Dr. Ian M. Gould Medical Microbiology

Aberdeen Royal Infirmary

The Many Paradoxes of Antibiotic Use

“At least the waiting lists are improving - I only had to wait one week to get MRSA”

International Society of Chemotherapy

<Infection and Cancer>

www.ischemo.org

Paradox 1 • Antibiotics initially led to poorer

hospital hygiene

Healthcare Environment Inspectorate

Report

“Haven’t you heard – we’ve got MRSA sweeping the hospital”

0

5

10

15

20

25

30

35

Jan-97 Jan-98 Jan-99 Jan-00 Jan-01 Jan-02 Jan-03 Jan-04 Jan-05 Jan-06

%MRSA in hospital clinical specimens. Successful Interventions (Mahamat et al IJAA’07,JHI’11)

Environmental Swabbing (p=0.03)

Bleach (p=0.002)

Hand Gel (p=0.03)

Admission Screen (p<0.01) Stop Bleach (p=0.03)

%M

RSA

in C

linic

al S

peci

men

s

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)

CID 2008:46 (Suppl 1) S25

MA of Risk of C diff v Antibiotic Exposure

0

5

10

15

20

25

30

35

40

45

500

550

600

650

700

750

800

850

Jan 96 Jan 97 Jan 98 Jan 99 Jan 00

% MRSA

Sum of lagged antimicrobial series

% M

RSA

Total ab. C

onsumption: D

DD

/1000 bed days Relationship between % MRSA and antibiotic use.

(3rd GC, FQ, MAC)

Emerg. Inf. Dis 2004, 1432

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

MDR K. aerogenes outbreak

Price and Sleigh Lancet 1971

HPS Reported bacteraemia

0

500

1000

1500

2000

2500

3000

Klebsiella E.coli

20012002200320042005200620072008

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 Exposure to fluoroquinolones,

ß-lactams - selection, increased adhesion, increased virulence, patient risk factors, etc.

MRSA negative Colonized Infected

New Bugs, not so new drugs

Paradox 5 No new antibiotics

0

5

10

15

20

1983-1987 1988-1992 1993-1997 1998-2002 2003-06/04

No.

of F

DA

app

rove

d an

tibac

teria

l NM

Es

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

Priority Medicines for Europe and the World, 2004.

Antibacterial New Molecular Entities (NMEs) Approved by the FDA for Use in the United States,

1983-June 2004 (topical drugs excluded)

R2=0.99 p=0.007

Paradox 6 • Are new antibiotics really the

answer? (can we ever win the war?)

Integron

conserved DNA 4FQ integrase tet macrolide β-lactam promoter

Amino- glycoside

conserved DNA

MULTIPLE ANTIBIOTIC RESISTANT DETERMINANT

GENE CASSETTES

Paradox 7 • Generics and Counterfeits