chemotherapy-induced neutropenia?
Bacteria are the primary pathogens associated with infection in febrile neutropenic
patients, especially those occurring early.
16 Bacteremia (reported in approximately
25% of febrile neutropenic patients) is most often caused by aerobic gram-negative
bacilli (including Pseudomonas aeruginosa, Escherichia coli, and Klebsiella
pneumoniae) or aerobic gram-positive cocci (i.e., coagulase-negative staphylococci,
S. aureus, enterococci, viridans streptococci).
17 Since the mid-1990s, the proportion
of gram-negative infections has decreased with a proportional increase in grampositive infections.
18 Gram-positive bacteria now account for approximately 60%
to 70% of microbiologically documented infections in neutropenic cancer patients.
This is likely attributable (in part) to the frequent use of indwelling IV catheters,
intensive chemotherapy, and widespread use of broad-spectrum antibiotics.
S. aureus (including MRSA) and coagulase-negative staphylococci, streptococci
(including S. pneumoniae and viridans streptococci), and Corynebacterium species
are increasingly important pathogens.
19 Moreover, enterococcal infections (including
vancomycin-resistant enterococci [VRE]) are increasing in frequency. Meningitis
caused by the intracellular organism Listeria monocytogenes can be observed in
patients with defective cellular immunity caused by disease or prolonged
corticosteroid use. In general, anaerobic bacteria are an
infrequent cause of infection in granulocytopenic patients with hematologic
20 However, they should be suspected in patients with GI malignancies
or with significant disruption of the GI tract.
20 Clostridium difficile is another
anaerobic pathogen that may cause infection in this population.
Pneumocystis jiroveci (formerly known as Pneumocystis carinii or PCP) is a
pathogen responsible for lung infections primarily in patients with HIV infection.
However, PCP can also be responsible for lung infections in some cancer
22 Seen predominantly in patients with solid tumors or hematologic
malignancies receiving long-term corticosteroids, PCP may present as subacute,
febrile, hypoxemic, and diffuse pulmonary involvement.
Invasive fungal infections (IFIs) are a major cause of morbidity and mortality
among neutropenic cancer patients and patients undergoing HSCT.
of invasive fungal infections in febrile neutropenic patients varies widely because of
differences in definitions, methods of detection, patient populations, and prior use of
antifungal prophylaxis. In general, patients with hematologic malignancies have a
higher incidence of fungal infections than those with solid tumors.
risk of bacterial infections, the risk of invasive fungal infections is also related to the
degree and duration of neutropenia. IFIs tend to occur later in the illness. Patients
with prolonged neutropenia (>7 days) or with acute myelogenous leukemia (AML)
undergoing intensive induction therapy, allogeneic HSCT recipients, and those
undergoing therapy for GVHD are at increased risk of acquiring systemic fungal
24 Up to 50% of patients who die during prolonged periods of
neutropenia have evidence of deep-seated mycoses.
23 Before the use of fluconazole
prophylaxis in selected populations, Candida species were responsible for most
invasive fungal infections. Most fungal infections in neutropenic cancer patients are
caused by Candida and Aspergillus species.
26–28 Other less common but important
pathogenic fungi are those associated with zygomycosis (e.g., Mucor and Rhizopus
species) and other emerging pathogens (non-albicans Candida, Trichosporon
beigelii, Malassezia species, Cryptococcus neoformans, and Fusarium species).
Today, invasive infections attributable to Aspergillus species and other molds are a
major cause of IFI-related death (particularly in those with prolonged neutropenia
29 Recent reports of improved survival from IFIs are likely related to
newer prophylactic and treatment options and advances in cancer chemotherapy.
