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

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Presentation on theme: "Neutropenic Fever: Challenges and Treatment Dong-Gun Lee Div. of Infectious Diseases, Dept. of Internal Medicine, The Catholic Univ. of Korea."— Presentation transcript:

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 1 st onset of NF When using Glycopeptides…

3 Question (1) What is the most common pathogen during neutropenia in your institution in these days? 1.Pseudomonas aeruginosa 2.Escherichia coli 3.Staphylococcus aureus 4.Coagulase negative Staphylococci 5.viridans streptococci 6.fungi

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

5 Clin Infect Dis 2003;36: Epidemiology, US [SCOPE] Project

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 Korean J Intern Med 2011;26: Infect Chemother 2011;43: NA09-013

10 초기 항균요법 (2) No. (%) ReferenceRho et al.Rhee et al.Choi et al.Kim et al.Park et al. Period (year) HospitalABCDC Patientsleukemiaallo-HSCTacute leukemiacancerHSCT ProphylaxisNACotrimazole Nystatin gargle Ciprofloxacin, roxithromycin, fluconazole NACiprofloxacin, fluconazole/ itraconazole, TMP/SMX No. of MDI27 (100)78 (100)158 (100)42 (100)72 (100) Gram (+) bacteria11 (40.7)36 (46.2)75 (47.5)11 (26.2)25 (34.7) Streptococcus1 (3.7)-24 (15.2)2 (4.8)9 (12.5) CoNS4 (14.8)15 (19.2)20 (12.7)4 (9.5)7 (9.7) Staphylococcus aureus4 (14.8)-13 (8.2)3 (7.1)2 (2.8) Enterococcus2 (7.4)-14 (8.9)2 (4.8)6 (8.3) Gram (-) bacteria16 (59.3)42 (53.8)83 (52.5)31 (73.8)47 (65.3) Escherichia coli4 (14.8)-43 (27.2)2 (4.8)32 (44.4) Pseudomonas aeruginosa1 (3.7)-12 (7.6)5 (11.9)4 (5.6) Klebsiella pneumoniae6 (22.2)-12 (7.6)8 (19.0)4 (5.6) Enterobacter--5 (3.2)4 (9.5)3 (4.2) Acinetobacter baumanii2 (7.4)--2 (4.8)2 (2.8) Aeromonas hydrophila1 (3.7)-6 (3.8)-- Citrobacter freundii---2 (4.8)1 (1.4) Salmonella---4 (9.5)- Epidemiology, Korea

11 Catholic HSCT Center (Pre-engraftment) ’83 ~ ’88’89 ~ ’92’93 ~ ’96’98 ~ ’99’01 ~ ’02 No. of isolates G (+) CNS (6) S. aureus (4)S. epidermidis (10)Streptococcus (9) S. aureus (2)S. aureus (3)S. epidermidis (3)Streptococcus (5)CNS (7) Enterococcus (3)Enterococcus (2)E. faecalis (1)Staphylococcus (3)S.aureus (2) Streptococcus (2)Streptococcus (3) E. faecium (4)E. faccium (4) E. faecalis (2) Micrococcus (1) G (-) P. aeruginosa (11)P. aeruginosa (8)P. aeruginosa (6)E. coli (32) Klebsiella (2)Klebsiella (1)E. coli (5)Klebsiella (3)K. pneumoniae (4) E. coli (1) Enterobacter (5)Enterobacter (2)P. aeruginosa (4) Other (1)Others (2)Klebsiella (3)P. aeruginosa (1)Enterobacter (3) Others (5)Others (2)A. baumanii (2) Others (2) Epidemiology, Catholic BMT Center (Pre-engraftment Period) J Korean Med Sci 2006;21:

