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PK-PD of antimicrobial therapy

PHCL-L3-AntiMicro-lecture12

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Antibacterial Activity

• Classification

• Action

• Host – Drug – Pathogen Interaction

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Classification of Antimicrobial Drugs

• Classification– Structure – primary organization of lectures– Predicted spectrum– Action

Optimising outcomes requires more than just selecting the right drug

Optimising outcomes requires more than just selecting the right drug

BacteriaBacteria

Pharm

acod

ynam

icsToxicity

Resist

ance

Pharmacokinetics

Infection

Host defences

DrugDrug

HostHost

Right drug+

Right dose

McKinnon, Davis. Eur J Clin Microbiol Infect Dis 2004;23:271–288

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Host-Drug-Organism Interaction• Pharmacokinetics

– Concentration at site of pathogen– WHY IS THIS MORE IMPORTANT CONSIDERATION THAN FOR MANY

OTHER DRUGS?

• Pharmacodynamics– effects of drug on patient or organism

• Immunity– patient on pathogen

• Specific antigen-antibody• Non-specific complement-mediated opsonization

• Sepsis– pathogen on patient

• Alteration of pharmacodynamics and kinetics

• Resistance– pathogen to drug, e.g., destruction

• Selective toxicity– drug to pathogen, i.e., MOA

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Factors Affecting TissuePenetration of Antimicrobials

• Concentration in blood

• Molecular size

• Protein binding in plasma

• Lipid solubility

• Ionic charge

• Binding to exudate or tissue

• Inflammation – presence or absence

• Active transport mechanisms

• Pathways of excretion

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Achieve TherapeuticConcentrations in CSF

• Without inflammation– Trimethoprim– Sulfonamides– Chloramphenicol– Isoniazid– Rifampin– Flucytosine

• Likely with inflamed meninges– Penicillin G– Ampicillin– Ticarcillin– Carbenicillin– Piperacillin– Cefuroxime– Cefotaxime– Ceftizoxime– Ceftazidime– Ceftriaxone– Ciprofloxacin & others– Fluconazole– p-Aminosalicylic acid– Ethambutol

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Achieve TherapeuticConcentrations in CSF

Not likely!– Aminoglycosides

– Lincosamides

– Cephalosporins • First Gen.

– vancomycin

Important Host Determinants

• Hepatic function: – Erythromycin, clindamycin, rifampin, Chloramphenicol, etc depend on liver

metabolisms for the inactivation of antimicrobial mechanisms. – Patients with impaired liver function may accumulate in the body active form

of the drugs to a toxic level if the dosage adjustment is not made.• Kidney function:

– Normal kidney function is essential for disposal lactams, aminoglycosides, vancomycin, etc.

– Active form of these drugs may accumulate in the patient with renal diseases.

• Host defense mechanism: – A chemotherapeutic regimen that is perfectly adequate for immuno-

competent patient may be totally ineffective for immuno-incompetent patient. – Immuno-incompetence may be due to deficiencies in

i. immunoglobulin, ii. phagocytic cells and iii. cellular immune system.

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Untoward Effects of Antibiotics

1. Reactions due to toxic properties of antibiotics.

2. Hypersensitivity reactions3. Superinfection (or also

called Suprainfection)

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Action of Drugs

– Definition of resistance / sensitivity• MIC

• MBC

• Synergy

– Lethal vs Inhibitory (Cidal/Static)

– Post-antibiotic effect

– Concentration vs Time Dependent Killing– Mechanism of action

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Cidal / Static antimicrobials

• Group 1 – cidal– E.g.: aminoglycosides & beta-lactams

• Group 2 – static– E.g.: tetracyclines , sulfonamides, macrolides

• Combinations– Cidal (group 1) combinations often synergistic– Static (group 2) combinations indifferent or additive– Cidal / Static combinations often antagonistic

• Recommendation – Do not combine group 1 and group 2 drugs– Exceptions

• Mixed infections• Location

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Importance of Cidal / Static

• Immune compromised patients – use cidal• Severe acute infections – use cidal

•

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Cidal / Static Drug List

• Bactericidal agents– Aminoglycosides, bacitracin, beta-lactam

antibiotics, isoniazid, metronidazole, polymyxins, pyrazinamide, quinolones, quinupristin-dalfopristin, rifampin, vancomycin

• Bacteriostatic agents– Chloramphenicol, clindamycin, ethambutol,

macrolides, nitrofurantoin, novobiocin, oxazolidinones, sulfonamides, tetracyclines, trimethoprim

