Infection control for neutropenic cancer patients : the use of prophylactic antibiotics Jean A. Klastersky Institut Jules Bordet, Université Libre de Bruxelles (ULB) Brussels, Belgium
Complications and mortality associated with febrile neutropenia No Bacteremia Bacteremia Total Complications Deaths Total Complications Deaths Solid tumors 784 60 (8 %) 25 (3 %) Hematological cancer 859 111 (13 %) 32 (4 %) 135 30 (22 %) 17 (13 % ) 364 76 (21 %) 32 (9 %) J. Klastersky et al., 2007 2
Complications associated with febrile neutropenia Hypotension : systolic blood pressure less than 90 mmhg or need for pressor support to maintain blood pressure Respiratory failure : arterial oxygen pressure less than 60mmHg while breathing room air or need for mechanical ventilation Disseminated intravascular coagulation Confusion or altered mental state Congestive cardiac failure seen on chest X-ray and requiring treatment Bleeding severe enough to require transfusion Arrhythmia or ECG changes requiring treatment Renal failure requiring investigation and/or treatment with IV fluids, dialysis, or any other intervention J. Klastersky et al., 2000 3
Cost of febrile neutropenia Initial hospitalization Initial hospitalization plus all downstream neutropenia care 2.010 $ 14.407 $ D. Weyckler et al., 2008 4
Use of oral antibiotics in protected units environment : clinical effectiveness and role in the emergence of antibiotic-resistant strains «the incidence of proven infection was significantly reduced» «no advantage of isolation in addition to antibiotics could be detected» «bacteria isolated from decontamined patients were considerably more resistant» J. Klastersky et al., 1973 5
Infection-control interventions for cancer patients after chemotherapy : a systematic review and meta-analysis «protective isolation, including air quality control, prophylactic antibiotics and barrier isolation (29 studies) brought about a significant reduction in all-cause mortality : risk ratio 0.60» «inclusion of prophylactic antibiotics in the intervention was necessary to show the effect on mortality» A. Schlesinger et al., 2009 6
Occurrence of infections among placebo and trimethoprim-sulfamethoxazole (TMP-SXT)-treated patients Treatment group Total N of Patients No (%) Patients with Any Infection Bacteremia Placebo 165 64 (39) 32 (19) * TMP-SXT 177 46 (26) 22 (12) * p = 0.016 * P = 0.106 (p = 0.005 if patients with acute leukemia were excluded) EORTC Antimicrobial Therapy Project Group 1984 7
Prophylaxis with fluoroquinolones (Levofloxacin) in patients with expected neutropenia (adapted from L. Leibovici et al., 2006) Patients Acute leukemia and stem cell transplantation* Febrile neutropenia Bacterial Infection Solid Tumors and Lymphomas Febrile Neutropenia Bacterial Infection Relative Risk 0.76 0.56 0.71 0.82 Absolute Risk in the Control Group 85 39 15 42 N of treated Patients needed to prevent 1 Event * G. Bucaneve et al., 2005 M. Cullen et al., 2005 4 5 23 13 8
Deaths caused by infection in patients receiving prophylaxis for febrile neutropenia Levofloxacin Placebo P value Bucaneve et al. (2005) 10 / 373 (2.8 %) 18 / 363 (4.9 %) 0.15 Cullen et al. (2005) 4 / 781 (0.5 %) 3 / 784 (0.3 %) NS 9
Meta-analysis of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in patients with solid tumors or/and lymphomas (3.493 patients) Infection-related mortality Absolute Occurrence Relative Risk Reduction 1.5 % ( 2.8 %) 45 % (p = 0.018) Febrile neutropenia 22.4 % ( 39.5 %) 46 % (p < 0.0001) N. Kuderer et al., 2007 10
Meta-analysis of prophylaxis with granulocyte colonystimulating factors (G-CSF and GM-CSF) on febrile neutropenia and mortality autologous and allogeneic stem cell transplantation (2.669 patients) Relative Risk Reduction Documented infections 13 % (p = 0.05) Duration parenteral antibiotics - 1.39 days (p = 0.02) Infection-related mortality 24 % (p = 0.4) Grade 2-4 GVHD 0 % (p = 0.8) Treatment-related mortality 0 % (p = 0.9) A. Dekker et al., 2006 11