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

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

14 Organisms (n=243)Ward AWard BTotal (%) P value Gram (+) (n=122) (n=108)(n=14) S. aureus9211 (4.5) CoNS14014 (5.8) Viridans streptococci39 (18.6)5 (15.2)44 (18.1) S. pneumonia202 (0.8) Rothia mucilaginosa505 (2.1) Enterococcus spp (14.0) Corynebacterium spp.404 (1.6) Bacillus spp.303 (1.2) Others†505 (2.1) Gram (-) (n=119) (n=100)(n=17) E. coli58 (27.6)14 (42.4)72 (29.6) K. pneumonia28 (13.3)3 (9.1)31 (12.8) Pseudomonas spp.516 (2.5) Enterobacter spp.314 (1.6) Stenotrophomonas maltophilia404 (1.6) Others*202 (0.8) Fungus (n=2) Candida tropicalis101 (0.4) Trichosporon asahii101 (0.4) No. of microorganims Infect Chemother 2013;45: [in press] Epidemiology, Catholic BMT Center (‘09-’10)

15 Pathogens (No. of isolates) No. of isolates resistant to antibiotics/no. of isolates tested PCVOXACCLMEMCFTXCFPMGM CPFX or LVX VANIMPMAMP S. aureus (11)11/117/115/11 --4/116/110/11-- CoNS (14)14/1412/138/149/14--10/1413/140/14-- Streptococci other than pneumococcus (46) 24/46-11/4521/464/4517/45-0/10/45-0/2 S. pneumonia (2)0/2--2/20/ Enterococcus faecium (19)19/19- 17/ /197/1919/19 Enterococcus faecalis (15)6/15-15/1512/ /150/15 5/15 Gamella mibiliform (1)1/1-0/ Total no. of G (+)75/10819/2458/10566/1084/4817/4614/2552/627/10719/3424/36 % of resistance Resistance Patterns (GPC) Resistance Pattern, GPC

16 Pathogens (No. of isolates) No. of isolates resistant to antibiotics/no. of isolates tested ESBLAMCPIPCGMTOBCAZLVXSXTAZTNIMPMMRPN E. coli (72)22/6364/72 30/7233/7224/7265/7040/7223/720/72 K. pneumoniae (31)22/3131/3127/3118/3121/3122/3124/2920/3122/310/31 Pseudomonas spp. (6)--0/6 0/52/63/54/42/64/60/6 Enterobacter spp. (4)-4/4 0/4 1/4 3/41/40/4 S. maltophilia (4) /4 --- B. cepacia (1)-----0/1 -- C. indologenes (1)--1/1 0/11/1 Total no. of G (-)44/9499/10796/11449/11455/11350/11594/11467/11749/1145/1141/115 % of resistance Resistance Pattern, GNB

17 Antibiotics (susceptibility) Adults (≥ 20 years old) (n=140) Children (< 20 years old) (n=61) Penicillin57 (40.7)22 (36.1)0.535 Cefotaxime127 (90.7)39 (65.0)< Cefepime120 (85.7)39 (66.1)0.002 Vancomycin140 (100.0)61 (100.0)NA Linezolid140 (100.0)60 (98.4)0.303 Clindamycin121 (86.4)51 (83.6)0.601 Erythromycin78 (55.7)21 (34.4)0.006 Data from Catholic BMT Center [in press] Viridans Streptococci Bacteremia in NF

18 초기 항균요법 (1)  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. What is the major etiologic agents of neutropenic fever in Asia? What is the major etiologic agents of neutropenic fever in Asia?

19 Question (2) What is your strategy for the empirical Tx in 1 st onset of neutropenic fever? 1.Broad spectrum Cephalosporin monotherapy 2.Broad spectrum Penicillin monotherapy 3.Carbapenem monotherapy 4.Beta-lactam + Aminoglycoside 5.Beta-lactam + Quinolone 6.Double Beta-lactams

