RESISTANCE, USE, INTERVENTIONS Hugh Webb
EU Initiatives: EARSS and ESAC. Antimicrobial Use and Resistance The Relationship. Bias and confounding in published studies. Mathematical modelling of resistance and use. Spread of resistance/clonality clonality. Risk and the individual. Strategies to reduce resistance in primary care.
PHARMACOEPIDEMIOLOGY The study of the use and effects of drugs on populations Association vs Causality BIAS Information bias Selection bias CONFOUNDING Association eg age, comorbidity Indication eg colonisation in ICU Steinke and Davey. CID, 2001, 33 (Suppl 3) 5193
STUDY DESIGNS Bacterial cultures (clinically indicated sampling) Bacterial cultures linked to prescription Bacterial surveillance cultures Randomised controlled trials
There is a compelling weight of evidence showing that community prescribing of antibiotics is associated with increased prevalence of both colonisation and infection with drug resistant strains Steinke and Davey. CID, 2001, 33(Suppl 3) 5193
How do you establish a quantitative relationship between volume of drug use and frequency of resistance? Few longitudinal studies of use vs- resistance Mathematical modelling
BACTERIAL FITNESS Fitness cost of resistance genetic compensation Antibiotic influence on fitness ratio: Sensitive vs Resistant FITNESS - Prevalence of sensitive strain colonisation Transmission rate Prescribing rate Probability of acquiring resistance during treatment
ANTIBIOTIC CONSUMPTION THRESHOLDS 1. Threshold at which resistant strains emerge 2. Threshold at which sensitive strains are eradicated Close to the threshold small increases in consumption cause a sharp rise in resistance prevalence Once resistance becomes endemic reductions in consumption will only confer a small advantage to sensitive strains Austen D J et al. PNAS, 96, 1152 1156, 1999
ABOVE THE THRESHOLD The maintenance of resistance does not require increasing consumption Reduction in consumption will only bring about a slow reduction in resistance prevalence Austen D J et al. PNAS, 96, 1152 1156, 1999
SPREAD OF RESISTANCE/CLONALITY MSSA - MRSA Methicillin 1959 MRSA 1961 UK and Denmark Mec A genetic determinant Introduced into successful hospital S.aureus strains At least 20 times EVOLUTIONARY PROGRESSION: 5 Lineages : 11 clones Most EMRSA clones correspond to major MSSA clones Most VISA isolates from one clone Enright M et al, PNAS 2002 99, No 11, 7687-7692
COMMUNITY MRSA (CA-MRSA) NOT descended from hospital MRSA Simultaneous evolution in different Continents Only shared genetic determinants: Mec A and PVL locus Limited number of clones within Continents DRIVERS Fitness Antibiotic selection Vandenesch et al. Emerging Infectious Diseases 2003, 9, No 8, 978-984
ANTIBIOTIC USE AND RESISTANCE IN PNEUMOCOCCI Penicillin/β Lactams Macrolides Fluoroquinolones
PNEUMOCOCCAL β LACTAM 1960s Worldwide Intermediate High Level RESISTANCE Treatable DRIVERS: Treatment failure Failure of bacterial eradication Long courses (>5 days) Low doses Poor bioavailability (oral cephalosporin) Linked resistance (Macrolides( Macrolides: : Co trimoxazole) Clonality of pneumocci Baquero F et al. JAC 2002, 50, Suppl 52, 27-37
PNEUMOCCAL MACROLIDE RESISTANCE High prevalence/co selection with β lactam resistance Treatment failure DRIVERS - Guidelines eg ATS Long half life formulations Lack of local resistance data Clonality of pneumococci Klugman KP and Lanks JR. Emerg Inf Dis 2005. 11 (6) Baquero F et al. JAC 2002, 50, Suppl 52, 27-37
PNEUMOCOCCAL FLUOROQUINOLONE RESISTANCE Concentration dependant bactericidal action Efficacy correlates with PD parameters Older drugs poor Newer respiratory quinolones better BUT In North America resistance rising with use (IM scripts 1% rise) Treatment failure DRIVERS - Marginal PD parameters Underdosing Resistance development during therapy Prior quinolone exposure Pneumococcal clonality eg 9V, 23F Goldstein EJC and Garabedian-Ruffalo SM. 2002. CID; 35, 1505 Fuller JD and Low DE. 2005, CID 41, 118 McGee et al. 2002 JAC, 49, 173
RISK BENEFIT EVALUATION FOR ANTIBIOTIC CONSUMPTION What is the excess risk to personal health of excess antibiotic consumption? Does prudent prescribing increase risk to the individual? What is the personal risk from excessive antibiotic consumption by others? Baquero F, Rome 2003
RISK AND THE INDIVIDUAL TRIMETHOPRIM RESISTANCE: Practice data vs Patient data 8833 patients in 28 practices Tayside region, Scotland At the practice level there was no association between prescribing and resistance. For the individual patient multi level modelling showed that exposure to Trimethoprim or other antibiotics was highly significantly associated with Trimethoprim resistance. Trimethoprim exposure was significantly associated with Trimethoprim resistance for up to 6 months after exposure. Donnan PT et al. BMJ, 2004, 328
THE ECOLOGICAL FALLACY Population based studies about exposure and outcome are only valid if differences in exposure in the population reflect differences in exposure of all the individuals. Aggregate studies should not be used to assess the impact of changes in prescribing on resistance Donnan,, PT et al. BMJ 2004, 328
INTERVENTIONS Reduce unnecessary prescribing Prescribe correctly when necessary Optimise diagnosis Severity assessment Management alogarithms Resistance surveillance Pharmacodynamic parameters Measure outcomes Ball et al. JAC 2002, 49, 31-40
EDUCATION Evidence based guidelines (AGREE) Academic detailing Computer decision support Minor ailment strategies Public Education
Changing physician behaviour is considered by many to be an exercise in futility an unattainable goal intended only to produce premature ageing in those seeking the change. The more optimistic might describe the process as uniquely challenging. CID, 2001, 33 (Suppl 3) 5240