Prophylactic antibiotics or G-CSF for the prevention of infections and improvement of survival in cancer patients undergoing chemotherapy : The Cochrane Collaboration «there is no evidence for or against antibiotics compared to G(M)-CSF s for prevention of infections in cancer patients» C. Herbst et al., 2009 12
Bacterial isolates from cases of bacteremia due to a single organism Trial Total n of isolates Gram-negative Gram-positive I: 1973-1976 145 103 (71 %) 42 (29 %) II: 1977-1980 111 74 (67 %) 37 (33 %) III: 1980-1983 141 83 (59 %) 58 (41 %) IV: 1983-1985 219 129 (59 %) 90 (41 %) V: 1986-1988 213 78 (37 %) 135 (63 %) VIII: 1989-1991 151 47 (31 %) 104 (69 %) IX: 1991-1993 161 53 (33 %) 108 (67 %) EORTC International Antimicrobial Therapy Cooperative Group, 1999 13
Gram-positive organisms isolated during trial VIII Organism N isolated Streptococcus species 57 Viridans group 44 Group D 5 Streptococcus pneumoniae 4 Other 4 Coagulase-negative staphylococci 49 Staphylococcus aureus 20 Corynebacterium species 5 Other gram-positive organisms 3 EORTC International Antimicrobial Therapy Cooperative Group, 1999 14
«New» gram-positive pathogens in patients with neutropenia Viridans streptococci e.g., Streptococcus mitis, Streptococcus milleri Leuconostoc species Enterococcus species, especially vancomycin-resistant Corynebacterium jeikeium, Corynebacterium urealyticum Rhodococcus equi Stomatococcus mucilaginosus Lactobacillus rhamnosus Bacillus cereus Clostridium septicum, Clostridium tertium S.H. Zinner, 1999 15
«New» gram-negative pathogens in patients with neutropenia Stenotrophomonas (Xanthomonas, Pseudomonas) maltophilia Alteromonas (Pseudomonas) putrifaciens Legionella pneumophila, Legionella micdadei Vibrio parahaemolyticus Capnocytophaga species Alcaligenes xylosoxidans Chryseobacterium meningosepticum Burkholderia cepacia Fusobacterium nucleatum Leptotrichia buccalis Methylobacterium species Moraxella-like organisms S.H. Zinner, 1999 16
Antibiotic-resistant bugs in the 21st century a clinical super-challenge «we have come almost full circle and arrived at a point as frightening as the preantibiotic era : for patients infected with multidrugresistant bacteria, there is no magic bullet» C.A. Arias and B.E. Murray, 2009 17
Bacteremia due to viridans streptococci that are highly resistant to penicillin : increase among neutropenic patients with cancer (260 episodes of bacteremia) «rates of bacteremia due to highly penicillinresistant increased significantly from zero (1987) to 17 episodes (1992) per 1.000 admissions (p = 0.003)» «the administration of β-lactam antibiotics during the 2 previous weeks was the only factor significantly associated» J. Carratala et al., 1995 18
Use of fluoroquinolone prophylaxis and frequency of fluoroquinolone-resistant bacteremia isolates in neutropenic patients with cancer Variable 1983-1985 1986-1990 1991-1993 Patients given prophylaxis/all patients (%) Prophylaxis 3/219 (1.4) 228/694 (33) 318/706 (45) Isolate Escherichia coli Coagulase-negative staphylococci Pseudomonas aeruginosa Klebsiella pneumoniae Fluoroquinolone-resistant strains/strains tested (%) 0/26 0/22 1/25 (4) 0/3 0/66 44/172 (26) 1/39 (3) 1/17 (6) A. Cometta et al., 1994 11/40 (28) 23/38 (61) 1/13 (8) 1/13 (8) 19
Emergence of fluoroquinolone-resistant Escherichia coli at a cancer center : incidence of fluoroquinolone-resistant E. coli per yearly number of discharges from the medical service Year a P = 0.03 b P = 0.17 Incidence (per 10.000 discharges) Leukemia Other diseases P value 1988 69.2 a < 1.5 b 0.002 1989 80.6 3.7 0.008 1990 35.6 3.6 0.13 1991 153.8 3.8 0.00003 1992 327.3 a 3.6 b < 0.00001 W.V. Kern et al., 1994 20
