Dr. Ian M. Gould Medical Microbiology

Aberdeen Royal Infirmary

Empirical Antibiotic Therapy; a Need for

Innovation

Empirical Antibiotic Therapy; a Need for

Innovation

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

IF YOU DON’T LOOK PROPERLY,YOU WON’T SEE IT

How well do you know your enemy: How long have bacteria existed on our planet?How well do you know your enemy: How long have bacteria existed on our planet?

1. 3.5 billion years

2. 1 billion years

3. 500 million years

4. 200 million years

5. 50 million years

The EnemyMicrobes- Very old- Highly adaptable- Unparalleled ability to survive:

virulence factors, antigenic changes

- Generation time of 20 minutes vs 30 years in man

- Only 10% of cells in/on our bodies are human, the rest are bacteria

Stromatolites are thefossalized remains of a colony or mat ofCyanobacteria that normallyexhibits either a domed or a column-like shape. The oldest known stromatolites occur in rocks in Warrawoona Group of Western Australia and are some 3.4 to 3.5 billion years old. Homo sapiens lived from 250,000 years ago.

It is time to close the book on infectious diseases, and declare the war against pestilence won

Spellberg B: Dr William H, Stewart: mistaken or maligned?

Clin Infect Dis 2008, 47:294.

Paradox 1Paradox 1• Antibiotics initially led to poorer

hospital hygiene

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

MRSA

Infection Control

MRSA

Infection Control

Just the hands

Frickerson!

Environmental contaminationEnvironmental contamination

20-50 % antibiotic use in humans not

necessary

40-80% antibiotics used for animals

questionable value

IntegronIntegronIntegronIntegron

conserved conserved DNADNA 4FQ4FQintegraseintegrasetettetmacrolidemacrolide-lactam-lactampromoterpromoter

Amino-Amino-glycosideglycoside

conserved conserved DNADNA

MULTIPLE ANTIBIOTIC RESISTANT MULTIPLE ANTIBIOTIC RESISTANT DETERMINANTDETERMINANT

GENE CASSETTESGENE CASSETTES

Paradox 3Paradox 3• Antibiotics increase infections

Deaths from HAI, USADeaths from HAI, USA

• 1992………..13,300

• 2008……… 100,000Antibiotics and Resistance,(IDSA

website/Researchandmarket.com)

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

RS

AT

otal ab

. Co

nsu

mp

tion

: DD

D/1000 b

ed d

aysRelationship between % MRSA and antibiotic use.

(3rd GC, FQ, MAC)

Emerg. Inf. Dis 2004, 1432

3rd GC lags = 4 – 7 monthsFQ lags = 4 & 5 monthsMAC lags = 1 – 3 months

CID 2008:46 (Suppl 1) S25

MA of Risk of C diff v Antibiotic Exposure

HPS Reported bacteraemiaHPS Reported bacteraemia

0

500

1000

1500

2000

2500

3000

Klebsiella E.coli

2001

2002

2003

2004

2005

2006

2007

2008

The Antibiotic Resistance Spiral

Adapted from: J. Carlet.

resistance

RESISTANCE

CONCERN

SELECTION

BROAD-SPECTRUMEMPIRIC THERAPY

cross-transmission

dosageduration

new antibiotics(promotion from pharmaceutical

industry)

Current MDR ConcernsCurrent MDR Concerns

• ESBLS• 16S rRNA Methylase +/- ESBL/MBL. HL res to

all aminoGs, transposon/plasmid born• PMQR +/- ESBL. (Gyr/Topo,efflux and

hydrolysis)• Carbapenemases• Acinetobacter• Burkholderia• Stenotrophomonas

ESBLsESBLs

• TEM(Temoneira)/SHV(sulhydril) (over 100 in Enterobacteriaceae)

• CTX-M (from Kluyvera spp)

• VEB/PER etc (uncommon in UK)

• OXA(Class D,Turkey)

• IRTs

Courtesy of D Livermore, HPA

CarbapenemasesCarbapenemases

• Class A inhib by clavulanate eg KPC (plasmid), SME IMI/NMC-A, GES

• Class B metalloenzymes eg IMP(SE Asia), VIM (Europe) aztreonam susc, plasmid/integron located

• Class C, CMY-10 in an E. aerogenes

• Class D in A. baumannii

Pseudomonas aeruginosa: proportion of invasive isolates resistant to carbapenems in 2006

McGowan & Tenover ‘04 Nature Reviews Microbiology 2 251

SPAIN – EARSS data 2007

Incidence of inadequate antibiotic therapy in hospitalsIncidence of inadequate antibiotic therapy in hospitals

0

10

20

30

40

50

60

70

Ref (1) Ref (2) Ref (3) Ref (4) Ref (5)

N=147

N =1255

N = 34

n = 146

N = 27

Bloodstream infection

Nosocomial/Ventialor-associated pneumonia

Ibrahim et al Chest 2000; 118:146-155Leibovici et al J Intern Med 1998; 244:379-386Luna et al Chest 1997; 111:676-685.Alvarez-Lerma Inten Care Med 1996; 22:387-394Rello et al Am J Respir Crit Care 1997; 156:196-200

0

20

40

60

80

100

Ref (1) Ref (2) Ref (3) Ref (4) Ref (5)

Adequate therapy

Inadequate therapy

Bloodstream infections

Nosocomial/Ventilator-associated pneumonia

Influence of inadequate antibiotic therapy on mortality

Ibrahim et al Chest 2000; 118:146-155

Leibovici et al J Intern Med 1998; 244:379-386

Luna et al Chest 1997; 111:676-685.

Alvarez-Lerma Inten Care Med 1996; 22:387-394

Rello et al Am J Respir Crit Care 1997; 156:196-200

For Septic shock: Each hour delay in antibiotic initiation over the first 6 hours has been shown to

be associated with an average decrease in survival of 7.6%

For Septic shock: Each hour delay in antibiotic initiation over the first 6 hours has been shown to

be associated with an average decrease in survival of 7.6%

Adapted from Kumar A, Critical Care medicine 2006 Vol.34, No 6.

ViResiST

ConclusionsConclusions

• Antibiotic resistance is increasing at an unprecedented rate.

• The correct empiric therapy saves lives (not too little) and prevents resistance (not too much)

• Local data is essential to inform local empiric therapy protocols.

Thanks