Annual Meeting

Infectious Diseases PRN Focus Session—Infectious Diseases 102: Applying the Basics to Clinical Practice Activity No. 0217-0000-11-093-L01-P (Knowledge-Based Activity) Tuesday, October 18 1:15 p.m.–3:15 p.m. Convention Center: Spirit of Pittsburgh Ballroom A Moderator: Jason Gallagher, Pharm.D., BCPS Associate Professor, Clinical Specialist, Infectious Diseases, Director, Infectious Diseases Pharmacotherapy Residency, Temple University, Philadelphia, Pennsylvania Agenda 1:15 p.m. Microbiology, Revisited

Conan MacDougall, Pharm.D., MAS, BCPS Associate Professor of Clinical Pharmacy, University of California–San Francisco, School of Pharmacy, San Francisco, California

1:55 p.m. Mechanisms of Antimicrobial Resistance Brian A. Potoski, Pharm.D., BCPS Associate Professor, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania

2:35 p.m. Antimicrobial Pharmacodynamics, from Bench to Bedside

C. Andrew DeRyke, Pharm.D. Medical Education & Research Liaison, Optimer Pharmaceuticals, Orlando, Florida

Faculty Conflict of Interest Disclosures C. Andrew DeRyke: employee of Optimer Pharmaceuticals. Conan MacDougall: no conflicts to disclose. Brian A. Potoski: no conflicts to disclose. Learning Objectives

1. Describe the physiological characteristics of bacteria that lead to their pathogenicity and virulence.

2. Determine the relevance of biofilm production in the treatment of infection. 3. Illustrate how normal flora prevent pathogenic invasion by opportunistic bacteria. 4. Explain the four basic mechanisms of resistance employed by bacteria against antibacterial

agents. 5. Describe which mechanisms are employed by which bacteria against which drugs. 6. Illustrate the relationship between resistance and virulence, when it exists. 7. Apply knowledge gained in the preceding points to a patient case.

Annual Meeting

8. Explain the unique aspects that separate antimicrobial pharmacodynamics from that of other therapeutic areas

9. Describe and define post-antibiotic effects, concentration- and time-dependency, and bactericidal and bacteriostatic effects as they apply to clinical decision making.

10. Choose optimal dosing of an antibiotic based upon its pharmacodynamic profile and minimum inhibitory concentration.

11. Describe instances where pharmacodynamic optimization has been shown to improve clinical outcomes.

Self-Assessment Questions Self-assessment questions are available online at www.accp.com/am

Microbiology, Revisitedgy,Conan MacDougall, Pharm.D., MAS, BCPSAssociate Professor of Clinical PharmacyUniversity of California, San Franciscomacdougallc@pharmacy.ucsf.edu

Conflicts of Interest

No conflicts to disclose No conflicts to disclose.

Objectives

1) Illustrate how normal flora prevent pathogenic invasion by opportunistic bacteriainvasion by opportunistic bacteria.

2) Describe the physiological characteristics of b t i th t l d t th i th i it dbacteria that lead to their pathogenicity and virulence.

3) Determine the relevance of biofilm production in the treatment of infection.

Micro 1A Micro 102 Micro 212Micro 1A    Micro 102   Micro 212

The Normal Flora

• You probably already know…most bacterial infections are caused by patient’s own…most bacterial infections are caused by patient’s own 

bacteria

• You might not know• You might not know……the “defensive” role of commensal bacteria

• What you can do about it now……selective digestive decontamination?

• What’s next……using estimated risk of resistance to drive drug selectiong g

The Human “Superorganism”~1013 human cells~1014 bacterial cells on/in bodycells on/in body

Prescott et al, Microbiology 4E, McGraw‐Hill, 1999http://biology.kenyon.edu/slonc/bio3/symbiosis.html

Intestinal MicrobiomeOrganism

Log10 organisms (cfu/ml)

Oropharynx Stomach Jejunum Ileum Colon

Total 8‐10 0‐4 0‐5 4‐8 10‐12Total  8‐10 0‐4 0‐5 4‐8 10‐12

Aerobes

Streptococcus 6‐8 0‐3 0‐4 2‐4 3‐5

Enterococcus rare rare 0‐2 2‐4 5‐10

Enterobacteriaceae rare 0‐2 0‐3 2‐7 4‐10

Yeasts 0 3 0 2 0 2 2 4 2 5Yeasts 0‐3 0‐2 0‐2 2‐4 2‐5

Anaerobes

Peptostreptococcus 4‐6 0‐3 0‐3 2‐6 10‐12

Bifidobacterium 0‐2 0‐2 0‐4 3‐9 8‐11

Lactobacillus 0‐3 0‐3 0‐4 2‐5 6‐8

Clostiridium rare rare rare 2 4 6 9Clostiridium rare rare rare 2‐4 6‐9

Bacteroides rare rare 0‐3 3‐7 10‐12

Orhage K, et al. Drugs Exptl Clin Res 2000;26:95‐111

Colonization Resistance• Ability to resist overgrowth of potentially pathogenic endogenous & exogenous organisms (primarily g g g (p yaerobes)

• Physical & anatomic barriers– Intact mucosa, GI motility

• Chemical & immunologic factors– Gastric pH, secretory IgA

• Microbiologic factors– Indirect: stimulation of immune response, enhancement of epithelial barrier

– Direct: Competition for resources production of antibacterial– Direct: Competition for resources, production of antibacterial

Direct Effects of Antimicrobials on GI Flora

Jernberg C, et al. Microbiology 2010;156:3216‐3223. Reprinted with permission.

