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.