Dougherty, Pucci, Bronson, Davison & BarrettAntimicrobial resistance - why do we have it and what can we do about it?

Monthly Focus: Anti-infectives

Antimicrobial resistance - why do we haveit and what can we do about it?

Thomas J Dougherty, Michael J Pucci, Joanne J Bronson, DanielB Davison & John F Barrett

Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT06492, USA

Exp. Opin. Invest. Drugs (2000) 9(8):1707-1709

An accurate, but oversimplified statement is that the time of use of antimi-crobial agents has ‘built-in obsolescence’ due to resistance emergence.Every antimicrobial agent in use loses efficacy as a result of either geneticacquisition of resistance encoding genes or by mutation of the target(s) ofthe drug. The end result is the survival and proliferation of the resistantorganism. The powerful selection imposed by antimicrobial agentseliminates the susceptible organism, thereby enlarging the niche for thesurviving, resistant forms to proliferate. At one point, it was believed thatthe resistant organisms might be at a selective disadvantage (due to thegenetic load imposed by the resistance genes) relative to susceptible strainsin the absence of antibiotic challenge. This suggested that cycling of antibi-otic use might be an effective strategy to combat resistance to classes ofantibiotics. Recent studies on the role of intragenic and extragenic compen-satory mutations in increasing the fitness of resistant mutants have strippedus of this simple notion and makes the picture all the more complex anddismal.

Many classes of antibiotics are derived from natural products. The parentproducing organism, often a soil bacterial or fungal species, carries genesthat render the producing organism immune to the action of the compound.This ancient form of ‘microbial warfare’ has been capitalised upon by thepharmaceutical industry and many variants and derivatives of antimicrobialnatural products have been produced over the last half-century. Thisman-made ‘amplification’ of natural production of antimicrobials hasunleashed an enormous selective evolutionary pressure. The producingorganisms have acted as a source and reservoir of resistance genes andthese have been transmitted via several genetic mechanisms to a widevariety of microbes, most notably a broad range of pathogens. The range ofresistance spread, via integrons, transposons, plasmids, phage and othergenetic mechanisms, is truly astonishing and humbling to the practitioner ofmedicine. Even in the case of ‘synthetic’ antimicrobials, such as thequinolones and phosphonomycin, mutational mechanisms readilygenerate resistance in the absence of sources of producer resistance genes.

The net result is that even in a perfect world, in which the use of antimicro-bials is 100% accurate (diagnosis of the true pathogen causing the diseasestate; correct identification of the species and measurement of suscepti-bility; correct selection, use and compliance of antimicrobial therapy), wewould still have resistance emergence problems. In short, no antimicrobialis immune from resistance emergence and all are at risk of loss of efficacy in

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the clinic. Therefore, the ‘built-in obsolescence’ needsto be understood and managed, but how?

If antibiotics are viewed as a resource to be managedand sustained, one needs to treat their use with somedegree of rational forethought. As it is, we use, misuseand overuse antimicrobial agents in the clinic, inanimal therapy and feed markets and in pharmaciesworldwide where generic agents are sold over thecounter. However, is this really a driver of resistance,or is it just a widely held convenient notion (whatStephen J Gould terms ‘A just-so story’, an idea thatmakes sense without a solid foundation of formalproof) by key opinion leaders (KOLs) that chastise theabusive properties of the discoverers/developers,marketers, providers, insurers, practitioners and usersof antimicrobials? It is not as straightforward as onemight believe to determine this, for virtually everystudy suggesting a particular linkage of resistance tosome abuse factor has certain l imitat ions(geographical niche, small study sample size, extenu-ating circumstances, absence of certain controls etc.).This precludes a definitive answer with a formaldeclaration of guilt for many of these practices,leading to regulatory mandates to solve the resistanceproblems.

However, we do have enough evidence to intelli-gently ascertain that many processes and humanbehaviours indeed contribute to the increased riskand therefore many of the KOLs concerns are in factlegitimate and should have some mitigable actionplan. The 1994 ASM Antibiotic Task Force onResistance declared, ‘Although defining the precisepublic health risks of emergent antibiotic resistance isnot a simple undertaking, there is little doubt that theproblem is global and very serious’. So what do we doto improve the situation?

To start, recognise, admit and acknowledge acontributory negligence by all aforementioned partiesand add in political agendas, healthcare cost burdens(governmental and private) and lastly the factor of alegal system built on the premise that ‘someone is toblame’ when something does not work out with a100% success rate. Since one cannot sue the microbesfor damages, next in line would be the providers whowere unsuccessful in eliminating the microbe. All ofthis leads to a worldwide delivery system of mostlyempirical therapy, with antibiotic overuse and misuse,because it is easy and cheap and has a reducedrisk-of-failure. This approach appears on the surfaceto be largely successful in terms of treating most

patients, but there are hidden costs in terms ofresistance selection and proliferation. Inappropriateand suboptimal therapy exacts a price in terms ofresistance selection in the community. Even optimaltherapy has unforeseen consequences in generatingthe potential for resistance emergence. For example,recent studies have revealed significant antibioticresistance arising in the skin flora of patients treatedsystemically with certain classes of antibiotics. Thepotential for spread of these resistant organisms byhealthcare workers is obvious.

