UPDATE ON FEBRILE NEUTROPENIA

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2 UPDATE ON FEBRILE NEUTROPENIA Clinical approach and management Dr.Shafiq A. Alimad Head of medical department at university of science and technology hospital YICID 15-December-2014

3 INTRODUCTION Cancer patients receiving cytotoxic antineoplastic therapy sufficient to adversely affect myelopoiesis and the developmental integrity of the gastrointestinal mucosa are at risk for invasive infection due to colonizing bacteria or fungi that translocate across intestinal mucosal surfaces. Since the magnitude of the neutrophil-mediated component of the inflammatory response may be muted in neutropenic patients an elevated body temperature may be the earliest and only sign of infection.

4 It is critical to recognize neutropenic fever and associated sepsis syndromes early and to initiate empiric systemic antibacterial therapy promptly in order to avoid progression to a sepsis syndrome and possibly death.

5 Prior to the era of empiric antibiotic therapy, infections accounted for most episodes of neutropenic fever and approximately 70 percent of the mortality in neutropenic acute leukemia patients. Because of the routine use of prompt empiric antibiotics, infections are documented less frequently today.

6 Although the majority of patients with neutropenic fever do not have a documented infection, consensus guidelines recommend that all patients with neutropenic fever be promptly evaluated and treated with empiric broad-spectrum antibiotics. This approach is indicated since it is difficult to distinguish life-threatening infections from less serious infections in this patient population, and infection may progress rapidly in such patients. Furthermore, better outcomes are seen with prompt therapy

7 DEFINITIONS FEVER Single oral T 38.3 o C ( 101 o F ) OR T 38 o C ( o F ) sustained over 1 h NEUTROPENIA ANC < 500 cells/mm 3 OR ANC expected to decrease to < 500 cells/mm 3 during the next 48 hrs PROFOUND NEUTROPENIA ANC < 100 cells/mm 3

8 EPIDEMOLOGY Fever occurs in: 10 % 15 % of patients with solid tumors 80 % of hematologic malignancies during 1 chemotherapy cycle Most patients have NO infectious etiology Clinically documented infections occur in 20 % 30 % of cases Site: GI, Lung, Skin

9 BACTEREMIA Occur in 10 % - 25 %, especially profound neutropenia 57 % gram +ve 34 % gram ve 9 % polymicrobial Mortality: 18 % gram ve 5 % gram +ve : gram ve > gram positive : gram positive > gram ve

10 Coagulase-Negative Staphylococci are the most common blood isolates due to increase use of indwelling venous catheters Resistant Organisms: ESBL KPC MRSA, VRE 20 % - 50 % Penicillin resistant strept viridans

11 Candida: usually > 1st week of prolonged neutropenia Molds: Sinuses Lungs Typically 2 weeks of neutropenia

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13 RISK ASSESSMENT High-risk and Low-risk Patients with Fever and Neutropenia Type Of Empirical Antibiotic Therapy ( PO vs IV ) Venue Of Treatment ( Inpatient vs Outpatient ) Duration Of Antibiotic Therapy

14 PATIENTS WITH NEUTROPENIC FEVER WHO ARE AT HIGH RISK FOR SERIOUS COMPLICATIONS Patients with any of the following characteristics are considered to be at high risk for serious complications during episodes of neutropenic fever: Neutropenia (absolute neutrophil count <500 cells/microl) anticipated to last >7 days* Presence of any comorbid medical problems, including, but not limited to: Hemodynamic instability Oral or gastrointestinal mucositis that interferes with swallowing or causes severe diarrhea Gastrointestinal symptoms, including abdominal pain, nausea and vomiting, or diarrhea Neurologic or mental status changes of new onset Intravascular catheter infection, especially catheter tunnel infection New pulmonary infiltrate or hypoxemia Underlying chronic lung disease Complex infection at the time of presentation Alemtuzumab use within the past two months Inpatient status at the time of development of fever Uncontrolled or progressive cancer Evidence of hepatic insufficiency (defined as aminotransferase levels >5 times normal values) or renal insufficiency (defined as a creatinine clearance of <30 ml/min) Multinational Association for Supportive Care in Cancer (MASCC) risk index score <21 Δ

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16 HIGH RISK PATIENTS Should be hospitalized for IV antibiotics Usually : Acute Leukemia Hematopoietic Stem Cell Transplantation ( HSCT )

