| Drug Name | Administration | Spectrum of Activity | Toxicity | Refs |
Amphotericin B Deoxycholate | 0.6–1 mg/kg intravenously over 2–6 hours, daily | Amphotericin B (as deoxycholate or in a lipid formulation) has activity against most yeasts, Aspergillus and agents of mucormycosis. It is not active against Scedosporium, Fusarium, and dematiaceous molds | Most toxic. High incidence of renal insufficiency. One liter of 0.9% sodium chloride injection before or around the infusion may prevent nephrotoxicity | 8, 9 |
Acetaminophen 650 mg orally ± diphenhydramine 12.5–50 mg orally or intravenously may be given prior to amphotericin. Additional doses of acetaminophen and diphenhydramine may be given PRN or on a preset schedule. Alternatively one can observe a patient's response to an initial dose of amphotericin and give premedication only if amphotericin was not tolerated Meperidine 25 mg/dose may be given IV for rigors (oral administration is not effective). An additional 2 doses of meperidine may be administered at 10-minute intervals (total 3 doses) if rigors persist. Decreasing the rate of amphotericin administration may mitigate infusion-related effects |
| AmBisome (liposomal amphotericin B) | 3–7.5 mg/kg intravenously over 120 minutes, daily (may be reduced to 60 minutes if infusion over 120 minutes was tolerated) | See above | Less toxic than amphotericin B deoxycholate, but not more effective | 10 |
| Voriconazole | Initial dose: 6 mg/kg intravenously every 12 hours for 24 hours (2 doses), followed by Maintenance dose: 4 mg/kg intravenously every 12 hours | Treatment of choice for aspergillosis. No significant activity against agents of mucormycosis. May be preferable to lipid formulations of amphotericin B against Fusarium and Scedosporium | Interact with multiple drugs metabolized by cytochrome P450 enzymes, so that the dose of other drugs may need to be adjusted. Liver enzyme abnormalities have been described with all the azoles, and hepatic failure has been reported. Monitor LFT's weekly to biweekly, then monthly | No need for adjustment in renal insufficiency. Monitor levels and aim for 2–5 mcg/mL | 11 |
| Posaconazole | Initial and maintenance doses: 400 mg or 200 mg orally every 6 hours always with food | Active against yeast, Aspergillus, and some dematiaceous molds | There is NO intravenous formulation. Therapeutic levels are not reached for 5 to 7 days | 12 |
| Fluconazole | 400 mg intravenously or orally once or twice daily | Inactive against molds. Empirical administration for persistent fever and neutropenia should be considered only where a risk of aspergillosis is very low | Adjust dose in renal insufficiency: 50% doses for creatinine clearance <50 mL/min | 13 |
| Caspofungin | Loading dose: 70 mg intravenously on the first day of treatment followed on subsequent days by Maintenance dose: 50 mg intravenously daily | Active only against Candida and Aspergillus | Caspofungin has been shown to be equivalent to AmBisome in the management of persistent fever during neutropenia, but its efficacy compared to other agents in the treatment of established fungal infections in neutropenic patients is unknown | 14, 15 |
| Micafungin | 100–150 mg daily intravenously | Active only against Candida and Aspergillus | Micafungin has been shown to be effective for the management of candidemia and disseminated candidiasis, and equivalent to fluconazole as antifungal prophylaxis. Its efficacy compared to other agents in the treatment of established fungal infections in neutropenic patients is unknown | |
| Anidulafungin | Loading dose: 200 mg intravenously on the first day of treatment followed on subsequent days by Maintenance dose: 100 mg intravenously daily | Active only against Candida and Aspergillus | Anidulafungin has been shown to be effective for the management of candidemia and disseminated candidiasis, and equivalent to fluconazole as antifungal prophylaxis. Its efficacy compared to other agents in the treatment of established fungal infections in neutropenic patients is unknown | |
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| Management of Specific Clinical Syndromes During Neutropenia |
| Diagnostic Considerations | Management |
| Skin/Soft-Tissue Infections |
Prompt biopsy with histologic staining and culture for bacteria, mycobacteria, viruses, and fungi A vesicle should be unroofed and a scraping of the base examined by direct fluorescence assay (DFA) to make the diagnosis of VZV. The scrapings should also be sent for HSV testing |