Surveillance studies tell us that virtually every class ofantimicrobial in the marketplace is experiencing somelevel of resistance emergence. While the relevance ofthis in vitro assessed emergence of resistance may bedisputed by some experts, in terms of impact onclinical outcomes, it cannot be a good sign to findoutright pathogens and commensal organismsdeveloping a defence to microbial infection control(i.e., antimicrobial agents). We must halt, if notreverse (if this is possible) both the trend andexistence of this resistance microbial pool, but how?

We propose certain solutions:

• Interlink surveillance data on a global basis, withthe establishment of ‘standards’ to minimallynormalise results and allow consistent interpreta-tion of the data. Study the data with a willingness inspirit to collaboratively seek solutions

• Stop having cost-risk-assessments drive whatshould be a medical needs decision in determiningtreatment options. Cease allowing cost-risk assess-ments to put a dollar value on the acceptable lossof human life due to microbial infection wherethere exists a therapy to combat the disease state

• Decide what will work to reduce both morbidityand mortality worldwide and build a plan toimplement this initiative

• Reinvest in basic research to better understand thebasic biology/biochemistry/genetics of pathogensresponsible for the disease state. Do this in both theacademic community and in the industrial setting?

• Actively encourage the research community to findcreative solutions that are not limited by regulatoryconstraints , legal (patent) constraints ,cost/insurance constraints, or political constraints(e.g., why do we have to decide among cancerresearch or AIDS research or antimicrobial researchversus finding funding for all to succeed?)

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs (2000) 9(8)

1708 Antimicrobial resistance - why do we have it and what can we do about it?

• Build a model to reduce empirical therapy by thedesign, development and implementation of ahealthcare system that allows for worldwidediagnosis of the nature of the infectious diseasepathogen in ‘real time’ and the subsequenttreatment with the optimal drug therapy

• Invest in the basic research to understand the valueof preventative medicine, be it a worldwidevaccination program or a worldwide initiative toimprove sanitation to decrease risk of contagionspread

• Stop providing ‘ownership’ of genes in nature thatlimit technical solutions by reducing access to thegenomic information that allow researchers to seekdrugs to combat infectious diseases

• Invest in a new informatics analyses of outcomesresearch that enables the medical community tounderstand the best practices of drug therapy,instead of the current superficial reporting of a‘cure’ or ‘improved’ outcomes

• Limit the penalty of ‘lack-of-success’ in animperfect world and cap damages as was done toprovide incentives for vaccine work in the USA

• Fund collaborative research to allow academia,government and industry to better understand howto address antibiotic resistance

• Provide incentives for commercial units (start-ups,capital venture, biotech, big pharma) to go afterantimicrobial resistance mechanisms as adjuncttargets

We need to make this effort a global priority. In aworst case scenario, the balance of survival could tipin favour of the microbes if an ‘Andromeda’ strain ofbacteria were to emerge (e.g., high-level vancomycinresistance in multiply-resistant MRSA). In a best casescenario, we still have millions of people dying

worldwide from microbes that theoretically could becontrolled by existing drug therapy. We need tomobilise now, we need to act now and we need to actas rational, compassionate, co-members of societythat intend to ‘do the right thing’. We need to makethis a worldwide mission, just as we’ve done in tryingto address pollution or ozone depletion.

Where do we start? Form a global taskforce of KOLsfrom both academia and government, together withcommercial interests (pharmaceuticals, vaccines,preventive medicines, diagnostics), healthcareproviders, researchers, informatics experts, legal andpolitical representatives throughout the world. Thistaskforce would develop a sustained, committed,‘actionable’ plan built on the accumulation, analysesand sharing of worldwide data and turn the data intoknowledge. The goal would be to build an integratedglobal plan, set the priorities for order of implementa-tion and then figure out a way to fund it for success.Perhaps this would evolve into a not-for-profitpseudo-commercial enterprise that could actuallydeliver on the plan. In other words, a sort of ‘unitednations’ of antiresistance emergence technology.

What will happen if we do not act on this cause?Failure to act poses a tremendous human risk, as thetrends from surveillance data clearly demonstrate theincreased incidence of multiple resistant bacteria. Inthe best case scenario, we will forever battle nature’sevolutionary mechanisms for ‘built-in obsolescence’as an intrinsic price for cavalier use of antibiotics. Inthe darkest scenario, it might be that human interven-tion purposely releases a bio-terror agent based onthe artificial manipulation of antimicrobial resistancefactors. We need to act now.

Thomas J Dougherty† , Michael J Pucci, Joanne J Bronson, Daniel BDavison & John F Barrett† Author for correspondenceBristol-Myers Squibb Pharmaceutical Research Institute,Wallingford, CT 06492, USA

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs (2000) 9(8)

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