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

7. 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!

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

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

10. C. difficile cases in England - HPA reporting

11. 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

12. 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.

13. 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.

14. 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

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

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

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

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

27. The situation is not yet hopeless – I think!

28. 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

29. 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

30. 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:
Copyright restrictions may apply.

31. 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

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

35. 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

36. 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.
1-1.99
2-2.99
3-3.99
4-4.99
5-5.99
6-8.99
>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)

38. 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

39. 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

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

41. 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?

42. 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?