Bakteriella Infektioner hos Neutropena

1. Bakteriella Infektioner hos Neutropena Mats Kalin Infektionsklinken Karolinska universitetssjukhuset, Solna mats.kalin@karolinska.se

2. Cytoreductive chemotherapy primarily affects cells with a high rate of division, like bone marrow cells and epithelial cells Mucous membranes are affected causing mucositis, which may be especially severe in the oral cavity, in the lower oesophagus and in the perianal region. Necrotising enterocolitis may also occur Mucositis may be aggravated by reactivation of Herpes simplex virus infection, which may affect all parts of the GI tract Also increased yeast colonisation of the GI tract may aggravate mucositis. Mucositis severely compromises the barrier function. Therefore, translocation of bacteria from the entire GI canal to the blood occurs with increased frequency In case of granulocytopenia (<0.5) bacteremia with signs and symptoms of sepsis will develop

3. Blood stream Pathogens at the Center for Haematology, Karolinska hospital Candida spp 1.7 % 1988-2001 n=1402 Other Gramneg CNS Stenotrophomonas maltophilia Enterobacter spp Pseudomonas aeruginosa S.aureus Klebsiella spp Alpha-strept E.coli Enterococci Cherif et al 2004 The Haematology J 4:240 Pneumococci Other Grampos

4. In addition to mucositis and granulocytopenia cancer chemotherapy • will cause • - T cell deficiencies • - - for long time periods • implying increased risks for infection w • intracellular bacteria, herpes viruses, PCP and other fungi • Ig-deficiency • With risk for severe pneumococcal ao infections • Steroids • and other drugs may compromise macrophage function

5. CNS • has become the most common etiology in neutropenic fever due to the frequent use of CVCs • Alpha-streptococci • - are increasing in frequency as a cause of neutropenic fever • - due to severe mucositis caused by e.g. high dose cytosin arabinoside. • The course may be fulminant with septic shock and ARDS • Enterococci • are increasing in many centers, especially E.faecium

6. Infections in Neutropenic Cancer Patients •The risk for bacterial infection is related to depth and length of neutropenia • Bacteria are translocated from the GI tract •GI flora may be affected by hospitalisation and ab therapy • The course may be fulminant with septic shock •Symptoms may be subtle due to lack of immune response •Fever is the signal for risk of serious infection Broad-spectrum antibiotic therapy must be started immediately when a neutropenic patient presents with fever: - Cephalosporin with Pseudomonas activity - Carbapenem - Piperacillin/Tazobactam ….

7. ..but only after blood cultures have been obtained •before start of antibiotics • 20 – 40 ml in 4-6 bottles, excluding anaerobic bottles? •>1 venipuncture does not facilitate interpretation • but if CVC or PAC is used peripheral specimen should also be obtained •Time to positive results from CVC/PAC and peripheral sample, respectively, can be used to diagnose line infection • Cultures should also be obtained fromurine, wounds and airways Lamy et al 2002, CID 35:842 Ortiz & Sande 2000, Am J Med 108:445 DesJardin et al 1999, Ann Intern Med 131:641

8. Treatment of Infections in Neutropenic Cancer Patients • Broad-spectrum antibiotic therapy • must be started immediately • when a neutropenic patient presents with fever: • Cephalosporin with Pseudomonas activity • Ceftazidime • (Cefepime) • Carbapenem • Imipenem • Meropenem • Piperacillin/Tazobactam • Paul et al, JAC Dec 12, 2005

9. Monotherapy probably superior to combination therapy • Similar if not better survival rate • Lower treatment failure rate •Lower rate of adverse events •Similar rate of secondary infections (Cochrane 2003;(3):CDOO3038) Betalaktamantibiotikum 4 x MIC Betalaktamantibiotikum 10 x MIC

10. • Cephalosporin with Pseudomonas activity • Ceftazidime ………….1 st choice G-(G+) • (Cefepime) • • Carbapenem ………………2 nd choice G- G+ • Imipenem • Meropenem • •Piperacillin/Tazobactam ….1 st choice G-G+ • No advantage of combination with aminoglycoside • except for septic shock (?) • aminoglycoside alone insufficient Gramneg coverage • Limited advantage of addition of • - vancomycin…………………………… G+ Treatment of Neutropenic Fever

