Medication Summary
Medications are used to treat fevers or possible infections and to stimulate bone marrow in order to increase the production of neutrophils. Current joint guidelines of the American Society of Clinical Oncology (ASCO) and the Infectious Diseases Society of America (IDSA) recommend that neutropenic cancer patients with fever receive initial doses of empiric antibacterial therapy within 1 hour of triage and be monitored for ≥4 hours before discharge. [5] Delays in administering the first dose are associated with higher mortality.
The antibiotics of choice are those shown by culture and sensitivity studies to be the most effective for the organism causing the infection. If no causative organism is identified, use empirical broad-spectrum antibiotic coverage. Granulocyte growth factors and general supportive care should also be provided. Cytokines (growth factors) are used to stimulate production of neutrophils by acting on precursor cells.
Antibiotics
Class Summary
Antibiotic therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.
Imipenem and cilastatin (Primaxin)
Imipenem-cilastatin is a broad-spectrum antibiotic formulation for the treatment of serious infections and neutropenic fever.
Meropenem (Merrem I.V.)
Meropenem is a bactericidal broad-spectrum carbapenem antibiotic that inhibits cell-wall synthesis. It is effective against most gram-positive and gram-negative bacteria. It has slightly increased activity against gram-negative bacteria and slightly decreased activity against staphylococci and streptococci compared to imipenem.
Ceftazidime (Fortaz, Tazicef)
Ceftazidime is a third-generation cephalosporin shown in randomized trials to be a safe alternative to double antibiotic regimens for treating neutropenic fever in patients with cancer. It has broad-spectrum, gram-negative activity. Ceftazidime has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. It arrests bacterial growth by binding to 1 or more penicillin-binding proteins.
Ciprofloxacin (Cipro, Cipro XR)
Ciprofloxacin is a fluoroquinolone with activity against pseudomonads, streptococci, methicillin-resistant S aureus (MRSA), Staphylococcus epidermidis, and most gram-negative organisms, but it has no activity against anaerobes. It inhibits bacterial DNA synthesis and, consequently, growth.
Continue treatment for at least 2 days (7-14 d typical) after signs and symptoms disappear.
Two prospective randomized clinical trials showed that oral antibiotics could be safely substituted for intravenous (IV) antibiotics in low-risk patients with neutropenic fever. Until this finding is validated in large randomized trials, routine outpatient treatment is not recommended. Chemoprophylactic use has shown decreased mortality resulting from aerobic gram-negative bacteria.
Ofloxacin
Ofloxacin is a quinolone antibiotic with a broad spectrum of activity against aerobic bacteria. It binds to DNA-gyrase, promoting the breakage of the double-stranded DNA helix for a bactericidal effect.
Amphotericin B
Amphotericin B is empirically indicated in persistent neutropenic fever after a minimum of 4 d of broad-spectrum antibiotics (eg, imipenem or ceftazidime). It is used for empirical therapy for fungal infections or for documented fungal infections. It is produced by a strain of Streptomyces nodosus and can be fungistatic or fungicidal. Amphotericin B binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak, with subsequent fungal cell death.
Liposomal amphotericin B (AmBisome)
Liposomal amphotericin B was found by a large, multicenter, randomized, double-blind trial to be as effective as standard amphotericin B for empiric treatment of neutropenic fever and showed less breakthrough fungal infections and toxicity. [48]
Amoxicillin-clavulanate (Augmentin, Augmentin XR)
Amoxicillin-clavulanate, a beta-lactam antibiotic with a beta-lactamase inhibitor (clavulanic acid), is the combination used to treat bacteria resistant to beta-lactam antibiotics. Two prospective randomized clinical trials showed that oral antibiotics were safely substituted for IV antibiotics in low-risk patients with neutropenic fever. Until this is validated in large randomized trials, routine outpatient treatment for these patients is not recommended.