As previously stated, most viral infections in neutropenic cancer patients are
caused by a reactivation of latent infection rather than new infection.
may include hepatitis B virus (HBV), herpes simplex virus (HSV), and Varicella
zoster virus (VZV). Other viruses, such as CMV, can be either reactivation or newly
acquired during HSCT. The risk of viral reactivation in these patients increases in
patients who are seropositive prior to transplant. Respiratory viruses (e.g.,
respiratory syncytial virus [RSV], influenza, parainfluenza), GI viruses (such as
rotavirus and norovirus), and other seasonal viruses may occasionally cause
STRATIFICATION FOR RISK OF INFECTION
Risk stratification to identify patients most likely to experience neutropenia has
important implications for decisions about prevention, diagnostic strategies, empiric
therapy (selection, route of administration, duration), and site of care.
general, the underlying malignancy, status of disease (i.e., active vs. inactive), degree
and duration of neutropenia, and chemotherapy type impact risk. Patients at highest
risk of complications include those with prolonged (>7 days) and profound (<100
cells/μL) neutropenia or with select comorbidities (hypotension, severe mucositis
interfering with swallowing or causing diarrhea, pneumonia, new-onset abdominal
pain, hepatic or renal insufficiency, or neurologic changes).
with shorter (≤7 days) anticipated durations of neutropenia without significant
comorbidities are generally considered at low risk of complications of infection.
Patients without fever but exhibiting new signs of infection should also be treated as
high risk. Presenting signs and symptoms, cancer type, chemotherapy regimen,
medical comorbidities, and prior history of febrile neutropenia (especially if severe
or prolonged) should also be considered. Patients with select solid tumors (breast,
lung, colorectal, ovarian) and lymphoma most frequently experience neutropenic
fever. Chemotherapeutic regimens associated with the highest (>20%) incidence of
neutropenia are summarized in detail elsewhere
The factors impacting risk have been utilized by the National Comprehensive
Cancer Network in assigning infection risk in cancer patients as low, medium, and
3 Other risk assessment tools have been proposed,
Multinational Association for Supportive Care in Cancer (MASCC) index.
at least 60 years, presence of hematologic malignancies with a history of prior fungal
infections, severe symptoms (particularly hypotension), inpatient site of care, organ
dysfunction (hepatic and renal), and presence of chronic obstructive pulmonary
disease are important variables that result in a low MASCC score (i.e., <21), and
(consequently) patients with any of these factors are considered at highest risk.
Young patients (<20 years) with solid tumors and no or mild symptoms (including the
absence of hypotension) or organ dysfunction are generally at low risk for
yes, which agents should be used?
Exogenous contamination can be prevented by strict protective isolation of patients
in specially designed rooms that maintain a sterile environment. These laminar
airflow rooms are ventilated with air that is passed through a high-efficiency
particulate air filter, which removes greater than 99% of all particles larger than 3
μm. Total protective isolation is accomplished by strict isolation in conjunction with
the administration of sterile food and water, local skin care, and intensive microbial
surveillance. However, this regimen is burdensome, difficult to accomplish, and
expensive, and is recommended only for high-risk patients (such as allogeneic HSCT
4 HSCT recipients and candidates undergoing conditioning therapy should
avoid exposure to plants, flowers, and certain foods (such as uncooked fruits and
vegetables), which increase the risk of exposure to fungi.
adherence to adequate hand-washing procedures is essential. In addition, contact
isolation is advocated in circumstances in which the patient may be colonized or
potentially contagious respiratory viral illnesses is advocated.
Early administration of antibiotics (i.e., antibacterials, antifungals, and antivirals)
during the afebrile, neutropenic period in select high-risk patients may result in a
reduction in the number of febrile episodes and subsequent risk of infection. The
goals of such prophylactic regimens are intended to reduce pathogenic endogenous
microflora or prevent the acquisition of new microorganisms. The potential benefits
of such prophylaxis must outweigh the risks of antibiotic-related adverse effects
including drug interactions, the development of resistance (most notable with
antibacterials), and the potential for superinfection. Use of agents for prophylaxis
(such as a fluoroquinolone for antibacterial prophylaxis) may also preclude the use
of the class as empiric therapy for subsequent suspected or documented infections.