Direct Effects of Antimicrobials on GI Flora

Willing BP, et al. Nat Rev Microbio 2011;9:233‐243.  Reprinted with permission.

Direct Effects of Antimicrobials on GI FloraDrug B. fragilis Mean peak blood 

concentration (mg/L)Mean fecal concentration (mg/kg)MIC50 MIC90

Ertapenem 0.25 2 275 32.7 

Ceftriaxone 32 >64 150 258

Pletz MWR, et al. Antimicrob Agents Chemother 2004;48:3675‐3772 Reprinted with permission.

Protective Piperacillin/taz

obactamanaerobic organisms

Pathogenic aerobes

Acquired pathogenic aerobes

g

ClindamycinFosfomycin

Selective Digestive Decontamination

Levofloxacin

Vollaard E, et al. Antimicrob Agents Chemother 1994;38:409‐414

Selective Digestive Decontamination• Antimicrobials administered: 

– in patients at high risk (ICU) of infection (VAP), toin patients at high risk (ICU) of infection (VAP), to– selectively reduce endogenous potential pathogens (enteric, aerobic), and/or

– reduce likelihood of colonization with exogenous potential pathogens

• Approach:• Approach:– Selective oropharyngeal decontamination (SOD)

• Oral administration of non‐ or‐minimally absorbabed antibioticsy– E.g. Tobramycin + Colistin + Amphotericin

– Selective digestive decontamination (SDD)• SOD + short duration IV antibiotics (e g cefotaxime x4 days)• SOD + short‐duration IV antibiotics (e.g cefotaxime x4 days)

Selective Digestive Decontamination• ~70 RCTs for SDD, ~11 meta‐analyses• Cochrane review (2009)

Odds ratios (95% confidence interval)– SDD: RTI: 0.28 (0.20‐0.38)  Mortality: 0.75 (0.65‐0.87)SOD RTI 0 44 (0 31 0 63) Mortality 0 97 (0 82 1 16)– SOD: RTI: 0.44 (0.31‐0.63) Mortality: 0.97 (0.82‐1.16)

• Unresolved issues:– Single‐center RCTsSingle center RCTs– Recruitment bias– Various SDD & SOD regimens– Long‐term ecologic effects– Effects in areas with high prevalence of resistance– Cost‐effectivenessCost effectiveness– Instinctive revulsion 

Liberati A, et al. Cochrane Database Syst Rev 2009;9

Selective Digestive Decontamination

• de Smet et al (NEJM 2009) Cluster randomized trial 13 Dutch ICUs– Cluster‐randomized trial 13 Dutch ICUs

– Anticipated ventilation >48 hours or ICU stay >72 hours

A i d SDD/SOD/ t d d f ll t 6 th– Assigned SDD/SOD/standard care for all pts x6 monthsOutcome Std care SDD (vs Std Care) SOD (vs Std Care)

28 day mortality 27 5% 26 9% [0 83 (0 72 0 97)] 26 6% [0 86 (0 74 0 99)]28‐day mortality 27.5% 26.9% [0.83 (0.72‐0.97)] 26.6% [0.86 (0.74‐0.99)]

Bact/fungemia 9.3% 4.3% [0.44 (0.34‐0.57)] 6.5% [0.68 (0.53‐0.86)]

eGNR 4.4% 0.9% [0.19 (0.12‐0.32)] 3.1% [0.28 (0.16‐0.47)]

Enterococcus 2.8% 2.3% [0.85 (0.57‐1.25)] 2.6% [0.91 (0.61‐1.36)]

Systemic antibiotics DDD 33,688 29,663 [‐11.9%]  30,299 [‐10.1%]

Cephalosporins 4,451 8,473 [+86.6%] 995 [‐25.4%]

de Smet AMGA, et al. NEJM 2009;360:20‐31

p p , , [ ] [ ]

Carbapenems 1,334 724 [‐45.7%] 3,935 [‐13.3%]

Selective Digestive Decontamination

• Oostdijk et al (Am J Resp Crit Care Med 2010) Resistance prevalence surveys from de Smet study– Resistance prevalence surveys from de Smet study

