optimized antibiotic therapy and resistance … · current status of antibiotic research &...

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OPTIMIZED ANTIBIOTIC THERAPY AND

RESISTANCE DEVELOPMENT PREVENTION:

PHARMACOLOGICAL AND CLINICAL STRATEGIES

FEDERICO PEA

INSTITUTE OF CLINICAL PHARMACOLOGY AND TOXICOLOGY

UNIVERSITY TEACHING HOSPITAL OF UDINE

ITALY

Villach, October 13th, 2010Institute of Clinical Pharmacology & Toxicology – University Hospital of Udine

WHY DO WE NEED

CONTROL OF ANTIBIOTIC RESISTANCE ?

103

MRSAMSSA

105

MSSA106

MRSA

106

VRECandida

Pre-admissionDay 2 Day 7 Day 21

90% Home

Cefazolin Ceftazidime Vancomycin

Schentag JJ Crit Care Med 2001; 29, Suppl: N100-N107

ANTIBIOTIC USE AND SELECTIVE PRESSURE

Institute of Clinical Pharmacology - UniUD

TIMELINE SHOWING THE PROGRESSION IN THE ESTIMATED

PREVALENCE OF ANTIMICROBIAL RESISTANCE IN THE UNITED STATES

Adapted from Wenzel RP et al. Infect Control Hosp Epidemiol 2008; 29:1012-1018

Institute of Clinical Pharmacology & Toxicology – University Hospital of Udine

THE 10 x ‘20 INITIATIVE: PURSUING A GLOBAL COMMITMENT

TO DEVELOP 10 NEW ANTIBACTERIAL DRUGS BY 2020Infectious Diseases Society of America. Clin Infect Dis 2010 Apr 15; 50:1081–1083

CURRENT STATUS OF ANTIBIOTIC RESEARCH & DEVELOPMENT

2

UniUD

Antimicrobial Resistance:Key Prevention Strategies

Optimize Use

PreventTransmission

EffectiveDiagnosis& Treatment

Pathogen

Antimicrobial Resistance

Antimicrobial Use

Infection

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Antimicrobial-ResistantPathogen

PreventInfection

Susceptible Pathogen

www.cdc.gov

UniUD

Infectious Diseases Expert Resources

Infectious Diseases Specialists

Optimal Patient CareOptimal

Patient Care

Infection Control Professionals

Healthcare Epidemiologists

ClinicalPharmacists

Clinical Pharmacologists

Surgical InfectionExperts

ClinicalMicrobiologists

12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults

Step 6: Access the experts

www.cdc.gov

Istituto di Farmacologia Clinica - UniUD

MANAGING ANTIMICROBIAL RESISTANCE IN ICUs

Ghandi TN et al. Crit Care Med 2010; 38 Suppl : S315–S323

STRATEGIES TO MANAGE ANTIMICROBIAL RESISTANCE IN THE ICU


Con

centration

Time

Pharmacokinetics (PK)Concentration vs Time

Effect

Concentration (log)

Pharmacodynamics (PD)Effect vs Concentration

Pharmacokinetics� Absorption

� Distribution

� Metabolism

� Excretion

Pharmacodynamics� Spectrum of activity (MIC)

� Antibacterial activity

– Time-dependent

– Concentration-dependent

Clinical efficacyClinical efficacy

Antibiotic choiceAntibiotic therapy

ANTIBIOTIC THERAPY: HOW?

Effect

Time

PK - PDEffect vs time

Viale P & Pea F in: Nosocomial pneumonia - strategies for management, Ed J. Rello, 2007


USE OF BROAD-SPECTRUM ANTIMICROBIALS FOR THE TREATMENT OF

PNEUMONIA IN SERIOUSLY ILL PATIENTS: MAXIMIZING CLINICAL OUTCOMES

AND MINIMIZING SELECTION OF RESISTANT ORGANISMS

Niedermann MS, Clin Infect Dis 2006; 42:S72–81

ALAVREZ LERMA1996

RELLO1997

LUNA1997

KOLLEF1998

KOLLEF1999

IBRAHIM2000

STUDY

MORTALI

TY R

ATE (%)

100

80

60

40

20

0

INITIAL ADEQUATE THERAPY

INITIAL INADEQUATE THERAPY


CRITICAL ISSUES

• Appropriate antibiotic therapy in patients with severe sepsis and septic shock should

mean prompt achievement and maintenance of optimal exposure at the infection site with

broad-spectrum antimicrobial agents administered in a timely manner.

• Once that causative pathogens have been identified and tested for their in vitro

susceptibility, subsequent de-escalation of antimicrobial therapy should be applied

whenever feasible.

• The goal of appropriate antibiotic therapy must be pursued resolutely and with

continuity in the light of the ongoing explosion of antibiotic-resistant infections which

plague the ICU setting and of the continue decrease of antibiotic pipeline.

