1. Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer 2010 Update by IDSA Moon, Soo-youn Division of Infectious Diseases, Department of Internal Medicine Kyung Hee University Medical Center

2. Fever: Etiology and Epidemiology ▶ During chemotherapy induced neutropenia 1) 10-50% of patients with solid tumors 2) >80% of patients with hematologic malignancy ▶ Clinically documented infections 1) 20-30% of febrile episodes 2) Common sites: intestinal tract, lung and skin 3) Bacteremia – 10-25% of all patients

3. ESBL, carbapenemase-producing isolates

4. Definitions ▶ Fever 1) Single oral temperature ≥38.3 ℃ or ≥38.0 ℃ sustained over 1 hour ▶ Neutropenia 1) Absolute neutrophil count (ANC) <500 cells/mm 3 2) ANC expected to decrease to <500 cells/mm 3 during the next 48h

6. I. Risk Assessment 1. Assessment of risk for complications of severe infection at presentation of fever (A-II) 2. High-risk patients (A-II) 1) Prolonged (>7 days duration) and profound (ANC ≤100 cells/mm 3 ) and/or 2) Significant medical co-morbid conditions, including hypotension (hemodynamic instability), pneumonia (underlying chronic lung disease), new-onset abdominal pain (nausea, vomiting or diarrhea), or neurologic changes, (intravascular catheter infection, especially catheter tunnel infection, mucositis) 3) Hepatic insufficiency (aminotransferase >5X normal values) or renal insufficiency (creatinine clearance <30mL/min)

7. 3. Low-risk patients (A-II) 1) Brief (≤7 days duration) neutropenic period or 2) No or few co-morbidities 4. Multinational Association for Supportive Care in Cancer (MASCC) scoring system (B-I) 1) High-risk patients: <21 2) Low-risk patients: ≥21

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9. II. Tests and Cultures during Initial Assessment 5. Lab tests – CBC/DC, BUN/Cr, electrolytes, hepatic transaminase enzymes, and total bilirubin (+CRP, IL-6, IL-8 and procalcitonin) (A-III) 6. At least 2 sets of blood cultures (C-III) 1) Each lumen of an existing CVC + 1 peripheral vein 2) 2 blood culture sets from separate venipunctures 7. Culture specimens form other sites of suspected infection (A-III) 1) Diarrhea – stool culture, stool CDTA 2) Signs and symptoms of UTI or urinary catheter in situ – urine culture 3) Suspected meningitis – CSF examination and culture 4) Skin lesion – aspiration or biopsy for cytologic testing, Gram stain and culture 8. Chest radiography (A-III) 1) CT of head, sinuses, abdomen and pelvis

10. III. Empirical Antibiotic Therapy ▶ Goal: to prevent serious morbidity and mortality due to bacterial pathogens, until the results of blood cultures are available to guide more precise antibiotic choices ▶ Bacteremia: GPC>GNB>polymicrobial ▶ P. aeruginosa and gram-negative pathogens ▶ Bactericidal activity in the absence of WBC, anti-pseudomonal activity, and minimal toxicity 9. High-risk patients – hospitalization for IV antibiotics therapy 1) Monotherapy with an anti-pseudomonal β -lactam agent (A-I)  Cefepime, carbapenem, pip/taz, ceftazidime  Cefepime – increased mortality? 2) Addition of aminoglycosides, fluoroquinolones, and/or vancomycin (B-III)  Management of complications or suspected/proven resistance

11. 10. Vancomycin (or other agents active against aerobic GPC) (A-I) 1) Not recommended as a standard part of the initial antibiotic regimen  No significant reduction in either the duration of fever or overall mortality 2) Considered for suspected catheter-related infection, SSTI, pneumonia, or hemodynamic instability