In general, lowest-risk cancer patients (such as those receiving standard
chemotherapy for many solid tumors, and neutropenia anticipated to be <7 days)
should not routinely receive antibacterial and antifungal prophylaxis.
administration of antivirals in such patients is generally restricted to those with a
history of prior infection (such as HSV). In contrast, allogeneic HSCT recipients and
and should receive antibacterial, antifungal, and (in select cases) antiviral
Routine antifungal prophylaxis is not indicated in patients with neutropenia at low
risk of infection. However, select patients are at increased risk of developing
23 Because of the frequency with which such infections are
encountered, difficulties in establishing a diagnosis, poor response rates in patients
with serious invasive infection who are immunocompromised, and effective
prophylactic strategies are necessary in select intermediate and all high-risk patients.
In patients for whom antifungal prophylaxis is indicated, the choice of the agent
depends largely on the risk of invasive mold infections.
Nonabsorbable Antifungal Agents
Nonabsorbable antifungal agents, such as oral nystatin,
38 have been studied. Although oral amphotericin B and clotrimazole
reduce the frequency of oropharyngeal candidiasis, none of these antifungals has a
role as primary prophylaxis of invasive fungal infections.
activity while minimizing side effects associated with IV administration, aerosolized
delivery of amphotericin B deoxycholate has been investigated for the prevention of
invasive fungal infections in this patient population,
amphotericin B has been used in leukemic and HSCT patients.
the optimal dose, delivery device, and duration for aerosol administration of
amphotericin B preparations have not yet been determined.
The use of systemic antifungals for prophylaxis has been summarized elsewhere.
Many of the earlier studies evaluated the prophylactic role of IV amphotericin B.
In general, use of amphotericin B deoxycholate is limited in this setting due to its
toxicities (i.e., infusion-related reactions, nephrotoxicity, and electrolyte
disturbances) relative to available options for prophylaxis. Consequently,
amphotericin B is generally discouraged for primary prophylaxis in high-risk
patients, unless the patient is unable to receive other mold-active prophylactic agents.
If required, a lipid-based formulation would be preferred, especially in patients at
increased risk of amphotericin B-induced nephrotoxicity.
Systemic azole antifungals (e.g., itraconazole, fluconazole, voriconazole,
posaconazole) may also be considered in select patients, but differ considerably in
their spectrum of activity, adverse reaction profile, drug interactions, and need for
serum concentration monitoring. The newest member of this class, isavuconazole,
while representing potential advantages over comparator agents, has not yet been
Itraconazole has been well studied as an antifungal prophylaxis. In addition to in
vitro activity against many Candida species (e.g., Candida albicans), itraconazole is
active in vitro against Aspergillus species and reduces systemic Candida
45–47 Although itraconazole oral solution demonstrates improved
bioavailability over the capsule formulation, it is associated with significant GI
Itraconazole is contraindicated in patients with reduced cardiac
ejection fraction due to its negative inotropic effect. Use of newer azoles (such as
posaconazole and voriconazole) has largely replaced the use of itraconazole for
prophylaxis in patients at increased risk of mold infections (such as those patients
undergoing immunosuppressive therapy for GVHD).
Fluconazole prophylaxis decreases the frequency of both superficial (e.g.,
oropharyngeal candidiasis) and systemic fungal infections in HSCT patients
not in patients with leukemia.
52,53 Fluconazole is available as both oral and IV
formulations, and its oral bioavailability is not significantly influenced by changes in
gastric acidity. The IV formulation enables fluconazole to be administered to
critically ill patients or patients who have difficulty swallowing. Although
fluconazole is useful prophylactically, concern about its lack of reliable in vitro
activity against molds limits its use in highest-risk patients. An increased frequency
of isolation of non-albicans Candida (e.g., Candida krusei, Candida glabrata,
Candida parapsilosis) has also been noted in some institutions.
Posaconazole has demonstrated improved survival, a reduction in proven or
probable IFI, and a reduction in invasive aspergillosis when compared with standard
prophylaxis (either itraconazole or fluconazole) for the prevention of fungal infection
in patients undergoing chemotherapy for AML or myelodysplastic syndrome.
