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Infectious Diseases and the Oncology Patient Seema Mehta, MD, MS Faculty Seema Mehta, MD, MS Clinical Associate Johns Hopkins School of Medicine Baltimore, MD Learning Objectives 1. Review risk stratification for neutropenic and high risk patients 2. Review best practices for treatment of febrile neutropenia 3. Identify organ specific infections in oncology patients 4. Discuss case examples of complex patients Definitions • Fever – A single oral temperature of >38.3ºC (101ºF) OR – A temperature of >38ºC (100.4ºF) sustained for >1 hour Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infec Dis 2011; 52:e56 US Department of Health and Human Services, National Institute of Health, National Cancer Institute. Common terminology criteria for adverse events (CTCAE) Definitions • Neutropenia – Absolute neutrophil count (ANC) <1500 cells/microL • Severe neutropenia – ANC <500 cells/microL (μL) OR – An ANC that is expected to decrease to <500 cells/µL over the next 48 hours Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update b y the infectious diseases society of America. Clin Infec Dis 2011; 52:e56 Risk Stratification of Neutropenic Patients • Risk of clinically important infections rise – As neutrophils drop below 500 cells/μL – As the duration of neutropenia prolongs (>7 days) • High-risk and low-risk strata – Infectious Diseases Society of America (IDSA), National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCN) have varying definitions Febrile Neutropenia: High Risk • ANY of the following: – – – – – – – -Hemodynamic instability -Oral or GI mucositis ANC <500 cells/µL* anticipated to last >7 days -GI symptoms – abd Alemtuzumab use within the past 2 months pain/n/v/diarrhea -New neurologic or mental Inpatient status at the time of fever development status change -IVC infection, especially Uncontrolled or progressive cancer* catheter tunnel infection Evidence of hepatic insufficiency (AST, ALT >5x ULN) -New pulmonary infiltrate or hypoxemia Evidence of renal insufficiency (CrCl <30mL/min) -Underlying chronic lung Multinational Association for Supportive Caredisease in Cancer (MASCC) risk score <21 -Complex infection at time of presentation – Presence of any comorbid disease Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update b y the infectious diseases society of America. Clin Infec Dis 2011; 52:e56 National Comprehensive Cancer Network (NCC) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2017 Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2013 MASCC Score • Validated tool for measuring the risk for neutropenic fever-related medical complications – Burden of illness • No or mild symptoms = 5 • Moderate symptoms = 3 • Severe symptoms/moribund = 0 – Systolic BP >90 mmHg = 5 – No COPD = 4 BP = blood pressure; COPD = chronic obstructive pulmonary disease Klastersky J et al. The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000; 13:3038 Paesmans M et al. Outpatient oral antibiotics for febrile neutropenic cancer patients using a score predictive for complications. J Clin Oncol 2006; 24: 4129 Uys A, et al. Febrile neutropenia: a prospective study to validate the Multinational Association of Supportive Care of Cancer (MASCC) risk-index score. Support Care Cancer 2004; 12:555 Klatersky J, et al. Outpatient oral antibiotics for febrile neutropenic cancer patietns using a score predictive for complications. J Clin Oncol 2006; 24:4129 Klastersky J, et al. The Multinational Association for Supportive Care in Cancer (MASCC) risk index score: 10 years of use for identifying low-risk febrile neutropenic cancer patients. Support Care Cancer 2013; 21:1487 MASCC Score – Solid tumor or hematologic malignancy WITHOUT prior history of fungal infections = 4 – No dehydration requiring parenteral fluids = 3 – Outpatient status = 3 – Age <60 years = 2 Klastersky J et al. The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000; 13:3038 Paesmans M et al. Outpatient oral antibiotics for febrile neutropenic cancer patients using a score predictive for complications. J Clin Oncol 2006; 24: 4129 Uys A, et al. Febrile neutropenia: a prospective study to validate the Multinational Association of Supportive Care of Cancer (MASCC) risk-index score. Support Care Cancer 2004; 12:555 Klatersky J, et al. Outpatient oral antibiotics for febrile neutropenic cancer patietns using a score predictive for complications. J Clin Oncol 2006; 24:4129 Klastersky J, et al. The Multinational Association for Supportive Care in Cancer (MASCC) risk index score: 10 years of use for identifying low-risk febrile neutropenic cancer patients. Support Care Cancer 2013; 21:1487 MASCC Score • Max score = 26 • >21 predicts patients at LOW risk for serious medical complications who can be managed with an oral empiric antibiotic regimen • <21 HIGH risk • Correctly classifies low-risk patients 98% of the time and high-risk patients 86% of the time – Sensitivity 95%, Specificity 95% Klatersky J, et al. Outpatient oral antibiotics for febrile neutropenic cancer patietns using a score predictive for complications. J Clin Oncol 2006; 24:4129 Uys A, et al. Febrile neutropenia: a prospective study to validate the Multinational Association of Supportive Care of Cancer (MASCC) risk-index score. Support Care Cancer 2004; 12:555 MASCC Score • May also predict death – <15 = 29% likelihood of death – > 15, <21 = 9% – > 21 = 2% • Some criticisms of the MASCC Score – Lack of standardization when defining “burden of febrile neutropenia” – Does not include duration of neutropenia Paesmans M et al. Outpatient oral antibiotics for febrile neutropenic cancer patients using a score predictive for complications. J Clin Oncol 2006; 24: 4129 Febrile Neutropenia: Low Risk • ANC <500 cells/µL for < 7 days AND who have no active comorbidities or no evidence of renal or hepatic insufficiency • Most patients receiving chemotherapy for solid tumors are deemed low risk Learning Objectives 1. Review risk stratification for neutropenic and high risk patients 2. Review best practices for treatment of febrile neutropenia 3. Identify organ specific infections in oncology patients 4. Discuss case examples of complex patients General Principles: Febrile Neutropenia • Febrile neutropenia (FN) should be considered a medical emergency • Broad-spectrum antibiotics should be given as soon as possible (within 60 minutes of triage) • Diagnostics should be obtained quickly Antibiotic Pearls • Always include appropriate coverage for known/suspected infections • Even when a pathogen is known, the antibiotic regimen should provide broad-spectrum coverage for possibility of other pathogens • Moxifloxacin does not penetrate the urinary system • PCN allergy – Use clindamycin, doxycycline, trimethoprim/sulfamethoxazole – Remember that erythromycin resistance for staph aureus indicates clindamycin will become resistant while on therapy • Linezolid can induce myelosuppression – After 2 weeks of use • Fluoroquinolones -- not good for staph or enterococcus Learning Objectives 1. Review risk stratification for neutropenic and high risk patients 2. Review best practices for treatment of febrile neutropenia 3. Identify organ specific infections in oncology patients 4. Discuss case examples of complex patients Organ-specific Infections • When initially evaluating the patient it is vital to take a thorough history and physical examination – Seek out sites suspicious for infection – Guide selection of cultures and imaging – Recall that pus is often not found because of lack of neutrophils – Abdominal pain may suggest neutropenic enterocolitis (i.e. typhlitis) – Perianal or hemorrhoidal tenderness may suggest gramnegative or anaerobic infections Mouth/Mucosal Membranes: Necrotizing Ulcerations • Necrotizing ulceration – Viral diagnostics – Culture and gram stains • Fungal • Consider leukemic infiltrates – Biopsy suspicious lesions • Treatment: – Include anaerobic coverage – Consider antiviral (antiHSV) therapy – Consider systemic antifungal therapy National Comprehensive Cancer Network (NCC) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2017 Necrotizing ulcers Mouth/Mucosal Membranes: Thrush • Add antifungal therapy – Fluconazole is first line therapy – Voriconaozle, posaconazole, or echinocandin if refractory to fluconazole National Comprehensive Cancer Network (NCC) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2017 Mouth/Mucosal Membranes: Vesicular Lesions • Add Anti-HSV therapy National Comprehensive Cancer Network (NCC) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2017 Esophagus • Complaints of • Consider endoscopy if retrosternal burning no response to therapy • Dysphagia/ • Consider CMV Odynophagia esophagitis in high risk patients • Consider viral diagnostics, fungal culture of oral lesions National Comprehensive Cancer Network (NCC) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2017 Sino-Nasal Area • Physical Exam – – – – Sinus tenderness Periorbital cellulitis Nasal ulcerations Unilateral eye tearing • If periorbital cellulitis need to add vancomycin • If CT is suspicious and high-risk patient start liposomal amphotericin B • HR CT sinuses/orbit • ENT/ophtho evaluations (URGENT) • Culture and stains/ biospy HR = high-resolution; CT = computed tomography National Comprehensive Cancer Network (NCC) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2017 Sino-Nasal Area Lung