12. 11. Modifications to initial empirical therapy (B-III) 1) Patients at risk for antibiotic-resistant organisms 2) MRSA (vancomycin, linezolid, or daptomycin), VRE (linezolid or daptomycin), ESBLs (carbapenem), KPCs (polmyxin-colistin or tigecycline) 12. Penicillin-allergic patients (A-II) 1) Cephalosporins – tolerable 2) History of immediate-type hypersensitivity reaction – ciprofloxacin + clindamycin/aztreonam+ vancomycin 13. New signs or symptoms suggestive of infection in afebrile neutropenic patients – high-risk patients (B-III)

13. 14. Low-risk patients – transition to outpatient oral or IV treatment (A-I) 1) Ciprofloxacin + amox/clav (A-I)  Levofloxacin (500mg vs. 750 mg) or ciprofloxacin monotherapy, ciprofloxacin + clindamycin (B-III) 2) Patients receiving fluoroquinolone prophylaxis – no empirical therapy with fluoroquinolone (A-III) 3) Hospital re-admission or continued admission for persistent fever or worsening infection (A-III) ▶ Factors predicting re-admission: age >70 yr, grade of mucositis >2, poor performance status, ANC <100 cells/mm 3 at the onset of fever

15. IV. Modification of Antimicrobials 15. Modification to the initial antibiotic regimen – guided by clinical and microbiologic data (A-II) 1) Daily P/Ex, review of systems for new symptoms, culture &/or images 2) Median time to defervescence  Hematologic malignancies, including HSCT – ~5 days  Low risk with solid tumor – 2 days 16. Unexplained persistent fever and stable patient’s condition (A-I) 1) Rarely required empirical change to the initial regimen 2) Identified infection  adjustment of antibiotics accordingly

16. 17. Documented clinical and/or microbiological infections – appropriate antibiotics for the site and the susceptibilities of isolated organisms (A-I) 1) Gram-negative BSI: β -lactam/carbapenem + AG/fluoroquinolones 2) Pneumonia: HCAP  β -lactam/carbapenem + AG or antipseudomonal fluoroquinolone ±vancomycin or linezolid 3) Gram-positive BSI or SSTIs: Vancomycin or linezolid or daptomycin 4) Oral ulceration or symptoms of esophagitis: Acyclovir and/or fluconazole 5) Severe abdominal pain  CT to r/o neutropenic enterocolitis (typhlitis)  Pip/taz, carbapenems, or antipseudomonal cephalosporins + metronidazole

17. 18. Vancomycin or other coverage for gram-positive organisms – stopped after 2 days without evidence for a gram-positive infection (A-II) 19. Hemodynamically unstable patients – broader spectrum antibiotic regimen including coverage for resistant gram-negative, gram- positive and anaerobic bacteria and fungi (A-III) 20. Clinically stable low-risk patients – simplified treatment approach (A-I) 1) IV-to-oral switch: clinically stable and adequate GI absorption (A-I) 2) Transition to OPD - adequate daily f/u (B-III) ▶ Readmission if persistent or recurred fever within 48h (A-III) 21. Empirical antifungal coverage – high-risk patients with persistent fever after 4-7 days of broad-spectrum antibacterial regimen and no identified fever source (A-II)

19. Duration of Empirical Antibiotic Therapy 22. Patients with clinically or microbiologically documented infection (B-III) 1) Duration – dictated by the particular organism and site 2) At least the duration of neutropenia (until ANC ≥500 cells/mm 3 ) or longer if clinically necessary 3) Most bacterial BSIs, SSTI, and pneumonia – 10-14days 23. Patients with unexplained fever (B-II) 1) Until there are clear signs of marrow recovery – increasing ANC >500 2) Low-risk: IV  oral ciprofloxacin + amox/clav 3) High-risk: CT of chest to look for invasive fungal disease 24. Patients with remained neutropenia after completion of appropriate treatment course and resolved sign and symptoms of documented infection - Oral fluoroquinolone prophylaxis until marrow recovery (C- III)