17 LOW RISK PATIENTS Anticipated 7 days duration No or few comorbidities Candidates for oral empirical therapy

18 DETAILED HISTORY New symptoms Antimicrobial prophylaxis Infection exposure Prior documented infections Prior pathogen colonization Non-infectious cause of fever, e.g. blood product Co-morbid diseases Recent surgical procedures

19 PHYSICAL EXAMINATION Site of previous procedures or catheters Catheter entry and exit site BM aspiration site Oropharynx: periodontium GI, Lungs, Perineum

20 ECTHYMA GANGRENOSUM

21 NECROTIC SKIN LESION OF MUCORMYCOSIS

22 FUSARIUM SKIN LESIONS ON LOWER EXTREMITIES

23 DIAGNOSTIC EVALUATION OF PATIENTS WITH FEVER AND NEUTROPENIA Item Purpose Comments Targeted history Seek sites suspicious for infection Allows detection of symptoms of infection Physical exam with emphasis on skin, oral cavity, oropharynx, lungs, abdomen, perianal area* Detection of sites suspicious for infection; guides selection of cultures and imaging Pain and/or erythema may point to infection; pus is not found due to lack of neutrophils; chest exam may be unremarkable even with pneumonia; abdominal tenderness may suggest Neutropenic enterocolitis; perianal or hemorrhoidal tenderness may point to gram-negative or anaerobic infection Complete blood count with differential Defines the depth of neutropenia The lower the initial neutrophil count, the greater the likelihood of serious infection or bacteremia; daily counts allow prognostication

24 NEUTROPENIC ENTEROCOLITIS (TYPHLITIS)

25 Creatinine, liver function tests, electrolytes Blood cultures (2 sets, one peripheral and one from central venous catheter); antimicrobial susceptibility testing Cultures and stains of samples from suspected sites of infection Defines comorbid conditions Detection of bacteremia Detection of infectious etiology Allows optimal selection and dose of antimicrobial agent(s) and serial monitoring of toxicities Fever may be the only sign of bacteremia; allows adjustment of antibiotic regimen if necessary Bacterial and fungal stains can be helpful Imaging studies (generally recommended only if site is suspected from history or exam) Detection of infectious site Computed tomography (CT) scans are generally more useful than plain radiographs; pulmonary infiltrates may be inapparent by plain radiography during deep neutropenia and may become manifest only upon neutrophil recovery; thickened bowel walls are seen by CT scan with neutropenic enterocolitis Digital rectal examination is avoided in neutropenic patients

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29 TESTS AND CULTURES CBC count with differential Creatinine, urea, electrolytes, hepatic transaminase enzymes and total bilirubin At least 2 sets of blood cultures: Each set from each lumen of central venous catheter ( CVC ) if present and from peripheral vein simultaneously If No CVC : 2 blood culture sets from separate veins RE-culture: next 48 hrs or refever

30 20 ml of blood: aerobic and anaerobic blood culture bottle Blood culture volume should be less than 1% of total blood volume (70 ml/kg) Cultures from other sites of suspected infection should be obtained as clinically indicated Chest X-ray is indicated for patients with respiratory signs and symptoms Stool : if diarrhea C. diff. toxin assay

31 Urine culture is indicated if: Signs or symptoms Urinary catheter Abnormal urine analysis CSF culture: if meningitis is suspected Skin lesion: aspiration or biopsy for cytology and culture

32 Respiratory: Sputum culture if productive cough BAL if abnormal CXR Nasal wash or BAL for viral detection: adenovirus, influenza A, B, RSV and parainfluenza Radiography: CXR if symptoms CT if clinically indicated

33 Type of infection Stain Culture Other Bacteria Gram stain Aerobic and anaerobic culture Fungi KOH smear Fungal culture Aspergillus galactomannan antigen Mycobacteria AFB Mycobacterial culture Pneumocystis jirovecii (formerly P. carinii) Fluorescein-conjugated monoclonal antibodyδ N/A PCR Nocardia spp Modified AFB Fungal culture Legionella spp N/A Legionella culture using BCY E medium Mycoplasma pneumoniae N/A N/A PCR Viruses Cytomegalovirus N/A Shell vial culture, conventional culture PCR, cytology

34 Influenza virus N/A Viral culture Reverse transcriptase PCR, direct or indirect fluorescent antibody, rapid antigen test Parainfluenza virus N/A Viral culture Direct or indirect fluorescent antibody, PCR Respiratory syncytial virus N/A Viral culture PCR, rapid antigen test Adenovirus N/A Viral culture PCR Herpes simplex virus N/A Viral culture Direct fluorescent antibody Varicella-zoster virus N/A Viral culture Direct fluorescent antibody

