Therapeutic Drug Monitoring of antibiotics

Is the time ripe ?

Dr Ashok Rattan,Chief Scientific Officer, RAK Hospital

COO & Medical Director, Star Metropolis Clinical Laboratories

Therapeutic Drug Monitoring

• Definition: TDM refers to analysis and subsequent interpretation of drug concentration in biological fluids.

• TDM should be used to– Maximize efficacy– Minimize toxicity

Personalized dosing

• To increase probability of therapeutic success

• To decrease probability of toxicity

• To prevent development of resistance

Personalized dosing

Consequences of antibiotic use

•Clinical cure

•Inhibition of non pathogenic bacteria

•Selection of resistant mutants

•Toxicity / side effects

PK / PD consideration & application

Clinical cureClinical cure

•Inhibition of non pathogenic bacteria•Selection of resistant mutants

•Toxicity / side effects

Maximize efficacy & Minimize toxicity &

decrease development of MDR

• Determination of correct antibiotic to which pathogen is susceptible in vitro

• Understanding PK & PD of antibiotic determining antibiotic efficacy

• Use the correct dose and frequency

TDM is NOT required• Drugs whose clinical end points can be easily

monitored– Blood Pressure– Blood cholesterol– Body temperature– Urine volume

• Drugs whose serum concentration doesnot correlate with therapeutic or toxic effects

• Drugs that are not used to treat life threatening conditions

Drugs suitable for TDM

• Anticancer drugs• Immunosuppressive drugs• Cardiac drugs• Anti epileptic drugs• Bronchodilators• Psychotic drugs• Antibiotics– Toxicity : aminoglycosides, glycopeptides– efficacy :

Drugs suitable for TDM• Drug Factors:– Large between subject variability– Small therapeutic index– An established concentration effect relationship– Therapeutic response is not obvious

• Patient Factors :– Suspected drug interaction– Suspected drug toxicity– Unexplained failure of therapy– Suspected noncomplince

Discovery & Development of Anti-bacterials is one of the most

important discovery of the 20th Century

                 

         

Power of antibioticsDisease Pre Antibiotic era

deathsDeaths with antibiotics

Change in deaths due to antibiotics

CAP (1) 35% 10% - 25%

HAP (2) 60% 30% - 30%

Heart Infection (3) 100% 25% - 75%

Brain Infections (4) > 80% < 20% - 60%

Skin Infection (5) 11% < 0.5% -10%

By comparison…. Treatment of heart attacks with aspirin or clot busting drugs (6) - 3%

Ref.: (1) IDSA Position Paper. Clin Infect Dis 2008; 47 (S3): S 249 – 65 (2) IDSA/ACCP/ATS/SCCM position paper. CID 2010; 51 (S1): 51 – 3 (3) Kerr AJ. SABE Lancet 1935; 226: 383 – 4 (4) Waring et al. Am J Med 1948; 5: 402 – 18 (5) Spellberg et al CID 2009; 49: 383 – 91 (6) Lancet 1998; 351 : 233 – 41.

“By the year 2000, nearly all experts agree that bacterial and viral diseases will have been virtually wiped out…”

The futurists: looking toward year 2000(Time magazine, february 25, 1966)

US surgeon general William Stewart:

“The time has come to close the book on infectious diseases” (1969)

Mankind has always had the benefit of “good” advice

100

80

60

40

20

0

19801975 1985 1990 1995 20001997

VISAVISA

VREVRE

PRSPPRSP

MRSAMRSA

MRSEMRSEPercentage ofPathogensResistant toAntibiotics

Increasing Incidence of Resistance in the USMRSE, MRSA, VRE, PRSP, GISA

1980-2006

VRSAVRSA

2006

We have a basic problem

Resistance in important pathogens

New and novel antibiotics

We must make the best use of what we have

In vitro Parameters of Antimicrobial Activity

• Potency:– MIC– MBC

• Time course of activity– Rate of killing & effect of increasing

concentration– Persistant effects• PAE, SMPAE, PALE

What the body does to the drug

Dosage Regimen

Time course ofserum levels

Time course of levels in tissues

Time course of pharma & tox effect

Time course oflevels at site

Time course of antimicrobial activity

AbsorptionDistributionMetabolismElimination

Pharmacokinetics PharmacodynamicsWhat the drug does to the body &

bacteria

In vivoPharmacology of Antimicrobial Therapy

What body does to the drug What drug does to the body & the bacteria

PK/PD terminology & central role of MIC

0

SerumConc.(ug/ml)

