1. Inhaled Colistin Use in Adults With Hospital-Acquired and Ventilator-Associated Pneumonia
Samantha L Gauthier, Pharm.D.
PGY-1 Pharmacy Resident Unity Health – White County Medical Center

2. Disclosure I have nothing to disclose
Neither I, nor my spouse, have at present and/or have had within the past 12 months a relevant financial relationship with a commercial interest

3. Pharmacist Objectives
Differentiate between available formulations
Compare doses of inhaled colistimethate, considering formulations and patient prognosis/severity
Identify patients that qualify to receive inhaled colistimethate per the IDSA and ATS HAP/VAP guidelines
Summarize appropriate use of inhaled colistimethate per the IDSA and ATS HAP/VAP guidelines

4. Technician Objectives
Identify which patients should receive inhaled colistimethate per the IDSA and ATS HAP/VAP guidelines.
Compare the different formulations of colistimethate.
Discuss the dosing techniques for colistimethate based on the patient’s severity.

5. Abbreviations HAP: hospital-acquired pneumonia
VAP: ventilator-associated pneumonia
CMS: colistimethate sodium
CBA: colistin base activity
GNB: gram-negative bacilli
AG: aminoglycosides
MDR: multi-drug resistant

6. Outline Background Dosing/Administration Patient Qualifications
Recommendations per IDSA/ATS
Summary

7. Background Class: polymyxin MOA: disruption of outer cell membrane
Bactericidal
Spectrum of Activity:
Narrow
P. aeruginosa
A. baumannii
Resistance: uncommon
Formulations:
Colistin sulfate
Colistimethate sodium (CMS)
Colistin Base Activity (CBA)
1mg CBA = 2.67mg CMS
Colistimethate Sodium (CMS)
1mg CMS = units CMS
Half-life:
CMS: 124 minutes
CBA: 251
MOA: binds to lipopolysaccharides and phospholipids in the outer cell membrane of GN bacteria. It competitively displaces dilvalent cations from the phosphate groups of the membrane lipids, which leads to disruption of the outer cell membrane, leakage of intracellular contents,
Deeming it as bactericidal
Resistance is relatively uncommon, although there are increasing reports of colistin resistance in carbapenem-resistant GNB
It’s SOA is narrow in that all gram + and GNC are inherently resistant, as it is primarily used for infections with pseudomonas aeruginosa and Acinetobacter baumannii.
Colistin sulfate is formulated only as a topical and nonabsorbable oral product and will not be discussed in this presentation.
Both of these forms are not absorbed in the GI tract which attributes to the lack of oral formulations
CMS is an inactive prodrug, but only ~30% of CMS is converted to the CBA
Half life of ____, and is tightly bound to membrane lipids of cells in the liver, lung, kidneys, brain, heart, and muscles. Which contributes to our dosing regimen discussed in the next slide.

8. Dosing/Administration
HAP/VAP due to MDR GNB
Nebulized: 150mg CMS every 8 hours delivered over 60 minutes for 14 days*
Bronchodilator within 15 minutes prior to administration
Or until successful wean from mechanical ventilation, with a treatment duration range of 7-19 days.
It is prepared by reconstituting 150mg vial of CBA with SWFI to a final dilution of 15mg of CBA per mL. Our prior references of 1mg CBA = 2.67mg CMS may be useful during the process of reconstitution.
The use of inhaled colistimethate may result in broncoconstriction, so a recommendation for use is a bronchodilator, such as albuterol, 15 minutes prior to use

9. Well where does inhaled colisimethate come in
[1] Page 3

10. Patient Qualifications
VAP due to GNB susceptible to AG or polymyxins
Not responding to IV antibiotics alone
HAP/VAP due to Acinetobacter sensitive only to polymyxins
HAP/VAP due to carbapenem-resistant pathogens
This recommendation places a high value on achieving clinical cure and survival, it places a lower value on burden and cost
Patients who do not qualify include:
(1) Patients with suspected VAP if there are alternative agents with adequate gram negative activity available.