20 Question (3) Do you think ESBL producing organisms show higher mortality? 1.YES 2.NO

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

22 Ann Hematol 2013; [in press] ESBL vs. Non-ESBL BSI in NF No. (%) E. coliK. pneumoniae ESBL (n=15) Non-ESBL (n=72) ESBL (n=11) Non-ESBL (n=3) Age, median (range), yr44 (15-64)42 (17-74)39 (16-59)31 (23-42) Sex, M:F9:639:336:53:0 Underlying disease AML ALL MM Others* 10 (66.7) 2 (13.3) 1 (6.7) 2 (13.3) 33 (45.8) 31 (43.1) 4 (5.6) 5 (45.5) 4 (36.4) 0 (0.0) 2 (18.1) 1 (33.3) 0 (0.0) 2 (66.6) Undergoing therapy Chemotherapy HSCT 10 (66.7) 5 (33.3) 59 (81.9) 13 (18.1) 8 (72.7) 3 (27.3) 3 (100.0) 0 (0.0) 1 st set fever † 13 (86.7) 72 (100.0) 4 (36.3) 3 (100.0) Empirical therapy 3 rd generation cephalosporin Cefepime Piperacillin-tazobactam Carbapenem Aminoglycoside combination 13 (87.0) 2 (13.0) 0 (0.0) 14 (93.3) 60 (83.0) 3 (4.0) 8 (11.1) 1 (1.4) 71 (98.6) 4 (36.0) 1 (9.0) 0 (0.0) 6 (54.5) 5 (45.5) 1 (33.3) 0 (0.0) 1 (33.3) 3 (100.0)

23 Ann Hematol 2013; [in press] Susceptibility

24 Characteristics Unadjusted OR (95% CI) p- value Adjusted OR (95% CI) p- value Disease status, non-remitted ( ) History of ICU admission within prior 3 months ( ) Hospital stay for >2 weeks within the preceding 3 months7.874 ( ) ( )0.008 Previous antibiotics use within the preceding 4 weeks Broad-spectrum cephalosporins ( ) ( )0.008 β-lactam/β-lactamase inhibitors ( ) Aminoglycosides ( ) Glycopeptides ( ) Factors associated with ESBL BSI Ann Hematol 2013; [in press]

25 No. (%) E. coliK. pneumoniae ESBL (n=15) Non-ESBL (n=72) P ESBL (n=11) Non-ESBL (n=3) P Early response (72hr) CR PR Treatment failure 5 (33.3) 9 (60.0) 1 (6.7) 29 (40.3) 41 (56.9) 2 (2.8) NS 2 (18.2) 6 (54.5) 3 (27.3) 1 (33.3) 2 (66.7) 0 (0.0) NS Mortality Overall at 7 day at 30 day Bacteremia attributable 0 (0.0) 1 (6.7) 1 (1.4) 3 (4.2) NS 0 (0.0) 2 (20.0) 2 (22.0) 0 (0.0) 1 (33.3) 0 (0.0) NS S Ann Hematol 2013; [in press] Factors associated with Mortality

26 CharacteristicsUnadjusted OR (95% CI)p-valueAdjusted OR (95% CI) * p-value ESBL production3.227 ( ) ( )0.602 Inappropriate empirical antimicrobial therapy4.286 ( ) ( )0.699 Disease status, non-remitted4.843 ( ) * ( )0.305 Duration of neutropenia >3 weeks7.731 ( ) ( )0.248 Septic shock at presentation ( )< ( )0.036 Infecting organism, Klebsiella pneumoniae8.300 ( ) ( )0.046 Copathogen7.731 ( ) ( )0.554 Ann Hematol 2013; [in press]

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

28 Role of Aminoglycoside in NF (2) Ann Hematol 2012;91: [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: [Australian Guideline]

30 초기 항균요법 (1)  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… in high incidence of ESBL producing Enterobacteriaceae area… in high incidence of ESBL producing Enterobacteriaceae area…

31 Question (4) What do you use mainly for MRSA bacteremia in NF? 1.Vancomycin 2.Teicoplanin 3.Arbekacin 4.Linezolid 5.Fusidic acid 6.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

34 What can we learn from studies comparing Linezolid with Vancomycin in neutropenic patients when vancomycin doses are not optimized? Clin Infect Dis 2006;42: 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

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

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

37 Empirical Teicoplanin in Neutropenic Fever in Korea: Comments TPV 400 mg qd and then 200 mg qd ; is that enough? 1.Only one strains of S. aureus, 2.CNS can be affected by catheter removal 3.Four out of 6 strains of E. faecium were vancomycin resistant. 4.Viridans streptococci would be susceptible with cefepime. Infect Chemother 2004;36:83-91

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

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

40 Yonsei Med J 2011;52:616-23

41 초기 항균요법 (1)  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 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. When using glycopeptide to NF patients, Consider… When using glycopeptide to NF patients, Consider…

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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