1. Therapeutic Drug Monitoring of
antibiotics
Is the time ripe ?
Dr Ashok Rattan,
Chief Scientific Officer, RAK Hospital
COO & Medical Director,

2. 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

3. Personalized dosing
• To increase probability
of therapeutic success
• To decrease probability
of toxicity
• To prevent
development of
resistance

4. Personalized dosing

5. Consequences of antibiotic use
•Inhibition of non pathogenic bacteria
•Selection of resistant mutants
•Toxicity / side effects
•Clinical cure

6. PK / PD consideration
& application
•Inhibition of non pathogenic bacteria
•Selection of resistant mutants
Clinical cure
•Toxicity / side effects

7. 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

8. 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

9. Drugs suitable for TDM
•
•
•
•
•
•
•
Anticancer drugs
Immunosuppressive drugs
Cardiac drugs
Anti epileptic drugs
Bronchodilators
Psychotic drugs
Antibiotics
– Toxicity : aminoglycosides, glycopeptides
– efficacy :

10. 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

11. Discovery & Development of
Anti-bacterials is one of the most
important discovery of the
20th Century

12. Power of antibiotics
Disease
Pre Antibiotic era
deaths
Deaths with
antibiotics
Change in deaths due
to antibiotics
CAP (1)
35%
10%
- 25%
HAP
60%
30%
- 30%
100%
25%
- 75%
> 80%
< 20%
- 60%
11%
< 0.5%
-10%
(2)
Heart Infection
(3)
Brain Infections
Skin Infection
(5)
(4)
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.

13. Mankind has always had
the benefit of “good” advice
“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)
“

14. Increasing Incidence of Resistance in the US
MRSE, MRSA, VRE, PRSP, GISA
1980-2006
100
Percentage of
Pathogens
80
Resistant to
Antibiotics
60
MRSE
MRSA
PRSP
40
VRE
20
VRSA
VISA
0
1975
1980
1985
1990
1995
1997
2000
2006

15. We have a basic problem
We must make the best use of what we have
Ne
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17. 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

18. In vivo
Pharmacology of Antimicrobial Therapy
Time course of levels
in tissues
Dosage
Regimen
Time course of
pharma & tox effect
Time course of
serum levels
Absorption
Distribution
Metabolism
Elimination
Time course of
levels at site
Pharmacokinetics
What the body does to the drug
Time course of
antimicrobial activity
Pharmacodynamics
What the drug does to the body &
bacteria

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

20. PK/PD terminology &
central role of MIC
C max/ MIC
AUC / MIC
t > MIC
32
16
8
Serum
Conc. 4
(ug/ml)
C max
2
1
0.5
MIC
0.25
Time > MIC
0.12
0.06
0

21. PK/PD parameters predictive of success
• Cmax / MIC
• AUC / MIC
• T > MIC
> 10
> 100
> 40 % of dosing interval
• Variables affecting concentration:
• Volume of distribution (Vd)
• Clearance (Cl)
• T ½ = 0.693 x Vd
Cl

24. Patterns of antimicrobial activity
Kill Kinetics of Synercid IV
against MRSA 562
12
9
log cfu/ml
•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
6
3
0
0hr
1hr
3hr
6hr
24hr
Hours
X MIC
32X MIC
2X MIC
control
4X MIC
8X MIC
16X MIC

25. Patterns of antimicrobial activity
Kill Kinetics Of Linezolid
Against E.faecalis Sp346
Logcfu/ml
•Concentration independent
killing
•Minimal to moderate persistent
effects
•Seen with all β lactams,
clindamycin, macrolides,
oxazolidinones, Flucytosine
•Goal of dosing: Optimize
duration
•t > MIC major parameter of
efficacy
10
9
8
7
6
5
4
3
2
1
0
0
1
2
4
6
24
hours
1X MIC
8x MIC
2X MIX
16X MIC
4X MIC
32x MIC

26. 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)

29. K. pneumoniae & Imipenem

30. K. pneumoniae & Imipenem

31. S. pneumoniae & Levofloxacin

32. PK/PD relationship is class dependent

33. 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

34. Mortality after 4 days of therapy (%)
Relationship between time > MIC and efficacy in
animal infection models infected with S. pneumoniae
100
Penicillins
Cephalosporins
80
60
40
20
0
0
20
40
60
80
Craig W.Time serum conc. is above MIC25:213–217.
Diagn Microbiol Infect Dis 1996; (%)
100

38. Levofloxacin PK/PD correlation

39. PK PD for new break points
PK of Imipenem
500 mg x 4 1G x 4
Epidemiological cut offs
Dosage
Cmax (mg/L) 30 – 40
Cmin
0.25 – 0.5
Total body
Clearance (L)
T ½ (hr)
1
Fraction
Unbound
80
Volume of
Distribution
(L/kg)
14 – 15
60 – 70
0.5 – 1
11 – 15
1
11 – 15
80
14 – 15
PD of Imipenem
% f T>MIC
(experimental)
% f T>MIC
(clinical)
GNB
25 – 40
54
GPC
15 – 20
Probable Target Attainments

41. 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

42. 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

43. 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

44. • 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

45. 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

46. •
•
•
•
•
•
•
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

47. 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

48. 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

49. •
•
•
•
•
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

50. 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

51. • 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

52. 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