11. IDSA/ATS HAP/VAP Guidelines Recommendations
VAP due to GNB susceptible to AG or polymyxins
IV + Inhaled
Compared: tobramycin, gentamicin, colistin
Organisms:
MDR Klebsiella pneumoniae
Pseudomonas aeruginosa
Acinetobacter baumannii
Improved clinical cure rate
No additional harmful effects
Reduced duration of mechanical ventilation
9 studies were found of inhaled abx as adjunctive therapy for VAP due to GNB. Five were randomized trials and 4 were observational studies
Improved clinical cure rate but had no definitive effects on mortality or nephrotoxicity
One trial found that inhaled abx reduced the frequency of requiring additional IV abx
2 studies looked for, but did not find, increased abx resistance among patients who received an adjunctive inhaled abx
The effects of adjunctive inhaled abx on the ICU length of stay and hospital length of stay were not evaluated
These recommendations are a compromise between the competing goals of providing early appropriate antibiotic coverage and avoiding superfluous treatment that may lead to adverse drug effects, C. diff, abx resistance, and increased cost

12. IDSA/ATS HAP/VAP Guidelines Recommendations (continued)
HAP/VAP due to Acinetobacter sensitive only to polymyxins
IV Polymyxin + Inhaled (adjunctive)
Higher clinical response
No increase in harm
Two observational studies
Higher clinical response than IV colistin alone, but not mortality benefit
Not completely unrelated to this presentation, the guidelines make references to the use of IV colistin with rifampin and it is not suggested because it does not improve clinical outcomes

13. IDSA/ATS HAP/VAP Guidelines Recommendations (continued)
HAP/VAP due to carbapenem-resistant pathogens
IV Polymyxin + Inhaled (adjunctive)
Potential pharmacokinetic advantage
Improved clinical outcomes
Improved mortality
No increase in harm
Routine antimicrobial susceptibility testing
3 observational studies and one randomized trial evaluated the effects of combination therapy with inhaled and IV colistin.
meta-analysis of these 4 studies showed an improved clinical cure rate and trend toward improved mortality when the combination of adjunctive inhaled colistin plus IV colistin was compared to IV alone
1 study was removed due to bias and the repeated meta-analysis found that combination with inhaled therapy was still superior to IV monotherapy
Inhaled colistin was not associated with nephrotoxicity, bronchospasm, and neurotoxicity

14. Summary IV + Inhaled colistin
VAP due to GNB susceptible to AG or polymyxins
Not responding to IV antibiotics alone
HAP/VAP due to Acinetobacter sensitive only to polymyxins
HAP/VAP due to carbapenem-resistant pathogens
No differences in clinical response rates, mortality, or nephrotoxicity.
Exception: improved mortality in carbapenem-resistant pathogens
Reasonable component of empiric regimens in intensive care units with high rates of resistance to agents from other classes.
Over use of polymyxins may jeopardize its current role as the antibiotic of last resort for resistant gram-negative pathogens.
No RCT were identified assessing colistin as empiric therapy for VAP, but systemic review and meta-regression of observational studies comparing colistin to other abx found no differences in clinical response rates, mortality, or nephrotoxicity.
Although there are no RCT, polymixins may yet be a reasonable component of empiric regimens in unites with high rates of resistances to agents from other classes. In some ICUs, organisms sensitive to colistin alone are responsible for >20% of Gn VAP. In ICUs operating under these difficult conditions, including colistin in empiric regimens may increase the frequency of initially appropriate empiric abx treatment. However, there are limited data on how this might affect nephrotoxicity rates, colistin resistance rates, and mortality rates over the long erm. Over use of polymixins may jeopardize its current role as the GN abx of last resort.
I would also like to add that colistimethate may be beneficial for the treatment of non-VAP infections, such as patients with bronchiectasis and severe chronic COPD with recurrent GN infections, and select patients with CF and non-CF

15. References
[1] Management of Patients with Hospital-acquired and Ventilator- associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Disease Society of American and the American Thoracic Society [2] Colistin: An overview, UpToDate. MacLaren, Spelman. March 14, 2017 [3] Colistimethate, Lexi-Drugs

16. Questions?