Neutropenia medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [2]

Overview

There is no specific medical therapy for neutropenia. The goal of the medical therapy for neutropenia is to remove the offending agents in drug-induced cases, and treat the underlying disease in others. Recombinant granulocyte-colony stimulating factor (G-CSF) may be considered to accelerate myeloid reconstitution.

Medical Therapy

There is no specific medical therapy for neutropenia.

The goal of the medical therapy for neutropenia is to remove the offending agents in drug-induced cases, and treat the underlying disease in others. Recombinant granulocyte-colony stimulating factor (G-CSF) may be considered to accelerate myeloid reconstitution.

Asymptomatic, mild to moderate neutropenia can often be monitored closely on an outpatient basis with serial CBCs and evaluation for medications, infections, or alternative sources of neutropenia. Offending medications are often temporarily halted and the patient is monitored for response to discontinuation. With mild neutropenia, medications can often be reintroduced after neutrophil counts recover as the neutropenia is typically dose-dependent.

Patients who are febrile, acutely ill, or with severe neutropenia often warrant urgent hospitalization for close monitoring and treatment. Offending medications must be discontinued as drug-induced agranulocytosis presents up to a 10% mortality and is very likely to recur if the offending agent is restarted.

Empiric antibiotics should be implemented as early as possible after cultures are drawn and within 60 minutes of presentation, as there is significantly higher mortality when antibiotic administration is delayed. Initial antibiotic selection should provide broad coverage of the most common, virulent, and likely pathogens, and should be bactericidal so as not to rely on assistance from the host's impaired immune system. Central venous catheters should be removed when possible if there is suspicion for infection or with positive blood cultures.

Low risk patients

ANC>100 cells/microliter, normal liver and renal function, normal chest x-ray, no evidence of central line infection, MASCC >21, and duration of neutropenia expected <7 days in a patient with close monitoring and access to medical care.

• Ciprofloxacin 500mg PO BID + amoxicillin/clavulanate 500mg PO TID

High risk patients

Hospitalize and initiate empiric parenteral antimicrobial therapy. IDSA guidelines recommend initial monotherapy with:

• Cefepime 2 g IV Q8H

• Meropenem 1 g IV Q8H

• Imipenem/cilastatin 500 mg IV Q6H

• Piperacillin/tazobactam 4.5 g IV Q6H

• Ceftazidime 2 g IV Q8H (recent data shows increasing resistance to ceftazidime and inferior Gram-positive coverage to alternative regimens)

Indications for resistant Gram-positive coverage

Vancomycin or linezolid is NOT recommended as part of initial treatment unless one of the following is present and, if started, should be discontinued after 2-3 days if there is no evidence of Gram-positive infection:

• Hemodynamic instability
• Suspected catheter-associated infection
• Mucositis or cellulitis
• Pneumonia
• History of MRSA infection or colonization
• Gram-positive bacteremia prior to final culture results
• Recent fluoroquinolone prophylaxis

Alternative regimens

• Pneumonia: Broaden coverage to include Vancomycin or Linezolid and a macrolide or fluoroquinolone. Consider PJP.
• Diarrhea: Evaluate for C.diff
• Sinusitis: Urgent ENT evaluation. Broaden coverage to include invasive fungi.
• Oral ulceration: Consider broadening coverage to include Acyclovir for HSV and/or Fluconazole for Candida.
• Bone marrow transplantation: Evaluate for CMV. Consider broadening coverage to include Ganciclovir.
• Hemodynamic instability: Broaden coverage to include resistant Gram-positive, Gram-negative, and anaerobic bacteria and fungi, typically with Vancomycin or Linezolid, a Carbapenem, and Amphotericin, Voriconazole, or Caspofungin.

Persistent Fever

Continue empiric therapy until either culture data is available to direct management or after 3-5 days if the patient fails to improve. The median time to defervescence in adequately treated patients is 5 days with hematologic malignancies and 2-3 days with solid tumors. If the patient is still febrile or develops recurrent fevers after this time period further work up is suggested.

1. Re-evaluate sources of infection
2. Re-evaluate indications for resistant Gram-positive coverage and consider adding vancomycin or linezolid.
3. Re-evaluate indications for resistant Gram-negative organisms and anaerobes and consider broadening to carbapenem antibiotics.
4. Consider fungal coverage in high risk patients if fevers persist after 4-7 days of appropriate antibiotic coverage and duration of neutropenia is expected to last >7 days.
   • Caspofungin 70 mg IV x 1 dose, then 50mg IV daily
   • Liposomal Amphotericin B 3 mg/kg/day
   • Voriconazole 6 mg/kg IV Q12H x 2 doses, then 4 mg/kg IV Q12H

Caspofungin provides excellent coverage for Candida and is well tolerated, however nodular pulmonary infiltrates warrant coverage of Aspergillus with Voriconazole or Amphotericin B as echinocandins do not provide adequate coverage of Aspergillus or endemic fungi.

In cases of severe or refractory febrile neutropenia, consider granulocyte colony stimulating factor (G-CSF) to facilitate neutrophil count recovery, however routine use is NOT recommended as it does not reduce duration of fever or mortality despite shortening duration of neutropenia.

Duration of Antimicrobials

Documented infection: Continue antimicrobials as directed by culture data. Continue treatment for the standard duration for that particular infection and until myeloid recovery (ANC>500 cells/microliter). If counts recover prior to completing the treatment course, consider transition to an oral regimen guided by culture data.

Negative Cultures: Continue empiric antimicrobial regimen until myeloid recovery (ANC>500 cells/microliter). If afebrile with no evidence of ongoing infection, consider transition to oral regimen (e.g. Ciprofloxacin + Amoxicillin/Clavulanate) and continue until myeloid recovery.