heat-inactivated E coli Unproven or minimal effectiveness rifaximin Lactobacillus GG Saccharomyces boulardii

31. Themes of this journal club presentation 1. Why would Montezuma want revenge? Loss of the Aztec empire seems like a valid reason. 2. What “new” bugs should you be aware of? EAEC, microsporidia, Aeromonas. 3. Why do some travelers get sick and others don’t? Avoiding exposure to bugs, good luck, and having favorable immunoregulatory genes are key.

32. Themes of this journal club presentation 5. Are there new treatments for travelers diarrhea? Rifaximin and azithromycin--but you might get better faster with quinolones, unless you get Campylobacter infection in Thailand. 6. What about prophylaxis? If you must, quinolones for most places, but not for Thailand. Pepto-Bismol if you have a very large suitcase. Non-absorbable antibiotics like rifaximin may be the future.

33. Mictlantecuhtli, the Aztec god of the dead, found near Tenochtitlan’s Great Pyramid. Note the prominent liver and gallbladder, thought by the Aztecs to be the seat of the spirit.