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)

24

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%)

25

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, …

Thank you for your attention!

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