APPROPRIATE ANTIBIOTIC THERAPY IN SEVERE SEPSIS AND SEPTIC SHOCK: DOES THE DOSE MATTER ?

Pea F and Viale P. Crit Care 2009; 13 (3) 214

3


1764-1771


PK-PD RELATIONSHIPS

• Time-dependent antibacterial activity

• TARGET �� MAINTENANCE OF CMIN > MIC

REFRACT DOSAGES

UNTIL TO CONTINUOUS INFUSION

BETA-LACTAMS, GLYCOPEPTIDES, OXAZOLIDINONES

t > MICt > MIC

Antibiotic concentration (µg/mL)

MIC (µg/mL)

Dosing interval (h)

t > MIC

Optimal exposure:Cmin > MIC



• Concentration-dependent antibacterial activity

• TARGET �� ACHIEVEMENT OF THE HIGHEST CMAX AND/OR AUC

PK-PD RELATIONSHIPS

AMINOGLYCOSIDES, FLUOROQUINOLONES

Cmax/MIC > 10

AUC/MIC > 125


Dosing interval (h)

Concentration (µg/mL)

MIC (µg/mL)

Cmax

AUC

Optimal exposure:Cmax/MIC > 10

AUC/MIC > 40-50 vs G+AUC/MIC > 125 vs G-

ONCE DAILY DOSING WHENEVER FEASIBLE

Istituto di Farmacologia Clinica – Università di Udine

INFECTION SITE

THE ANTIMICROBIAL THERAPY PUZZLE:

COULD PK/PD RELATIONSHIPS BE HELPFUL IN ADDRESSING THE ISSUE OF

APPROPRIATE PNEUMONIA TREATMENT IN THE CRITICALLY ILL PATIENTS ?

Pea F and Viale P. Clin Infect Dis 2006; June 15, 1764-1771

ANTIBIOTIC INFECTION SITE

PATHOGEN

+

MIC


� LIMITED VOLUME OF DISTRIBUTION

� UNABLE TO PASSIVELY DIFFUSE THROUGH PLASMATIC

MEMBRANE OF EUKARYOTIC CELLS

� INACTIVE AGAINST INTRACELLULAR PATHOGENS

� ELIMINATED RENALLY AS UNCHANGED DRUG

HYDROPHILIC ANTIBIOTICS LIPOPHILIC ANTIBIOTICS

• BETA-LACTAMS

� PENICILLINS

� CEPHALOSPORINS

� CARBAPENEMS

� MONOBACTAMS

• GLYCOPEPTIDES

• AMINOGLYCOSIDES

• MACROLIDES

• FLUOROQUINOLONES

• TETRACYCLINES

• CHLORAMPHENICOL

• RIFAMPICIN

• OXAZOLIDINONES

� LARGE VOLUME OF DISTRIBUTION

� FREELY DIFFUSE THROUGH PLASMATIC MEMBRANE OF

EUKARYOTIC CELLS

� ACTIVE AGAINST INTRACELLULAR PATHOGENS

� ELIMINATED BY HEPATIC METABOLISM

Pea F, Viale P, Furlanut M. Clin Pharmacokinet 2005; 44: 1009-1034

Pea F & Viale P. Clin Infect Dis 2006; 42: 1764-1771


PLASMA AND LUNG CONCENTRATIONS OF CEFTAZIDIME ADMINISTERED AS

CI TO CRITICALLY ILL PATIENTS WITH SEVERE NOSOCOMIAL PNEUMONIABoselli e et al. Intensive Care Med 2004; 30: 989–991

CEFTAZIDIME 4G CICEFTAZIDIME 4G CI

80

60

40

20

08 12 18

TIME (H)

CEFTAZIDIME CONCENTRATION (MG/L

)

MIC BP

ELFELF

PLASMAPLASMA

4


1764-1771

PATIENT’S

PATHOPHYSIOLOGY


ANTIMICROBIAL THERAPY IN THE CRITICALLY ILL PATIENTS:A REVIEW OF THOSE PATHOPHYSIOLOGICAL CONDITIONS RESPONSIBLE FOR HUGE PK VARIABILITY

Pea F, Viale P, Furlanut M

Clin Pharmacokinet 2005; 44: 1009-1034

VARIATIONS IN EXTRACELLULAR FLUID

VARIATIONS INRENAL CLEARANCE

Critically ill patients

Antimicrobial dilution or loss

ConsiderDOSAGE INCREASE

Enhanced antimicrobialrenal excretion

ConsiderDOSAGE INCREASE

Reduced antimicrobialrenal excretion

ConsiderDOSAGE DECREASE

PLEURAL EFFUSION

FLUID THERAPY

ASCITES

OEDEMA

MEDIASTINITIS

POST-SURGICALDRAINAGES

Increased ifDRUG ABUSE

HAEMODYNIMICALLY ACTIVE DRUGS

BURNS

LEUKEMIA

HYPERDYNAMICS

Increased if

RENAL IMPAIRMENT

DIALYSIS

Decreased if

HYPOALBUMINAEMIAHYPOALBUMINAEMIA


IMIPENEM LEVELS ARE NOT PREDICTABLE

IN THE CRITICALLY ILL PATIENTBelzberg H et al. J Trauma 2004; 56: 111-117


CONCLUSIONS

• Appropriateness of treatment is rarely assessed in terms of adequate dosing schedule

regimens.

