antimicrobial,resistance,intyphoid:, implicationsfor ......study, country drinking water handwashing...
TRANSCRIPT
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Antimicrobial Resistance in Typhoid: implications for policy & immunization
strategies
Zulfiqar A Bhutta, Imran Ahmed, Daina Als, Amruta Radhakrishnan, Farah Qamar, Jeffrey
Stanaway, Christopher Parry
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Outline • Typhoid trends & brief overview of current control strategies (Typhoid Trends Project T2)
• Issues with anti-‐microbial resistance (AMR) in typhoid– recent trends and challenges – Implications for disease severity & response– Cost of therapy and potential infectivity/spread
• Potential impact of vaccination strategies on disease burden and AMR burden/spread
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Methodology & data sources
• Systematic review and country case studies T2 project (2015-‐2017) [PLoS NTD Supplement planned for 2018]
• Update Cochrane Review of Antimicrobial therapy of Typhoid (Fluoroquinolones) 2018
• Systematic review of typhoid features in cohorts [Update of JoGHreview 2016].
• Review of cohort data from AKUH information systems (ambulatory and inpatient data 1990-‐2017) with outcomes and costs of care.
• Review of GBD data on Typhoid for South Asia based on drug resistance patterns and outcomes (in partnership with IHME)
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Typhoid trends & preventive strategies (sans vaccination)
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The changing typhoid map: incidence rate in 1990 & 2015
1990
2015
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Study Country Drinking water
Hand washing Open defecation
Sur 2007 India
Alba et al 2016
Indonesia
Hosoglu2006
Turkey
Puran et al 2009.
India
Khan 2012 Pakistan
Ram 2007 Bangladesh
Srikantiah2007
Uzbekistan
Gasem2001
Indonesia
Sharma 2009
India
Tran 2005 Vietnam
Vollard2004
Indonesia
Kabwama2017
Uganda
Contextual risk factors for typhoid
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Study Country Drinking water
Hand washing Open defecation
Consumption of raw vegetables/fruits
Street Foods
Sur 2007 India
Alba et al 2016
Indonesia
Hosoglu2006
Turkey
Puran et al 2009.
India
Khan 2012 Pakistan
Ram 2007 Bangladesh
Srikantiah2007
Uzbekistan
Gasem2001
Indonesia
Sharma 2009
India
Tran 2005 Vietnam
Vollard2004
Indonesia
Kabwama2017
Uganda
Contextual risk factors for typhoid
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Study Country Drinking water
Hand washing Open defecation
Consumption of raw vegetables/fruits
Street Foods
Household size
Literacy rates
Use of Antibiotics two weeks prior
Sur 2007 India
Alba et al 2016
Indonesia
Hosoglu2006
Turkey
Puran et al 2009.
India
Khan 2012 Pakistan
Ram 2007 Bangladesh
Srikantiah2007
Uzbekistan
Gasem2001
Indonesia
Sharma 2009
India
Tran 2005 Vietnam
Vollard2004
Indonesia
Kabwama2017
Uganda
Contextual risk factors for typhoid
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Thailand contextual factor trends
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Thailand incidence trend
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Typhoid & Antimicrobial Resistance
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1950 1960 1970 1980 1990 2000 2010 2020
Chloramphenicol
Ampicillin/Amoxycillin
Co-‐trimoxazole
CeftriaxoneCefixime
CiprofloxacinOfloxacin
Azithromycin
Gatifloxacin
CR
CROR
AZMR
CIPR
GatR
Chromosome
NalRDCS mutation
H58
MDR Plasmid
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Variable MDR + FQ resistant + Cef resistantVariable MDR + FQ resistantMDR + DCSMDRDCSSusceptibleInsufficient data
Anti-‐microbial resistance in Typhoid (2017)
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The Case Study from Karachi(Trends in AMR for typhoid)
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580
97
18
1112
280
48
58
203
16
1434
424
314
2859
123 32
14
465
4081314
2002
Towns Included Towns Not IncludedPotentials towns
140
121
90
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0501001502002503003504004505005506006507007508008509009501000105011001150120012501300
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
Number of Culture Positive Typhoid SpecimensNon Admission data 1991-‐2017
71% of cases are children under 18 years of age
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0
20
40
60
80
1001991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
% Resistant
Antimicrobial Resistance for S. Typhi & Para TyphiNon Admission data 1991-‐2017
MDR MDR + FQs Resistant MDR + Cef Resistant FQs ResistantCef Resistant XDR Sensitive
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What about Antimicrobial Therapy?
