travelers diarrhoea and antibiotic resistance
TRANSCRIPT
Antwerpen, 11 maart 2015
Travelers diarrhoea
and antibiotic resistance
Erika Vlieghe, MD PhD
Institute of Tropical Medicine, Antwerp
Department of Tropical Diseases, University Hospital Antwerp
Disclosures
• Pfizer (educational grant)
• Pfizer, J&J, Boehringer, Gilead, BMS, Roche, BD (conference participation)
Travelers diarrhoea
• the passage of ≥ 3 unformed stools/24 h
+ one or more symptoms: nausea, abdominal cramps, vomiting, fever, fecal urgency
• Incidence during 2 w trip: 10-40% risk
(~destination, travel type, host)
• Impact – Short term: incapacity, economical >> major morbidity)
– Long term: PI-IBS, other chronic GI disease, extra-intestinal
Steffen, JAMA 2015; de la Cabada Gastro Hepatol 2011
Questions…
• Which pathogens cause TD, and what about AB resistance?
– Any geographical differences, recent evolutions?
• How to translate resistance data into treatment guidelines?
– Pro-con of AB use
– Which patients to treat/not to treat?
What causes TD: top 10
• 1. ETEC • 2. E Aggr EC • 3. DIAEC • 4. Norovirus • 5. Rotavirus • 6. Salmonella (NTS) • 7. Campylobacter • 8. Shigella • 9. Aeromonas • 10. Plesiomonas • New kid: Arcobacter
• Regional differences
• Based on which surveillance data…? • Bias towards easy to detect,
current knowledge,… • Travelers data or local country
data?
• Carriage versus pathogen • Role of mixed infections • Reservoir and transmission?
Okeke J Infect Dev Ctries 2009, Steffen JAMA 2015,
What causes TD: regional differences
Steffen, JAMA 2015
Antibiotics for treatment of TD
De Saussure, Ther Adv Gastroenterol 2009
Efficacy in invasive infections?
Induction of rifampicin resistance?
Resistance?
Resistance?
Drug interactions?
http://www.ecl-lab.ca/en/ecoli/
Courtesy Y. Glupczinsky
ESBL-producing E. coli
Korea
Japan
HK
Taiwan
Sri Lanka
Vietnam
India
Saudi
Arabia
Thailand
Philippines
Singapore
Malaysia
China
Indonesia
1st APEC
Expert Forum
< 1 %
5-10 %
10-25 %
25-50 %
> 50 %
1-5 %
unknown
Resistance %
Korea 10-25%
Japan 10-25%
China >50%
Hong Kong 25-50%
Taiwan 10-25%
Philippines 10-25%
Thailand 25-50%
Vietnam >50%
Malaysia 10-25%
Singapore 25-50%
Indonesia 25-50%
India >50%
Sri Lanka ?
Saudi Arabia 25-50%
Source: Hsueh PR, 2012
www.cdc.gov
Human-animal overlapping resistance
Source: WHO 2005
ETEC from TD (Mexico, Guatemela, India)
Ouyang-Latimer, AAC 2011
10 year trend (1998-2008):
4-10 x increase of MIC90 for:
ceftriaxone, ciprofloxacin, levofloxacin, azithromycin
NOT (yet?) for rifaximin…
Diarrhoeagenic E. coli (DEC) southeastern China 2009-2011
All DEC (n = 347) EAggEC (n = 214) ETEC (n = 61)
Ciprofloxacin R 25.4% 31.8% 6.6%
ESBL 34.5% 40.7% 11.5%
MDR 70.2% 77.1% 34.4%
Chen, CMI 2014
DEC = 14.1% of all fecal samples High rates of MDR and ESBL Genetic variety +++
Predominantly DEC, NTS, Shigella Very low levels of resistance Rare cases of nalidixic acid resistance
Shigella, India
N = 88 N = 74
N = 162 Shigella spp. from India, Andaman Islands
2000-2011
Bhattacharya, Epid Infectiol 2015
Shigella, Southern Vietnam (n = 228)
S. flexneri S. sonnei
1995-1996 2007-2008 Vinh, BMC Infect Dis 2009
Salmonella spp.
• ‘Multi drug resistance’ (R to ampicillin+ SMX-TMP + chloramphenicol)
• Fluoroquinolones
• ESBL and other cephalosporin resistance
• Emerging – Azithromycin – Carbapenemases
Asia 25-90%
Africa 30-40%
Asia: 50-90%
Africa: 5-15%
Non-typhoid salmonella >> S. Typhi
Hakanen EID 2004, Parry Curr Op Infect Dis 2008, Crump CID 2010, Morpeth CID 2009
Gunnell, EID 2014
Non-typhoid Salmonella from travelers, Finland cefotaxime resistance
Middle East Thailand
Campylobacter resistance in travelers at ITM (Antwerp) 1994-2006
Annual rates of norfloxacin resistance in Campylobacter from travelers
Asia 75%
Africa 37%
Vlieghe & Jacobs, J Trav Med 2008
+ emerging erythromycin resistance (mean 3.1% +/- 2.8%)
N = 724
Ciprofloxacin resistance
57.1% (43.5-72.2)
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Results – Overall resistance
Azithromycin resistance
7.4% (3.1-13.0) 0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
2007 2008 2009 2010 2011 2012 2013 2014 2015
n = 163 Campylobacter spp. from enteritis
% Resistance ciprofloxacin % Resistance azithromycin
Campylobacter resistance in travelers at ITM (Antwerp) 2008-2014
Cip + Azi resistance
4.9% (n = 8) 6 from South Asia
Van Waterschoot, BVIKM meeting 2014
Region Resistance ciprofloxacine Resistance azithromycin
Caribbean, Central- and South America
11/16 (68.8%) 2/16 (12.5%)
Asia - Southern Asia
50/66 (75.8%)* - 33/38 (86.8%)*
7/66 (10.6%) - 6/38 (15.8%)
Africa 28/72 (38.9%)* 3/72 (4.2%)
HIV/STI 19/21 (90.5%) 4/21 (19.0%)
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Results
*P<0.05
Van Waterschoot, BVIKM meeting 2014
Koningstein, CID 2011
Prior use of antibiotics and risk of acquiring Campylobacteriosis
MACROLIDES
QUINOLONES Disruption of microbiome…?