20. Antibiotic Prophylaxis 25. Fluoroquinolone prophylaxis – high-risk patients with expected prolonged and profound neutropenia (B-I) 1) Levofloxacin and ciprofloxacin (A-II)  Levofloxacin preferred in situations with increased risk for oral mucositis- related invasive viridans group streptococcal infection  Monitoring development of fluoroquinolone resistance  Increased C. difficile enterocolitis 2) Until neutrophil recovery (ANC 500-1000 cells/mm 3 ) 3) TMP-SMZ  All patients at risk for PCP  Allogeneic HSCT recipients, autologous HSCT recipients, high dose corticosteroid therapy, T-cell depleting agents, or anticancer therapy d/t acute leukemia

21. 26. Addition of gram-positive active agent – not recommended (A-I) 1) Penicillins, rifampin, or macrolides  Infections d/t staphylococci or streptococci & incidence of NF – ↓  Infection-related mortality – no change  GI upset & breakthrough resistant gram-positive infections – ↑ 27. Low-risk patients with expected duration <7 days – no routine prophylaxis recommended (A-III)

22. Empirical or Pre-emptive Antifungal Therapy 28. High-risk patients with persistent or recurrent fever after 4-7 days of antibiotics and whose overall duration of neutropenia is expected to be >7 days – empirical antifungal therapy and investigation for invasive fungal infections (B-III) 1) Yeast (Candida spp.) and molds (Aspergillosis, zygomycosis, and fusariosis) ▶ Without antifungal prophylaxis – Candidemia ▶ Antifungal prophylaxis – fluconazole-R Candida infections or invasive mold infection 2) Amphotericin B, liposomal amphotericin B, itraconazole or voriconaozle, and caspofungin

23. 29. Preemptive antifungal management – alternative to empirical therapy 1) High-risk neutropenic patients with persistent or recurrent fever after 4- 7days of antibiotics ▶ Clinically stable, no clinical or chest & sinus CT signs of fungal infection, negative serologic assay results for invasive fungal infection, no recovery of fungi (such as Candida or Aspergillus spp.) from any body site  no antifungal therapy (B-II) ▶ β -(1-3)-D glucan test – Candida spp., Aspergillus spp., Pneumocystis spp., and Fusarium spp. (not zygomycetesagents or Cryptococcus spp.) ▶ Galactomannan test – Aspergillus spp. only (Penicillium spp., cross- reactivity to Histoplasma capsulatum) ▶ Indicators of possible invasive fungal infection  antifungal therapy 30. Low-risk patients – no routine use of empirical antifungal therapy (A- III)

25. Antifungal Prophylaxis 31. Prophylaxis against Candida infection (A-I) 1) Patient group in whom the risk of invasive candidal infection is substantial (HSCT recipients, those undergoing intensive remission- induction or salvage-induction chemotherapy for acute leukemia) 2) Fluconazole, itraconazole, voriconazole, posaconazole, micafungin, and caspofungin 32. Prophylaxis against Aspergillus infection with posaconazole (B-I) 1) Patients ≥13 years of age who are undergoing intensive chemotherapy for AML or MDS 2) Itraconazole, voriconazole, and posaconazole

26. 33. Prophylaxis against Aspergillus infection in pre-engraftment allogenic/autologous transplant recipients – not shown to be efficacious 1) Mold-active agent – prior invasive aspergillosis (A-III), anticipated prolonged neutropenic periods of ≥ 2wks (C-III) or prolonged periods of neutropenia immediately prior to HSCT (C-III) 34. Low-risk patients with anticipated duration of neutropenia <7 days – no antifungal prophylaxis recommended (A-III)

27. Antiviral Prophylaxis 35. HSV-seropositive patients undergoing allogenic HSCT, autologous HSCT recipients at high risk for mucositis, or leukemia induction therapy, T-cell depleting monoclonal Ab – acyclovir or valacyclovir (A-I) 36. Antiviral treatment for HSV or VZV infection – clinical or laboratory evidence of acute viral disease (C-III) 1) CMV, HHV6 – no prevention strategies 37. Respiratory virus testing (influenza, parainfluenza, adenovirus, RSV, and human metapneumovirus) and chest radiography – patients with upper respiratory symptoms and/or cough (B-III)

