1) PK/PD analysis and determining MIC values are important for optimizing antimicrobial therapy in critically ill patients. MIC breakpoints help guide therapy based on susceptibility. 2) Inappropriate antimicrobial therapy is common, especially for hospital-acquired infections, and is associated with increased mortality. Optimizing therapy based on PK/PD principles like maximizing time above MIC can improve outcomes. 3) Determining the MIC of pathogens is important to predict treatment success and interpret susceptibility results based on clinical breakpoints. Automated systems are commonly used to efficiently obtain MICs in clinical microbiology laboratories.

1. PK-PD ANALYSIS AND MIC
INTERPRETATION
Maj (Dr) Shilpi Gupta
MD (Microbiology)

2. OBJECTIVES
• Using PK/ PD analysis and MIC for optimizing
antimicrobial prescription in critically ill patients
• Guiding antimicrobial therapy based on MIC
breakpoint values

3. GOLDEN RULES OF ANTIMICROBIAL PRESCRIBING
M • Microbiology guides therapy wherever possible
I • Indications should be evidence based
N • Narrowest spectrum prescribed
D • Dosage appropriate to the site and type of infection
M • Minimise duration of therapy
E •Ensure monotherapy in most cases
Adapted from Therapeutic guidelines: Antibiotic version 15, 2014

4. SEPSIS IN THE CRITICALLY ILL

5. Inappropriate Antimicrobial Therapy:
Prevalence Among Intensive Care Patients
Source: Kollef M, et al: Chest 2014;115:462-74
0%
10%
20%
30%
40%
50%
Community-acquired infection
Hospital-acquired infection
Hospital-acquired infection after
initial community-acquired infection
Inappropriate Antimicrobial Therapy
(n = 655 ICU patients with infection)
Patient Group
17.1%
34.3%
45.2%

6. Inappropriate Antimicrobial Therapy:
Impact on Mortality
Source: Kollef M, et al: Chest 2014;115:462-74
0
100
200
300
400
500
600
42.0% mortality
17.7% mortality
Relative Risk = 2.37
(95% C.I. 1.83-3.08; P < .001)
# Deaths
# Survivors
Inappropriate
Therapy
Appropriate
Therapy

7. PRINCIPLES OF ANTIMICROBIAL THERAPY
HOST
BUG
DRUG
Pharmacokinetics (PK)
Infection &
inflammation
(Effect)
Pharmacodynamics (PD)
MIC
Dose

8. Interplay Between PK and PD
Of Antimicrobial Agents

9. Antimicrobial Pharmacokinetic Characteristics
HYDROPHILIC ANTIBIOTICS
Beta lactams
Aminoglycosides
Glycopeptides
Linezolid
Colistin
Low Vd
Predominant renal
clearance
Increase Vd
LIPOPHILIC ANTIBIOTICS
Flouroquinolones
Macrolides
Lincosamides
Tigecycline
High Vd
Predominant hepatic
clearance
Vd largely unchanged
Examples
General PK
Altered PK-
ICU
INCREASE INITIAL
ANTIMICROBIAL
DOSE
INITIAL
ANTIMICROBIAL DOSE
UNCHANGED
ANTIMICROBIAL
ADAPTATION

10. Pharmacodynamic Indices

11. ANTIMICROBIAL PHARMACODYNAMIC
CHARACTERISTICS
Optimal PD
index
T > MIC
Cmax / MIC
AUC/ MIC
PD kill
characteristics
Time dependent
Concentration
Conc-dependent with
time dependence
Antibiotics
Beta-lactams
Carbapenems
Linezolid
Erythromycin
Aminoglycosides
Metronidazole
Fluoroquinolones
Vancomycin
Tigecycline 11

12. How to optimize therapy based on PD
• Time dependent antibiotics
• Concentration dependent antibiotics
 Give frequent doses
 Give prolonged infusion
 Give single shot of high dose

13. Optimizing -lactam Therapy: Maximizing T>MIC
Concentration
(mg/L)
Time Since Start of Infusion (h)
MIC
32
16
8
4
2
1
0 6
4
2 8 10 12
Conventional
infusion (0.5hr)
Prolonged
infusion (3hr)
T>MIC is significantly increased with
prolonged infusion
Leads to ↑ efficacy,
Overcome resistance,
cover high MIC/intermediate sensitive
pathogens
↓ failure, ↓ emergence of resistance

14. Antibiotic dose adjustment in renal failure
• Initial dose of antibiotic related to
Vd and not elimination. Hence
subsequent doses, NOT first dose
should be adjusted for renal
failure.
• For Conc dependant antibiotics,
prolong interval b/w doses but
DO NOT decrease dose.
Eg : aminoglycosides, quinolones
• For Time dependant antibiotics,
decrease dose but maintain same
dosing interval.
Eg : β-lactams, carbapenems,
vancomycin.