Posaconazole was also effective prophylaxis in allogeneic HSCT recipients
56 Posaconazole is currently available in both oral
(solution and tablet) and parenteral (IV) formulations. The oral solution has been
replaced largely by the tablet formulation due to its improved bioavailability and
reduced dependency on the need for coadministration with high-fat meals for optimal
58 Absorption of oral posaconazole may be reduced in patients with
mucositis and in patients receiving acid-suppressing therapy.
IV posaconazole is not recommended in patients with significant renal impairment
because of the potential toxicity of the vehicle.
Voriconazole’s use as an antifungal prophylaxis in cancer patients at increased
risk of mold infections is not well supported by clinical data despite its established
use in the treatment of invasive aspergillosis.
60–62 Side effects (most notably
hepatotoxicity, rash, phototoxicity) and the increased potential (relative to other
azoles and the echinocandins) for drug interactions with voriconazole may limit its
prophylactic use to patients at highest risk of mold infections. Similar to IV
posaconazole, the use of IV voriconazole should be avoided in patients with
significant renal impairment because of the potential toxicity of the vehicle. Oral
voriconazole should be administered either 1 hour before or after a meal to optimize
The echinocandins (e.g., caspofungin, micafungin, and anidulafungin) may be useful
as a prophylactic strategy in high-risk patients. Micafungin has been compared with
fluconazole in autologous and allogeneic HSCT recipients.
endpoint (which included absence of breakthrough fungal infection and absence of
empiric modifications to the antifungal regimen owing to neutropenic fever),
micafungin was found to be superior. Although breakthrough candidemia, survival,
and adverse events were similar in both groups, a trend toward a reduction in
invasive aspergillosis in the allogeneic HSCT population was noted in the
micafungin group. Micafungin is currently US Food and Drug Administration (FDA)–
approved for the prevention of Candida infections in HSCT patients.
SELECTION AND MONITORING OF PROPHYLACTIC ANTIFUNGALS
The use of primary antifungal prophylaxis in cancer patients with neutropenia should
be reserved for patients at intermediate or high risk of invasive fungal infections
4 Patients with acute lymphocytic leukemia receiving remission or salvage
induction chemotherapy are at intermediate risk and should be considered for
prophylaxis. Although autologous HSCT recipients may not routinely benefit from
fungal prophylaxis (most notably those without evidence of mucositis), those with
prolonged neutropenia, mucosal damage, or receipt of purine analogs should receive
9 Acceptable options for prophylaxis against Candida species
include azoles (e.g., fluconazole, itraconazole, voriconazole, posaconazole) and the
echinocandins (micafungin and caspofungin).
4 Of these options, fluconazole is the
most commonly used agent. In the setting of colonization with fluconazole-resistant
Candida species (such as C. krusei, C. glabrata), an echinocandin (such as
In contrast, patients with higher risk for mold
infections (such as AML/MDS patients, or those with GVHD receiving intensive
immunosuppressive therapy regardless of neutropenia) should be considered for
prophylaxis with mold-active drugs (such as posaconazole, voriconazole,
echinocandins, or amphotericin B) during periods of risk.
also recommended in the setting of anticipated periods of prolonged (at least 2
weeks) neutropenia, or prolonged neutropenia immediately before HSCT.
Use of itraconazole, posaconazole, and voriconazole for prevention of fungal
infections should be avoided in patients receiving vinca alkaloids (such as
vincristine) due to their inhibition of the cytochrome P4503A4 (CYP3A4) isoenzyme
and the resulting reduction in drug clearance of the vinca alkaloid. Fluconazole,
while a CYP34A inhibitor, is less potent than these other azoles. Voriconazole also
inhibits other cytochrome P450 isoenzymes to the greatest extent, expanding its
potential for significant drug–drug interactions. The impact of isavuconazole on vinca
alkaloids has not yet been report, but the potential for interactions does exist.
