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Neutropenic Fever: Challenges and Treatment

Neutropenic Fever: Challenges and Treatment. Dong-Gun Lee Div. of Infectious Diseases, Dept. of Internal Medicine, The Catholic Univ. of Korea. Contents. Epidemiology Focus in Asia ; Etiologic microorganisms & Resistance ESBL producing Enterobacteriaceae

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Neutropenic Fever: Challenges and Treatment

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  1. Neutropenic Fever: Challenges and Treatment Dong-Gun Lee Div. of Infectious Diseases, Dept. of Internal Medicine, The Catholic Univ. of Korea

  2. Contents • Epidemiology Focus in Asia ; Etiologic microorganisms & Resistance • ESBL producing Enterobacteriaceae ; Empirical therapy as 1st onset of NF • When using Glycopeptides…

  3. Question (1) What is the most common pathogen during neutropenia in your institution in these days? Pseudomonas aeruginosa Escherichia coli Staphylococcus aureus Coagulase negative Staphylococci viridans streptococci fungi

  4. Epidemiology, EU Clin Infect Dis 2005;40:S240-5

  5. Epidemiology, US [SCOPE] Project Clin Infect Dis 2003;36:1103-10

  6. Epidemiology, Malaysia (2004) Int J Infect Dis 2007;11:513-7

  7. Epidemiology, Taiwan (‘99-02) Chemotherapy 2005;51:147-53

  8. Epidemiology, Taiwan (‘02-06) Epidemiol Infect 2010;138:1044;51

  9. NA09-013 Korean J Intern Med 2011;26:220-52 Infect Chemother 2011;43:285-321

  10. 초기 항균요법 (2) Epidemiology, Korea

  11. Catholic HSCT Center (Pre-engraftment) Epidemiology, Catholic BMT Center (Pre-engraftment Period) J Korean Med Sci 2006;21:199-207

  12. Catholic HSCT Center (Pre-engraftment) Epidemiology, Catholic BMT Center GNB

  13. Catholic HSCT Center (Pre-engraftment) Epidemiology, Catholic BMT Center GPC

  14. No. of microorganims Epidemiology, Catholic BMT Center (‘09-’10) Infect Chemother 2013;45: [inpress]

  15. Resistance Patterns (GPC) Resistance Pattern, GPC

  16. Resistance Pattern, GNB

  17. Viridans Streptococci Bacteremia in NF Data from Catholic BMT Center [in press]

  18. 초기 항균요법 (1) What is the major etiologic agents of neutropenic fever in Asia? • In contrast to western countries, Gram-negative bacteria are the prevailing etiological agents of infections in neutropenic fever patients in Asia. • Because of the reported etiologic bacteria and their antimicrobial resistance rates causing neutropenic fever vary widely by times, area, even wards, every hospital should continue to monitor the changing patterns of etiology and adjustment of empirical antibiotics may be necessary.

  19. Question (2) What is your strategy for the empirical Tx in 1st onset of neutropenic fever? Broad spectrum Cephalosporin monotherapy Broad spectrum Penicillin monotherapy Carbapenem monotherapy Beta-lactam + Aminoglycoside Beta-lactam + Quinolone Double Beta-lactams

  20. Question (3) Do you think ESBL producing organisms show higher mortality? YES NO

  21. Mortality: ESBL vs. Non-ESBL BSI J Antimicrob Chemother 2012;67:1311-20

  22. ESBL vs. Non-ESBL BSI in NF Ann Hematol 2013; [inpress]

  23. Susceptibility Ann Hematol 2013; [inpress]

  24. Factors associated with ESBL BSI Ann Hematol 2013; [inpress]

  25. Factors associated with Mortality Ann Hematol 2013; [inpress]

  26. Factors associated with Mortality Ann Hematol 2013; [inpress]

  27. Role of Aminoglycoside in NF (1) EJC Suppl 2007;5:13-22 [ECIL-1]

  28. Role of Aminoglycoside in NF (2) Ann Hematol 2012;91:1161-74 [DGHO]

  29. Role of Aminoglycoside in NF (3) • While the addition of an aminoglycoside has not been shown to be of clinical advantage compared with beta-lactam monotherapy in systematic reviews, there are particular circumstances where the choice of aminoglycoside may be important. These include severe sepsis where there is a risk of resistance in Gram-negative bacilli and in Pseudomonas infection. Intern Med 2011;41:90-101 [Australian Guideline]

