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 ESBL producing Enterobacteriaceae ; Etiologic microorganisms & Resistance ESBL producing Enterobacteriaceae ; Empirical therapy as 1st onset of NF When using Glycopeptides…

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

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

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

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

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

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

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

Epidemiology, Korea 초기 항균요법 (2) No. (%) Reference Rho et al. Rhee et al. Choi et al. Kim et al. Park et al. Period (year) 1996-2001 1996-2003 1998-1999 1999-2000 2001-2002 Hospital A B C D Patients leukemia allo-HSCT acute leukemia cancer HSCT Prophylaxis NA Cotrimazole Nystatin gargle Ciprofloxacin, roxithromycin, fluconazole Ciprofloxacin, fluconazole/ itraconazole, TMP/SMX No. of MDI 27 (100) 78 (100) 158 (100) 42 (100) 72 (100) Gram (+) bacteria 11 (40.7) 36 (46.2) 75 (47.5) 11 (26.2) 25 (34.7) Streptococcus 1 (3.7) - 24 (15.2) 2 (4.8) 9 (12.5) CoNS 4 (14.8) 15 (19.2) 20 (12.7) 4 (9.5) 7 (9.7) Staphylococcus aureus 13 (8.2) 3 (7.1) 2 (2.8) Enterococcus 2 (7.4) 14 (8.9) 6 (8.3) Gram (-) bacteria 16 (59.3) 42 (53.8) 83 (52.5) 31 (73.8) 47 (65.3) Escherichia coli 43 (27.2) 32 (44.4) Pseudomonas aeruginosa 12 (7.6) 5 (11.9) 4 (5.6) Klebsiella pneumoniae 6 (22.2) 8 (19.0) Enterobacter 5 (3.2) 3 (4.2) Acinetobacter baumanii Aeromonas hydrophila 6 (3.8) Citrobacter freundii 1 (1.4) Salmonella

Epidemiology, Catholic BMT Center (Pre-engraftment Period) Catholic HSCT Center (Pre-engraftment) Epidemiology, Catholic BMT Center (Pre-engraftment Period) ’83 ~ ’88 ’89 ~ ’92 ’93 ~ ’96 ’98 ~ ’99 ’01 ~ ’02 No. of isolates 13 14 8 24 25 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) 15 12 40 47 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) E. coli (1) Enterobacter (5) Enterobacter (2) P. aeruginosa (4) Other (1) Others (2) P. aeruginosa (1) Enterobacter (3) Others (5) A. baumanii (2) J Korean Med Sci 2006;21:199-207

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

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

Epidemiology, Catholic BMT Center (‘09-’10) No. of microorganims Epidemiology, Catholic BMT Center (‘09-’10) Organisms (n=243) Ward A Ward B Total (%) P value Gram (+) (n=122) (n=108) (n=14) S. aureus 9 2 11 (4.5) 0.649 CoNS 14 14 (5.8) 0.227 Viridans streptococci 39 (18.6) 5 (15.2) 44 (18.1) 0.635 S. pneumonia 2 (0.8) Rothia mucilaginosa 5 5 (2.1) Enterococcus spp. 27 7 34 (14.0) 0.198 Corynebacterium spp. 4 4 (1.6) Bacillus spp. 3 3 (1.2) Others† Gram (-) (n=119) (n=100) (n=17) E. coli 58 (27.6) 14 (42.4) 72 (29.6) 0.083 K. pneumonia 28 (13.3) 3 (9.1) 31 (12.8) Pseudomonas spp. 1 6 (2.5) Enterobacter spp. Stenotrophomonas maltophilia Others* Fungus (n=2) Candida tropicalis 1 (0.4) Trichosporon asahii Infect Chemother 2013;45: [in press]

Resistance Patterns (GPC) Resistance Pattern, GPC Pathogens (No. of isolates) No. of isolates resistant to antibiotics/no. of isolates tested PCV OXAC CLM EM CFTX CFPM GM CPFX or LVX VAN IMPM AMP S. aureus (11) 11/11 7/11 5/11 - 4/11 6/11 0/11 CoNS (14) 14/14 12/13 8/14 9/14 10/14 13/14 0/14 Streptococci other than pneumococcus (46) 24/46 11/45 21/46 4/45 17/45 0/1 0/45 0/2 S. pneumonia (2) 2/2 Enterococcus faecium (19) 19/19 17/19 7/19 Enterococcus faecalis (15) 6/15 15/15 12/15 14/15 0/15 5/15 Gamella mibiliform (1) 1/1 Total no. of G (+) 75/108 19/24 58/105 66/108 4/48 17/46 14/25 52/62 7/107 19/34 24/36 % of resistance 69.4 79.2 55.2 61.1 8.3 37.0 56.0 83.9 6.5 55.9 66.7