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Post-Antibiotic Effect

• Definition: – Persistent suppression of bacterial growth after

limited exposure to an antimicrobial agent

• Mechanism(s) not certain– may be extension of bacterial growth lag phase

recovery after reversible nonlethal damage– persistence of drug at binding site– need to synthesize new enzymes before growth

resumes

•

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Conc. vs Time Dependent Killing(Concentration)

• Concentration-dependent killing– Rate and extent of killing increase with increasing

drug concentrations

• Consequences• Maximize peak concentrations increases efficacy and

decreases selection of resistant bacteria

– eg Fluoroquinolones -- Serum concentrations need to average 4 times the MIC for each 24-hr period to produce almost 100% survival of the patient

• Aminoglycosides -- Peak should be 8- to 10-fold higher than the MIC to produce >=90% clinical response

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Conc. vs Time Dependent Killing(Time)

• Time-dependent killing– Increasing concentrations above MBC do not

result in proportionate increases in killing– Killing continues as long as concentrations

are above MBC– Lack post-antibiotic effect and should be

maintained above MIC for entire dosage interval

– Examples: beta-lactams, vancomycin• But note that beta lactams have some post-antibiotic

effect, although not dramatic

Pharmacodynamic (PD) parameters predictive of outcome

Parameter correlating with efficacy Cmax:MIC AUC:MIC T>MIC

Examples AminoglycosidesFluoroquinolones

AzithromycinFluoroquinolones

Ketolides

CarbapenemsCephalosporins

MacrolidesPenicillins

Organism kill Concentration-dependent

Concentration-dependent

Time-dependent

Therapeuticgoal

Maximiseexposure

Maximiseexposure

Optimise durationof exposure

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

Vesga, et al. 37th ICAAC (1997)

Aminoglycoside peak/MIC ratio

Moore, et al. J Infect Dis 1987;155:93–99

Cli

nic

al r

esp

on

se (

%)

Cmax:MIC

0

20

40

60

80

100

2 4 6 8 10 12

55

6570

8389 92

Application of PD ‘targets’

• What are the PD ‘targets’ in a given patient?• Aminoglycosides:

– Peak concentration:MIC ratio = 8–12:1

• How do we know whether our patients are achieving these targets?– Volume of distribution (Vd) ~0.3 L/kg– ‘Rule of thumb’: mg/kg dose x 3 = estimate of peak– For example, 4 mg/kg = ~12 µg/mL– Verify peak with levels

β-lactam pharmacodynamics

Antibiotic Organism/classOutcome parameter and value Source

Ceftriaxone S. pneumoniae T>MIC = 100% Rabbit meningitis model

Cefazolin Escherichia coli T>MIC, max. effect 4 x MIC

In-vitro PD model

Cephalosporins EnterobacteriacaeStreptococciS. aureus

T>MIC 60–70%T>MIC 60–70%T>MIC 40–50%

Animal data review

Cefazolin, ticarcillin, penicillin

E. coliS. aureusP. aeruginosaS. pneumoniae

T>MIC 100%T>MIC 55%T>MIC 100%T>MIC 100%

Neutropenic murine thigh infection model

Cefmenoxime Gram-negative T>dynamic response concentration (DRC)

Human, nosocomial pneumonia

Gunderson, et al. Pharmacotherapy 2001;21(11 Pt 2):302S–318S

Extended or continuous infusion

• Allows maximisation of T>MIC for drugs with a short half-life

• Generally, maximisation is achieved at a reduced dosage

• Reduced dosage minimises adverse events and cost

Application of PD ‘targets’: β-lactams

• What are the PD ‘targets’?– Time >MIC

• ~ 60–70% for cephalosporins• ~ 50% for penicillins• ~ 40% for carbapenems

– AUC/MIC • 4 x MIC x 24 hrs ~ 100• AUC/MIC = 125 (for clinical cure)• AUC/MIC = 250 (to prevent resistance)

• How do we know whether our patients are achieving these targets?– Literature estimates for various agents– Extrapolation from predicted concentrations

Drusano. Clin Infect Dis 2003;36(Suppl. 1):S42–S50

‘Bedside’ application of PD ‘targets’

• Time >MIC

– 100% of interval (e.g. Cmin >MIC)

– Cmin = 4 x MIC

• Is my ‘trough’ above the MIC?

• Need to know:

– Estimated expected Cmax

– Usual t½ for antibiotic

– Dosing interval

• Divide the serum concentration in half based on the half-life for the number of times within the dosing interval

• E.g. cefepime 2 g IV q 12 h: – Peak ~193 g/mL (estimated 200)

– t½ ~2 hours

MIC

T>MIC

0 2 4 6 8 10 12

CpCpmaxmax = 200 = 200

Lnconc.

