Building a Better Mousetrap for Nosocomial Drug-resistant Bacteria:

krankenhaus.hygiene.at

Building a Better Mousetrap for Nosocomial Drug-resistant Bacteria:

Building a Better Mousetrap

for Nosocomial Drug-resistant Bacteria:

use of available resources

to optimize the antimicrobial strategy

Leonardo Pagani MD

Director

Unit for Hospital Antimicrobial Chemotherapy (UHAC)

Antimicrobial Management Program

Division of Infectious Diseases – Bolzano Hospital

Clinic of Infectious Diseases – Udine University

Villach (A), 16.10.08


CURRENT HEALTHCARE SYSTEM

Home

Care

Acute

Care

Facility

Outpatient/

Ambulatory

Facility

Tranquil Gardens

Nursing Home

Long Term Care

Facility


Environments Where Antibiotic Resistance Develops

and Their Relationships

Nursing

Homes

Daycare

Tertiary

Hospitals

Community

Hospitals

Homecare

Community

Foreign

Feedlots

Adapted from B. Murray


Clinical & Economic Impact

of Resistance


Clinical impact of resistance will be modulated by:

– Mechanism of R → how much does the MIC change

– Ability to delivery sufficient antibiotic concentrations

to site of infection

• Dose, penetration,....


The cost of failure is HIGH:

– Mortality

– LOS & cost of care

– Cost saved by avoiding treatment failure greater than

costs spent by on antimicrobial therapy


! OVERUSE !

“The desire to ingest medicines is

one of the principal features

which distinguish man from the

animals”

Osler W. Aecquanimitas, 1920


Dangerous macro-organism: organism: MRMS

Multi-Resistant

Medical Specialist


MRMS







Resistant to good advice

Allergic to professional guidelines

Non-compliant with infection control

Blind to nosocomial infections

Other priorities

Missing feeling of accountability


My son, My son,

if they don’t get me,

you will become

multiresistant


THE ANTIMICROBIAL THERAPY PUZZLE

ANTIMICROBIAL

SITE

PATHOGEN

BATTERI

+

MIC

PATIENT


Defining pharmacokinetics and pharmacodynamics


Pharmacokinetics (PK):

– reflects how a drug is absorbed, distributed and eliminated in the

body

– these factors, along with the dosing regimen of the drug,

determine the time course of drug concentration in the serum,

tissues and body fluid


Pharmacodynamics (PD):

– the relationship between a drug’s serum concentrations and its

pharmacological and toxicological effects

– in other words, PD integrates PK with drug potency (measured by

the drug’s minimum inhibitory concentration [MIC] against a

bacterium)

Craig. Clin Infect Dis 1998; 26:1–12


Antimicrobial drugs & pattern of activity


Time-dependent


Concentration-dependent





β-lactams

Glycopeptides

Oxazolidinones

Carbapenems





Aminoglycosides

Rifampin

Quinolones

Azalides



Usually no PAE

Stable, unfloating

concentrations over 24

hrs.



High PAE

Peak over the MIC,

regardless of timing


PK-PD correlations

Concentration (mg/L)

40

30

20

10

0

C max /MIC

T > MIC

Betalactams

Oxazolidinones

Aminoglycosides

Fluoroquinolones

AUC/MIC

0,5 10

Vancomycin

Teicoplanin

0 8 16

24

Hours

PAE

MIC


Post-antibiotic effect (PAE)


The persistent suppression of bacterial growth after exposure

to an antibacterial agent


Observed for all antibacterials against Gram-positive cocci, such

as staphylococci. However, minimal in vivo PAEs for β-lactams

with streptococci


Moderate to prolonged in vivo PAEs for inhibitors of protein and

nucleic acid synthesis (aminoglycosides, quinolones, rifampin,

macrolides and tetracyclines) with Gram-negative bacilli


Short or no in vivo PAEs for β-lactams with Gram-negative bacilli

(only exception: carbapenems with some strains of Pseudomonas

aeruginosa)


