The Global Public Health Threat of Antibiotic Resistancereactgroup.org/uploads/publications/presentations/... · The drug development pipeline is virtually empty from antibiotics

The Global Public Health Threat of Antibiotic Resistance

Andreas Heddini, MD, PhD

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Penicillin

Untreated

Dagar

Penicillin increased the chance of survivalfrom 10% to 90%

Patients withpneumoniaand bacteriain blood

Discovery of antibiotics

• Enormous medical gains– Reduced morbidity and

mortality due to bacterial infections

– A requirement for modern health care

• Larger surgical interventions

• Treatment of the immunosuppressed, including cancer patients

• Transplantations• Neonatal care

The time has come to close the book

on infectious diseases…..

To the Congress in 1969:

William H. Stewart Surgeon General 1965-69

A Global Challenge

Antibiotics are losing their effectiveness ata pace that was unforeseen just 5-10 years ago

The drug development pipeline is virtually emptyfrom antibiotics with a novel mechanism of action

The Current Paradox:

AntibioticResistance

DrugDevelopment

MorbidityMortality

Costs

Use - Rational and IrrationalAccess, quality, marketing, financing

Spread of resistant bacteriaPoor hygiene and sanitation in hospitals and the community, travel

Lack of new antibioticsScientific hurdlesLow return of investment

AntibioticResistance

Marketing

Overconsumption New antibiotics

Resistance

60 years of antibiotic use….Millions of tons.........

Sulphonamides

Tetracyclines

PenicillinsAminoglycosides

Macrolides

Glycopeptides

Streptogramins

ChloramphenicolQuinolones

Trimetoprim

Lincosamides

1930´s 1940´s 1950´s 1960´s 1970’s 1980´s 1990´s 2000´s

Oxazolidinones

The dwindling antibiotic pipeline...

Lipopeptides

The survival of the fit

Bacteria can develop resistanceagainst all antibiotics

• Cause• Spontaneuous mutations• Transfer of genetic information between bacteria

• Selection• Under the pressure of antibiotics resistant bacteria are selected

• Spread• Resistant bacteria• Epidemic strains (outbreaks)• Endemic situation

What happens during antibiotictreatment?

• Empirical treatment• Based on experience and previous knowledge –

educated guess – treatment often started beforeconfirmation of diagnosis

• Aim• To eliminate or quell presumed pathogen

• Side effects• Affects the normal bacterial flora• Selects the bacteria, which have aqcuired/have natural

resistance to the antibiotic

“It is not difficult to make microbes resistant to penicillin ….

…. The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.”

Alexander Fleming's Nobel Lecture, 1945

Athens, Greece (174 pharmacies) 2008:

-100% of all visited pharmacies sold Amoxicillin/clavulanic acid OTC

- 53% sold Ciprofloxacin OTC, despite extra restrictions for fluoroquinolone prescriptions

Plachouras et al. Euro Surveill. 2010

Illegal OTC antibiotic sale in the EU

Bacteria with a genetic mechanism

for antibiotic resistance•Spontaneous mutation

•Transfer of resistance genes

Antibiotics Selection

Bacteria with a genetic mechanism

for antibiotic resistance•Spontaneous mutation

•Transfer of resistance genes

AntibioticsCrowding TravelPoor hygiene &infection control

Food-chainSelection

Spread

Bacteria with a genetic mechanism

for antibiotic resistance•Spontaneous mutation

•Transfer of resistance genes

AntibioticsCrowding TravelPoor hygiene &infection control

Food-chain

Increasing resistance in hospitals and the community

Selection

Spread

The more we use them, the more we lose them…

Albright et al. EID 2004;10(3):514-7

A Global Problem

France

USA

Mexico

Colombia

Argentina Brazil S. Africa

U. K

Taiwan

Japan

Korea

Thailand

Singapore

Worldwide spread of the 23F clone of penicillin resistant pneumococci

ESBL (CTX-M) producing Enterobacteriaceae2001-2002

Endemicity Sporadic reports

Endemicity Sporadic reports2005

2007

Orphanage in Bamako, MaliESBL colonized 100% of the children and 63%, of the adult staff studied. Tandé et al. Emerg Infect Dis. 2009 Mar;15(3):472-4.

Mumhibili hospital, TanzaniaThe mortality rate from Gram-negative bloodstream infection was 43 %, more than double that of malaria..Blomberg et al. BMC Infect Dis. 2007 May 22;7:43.