CpCp2h2h = 100 = 100

CpCp4h4h = 50 = 50

CpCp6h6h = 25 = 25

CpCp8h8h = 12.5 = 12.5

CpCp10h10h = 6.25 = 6.25

CpCpminmin = 3.125 = 3.125

Caveats:• Usual PK — based on 70 kg patient, normal renal function• Single-dose estimates do not account for accumulation• Multi-dose PK will have higher CminCp = plasma concentration

Bedside pharmacodynamics applied to present case study

• Patient summary: 54-year-old male, 60 kg, estimated creatinine clearance = 80 mL/min

• Culture grew 105 CFU/mL P. aeruginosa with the following susceptibilities:– Cefepime 8 µg/mL

S– Gentamicin 4 µg/mL S– Tobramycin <1 µg/mL S– Ciprofloxacin >4 µg/mL R– Piperacillin/tazobactam >128 µg/mL R– Meropenem <2 µg/mL S– Ceftazidime >64 µg/mL R

Evaluation of antibiotic dosing– Cefepime 8 µg/mL S– Gentamicin 4 µg/mL

S– Tobramycin <1 µg/mL S– Ciprofloxacin >4 µg/mL R– Piperacillin/tazobactam 128 µg/mL R– Meropenem <2 µg/mL S

MIC-8T>MIC

0 2 4 6 8 10 12

CpCpmaxmax = 100 = 100

Lnconc.

CpCp2h2h = 50 = 50

CpCp4h4h = 25 = 25

CpCp6h6h = 12.5 = 12.5

CpCp8h8h = 6.25 = 6.25

CpCp10h10h = 3.125 = 3.125

CpCpminmin = 1.5 = 1.5

Cefepime: 1 g IV q 12 hT>MIC ~50%

Gentamicin: 100 mg IV q 12 h

Patient 60 kg: Vd ~18

Dose/Vd = Cmax

100/18 = 5.5

5.5 µg/mL / 4 µg/mL = 1.3

Peak: MIC = 1.3

How could you optimise the antibiotic regimen?

• Increase cefepime dosing and reduce dosing interval to optimise time above the MIC

• Increase gentamicin dose to optimise Cmax to MIC ratio• Change gentamicin to tobramycin because MIC is lower and drug

concentrations are similar (dose for dose)• Optimise tobramycin by increasing dose to maximise Cmax to MIC

ratio

Cefepime 2 g IV q 8 h +/- tobramycin 420 mg IV q 24 h

or

Meropenem 500–1000 mg IV q 8 h over 3 hours +/- tobramycin

Vancomycin is not needed as no significant Gram-positive pathogen was isolated on bronchoscopy

How long would you treat this patient with antibiotics?

1. 5–7 days

2. 7–10 days

3. 10–14 days

4. 14–21 days

5. >21 days

Combination therapy

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Antibiotic combination therapy- use 2 or more drugs in combination to treat infections known or thought to be caused by multiple microorganisims, to get a synergistic effect, to prevent emergence of drug-resistance organisims, or to treat clients whose immune system is suppressed or client with bone marrow or organ transplant

Goal of Combination Therapy

• To prevent the emergence of resistance - M.tuberculosis

• To treat polymicrobial infections• Initial empiric therapy• Synergy

Combination TherapyCombination Therapy For antibiotics “A” and “B” used in combination:

Actual killing rate = A + B Additive

Actual killing rate > A + B Synergistic

Actual killing rate < A + B Antagonistic

Typically bacteriostatic agents are antagonistic to bactericidal agents.

Bacteriocidal agents can be synergistic (think of the latter as one antibiotic weakens more bacteria than it kills, making the not-killed bacteria more susceptible to additional insult by the second antibiotic).

Additive means that the two (or more) antibiotics neither hinder nor help each other’s ability to kill.

Also relevant to rates of mutation to resistance.

When is Combination Therapy Considered When is Combination Therapy Considered Appropriate?Appropriate?

• Initial empirical “coverage” of multi-drug resistant pathogens until culture results are available (increases chances of initial active therapy)

• Enterococcus (endocarditis, meningitis?)• P. aeruginosa (non-urinary tract = controversial; limit

aminoglycoside component of combination after 5-7 days in responding patients)

• S. aureus, S. epidermidis (Prosthetic device infections, endocarditis)-Rifampin/gentamicin+ vancomycin (if MRSA or MRSE) or antistaphylococcal penicillin

• Mycobacterial infections• HIV

Disadvantages Combination Therapy

• Why not use 2 antibiotics all the time?• Antagonism• Cost• Increased risk of side effects• May actually enhance development of resistance

inducible resistance• Interactions between drugs of different classes• Often unnecessary for maximal efficacy

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