Pathogens: Gram-negative bacilli (eg, Pseudomonas aeruginosa, Aeromonas spp., Plesiomonas shigelloides, Enterobacteriaceae) Streptococcus pyogenes Staphylococcus aureus | Management: Empirical management should include coverage against MRSA: Vancomycin 1000 mg intravenously every 12 hours or Daptomycin 4 mg/kg intravenously every 24 hours or Linezolid 600 mg intravenously or orally every 24 hours (can prolong the duration of neutropenia) For ecthyma gangrenosum include coverage of Pseudomonas: Treat Streptococcus pyogenes infections aggressively with: In case of streptococcal shock syndrome, intravenous immune globulin, human (IVIG) may be helpful: Treat perianal cellulitis with broad-spectrum coverage including anaerobes: Imipenem 500–1000 mg + Cilastatin 500–1000 mg administer intravenously every 6 hours or Meropenem 1000 mg administer intravenously every 8 hours or Piperacillin 4000 mg + Tazobactam 500 mg, intravenously every 6 hours |
| | |
Candida spp. Agents of mucormycosis (eg, Rhizopus, Mucor) Fusarium and dematiaceous molds | |
| Sinusitis |
Evaluate with CT scan and examination by otolaryngologist Tissue should be biopsied if there is suspicion of fungal infection or no response to antibiotic therapy after 72 hours |
Pathogens: Pseudomonas aeruginosa Staphylococcus aureus Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Enterobacteriaceae | Management: |
| Fungi: | |
| Pulmonary Infections |
CT scan and bronchoalveolar lavage should be performed early Pneumonia during neutropenia is often caused by Gram-negative bacilli and Staphylococcus aureus but can also be caused by community-acquired pneumonia pathogens Neutropenic patients are at risk for invasive fungal infections particularly aspergillosis |
Pathogens: Gram-negative bacilli Staphylococcus aureus Streptococcus pneumoniae Haemophilus influenzae Legionella spp Chlamydophila pneumoniae | Management: Cefepime, imipenem, and meropenem have better activity than ceftazidime against Streptococcus pneumoniae: Cefepime 2000 mg intravenously every 8 hours or Imipenem 500–1000 mg + Cilastatin 500–1000 mg intravenously every 6 hours or Meropenem 1000 mg intravenously every 8 hours or Piperacillin 4000 mg + Tazobactam 500 mg intravenously every 6 hours Adding coverage for atypical pathogens (mainly Legionella) is recommended: Adding coverage for MRSA in severely hypoxic or extensive infiltrates is recommended: |
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| Gastrointestinal Tract Infections |
| Mucositis or esophagitis: Lesions associated with mucositis or esophagitis can become superinfected |
| Pathogens: | Management: |
| Diarrhea: most commonly caused by Clostridium difficile (send toxin assay) but can also be caused by other organisms |
Pathogens: Salmonella spp Shigella spp Aeromonas spp Campylobacter spp Viruses (rotavirus, adenovirus, astrovirus, calicivirus) Parasites (Giardia, Cryptosporidium) | For diarrhea caused by Clostridium difficile: Note: For Clostridium difficile, no follow-up testing is recommended, as up to one-third of patients remain carriers, and treatment of carriers is not recommended |
| Enterocolitis: Enterocolitis in neutropenic patients (typhlitis) is most commonly caused by a mix of bowel organisms including Clostridium species and Pseudomonas |
| Pathogens: | |
| Urinary Tract Infections |
Treat bacteriuria in neutropenic patients Consider whether candiduria may represent disseminated candidiasis |
Pathogens: Enteric Gram-negative bacilli (Escherichia coli, Klebsiella spp.) Pseudomonas aeruginosa (prior antibiotics, instrumentation, stents) Enterococcus spp. (including VRE) Candida spp. | Management: Remove Foley catheter to clear colonization In a neutropenic patient, treat bacteriuria/candiduria regardless of symptoms Treat bacteriuria according to susceptibility testing Candiduria may be treated with fluconazole 400 mg intravenously or orally every day |
| CNS Infections |
Bacteria cause most cases of meningitis (Streptococcus pneumoniae, Listeria monocytogenes, Neisseria meningitidis, other Gram-negative bacilli, Rothia mucilaginosa [formerly Stomatococcus mucilaginosus]) In patients with cell-mediated immunodeficiency, also consider Listeria or Cryptococcus neoformans |
