While MIC is a good measure of antibiotic activity, it is static and reflects in vitro activity. PK and PD of the drug needs to be considered together with MIC if we wish to obtain an in vivo prediction of drug action and success.

1. Antibiotic Stewardship:
Demystifyimg MIC,
using PK PD aspects to improve patient care
Prof. Ashok Rattan,
MD, MAMS, INSA DFG, SEARO TA, WHO Lab Director (CAREC/PAHO)
Adviser : PathKind Labs, Knowledge Forum, R & D, Quality

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

3. Power of antibiotics
Disease Pre Antibiotic era deaths Deaths 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.

4. 1940 1950 1960 1970 1980 1990 2000 2002 2004 2006 2007 2008 2012
Introductions of New Antibiotic Classes
Sulfas 1936
Penicillin 1940
Tetracycline 1949
Aminoglycosides 1950
Macrolides 1952
Glycopeptides 1958
Streptogramin 1962
Quinolones 1962
Oxazolidinone 2000
Daptomycin 2003
Tigecycline 2006
Telithromycin 2004
Doripenem 2007
Me too drugs
Different Generations
Ertapenem 2001
Ceftaroline 2010

5. “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

6. 100
80
60
40
20
0
1980
1975 1985 1990 1995 2000
1997
VISA
VRE
PRSP
MRSA
MRSE
Percentage
of
Pathogens
Resistant to
Antibiotics
Increasing Incidence of Resistance in the US
MRSE, MRSA, VRE, PRSP, GISA
1980-2006
VRSA
2006

8. We have a basic problem
New Antimicrobials

9. Problem of MDR
• Act of GOD
• Resistance arises as a mutation in
the target gene
• Act of MAN
• Inappropriate use of antibiotic will
provide selective pressure
• Inadequate Infection control
practices also transfer of MDR
from one to another

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

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

12. The First Choice Diagnostic Laboratory

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

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

17. Patterns of antimicrobial activity
In vitro activity
• Concentration dependent
killing and prolonged
persistent 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 IV
against 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 MIC
32X MIC control

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

19. 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)

22. The First Choice Diagnostic Laboratory

23. S. pneumoniae & Levofloxacin

24. PK/PD relationship is class dependent

25. Type of anti-microbial activity
• Time dependent or concentration
independent killing
• T > MIC
• Penicillin
• Cephalosporins
• Carbapenems
• Monobactam
• Macrolides
• Clindamycin
• Oxazolidinones
• Glycylcyclines
• Flucytosine
• Concentration dependent killing
• AUC or Cmax/MIC
• Aminoglycosides
• Fluoroquinolones
• Metronidazole
• Daptomycin
• Ketolides
• Azithromycin
• Streptogramin
• Glycopeptides
• Amphotericin
• Fluconazole

26. Time serum conc. is above MIC (%)
Craig W. Diagn Microbiol Infect Dis 1996; 25:213–217.
0 20 40 60 80 100
0
20
40
60
80
100
Penicillins
Cephalosporins
Relationship between time > MIC and efficacy in
animal infection models infected with S. pneumoniae

30. Levofloxacin PK/PD correlation

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

32. 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

33. Maturity of Physiological Processes affecting
Pharmacokinetics in Children
Variable Neonates Age group reaching adult values
Absorption
1. Gastric pH Increase child
2. Gastric emptying time Increase Child
3. Biliary function Decrease Infant
4. IM absorption Decrease Child
5. Skin permeability Increase child
Distribution
1. Total body water Increase Late childhood
2. Total body fat & muscle mass Decrease Child
3. Total plasma binding proteins Decrease Early childhood

34. PK / PD Parameters of successful antimicrobial action
Cmax/MIC or AUC /MIC
>10 >100
• Aminoglycosides
• Fluoroquinolones
• Metronidazole
• Daptomycin
• Ketolides
• Azithromycin
• Streptogramin
• Glycopeptides
• Amphotericin B
• Fluconazole
T > MIC (>40%)
• Penicillin
• Cephalosporins
• Carbapenems
• Monobactam
• Macrolides
• Clindamycin
• Oxazolidinones
• Glycylcyclines
• Flucytosine

35. PK PD for new break points
Epidemiological cut offs
Probable Target Attainments
PK of Imipenem
Dosage 500 mgx4 1Gx4
Cmax (mg/L) 30 – 40 60 – 70
Cmin 0.25 – 0.5 0.5 – 1
Total body
Clearance (L) 11 – 15 11 – 15
T ½ (hr) 1 1
Fraction
Unbound 80 80
Volume of
Distribution
(L/kg) 14 – 15 14 – 15
PD of Imipenem
GNB GPC
% f T>MIC 25 – 40 15 – 20
(experimental)
% f T>MIC 54
(clinical)

39. Potency of anti-TB drugs against
M. tuberculosis
Gatifloxacin

41. 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

42. Proof of the pudding is in the eating
How to convert Good intention into reality ?
Dr. Dharmendra Sharma
Excel Program
Will give free to
Microbiologists
interested in
Using this

43. Home Screen

50. It is not because things are difficult that
we do not dare,
It is because we do not dare that
they are difficult
Lucio Anneo Seneca
(4 BC – 65 AD)