1. Colistin Re-emerging antibiotics VS Adverse effects – respiratory failure 1 R4 김선혜 / Fellow. 임효석

2. COLISTIN 1> the choice of antibiotic therapy 2> the extent of testing to determine the cause 3> the appropriate location of treatment (home, GW, or ICU) Collistin were initially isolated from Bacillus species in 1949, and have been used in clinical practice since 1959. Colistin methane sulfonate (CMS) was introduced as a less toxic form of polymyxin in 1961. Spectrum of activity narrow antibacterial spectrum (Gram negative bacilli) primarily used for infections with P. aeruginosa & A. baumannii. other susceptible organisms : E. coli, some Enterobacter spp, Haemophilus influenzae, Bordetella pertussis, Legionella pneumophila, Klebsiella spp, Salmonella spp, Shigella spp, and the majority of Stenotrophomonas maltophilia strains Spapen et al. Annals of Intensive Care 2011, 1:14. Li J, et al. Lancet Infect Dis 2006;6:589-601.

3. COLISTIN 1> the choice of antibiotic therapy 2> the extent of testing to determine the cause 3> the appropriate location of treatment (home, GW, or ICU) Spapen et al. Annals of Intensive Care 2011, 1:14. Li J, et al. Lancet Infect Dis 2006;6:589-601.

4. COLISTIN vs COLISTIN METHANESULFONATE (CMS) Li J, et al. Lancet Infect Dis 2006;6:589-601.

5. COLISTIN vs COLISTIN METHANESULFONATE (CMS) Expert Rev Anti Infect Ther. 2012;10(8):917-934.

6. CMS : NOT Stable in vitro or in vivo * Li J, et al. J Antimicrob Chemother 2003;52:987-992. Renal tubular secretion !! Renal tubular reabsorption !! CMS (124  52 min) vs Colistin (251  79 min) * Half life

7. COLISTIN : Adverse effects most common adverse effect of colistin dose-dependent wide range of nephrotoxicity rates : 8 ~ 58% a/w hematuria, proteinuria, & oliguria and ARF d/t ATN difficult to determine the relative contribution of colistin to development of ARF monitoring of renal function & dose adjustment is critical. Clin Infect Dis. 2009;48(12):1724. BMC Infect Dis. 2005;5:1.

8. COLISTIN : Adverse effects the proposed mechanism: noncompetitive myoneuronal pre- synaptic blockade of Ach release; the ability of colistin to modify or disrupt the lipid membrane may help to explain the toxic vulnerability of the highly lipid neurons. a/w facial & pph paresthesia, vertigo, visual disturbances, confusion, ataxia, and neuromuscular blockade, which can lead to respiratory failure or apnea Contributing factors: high doses, hypoxia, hypocalcemia, &renal disease Concomitant drug: other neurotoxic drugs (anesthetics, aminoglycosides, and paralytics), corticosteroids, narcotics, and/or muscle relaxants Spapen et al. Annals of Intensive Care 2011, 1:14. Li J, et al. Lancet Infect Dis 2006;6:589-601.

9. COLISTIN: THE RE-EMERGING ANTIBIOTIC 1> the choice of antibiotic therapy 2> the extent of testing to determine the cause 3> the appropriate location of treatment (home, GW, or ICU) Colistin was abandoned from clinical use in the 1970s because of significant renal and, to a lesser extent, neurological toxicity, including neuromuscular blockade.. Increasingly put forward as salvage or even 1st-line treatment for severe multidrug-resistant (MDR), Gram-negative bacterial infections, in particular Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. Despite large variations in dose and duration, relatively high clinical cure rates. Spapen et al. Annals of Intensive Care 2011, 1:14. Li J, et al. Lancet Infect Dis 2006;6:589-601.

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11. Clinical course Voriconazole Admission to ICU Admission to ICU Open lung biopsy Linezolid PBSCT post 64d 1 week 3 weeks 4 weeks 5weeks 6weeks 7weeks PBSCT 2nd PBSCT 2nd Post-transplantation course : BK viruria, CMV viremia/ pneumonitis, and GVHD of GI tract. Discharge CXR & chest CT : new bilateral nodular infiltrates c consolidation on Rt lung  r/o aspergillosis GW transfer GW transfer DAH interstitial pneumonia Colistin(CMS) IV Culture: MDR A. baumannii Weekness, dyspnea, tachypnea extremity pain ICU transfer ICU transfer Ampicillin/sulbctam CMS inhaled f/u chest CT : slow improvement GW transfer GW transfer ICU transfer ICU transfer

12. Discussion 1> the choice of antibiotic therapy 2> the extent of testing to determine the cause 3> the appropriate location of treatment (home, GW, or ICU) Our patient developed neuromuscular toxicity associated with the use of intravenous and, later, inhalational CMS, manifesting as apnea and respiratory failure. Neurotoxicity associated with colistin was reported more frequently when the drug was used decades ago. The reported incidence from the largest study(713 patients) was 7.3% in 1970s Recent reports have not described neurotoxicity associated with iv CMS, with the exception of in the cystic fibrosis population. The onset of symptoms usually occurred < 4 days after the commencement of therapy and resolved on drug discontinuation. CID 2010:50

13. Discussion 1> the choice of antibiotic therapy 2> the extent of testing to determine the cause 3> the appropriate location of treatment (home, GW, or ICU) In the current era, when the drug is most commonly administered to critically ill patients with multiple comorbidities, a direct causal relationship for respiratory failure is difficult to establish. Establishment of a relationship between the daily dosage of colistimethate, colistin levels, and neurological events is needed, and development of a tool to monitor neurological toxicity is essential. CID 2010:50

14. Discussion 1> the choice of antibiotic therapy 2> the extent of testing to determine the cause 3> the appropriate location of treatment (home, GW, or ICU) A screening tool focusing on assessment for adverse events and objective measurements of Forced Vital Capacity (FVC) may be helpful for early diagnosis of neurotoxicity. Calcium infusions and anti-histamines may have some benefit in reversing the paralysis, although definitive clinical data are not available. Continuous renal replacement therapy or hemodialysis may help in patients with acute renal failure or in patients with known toxic serum levels of colistin. CID 2010:50

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