Kantele, Clin Infect Dis 2015
From colonisation to infection…
Asia travel is a risk
factor for CA-ESBL+
UTI: OR 21 (4.5-97)
Soraas, Plos One 2013
Travel is a risk factor for
severe sepsis after prostatic
Bx: RR 2.7 (1.0-7.1)
Patel, BJU, 2011
Antibiotics for TD…
PRO • Treatment of severe & invasive
infections: prevents complications
• Treatment of mild/moderate infections: reduces incapacity (- 1-2 d)
• Standby: prevents inappropriate healthcare abroad (Wyss, J Travel Med 2009)
• Prophylaxis: can prevent TD in high risk travelers
CON • Majority of TD: limited clinical
impact (not ‘life saving’)
• Increased risk for colonisation & infection with (MDR)-enteropathogens
• Further selection pressure for patient & environment
• Side-effects, Cost
Individual health/wellbeing >< public health/ecology
De la Cabada 2011
What do travelers think/do… (1)?
• Dutch travelers (Soonawala D et al, BMC Infect Dis 2011)
– N = 144 TD questionnaire on inconvenience of TD
– Objective impact • 21% adaption of travel program
• 13% stayed in hotel for ≥ 1 d
– Subjective impact • 34% ‘moderate’
• 27% ‘severe’ (n of loose stools, nausea, fever)
– Those who experienced TD would estimate the impact lower in retrospect!
Do we overestimate the
incovenience?
What do travelers think/do… (2)?
• US travelers (Lalani T, J Travel Med 2015)
• N = 1120 US beneficiaries of DoD
• N = 212 TD
– 42% mild
– 58% moderate to severe high risk for suboptimal AB use (OR 10.4 (4.92-22.0)
Are our travelers enough informed about when/when not to take AB?
Conclusions (1)
• Increasing resistance in all enteropathogens
shift towards use of macrolides (and beyond)
• Revise AB use in the era of MDRO
total scope of risks versus genuine benefits?
• Understand better role of disrupted microbiome
risk factors, impact, duration, recovery
Conclusions (2)
• Select TD patients who will benefit most from AB
– Severe/invasive presentations
– Vulnerable/at risk travelers
• Adapt AB by region
– Asia, (Latin America) azithromycin
– Africa fluoroquinolones
• Inform/involve travelers in risk-benefit of AB use
• Invest more in prevention research
– Vaccines, non-absorbables, …
Lees zeker
• review van Okeke
• Lalani: subutilisation of AB for TD in military
• Youmans: TD and gut microbioma
• Alabegovic: rifaximin and FQ similar in prevention of TD and side effects hoe gemeten..?
• Soonawala: how important is really the inconvenience?
• Yin: effect of different AB on mouse microbiota
• My plan was to give an overview on AB resistance world wide (with focus on enteropathogens, of course), and how this reflects in travelers in gut colonization with e.g. ESBL E coli (summary of the Scandinavian & Canadian studies) and the risks this carriage can bring along once back home.
• That would bring me to speak about the doubtful role of AB use for TD in this high resistance setting (with a bit a believers-non-believers slope in it; it is also the discussion of travelers comfort versus underestimated risks of taking antibiotics). This can bring us to the discussion of 'what are genuine indications for AB for TD, and which AB, for whom', what do we know of alternatives, what with risk groups (e.g. immunecoprimosed travelers) Finally (if still time left) I will speak briefly about 'how to further survey this situation? What data are the best proxy to resistance in enteropathogens world wide.
• I have the impression we can all learn a lot from this joint session! • Will be happy to share beforehand my slides to make sure we align well.
• Nieuwe finse publicatie in CID • Discussie van indicatie
– Wanneer AB, voor wie – Welk product
• Waarde van surveillance data voor diarrhoea – lokale kinderen als sentinel? Ander microbioom??
Extrapoleerbaar?
• Van surveillance naar guidelines • Discussie CISTM Fons: believers-non believers • Comfort patient versus opbouw resistance
Risico factors
• Risico factors voor kolonisatie
– Reizigers studies
– Quid microbioom…?
• Risico factors voor infectie door MDR enteropathogeen Kantele studie
AB en microbioom
• Pro/con
• Systemisch versus topische AB
http://www.antibiotics-info.org
Mechanism of resistance for azithromycin
Iovine, Virulence 2013
Treatment
Steffen, JAMA 2015