COLISTIN

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 ✓ E nterococcus faecium ✓ S taphylococcus aureus ✓ K lebsiella pneumoniae ✓ A cinetobacter baumannii ✓ P seudomonas aeruginosa ✓ E nterobacter 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). 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. 2015 Jul;109(5):228-35

8. 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

9. 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)

10. Colistin

11. 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

12. 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.

13. Anti-endotoxin activity Cell death

14. 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

15. 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%

16. 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.

17. 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.

18. 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

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

20. 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

21. INDIAN D ATA 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

22. 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 Cmax ss 8681.97 ng/ml MIC Acinetobacter Cmax /MIC Fo Colistin IV 2 MIU thrice daily did not reach the desired PK/PD 4000 3000 2000 1000 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

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

24. 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

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

26. 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

27. Clinical Evidence PK/PD Rationale

28. 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

29. Clinical Evidence Clinical Efficacy

30. 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%) VA P. ✓ Colistin was administered as loading dose of 9 MIU(+4.5 MIU q12 hr). Clin Infect Dis 2012;54(12):1720–6

31. 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

32. Clinical Evidence Comparative data on Clinical Efficacy

33. 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

34. 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

35. Clinical Evidence Clinical Safety

36. 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

37. 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

38. 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

39. 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

40. Recommendation as per CHMP(EMEA)

41. 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

42. 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

43. RECENT UPDATES

44. 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

45. 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 -

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

47. 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

48. 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.

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

50. Important Recommendations

51. Important Recommendations

52. Important Recommendations

53. COLISTIN RESISTANCE Resistance Mortality associated with dual carbapenem and colistin-resistant Klebsiella pneumoniae bloodstream infections Kaur et al. (2017). 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

54. THANK YOU