Drugs

1. Optimizing Use of Colistin
Dr Amith Sreedharan

2. Burden of MDR Infections
• Result in a considerable clinical and economic burden
• Additional cost of multidrug resistance in hospitalized patients with
infections has been estimated at $6,000 to $30,000 (per patient):
– More due to the higher rate of inappropriate empiric antimicrobial
treatment than virulence
– Increased morbidity and length of stay
– Increased mortality up to fivefold when the causal organisms were
MDR
N Engl J Med 2014;370:1198-208

3. Bad Bugs, No Drugs: No ESKAPE !
ESKAP The Effects of Antibacterial
Drugs
ESKAPE
✓ Enterococcus faecium
✓ Staphylococcus aureus
✓ Klebsiella pneumoniae
✓ Acinetobacter baumannii
✓ Pseudomonas aeruginosa
✓ Enterobacter species
Clinical Infectious Diseases 2009;48:1–12

4. Rev Bras Anestesiol. 2013;63(1):73-84

5. The Indian Scenario

6. Resistance
scenario in India
Carbapenem class of
antibiotics is one of the last-
resort antibiotics to treat
serious bacterial infections
Resistance to carbapenems
among various gram-negative
bacteria -extremely high
Carbapenem (meropenem/ imipenem) resistance among
various bacteria isolated from blood culture
Source: Gandra et al. (2016); ICMR (2015).
1.AMR India Scoping Report. Available from
http://dbtindia.gov.in/sites/default/files/ScopingreportonAntimicrobialresistanceinIndia.pdf Last accessed on 30.12.19
Carbapenem class of antibiotics is one
of the last-resort antibiotics to treat
serious bacterial infections.
Resistance to carbapenems among
various gram-negative bacteria -
extremely high
Resistance to carbapenems among
various gram-negative bacteria -
extremely high
Resistance scenario in India

7. Antimicrobial resistance pattern of the causative
organisms : MDR in ICU
Indian tertiary care hospital
Conditions %
MDR GNB %
63
Pneumonia 49
MDR Acinetobacter baumannii
MDR Pseudomonas aeruginosa
Urosepsis 21.8
10.3 64.4
Bloodstream infection (BSI)
Catheter-related bloodstream infection (CRBSI) 5
Resistance to carbapenems was 35.2% in
this study
Pathog Glob Health. 2015Jul;109(5):228-35

9. Resistance among gram negative bacilli including Acinetobacter spp, E. coli,
Klebsiella, and Pseudomonas
◼ MDR: Resistant to at 3
classes of antimicrobial
agents - all penicillins and
Study of a rural hospital at Sevagram, Maharashtra
Total GN Sensitive
isolates isolates
Resistant isolates
cephalosporins
inhibitor
fluoroquinolones,
aminoglycosides.
(including
combinations),
MDR
No.
261 16.2 435 26.9 120
XDR
No.
PDR
No. %
7.4 32 1.9
and
No. % % %
1616
◼
◼
XDR: The isolate that is
resistant to MDR
carbapenems.
+
PDR: The isolate that is
resistant to polymyxins and
tigecycline.
J Global Infect Dis 2010;2:291-304
Int J Cur Res Rev. February 2015;7(3):43-47

10. Three-way Solution
Better infection management & prevention
Rational use of antibiotics
Restocked drug pipeline filled of not only new but the old ones and
Revival of older antibiotics (Colistin)

11. Colistin

12. History of Polymyxins
✓ Polypeptide antibiotics from Japan
✓ 5 different chemical components ; B and E were used in clinical practice.
✓ Polymyxin E (colistin) discovered in 1949; Bacillus polymyxa var. colistinus.
✓ 1950s : Used in Japan and Europe.
✓ 1959 : USA as colistimethate sodium (CMS).
✓ Used extensively for two decades ; but then disappeared from clinical use due to
concerns over toxicity and availability of safer alternatives

13. Mechanism of action (PD)
Colistimethate salt is the inactive prodrug
which is hydrolysed to colistin, which acts as a
cationic detergent and damages the bacterial
cytoplasmic membrane causing leaking of
intracellular substances and cell death.

