Infection control for neutropenic patients : the Libraryuse of prophylactic Lecture author Jean A. Klastersky Onlineby Institut Jules Bordet,© Université Libre de Bruxelles (ULB) Brussels, Belgium ESCMID Complications and mortality associated with Library

No Bacteremia Bacteremia

Total ComplicationsLectureDeaths Total Complications Deaths author Solid tumors 784 60 (8 %) 25 135 30 (22 %) 17 Onlineby (3 %) (13 % ) © Hematological cancer 859 111 (13 %) 32 364 76 (21 %) 32 (4 %) (9 %)

ESCMID J. Klastersky et al., 2007 2 Complications associated with febrile neutropenia Library : systolic 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 needLecture for mechanical ventilation Disseminated intravascular coagulation Confusion or altered mental state author Congestive cardiac failure seen on chest X-ray and requiring treatment Onlineby 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 ESCMID J. Klastersky et al., 2000 3 Cost of febrile neutropenia Library

Initial hospitalization Initial hospitalization plus all downstreamLecture neutropenia care author 2.010 $ Onlineby 14.407 $ ©

ESCMID D. Weyckler et al., 2008 4 Use of oral antibiotics in protected units environment : clinical effectiveness and role in the emergence of -resistantLibrary strains

„ « … the incidence of proven was significantly reduced … Lecture» „ « … no advantage of isolationauthor in addition to antibiotics could be detected … » Onlineby „ « … isolated© from decontamined patients were considerably more resistant … »

ESCMID J. Klastersky et al., 1973 5 Infection-control interventions for cancer patients after : a systematic review and meta-analysis Library

„ « … protective isolation, including air quality control, prophylactic antibioticsLecture and barrier isolation (29 studies) brought about a significant reduction in all-cause mortalityauthor : risk ratio 0.60 … »

„ « … inclusion ofOnline prophylacticby antibiotics in the © intervention was necessary to show the effect on mortality … » ESCMID A. Schlesinger et al., 2009 6 Occurrence of among placebo and trimethoprim-sulfamethoxazole (TMP-SXT)-treated patientsLibrary

Treatment group Total N of No (%) Patients with Patients LectureAny Infection Bacteremia

Placebo 165 author64 (39) • 32 (19) *

TMP-SXT Online177 by 46 (26) • 22 (12) * © • p = 0.016

* P = 0.106 (p = 0.005 if patients with leukemia were excluded) ESCMID EORTC Antimicrobial Project Group 1984 7 Prophylaxis with fluoroquinolones (Levofloxacin) in patients with expected neutropenia (adapted from L. Leibovici et al., 2006) Library Patients Relative Absolute Risk in the N of treated Patients Risk Control Group needed to prevent 1 Event Acute leukemia and stem cell transplantation* Lecture Febrile neutropenia 0.76 85 4 Bacterial Infection 0.56 39 5 author Solid Tumors and Lymphomas • Onlineby Febrile Neutropenia 0.71© 15 23 Bacterial Infection 0.82 42 13

ESCMID * G. Bucaneve et al., 2005 • M. Cullen et al., 2005 8 Deaths caused by infection in patients receiving prophylaxis for febrile neutropenia Library

Levofloxacin Placebo P value Lecture

Bucaneve et al. (2005) 10 / 373 (2.8 %)author18 / 363 (4.9 %) 0.15 Onlineby © Cullen et al. (2005) 4 / 781 (0.5 %) 3 / 784 (0.3 %) NS

ESCMID 9 Meta-analysis of primary prophylaxis with colony-stimulating factor on febrile neutropenia and mortality in patients with solid tumors or/and lymphomas (3.493 patients) Library

Absolute Occurrence Relative Risk Reduction Lecture Infection-related 1.5 % (← 2.8author %) 45 % (p = 0.018) mortality Onlineby Febrile neutropenia 22.4© % (← 39.5 %) 46 % (p < 0.0001)

ESCMID N. Kuderer et al., 2007 10 Meta-analysis of prophylaxis with granulocyte colony- stimulating factors (G-CSF and GM-CSF) on febrile neutropenia and mortality autologous and allogeneic stem cell transplantation (2.669 patients)Library

Relative Risk Reduction Documented infections Lecture13 % (p = 0.05) Duration parenteral antibiotics - 1.39 days (p = 0.02) Infection-related mortality author24 % (p = 0.4) Grade 2-4 GVHD Onlineby 0 % (p = 0.8) Treatment-related mortality © 0 % (p = 0.9)