35 SERUM FUNGAL MARKERS Checking fungal markers from the serum, such as the Aspergillus galactomannan antigen and the beta-d-glucan assay, should also be considered in high-risk patients. Some centers perform serial monitoring of these twice weekly in hematopoietic cell transplant recipients and acute leukemia patients. The Aspergillus galactomannan antigen is a specific test for invasive aspergillosis, whereas the beta-d-glucan assay is a nonspecific test for several invasive fungal infections, including aspergillosis and candidiasis

36 EMPIRIC THERAPY Fever in a neutropenic patient should be considered a medical emergency. Assessment by a physician should occur soon (eg, within 15 minutes) after triage for patients presenting with neutropenic fever within six weeks of having received chemotherapy for malignancy. Broad-spectrum antibacterials should be given as soon as possible (within 60 minutes of triage) and at full doses, adjusted for renal and/or hepatic function. Antibiotics should be: Bactericidal,Anti-pseudomonal,Minimal toxicity. In addition, the diagnostic evaluation should be obtained quickly.

37 TIMING OF ANTIBIOTICS In all febrile neutropenic patients, empiric broad-spectrum antibacterial therapy should be initiated immediately after blood cultures have been obtained and before any other investigations have been completed. Antimicrobial therapy should be administered within 60 minutes of presentation (algorithm 1)

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39 WHAT EMPIRIC ANTIBIOTIC THERAPY AND IN WHAT VENUE

40 LOW RISK PATIENTS Initial oral or IV antibiotic doses in clinic or hospital May be transitioned to outpatient IV/PO treatment if they have specific clinical criteria ORAL EMPIRICAL TREATMENT Ciprofloxacin+Amoxicillin-Clavulanate Others: less well studied and NO enough data Levofloxacin or Ciprofloxacin as monotherapy Ciprofloxacin+Clindamycin

41 ELIGIBILITY CRITERIA FOR OUT PATIENT MANAGEMENT [ANC] <500 cells/microl) for 7 day. No active comorbidities or evidence of significant hepatic or renal dysfunction. Normal finding on CXR. Hemodynamic stability. Solid malignancy. No documented bacterial, viral, or fungal infection. No evidence of VAD related infection. No abdominal pain, nausea, vomiting or diarrhea

42 ELIGIBILITY CRITERIA FOR OUT PATIENT MANAGEMENT No neurological or mental-status changes. Ability to swallow oral medications. The patient was not on quinolone prophylaxis. The patient can be reliably monitored and has ready access to appropriate medical care. The patient needs less than one hour car ride to reach the center.

43 High risk patients should be hospitalized for IV empirical antibiotic therapy Monotherapy with an anti-pseudomonal β-lactam agent: Cefepime Carbapenem: meropenem or imipenem-cilastatin Piperacillin-tazobactam

44 Other antibiotics: aminoglycoside, fluoroquinolones, vancomycin: May be added to initial regimen For 1. Treatment of Complications ( hypotension, pneumonia ) or 1. If antimicrobial resistance is suspected or proven

45 β-lactam monotherapy: Ceftazidime is NO longer used Aminoglycoside monotherapy should NOT be used Vancomycin is NOT recommended as a standard part of initial regimen for febrile neutropenia

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47 Modifications to initial empirical therapy may be considered for patients at risk for infection with the following antibiotic-resistant organisms: 1.Risk factors include previous infection or colonization or hospital with high rate of endemicity 2.MRSA: Vancomycin, Linezolid, or Daptomycin 3.VRE: Linezolid, or Daptomycin 4.ESBL: Carbapenem 5.KPCs: Polymyxin-colistin or Tigecycline

48 PENICILLIN-ALLERGIC PATIENTS: SEVER FORM Ciprofloxacin+ Clindamycin OR Aztreonam+Vancomycin

49 ANTIBIOTIC MODIFICATIONS DURING THE COURSE OF FEBRILE NEUTROPENIA Modifications to the initial antibiotic regimen should be guided by clinical and microbiologic data Unexplained persistent fever in a patient who is stable rarely requires an empirical change to the initial antibiotic or adding vancomycin If an infection is identified, antibiotics should be adjusted accordingly