Infiltrates • Depending on risk – must consider the following: – Nasal swab/wash for respiratory viruses/rapid tests – Serum Glactomannan or β-glucan – CT of chest – Bronchoscopy – Diagnostic lung biopsy • Add azithromycin or fluoroquinolone to cover atypical bugs • Consider adding: – Mold-active azole – Antiviral during peak influenza/RSV season – Vancomycin or linezolid if MRSA suspected – Bactrim if concerned for Pneumocystis (PJP) RSV = respiratory syncytial virus National Comprehensive Cancer Network (NCC) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2017 Abdominal Pain • Obtain CT (preferred) or Ultrasound • Consider treating for c.difficile • Check LFTs and pancreatic enzymes • Ensure adequate anaerobic coverage • Diarrhea? LFTs = liver function tests National Comprehensive Cancer Network (NCC) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2017 Perirectal Pain • Physical examination • Consider CT • Ensure adequate anaerobic coverage • Consider enterococcal coverage • Consider local wound care National Comprehensive Cancer Network (NCC) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2017 Diarrhea • Send c.difficile assay • Consider evaluation for viral pathogens, bacterial cultures, and/or parasite examination • Start oral vancomycin (preferred) or metronidazole if c.difficile is highly suspected or confirmed National Comprehensive Cancer Network (NCC) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2017 Urinary Tract Symptoms • Send for urinalysis and urine culture • Identify specific pathogen and start therapy/tailor antibiotics accordingly National Comprehensive Cancer Network (NCC) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2017 Skin • Cellulitis/Skin and soft tissue infection – Treat based on clinical evaluation – Can consider biopsy or culture of drainage – Ensure gram positive coverage • Clindamycin, trimethoprim/sulfamethoxazole, cephalexin, doxycycline National Comprehensive Cancer Network (NCC) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2017 Skin • Vesicular lesions – Aspirate or scrape for VZV or HSV PCR (can do a DFA or culture if PCR unavailable) – If scraping the vesicle – remember to take sample from edge as that is where the virus lives • Start treatment with anti-viral agent: – Acyclovir/Valacyclovir – Famciclovir – Recall that ValGanciclovir is the only oral antiviral active against CMV VZV = varicella-zoster virus, HSV = herpes simplex virus, PCR = polymerase chain reaction, DFA = direct fluorescentantibody, CMV = cytomegalovirus National Comprehensive Cancer Network (NCC) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2017 Disseminated papules or other lesions • Aspiration or biopsy • Consider evaluation for VZV • Consider vancomycin addition • Consider mold-active azole in high-risk patients National Comprehensive Cancer Network (NCC) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2017 Learning Objectives 1. Review risk stratification for neutropenic and high risk patients 2. Review best practices for treatment of febrile neutropenia 3. Identify organ specific infections in oncology patients 4. Discuss case examples of complex patients Case #1 • 67 yo woman w/ a hx of relapsed AML receiving Vidaza while awaiting SCT. • Presented to clinic C2D10 with baseline chronic pancytopenias. – ANC 0.5, Hgb 8.8, Plts 22,000 • Notes a new, small bullous lesion on her hand • What would you treat with? Three Days Later… • Presented to the ER for increased pain and swelling. • Taken to OR that night by ortho for I&D • Intraoperative findings show seropurulent fluid and multiple indurated purpuric lesions • What would you treat with empirically at this time? Cultures and beyond • Cultures grew MRSA – would this change your management? • Required repeat I&D 5 days later to debride necrotic tissue. Cultures negative • Required 5 weeks of wound care/antibiotics which delayed SCT • 1 year outcome: doing well! Seen in clinic Feb 2017 Case 2 • 58yo woman w/ classical Hodgkin’s lymphoma presenting to clinic C1D8 of ABVD w/ day 2 pegfilgrastim complaining of ear drainage, h/a, and low grade fevers x 3 days • ANC 0.5. Afebrile in clinic. Right ear with black drainage. • Seen by PCP earlier that week – given clarithromycin • Allergies: Sulfa, PCN, fluoroquinolones • What would you do at this time? Work up and Cultures • CT sinuses – nonspecific right middle ear mastoid disease, incompletely visualized • Cultures – growing mold • What would you do at this time? Outcome • Direct admission for ENT and ID services for presumed invasive fungal OE and mastoiditis • 48h after admission, cultures resulted: Aspergillus spp, not fumigatus • MRI confirmed no mastoiditis • What would you treat with?