14. Anti-endotoxin activity
Cell death

15. Spectrum of activity
Bactericidal action
against
Potentially active against Inactive against
✓ P
. aeruginosa,
✓ Acinetobacter
✓ Stenotrophomonas
maltophilia strains
✓ Several mycobacterial
✓ Gram negative:
▪ Proteus species,
▪ Serratia species,
✓ Gram positive bacteria
✓ Anaerobes
species,
species
✓ Klebsiella species,
✓ Enterobacter species,
✓ Escherichia coli, ✓ Fungi and Parasites
✓ Salmonella species,
✓ Shigella species,
✓ Citrobacter species
In vitro data has shown susceptibility against MDR and XDR GNB

16. Pharmacokinetics
Absorption: Not absorbed from the GI tract, mucous membranes, or intact skin (Note: GI
absorption has been observed in infants).
Distribution: Distributes widely, except for CNS, synovial, pleural, and pericardial fluids
• Healthy volunteer: IV: Colistimethate: V : 8.92 L; Colistin: V : 12.4 L.
d d
• Critically ill: IV: Colistimethate: V : 5.3 to 13.5 L; Colistin: V : 7.2 to 189 L.
d d
• Cystic fibrosis: Adolescents and Adults: IV: Colistimethate: V : 0.09 ± 0.03 L/kg
dss
(Reed 2001)
Protein binding: 50%

17. Pharmacokinetics
Metabolism: Colistimethate sodium (inactive prodrug) is hydrolysed to colistin (active
form).
– Half-life elimination: IV: Colistimethate: 2 to 3 hours
– Critically ill: Infants (including premature infants), Children, Adolescents, and
Adults: IV: Colistimethate: 2.3 hours; Colistin: 14.4 hours (Plachouras 2009)
– Cystic fibrosis: IV: Colistin: ~4 hours (Li 2003)
Elimination:
➢ T in
1/2
– Adults with normal renal function: 1.5 – 8 hrs.
– creatinine clearances < 20 mL/min - 10-20 hours
– anuric patients - 2-3 days.

18. Indications of IV Colistin
✓ Colistimethate sodium (CMS) by intravenous administration is indicated in adults
and children including neonates for the treatment of serious infections due to
selected aerobic Gram-negative pathogens, including those of the:
✓ Lower respiratory tract
✓ Urinary tract in patients with limited treatment options.
✓ Consideration should be given to official guidance on the appropriate use of
antibacterial agents.

19. Concerns : Colistin in India
High prevalence of MDR gram negative infections
Colistin often the most Commonly used last resort drug in Indian ICU
No clear dosing guidelines
Resistance now being reported to colistin, linked to suboptimal
dosing

20. Colistin dosing in critically ill patients -
Need for Re-evaluation

21. Rationale for High Dose Colistin
Concentration dependent
• Pharmacodynamically potent , against MDR Gram negative
• “Colistin has a concentration dependent activity, a high dose could achieve a
higher C > MIC, which is an important parameter for the in vivo efficacy”.
max
• It appears that peak concentrations of colistin 16 times the MIC or greater are
required for complete in vitro killing of P
. aeruginosa within 24 hours.
Antimicrob Agents Chemother 2009;53(8):3430-6
Journal of Infection 2008;56: 432-436
Critical Care 2003,7:R78-R83

22. INDIAN DATA
Pharmacokinetics of intravenous Colistin in patients with nosocomial
infections caused by Multi Drug Resistant Gram Negative Bacilli (MDRGNB)
PK-PD Parameters
MIC(range)
mcg/ml
AUC /MIC Cmax
N= 15
Dose: 2MIU TID
0-∞ SS
/MIC
Acinetobacter 0.57 ( 0.25- 644.3 15.201
5.787
2.0)
Pseudomonas 1.5 (1-2) 105.03
Presented at ISCCM, Feb 2011

23. Pharmacokinetics of Colistin* after single and multiple doses
in Indian patients with MDR GNB
Multiple doses
10000
9000
8000
Single Dose
Total Colistin
MIC Pseudomonas
Cmaxss 8681.97ng/ml
MIC Acinetobacter
Cmax /MIC
FoColistin IV 2 MIU thrice daily did not reach
the desired PK/PD
4000
3000
2000
1000
0
P: 1.5 mcg/ml
A: 0.571 mcg/ml
*2 MIU every 8 hours
• N=15, VAP
27 years, 62 kg
Eur J Clin Pharmacol (2013)69:1429–1436

24. Results
• Survival was 67%
• AUC/MIC > 125 and Cmax /MIC > 8 was achieved in:
– 7/8 patients with Acinetobacter infection
– 1/4 patients with Pseudomonas
• No renal or other significant side effects attributed
• It appears that current dose may be insufficient for
to the drug were observed
Pseudomonas infections

25. Need of High Loading Dose……………
If loading dose is not given, time taken to reach Css
would be 2 -3 days and concentration attained could be
below MIC