Prophylaxis is generally continued during the period of neutropenia. In those with
acute leukemia, myelodysplastic syndrome (MDS), or autologous HSCT recipients,
prophylaxis should continue until day 75 after transplant or through induction therapy
64 Patients with a history of documented Aspergillus
infection undergoing intensive chemotherapy should be considered for voriconazole.
Although the addition of a second prophylaxis (e.g., echinocandin) may be
considered, the benefits of combination therapy for secondary prophylaxis are
Prophylactic use of antifungals may also be used in patients with a prior history of
invasive disease due to Candida spp. or filamentous fungi. Such prevention (known
as secondary prophylaxis) should be considered in such patients during subsequent
chemotherapy or stem cell transplantation for the duration of immunosuppression.
In contrast to the predictable serum concentrations resulting from fluconazole
administration, itraconazole, voriconazole, and posaconazole exhibit significant
variability in drug concentration, most notably following oral administration.
Therefore, serum concentration monitoring of these agents may help assure optimal
drug exposure while reducing the potential for concentration-related toxicities.
However, determination of definitive target concentrations for prophylactic use is
hampered by the lack of controlled, prospective clinical trials. For itraconazole,
steady-state trough concentrations of >0.5 mcg/mL or greater have been
recommended. Voriconazole steady-state serum concentration of >0.5 to 4 mcg/mL
has been recommended for use as prophylaxis. Studies regarding the optimal trough
concentration of posaconazole for prophylaxis differ, but range between 0.5 and 0.7
Because the GI tract is an important reservoir of potential pathogens, gut
decontamination has been investigated.
19 However, use of nonabsorbable
antibacterial agents has been replaced by oral, absorbable antibiotics.
ABSORBABLE (SYSTEMIC) ANTIBACTERIALS
Although trimethoprim–sulfamethoxazole (TMP–SMX) decreases bacterial
infections in neutropenic patients,
it may not reduce mortality in this patient
population. The potential benefits of TMP–SMX prophylaxis must be carefully
balanced against the potential for drug-induced bone marrow suppression,
hypersensitivity reactions, hyperkalemia, nephrotoxicity, pancreatitis, the emergence
of resistant organisms (e.g., E. coli), and the development of superinfections. In
addition, leukemic patients receiving mucotoxic chemotherapy and TMP–SMX
prophylaxis may be at increased risk for infections caused by viridans
70 Therefore, TMP–SMX should not be routinely used for primary
prophylaxis (except as noted below).
TMP–SMX prevents P. jiroveci (PCP) pneumonia in both ALL and HSCT patient
populations. Patients with malignancy at highest risk for experiencing P. jiroveci
(PCP) pneumonia (i.e., patients with acute lymphocytic leukemia receiving intensive
chemotherapy, those with acquired immunodeficiency syndrome, allogeneic HSCT
recipients, those receiving alemtuzumab, patients with GVHD, and those in whom
neutropenia is anticipated to exceed 10 days) should receive TMP–SMX
9 Recipients of T-cell-depleting agents (e.g., fludarabine or cladribine),
cancer patients receiving prolonged or high-dose corticosteroids (>20 mg of
prednisone or its equivalent daily), and autologous HSCT recipients should also be
considered for prophylaxis with TMP–SMX.
In such settings, primary prevention
should be continued for up to 6 months (in the case of HSCT recipients) or longer (in
cases in which immunosuppression is continued). In the setting of alemtuzumab
therapy, such prophylaxis would generally continue for at least 2 months and until the
CD4 count exceeded 200 cells/μL.
In patients requiring PCP prophylaxis but unable
to tolerate TMP–SMX, patients should receive alternate prophylaxis with either
atovaquone, dapsone, or pentamidine (either IV or via aerosol).
