Preserving antibiotics – what do we do while waiting for new

drugs?

Andreas Heddini, MD, PhD

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!

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The bacterial challenge - time to reactJoint Technical Report from ECDC and EMEA

The antibacterial pipeline against selectedmultiresistant Gram-negative bacteria

Assumed

Proven

Activity (in the lab)

Current status of antibiotic R&D activity

• Weak late-stagepipeline

• Few agents againstGram-negativebacteria

IMS HealthNature, Vol 9, Sep 2010

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

3 R’s: Sharing Resources, Risks and Rewards

Discovery Pre-Clinical Clinical DevelopmentPost-

marketing

Lead Identification

Medicinal Chemistry

Crossing the Valley of Death

Regulatory Approval

Rational Use

Sharing RESOURCES

Sharing RISKSSharing REWARDS

Towards New Business Models for Antibiotic R&D

• Setting priorities through target product profiles

• Improving lead identification and medicinal chemistry

• Open innovation approaches– OSDD in India

• Testing drug combinations – learn from TB

Towards New Business Models for Antibiotic R&D

• “Incentives that separate the financial return from the use of a product are the only way to change this behavior”- Richard Bergström, Director-General of the trade association for the research-based pharmaceutical industry in Sweden and IFPMA

• PDP-model with the right mix of incentives• How to ensure global access and

affordability??

A framework for prioritisingamongst health technologies?

• Based on global surveillance of ABR• Not rigid – provide guidance• Parameters

– Disease prevalence– Mortality & morbidity– Deaths averted by new product– Access to antibiotics and their use– Risk / likelihood of success

• Feasible?

Other options

Novel antibacterials:• Antibacterial peptides

– Often short half-life, making them unsuitable for systemic use

– Toxic• Bacteriophages• Small molecules

– E.g. inhibiting virulence factors (would leavenormal flora unharmed), TTS, QS, adhesion etc

Future prospects

• Most antibiotic resistance mechanisms are associated with a fitness cost

• The fitness cost is the main driver of resistance reversibility at community level.

Future prospects II

• Thus, the bigger the fitness cost, the faster the reversibility.

• However, recent data suggests that reversibility might not occur as previously thought(D. Andersson et al. Nat. Rev. Microbiol. Apr. 2010)

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Reversibility of trimethoprim resistance in E. coli following a drastic 2-year reduction in trimethoprim use

Adapted from Sundqvist et al. Antimicrob Chemother. 2010

Trimethoprim resistance, E.coli , Kronoberg, 1991-2006 (Resistance defined as nonsusceptibles using epidemiological cut-offs)

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Adapted from Sundqvist et al. Antimicrob Chemother. 2010

V.cholerae O1: Reversibility of resistance

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W. A. Khan, ICDDR,B, Bangladesh

Resistance reversibility

• More complicated than expected• Co-selection, resistance genes remain in

gene-pool• Antibiotic cycling not generally promising, but

for certain antibiotics it might be!• Malaria: Malawi study showing that after CQ

had been removed from the arsenal –susceptibility came backM.K. Laufer et al. N Engl J Med. 2006

Strategies for preserving drugefficacy

• Dosage based on revisiting pharmacokinetic(pk) and pharmacodynamic (pd) principles– Exposure over time

• Finding the right dose for old antibiotics– Obtain exposure-response relationships– Re-evaluate registration and indication for

available antibiotics– Create a mandatory process of re-evaluating

indications and dosing, e.g. 5-year intervals

Strategies for preserving drugefficacy II

• Learn from e.g. malaria drug studies – e.g. Guinea Bissau (Ursing et al, Infect Genet Evol Sep, 2007)

• Reducing treatment duration (exposure)• Combination therapy

– For severely ill patients– Specific indications (e.g. psudomonas)

• Better use of biomarkers to differentiate betweenbacterial and other infections, e.g. procalcitonin, CRP

Use of biomarkers for severe bacterialpneumonia in rural Mozambique

• INDEPTH HDSS Manhica study of 835 children < 5 yrs

• CRP• PCT• Malaria, HIV

Díez-Padrisa et al. PLoS One Oct 2010

Use of biomarkers for severe bacterialpneumonia in rural Mozambique

• PCT and CRP cannot differentiate betweenviral and bacterial pneumonia in hospitalisedchilldren in the presence of malaria parasites

• However, in patients without malaria bothtests can do this independently of HIV-status

• PCT expensive

Díez-Padrisa et al. PLoS One Oct 2010

Towards a Global surveillancesystem of abr?

Global surveillance of ABR

• Build on exisiting networks and efforts• Speak the same languange - harmonize

break points world-wide• Maintain over time

Why Surveillance?

• Develop appropriate local treatment guidelines – SAVE LIVES

• Detect new resistant pathogens and to better understand the dynamics of the spread of resistance genes

• Allow better basis for calculation of socio-economic burden of ABR

• Inform reinvigorated R&D efforts

War wound infections

• A. baumanni, pseudomonas– Biofilm formation -> non healing wounds

• Immunization– Passive (Ig)– Active (cellular, LPS)

Dallo et al. Adv Skin Wound Care. 2010 Apr;23(4):169-74

Requirements

• A sustained, systematic effort of discoveryand development – many years

• Financing mechanisms for clinical trials?• A mechanism for prioritizing amongst

different antibiotics, diagnostics and otherhealth technologies needs to be based on:– Surveillance -> information on global prevalence

of resistant pathogens– Predictions, modelling and analyses of trends

Priorities?

• Drugs against Gram-negative bacteria• Could antibiotics and diagnostics be co-

developed and marketed together?• Better use of existing antibiotics

– Dosage and intervals– Fixed-dose combinations?

• Surveillance -> Start with what is there!• Diagnostics, especially POC tests• Vaccines where feasible

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

MSFs reality?

• Need to be generous with AB in disaster situations!

• Strive to be updated with regard to availablelocal resistance data

• Follow and revisit treatment guidelines• Prevention of health care associated

infections and improved hospital hygiene.