Antibiotic susceptibility proportions for NDM-1-positive Enterobacteriaceae isolated in the UK and India

From Kumarasamy et al. Lancet Infect Dis 2010

UK (n=37) Chennai (n=44) Haryana (n=26)

Imipenem 0% 0% 0%

Meropenem 3% 3% 3%

Piperacillin-taz 0% 0% 0%

Cefotaxime 0% 0% 0%

Ceftazidime 0% 0% 0%

Cefpirome 0% 0% 0%

Aztreonam 11% 0% 8%

Ciprofloxacin 8% 8% 8%

Gentamicin 3% 3% 3%

Tobramycin 0% 0% 0%

Amikacin 0% 0% 0%

Minocycline 0% 0% 0%

Tigecycline 64% 56% 67%

Colistin 89% 94% 100%

Spread of NDM-1

Rolain et al. Clin Microb Inf 2010

Black et al (Lancet 2010)

Newborn infections, pneumonia and diarrhea acocunt for almost 40% of all child

deaths globally

The UN Millenium Goals and antibioticresistance…

Goal 4: Reduce child mortality

Goal 5: Improve maternal health

Hip replacement

Organ transplants

Cancer chemotherapy

Care of preterm babies

Modern medicine is not possible without effective antibiotics

Nor is fundamental health care…

Neonatal sepsis and antibioticresistance – does it matter?

Case Fatality Rates (Neonatal sepsis)

OrganismSusceptibility

Resistant Sensitive

STAPHYLOCOCCUS AUREUS 15.4 % 3.5 %

KLEBSIELLA 22.8 % 16.1 %

ENTEROBACTER 28.0 % 21.6 %

ACINETOBACTER & PSEUDOMONAS 42.7 % 14.0 %

ESCHERICHIA COLI 44.0 % 26.7 %

%

Zulfiqar Bhutta presentation at ReActconference Sep 2010

Mortality outcomes are worse in neonates with resistant infections

(Tanzania)

149

58

369

151

91

5523

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10

20

30

40

50

60

Culture Gram Reaction ESBL MRSA

Dea

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)

Parameter

Positive

Negative

Kayange M et al, BMC Pediatrics 2010

Childhood pneumonia – are weovertreating?

• Double-blind, randomized trial in 4 tertiary hospitals in Pakistan

• 900 children aged 2–59 months with WHO defined non-severe pneumonia were randomized to receive either 3 days of oral amoxicillin or placebo;

• Clinical outcome in children aged 2–59 months with WHO-defined non-severe pneumonia is not different when treated with an antibiotic or placebo.Hazir et al. Clin Infect Dis. Feb 2011

Loss of first line drugs increases drug costs

Source: WHO Policy Perspective 2005, adapted from WHO Model Formulary, WHO Clinical Guidelines and Management Sciences for Health’s 2004 International Drug Price Indicator Guide (slide courtesy: David Heymann)

ICU

Hospital

Community

Ecology

The tip of the iceberg

ANTIBIOTICS…OVERCROWDING….SPREAD……..

Preserving antibiotics – what do we do while waiting for new

drugs?

There will be no magic bulletsolution to the problem of

antibiotic resistance

Looking ahead

• Economic development -> increased consumption!

• Antibiotics (azithromycin and clindamycin) proposed to be used for ”vaccination”againstmalaria - > how to balancehealth benefits?

• Effects of antibiotics in the environment and in the food-chain – keep separate!

Action is needed now

• People are dying from bacterial infections because the lack of effective therapy

• Antibiotic resistance is causing significant costs for health care

• The market driven system for research and development of new antibiotics is failing

Strategies for the management of Antibiotic Resistance

Surveillance Decrease the need for antibiotics

Use antibiotics properly

Non medical usage

Monitor:

Resistance patterns

Antibiotic use

Reduce diseaseincidence

prevent spread of bacteria

Improve diagnostics and use

Environment, food, plants etc.

Coordinate national activities

International collaboration

Knowledgeeducation, informationresearch

Health systems perspective

Antibiotic resistance is not onedisease - crosscutting

Pneu

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Seps

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Men

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Wou

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Gyn

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Antibiotic Resistance

A fine balance

Immediatebenefit to the

individual

Global need ofeffective

antibiotics

Rational use of antibioticsButler C et al. JAC 2001; 48:435–440

Managing antibiotic resistance

Prolong the lifespan of existing drugs• Rational Use• Better diagnostics• Combinations?