The fluoroquinolones ciprofloxacin and levofloxacin are used by some centers as
prophylaxis for adult patients at high risk of infection.
the increasing frequency of gram-positive infections (including viridans streptococci)
and resistant gram-negative bacilli (most notable in P. aeruginosa and E. coli)
patients receiving fluoroquinolone prophylaxis.
reductions in mortality in high-risk patients receiving prophylaxis with these
fluoroquinolone prophylaxis is offset by the emergence of resistant organisms,
routine prophylactic use in low-risk patients should generally be avoided.
those at intermediate or high risk of bacterial infections (i.e., those patients with an
ANC ≤100 neutrophils/μL for >7 days) should be considered for fluoroquinolone
prophylaxis until either the onset of fever (at which time empiric antibacterials
would be started) or resolution of severe neutropenia.
fluoroquinolone chosen, local resistance patterns should be closely monitored before
Because of the increased risk of invasive pneumococcal infections, select patient
populations (notably asplenic patients, allogeneic HSCT recipients [owing to
functional asplenia and impaired B-cell immunity], and those undergoing
immunosuppression for GVHD) should be considered for prophylaxis with
penicillin. In patients with chronic GVHD, penicillin prophylaxis may be continued
during the administration of immunosuppressives. In HSCT recipients, prophylaxis
should begin 3 months after transplant and continue for 1 year after transplant.
Alternative prophylaxis should be considered in areas where penicillin resistance in
Most HSV disease in cancer patients is a consequence of reactivation from latent
infection. High-risk patients (e.g., seropositive for HSV undergoing allogeneic HSCT
or induction or re-induction therapy for acute leukemia) or patients previously
requiring treatment for HSV reactivation should be given antiviral prophylaxis. Both
oral or IV acyclovir and oral valacyclovir are appropriate initial choices in most
patients. Published data for famciclovir for this indication are lacking. Those
receiving foscarnet or ganciclovir (most commonly for prevention and treatment of
CMV infection) do not require additional prophylaxis for HSV, given the activity of
these against H. simplex. Prophylaxis should be administered during periods of
neutropenia and for at least 1 month after HSCT.
4 The duration may be extended in
those undergoing allogeneic HSCT with GVHD. Patients receiving alemtuzumab may
also require extended prophylaxis of up to 2 months after completion of therapy or
+ cells count >200 cells/μL, whichever is later.
Similar to HSV, VZV in cancer patients is most commonly reactivation. HSCT
patients who are seropositive for VZV should also be given long-term prophylaxis
(6–12 months for autologous HSCT and at least 1 year for allogeneic HSCT
4 particularly with receipt of either bortezomib or alemtuzumab.
prophylaxis in allogeneic HSCT patients should be considered in the setting of
continued immunosuppressive therapy. Like for HSV, patients receiving alemtuzumab
may also require extended prophylaxis of up to 2 months after completion of therapy
or recovery of CD4+ cells count >200 cells/μl, whichever is later. Agents active
against HSV are also useful for VZV prevention. In one study, low-dose (i.e., 500
mg/day, 3 times weekly) valacyclovir prophylaxis after a 35-day course of IV
acyclovir is safe and effective in allogeneic HSCT recipients.
Patients at highest risk of either CMV reactivation or primary infection (e.g.,
allogeneic HSCT patients, those receiving alemtuzumab, and those with GVHD
requiring high-dose steroids) should be considered for antiviral prophylaxis against
this pathogen. One strategy is the administration of all patients at risk (universal
prophylaxis). Given the toxicity of ganciclovir IV, valganciclovir PO, foscarnet IV,
and cidofovir IV (the most potent agents for CMV), a second strategy, known as
preemptive, involves administration of antivirals prior to symptoms by following
serologic evidence (based on CMV pp65 antigen or two consecutive CMV PCR
tests) of viral replication. Foscarnet and cidofovir IV are generally reserved as
second-line agents for preemptive therapy (such as in the setting of neutropenia
secondary to ganciclovir). The potential role of valganciclovir PO (an oral pro-drug
of ganciclovir) as a preemptive strategy in this population has been evaluated and is
now considered a viable option in the absence of GVHD involving the GI tract.