Resistance Pattern, GNB Pathogens (No. of isolates) No. of isolates resistant to antibiotics/no. of isolates tested ESBL AMC PIPC GM TOB CAZ LVX SXT AZTN IMPM MRPN E. coli (72) 22/63 64/72 30/72 33/72 24/72 65/70 40/72 23/72 0/72 K. pneumoniae (31) 22/31 31/31 27/31 18/31 21/31 24/29 20/31 0/31 Pseudomonas spp. (6) - 0/6 0/5 2/6 3/5 4/4 4/6 Enterobacter spp. (4) 0/4 1/4 3/4 S. maltophilia (4) B. cepacia (1) 0/1 C. indologenes (1) 1/1 Total no. of G (-) 44/94 99/107 96/114 49/114 55/113 50/115 94/114 67/117 5/114 1/115 % of resistance 46.8 92.5 84.2 43.0 48.7 43.5 82.3 57.3 4.4 0.9

Viridans Streptococci Bacteremia in NF Antibiotics (susceptibility) Adults (≥ 20 years old) (n=140) Children (< 20 years old) (n=61) Penicillin 57 (40.7) 22 (36.1) 0.535 Cefotaxime 127 (90.7) 39 (65.0) < 0.001 Cefepime 120 (85.7) 39 (66.1) 0.002 Vancomycin 140 (100.0) 61 (100.0) NA Linezolid 60 (98.4) 0.303 Clindamycin 121 (86.4) 51 (83.6) 0.601 Erythromycin 78 (55.7) 21 (34.4) 0.006 Data from Catholic BMT Center [in press]

What is the major etiologic agents of neutropenic fever in Asia? 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.

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

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

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

ESBL vs. Non-ESBL BSI in NF E. coli K. pneumoniae ESBL (n=15) Non-ESBL (n=72) (n=11) (n=3) Age, median (range), yr 44 (15-64) 42 (17-74) 39 (16-59) 31 (23-42) Sex, M:F 9:6 39:33 6:5 3:0 Underlying disease AML ALL MM Others* 10 (66.7) 2 (13.3) 1 (6.7) 33 (45.8) 31 (43.1) 4 (5.6) 5 (45.5) 4 (36.4) 0 (0.0) 2 (18.1) 1 (33.3) 2 (66.6) Undergoing therapy Chemotherapy HSCT 5 (33.3) 59 (81.9) 13 (18.1) 8 (72.7) 3 (27.3) 3 (100.0) 1st set fever† 13 (86.7) 72 (100.0) 4 (36.3) Empirical therapy 3rd generation cephalosporin Cefepime Piperacillin-tazobactam Carbapenem Aminoglycoside combination 13 (87.0) 2 (13.0) 14 (93.3) 60 (83.0) 3 (4.0) 8 (11.1) 1 (1.4) 71 (98.6) 4 (36.0) 1 (9.0) 6 (54.5) Ann Hematol 2013; [in press]

Susceptibility Ann Hematol 2013; [in press]

Factors associated with ESBL BSI Characteristics Unadjusted OR (95% CI) p-value Adjusted OR (95% CI) Disease status, non-remitted 3.569 (1.375-9.263) 0.009 - 0.110 History of ICU admission within prior 3 months 13.455 (1.429-126.686) 0.023 0.162 Hospital stay for >2 weeks within the preceding 3 months 7.874 (2.177-28.475) 0.002 5.887 (1.572-22.041) 0.008 Previous antibiotics use within the preceding 4 weeks   Broad-spectrum cephalosporins 9.397 (2.584-34.179) 0.001 6.186 (1.616-23.683) β-lactam/β-lactamase inhibitors 4.226 (1.040-17.173) 0.044 0.083 Aminoglycosides 6.088 (1.906-19.447) 0.565 Glycopeptides 8.690 (1.572-48.056) 0.013 0.436 Ann Hematol 2013; [in press]

Factors associated with Mortality No. (%) E. coli K. pneumoniae ESBL (n=15) Non-ESBL (n=72) P (n=11) (n=3) 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) Mortality Overall at 7 day at 30 day Bacteremia attributable 1 (1.4) 3 (4.2) 2 (20.0) 2 (22.0) S Ann Hematol 2013; [in press]

Factors associated with Mortality Characteristics Unadjusted OR (95% CI) p-value Adjusted OR (95% CI) * ESBL production 3.227 (0.745-13.982) 0.117 0.735 (0.231-2.338) 0.602 Inappropriate empirical antimicrobial therapy 4.286 (0.393-46.785) 0.233 1.401 (0.254-7.722) 0.699 Disease status, non-remitted 4.843 (1.131-20.735)* 0.034 1.990 (0.534-7.416) 0.305 Duration of neutropenia >3 weeks 7.731 (1.465-40.787) 0.016 1.757 (0.675-4.570) 0.248 Septic shock at presentation 43.500 (7.180-263.552) <0.001 2.946 (1.075-8.073) 0.036 Infecting organism, Klebsiella pneumoniae 8.300 (1.791-38.459) 0.007 3.593 (1.023-12.628) 0.046 Copathogen 1.335 (0.513-3.471) 0.554 따라서, 이번연구에서는 ESBL production이 mortality에는 관련이 없었다. 아마도 aminoglycoside combination 때문이 아닐까?? Ann Hematol 2013; [in press]

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

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

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]

in high incidence of ESBL producing Enterobacteriaceae area… 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…

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

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

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

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

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

N= 119, Hospital acquired infection, bacteremia 35%, pneumonia 45% 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

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

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

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

Yonsei Med J 2011;52:616-23

When using glycopeptide to NF patients, Consider… 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.

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

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