26. Need of High Maintenance Dose……………
High Loading & Maintenance Dose would result in faster
target concentration and need less frequent administration

27. Recent Data from PK/PD Suggests…
HIGH DOSE –EXTENDED INTERVAL
Colistin Regimen
Loading Dose of 9 MU or even 12 MU CMS and a Maintenance dose of 4.5 MU
CMS every 12 hours would result in faster target concentration and need less
frequent administration

28. Clinical Evidence
PK/PD Rationale

29. High Dose, Extended- Interval Colistin regimen
Results in faster target concentration
Loading Dose of 9 MU or even 12 MU CMS and a Maintenance dose of 4.5 MU
CMS every 12 hours would result in faster target concentration and need less
frequent administration
Model-Predicted ,Concentration in a typical patient following the use of the current dosing
regimen(3 MU as a 15 min infusion of CMS every 8 h and alternative dosing regimen with LD of 9 or
12 MU as infusion of 15 min or 2 h and a Maintenance dose of 4.5 MU CMS every 12 h.
Antimicrob Agents Chemother 2009;53(8):3430-6

30. Clinical Evidence
Clinical Efficacy

31. High Dose, Extended- Interval Colistin regimen
offers superior Efficacy
Study Design:
✓ Prospective, Observational, Cohort Study, included 28 critically ill patient with sepsis
due to COS GNB bacteria or minimally susceptible GNB
✓ 18 (64.3%) patients had Bloodstream infections (BSIs) and 10 (35.7%) VAP.
✓ Colistin was administered as loading dose of 9 MIU(+4.5 MIU q12 hr).
Clin Infect Dis 2012;54(12):1720–6

32. High Dose, Extended- Interval Colistin regimen offers
superior Efficacy
Results:
✓ Clinical Cure Rate was observed in 23 cases (82.1%).
✓ Bacteriological clearance was achieved in 73.9%(17) of the cured
infectious episodes.
Clin Infect Dis 2012;54(12):1720–6

33. Clinical Evidence
Comparative data on
Clinical Efficacy

34. High Dose, Extended- Interval Colistin regimen offers
superior efficacy
Study Design:
✓ Retro-prospective and comparative study of 2 group, included 92
Patients with MDR GNB infections.
✓ High Dose group received IV CMS with loading dose of 9 MIU followed
by maintenance dose 4.5 MIU/12 hourly.
✓ Standard dose group was retrospectively analysed and received CMS
IV without a loading dose at a dosage of 6 MIU/24hrs.
Chemotherapy 2015–16;61:190–196

35. High Dose, Extended- Interval Colistin regimen offers
superior efficacy
Results:
✓ Significantly greater proportion of patients were cured at the end of
treatment in high dose colistin group as compared to standard-dose
colisitn group.
% Cure rate
41.3%
63 %
High Dose Standard Dose
Chemotherapy 2015–16;61:190–196

36. Clinical Evidence
Clinical Safety

37. High Dose, Extended- Interval Colistin regimen does
not increase nephrotoxicity
Results:
✓ Risk of nephrotoxicity was similar between
high dose group and standard dose group.
✓ AKI was reported in 15 patients in the high-
dose colistin group (32.2%) and 12 in the
standard-dose colistin group (26%) with p =
0.64.
✓ The necessity for renal replacement therapy
in the subgroups with AKI was similar for the
2 groups (26.6 vs. 41%; p = 1).
Chemotherapy 2015–16;61:190–196

38. High Dose, Extended- Interval Colistin regimen does
not increase nephrotoxicity
Results:
✓ No deterioration of renal function was observed during 23 CMS treatment courses
(82.1%).
✓ AKI developed during 5 CMS treatment courses (17.8%) in 5 different patients
(one with pre-existing renal dysfunction)
✓ One, two, and two patients met the criteria for AKI stages I, II, and III,
respectively.
✓ No patients needed renal replacement therapy
✓ All patients completed CMS therapy by dose reduction.
Clin Infect Dis 2012;54(12):1720–6

39. High Dose, Extended- Interval Colistin regimen does not
increase nephrotoxicity & neurotoxicity
Can be used without increasing Nephrotoxicity and
Neurotoxicity
Chemotherapy 2015–16;61:190–196

40. Dosage and administration of IV Colistin
Adults:
✓Recommended dosage is Maintenance dose 9 million IU/day in 2-3 divided
doses.
✓In patients who are critically ill, a loading dose of 9 MIU should be
administered.
✓The most appropriate time interval to the first maintenance dose has not
been established.
✓Modelling suggests that loading and maintenance doses of up to 12 MIU
may be required in patients with good renal function in some cases.
✓Clinical experience with such doses is however extremely limited, and
safety has not been established

