neutropenia by D.r Denebo Jebeso 2024.pptx

update

1. Approach to Neutropenic Fever Presenter: Dr. Denebo J(IMR2) Moderator: Dr. Eyob ( MD,Consultant Internist,ID Subspecialist)

2. Outline Introduction Risk assessment Initial evaluation Management Prevention

3. Introduction One of the most frequent and serious complications of cancer chemotherapy Fever occurs in 5 to 10 % of solid tumor patients receiving cytotoxic therapy ,20 to 25% nonleukemic HM,85 to 95% of AL Clinically documented infections occur in 20%–30% of febrile episodes . Resistant Gram+ Pathogens MRSA and VRE and fluconazole-resistant Candida strains (e.g. Candida krusei and Candida glabrata ) have become more common Fungi are rarely identified as the cause of first fever early in the course of neutropenia; rather, they are encountered after the first week of prolonged neutropenia and empirical antibiotic therapy

4. Definition Fever is defined as a single oral temperature measurement of >38.3 C (101F) or a temperature of >38.0 C (100.4F) sustained over a 1-h period . Neutropenia is defined as ANC) <1500 or 1000 cells/ microL Severe neutropenia : ANC <500 cells/ microL or an ANC expected to decrease to <500 cells/ microL over the next 48 hours Profound neutropenia : ANC <100 cells/ microL Prolonged duration of neutropenia: > 7d Profound prolonged neutropenia: ANC <100 & >7d

5. Cont’d… Functional neutropenia Patients whose hematologic malignancy results in qualitative defects of circulating neutrophils. Should also be considered to be at increased risk for infection, despite a ‘‘ normal’’ neutrophil count .

6. Neutropenia vs Chemotherapy Clear relationship between the severity of neutropenia and the intensity of chemotherapy . Currently , the different regimens are classified as High risk (>20%) Intermediate risk (10%–20%) Low risk (<10%) of FN

7. Mortality and links Overall , bacteremia can be detected in ∼20% of patients with FN Mortality rate is 18% in Gram-negative and 5% in Gram-positive bacteremia Mortality is lower than 5% if the MASCC score is ≥21, but possibly as high as 40% if the MASCC score is <15

8. Neutropenic fever syndromes The International Immunocompromised Host Society has classified initial neutropenic fever syndromes into the three categories : Microbiologically documented infection: Clinical focus + an associated pathogen Clinically documented infection Only clinical focus Unexplained fever Neither a clinical focus nor an identified pathogen

9. Cont’d.. First neutropenic fever First febrile episode occurring during a given period of chemotherapy-induced neutropenia A persistent neutropenic fever syndrome Without defervescence after at least five days of initial empiric broad-spectrum antibacterial therapy in high-risk or after at least two days in low-risk A recrudescent neutropenic fever syndrome Recurs following initial defervescence during a course of broad-spectrum antibacterial therapy

10. Epidemiology 10%–50% of patients with solid tumors and 80% of those with hematologic malignancies will develop fever during >1 chemotherapy cycle associated with neutropenia . Most patients will have no infectious etiology documented Clinically documented infections occur in 20%–30% of febrile episodes; common sites of tissue-based infection include the intestinal tract, lung, and skin . Bacteremia occurs in 10%–25% of all patients, with most episodes occurring in the setting of prolonged or profound neutropenia

11. Etiology Commonly cultured Mos

12. Pathogenesis Contributory factors The direct effects of chemotherapy on mucosal barriers and the immune system. Underlying malignancy Chemotherapy-induced mucositis Occurs throughout the alimentary system , and seeding of the bloodstream from endogenous flora in the GIT is believed to cause the majority of episodes Obstruction of lymphatic channels, the biliary tract, and/or bronchial, gastrointestinal, or urinary systems by tumor(s) or as a result of surgical procedures are also common causes of infection.

