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The Many Paradoxes of Antibiotic Use

At least the waiting lists are improving - I only had to wait one week to get MRSA Dr. Ian M. Gould Medical Microbiology Aberdeen Royal Infirmary


International Society of Chemotherapy <Infection and Cancer> www.ischemo.org


Paradox 1 â&#x20AC;˘â&#x20AC;Ż Antibiotics initially led to poorer hospital hygiene


Healthcare Environment Inspectorate Report


Haven t you heard â&#x20AC;&#x201C; we ve got MRSA sweeping the hospital


%MRSA in hospital clinical specimens. Successful Interventions (Mahamat et al IJAA 07,JHI 11) Environmental Swabbing (p=0.03)

35 %MRSA in Clinical Specimens

Bleach (p=0.002)

30 Hand Gel (p=0.03)

25 20 15 10 5

Admission Screen (p<0.01)

Stop Bleach (p=0.03)

0 Jan-97

Jan-98

Jan-99

Jan-00

Jan-01

Jan-02

Jan-03

Jan-04

Jan-05

Jan-06


Environmental contamination

20-50 % antibiotic use in humans not necessary

40-80% antibiotics used for animals questionable value


Paradox 3 •  Antibiotics increase infections


Deaths from HAI, USA

•  1992………..13,300 •  2008……… 100,000 Antibiotics and Resistance,(IDSA website/ Researchandmarket.com)


MA of Risk of C diff v Antibiotic Exposure

CID 2008:46 (Suppl 1) S25


Relationship between % MRSA and antibiotic use. (3rd GC, FQ, MAC) 45 40

GC lags = 4 – 7 months FQ lags = 4 & 5 months MAC lags = 1 – 3 months

800

750

% MRSA

30

Sum of lagged antimicrobial series

25 20

700

650

15 600

10

% MRSA

5

550

500

0

Jan 96

Jan 97

Jan 98

Jan 99

Total ab. Consumption: DDD/1000 bed days

35

850

3rd

Jan 00

Emerg. Inf. Dis 2004, 1432


MDR K. aerogenes outbreak

Price and Sleigh Lancet 1971


HPS Reported bacteraemia 3000 2500

2001 2002 2003 2004 2005 2006 2007 2008

2000 1500 1000 500 0

Klebsiella

E.coli


Paradox 4 Antibiotics can increase severity of infection


Staphylococcal toxic shock syndrome

Taylor et al, BMJ, 2006


Causes of Increased Transmission,Adherence and Pathogenicity of MRSA when exposed to Antibiotics Biofilm formation Small colony variants Efflux Hypermutation Skin/RT colonization → transmissibility Fibrinonectin-binding protein Toxin production eg ∝, TSST-1 SOS response → horizontal gene transfer Phage induction Quorum sensing agr expression Autolysis Intracellular persistence Dancer JAC 08 61 246 Gould JAC 08 61 763

§  §  §  §  §  §  §  §  §  §  §  §  § 


A Reasonable Biological Model? (adapt. from Monnet D, 2006) Poor infection control MRSA colonization pressure MRSA in the environment Length of stay, medical devices Antimicrobial consumption

MRSA negative

Colonized

Exposure to fluoroquinolones, Ă&#x;-lactams - selection, increased adhesion, increased virulence, patient risk factors, etc.

Infected


New Bugs, not so new drugs


Paradox 5 No new antibiotics


Antibacterial New Molecular Entities (NMEs) Approved by the FDA for Use in the United States, 1983-June 2004 (topical drugs excluded) No. of FDA approved antibacterial NMEs

20

R2=0.99 p=0.007

15

10

5

0 1983-1987

1988-1992

1993-1997

1998-2002

2003-06/04

Adapted from: Nordberg P, et al. Antibacterial drug resistance [background paper].


Paradox 6 •  Are new antibiotics really the answer? (can we ever win the war?)


Integron conserved Aminoconserved promoter β-lactam macrolide tet integrase 4FQ DNA glycoside DNA

MULTIPLE ANTIBIOTIC RESISTANT DETERMINANT GENE CASSETTES


Paradox 7 •  Generics and Counterfeits



/dr_ian_gould