PK-PD of antimicrobial therapy

PHCL-L3-AntiMicro-lecture12

Antibacterial Activity
Classification Action Host Drug Pathogen Interaction

Classification of Antimicrobial Drugs

Classification
Structure primary organization of lectures Predicted spectrum Action

Optimising outcomes requires more than just selecting the right drug
Drug Right drug + Right dose

Bacteria

Infection Host defences

Host

McKinnon, Davis. Eur J Clin Microbiol Infect Dis 2004;23:271288

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

Factors Affecting Tissue Penetration 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 Therapeutic Concentrations 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

Achieve Therapeutic Concentrations 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 immunocompetent patient may be totally ineffective for immuno-incompetent patient. Immuno-incompetence may be due to deficiencies in
i. ii. iii. immunoglobulin, phagocytic cells and cellular immune system.
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Untoward Effects of Antibiotics

1.
2. 3.

Reactions due to toxic properties of antibiotics. Hypersensitivity reactions Superinfection (or also called Suprainfection)

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
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Pharmacodynamic (PD) parameters predictive of outcome

Parameter correlating with efficacy Examples Cmax:MIC Aminoglycosides Fluoroquinolones AUC:MIC Azithromycin Fluoroquinolones Ketolides Concentrationdependent Maximise exposure T>MIC Carbapenems Cephalosporins Macrolides Penicillins Time-dependent

Organism kill

Concentrationdependent Maximise exposure

Therapeutic goal

Optimise duration of exposure

Drusano, Craig. J Chemother 1997;9:3844; Drusano, et al. Clin Microbiol Infect 1998;4(Suppl. 2):S27S41; Vesga, et al. 37th ICAAC (1997)

Aminoglycoside peak/MIC ratio

100 89 83 92

Clinical response (%)

80
65 60 55 70

40

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0 2 4 6 8 10 12

Cmax:MIC

Moore, et al. J Infect Dis 1987;155:9399

Application of PD targets
What are the PD targets in a given patient? Aminoglycosides:
Peak concentration:MIC ratio = 812:1

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 g/mL Verify peak with levels

-lactam pharmacodynamics
Antibiotic Ceftriaxone Organism/class S. pneumoniae Outcome parameter and value T>MIC = 100% Source Rabbit meningitis model

Cefazolin
Cephalosporins

Escherichia coli
Enterobacteriacae Streptococci S. aureus E. coli S. aureus P. aeruginosa S. pneumoniae Gram-negative

T>MIC, max. effect 4 x MIC T>MIC 6070% T>MIC 6070% T>MIC 4050%
T>MIC 100% T>MIC 55% T>MIC 100% T>MIC 100% T>dynamic response concentration (DRC)

In-vitro PD model
Animal data review

Cefazolin, ticarcillin, penicillin

Neutropenic murine thigh infection model

Cefmenoxime

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: -lactams

What are the PD targets?
Time >MIC
~ 6070% 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):S42S50

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 t 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) t ~2 hours

Cpmax = 200 Cp2h = 100 Cp4h = 50 Cp6h = 25 Cp8h = 12.5 Ln Cp10h = 6.25 conc. Cpmin = 3.125

MIC

T>MIC

8 10 12

Cp = plasma concentration

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 Cmin

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 Gentamicin Tobramycin Ciprofloxacin Piperacillin/tazobactam Meropenem Ceftazidime 8 g/mL 4 g/mL <1 g/mL >4 g/mL >128 g/mL <2 g/mL >64 g/mL S S S R R S R

Evaluation of antibiotic dosing

Cefepime Gentamicin Tobramycin Ciprofloxacin Piperacillin/tazobactam Meropenem 8 g/mL 4 g/mL <1 g/mL >4 g/mL 128 g/mL <2 g/mL S S S R R S Gentamicin: 100 mg IV q 12 h Patient 60 kg: Vd ~18 Dose/Vd = Cmax 100/18 = 5.5 5.5 g/mL / 4 g/mL = 1.3 Peak: MIC = 1.3

Cpmax = 100 Cefepime: 1 g IV q 12 h Cp2h = 50 T>MIC ~50% Cp4h = 25 Cp6h = 12.5 MIC-8 Cp8h = 6.25 T>MIC Ln Cp10h = 3.125 conc. Cpmin = 1.5

0 2 4 6 8 10 12

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 5001000 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. 2. 3. 4. 5. 57 days 710 days 1014 days 1421 days >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 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 others ability to kill. Also relevant to rates of mutation to resistance.

When is Combination Therapy Considered 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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