– Rectal & respiratory samples from all ICU pts

Sample DrugResistance prevalence

Prior to SDD During SDD After SDD

Rectal Ceftazidime 6% 5% 15%

Ciprofloxacin 12% 7% 13%

T b i 9% 7% 13%Tobramycin 9% 7% 13%

Respiratory Ceftazidime 10% 4% 10%

Ciprofloxacin 10% 5% 12%

Oostdijk EAN, et al. Am J Resp Crit Care Med 2010;181:452‐457

Ciprofloxacin 10% 5% 12%

Tobramycin 14% 6% 12%

SDD by Any Other Name?No preventive antibiotics for anyone

Single‐dose surgical prophylaxis

Multi‐doseMulti‐dose surgical prophylaxis “until drains out”

Preemptive antibiotics for cirrhotic patients with ascites

Prophylaxis for neutropenicpatients

SDD for ventilated ICU patients?

patients

Broad‐spectrum prophylaxis on admission

p

What’s Next: Quantifying Collateral Damage of AntimicrobialsDamage of Antimicrobials

• Implicit calculation of risks & benefitsRisk (abx tx) = Risk (untreated infection) Risk– Risk (abx tx) = Risk (untreated infection) - Risk (ADR) - “Risk” (cost) [- Risk (antibiotic resistance)]

Risk (antibiotic resistance) not well defined– Risk (antibiotic resistance) not well-defined

• Paul et al J Antimicrob Chemother 2006d d– Created computerized expert system

– Assigned “antibiotic resistance coefficients” for each ddrug

– Used in selection of “optimal” antibiotic regimen

Paul M et al. J Antimicrob Chemother 2006;58:1238-1245.

What’s Next: Quantifying Collateral Damage of Antimicrobialsg

Paul M et al. J AntimicrobAntimicrobChemother2006;58:1238-1245 Reprinted with permission

Virulence Factors

• You probably already know…whether a bacterium causes disease often related to its…whether a bacterium causes disease often related to its 

production of virulence factors

• You might not know• You might not know……how virulence factors contribute to disease process

• What you can do about it now……protein synthesis inhibitors as antitoxins

• What’s next……anti‐virulence‐factor antibodies in developmentp

Invasion Adhesins Type IIIsecretion signaling

ProteasesGlycanasesGlycanases

Defense

Capsule

Survival insidephagolysosome

Sequestrationinside vacuole

Damage Superantigens

Pore formers Unrestrainedimmune activation

Pore‐formers

Cell lysis

Second messengeractivators

yProtein synthesis

inhibitorsParalysis

Various effects

Neurotransmitterrelease inhibitors

(proteases)Various effects

Bacterial Exotoxins and CountermeasuresToxin Organism Class CountermeasureDiphtheria toxin C. diptheriae Protein synthesis 

inhibitorDiphtheria antitoxinDiphtheria toxoid vaccineinhibitor Diphtheria toxoid vaccine

Tetanus toxin C. tetani Protease Tetanus antitoxinTetanus toxoid vaccine

Botulinum toxin C. botulinum Protease Botulinum antitoxin

Lethal factor B. anthracis Protease Anthrax killed vaccine

Pertussis toxin B pertussis 2nd messenger activator Pertussis acellular vaccinePertussis toxin B. pertussis 2 messenger activator Pertussis acellular vaccine

Panton‐Valentineleukocidin

S. aureus Pore‐former

P i i S S ti

None approved

Pyogenic exotoxin S. pyogenes Superantigen

Shiga toxin E. coli Protein synthesis inhibitor

Exotoxin A Pseudomonas Protein synthesisinhibitor

Toxin A/B C. difficile 2nd messenger activator

Protein Synthesis Inhibitors as Antitoxins

Cell‐wall‐activeagentsagents

Protein synthesisinhibitors

Protein Synthesis Inhibitors as Antitoxins: In Vitro DataIn Vitro Data

Sriskandan S, et al. J Antimicro Chemother 1997;40:275‐277. Reprinted with permission.

Protein Synthesis Inhibitors as Antitoxins: Animal ModelsAnimal Models

Stevens DL, et al. J Infect Dis 1988;158:23‐28. Reprinted with permission.

Protein Synthesis Inhibitors as Antitoxins: Clinical DataClinical Data

Cell wallProtein synthesis inhibitors with or

P‐value

SubpopulationCell wall agents only

inhibitors with or without cell wall agents

Superficial  12/25 (48%) 10/12 (83%) 0.07pinfections

/ ( ) / ( )

Deep infections 1/7 (14%) 10/12 (83%) 0.006

No surgery Surgical intervention

Superficialinfections

9/22 (41%) 3/3 (100%) 0.04infections

Deep infections 0/6 (0%) 1/1 (100%) 0.14

Zimbelman J, et al Ped Infect Dis J 1999;18:1096‐1100

Protein Synthesis Inhibitors as Antitoxins: Beyond Streptococci?Beyond Streptococci?

Dumitrescu O, et al Clin Microbiol InfectJ 2008;14:384‐388. Reproduced with permission.