ESCMID A. Dekker et al., 2006 11 Prophylactic antibiotics or G-CSF for the prevention of infections and improvement of survival in cancer patients undergoing chemotherapyLibrary : The Cochrane Collaboration

Lecture « … there is no evidence for or against antibiotics compared to G(M)-CSF’s forauthor prevention of infections in cancerOnline patientsby … » ©

ESCMID C. Herbst et al., 2009 12 Bacterial isolates from cases of bacteremia due to a single organism Library

Trial Total n of isolates Gram-negative Gram-positive I: 1973-1976 145 103 (71 %) 42 (29 %) II: 1977-1980 111 Lecture74 (67 %) 37 (33 %) III: 1980-1983 141 83 (59 %) 58 (41 %) IV: 1983-1985 219 author129 (59 %) 90 (41 %) V: 1986-1988 Online213 by 78 (37 %) 135 (63 %) VIII: 1989-1991 151 © 47 (31 %) 104 (69 %) IX: 1991-1993 161 53 (33 %) 108 (67 %)

ESCMID EORTC International Antimicrobial Therapy Cooperative Group, 1999 13 Gram-positive organisms isolated during trial VIII

Organism LibraryNisolated Streptococcus species 57 Viridans group 44 Group D Lecture 5 Streptococcus pneumoniae 4 Other author 4 Coagulase-negative staphylococci 49 Staphylococcus aureus Onlineby 20 species © 5 Other gram-positive organisms 3

ESCMID EORTC International Antimicrobial Therapy Cooperative Group, 1999 14 « New » gram-positive pathogens in patients with neutropenia Library Viridans streptococci e.g., Streptococcus mitis, Streptococcus milleri Leuconostoc species Enterococcus species, especially -resistant Corynebacterium jeikeium, CorynebacteriumLecture urealyticum Rhodococcus equi author Stomatococcus mucilaginosus Lactobacillus rhamnosusOnlineby Bacillus cereus © Clostridium septicum, Clostridium tertium

ESCMID S.H. Zinner, 1999 15 « New » gram-negative pathogens in patients with neutropenia

Stenotrophomonas (Xanthomonas, Pseudomonas) maltophiliaLibrary Alteromonas (Pseudomonas) putrifaciens Legionella pneumophila, Legionella micdadei Vibrio parahaemolyticus Capnocytophaga species Lecture Alcaligenes xylosoxidans Chryseobacterium meningosepticum author Burkholderia cepacia Onlineby Fusobacterium nucleatum © Leptotrichia buccalis Methylobacterium species Moraxella-like organisms ESCMID S.H. Zinner, 1999 16 Antibiotic-resistant bugs in the 21st century – a clinical super-challenge Library

« … we have come almost full circle and arrived at a point as frighteningLecture as the preantibiotic era : for patients infectedauthor with multidrug- resistant bacteria, there is no magic bullet … » Onlineby ©

ESCMID 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) Library

„ « … rates of bacteremia due to highly penicillin- resistant … increased significantly from zero (1987) to 17 episodes (1992)Lecture per 1.000 admissions (p = 0.003) … » author

„ « … the administrationOnlineby of β-lactam antibiotics during the 2 previous© weeks was the only factor significantly associated… »

ESCMID J. Carratala et al., 1995 18 Use of fluoroquinolone prophylaxis and frequency of fluoroquinolone-resistant bacteremia isolates in neutropenic patients with cancer Library Variable 1983-1985 1986-1990 1991-1993

Patients given prophylaxis/all patients (%)

Prophylaxis 3/219 (1.4) 228/694 (33) 318/706 (45) Lecture Fluoroquinolone-resistant strains/strains tested (%) Isolate author Escherichia coli 0/26 0/66 11/40 (28) Coagulase-negative Online0/22 by 44/172 (26) 23/38 (61) staphylococci © 1/25 (4) 1/39 (3) 1/13 (8) Klebsiella pneumoniae 0/3 1/17 (6) 1/13 (8)

ESCMID A. Cometta et al., 1994 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 Library

Incidence (per 10.000 discharges) Year Leukemia Other diseases P value 1988 69.2a Lecture< 1.5b 0.002 1989 80.6 author3.7 0.008 1990 35.6 3.6 0.13 1991 Online153.8 by 3.8 0.00003 1992 327.3a© 3.6b < 0.00001 a P = 0.03 b P = 0.17