16

8

4

2

1

0.5

0.25

0.12

0.06

32

C maxC max

MIC MIC

Time > MICTime > MIC

C max/ MICAUC / MICt > MIC

PK/PD parameters predictive of success• Cmax / MIC > 10 • AUC / MIC > 100 • T > MIC > 40 % of dosing interval

• Variables affecting concentration:

• Volume of distribution (Vd)• Clearance (Cl) • T ½ = 0.693 x Vd

Cl

Patterns of antimicrobial activity

•Concentration dependent killing and prolonged persistant effect•Seen with Aminoglycosides, Quinolones, daptomycin, ketolides, amphotericin B•Goal of dosing: maximize concentration•AUC/MIC and Cmax/MIC major parameters of efficacy

Kill Kinetics of Synercid IVagainst MRSA 562

0

3

6

9

12

0hr 1hr 3hr 6hr 24hr

Hours

log

cfu

/ml

X MIC 2X MIC 4X MIC 8X MIC 16X MIC32X MIC control

Patterns of antimicrobial activity

•Concentration independent killing•Minimal to moderate persistent effects•Seen with all lactams, clindamycin, macrolides, oxazolidinones, Flucytosine•Goal of dosing: Optimize duration•t > MIC major parameter of efficacy

Kill Kinetics Of Linezolid Against E.faecalis Sp346

0123456789

10

0 1 2 4 6 24

hours

Logc

fu/ml

1X MIC 2X MIX 4X MIC8x MIC 16X MIC 32x MICControl

Experimental models to investigate PK/PD relationships: Overview

• Use neutropenic animals• Evaluate 20 - 30 different dosing regimens (5 dose levels, 4-6

different intervals)• Measure efficacy by change in Log10 cfu per thigh or lung at end

of 24 hours therapy• Correlate efficacy with various PK/PD parameters

• (t > MIC, • Cmax/MIC, • 24 hours AUC/MIC)

K. pneumoniae & Imipenem

K. pneumoniae & Imipenem

S. pneumoniae & Levofloxacin

PK/PD relationship is class dependent

PK/PD correlation with efficacy•T > MIC–Penicillin–Cephalosporins–Carbapenems–Monobactam–Macrolides–Clindamycin–Oxazolidinones–Glycylcyclines–Flucytosine

•AUC or Cmax/MIC–Aminoglycosides–Fluoroquinolones–Metronidazole–Daptomycin–Ketolides–Azithromycin–Streptogramin–Glycopeptides–Amphotericin–Fluconazole

Time serum conc. is above MIC (%)

Mor

talit

y a f

ter 4

day

s o f

ther

a py

(%)

Craig W. Diagn Microbiol Infect Dis 1996; 25:213–217.

0 20 40 60 80 100

0

20

40

60

80

100Penicillins

Cephalosporins

Relationship between time > MIC and efficacy in animal infection models infected with S. pneumoniae

Levofloxacin PK/PD correlation

PK PD for new break points

Epidemiological cut offs Probable Target AttainmentsPK of Imipenem

Dosage 500 mg x 4 1G x 4

Cmax (mg/L) 30 – 40 60 – 70Cmin 0.25 – 0.5 0.5 – 1Total body Clearance (L) 11 – 15 11 – 15T ½ (hr) 1 1Fraction Unbound 80 80Volume ofDistribution (L/kg) 14 – 15 14 – 15

PD of Imipenem

GNB GPC% f T>MIC 25 – 40 15 – 20(experimental)% f T>MIC 54(clinical)

What are the PK/PD parameters predictive of antimicrobial’s success ?