What’s Next: Novel Virulence Factor CountermeasuresCountermeasures

Factor Organism Countermeasure Stage

Panton‐ S. aureus Linezolid Clinical practiceValentineleukocidin

PVL subunit vaccinep

Animal models

P i S Cli d i Cli i l iPyogenic exotoxin

S. pyogenes ClindamycinEngineered soluble T‐cell receptor

Clinical practicePreclinical development

Shiga toxin E. coli Urtoxazumab, monoclonal antibody

Phase II trial

Exotoxin A Pseudomonas Exotoxin A toxoid vaccine

Animal models

Toxin A/B C difficile Humanized anti‐toxin Phase II trialToxin A/B C. difficile Humanized anti‐toxin monoclonal antibodies

Phase II trial

Biofilms

• You probably already know…infections associated with prosthetic materials are…infections associated with prosthetic materials are 

difficult to eradicate

You might not knowYou might not know……how biofilms are associated with antibiotic resistance

• What you can do about it now……rifampin as an anti‐biofilm agent

• What’s next……quorum‐sensing inhibitorsq g

Biofilm Architecture

www.hygienia.net

Biofilms in Human InfectionsNative Tissue Prosthetic Device

Vascular access fistulas Vascular cathetersascu a access stu as ascu a cat ete s

Prostate gland Urinary catheters

Heart valves (often  Artificial heart valves (metal & w/abnormalities) bioprosthetic)

Lungs in cystic fibrosis Orthopedic implants

Periodontitis Contact lenses

Biofilms and Antibiotic ResistanceDrug % Planktonic MSSA Strains

Inhibited% Biofilm MSSA Strains Inhibited

Vancomycin 100% 18%

Linezolid 100% 0%

O illi 100% 9%Oxacillin 100% 9%

Cefazolin 100% 27%

M h i f i t• Mechanisms of resistance– Reduced penetration

– Altered metabolism

– Upregulation of efflux pumps

– Higher inocula

Saginur R, et al. Antimicrob Agents Chemother 2006;50:55‐61 

Rifampin as Anti‐Biofilm Agent

Olson ME, et al. J Antimicrob Chemother 2010;65:2164‐2171. Reprinted with permission. 

Rifampin as Anti‐Biofilm AgentPros Cons

Active vs organisms in various  Extensive drug interactionsct e s o ga s s a ousmetabolic states

te s e d ug te act o s

Bactericidal activity Added toxicity

Penetrates into biofilm well Rapid emergence of resistance as monotherapy & with high organismburdenburden

Displays additive to synergisticactivity in many combinations

Combination activity not always predictable; indifferent to antagonistic in some organisms/models

Extensive tissue distributionExtensive tissue distribution

Clinical Data Supporting Adjunctive Use of Rifampin in Biofilm InfectionsRifampin in Biofilm Infections

Infection Data Outcomes

N ti tiNative tissueNative valve endocarditis Randomized controlled trial +/‐

Chronic osteomyelitis Cohort +/‐y /

Prosthetic materialVascular catheter (prevention) Randomized controlled trial ++

Prosthetic valve endocarditisS. epidermidisS. aureus

Cohort studies, case seriesCase series

++

Ventricular shunts Case series +

Orthopedic implants Randomized controlled trial ++

++=very beneficial +=beneficial +/‐=equivocal++=very beneficial +=beneficial +/‐=equivocal

Forrest GN, et al. Clin Microbiol Rev 2010;23:14‐34

Staphylococcal knee/hip PJI <1 yearDebridement & retention

R d i d d bl bli d (?)

Zimmerli W, et al. JAMA 1998;279:1537‐1541

Randomized, double‐blind (?)Flucloxacillin (MSSA) or Vancomycin (MRSA)

l f l l b

18 patients 15 patientsy ( )

Plus Rifampin Plus Placebo2 weeks 2 weeks

Hi 3 thRifampin/Ciprofloxacin Placebo/Ciprofloxacin

Hips x3 monthsKnees x6 monthsOr until failure

Clinical cure (lack of symptoms, CRP<5, stable joint)24 months after initial therapy

Endpoint RIF Placebo P‐value

Per‐protocol 12/12 7/12 0.02

Intention‐to‐treat 16/18 9/15 0.10

Rifampin resistance 0/0 3/4 ‐‐

What’s Next: Quorum‐Sensing Inhibitors

Brackman G, et al. Antimicrob Agents Chemother 2011;55:2655‐266. Reprinted with permission

Summary• The “War on Bugs”

– Old paradigm: thermonuclear warfare – kill all bugs dead– New paradigm: neutron bomb – kill bad bugs, leave infrastructure

– Future paradigm: electromagnetic pulse – disruptFuture paradigm: electromagnetic pulse  disrupt communication & cooperation

• What are we doing now?– Best evidence – least used: Selective digestive decontamination

– Moderate evidence – standard of care: rifampin for pprosthetic device infections

– Weak evidence – variously used: clindamycin for toxigenic Strep infectionsStrep infections

Antimicrobial Pharmacodynamics:f B h B d idfrom Bench to Bedside

d k hC. Andrew DeRyke, Pharm.D. Optimer Pharmaceuticals, Inc.

