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

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

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 2016 IDSA and ATS HAP/VAP guidelines Summarize appropriate use of inhaled colistimethate per the 2016 IDSA and ATS HAP/VAP guidelines

Technician Objectives Identify which patients should receive inhaled colistimethate per the 2016 IDSA and ATS HAP/VAP guidelines. Compare the different formulations of colistimethate. Discuss the dosing techniques for colistimethate based on the patient’s severity.

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

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

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 = 12500 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.

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

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

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.

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

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

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

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

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

Questions?