15. CORRELATION BETWEEN PK/PD/MIC
Activity in vitro
(MIC)
Concentrations in
vivo (PK)
Dosing regimen (PD)
Antimicrobial efficacy
(Microbioloical cure)
Other factors Clinical efficacy
(Clinical cure)

16. What is an MIC ?
• Minimum inhibitory concentration (MIC) is the key component
of relationship between antimicrobials and microorganisms
• Defined as lowest antimicrobial concentration that inhibits the
growth of bacteria/ fungi
16
CLINICAL MIC BREAKPOINT
A clinical breakpoint is a concentration of an antimicrobial which
defines whether a bacterial species is susceptible or resistant to a
particular antimicrobial

17. USE OF MIC
To measure the susceptibility of a pathogen
to antimicrobial in vitro
A low MIC indicates higher susceptibility to
the antimicrobial
A high MIC indicates lower susceptibility and
potential resistance to the antimicrobial
17

18. • Aim of susceptibility testing and MIC
measurement is to predict the likely
treatment success or failure of a
chosen therapy

19. AUTOMATED SYSTEM FOR MIC
DETERMINATION
19

20. 20

21. INTRINSIC RESISTANCE
21
Antibiotics
Organisms
Ampicillin
Amoxicillinlavulanate
Piperacillin
Cephalosporin
I:
Cephalosporin
II:
Cephalosporin
III:
Imipenem
Meropenem
Tetracyclines
Tigecycline
Nitrofurantoin
Polymyxin
B
Colistin
Aminoglycosides
Cotrimoxazole
Fosfomycin
E. coli No inherent resistance known
Klebsiella
pneumoniae
R
Proteus mirabilis R R R R
Proteus spp. R R R R R R R
Enterobacter spp R R R R
Serratia marcescens R R R R R R
Citrobacter freundii R R R R
Citrobacter koseri R R

22. INTRINSIC RESISTANCE
Antibiotics
Organisms
Ampicillin
Amoxicillinclavulanate
Piperacillin
Cephalosporin
I:
Cephalosporin
II:
Ceftriaxone
Imipenem
Meropenem
Tetracyclines
Tigecycline
Nitrofurantoin
Polymyxin
B
Colistin
Aminoglycosides
Cotrimoxazole
Fosfomycin
Acinetobacter
baumanii
R R R R
Pseudomonas
aeruginosa
R R R R R R R R
Burkholderia
cepacia
R R R R R R R R R R R R
Stenotrophomonas
maltophilia
R R R R R R R R R R R R R
22

23. 23

24. Mechanism Isolates Affected/
Hydrolysed
Not affected/
Effective
therapy
ESBL (Extended
spectrum 
lactamases)
Most GNB 3nd and 4th
generation
Cephalosporins
Carbapenems
BL-BLI
Amp C
inducible
Hyperproducers
Enterobacter,
Pseudomonas,
Serratia, Proteus
Citrobacter
Above drugs +
BL / BLI
? Cefepime
Carbapenems
Carbapenemase Kleb pneumoniae
Acinetobacter
Above drugs+
carbapenem
Polymixins
Tigecycline
KNOW YOUR ENEMY ( LACTAMASES)

25. 25

26. Optimization of antibiotic exposure
• Antibiotic selection depends on
- Therapeutic index (TI):
• High TI predicts therapeutic success
Therapeutic index = “S” Breakpoint
MIC

27. Patient A
• 30 year old male
• Outpatient
• Clinical features suggestive of UTI
• Urine C/S
27

29. Antimicrobial Therapy Interpretation MIC “S” Breakpoint
(CLSI)
TI
Amoxicillin/clavulanic
acid
S 8 8 1
Piperacillin/tazobactam S ≤4 16 4
Gentamicin S ≤1 4 4
Nitrofurantoin S ≤16 32 2

30. Patient B
• 65 year old male
• Med I Inpatient
• Presented with Urosepsis
• A known case of DM type II, HTN
• Blood C/S

32. Antimicrobial Therapy Interpretation MIC “S” Breakpoint
(CLSI)
TI
Piperacillin/tazobactam S 8 16 2
Cefoperazone/sulbactam S 16 16 1
Imipenem S ≤0.25 1 4
Meropenem S ≤0.25 1 4

33. Patient C
• 12 year old girl
• Abscess Rt axilla
• I/D done
• Pus C/S

35. Antimicrobial Interpretation MIC “S” Breakpoint
CLSI
TI
Erythromycin S <=0.25 0.5 2
Clindamycin S 0.25 0.5 2
Linezolid S 2 4 2
Vancomycin S 1 2 2

36. AES findings for Staph aureus
Cefoxitin screen Positive MRSA
Inducible
Clindamycin
resistance
Positive
Either Erythromycin
& Clindamycin not
used

37. THANK YOU