Cefepime (Maxipime)
Cefepime is a fourth-generation cephalosporin with good gram-negative coverage. It is used as monotherapy for the treatment of febrile neutropenia. It is similar to third-generation cephalosporins but has better gram-positive coverage.
Vancomycin (Vancocin)
Vancomycin is a potent antibiotic directed against gram-positive organisms and active against Enterococcus species. It is useful in the treatment of septicemia and skin structure infections. Vancomycin is indicated for patients who cannot receive or whose condition has failed to respond to penicillins and cephalosporins or for patients who have infections with resistant staphylococci. For abdominal penetrating injuries, this drug is combined with an agent active against enteric flora and/or anaerobes.
To avoid toxicity, the current recommendation is to assay vancomycin trough levels after the third dose, drawn 0.5 h before the next dosing. Use the creatinine clearance to adjust the dose in patients diagnosed with renal impairment.
Vancomycin is used in conjunction with gentamicin for prophylaxis in penicillin-allergic patients undergoing gastrointestinal or genitourinary procedures.
Gentamicin
Gentamicin is a bactericidal drug that blocks the functioning of the initiation complex and causes misreading of mRNA. Gentamicin or another aminoglycoside should be added to other broad-spectrum antibiotics if the neutropenic patient's condition is unstable or the individual appears septic. Gentamicin is an aminoglycoside antibiotic for gram-negative coverage. It is used in combination with both an agent against gram-positive organisms and one that covers anaerobes.
Gentamicin is not the drug of choice. It should be considered if penicillins or other less toxic drugs are contraindicated, if it is clinically indicated, and if the patient has a mixed infection caused by susceptible staphylococci and gram-negative organisms.
Piperacillin-tazobactam (Zosyn)
Piperacillin is a fourth-generation penicillin that has broad-spectrum coverage with activity against Pseudomonas aeruginosa. Piperacillin interferes with bacterial cell wall synthesis during active multiplication. Tazobactam prevents degradation of piperacillin by binding to the active site on beta lactamase.
Antifungal Agents
Class Summary
Antifungal agents exert their action by inhibiting fungal cell membrane formation or the inhibition of essential components of the cell wall of susceptible fungi.
Voriconazole (VFEND)
Voriconazole is a triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.
Caspofungin (Cancidas)
Caspofungin inhibits synthesis of beta-(1,3)-D-glucan, an essential component of the fungal cell wall.
Hematopoietic Growth Factors
Class Summary
Hematopoietic growth factors are administered to accelerate neutrophil recovery and shorten the duration of neutropenic fever. These agents are also indicated to treat patients with chronic neutropenia. However, although many benefits exist with using hematopoietic growth factors in acute neutropenic fever after chemotherapy, a survival benefit has not been shown.
Agents in this class include recombinant human granulocyte colony-stimulating factor (G-CSF) and the granulocyte-macrophage colony-stimulating factor (GM-CSF) sargramostim. Available forms of G-CSF include filgrastim, the biosimilar filgrastim-sndz, pegylated filgrastim (pegfilgrastim-jmbd), and the biosimilar pegfilgrastim-sndz.
Filgrastim (Neupogen, tbo-filgrastim, Granix, Zarxio, filgrastim-sndz)
Filgrastim is a granulocyte colony-stimulating factor (G-CSF) that activates and stimulates the production, maturation, migration, and cytotoxicity of neutrophils. It has been shown to accelerate neutrophil recovery and shorten the duration of neutropenic fever. Antibiotic treatment duration, amphotericin B use, hospital stay duration, and mortality, however, are unchanged. Filgrastim is most efficacious in severe neutropenia and documented infections.
Sargramostim (Leukine)
Sargramostim is a granulocyte-macrophage colony-stimulating factor (GM-CSF) that is indicated in the acceleration of neutrophil recovery after chemotherapy, the mobilization of autologous peripheral blood progenitor cells, bone marrow transplantation, and the delay or failure of bone marrow transplant engraftment.