28. 38. Yearly influenza vaccination with inactivated vaccine – all patients treated for cancer (B-III) 1) Between chemotherapy cycles (>7 days after the last treatment) or >2 weeks before chemotherapy start 39. Influenza – neuraminidase inhibitors (C-III) 1) Oseltamivir and zanamivir 2) Exposure to influenza – 5-day PEP regardless of vaccination status 40. Routine treatment of RSV infection – not given (B-III) 1) Aerosolized and oral ribavirin  Not effective against RSV pneumonia, parainfluenza virus 2) Monoclonal Ab (palivizumab) and RSV IG – no preventive efficacy 3) Adenovirus – no proven effective therapy, cidofovir/ribavirin

29. Hematopoietic Growth Factors (G-CSF or GM-CSF) 41. Prophylactic use of CSFs – patients with anticipated risk of fever and neutropenia ≥20% (A-II) 42. CSFs – not recommended for treatment of established fever and neutropenia (B-II)

30. Catheter-Related Infections 43. Differential time to positivity (DTP) >120 min of qualitative blood cultures  central line-associated blood stream infection (CLABSI) (A- II) 1) Colonizer of the skin and mucosa (CNS, S. aureus, Candida spp.), Bacillus spp., Corynebacterium jeikeium, enterococci, rapid growing mycobacteria, and non-fermentative GNB 2) Skin swab culture from the exit site of the catheter 44. S. aureus, P. aeruginosa, fungi or mycobacteria, Bacillus spp., Corynebacterium jeikeium, Acinetobacter spp., S. maltophilia, VRE 1) Catheter removal + systemic antimicrobial therapy for at least 14 days (A-II) ▶ Catheter removal – tunnel infection or port pocket site infection, septic thrombosis, endocarditis, sepsis with hemodynamic instability, persistent BSI despite ≥72 h of appropriate therapy (A-II)

31. 45. CNS – catheter can be retained (B-III) 1) Antibiotic lock therapy 46. Prolonged treatment (4-6 wks) – complicated CLABSI (deep tissue infection, endocarditis, septic thrombosis) (A-II) or persistent infection occurring >72 h after catheter removal (S. aureus (A-II), other pathogens (C-III)) 1) S. aureus – longer than 2 wks of antimicrobial therapy 47. Hand hygiene, maximal sterile barrier precautions and cutaneous antisepsis with chlorhexidine during CVC insertion (A-I)

32. Environmental Precaution 48. Hand hygiene – most effective means of preventing transmission of infection (A-II) 1) Before entering and after leaving the rooms 2) Food – well-cooked foods, well-cleaned, uncooked raw fruits and vegetables 49. Standard barrier precautions – all patients (A-III) 1) Contact with body fluids is anticipated 2) No specific protective gear (gowns, gloves, and masks) - routine care of neutropenic patients 3) Infection-specific isolation for patients with certain signs or symptoms 50. HSCT recipients in private rooms (B-III) 1) Allogeneic HSCT recipients – rooms with >12 air exchanges/h and HEPA filtration (A-III), positive pressure

33. 51. Plants and dried or fresh flowers – not allowed (B-III) 1) Household pets – not allowed 52. Hospital work exclusion policies – HCWs reporting their illnesses or exposures (A-II) 1) Vaccination of HCWs and visitors, households **Skin and oral care 1) Daily showers or baths 2) Daily inspection of skin sites likely to be portals of infection 3) Good perineal hygiene 4) Rectal thermometers, enemas, suppositories, and rectal exam – CIx 5) Oral rinses 4-6 times/d with sterile water, NS, or sodium bicarbonate solutions 6) Tooth brushing ≥2 times/d