Time-dependent killing with minimal postantibiotic

effects


Goal of dosing regimen: to optimize duration of antibacterial exposure

at the site of infection


Major parameter correlating with efficacy is the percentage of the

dosing interval for which the serum concentration exceeds the MIC of

the drug against the pathogen, or ‘Time above MIC’

– Seen with all β-lactams:

• penicillins

• Cephalosporins


For these drugs, ‘Time above MIC’ target for efficacy is > 40–50% of

the dosing interval


The concentration of drug achieved for > 40–50% is defined as the

PK/PD breakpoint

Andes et al. Clin Lab Med 2004; 24:477–502


β-lactams

Relationship between T > MIC and eradication

Log change in CFU/ml

T>MIC

(% of 24 h)

Static

effect

2-log

kill

Maximum

effect

MacGowan AP, Clin Microbiol Infect, 2004


Ceftazidime PD profile(T>MIC) in patients with nosocomial

pneumonia (continuous vs. intermittent infusion)

Nicolau et al, Clin Drug Invest, 1999

3 g IC/24 h

100

100

2 g tid

82% (56-95)

90%

MIC = 8 mg/L

1 g tid

61

79

MIC = 4 mg/L

1 g bid

37

52

0 50 100


Next dose


35

C max

C min

30

Drug concentration (µg/mL)

25

20

15

10

MIC ≤ 8

5

0

0 12 24 36 h

Time-dependent antimicrobials


“Dynamic” MICs achieved with

optimized infusions

drug Daily dose MIC reached

Pip/tazo 18 g 60

Pen G 18 MU 9

Amoxicillin 12 g 21

Oxacillin 12 g 1

Ampicillin 12 g 28

Ceftazidim 6 g 11

Meropenem 12 g 16


CLSI 2006

New Vancomycin MIC Breakpoints


Modification of

vancomycin MIC

breakpoints for

S. aureus

criteria

2005 MIC

(ug/ml)

2006 MIC

(ug/ml)

S ≤ 4 ≤ 2


MIC = 4 um/mL now

VISA

I

(VISA)

8-16 4-16


CLSI: Clinical and

Llaboratory Standard

Institute

R

(VRSA)

≥ 32 ≥ 32


Different tissue penetration (PD) of AMs

(% tissue-to-plasma ratio)

Tissue/fluid Linezolid Teicoplanin Vancomycin

ELF (epithelial

lining fluid)

238-450% - 11-17%

Interstitial fluid 104% 43% -

Bone 60% ∼ 50-60% 7-13%

Muscle 94% ∼ 40% ∼30%

CSF 70%* ∼ 10% 0-18%

Intraperitoneal

dialysis fluid

61% 40% ∼ 20%

A.R. De Gaudio et al Farmaci e Terapia 2002;XIX (Suppl.2): 1-56


“MIC DRIVEN” ANTI STAPHYLOCOCCAL THERAPY OF HAP

ADD EMPIRIC ANTISTAPHYLOCOCCAL THERAPY IN PRESENCE OF:

≥ 2 major risk factors for MRSA ( >7 days in ICU, previous antibiotic exposure, age > 65 yrs, staph nasal carriage, Gram

+ cocci at gram stain) or severe sepsis

1 st line standard therapy: vancomycin 15 mg/kg LD followed by 30 mg/kg/q24h by CI + rifampicin 600 mg q24h

teicoplanin 12 mg/kg LD followed by 6 mg/kg/24 h + rifampicin 600 mg q24h

within 48 hours

CULTURE RESPONSE

MSSA

NO STAPH

MRSA

MIC < 0.5 mg/L

Switch to oxacillin 12g/q24h by CI Stop vancomycin Continue vancomycin

and optimize exposure

by means of TDM

MIC > 1 mg/L

Pea F & Viale P. Clin Infect Dis 2006

switch to LINEZOLID 600 mg q12h


Concentration-dependent killing with prolonged

post-antibiotic effects




Goal of dosing regimen: to maximize drug concentration at the site of

infection

Major parameters correlating with efficacy:

– AUC/MIC – the ratio of the 24-hour ‘area under the curve’ (free serum drug

concentration–time curve; AUC) to the MIC

and/or

– C max /MIC – the ratio of the peak free serum drug concentration

(C max )

to the MIC

Seen with:

– aminoglycosides – daptomycin

– fluoroquinolones – amphotericin B

For Gram-negative bacteria – AUC/MIC target is ≥ 100–125


For Gram-positive bacteria – AUC/MIC target is ≥ 25–35, or C max /MIC

≥ 12

Andes et al. Clin Lab Med 2004; 24:477–502


3.5

C max

C min

3.0

Drug concentration (µg/mL)

2.5

2.0

1.5

1.0

MIC ≤ 1

0.5

0

0 12 24 36 48h

Concentration-dependent antimicrobials


Antimicrobial Stewardship Program May Help

Reduce Antimicrobial Resistance in ICU

Jan 2003 - Dec 2007

Pagani L, et al. Clin Microbiol Infect 2008


surveillance of nosocomial pathogen susceptibilities in significant clinical

samples from patients admitted to ICU > 48-72 hrs.

Blood, TBA/BAL, surgical wounds, urine, CSF, drainages, ...

– a) withdrawal of 3 rd -Ceph prophylaxis in critical patients at

admission to ICU

– b) empirical therapy for suspected ICU-acquired infections

according to protocols based on local epidemiology data and on

pharmacokinetic/pharmacodynamic (PK/PD) criteria

– c) subsequent regular tailoring of antimicrobial therapy according to

microbiologic findings with commitment to streamlining


Antimicrobial therapy in the critically ill patients: a review of those

patho-physiological conditions responsible for huge pk variability

Pea F et al., Clin Pharmacokinet 2005

VARIATIONS OF

EXTRACELLULAR FLUID

VARIATIONS OF

RENAL CLEARANCE

Increased if

PLEURAL EFFUSION ASCITES MEDIASTINITIS

Increased if

DRUG ABUSE BURNS HYPERDYNAMICS

Decreased if

RENAL IMPAIRMENT

FLUID THERAPY OEDEMA DRAINAGES

HAEMODYNIMICALLY ACTIVE DRUGS

LEUKEMIA

DYALISIS

AGING

HYPOALBUMINAEMIA

HYPOALBUMINAEMIA

Dilution

or loss of antibiotic

Enhanced antibiotic

renal excretion

Reduced antibiotic

renal excretion

Consider

DOSAGE INCREASE

Consider

DOSAGE INCREASE

Consider

DOSAGE DECREASE


RESULTS (i)

antimicrobial consumption

ATB 2002-DDD 2006-DDD %

VAN 390 103 -73.3

TEC 100 5 -95

CIP 1136 624 -45

AMK 290 20 -93

CAZ 70 15 -78.6

AMP/SB 1887 798 -57.7

PIP/TZ 366 369 -

MEM 25 405 +1620

LIN 156* 760 +487


MRSA and ICU

Pagani L, et al. Infect Control Hosp Epidemiol 2008; in press


RISK ADJUSTED APPROACH to CHOOSE “OPTIMAL” THERAPY

Severity of illness (SIRS / PIRO scale)

Organ dysfunction (SOFA score)

Age & Co-morbidities (Mc Cabe score)

Community vs Hospital acquisition

Site-related

Microorganism-related risk factors

Resistance-related

DRUGS’ CHOICE

PK/PD knowledge

Physiopathological status

Site of infection

REGIMENS’ CHOICE


Principles for prescribing







Identification of bacterial infection by optimized diagnosis

Severity assessment

Recognition and incorporation of local resistance data

Targeting bacterial eradication (or maximal reduction in

bacterial load)

Use of pharmacodynamic (PD) indices to optimize choice and

dosage

Objective assessment of true (overall) costs of resistance

and related treatment failure

Ball et al. J Antimicrob Chemother 2002; 49:31–40


THANK YOU FOR YOUR ATTENTION!

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