  30. 초기 항균요법 (1) in high incidence of ESBL producing Enterobacteriaceae area… • We may still use the beta-lactam + aminoglycoside combination strategy for empirical therapy of NF. When ESBL is not proven, aminoglycoside is only used for 3-5 days. • Adjustment for inadequate empirical therapy can lead to a reduction of mortality. For example, combination therapy with aminoglycoside…

  31. Question (4) What do you use mainly for MRSA bacteremia in NF? Vancomycin Teicoplanin Arbekacin Linezolid Fusidic acid Others

  32. PKs in Neutropenia • Reduced serum, tissue, and body fluid concentrations of antibacterial agents have been reported in neutropenic patients and animal models, potentially reducing the bactericidal activities of these agents. • PK changes in neutropenic patients are probably not only related to neutropenia per se, but also to the severity of sepsis, as has been in ICU patients.  host defense mechanism… Lancet Infect Dis 2008;8:612-20

  33. PK of Glycopeptides in Neutropenia Lancet Infect Dis 2008;8:612-20

  34. What can we learn from studies comparing Linezolid with Vancomycin in neutropenic patients when vancomycin doses are not optimized? • PK of vancomycin therapy in neutropenic patients is different. • ; 3-fold increases of initial Vd, shorted half-life (vs. healthy • volunteer) • 2. Achievement of trough serum conc. ≥15 mg/L? • 3. T>MIC 100% • 4. 1 g iv q12hrs fixed dose  30 mg/kg/day Clin Infect Dis 2006;42:1813-4

  35. Vancomycin TDM Consensus Am J Health Syst Pharm 2009;66:82-98

  36. Continuous vs. Intermittent Infusion of Vancomycin in Severe Staphylococcal Infection France, Prospective study, CIV (plateau 20-25 mg/L), IIV (trough 15-20 mg/L) N= 119, Hospital acquired infection, bacteremia 35%, pneumonia 45% Antimicrob Agents Chemother 2001;45:2460-7

  37. Empirical Teicoplanin in Neutropenic Fever in Korea: Comments TPV 400 mg qd and then 200 mg qd ; is that enough? • Only one strains of S. aureus, • CNS can be affected by catheter removal • Four out of 6 strains of E. faecium were vancomycin resistant. • Viridans streptococci would be susceptible with cefepime. Infect Chemother 2004;36:83-91

  38. Loading Dose of Teicoplanin J Antimicrob Chemother 2003;51:971-5

  39. Teicoplanin Dose in Acute Leukemia and Febrile Neutropenia H : q12h, 800-400-600-400-400-400 S : 400 mg q12hrs (×3), 400 mg q24h Clin Pharmacokinet 2004;43:405-15

  40. Yonsei Med J 2011;52:616-23

  41. 초기 항균요법 (1) When using glycopeptide to NF patients, Consider… • PK of glycopeptides in neutropenic patients is different with that of normal volunteers. We need their PK data!!! • may need higher doses than usual • Vancomycin trough concentrations 15-20 mg/L or AUC/MIC >400 would be required in neutropenic fever as well as in severe staphylococcal infection. • Teicoplanin PK/PD magnitude for neutropenic fever is not established yet (trough >10 or 20 mg/L, AUC/MIC >345??). However, TDM would be needed for monitoring TAR. Teicoplanin dose would be needed more than we usually prescribe.

  42. Summary • Etiology of NF is different according to the area, time, even the wards in the same hospital.  We need to continue monitoring the changing patterns. • ESBL producing organisms are common. High index of suspicion (prior use of beta-lactams, Hx of long hospital stay…) is important. For empirical Tx against ESBL organisms, consider the susceptibility patterns and adjust for inadequate antibiotics… • PK of glycopeptides in neutropenic patients is different with that of normal volunteers.  We need their PK data!!! Population PK

  43. Thank You for Your Attention

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