• Inadequate dosing schedules may lead to suboptimal exposure at the infection site,

increasing the risk for therapeutic failure or selection of resistant bacteria.

• However, administration of higher antibiotic doses than are required increases the risk

for adverse events.

•Therefore, TDM of plasma concentrations should be encouraged whenever possible,

because these concentrations are difficult to predict in critically ill patients, even when

their renal function is estimated using different formulae.




� LIMITED VOLUME OF DISTRIBUTION

� UNABLE TO PASSIVELY DIFFUSE THROUGH PLASMATIC

MEMBRANE OF EUKARYOTIC CELLS

� INACTIVE AGAINST INTRACELLULAR PATHOGENS

� ELIMINATED RENALLY AS UNCHANGED DRUG

HYDROPHILIC ANTIBIOTICS LIPOPHILIC ANTIBIOTICS

• BETA-LACTAMS

� PENICILLINS

� CEPHALOSPORINS

� CARBAPENEMS

� MONOBACTAMS

• GLYCOPEPTIDES

• AMINOGLYCOSIDES

• MACROLIDES

• FLUOROQUINOLONES

• TETRACYCLINES

• CHLORAMPHENICOL

• RIFAMPICIN

• OXAZOLIDINONES

� LARGE VOLUME OF DISTRIBUTION

� FREELY DIFFUSE THROUGH PLASMATIC MEMBRANE OF

EUKARYOTIC CELLS

� ACTIVE AGAINST INTRACELLULAR PATHOGENS

� ELIMINATED BY HEPATIC METABOLISM

Pea F, Viale P, Furlanut M. Clin Pharmacokinet 2005; 44: 1009-1034

Pea F & Viale P. Clin Infect Dis 2006; 42: 1764-1771


Plasma vancomicina Cmin (µg/ml)

0 5 10 15 20 25

0

10

20

30

40

50

Plasma vancomicina Cmin (µg/ml)0 5 10 15 20 25

(µg/ml)

Plasm

a vancom

icina C

max

Plasm

a vancom

icina c

max(µg/ml)

0

10

20

30

40

50

MEAN ± SD CMIN E CMAX VANCOMYCIN

Group A

Group B

Pea F. et al. Int J Antimicrob Agents, 2002; 20: 326-332

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Pea F, et al. Clin Pharmacokinet 2005; 44: 1009-1034Institute of Clinical Pharmacology & Toxicology – University Hospital of Udine Institute of Clinical Pharmacology - UniUD

WHICH STRATEGIES IN THE CRITICALLY ILL PATIENTS?

CONCENTRATION-DEPENDENT ANTIMICROBIAL AGENTS


SHORT COURSE HIGH-DOSAGE APPROACH

WHICH DRUG SCHEDULE FOR CONCENTRATION-DEPENDENT ANTIMICROBIALS IN THE CRITICALLY ILL PATIENTS ?

HIT HARD!! HIT FAST!!

P. Erlich, Lancet 1913


CRITICAL ISSUES FOR CONCENTRATION-DEPENDENT ANTIMICROBIALS



• It may be speculated that high-dosage, short-course regimens with concentration-

dependent antimicrobials may be especially useful in terms of shortening the time to

resolution of symptoms in seriously ill patients

• High dosage, short-course therapy regimens with a once daily administration schedule

may yield more rapid bacterial killing or prevention of resistance development


WHICH DRUG SCHEDULE FOR TIME-DEPENDENT ANTIMICROBIALS IN THE CRITICALLY ILL PATIENTS ?

1. MULTIPLE DAILY DOSE

2. MULTIPLE DAILY DOSE + EXTENDED INFUSION

3. CONTINUOUS INFUSION

ACHIEVE THE TARGET QUICKLY AND MAINTAIN IT!!

Adapted from Pea F and Viale P. Critical Care 2009; 13 (3) 214 Institute of Clinical Pharmacology & Toxicology – University Hospital of Udine

CRITICAL ISSUES FOR TIME-DEPENDENT ANTIMICROBIALS

• It could reasonably be suggested that continuous infusion is a promising tool for

improving clinical cure with time-dependent antimicrobials, especially among the critically

ill.

•This may be more relevant in infections with borderline susceptible pathogens and/or in

patients with glomerular hyperfiltration.