41. Recommendation as per CHMP(EMEA)

42. Recommendation as per CHMP(EMEA) for Colistin based on
population-Pharmacokinetics data in Critically patients
Adults and adolescents
Loading Dose: of 9 MIU should be administered.
Maintenance Dose: 9MIU/day in 2-3 divided doses.
• Loading and maintenance doses of up to 12 MIU may be required in patients
with good renal function in some cases.
• Clinical experience with such doses is however extremely limited, and safety
has not been established.
• The loading dose applies to patients with normal and impaired renal functions
including those on renal replacement therapy
https://www.medicines.org.uk/emc/medicine/1590

43. Special Population
Hepatic impairment: No data in patients with hepatic impairment.
Renal impairment: Dose adjustments in renal impairment are necessary,
but pharmacokinetic data available for patients with impaired renal
function is very limited.
Children: Children ≤ 40kg: 75,000-150,000 IU/kg/day divided into 3 doses. For
children with a body weight above 40 kg, use of the dosing recommendation
for adults should be considered

44. RECENT UPDATES

45. MIC Breakpoint according to the latest 2020 criteria
Colistin Interpretive Categories and Zone
diameter Breakpoints, nearest
whole mm
Interpretive Categories and MIC
Breakpoints, µg/mL
S
-
I
-
-
R
-
S
-
I R
Acinetobacter
Pseudomonas
≤ 2
≤ 2
≥ 4
≥ 4
- - -
Enterobacteriacea - - - - ≤ 2 ≥ 4
http://em100.edaptivedocs.net/GetDoc.aspx?d
oc=CLSI%20M100%20ED29:2019&scope=user

46. MIC Breakpoint according to the latest 2020 criteria
EUCAST Enterobacterales Pseudomonas Acinetobacter
MIC DISC (mm) MIC (mg/L) DISC (mm) MIC (mg/L) DISC (mm)
(mg/L)
S I R S I R S
- - 2
I R S I R S
- 2 - - - 2
I R S I R
- 2 - - -
Colistin 2 - 2 -

47. Clinical Infectious Diseases®
2017;64(5):565–71

49. Suggested loading and daily doses of CMS in critically
ill patients and those on CRRT
Dose Category of Dosing Suggestions for a Desired Target colistin Css,avg
Critically Ill
Patient
of 2 mg/L
Loadin All patient
g dose categories
300 mg CBA (9 million IU)
The 1st regular daily dose should be administered 12 hr
later.
Daily
dose
Intermittent Nondialysis day: CBA dose of 130 mg/d (3.95 million IU/d),
hemodialysis ie, baseline dosing for a Css,avg of 2 mg/L;
Dialysis day supplement: add 30% or 40% to baseline daily
dose after a 3- or 4-h session, respectively.
CRRT During CRRT: add 10% per 1 hr of CRRT to the baseline
daily dose for a Css,avg of 2 mg/L; the suggested CBA dose
is 440 mg/d (~13 million IU/d).
Clinical Infectious Diseases®
2017;64(5):565–71

51. Key Points
✓ The dosing regimen of colistin should be adapted to the renal function of
patients, and the use of a loading dose is recommended.
✓ Therapeutic drug monitoring of colistin is recommended.
✓ Because the resistance of bacteria to colistin is increasing, its use in
combination seems necessary.

52. Pharmacotherapy. 2019;39(1):10–39)doi: 10.1002/phar.2209

53. Important Recommendations

54. Important Recommendations

55. Important Recommendations

56. COLISTIN RESISTANCE
Resistance
Mortality associated with dual carbapenem and colistin-
resistant Klebsiella pneumoniae bloodstream infections
Kaur et al. (2017).
1.AMR India Scoping Report. Available from
http://dbtindia.gov.in/sites/default/files/ScopingreportonAntimicrobialresistanceinIndia.pdf Last accessed on 30.12.19
With increasing use of colistin for
treatment of carbapenem-resistant
gram-negative bacterial infections,
colistin resistance among gramnegative
bacteria has emerged in India
Bloodstream infections due to dual
carbapenemand colistin-resistant K.
pneumoniae are associated with 69.3%
mortality among Indian patients
With increasing use of colistin for
treatment of carbapenem-
resistant gram-negative bacterial
infections, colistin resistance
among gram negative bacteria
has emerged in India.
Bloodstream infections due to
dual carbapenem and colistin-
resistant K. pneumoniae are
associated with 69.3% mortality
among Indian patients

57. THANK YOU