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Treatment guidelines & trends
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Impact on fever clearance time
Effa et al (Cochrane Library) update 2018(unpublished)
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Impact on clinical failure
Effa et al (Cochrane Library) update 2018(unpublished)
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Does Antimicrobial Resistance Matter in Typhoid?
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• An extensive literature search covering January 1964 to Sep 2017 was conducted to assess unselected cohorts of cases with case descriptions
• Inclusion criteria necessitated– A sample size greater than 5 & documented clinical features– Blood culture confirmed cases– All levels of disease severity– Patients not representing special populations (ie; all HIV positive, only malnourished children etc.)
– Outcome information where available
Methods
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Complications & Clinical Outcomes
Multi-‐drug and/or fluoroquinoloneresistant
2311 cases from 19 Studies
Sensitive 3236 cases from 26 Studies
n N % Studies n N % StudiesShock or hypotension
22 133 16.5 4 7 105 6.7 3
Toxicity 208 427 48.7 5 310 968 32.0 5
GI Bleeding 29 316 9.2 8 13 365 3. 6 10
GI Perforation 4 142 2.8 2 2 493 0.4 4
Relapse rates (%) 36 942 3.8 10 13 524 2.5 8
Case Fatality (%) 24 1582 1.5 14 31 2399 1.3 15
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Complications & Clinical Outcomes
Multi-‐drug and/or fluoroquinoloneresistant
2311 cases from 19 Studies
Sensitive 3236 cases from 26 Studies Comparison
n N % Studies n N % Studies Odds Ratio 95% CIShock or hypotension
22 133 16.5 4 7 105 6.7 3 2.77 (1.14, 6.78)
Toxicity 208 427 48.7 5 310 968 32.0 5 2.02 (1.60, 2.54)
GI Bleeding 29 316 9.2 8 13 365 3. 6 10 2.74 (1.40, 5.36)
GI Perforation 4 142 2.8 2 2 493 0.4 4 7.12 (1.29, 39.26)
Relapse rates (%) 36 942 3.8 10 13 524 2.5 8 1.56 (0.82, 2.97)
Case Fatality (%) 24 1582 1.5 14 31 2399 1.3 15 1.18 (0.69, 2.01)
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Does Antimicrobial Resistance Matter in Hospitalized cases of Typhoid?
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0
20
40
60
80
100
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
% Resistant
Antimicrobial Resistance for S.Typhi & Para TyphiHospitalized children < 15 years age 2001-‐2017
MDR MDR + FQs Resistant MDR + Cef Resistant FQs ResistantCef Resistant XDR Sensitive
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Outcome data
0
1
2
3
4
5
6
7
Sensitive MDR XDR
Length of Stay (days)
Relapse Rates (%)
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0
10000
20000
30000
40000
50000
60000
Sensitive Resistant
Physician & Nursing Care Diagnostics Medications Others
Cost of care PKR
Cost of therapy of resistant casesalmost 72% greater than sensitive Typhoid cases
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Methods: YLD adjustments• Estimated YLDs per case for resistant and sensitive infections based on frequency of clinical outcomes in each group
• Calculated YLD per case multipliers for sensitive and resistant infections as
𝑀"#$" =𝑌𝐿𝐷"#$"𝑌𝐿𝐷)*+
𝑀,#"-". =𝑌𝐿𝐷,#"-".𝑌𝐿𝐷)*+
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Methods: AMR split
• Estimated the proportion resistant by year based on Karachi data– Incorporated uncertainty using beta distribution and posterior simulation with 1,000 draws
• Split deaths, cases, YLLs, and YLDs between sensitive and resistant
• Adjusted YLDs for sensitive and resistant infections using YLD multipliers
• Re-‐calculated DALYs as sum of YLLs and updated YLDs
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Each year the odds of a infection being resistant increase 30% (24 -‐ 35%)
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Each year the odds of a infection being resistant increase 30% (24 -‐ 35%)
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Conclusions• The increase in AMR in typhoid is real and of special concern is the rise of
XDR typhoid (MDR plus FQ and Ceftriaxone resistant strains), severely limiting treatment options. These strains pose a major threat of trans-‐continental and regional spread.
• In general MDR typhoid appears to be a more severe disease with excess morbidity, at least 1.5 days longer hospitalization & 72% higher direct costs of illness.
• Of the DALYs and YLDs associated with typhoid, the bulk now appears to be due to antimicrobial-‐resistant typhoid, projected to almost replace all sensitive typhoid infections in South Asia
• Of potential interventions in the near future, large scale vaccination strategies for typhoid are the most promising to reduce the burden of illness, especially the incidence of MDR and XDR typhoid