50 Documented clinical and/or microbiological infections should be treated with antibiotics appropriate for the site and for the susceptibilities of any isolated organisms: Pneumonia: health-care acquired infection ( β-lactam+amino OR antipseudomonal FQ ± anti-mrsa ) If vancomycin or other coverage for gram-positive organisms was started initially, it may be stopped after 2 days if there is NO evidence for a gram-positive infection

51 Patients who remain hemodynamically unstable after initial agents for neutropenic fever should have their antibiotics broadened to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria and fungi For Low-risk patients if clinically stable: Their treatment may be simplified IV to Po switch if clinically stable and adequate GI absorption If fever persists or recurs within 48 hrs in outpatient, readmit and treat as high risk patient

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53 HOW LONG SHOULD EMPIRICAL ANTIBIOTIC THERAPY BE GIVEN In patients with clinically or microbiologically documented infections, the duration of therapy is dictated by the particular organism and site and antibiotics should be continued for at least the duration of neutropenia (until ANC is 500 cells/mm3) or longer if clinically necessary Blood stream infection, soft tissue infection and pneumonia: days of antibiotics

54 In Patients with Unexplained Fever: Continue the initial antibiotics until there are signs of marrow recovery (ANC exceeds 500 cells/mm3) OR If an appropriate treatment course has been completed and all signs and symptoms of a documented infection have resolved, patients who remain neutropenic may resume oral fluoroquinolone prophylaxis until marrow recovery

55 EMPIRICAL OR PRE-EMPTIVE ANTIFUNGAL THERAPY 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 In low risk patients: routine use of antifungal therapy is NOT recommended Treatment: 1) Ampho B 2) Lipid soluble Ampho B 3) Voriconazole 4) Caspofungin

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57 EMPIRICAL OR PRE-EMPTIVE ANTIFUNGAL THERAPY The choice of antifungal agent for empiric therapy depends upon which fungi are most likely to be causing infection, as well as toxicity profiles and cost: For persistently febrile patients who have not been receiving antifungal prophylaxis and who have no obvious site of infection, such as pulmonary nodules, start caspofungin (or another echinocandin) since Candida spp is the most likely cause in such patients. For persistently febrile patients with pulmonary nodules or nodular pulmonary infiltrates, invasive mold infection should be strongly suspected. In such patients, start voriconazole or a lipid formulation of amphotericin B. For persistently febrile patients who have been receiving anti-mold prophylaxis, a different class of antifungal agent with activity against molds should be used for empiric therapy

58 EMPIRICAL OR PRE-EMPTIVE ANTIFUNGAL THERAPY Dosing The dosing of the various antifungal agents recommended above is as follows: Caspofungin Loading dose of 70 mg IV on day one, then 50 mg IV once daily Voriconazole Loading dose of 6 mg/kg IV every 12 hours on day one, followed by 4 mg/kg IV every 12 hours Amphotericin B lipid complex 5 mg/kg IV once daily Liposomal amphotericin B 3 to 5 mg/kg IV once daily

59 TREATMENT OF CATHETER-RELATED INFECTION IN NEUTROPENIC PATIENTS CATHETER REMOVAL for CLABSI Caused By: S. aureus P. aeruginosa Fungi Mycobacteria Tunnel Infection Port Pocket Site Infection Septic Thrombosis, Endocarditis Sepsis with Hemodynamically Unstable Blood Stream Infection Persists 72 hrs after therapy with appropriate antibiotics

60 TREATMENT OF CATHETER-RELATED INFECTION IN NEUTROPENIC PATIENTS CLASBI caused by Coagulase-Negative Staphylococci (CONS): the catheter may be retained using systemic therapy with OR without antibiotic lock therapy Prolonged treatment (4 6 weeks) is recommended for complicated CLABSI: Deep tissue infection Endocarditis Septic thrombosis Persistent bacteremia or fungemia occurring > 72 h after catheter removal in a patient who took appropriate antimicrobials

61 TREATMENT OF CATHETER-RELATED INFECTION IN NEUTROPENIC PATIENTS Hand hygiene Maximal sterile barrier precautions Cutaneous antisepsis with chlorhexidine during CVC insertion are recommended for all CVC insertion

62 PREVENTION ENVIRONMENTAL PRECAUTION Hand Hygiene is the most effective means of preventing transmission of infection in the hospital Standard barrier precautions and infection-specific isolation should be used for patients with certain signs or symptoms HSCT patients: in private single-patient room Allogeneic HSCT: room with > 12 air exchanges/hr and high efficacy particulate air(hepa) filtration