13. Risk relevant to the assessment of neutropenic patients At least three different categories: Risk factors for neutropenic fever Risk of serious complications Risk of treatment failure

14. Risk factors Divided into three subcategories : Patient-related Disease-related Treatment-related predictors

15. Risk of serious complications What is the role of risk assessment ? Determine type of antibiotic therapy (Oral Vs IV ) Venue of treatment ( Inpatient Vs Outpatient ) Duration of antibiotic therapy Thorough evaluation and if needed specific scoring tools should be implemented to identify those patients who require inpatient management

16. Cont’d… Validated scoring systems used to estimate the risk for medical complications Talcott rules The Multinational Association for Supportive Care in Cancer (MASCC) score The Clinical Index of Stable Febrile Neutropenia (CISNE) score

17. Cont’d… High-risk patients require Admission to hospital for IV antibiotics and often require a prolonged length of stay Low-risk patients may be treated with Oral antibiotics as outpatients after a brief period of observation or a short hospital admission

18. MASCC score The maximum attainable score is 26 A score ≥21 predicts those patients at low risk A score <21 predicts those patients at high risk May predict the likelihood of death 15: 29 percent ≥ 15 but <21: 9 percent ≥ 21: 2 percent

19. CISNE index

20. Talcott’s Rules

21. Risk of sepsis

22. Risk of treatment failure Defined by one or more of the following events occurring within 30 days of the start of treatment Death Persistence , progression, or recrudescence of signs and symptoms of infection Modification of the initial empiric antibacterial regimen For outpatients, readmission to the hospital

23. Initial evaluation C areful history and detailed physical examination Laboratory Microbiology Imaging studies

24. Cont’d… Note the presence of indwelling IV catheters ( peripheral and central ). S/S suggesting an infection focus: Respiratory system Gastrointestinal tract Skin Perineal region/genitourinary discharges Oropharynx Central nervous system Knowledge of previous positive microbiology results by checking clinical records

25. Investigations Routine investigations Further investigations (profound/prolonged neutropenia/following allografts) CBC , RFT , LFT Coagulation screen CRP Blood cultures (minimum of two sets) including cultures from indwelling IV catheter Urinalysis and culture Sputum microscopy and culture Stool microscopy and culture Skin lesion (aspirate/biopsy/swab) Chest radiograph HRCT (if pyrexia despite 72 h of appropriate antibiotics) BAL

26. Cont’d… At least 2 sets of blood cultures are recommended, with a set collected simultaneously from each lumen of an existing CVC, if present, and from a peripheral vein site . 2 blood culture sets from separate venipunctures should be sent if no central catheter is present . A ‘‘set’’ consists of 1 venipuncture or catheter access draw of ≈20 mL of blood divided into 1 aerobic and 1 anaerobic blood culture bottle

27. Management High-risk patients Require hospitalization for IV empirical antibiotic therapy . Monotherapy with an anti- pseudomonal b-lactam agent , such as cefepime , ceftazidime , a carbapenem ( meropenem or imipenem-cilastatin ), or piperacillin- tazobactam , is recommended. Other antimicrobials (aminoglycosides, fluoroquinolones, and/or vancomycin) may be added for management of complications ( eg,hypotension and pneumonia) or if antimicrobial resistance is suspected or proven . Vancomycin (or other agents active against aerobic gram positive cocci) is not recommended as a standard part of the initial antibiotic regimen for fever and neutropenia

28. Cont’d… When to add antibiotics active against GPOs to the empirical regimen?

29. Cont’d… Most penicillin-allergic pts tolerate cephalosporins , but those with a h/o type 1 HSR s/b treated with a combination that avoids b-lactams and carbapenems , such as ciprofloxacin plus clindamycin or aztreonam plus vancomycin . Afebrile neutropenic pts who have new s/s suggestive of infection should be evaluated and treated as high-risk pts . Low-risk pts should receive initial oral or IV empirical antibiotic doses in a clinic or hospital setting . Ciprofloxacin plus amoxicillin- clavulanate in combination is recommended for oral empirical treatment

30. Cont’d… Patients receiving fluoroquinolone prophylaxis should not receive oral empirical therapy with a fluoroquinolone. Hospital re-admission or continued stay in the hospital is required for persistent fever or s/s of worsening infection

31. When to modify therapy ? Modifications to initial empirical therapy may be considered Antibiotic resistant organisms, particularly if the patient’s condition is unstable or Positive blood culture results suspicious for resistant bacteria . MRSA : Consider early addition of vancomycin, linezolid, or daptomycin . VRE : Consider early addition of linezolid or daptomycin . ESBL s: Consider early use of a carbapenem . KPCs : Consider early use of polymyxin-colistin or tigecycline

32. Cont’d… Modifications to the initial antibiotic regimen s/b guided by clinical and microbiologic data. Unexplained persistent fever in a patient whose condition is otherwise stable rarely requires an empirical change to the initial antibiotic regimen. If an infection is identified, antibiotics should be adjusted accordingly. Documented clinical and/or microbiological infections should be treated with antibiotics appropriate for the site and for the susceptibilities of any isolated organisms.

