BEST OF AASLD 2004: BASIC SCIENCE GBM

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Montezumas Revenge A journal club presentation
on Travelers Diarrhea George B. McDonald, M.D.
Division of Gastroenterolgy February 4, 2005
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• 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 dont?
• Are there new treatments for travelers diarrhea?
• What about prophylaxis?

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Motecuhzoma Xocoyotzin (Montezuma II) (1467-1520)
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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.
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• 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 dont?
• Are there new treatments for travelers diarrhea?
• What about prophylaxis?

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Causes of Travelers Diarrhea, circa 2005
Bacteria Viruses Parasites ETEC
Noravirus G. lamblia EAEC Rotavirus Crypto
sporidia Shigella Adenovirus E.
histolytica Salmonella Microsporidia Campylo
bacter Cyclospora Helicobacter sp.
Aeromonas Plesiomonas Vibrios to be
discussed today
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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
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Prevalence of enteric pathogens among travelers
with diarrhea acquired in Kenya, India, or
Jamaica. JID 2002 185 497-502
Results Goa Mombasa Jamaica (N293)
(N464) (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
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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
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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 (N86) compared to culture-negative
patients (N90).
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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 (plt.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.
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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
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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
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Aeromonas spp. and travelers 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
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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
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• 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 dont?
• Are there new treatments for travelers diarrhea?
• What about prophylaxis?

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Genetic susceptibility to enteroaggregrative E
coli diarrhea Polymorphism in the IL-8 promotor
region. JID 2003188506-11
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.
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Genetic susceptibility to enteroaggregrative E
coli diarrhea Polymorphism in the IL-8 promotor
region. JID 2003188506-11
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
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Results IL-8 genotype AA AT
TT P-value IL-8 phenotype ? ?
? EAEC/diarrhea (N23) 87 13
0 EAEC/diarrhea- (N7) 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
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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 ones
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 dont get sick, but the turista does.
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• 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 dont?
• Are there new treatments for travelers diarrhea?
• What about prophylaxis?

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Montezumas 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
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Rifaximin vs. Ciprofloxacin for treatment of
travelers 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.
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Rifaximin vs. Ciprofloxacin for treatment of
travelers 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.
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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.
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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 Controls O.R.
(N169) (N77) 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 plt.05). 2
Campylobacter were resistant to ciprofloxacin in
96 of isolates and resistant to azithromycin in
none of isolates.
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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
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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
(N105) (N106) 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.
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• 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 dont?
• Are there new treatments for travelers diarrhea?
• What about prophylaxis?

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Rendi-Wagner P, Kollaritsch H. Drug prophylaxis
for travelers 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 rifaximi
n Lactobacillus GG Saccharomyces boulardii
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• 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
  dont?
• Avoiding exposure to bugs, good luck, and having
  favorable immunoregulatory genes are key.

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• 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.

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