Pegfilgrastim (Neulasta, Fulphila, pegfilgrastim-jmbd)
Pegfilgrastim is a long-acting filgrastim created by the covalent conjugate of recombinant G-CSF (ie, filgrastim) and monomethoxypolyethylene glycol. Like filgrastim, it acts on hematopoietic cells by binding to specific cell surface receptors, thereby activating and stimulating the production, maturation, migration, and cytotoxicity of neutrophils. Although no clinically meaningful differences in safety, purity, and potency between the biosimilar product and Neulasta were noted, pegfilgrastim-jmbd has not been approved as an interchangeable product.
Eflapegrastim (Rolvedon)
Recombinant human granulocyte growth factor (G-CSF) that binds to G-CSF receptors on myeloid progenitor cells and neutrophils, triggering signaling pathways that control cell differentiation, proliferation, migration, and survival. It is indicated to decrease incidence of infection, as manifested by febrile neutropenia, in adults with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with clinically significant incidence of febrile neutropenia.
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The margins of this massive spleen were palpated easily preoperatively. Medially, the 3.18-kg (7-lb) spleen crosses the midline. Inferiorly, it extends into the pelvis.
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Doppler sonogram at the splenic hilum reveals hepatofugal venous flow in a patient with portal hypertension.
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Two neutrophils among red blood cells. Courtesy of Britannica (https://www.britannica.com/science/neutrophil).
Tables
Syndrome |
Inheritance |
Gene |
Clinical Features |
Cyclic neutropenia |
Autosomal dominant |
ELA2 |
Alternate 21-day cycling of neutrophils and monocytes |
Kostmann syndrome |
Autosomal recessive |
Unknown |
Stable neutropenia, no MDS or AML |
Severe congenital neutropenia |
Autosomal dominant |
ELA2 (35-84%) |
Stable neutropenia, MDS or AML |
Autosomal dominant |
GFI1 |
Stable neutropenia, circulating myeloid progenitors, lymphopenia |
|
Sex linked |
Wasp |
Neutropenic variant of Wiskott-Aldrich syndrome |
|
Autosomal dominant |
G-CSFR |
G-CSF–refractory neutropenia, no AML or MDS |
|
Hermansky-Pudlak syndrome type 2 |
Autosomal recessive |
AP3B1 |
Severe congenital neutropenia, platelet dense-body defect, oculocutaneous albinism |
Chediak-Higashi syndrome |
Autosomal recessive |
LYST |
Neutropenia, oculocutaneous albinism, giant lysosomes, impaired platelet function |
Barth syndrome |
Sex linked |
TAZ |
Neutropenia, often cyclic; cardiomyopathy, methylglutaconic aciduria |
Cohen syndrome |
Autosomal recessive |
COH1 |
Neutropenia, mental retardation, dysmorphism |
Thrombocytopenia with absent radii (TAR) |
Autosomal recessive |
RBM8A |
Thrombocytopenia, MDS, absent radii, abnormal ulna |
Diamond-Blackfan anemia |
Autosomal dominant, X-linked recessive |
RPS19, RPL5, RPS26 |
Macrocytic anemia, other cytopenias, solid tumors, short stature, abnormal thumbs, cardiac septal defect |
Fanconi syndrome |
Autosomal recessive (rarely, X-linked recessive or autosomal dominant) |
FANCA, FANCC, FANCG |
Pancytopenia, solid tumors, skin hyperpigmentation and café au lait spots, abnormal thumbs |
Dyskeratosis congenita |
X-linked recessive, autosomal dominant, autosomal recessive |
DKC1, TINF2 |
Pancytopenia, MDS, nail dystrophy, leukoplakia, solid tumors |
Source: Modified from Berliner et al, 2004. [23] AML = acute myeloid leukemia; G-CSF = granulocyte colony-stimulating factor; MDS = myelodysplastic syndrome. |
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