ESCMID W.V. Kern et al., 1994 20 Emergence of fluoroquinolone-resistant Escherichia coli at a cancer center Library „ « … bacteremia … increased from < 0.5 % in 1988-1989 and 0.8 % in 1990-1991 to 4.5 % in 1992-1993 (p < 0.01) … » Lecture „ « … MIC raised between 8-16 µg/ml… and indicated resistance to TMP/SXT, ampicillin,author doxycycline and chloramphenicol … » Onlineby „ « … 4 genotypes were identified,© suggesting both independant development and horizontal spread… »

ESCMID 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 Library

Pre-intervention Discontinuation of Post-intervention (1995-1997) fluoroquinolones (1999) (1998) Resistance Lecture rate > 50 % 15 % > 50 % author E. coli bacteremia 8 Online% • by 20 % • * 9 % * © • p < 0.01 * p = 0.03

ESCMID W.V. Kern et al., 2005 22 Recent changes in bacterial epidemiology and the emergence of fluoroquinolone- resistant Escherichia coli among patients with hematological malignancies : results of a prospective study of 823 patients at a single institution

Percentage (%) of pathogensLibrary responsible for microbiologically documented infections Prophylaxis No prophylaxis 66 43 Staph. aureus Lecture4.5 18.6 * Coagulase negative staphylococci 13.9 13.9 Enterococci 10.6author 11.6 • E. coli by42.4 20.1* Other enterobacteriacae Online 9.1 13.9 Pseudomonas © 7.6 9.3

* P < 0.05 • fluoroquinolone-resistant E. coli accounted for 86.8 % of all isolatesESCMID of E. coli C. Cattaneo et al., 2008 23 Prediction of the outcome of febrile neutropenia : the MASCC scoring system Library Characteristic Weight Burden of illness : no or mild symptoms 5 No hypotension 5 No chronic obstructive pulmonary diseaseLecture 4 Solid tumour or no previous fungal infection 4 No dehydration author 3 Burden of illness : moderateOnline symptomsby 3 Outpatients status © 3 Age < 60 years 2 The maximum score is 26 Scores ≥ 21 predict for a risk of severe complications < 5 % ESCMID J. Klastersky, 2000 24 Oral moxifloxacin or intravenous ceftriaxone for the treatment of low-risk (MASCC score ≥ 21) neutropenic in cancer patients suitable for early hospital discharge Library Results according to the treatment

Ceftriaxone IV Moxifloxacin PO 46 48 Lecture Overall success of 34 (73.9 %) 38 (79.2 %) home-antibiotic strategy author Onlineby Response in FUO © 28/33 26/33 Response in MDI 2/7 8/9 Discontinuation for toxicity 2 (4.3 %) 0 (0 %) ESCMID 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 (MASCCLibrary score ≥ 21)

Reason LectureN of patients % Antibacterial prophylaxis and/or treatment 179 71 Inability to swallow author 27 11 Contraindication(s) to oralOnline therapyby 17 6 Protocol violation © 16 6 Refusal (by patient or ) 11 5 to penicillin or quinolones 2 1 ESCMID 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 Library

Lecture author Onlineby ©

ESCMID L.R. Baden, 2005 27 Caveats with the use of prophylactic antibiotics

„ Cost Library „ Side effects „ Impact on further therapy „ Decrease of colonization resistanceLecture (C. difficile, Salmonella sp) „ Emergence, amplification and dissemination of resistant strains • effect on patient’s and collectiveauthor flora • time dependencyOnline of theby process • impact on the use of© antimicrobials • need for close monitoring and extensive infection control

ESCMID L.R. Baden, 2005 28 Who should be considered for preventive strategies ?

Library „ 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 FNLecture during the next cycle is high

„ The risk of FN varies considerablyauthor by disease groups Onlineby „ A number of other factors© than tumor and chemotherapy affect the risk for FN

ESCMID J.R. Wingard and M. Elmongy, 2009 29 Patient assessment algorithm to decide prophylactic G-CSF usage

Library

Lecture author Onlineby ©

ESCMID M.S. Aapro et al., 2006 30 Final Conclusion Library The key questions

1) Who needs prophylaxisLecture ? author 2) G-CSF’s or antibiotics ? Onlineby ©

ESCMID 31 Thank you for your kind attention Library

Lecture author Onlineby © and « Au revoir » ESCMID 32