O l dOrlando, FL

Conflict of InterestConflict of Interest

E l f O ti Ph ti l IEmployee of Optimer Pharmaceuticals, Inc.

Learning Objectives3

Learning Objectives

Explain the unique aspects that separate antimicrobial• Explain the unique aspects that separate antimicrobial pharmacodynamics from that of other therapeutic areas.

• Describe and define post‐antibiotic effects, concentration‐p ,and time‐dependency, and bactericidal and bacteriostaticeffects as they apply to clinical decision making.Ch ti l d i f tibi ti b d it• Choose optimal dosing of an antibiotic based upon its pharmacodynamic profile and minimum inhibitory concentration.

• Describe instances where pharmacodynamic optimization has been shown to improve clinical outcomes

Pharmacokinetics“PK is what the body does to the drug”PK is what the body does to the drug

CmaxConcentration Absorption

AUC

pDistributionMetabolismEliminationAUC Elimination

Elimination half‐life (t k )Elimination half‐life (t1/2, k10)

Cmin

0 Time (hours)Time (hours)AUC = Area under the concentration‐time curveCmax = Maximum plasma concentrationCmin = Minimum plasma concentration

Pharmacodynamics“PD describes the critical interactionPD describes the critical interaction 

between drug and bug”

Describes the relationship between drug concentration and pharmacologic effectconcentration and pharmacologic effect– Antimicrobial Effect

• Antimicrobial PD is unique since only class of drugs that exert that intended activity on another living organism other than our own cells

• Links PK and drug effect on bacteria (minimum inhibitory concentration)

– Toxicity (toxicodynamics)

Minimum Inhibitory Concentration (MIC)(MIC)Lowest concentration of an antimicrobial

Known quantity of bacteria placed into each tube

Lowest concentration of an antimicrobial that results in the inhibition of visible 

growth of a microorganism

4.0µg/mL

0.25µg/mL

0.5µg/mL

1.0µg/mL

2.0µg/mL

8.0µg/mL

16µg/mL

Increasing antibiotic concentration

How is Resistance Reported?• Minimum Inhibitory Concentration (MIC):

– The most refined means of measuring in vitro antibacterial activityg y– Difficult to interpret for most clinicians

• Clinical Laboratory Standards Institute (CLSI) establishes• Clinical Laboratory Standards Institute (CLSI) establishes tentative MIC breakpoints:– Susceptible (S)I t di t (I) l l l f i t– Intermediate (I): low level of resistance

– Resistant (R): high level of resistance

FDA defines final breakpoints when agent is approved• FDA defines final breakpoints when agent is approved

• Discordance is not uncommon:– e.g., vancomycin, doripenem, cephalosporins against Gram‐negatives

Determination of Clinical BreakpointsBreakpoints

(where % S comes from)• Indicate at which MIC the chance of eradication (success) prevails significantly over failure

• Several approaches to determination:– Populations of pathogens with higher MICs in the bimodal or normal distributionbimodal or normal distribution

– Clinical trial data documenting success or failure with higher MIC strainshigher MIC strains

– Pharmacodynamics

Wrong way to interpretWrong way to interpret

“I i th fil d i k th“I review the profile and pick the antimicrobial agent with the lowest MIC”

MIC susceptibility breakpoints i t P d iagainst Pseudomonas aeruginosa

MICs (g/mL)S I RS I R

Piperacillin‐tazobactam ≤ 64 ≥128tazobactam

Ciprofloxacin ≤ 1 2 ≥ 4

Resident: “So an MIC of 16 µg/mL is very resistant to ciprofloxacin but quite sensitive to piperacillin‐tazobactam. How does this make sense?”

Comparing concentration‐time profile (drug exposure) of Pip‐tazo & ( g p ) p

CiprofloxacinPiperacillin tazobactam 3 375 g IV

100

mL

)

Piperacillin-tazobactam 3.375 g IV

Ciprofloxacin 400 mg IV

75

nc

(µg

/m P/T Cmax = 96 µg/mL

50

Dru

g C

on

CIP Cmax = 4.6 µg/mL

25

Fre

e D

P/T MIC = 16 µg/mL

0

0 1 2 3 4 5 6 7 8Time (hours)

Comparing concentration‐time profile (drug exposure) of Pip‐tazo &(drug exposure) of Pip tazo & 

CiprofloxacinPiperacillin-tazobactam 3.375 g IV

10

mL

)

p g

Ciprofloxacin 400 mg IV

7.5

nc

(µg

/m

5

Dru

g C

on

2.5

Fre

e D

CIP MIC = 0.25 µg/mL

0

0 1 2 3 4 5 6 7 8Time (hours)

Wrong way to interpretg y p

“I review the profile and pick the antimicrobial agent with the l C”lowest MIC”

