Antibiotics – Friend and enemy (or revenge of the microbes). Dr Neil Todd, Head of Microbiology, York Teaching Hospital NHS FT

Aims of this session To provide a realistic appraisal of the value of antibiotics – these are not ‘magic bullets’ To explore ways in which we can improve our use of these important drugs Persuade you that it is possible to have too much of a good thing!

Adverse effects are inherent in their use Cause collateral damage Enhance bacterial evolution Cause direct drug toxicity effects

Collateral damage Damage to normal flora Superinfection Physiological impacts Enhanced rates of cross infection Superinfection Altered host immunity

C. difficile cases in England - HPA reporting

Enhance bacterial evolution Act as a potent selective force Favour emergence of resistant bacterial strains (vertical selection) Increase rates of genetic interchange between bacteria (horizontal selection) Drive selection for new versions of old bugs

Emergence of Antimicrobial Resistance Campaign to Prevent Antimicrobial Resistance in Healthcare Settings Emergence of Antimicrobial Resistance Susceptible Bacteria New Resistant Bacteria Mutations XX Resistant Bacteria Resistance Gene Transfer Bacteria have evolved numerous mechanisms to evade antimicrobial drugs. Chromosomal mutations are an important source of resistance to some antimicrobials. Acquisition of resistance genes or gene clusters, via conjugation, transposition, or transformation, accounts for most antimicrobial resistance among bacterial pathogens. These mechanisms also enhance the possibility of multi-drug resistance.

Selection for antimicrobial-resistant Strains Campaign to Prevent Antimicrobial Resistance in Healthcare Settings Selection for antimicrobial-resistant Strains Resistant Strains Dominant Antimicrobial Exposure x Resistant Strains Rare x Once resistant strains of bacteria are present in a population, exposure to antimicrobial drugs favors their survival. Reducing antimicrobial selection pressure is one key to preventing antimicrobial resistance and preserving the utility of available drugs for as long as possible.

The tidal wave of MDR bacteria (resistant to 3 or more antibiotics) N. gonorrhoeae – MDR GC M. tuberculosis – MDR & XDR TB S. pneumoniae - PRP S. aureus – HA-MRSA & CA-MRSA Enterobacteriaceae – ESBLs, KPC, AmpC Ps. aeruginosa et al

Mortality associated with carbapenem resistant (CR) vs susceptible (CS) Klebsiella pneumoniae (KP) Patel G et al. Infect Control Hosp Epidemiol 2008;29:1099-1106

MIC creep – small incremental increases in MIC Vancomycin and S. aureus Cephalosporins and N. gonorrhoeae Quinolones and Salmonella spp. Penicillin and N. meningitidis

New strains of old bugs PVL +ve CA-MRSA Ribotype 027 C. difficile VTEC 0104 E. coli

Historically we have wheeled out the new model - But …….

The situation is not yet hopeless – I think!

Antibiotics are misused in hospitals “It has been recognized for several decades that up to 50% of antimicrobial use is inappropriate” IDSA/SHEA Guidelines for Antimicrobial Stewardship Programs http://www.journals.uchicago.edu/doi/pdf/10.1086/510393

Proportion of patients considered clinical successes in intention to treat population. Proportion of patients considered clinical successes in intention to treat population. Day 3=day of randomisation Moussaoui R e et al. BMJ 2006;332:1355 ©2006 by British Medical Journal Publishing Group

Figure 2. Kaplan-Meier Estimates of the Probability of Survival Probability of survival is for the 60 days after ventilator-assisted pneumonia onset as a function of the duration of antibiotic administration. Figure 2. Kaplan-Meier Estimates of the Probability of Survival Probability of survival is for the 60 days after ventilator-assisted pneumonia onset as a function of the duration of antibiotic administration. Chastre, J. et al. JAMA 2003;290:2588-2598 Copyright restrictions may apply.

How do we improve our use of antibiotics? Reduce use of high risk, broad spectrum antibiotics Maximise patient benefit through better targeting Avoid use in viral infection and limit use for self limiting bacterial infections e.g. abscesses Avoid treating colonising flora - poor quality sampling contributes Aim for reduced consumption overall

Targeted antibiotic consumption and nosocomial C. difficile disease Tertiary care hospital; Quebec, 2003-2006 Valiquette, et al. Clin Infect Dis 2007;45:S112.

Strategies for better targeting Ensure that severely septic patients are identified and receive prompt, effective treatment Identify infection through appropriate use of testing inc. rapid techniques Maximise use of directed, narrow spectrum treatment in suspected mild/moderate infection Make use of observation or wait and see/delayed prescribing if unsure

The Duration of Hypotension Prior to Initiation of Effective Antimicrobial Therapy is the Critical Determinant of Survival in Human Septic Shock Cumulative effective antimicrobial initiation following onset of septic shock-associated hypotension and associated survival. X axis represents time (hrs) following first documentation of septic shock-associated hypotension. 0-0-.49 0.5-.99 1-1.99 2-2.99 3-3.99 4-4.99 5-5.99 6-8.99 9-11.99 12-23.99 24-35.99 >36 1.0 0.8 0.6 0.4 0.2 0.0 Survival fraction Cumulative effective antimicrobial initiation Time from hypotension onset (hrs) Fraction of total patients Kumar et al. Crit Care Med 2006;34(6)1589-1596

Yes we can but There is no one easy answer It requires ongoing interventions to reinforce appropriate use It requires everybody to participate and follow a systematic approach to antibiotic prescribing using an Antibiotic Pathway

Antibiotic stewardship Synthesises multifaceted interventions into an overall programme designed to preserve the benefits of antibiotics and prolong their useful life This is everyone’s business and we all need to play our part in achieving the agreed goals of our programme

Clinical outcomes better with antimicrobial management program Percent RR 2.8 (2.1-3.8) RR 1.7 (1.3-2.1) RR 0.2 (0.1-0.4) AMP = Antibiotic Management Program UP = Usual Practice Fishman N. Am J Med. 2006;119:S53.

Key Questions How do we balance individual desire to access these drugs with adverse societal impact – can education achieve this? Where use is restricted how do we deal with adverse outcomes? Can we afford to use these agents in every situation where benefit has been shown?

Perhaps -the most difficult question How long can we continue with our current approaches before the adverse impacts are catastrophic or undermine significantly the benefits of the drugs?