Emergence of fluoroquinolone-resistant Escherichia coli at a cancer center «bacteremia increased from < 0.5 % in 1988-1989 and 0.8 % in 1990-1991 to 4.5 % in 1992-1993 (p < 0.01)» «MIC raised between 8-16 µg/ml and indicated resistance to TMP/SXT, ampicillin, doxycycline and chloramphenicol» «4 genotypes were identified, suggesting both independant development and horizontal spread» W.V. Kern et al., 1994 21
Fluoroquinolone resistance of Escherichia coli at a cancer center : epidemiologic evolution and effects of discontinuing prophylactic fluoroquinolone use in neutropenic patients with leukemia Resistance Pre-intervention (1995-1997) Discontinuation of fluoroquinolones (1998) Post-intervention (1999) rate > 50 % 15 % > 50 % E. coli bacteremia 8 % 20 % * 9 % * p < 0.01 * p = 0.03 W.V. Kern et al., 2005 22
Recent changes in bacterial epidemiology and the emergence of fluoroquinoloneresistant Escherichia coli among patients with hematological malignancies : results of a prospective study of 823 patients at a single institution Percentage (%) of pathogens responsible for microbiologically documented infections Prophylaxis No prophylaxis 66 43 Staph. aureus 4.5 18.6 * Coagulase negative staphylococci 13.9 13.9 Enterococci 10.6 11.6 E. coli 42.4 20.1* Other enterobacteriacae 9.1 13.9 Pseudomonas 7.6 9.3 * P < 0.05 fluoroquinolone-resistant E. coli accounted for 86.8 % of all isolates of E. coli C. Cattaneo et al., 2008 23
Prediction of the outcome of febrile neutropenia : the MASCC scoring system Characteristic Weight Burden of illness : no or mild symptoms 5 No hypotension 5 No chronic obstructive pulmonary disease 4 Solid tumour or no previous fungal infection 4 No dehydration 3 Burden of illness : moderate symptoms 3 Outpatients status 3 Age < 60 years 2 The maximum score is 26 Scores 21 predict for a risk of severe complications < 5 % J. Klastersky, 2000 24
Oral moxifloxacin or intravenous ceftriaxone for the treatment of low-risk (MASCC score 21) neutropenic fever in cancer patients suitable for early hospital discharge Overall success of home-antibiotic strategy Results according to the treatment Ceftriaxone IV 46 Moxifloxacin PO 48 34 (73.9 %) 38 (79.2 %) Response in FUO 28/33 26/33 Response in MDI 2/7 8/9 Discontinuation for toxicity 2 (4.3 %) 0 (0 %) C. Seblan et al., 2008 25
Outpatient oral antibiotics for febrile neutropenic cancer patients using a score predictive for complications : reasons for not administering oral treatment to patients predicted at low-risk of serious complication development (MASCC score 21) Reason N of patients % Antibacterial prophylaxis and/or treatment 179 71 Inability to swallow 27 11 Contraindication(s) to oral therapy 17 6 Protocol violation 16 6 Refusal (by patient or physician) 11 5 Allergy to penicillin or quinolones 2 1 J. Klastersky et al., 2006 26
Effect of antimicrobial prophylaxis on the rate of and time to infection : antimicrobial prophylaxis typically diminishes and delays the occurrence of an infection but rarely obviates the risk L.R. Baden, 2005 27
Caveats with the use of prophylactic antibiotics Cost Side effects Impact on further therapy Decrease of colonization resistance (C. difficile, Salmonella sp) Emergence, amplification and dissemination of resistant strains effect on patient s and collective flora time dependency of the process impact on the use of antimicrobials need for close monitoring and extensive infection control L.R. Baden, 2005 28
Who should be considered for preventive strategies? Many commonly used chemotherapy have a low risk for FN The risk of FN is the greatest in the initial cycle(s) If FN occurs, the likehood of FN during the next cycle is high The risk of FN varies considerably by disease groups A number of other factors than tumor and chemotherapy affect the risk for FN J.R. Wingard and M. Elmongy, 2009 29
Patient assessment algorithm to decide prophylactic G-CSF usage M.S. Aapro et al., 2006 30
The key questions Final Conclusion 1) Who needs prophylaxis? 2) G-CSF s or antibiotics? 31
Thank you for your kind attention and «Au revoir» 32