Rationale as to why this is not logical:y g1. We don’t give the same mg or g dose of different 

antibiotics to patients– Piperacillin 4g (e.g.. 4.5g dose) is 10 times more drugPiperacillin 4g (e.g.. 4.5g dose) is 10 times more drug 

than Ciprofloxacin 400 mg2. The resultant serum drug exposure (e.g., concentration‐

time curve) is different for different antibiotics)3. The MICs which harbor resistance mechanisms are 

different for different drug/bug combos4. In vitro, in vivo animal, and clinical outcomes data show4. In vitro, in vivo animal, and clinical outcomes data show 

clinical and microbiological success for drug/bug combos at different MICs 

Basics of AntimicrobialBasics of Antimicrobial Pharmacodynamics

Concentration‐Dependent vs. d d l llIndependent Bacterial Killing

9988

Tobramycin TicarcillinCiprofloxacin

Colony Forming Units per 

77

66

mL, Log1044

55

33 Control 4 MIC

22

33 1/4 MIC1 MIC

16 MIC64 MIC

0 2 4 6 0 2 4 6 0 2 4 6 8

Adapted from Craig WA et al. Scand J Infect Dis, Suppl 1991; 74: 63‐70.

Time (hours)Time (hours)

Common Pharmacodynamic IndicesIndices

Concentration

AUC:MIC

Cmax:MIC or Peak:MIC

AUC:MIC

Cmin:MIC

MIC

0

T>MIC

Time (hours)AUC = Area under the concentration–time curveMIC = Minimum Inhibitory ConcentrationCmax = Maximum or peak plasma concentrationCmin = Minimum or trough plasma concentration

Time (hours)

Pharmacodynamic parameters predictive of outcomepredictive of outcome

T>MICAUC:MICCmax:MIC

Examples PenicillinsCephalosporins CarbapenemsM b t

AzithromycinFluoroquinolonesKetolidesLi lid

AminoglycosidesFluoroquinolonesPolymyxins

MonobactamsMacrolides

LinezolidDaptomycinVancomycinTigecyclineTigecycline

Organism killTime‐dependent

Concentrationor Time‐dependent

Concentration‐dependent ppp

Therapeuticgoal

Optimize durationof exposure

Maximizeexposure

Maximizeexposure

Drusano GL & Craig WA. J Chemother 1997; 9: 38–44. Drusano GL et al. Clin Microbiol Infect 1998; 4 (Suppl. 2): S27–S41. 

Vesga et al. ICAAC 1997.

Definitions

• Bactericidal:Bactericidal:– MBC/MIC is  4– CLSI: > 3 log (99 9%) reduction in CFU/mL inCLSI: > 3 log (99.9%) reduction in CFU/mL in 18‐24 hours of incubation in liquid media

• Bacteriostatic:• Bacteriostatic:– MBC/MIC >16CLSI: < 3 log (99 9%) reduction in CFU/mL in– CLSI: < 3 log (99.9%) reduction in CFU/mL in 18‐24 hours of incubation in liquid media

MIC = minimal inhibitory concentrationCLSI = Clinical & Laboratory Standards InstituteCFU = colony‐forming unit.

Determination of Bactericidal Activity:The time kill methodThe time kill method

78 Control Static Cidal

456

CFU/mL 99.9% Kill

234

log 1

0

01

0 2 6 12 240 2 6 12 24

Hours

Bactericidal vs. BacteriostaticBactericidal vs. Bacteriostatic

B t i t ti B t i id lBacteriostatic• ErythromycinT li

Bactericidal• PenicillinsC b• Tetracyclines

• Clindamycin• Carbapenems• Cephalosporins• Aminoglycosides• Sulfa drugs

• Trimethoprim

• Aminoglycosides• Vancomycin• Fluoroquinolones• Chloramphenicol

• Tigecycline

• Fluoroquinolones• Metronidazole• Ketolides• Ketolides

Bactericidal vs. Bacteriostatic• Bactericidal antibiotics are not required to treat the vast majority of infections,to treat the vast majority of infections, exceptions include:

- EndocarditisEndocarditis- MeningitisN t i (?)- Neutropenia (?)

• Clinical experience with new agents in i i h hi hl i i ipatients with highly resistant strains is 

more valuable than classifications based on in vitro studieson in vitro studies

Finberg RW et al. Clin Infect Dis 2004; 39: 1314‐20.

d f h b ffPost‐antibiotic Effect (PAE)

Magnitude of persistent inhibitory effects of antimicrobial activity 

10

h

6

8Control Antibiotic 

FU/thigh

4 PAE = 5.8 Hrs

Log 1

0CF

0

2

T>MIC

L

Time (hours)0 4 8 12 16 20 24

Application of Antimicrobial Ph d i hPharmacodynamics at the 

Bedside

T>MICConcentration

T>MIC

MIC

0

T>MIC

Time (hours)Time (hours)

Beta‐Lactams: T t d PD ETargeted PD Exposure

The optimum level of exposure varies for• The optimum level of exposure varies for different agents within the beta‐lactam class

• Required %T>MIC for efficacy:~ 50%–70% for cephalosporins 50% 70% for cephalosporins

~ 50% for penicillins

~ 40% for carbapenems

Drusano GL. Clin Infect Dis. 2003; 36(suppl 1): S42‐S50.