Prevent the spread of resistant bacteria• Improved hygiene• Infection control• Hospital structure

Development of new antibiotics• New financial models required!

Rational use of antibiotics

• More restrictive use• Where there is need

• But…• Also an issue of access• Not at least in low-income countries

Adapted from Källander 2005

Access vs. Excess

A significant number of these babies died. Ten years ago these lives could have been saved, but today the remaining treatment options are way too costly for most parents.”

“ Almost half of the sampled sepsis patients could not be treated with available antibiotics due to resistance against these medicines – a majority of these patients were newborns.

In some cases, the medicine cabinet is already empty

Dr Florence Najjuka, Makerere, Ugandaat ReAct WHA briefing, WHO Geneva 2009

Access

• Will increased access per se lead to betterhealth outcomes?

• What about quality?

WHO/TDR, A. Crump

R&D for new antibiotics

• Desperate need for new classes of antibiotics

• Better diagnosticmethods – rapid diagnostic tests

• Vaccines

Simulation studies: Most lives saved from reducingdisease burden accrue to Africa, while other regions

benefit from reducing overuse

Issues

• Difficult to introduce a new diagnostic in a population that self-treats unless the sensitivity is high enough (~95%) to ensure that the overall number of individual livessaved is positive

• The benefit of any diagnostic test for severe ALRI depends on access to effective hospital care.

Study conclusion - diagnostics

• ALRI contributes annually to the deaths of >2 million children aged <5 years, 75% of whom were in Africa and southeast Asia

• A new diagnostic test for bacterial ALRI with at least 95% sensitivity, 85% specificity and minimal infrastructure requirements couldsignificantly improve global efforts to control ALRI, saving at least 405,000 children’s lives every year.

Antimalarial prescriptions for febrile patients

• Patients presenting to outpatient departments in northeast Tanzania with varying level of malaria transmission

• 2,425 Patients for whom a malaria test was requested were randomised to microscopy or rapid tests

• Outcome: proportion of malaria negative patients prescribed Antimalarial drugs

98% 51% 99% 54%Antimalarialsprescribed

MicroscopyN = 1204

Rapid testN = 1193

174 +(14%)

1.030 -(86%)

1.005 -(84%)

188 +(16%)

Reyburn et al BMJ 2007

Currently 37 sites in 19 countries24 sites in Africa9 sites in Asia1 site in Oceania

Over 2,000,000 people under surveillance

Prospective monitoring of demographic and health events

Verbal autopsy for cause of

death

Capturing episodes of disease and hospital

admission

Measure characteristics of environment or household

members (e.g. SES, vaccines, HIV, nutrition)

Intervention trials

(randomised)

Health and Demographic Surveillance System (HDSS)

INDEPTH cross-site research - 1

• Mortality levels, patterns, and trends• Causes of death in developing countries• Model life tables• Malaria transmission and mortality• Health equity studies• Migration and urbanization• Sexual and Reproductive Health

INDEPTH cross-site research - 2• NCD risk factor studies in Asia• Adult health and Aging• Climate Change and Health• Intervention trials platform

– Effects of ART scale-up on mortality and health systems

– Phase IV – Effectiveness and Safety Studies of antimalarias (INESS)

• Antibiotic resistance

Surveillance in Low-IncomeCountries

• ”Don’t let the best be the enemy of the good!”• Sentinel surveillance• Work with available structures• Few pathogens• Start!

Innovation and R&D for novelantibiotics

Many new initiatives targeted to address this health concern have been launched, notably in the area of R&D of new antibiotics

Need for global measures that ensure that new strategies and/or health technologies are applicable, accessible and affordable also in low- and middle income countries

Challenges in low-income countries

• High background mortality and morbidity of bacterial disease

• Rising incomes – greater access to antibiotics• Yet many patients do not have access to

effective antibiotics• Increasing levels of resistance to first line

drugs• Second line drugs may be unaffordable to

many low-income families

Policy options

• Encourage physician only prescribing?• Scale up rapid diagnostic tests?• Improve surveillance?

• Reduce incentives for over prescribing• Improve access to quality medicines• Pneumoccocal and HiB vaccination• Improve hospital infection control

Antibiotics – a finiteresource