11. Indications for Vancomycin •Clinically suspected serious CVC infection • Infection with multiresistant bacteria • Blood culture reported positive for Gram-pos bacteria in a patient with deteriorating condition before final identification and susceptibility report • Hypotension or other evidence of cardiovascular impairment and ?? Severe mucositis Quinolone prophylaxis due to risk of infection with penicillin resistant alpha-streptococci Hughes 2002 CID 34:730 (IDSA Guidelines)

12. It is of decisive importance to follow the course closely Therapy may have to be changed as a results of •deteriorating general condition • new signs and symptoms of focal infection • results of cultures, most importantly blood cultures • results of chest X ray or other investigations

13. Pulmonary Infiltrates in Neutropenic Patients Totally 1573 patients 1986-92 295 (17%) developed pulmonary infiltrates - 29 % microbiologically documented Complete Response - 61 % in patients with pulmonary infiltrates - 83 % in other documented infections Early deaths (<21 days): 22 % _________________________________________ Meschmeyer et al 1994, Cancer 73:2296 Medizinische Klinik 89:114 Annals Hematol 69:231

14. GI epithelial damage Bacterial translocation Bacteremia Increased GI yeast colonisation /focal infection Antibiotic therapy Yeast translocation I n v a s i v e y e a s t i n f e c t i o n

15. Invasive Fungal Infections in Cancer Patients • intensity of chemotherapy and improved antibiotic therapy More patients surviving for longer periods with severe immune defects  (?)Invasive Candidiasis  Pneumocystis J Pneumonia (PCP) Improved Fungal Therapy, Prophylaxis, Other factors (?)  mortality rate invasive candidiasis, especially C.albicans  non-albicans Candida  more patients with invasive aspergillosis  more patients with uncommon fungal infections

16. Clinical Condition after 72 h of Antibiotic Therapy Relation to Ultimate Outcome, n=1085 IMPROVING STABLE 25 % 65 % DETERIORATING 10 % 10% G- bacteremia 33% FUO 20% 15% 39% 23% 46% 18% CDI 25% G+ bacteremia 22% 21% 28% % ultimately surviving 1009011 De Pauw & Intercontinental Study Group, Ann Intern Med 1994

17. Cherif 2004, SJID 36:593

18. Observed and Predicted Rates of Fever Resolution • without serious complications • as a response to adequate ab therapy for neutropenic fever • in relation to points by the MASCC risk index score Characteristic Points Age < 60 y 2 No COPD 4 Solid tumor or no previous fungal dis 4 Burden of illness none or mild 5 or moderate 3 No dehydration 3 No hypotension 5 Outpatient status 3 8-16 17-18 19-20 21 22 23 24 25-26 n=71 67 67 172 52 102 127 98 Klastersky et al 2000, J Clin Oncol 18:3038

19. Prospective evaluation of MASCC at Hem C Karolinska • MASCC risk-index score < 21 (high risk): 176 pts (63%) w serious medical complications in 63% • > 21 (low risk)105 pts w serious medical complications in 15% - and in an additional 21% other facts precluded oral therapy Thus, a total of 24% of haematological patients with neutropenic fever could be discharged with oral therapy 24 h after defervescence, essentially w/o complications Cherif et al 2006 Haematologica

20. Quinolone consumption and resistance in Stockholm and at Karolinska Hospital Sörberg et al 2002, Scand J Infect Dis 34:372

21. Gramneg enterobacteriaQuinolones 5-10 % • ESBL rare findings • EnterobacterCephalosporin inducable resistance in high frequency • Quinolones 5-10 % • Pseudomonas aeruginosaImipenem 25 % Quinolones 12 % Ceftazidime 10 % Piperacillin 17 % • Stenotrophomonas maltophiliaImipenem 100 % Quinolones 30 % Ceftazidime 10 % Resistance problems according to ICU-”STRAMA” Hahnberger: http://e.lio.se/ivastrama/