Intermittent InfusionPiperacillin/Tazobactam 3 375g IVPiperacillin/Tazobactam 3.375g IV 

Q6H125

Healthy Volunteers 

100

µg/mL)

Healthy Volunteers 

% % ffT>MIC = T>MIC = 50%50%

50

75

ug Conc (µ % % ffT>MIC = T>MIC = 83%83%

25

50

Free Dru

MIC = 16 µg/mL

00 1 2 3 4 5 6

MIC = 2 µg/mL

Time (hours)

Johnson CA, et al., Clin Pharmaco Ther 1992; 51:32‐41

Intermittent InfusionIntermittent InfusionPiperacillin/Tazobactam 3.375g IV Q6H

100Healthy Volunteers

75

Healthy Volunteers

Hyperdynamic Patients

50 Healthy Volunteers‐ % fT>MIC = 50%Hyperdynamic Patients‐ % fT>MIC =33%

25 MIC = 16 µg/mL

Hyperdynamic Patients % fT MIC   33%

00 1 2 3 4 5 6

Johnson CA et al., Clin Pharmaco Ther 1992; 51:32‐41.Shikuma LR et al., Crit Care Med 1990; 18: 37‐41.

Probability of Achieving 50% fT>MIC Pip/Tazo 4.5g Q6H (0.5 H infusion)Pip/Tazo 4.5g Q6H (0.5 H infusion)

1.090% Target Attainment

tainment

0.7

0.8

0.9

f Target Att

0 4

0.5

0.6

0.7

50% f T>MIC

obability of

0 1

0.2

0.3

0.4

MIC (µg/mL)

0.06 0.125 0.25 0.5 1 2 4 8 16 32 64 128

Pro

0.0

0.1

S R

Adapted from DeRyke CA et al. Diagn Microbiol Infect Dis 2007; 58: 337‐44. 

MIC (µg/mL)

30‐day Mortality among patients withPseudomonas aeruginosa bacteremiaPseudomonas aeruginosa bacteremia

Stratified by piperacillin‐tazobactam MIC

80

100

(%)

60

80

mortality (

Pip/tazoControl

20

40

30‐day m

0MIC 32 or 64 µg/mL MIC ≤ 16 µg/mL

Adapted from Tam VH et al. Clin Infect Dis 2007; 46: 862‐7.

Maximizing T>MICg

• Higher dose

• Increased dosing frequency

• Increased duration of infusion

Intermittent vs Continuous Infusion Regimens

Intermittent Dosing Interval

Intermittent vs. Continuous Infusion Regimens

mL)

b

Conc (µg/m Antibiotic

concentration exceeding the MIC

MIC2

ree drug C MIC

Time (24 hour period)

Fr

MIC1

Time (24­hour period)

Intermittent Dosing Continuous Infusion

Piperacillin/tazobactam 3.375gmd d 5h h fadministered as a 0.5h or 4h Infusion

100 0

ation

ation

100.0

Rapid Infusion (30 min)

E d d I f i (4 h)

 Concentra

 Concentra

g/mL)

g/mL)

10.0Extended Infusion (4 h)

Free drug 

Free drug  (µg

(µg

MIC1.0

FF

0 2 4 6 80.1

Time (h)Time (h)

Pip/tazo for P. aeruginosa Infections:Clinical Implications of Extended Infusion DosingClinical Implications of Extended Infusion Dosing

Adapted from Lodise TP et al. Clin Infect Dis 2007; 44: 357‐63.

Continuous vs. Extended InfusionImplementation in Clinical PracticeImplementation in Clinical Practice

ContinuousP

Extended or Prolonged• Pros • Pros

– Once daily administration– Reduced costs for labor, 

• Pros– Daily antibiotic free‐interval 

(50% of day) Less frequent administration supplies, and administration

• Cons– Dedicated line

– Less frequent administration compared to intermittent 

– Same dose/delivery package as intermittent doses Dedicated line

– Compatibility issues– Stability and drug waste

– Ambulatory patient• Cons

– Daily intravenous access– Ambulatory patient

Daily intravenous access– Labor, supplies and 

administration resources– Timing of administration for non‐Timing of administration for non

compatible drugs Lodise TP et al. Pharmacotherapy 2006; 26: 1320‐32. 

Kim A et al. Pharmacotherapy 2007; 27: 1490‐7.

Cefepime PharmacodynamicsCefepime PharmacodynamicsProbability of achieving 50% fT>MIC for VAP patients (CrCL: 50 mL/min – 120 mL/min)

%) 100

90% Target Attainment

tainment (%

70

80

90

of Target Att

40

50

60

70

Probability o

20

30

40

1g Q12H ‐ 0.5 H infusion 2g Q12H ‐ 0.5 H infusion 1g Q8H ‐ 0.5 H infusion

MIC ( / L)

0.06 0.125 0.25 0.5 1 2 4 8 16 32 64 128

P

0

101g Q8H  0.5 H infusion2g Q8H ‐ 0.5 H infusion 

Nicasio AM et al, Antimicrob Agents Chemother 2009; 53: 1476‐81.