33. Cont’d… If vancomycin or other coverage for GPOs was started initially, it may be stopped after 2 days if there is no evidence for a gram-positive infection . Pts who remain hemodynamically unstable after initial doses with standard agents for neutropenic fever should have their antimicrobial regimen broadened to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria and fungi. An IV-to-oral switch in antibiotic regimen may be made if pts are clinically stable and GI absorption is felt to be adequate. Empirical antifungal coverage should be considered in high-risk patients who have persistent fever after 4–7 days of a broad-spectrum antibacterial regimen and no identified fever source

34. Cont’d…

35. Persistent fever Persistent fever is an episode of fever during neutropenia that does not resolve after 5 days of broad-spectrum antibacterial agents. The median time to defervescence following the initiation of empiric antibiotics in patients with hematological malignancies is five days , in contrast with only two days for patients with solid tumors.

36. How long should empirical antibiotic therapy be given? In pts with clinically or microbiologically documented infections, the duration of therapy is Dictated by the particular organism and site; appropriate antibiotics should continue for at least the duration of neutropenia (until ANC >500 cells/mm3) or longer if clinically necessary . In patients with unexplained fever, it is recommended that the initial regimen be continued Until there are clear signs of marrow recovery; the traditional endpoint is an increasing ANC that exceeds 500 cells/mm3 . Alternatively , if an appropriate treatment course has been completed and all s/s of a documented infection have resolved, pts who remain neutropenic may resume oral fluoroquinolone prophylaxis until marrow recovery

37. Prevention Fluoroquinolone prophylaxis s/b considered for high-risk pts with expected durations of prolonged and profound neutropenia (ANC <100 cells/mm3 for > 7 days). There were no significant differences between fluoroquinolone prophylaxis and TMP-SMX prophylaxis with regard to death from all causes or infection; however, fluoroquinolone prophylaxis was associated with fewer side effects . Addition of a gram-positive active agent to fluoroquinolone prophylaxis is generally NOT recommended . Antibacterial prophylaxis is NOT routinely recommended for low-risk patients who are anticipated to remain neutropenic for < 7 days.

38. Role of antifungal empirical therapy Empirical antifungal therapy and investigation for IFI s/b considered for pts with persistent or recurrent fever after 4–7 days of antibiotics and whose overall duration of neutropenia is expected to be >7 days. Aspergillus has surpassed Candida as a cause of IFI. In low-risk patients, the risk of invasive fungal infection is low, and therefore routine use of empirical antifungal therapy is not recommended.

39. Prophylaxis against Candida infections is recommended in pts in whom the risk of invasive candida infections is substantial, such as Allogeneic HSCT recipients or those undergoing intensive remission-induction or salvage induction chemotherapy for acute leukemia. Fluconazole , itraconazole , voriconazole , posaconazole , micafungin , and caspofungin are all acceptable alternatives. Fluconazole : prevents infection with all species of Candida except for C. krusei or C. glabrata ; no activity against Aspergillus or other molds .

40. Cont’d… Prophylaxis against invasive Aspergillus infections s/b considered for selected pts >13 years of age who are undergoing intensive chemotherapy for AML/MDS in whom the risk of invasive aspergillosis without prophylaxis is substantial. Itraconazole , Voriconazole , Posaconazole and AMB are equal alternatives. The NCCN Guidelines panel advises that prophylaxis with posaconazole , itraconazole and voriconazole s/b avoided in pts receiving vinca alkaloid-based regimens . Only agent effective against invasive Mucor mycosis : AMB

41. ANTIVIRAL PROPHYLAXIS HSV-seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive acyclovir antiviral prophylaxis. Antiviral treatment for HSV or VZV is only indicated if there is clinical or laboratory evidence of active viral disease

42. Role of G-CSF

43. Environmental precautions Hand hygiene is the most effective means of preventing transmission of infection in the hospital. Standard barrier precautions s/b followed for all patients. Plants and dried or fresh flowers should not be allowed in the rooms of hospitalized neutropenic patients

44. Reference Harrisson 21 st Edition Uptodate 2024 Online Approach to FN guidelines Management of febrile neutropenia: ESMO Clinical Practice Guidelines 2016 Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America.

45. THANK YOU