63 ENVIRONMENTAL PRECAUTION Plants and dried or fresh flowers should not be in the rooms of neutropenic patients Health-Care Workers (HCWs) to report their illnesses or exposures

64 ANTIBIOTIC PROPHYLAXIS Fluoroquinolone prophylaxis: should be considered for high-risk patients with expected durations of prolonged and profound neutropenia (ANC 100 cells/mm3 for > 7 days) Levofloxacin vs Ciprofloxacin: EQUIVALENT Levofloxacin is preferred in situations with increased risk for oral mucositis-related invasive viridans group streptococcal infection Monitoring for the development of fluoroquinolone resistance among gram-negative bacilli is recommended

65 ANTIBIOTIC PROPHYLAXIS 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

66 ANTIFUNGAL PROPHYLAXIS Candida Prophylaxis Allogenic HSCT Intensive remission-induction or salvage induction chemotherapy for acute leukemia Prophylaxis: Itraconazole Posaconazole Caspofungin Fluconazole Voriconazole Micafungin

67 ANTIFUNGAL PROPHYLAXIS Aspergillus Prophylaxis Intensive chemotherapy for AML MDS FOR BMTX 1)Prior invasive aspergillosis 2)Anticipated prolonged neutropenia 3)Prolonged neutropenia prior to HSCT Antimold antifungal is recommended At least 75 days after transplantation OR Stopping of immunosuppressive therapy

68 ANTIFUNGAL PROPHYLAXIS LOW RISK PATIENTS Antifungal is NOT recommended for prophylaxis in whom the anticipated duration of neutropenia is < 7 days

69 ANTIVIRAL PROPHYLAXIS Acyclovir Prophylaxis Herpes simplex virus (HSV)-seropositive patient for allogenic HSCT Leukemia induction therapy Till WBC or resolution of mucositis Antiviral treatment for HSV or varicella-zoster (VZV) infection is ONLY indicated if there is clinical or laboratory evidence of active viral disease

70 ANTIVIRAL PROPHYLAXIS If symptoms of upper respiratory tract (coryza, cough): Should Do CXR Respiratory virus testing: influenza, parainfluenza, adeno, RSV, human metapneumovirus Yearly Influenza Vaccination Inactivated vaccine is recommended for all patients treated for cancer Between cycles of chemotherapy: > 7 days after last treatment or > 2 wks before chemo or > 6 months after HSCT

71 ANTIVIRAL PROPHYLAXIS Influenza Infection Treatment with neuraminidase inhibitors if susceptible Post-Exposure Treatment: antiviral REGARDLESS of vaccination Routine treatment of RSV Infection in neutropenic patients with upper respiratory disease should NOT be given Adenovirus Infection Supportive Cidofovir? Ribavirin??

72 ROLE OF G-CSF OR GM-CSF Primary prophylaxis : Consider prophylactic use of G-CSF/GM-CSF for patients in whom: the anticipated risk of fever and neutropenia is 20%

73 When the estimated risk of neutropenic fever is between 10 and 20 percent : Age 65 and older Poor performance status Prior episodes of neutropenic fever Large radiation portals Cytopenias due to marrow involvement Poor nutritional status Open wounds or active infection Advanced cancer or other serious comorbidities

74 ROLE OF G-CSF OR GM-CSF Secondary prophylaxis: For patients who had an episode of neutropenic fever after an earlier cycle of palliative chemotherapy, they suggest dose reduction or delay as the primary therapeutic option rather than routine administration of CSFs (Grade 2C). However, in keeping with ASCO guidelines, when the risk of neutropenic fever would prevent the administration of full doses of potentially curative chemotherapy, they suggest the use of granulocyte CSFs for secondary prophylaxis rather than dose reduction (Grade 2C)

75 MYELOID RECONSTITUTION SYNDROME Clinicians should be aware of the myeloid reconstitution syndrome, a circumstance in which there may be onset or progression of an inflammatory focus defined clinically or radiologically that manifests at the time of neutrophil recovery. Because such processes may appear in the context of a persistent neutropenic fever syndrome, the likelihood of superinfection must be considered with respect to the antimicrobial spectrum of the patient s current empiric antibacterial therapy and the microbiologic differential diagnosis applicable to those circumstances

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77 HOME MESSAGES febrile neutropenia is an emergency especially high risk You should manage your patient based on risk assessment (individualization). Neutropenic patient commonly to present atypically. Treat empirically but follow guidelines and continue or change management according patient response. Prevention better then cure

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