A snapshot of polymyxin use around the world South America Alexandre P. Zavascki Infectious Diseases Service, Hospital de Clínicas de Porto Alegre Medical School, Federal University of Rio Grande do Sul - Brazil 1
A snapshot of polymyxin use of polymyxins in South America Focus on Brazil 1. Is the polymyxin in your setting used empirically or as definitive therapy when susceptibilities are known? 2. If empiric therapy, in what type of conditions is it used? 3. If definitive therapy, for what organisms and in what conditions? What are the mechanisms leading to bacterial resistance (if known)? 4. Is the polymyxin used in combination or as monotherapy? If combination therapy, combined with what? 5. What dosing regimen of polymyxin is typically used? Is a loading dose given? 6. Is there local experience on toxicity - its extent and risk factors for it? 7. What is the typical duration of polymyxin use? 8. What is the typical outcome of polymyxin use in your setting? 9. Is resistance to the polymyxins observed in your setting? 2
Many reports of carbapenemases in South American countries Few data on polymyxins use, except Brazil VIM KPC OXA NDM OXA KPC VIM KPC OXA KPC VIM KPC OXA NDM VIM NDM 3
Colistin Argentina Chile and Bolivia Polymyxin B Colombia 4
Brazil Largest Country Polymyxin B 60 80% Colistin 20 40 % 5
Polymyxins Use in Brazil Mid 90 s Small outbreaks CRPA / CRAB 3 major epidemics large scale polymyxins 2000: SPM-1 MbL- P. aeruginosa 2004: OXA-23-producing A. baumannii 2009: KPC-2-producing Enterobacteiraceae Gales et al. J Antimicrob Chemother 2003. Zavascki et al. J Antimicrob Chemother 2005. Dalla-Costa et al. J Clin Microbiol 2003. Prates et al. Epidemiol Infect 2011. Monteiro et al. Antimicrob Agents Chemother 2009. Zavascki et al. Int J Infect Dis 2009. 6
1. Polymyxins Empirically or as definitive therapy? Definitive, when susceptibilities were known ~2004 Epidemics of OXA-23 A. baumannii empirically in many hospitals Emergence of KPC-2 Enterobacteriaceae empirically in most hospitals 7
First empirical prescriptions after failure with carbapenems more common conditions After 2005... 2. Empiric therapy Which conditions is it used? Empirical use regardless the previous use of any antimicrobial agent 8
3. Organisms and conditions? SPM-1 (IMP-1)- P. aeruginosa Many OXA-23 (OXA-143)- A. baumannii - HAP / VAP KPC-2 Enterobacteriaceae - UTI Resistance mechanisms not routinely evaluated 9
4. Polymyxins Combination or monotherapy? Until the emergence of KPC-2 monotherapy Combination therapy more frequently almost always for severe infections High dose / extended infusion carbapenem Tigecycline (200mg LD 100mg bid) Aminoglycoside Three drugs 10
First years fear of toxicity Low doses prescribed Better clinical experience and understanding of toxicity + Improved knowledge of PK and PK/PD Highest recommended doses Loading doses still not commonly given More common for CMS 5. Polymyxins Dosing regimens 11
Polymyxin B: 2.5 3.0 mg/kg/day 12h Colistin: Garonzik et al.: 6MU to 9MU CMS 8h (12MU/day) 5. Polymyxins Dosing regimens 12
~ 50% some degree of renal dysfunction ~ 1/4 Mild (>50% <100% increase creatinine level) ~ 1/2 Moderate (> 100%) ~ 1/4 (10% of all) Severe (RRT) Main risk factor Daily Dose, but not cumulative dose Highly variable! 6. Toxicity extent and risk factors Less frequent? Elias et al. J Antimicrob Chemother 2010. 13
2009-2011 6. Toxicity extent and risk factors CMS (n=36) Polymyxin B (n=96) AKI - Any grade 15 42% 23 24% AKIN 1 4 11% 13 14% AKIN 2 6 17% 9 9% AKIN 3 5 14% 1 1% Dialysis 2 6% 1 1% Tuon et al. Unpublished data 14
7. Duration of polymyxin treatment 14 days most infections Pneumonia BSI 7 days non-complicated UTI 15
First years very poor outcomes Delay in initiation? Low doses? Monotherapy? 8. Polymyxins Outcomes Outcomes improving in latter years? Mortality rates STILL HIGH in critical patients 16
2003 2009: 276 patients 218 (79%) ICU pts 70 60 50 40 30 20 10 0 66.4 8. Polymyxins Outcomes Mortality % 63.2 47.9 <150 mg 150-199 mg 200 mg Elias et al. J Antimicrob Chemother 2010. P = 0.03 17
2009-2010 polymyxin B VAP A. baumannii or P. aeruginosa monotherapy 30-day mortality = 53% 2009-2011 8. Polymyxins Outcomes Polymyxin B 30-day mortality = 54% CMS 30-day mortality = 50% Rigatto et al. Infection 2013. Tuon et al. Unpublished data. 18
9. Is resistance to the polymyxins observed in your setting? Resistance rates highly variable low 5% of CR GNB Increasing in some centers, especially in CRE 10-15% 19
Concluding Remarks Very common drugs in most Brazilian institutions No perspective for decreasing polymyxins use NDM-1 detected in Brazil 20
Afonso Barth - BR Alan Forrest - EU Cornelia Landersdorfer - AU Ana Gales - BR Jian Li - AU Marines Martinho - BR The National Council for Scientific and Technological Development (CNPq) Acknowledgements Roger Nation - AU Vanessa Ribeiro - BR Jaime Rocha - BR Jorge Sampaio - BR Ana Sandri - BR Felipe Tuon - BR Federal University of Rio Grande do Sul Hospital de Clínicas de Porto Alegre 21