MIC (µg/mL)

Outcomes of Patients with Gram‐Negative Bloodstream InfectionsNegative Bloodstream Infections 

Treated with Cefepime

56% 53%60

80

y (%

)

23%28% 27%

40

60

ay mortality

0

20

1 / L 2 / L 4 / L 8 / L 16 / L

28‐da

≤ 1 µg/mL(n=116)

2 µg/mL(n=18)

4 µg/mL(n=11)

8 µg/mL(n=16)

≥16 µg/mL(n=15)

Cefepime MIC (µg/mL)

Bhat SV et al. Antimicrob Agents Chemother 2007; 51,: 4390‐5.

C :MICConcentration

Cmax:MIC

Cmax:MIC

MIC

0 Time (hours)Time (hours)

Cmax = Maximum plasma concentration

Once‐Daily Gentamicin vsC ti l (Q8H) R iConventional (Q8H) Regimen

20

g/mL)

181614

Once‐daily gentamicin 

Conventional regimen

tration(µg 14

12108

Concent 8

6420

1 2 4 6 8 9 10 12 14 16 17 18 20 22 24Time (hours)

Adapted from Nicolau DP et al.  Antimicrob Agents Chemother 1995: 39; 650‐5.

AUC:MIC

Concentration

AUC:MICAUC:MIC

MIC

0 Time (hours)Time (hours)

AUC = Area under the concentration–time curve

Vancomycin Pharmacodynamics in Patients with MRSA Pneumonia

100

in Patients with MRSA Pneumonia

80

sitive

AUC/MIC <400

40

60

t Culture Pos

P = 0.0402

20

40

Percent

AUC/MIC >400

0 10 20 30Day of Eradication

0

Adapted from Moise‐Broder P et al. Clin Pharmacokinet 2004; 43: 925‐42.

Evaluating Vancomycin AUC/MIC at the bedsideExample: 53 y F 95 kg non‐ICU CLCR = 66 mL/minExample: 53 y F, 95 kg, non ICU, CLCR = 66 mL/min

Vancomycin 1500 mg daily; MRSA bacteremia, MIC = 1µg/mL

Step 1Step 1 Estimate CLEstimate CLCRCR 66 66 mLmL/min/min

Step 2Step 2 Estimate Estimate VancoVanco CLCL††75% of CL75% of CLCRCR = 50 = 50 mLmL/min/minConvert to L/h = 3.0 L/hConvert to L/h = 3.0 L/h

Step 3Step 3 Estimate AUCEstimate AUCAUC = Dose/CLAUC = Dose/CL

AUC = 1500/3.0 = 500AUC = 1500/3.0 = 500

Step 4Step 4 Estimate AUC/MICEstimate AUC/MIC AUC/MIC = 500/1 = 500AUC/MIC = 500/1 = 500

† Creatinine clearance and vancomycin clearance are NOT a 1:1 ratio

DeRyke CA et al. Hosp Pharm 2009; 44,: 751‐65.

43Vancomycin Dosing Worksheet Name: ACCP

Age (years) 53

Sex (Male = 1, Female = 0) 0

Height Height 2 64062Height (cm) 162.5

Height (in) 64.0

Height (m)^2

2.640625

Actual Weight (kg) 95

Ideal Body Weight (kg) 54.1

Dosing Weight 54.1

Percent obese 1.75

Adjusted Body Weight (kg) 70.5

Serum Creatinine 1.1 Sawchuk-ZaskeSerum Albumin >=3.0 (Yes = 1, No=0) 1

Male Female Current Regimen:

Creatinine Clearance (ml/min) 77 66 Dose 1500

Creatinine Clearance (adjusted) 77 66 Interval 24

Creatinine Clearance (L/h) 3.9 e^-k(tau)0.269105

3

Salazar-Corcoran Estimate 88 time of infusion 1.5

1 ^ k(t') 0 08 0 081-e^-k(t') 0.08 0.08

Vancomycin Parameters 1-e^-k(tau) 0.73 0.73

Vancomycin Clearance (ml/min) approx. 0.7-0.8*ClCr 49 e^-k(tau - t') 0.29 0.29

Vancomycin Clearance (L/h) 3.0

Cmax = 36.4 37.0

V i Vd (L) C i 10 6 10 7Vancomycin Vd (L) Cmin = 10.6 10.7

0.57 L/kg (ABW) (Clcr >60ml/min) 54.2

0.83L/kg (ABW) (Clcr<60ml/min) 78.9 AUC(0-tau) ln trap log trap total

Is Clcr>60ml/min? YES 35 471 506

36 478 513

Eli i ti t t t (k) h 1 0 055Elimination rate constant (k) hr-1 0.055

terminal half life (h) 12.7

Time to steady-state (h) 63