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INSUFFICIENT BETA-LACTAM CONCENTRATIONS

IN THE EARLY PHASE OF SEVERE SEPSIS AND SEPTIC SHOCKTaccone FS et al. Crit Care 2010, 14:R126

ADEQUATE CONCENTRATIONS OF THE FOUR DRUGS, WITH REGARD TO RENAL DYSFUNCTION

Istituto di Farmacologia Clinica - UniUDInstitute of Clinical Pharmacology & Toxicology – University Hospital of Udine

MAY INAPPROPRIATE BEHAVIOURS FAVOUR

SPREAD OF RESISTANCE ?


961

560 547

442

233

51 38 36

0

200

400

600

800

1000

MULTIVITAMIN

IRON

CALCIUM

MAGNESIUM

ZINC

SUCRALFATE

ALUM

INIUM

DIDA

NOSINE

HIGH RATE OF COADMINISTRATION OF DI- OR TRI-VALENT CATION-CONTAINING

COMPOUNDS WITH ORAL FQs: RISK FACTORS AND POTENTIAL IMPLICATIONS

Barton TD et al. Infect Control Hosp Epidemiol 2005;26: 93-99

N = 3227

Jul 1999 – Jun 2001


COADMINISTRATION OF ORAL LEVOFLOXACIN WITH AGENTS THAT IMPAIR ITS

ABSORPTION: POTENTIAL IMPACT ON EMERGENCE OF RESISTANCE

Quain RD et al. Int J Antimicrob Agents 2005; 26: 327-330

CASE-CONTROL STUDY

N = 46 (32 LFX-R

vs

14 LFX-S)

0

10

20

30

40

50

60

70

80

90

% S

UBJECTS W

ITH F

Q-RESIS

TANT

ISOLATE

0-2 DAYS

(N=12)

3-4 DAYS

(N=11)

5-7 DAYS

(N=13)

8-31 DAYS

(N=10)

DAYS OF COADMINISTRATION (IN QUARTILES)


THE EDUCATIONAL INTERVENTION:

1. Hospital-wide educational program to be repeated almost twice per each year

concerning principles of good antimicrobials use;

2. Semi-annual collegial discussion of microbiological reports on the incidence of

different isolates and of their main resistance patterns;

3. Hospital-wide daily active consultation of the infectious disease specialists

4. Optimization over time of antimicrobial exposure in each single patient by means of

on “active TDM” carried out by the clinical pharmacologists.

THE EFFECT OF MULTIFACTORIAL, MULTIDISCIPLINARY EDUCATIONAL

INTERVENTIONS ON THE APPROPRIATE USE OF TEICOPLANIN

Pea F et al. Int J Antimicrob Agents, 2006, 27: 344-350


TDM = 2697

n = 605

384 CLCr >50 mL/min

127 CLCr 20-50 mL/min

94 CLCr <20 mL/min



Pea F, Viale P, et al. Int J Antimicrob Agents, 2006, 27: 344-350

Duration of therapy (days)

1 3 5 7 9 11 13 152 4 6 8 10 12 14

Teicop

lanin plasm

a C

min (mg/L)

0

5

10

15

20

25

30

35

40

(n=87)

(n=164)

(n=300)(n=297)

(n=239)(n=216)

(n=206)

(n=142)(n=112)

(n=98)(n=69)

(n=82)(n=78)

(n=408)

(n=45)

(n=56)

(n=84)

(n=85)

(n=65) (n=74)

(n=67) (n=48)

(n=49)

(n=30)(n=35)

(n=20)

(n=18)

(n=20)

(n=117)

(n=63)

(n=54)

>15

Current studyRestrospective study

7





38.6

66.660.4

78.4

26.8

59.8

5.4

27.7

0

10

20

30

40

50

60

70

80

90

100

ALL PTS CLCR > 50

ML/MIN

CLCR 20-50

ML/MIN

CLCR < 20

ML/MIN

COMPARATIVE % OF OPTIMAL LOADING

RETROSPECTIVE STUDY

(N = 202)

PROSPECTIVE STUDY

(N = 605)


46

72

46

14

62 6463

47

7076

70

52

98 98 100

0

10

20

30

40

50

60

70

80

90

100

MEDICAL WARDS SURGICAL WARDS ICUs HAEMATOLOGICAL

WARDS




ALL PATIENTS

CLCR > 50 ML/MIN

CLCR 20-50 ML/MIN

CLCR < 20 ML/MIN

TREND OF % OF OPTIMAL LOADING IN DIFFERENT HOSPITAL WARDS

NA

Istituto di Farmacologia Clinica – UniUD

1764-1771

CLINICAL MICROBIOLOGIST

CLINICAL PHARMACOLOGIST

CLINICIAN

optimized antibiotic therapy and resistance … · current status of antibiotic research &...

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