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 [email protected]
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