(4/9) Bulman Lecture: Febrile Neutropenia Febrile Neutropenia

- Definition: The occurrence of fever during a period of severe neutropenia in a patient with cancer and receiving chemotherapy. It is considered a medical emergency, noticeable at best by a Fever. If identified, it is imperative to initiate immediate empiric tx to prevent sepsis and reduce mortality

- Pathogenesis: Prior to chemo, normal ANC = ~ 2000. After receiving chemo, two detrimental events:

o (1) Neutropenia: ANCß < 500(cells/mm3) At this point, the patient is at the highest risk for infection

o (2) Mucositis: Chemotherapy threatens the integrity of the intestinal mucosal lining, making it possible for bacteria to pass across and disseminate as an infection

- Diagnosis/Decision to Treat: During the window of time while the patient is neutropenic, temperature readings showing a fever will qualify the patient for abx tx. Patients receiving chemotherapy are immunocompromised, and are at significantly increased risk of life threatening infections. If the following are met, treat:

o Fever: Single oral temperature ³ 38.3ºC (101ºF) or a temperature ³ 38ºC (100.4ºF) sustained x1h o Neutropenia: ANC < 500 (cells/mm3) or expected to decrease to < 500 during the next 48 hours

A closer look at neutrophils

- WBC (Leukocytes) are divided into multiple categories - Neutrophils are the most abundant – Innate Defense - As the neutrophil count drops, patients are at an

increased risk for infections Treatment Approach for Febrile Neutropenia

Pt has received chemotherapy within the last 6 weeks Patient is febrile and neutropenic (ANC < 500)

à Medical Emergency ß • Step 1: Assessment (Within 15 minutes)

- Assume Bacterial Infection o Though we are only using fever for this dx, it is the highest risk to the patient and will need to be

empirically treated - Collect Samples

o ³ 2 sets of blood cultures are needed before abx therapy is initiated o Need CBC with Leukocyte differential count (to calculate ANC)

- Systematic Patient Assessment o Patient interview, ROS, and examination of their Hx maximizes the chance of determining the site of

infection and the causative organism • Step 2: Empiric Treatment (Within 1 hour)

- Speed o Guidelines recommend initial IV dose within 1 hour of diagnosis. à Treat as soon as possible o Recent studies have shown that there is a lower mortality risk if treated within 30 minutes

- Choice of Abx o The choice of abx depends on: What is

most common AND what has the highest risk of mortality

o Gram(+) is more common o Gram(-) is more deadly

Abx therapy choices continued on next page

n 1 anti-pseudomonal beta-lactam (Cefepime, Meropenem, Imipenem/cilastatin, Pip-Tazo) The choice of abx depends on local resistance patterns, risk factors for gram(+) pathogens, and allergy status

o PCN-Anaphylactic-Rxn: All are contraX. Switch!à Cipro + Clindamycin -OR- Aztreonam + Vanco o ESBL-Suspected: à Carbapenems – Meropenem, Imipenem/cilastatin o MRSA-Suspected: à Vancomycin needed: Add to any anti-pseudomonal beta-lactam, besides Pip-Tazo

due to an increased risk of nephrotoxicity. Situations suggesting high risk for gram(+) infections include: • Hemodynamically instable (mortality risk) • Hx of MRSA or colonization (Ýrisk g(+)) • Suspected pneumonia (Ýrisk g(+)) • Skin or soft-tissue infection (Ýrisk g(+)) • Suspected catheter-related infection (Ýrisk g(+))

o Adding Vancomycin is generally not associated with clinical benefits and may promote resistance among the enterococci (VRE), so there is no need to overprescribe vanco

o Adding additional gram(-) abx is not superior to monotherapy for febrile neutropenia, avoid AG combos • Step 3: Confirm Neutropenia when labs return

- Thus far, the patient has been dosed with abx due to having received chemo in last 6w and presenting with a fever - Early treatment reduces mortality, but now we have to determine the appropriateness - ANC Calculation Mature = PMNs or “Segs” Immature = “Bands”

o Neutrophils reported as a %: ANC = 𝑇𝑜𝑡𝑎𝑙𝑊𝐵𝐶×[,-.%011

+ 34567%011

] o Neutrophils reported as a #: ANC = 𝑃𝑀𝑁𝑠 + 𝐵𝑎𝑛𝑑𝑠 ×1000

• Step 4: Can we push to outpatient treatment - The vast majority of cases will be treated inpatient. When considering candidates for outpatient, the physician will

need to consult: Their clinical judgement, the MASCC Index, Talcott’s Rules, and CISNE. - Patients selected for outpatient tx must live in close proximity to the clinic or hospital and agree to in home-

evaluations. Eligible patients also must have high medication adherence • Step 5: Reassess therapy and modify if necessary

- Duration of Therapy: Until the patient is afebrile for at least 2 days and ANC has recovered ( ³ 500) - Modifying therapy

o Persistent fever, even though no infection detected à Maintain current therapy, look harder o Persistent fever & hemodynamically unstable à Broaden empiric therapy, cover for resistant gram(-,+),

and anaerobes § Cefepime would need to be broadened to a carbapenem – cover ESBL + anaerobes

o Persistent fever >4 days after broadening abx à Add empiric antifungal therapy to current therapy § Amphotericin B is an add-on antifungal therapy

o Identified the cause of fever à Alter tx based on the specific infection’s guidelines o Afebrile for 2 days, cultures negative, and ANC > 500 à Discontinue therapy

- Outpatient Therapy o FQ is the only PO option for good pseudomonal coverage (Levo, Cipro) o No Allergy: FQ + Augmentin o PCN-ALL: FQ + Clindamycin o If fever is not reduced in 3 days à RETURN TO THE HOSPITAL

High-Risk Patient Prophylaxis - Patients considered to be at high-risk for febrile neutropenia are those with prolonged neutropenia, where the

predicted ANC £ 100 count will last for >7 days. Such cases include: o Allogenic hematopoietic cell transplant (HCT) o Induction chemotherapy for acute leukemia

- Prophylactic Tx o Antibacterial: à FQ PO. Helps cover the deadly GNB infections, with good pseudomonal coverage o Antiviral: In addition to being High Risk, antiviral prophylactic therapy is only indicated for those who

are ALSO seropositive for HSV ± VZV. If indicated à Acyclovir or Valacyclovir (+ annual flu shot) o Antifungal: High-risk patients require antifungal prophylaxis against Candida ± Aspergillus due to their

difficulty to diagnose and life-threatening prognosis § Patient receiving HCT: à Fluconazole § Patient receiving induction chemo for acute leukemia à Poasconaozle or Voriconazole

Duration: Discontinue at the end of the neutropenic period Best of luck to everyone! Remember, this should only act as a supplement! You learn best using your own methods first