In case of concentration dependent antibiotics like FQ, Aminoglycosides

In case of concentration independent of time dependent antibiotics like β lactams and cepahlosporins

PK/PD correlation with efficacy•T > MIC (>40%)

–Penicillin–Cephalosporins–Carbapenems–Monobactam–Macrolides–Clindamycin–Oxazolidinones–Glycylcyclines–Flucytosine

•AUC or Cmax/MIC•>100 >10

–Aminoglycosides–Fluoroquinolones–Metronidazole–Daptomycin–Ketolides–Azithromycin–Streptogramin–Glycopeptides

TDM for aminoglycosides• Small, hydrophilic molecules:– Streptomycin, Gentamicin, Tobramycin, Amikacin, Neomycin,

Spectinomycin, Paromomomycin– For t/t severe GNB infection, with Beta lactam for GPC– No activity against anaerobes

• Acts by binding to aminoacyl site of 16S rRNA• Leading to misreading of genetic code &• Inhibition of translocation, bactericidal• Resistance due to– Efflux pump, inactivating enzymes, methylation of RNA

• Volume of distribution 0.2 to 0.4 L/kg• Clearance proportional to GFR, excreted unchanged• C Max / MIC is predictor of efficacy, target > 10

• Drugs given OD so C Max no issue

• If pt has sepsis or sever burns, Vd • If compromised renal function, Clearance• Collect sample 6 hours post dose (trough level)• Increase or decrease dosing interval

TDM for Vancomycin

• Glycopeptide active against GPC, bactericidal activity on cell wall, no action against GNB

• Limited absorption orally, administered IV• Volume of distribution 0.4 to 1 L/kg• Limited CSF penetration• Excreted unchanged via urine • Related to creatinine clearance• Toxicities: Red man syndrome, Nephrotoxicity,

Ototoxicity

• Target : AUC / MIC > 400• Trough conc correlates with AUC• Dose: loading dose of 35 mg/ml• Daily dose: 1 G BD slow IV• Aim for trough value of 15 ug/ml before 4th dose • Collect sample 30 minutes before 4th or 5th dose• Creatinine Clearance data with nomogram as

surrogate dose adjustment method

Vancomycin TDM

• Whom to monitor :– Patient with invasive infection receiving prolonged

vancomycin treatment– Patient with fluctuating renal function, fluctuating

fluid balance, haemodynamic instability, critically ill, morbid obesity, receiving dialysis

– Patient with increased risk of nephrotoxicities or receiving aminoglycosides

Linezolid

• Nearly 100 % oral bioavailability• Low protein binding (30%)• Penetrates into all parts of the body• Volume of distribution equals total body

water (30 to 50 L)• Active only against Gram Positives• No activity against Gram Negatives

• Target : AUC/ MIC > 100• C min of 2 ug/ml correlates with this• C min of 10 ug/ml is associated with toxicity• Bone marrow depression common toxicity• Especially when co-administered with– Omeprezole– Aminodipine

Daptomycin (Cubicin)

• Discovered by Eli Lilly in 1960s• Cyclic lipopeptide active only against GPC• Calcium dependent depolarisation of bacterial cell wall• Lipophilic tail binds inserts itself into bacterial membrane

& forms a channel that causes efflux of intracellular potassium

• Inactivated by alveolar surfactant• Creatine phosphokinase (CPK) elevated, myopathy, rhabdomyolysin,

eosinophilic pneumonia• Dosed BD caused increased in CPK• Discontinued clinical development• Cubist acquired it for 0.5 million US$• Concentration dependent activity• Stays within the blood vessels, inactivated in lungs• Cmin > 24 ug/ml associated with increased CPK• Changed dosing frequency to OD• Monitor: Baseline CPK, CPK weekly, 5x normal

beta lactam antibiotics

• Large margin of safety• Blondiaux et al 2010 [Int J Antimicrobio Agents]– Initial dose of piperacillin + tazobactam– 50% pts achieved conc above redefined target level

of > 4 x MIC– Proportion increased ti 75% if TDM dose adjustment