Pathogens: Streptococcus pneumoniae Listeria monocytogenes Neisseria meningitidis Gram-negative bacilli Enterococcus spp. | Management: Bacterial meningitis during neutropenia should be treated with combination therapy: Ceftazidime 2000 mg intravenously every 8 hours or Cefepime 2000 mg intravenously every 8 hours or Meropenem 2000 mg intravenously every 8 hours (can lower seizure threshold) + Vancomycin 1000 mg intravenously every 12 hours + Ampicillin 2000 mg intravenously every 4 hours |
| Encephalitis: Most commonly caused by HSV but consider other viruses |
| Encephalitis: Acyclovir 10 mg/kg intravenously every 8 hours until HSV encephalitis has been ruled out For HHV-6: Ganciclovir 5 mg/kg every 12 hours or foscarnet 90 mg/kg every 12 hours (some experts recommend both) |
| Brain abscesses: During neutropenia are almost always caused by fungi |
Candida spp., Aspergillus spp. (brain abscess during neutropenia) Cryptococcus (meningitis in T-cell immunodeficiency) | Cryptococcal meningitis: Amphotericin B deoxycholate 1 mg/kg intravenously every day for at least 2 weeks or An amphotericin B lipid formulation 6 mg/kg intravenously every day for at least 2 weeks with Flucytosine 25 mg/kg per dose orally every 6 hours (adjust dosage for renal insufficiency) for at least 2 weeks followed by Fluconazole 400–800 mg orally every 24 hours |
| Viral Infections During Neutropenia |
| Herpes Simplex Virus (HSV) |
HSV may reactivate during neutropenia, and worsen chemotherapy or radiation therapy-induced mucositis Suspicious oral and genital lesions should be cultured for HSV Pending culture results, empirical treatment of suspicious lesions should be initiated Reactivation during 1 cycle of chemotherapy does not imply HSV recurrence will follow each cycle, and prophylactic treatment is not necessary. If reactivation occurs after several cycles of chemotherapy, attempt prevention with valacyclovir 500 mg per dose, orally twice daily or acyclovir 800 mg orally twice daily When to use IV versus oral therapy? Oral agents may be as effective as intravenous acyclovir; the decision is based on the presence of nausea, vomiting, or clinical situations that make absorption questionable | Acyclovir 5 mg/kg per dose intravenously every 8 hours or Valacyclovir 500–1000 mg per dose orally twice daily or Famciclovir 250 mg per dose orally twice daily |
| Varicella Zoster (VSZ) |
VZV reactivation is related more to defects in cell-mediated immunity than to neutropenia A maculopapular and vesicular rash in a dermatomal distribution suggests VZV infection, although HSV may have a similar presentation A vesicle should be unroofed and a scraping of the base examined by direct fluorescence assay (DFA) to establish a diagnosis The main risk of VZV in immunocompromised patients is visceral dissemination. If infection is documented, respiratory precautions should be instituted and treatment started with high-dose intravenous acyclovir | |
| Cytomegalovirus (CMV) |
CMV is an uncommon pathogen during neutropenia, but can occur in the setting of coexisting severe defects of cell-mediated immunity Determination of pp65 antigenemia cannot be used during neutropenia, as the test requires an ANC >1000/mm3 to quantify the number CMV-infected white blood cells CMV disease (organ damage caused by CMV, as opposed to CMV reactivation determined by PCR or pp65 antigenemia) is unusual except in HIV (retinitis, colitis) and after allogeneic stem cell transplantation (pneumonitis, enterocolitis) Diagnosis of CMV colitis requires rectosigmoidoscopy or colonoscopy with biopsy. The tissue sample should be processed both for viral culture and immunohistochemistry, as there are cases diagnosed by one modality and not the other. A common differential diagnosis includes acute graft versus host disease, Clostridium difficile colitis, and neutropenic enterocolitis (typhlitis). Tissue examination is mandatory, as more than 1 process may be present The diagnosis of CMV pneumonitis requires an appropriate host (typically an allogeneic stem cell transplant recipient), a consistent clinical presentation, and the presence of CMV in the respiratory secretions16 or lung biopsy For CMV pneumonitis, the treatment of choice is ganciclovir | CMV pneumonitis: Ganciclovir 5 mg/kg intravenously every 12 hours for 21 days (adjust dose for renal insufficiency). Consider adding IVIG 500 mg/kg intravenously every 48 hours for 3 weeks or Foscarnet 90 mg/kg intravenously every 12 hours (May be substituted for ganciclovir to avoid the potential bone marrow toxicity of ganciclovir) |