Finally, a third prevention strategy is to combine use of less effective yet safer agents
(such as acyclovir or valacyclovir) together with active surveillance (up to 6 months
in allogeneic HSCT patients) and, when serologic evidence of virus replication
exists, initiate PO valganciclovir or ganciclovir IV therapy. Surveillance for CMV
may be extended in patients with chronic GVHD receiving immunosuppressive
therapy until recovery of CD4+ count of 100 cells/μL or greater.
Patients with prior infections with hepatitis B virus (HBV) or hepatitis C virus
(HCV) can experience reactivation of infection secondary to immunosuppressive
therapy. Reactivation of infection can occur in patients infected with HBV
undergoing immunosuppressive therapy (most notably in allogeneic HSCT recipients
and those receiving anti-CD20 or anti-CD52 monoclonal antibodies). Therefore,
serologic screening (utilizing testing for hepatitis B surface antigen [HBsAg] and
hepatitis B core antibody [HBcAb]) is generally performed in patients at increased
risk of infection. Prophylaxis should be considered in patients with positive tests.
Patients with one or more of these screening tests positive often undergo further
testing for active viral replication (utilizing a quantitative PCR test for HBV DNA).
Preemptive therapy should be considered in patient with evidence of viral
replication. Despite limited data in cancer patients, the nucleos(t)ide analogs
adefovir and tenofovir have largely replaced lamivudine monotherapy in such
settings due to the high incidence of viral resistance with this strategy. Other agents
considered for HBV prophylaxis may include entecavir and telbivudine.
Respiratory tract infections caused by RSV, influenza, and parainfluenza are less
commonly observed in patients with neutropenia. Although response to influenza
virus vaccine may be attenuated, patients undergoing cancer treatment should receive
annual vaccinations with inactivated influenza vaccine.
timing of such vaccinations may be best between cycles (>7 days after or >2 weeks
before next treatment). In contrast, immunocompromised patients should not receive
the intranasal live virus vaccine.
Hematopoietic colony-stimulating factors (CSFs) such as granulocyte CSF (G-CSF;
patients receiving myelosuppressive or myeloablative chemotherapy have
demonstrated that concurrent use of the CSFs can reduce the duration of neutropenia.
The selection of one CSF agent over another is often based on practitioner preference
Hematopoietic growth factors (more specifically G-CSF [filgrastim] or pegylated
G-CSF [pegfilgrastim]) reduce the risk of chemotherapy-induced febrile
31,85–87 Risk factors for neutropenia include age (i.e., >65 years),
medical history (including prior history of febrile neutropenic episodes, nutritional
status, unstable comorbidities, and presence of active infections), disease
characteristics (especially those involving bone marrow resulting in cytopenias), and
myelotoxicity of the regimen (including both chemotherapy and radiation) used to
treat the underlying malignancy.
85–87 Routine use of CSFs for the prevention of
febrile neutropenia should be discouraged in patients at low risk (<10%) of
In contrast, guidelines advocate the use as primary
prophylaxis in patients at high risk (>20%) of fever and neutropenia. Some
guidelines also recommend administration of CSFs for primary prevention for
patients >65 years with diffuse aggressive lymphoma treated with curative
chemotherapy (especially in the setting of significant comorbidities and in those
receiving select dose-dense chemotherapy regimens). Although benefits of CSFs are
less clear in patients with intermediate risk (10%–20% risk of febrile neutropenia),
they should be considered on a case-by-case basis.
84 CSFs are generally avoided as
prophylaxis in patients undergoing radiation therapy concomitant with chemotherapy
because of the potential for thrombocytopenia
88 or reductions in tumor response.
Administration is generally continued 3 to 4 days after chemotherapy administration
and continued until a sufficient and stable postnadir ANC recovery is established.
Pegylated G-CSF may be preferred in some settings owing to the convenience of
Consideration of the use of CSFs as secondary prophylaxis (i.e., prevention of
febrile neutropenia in patients undergoing second or subsequent cycles of
chemotherapy) should be based on repeated assessments of patient risk of febrile
84 Patients experiencing prior episodes of febrile neutropenia or
neutropenia limiting the dose of chemotherapy without prior CSFs should be
considered for secondary prophylaxis.
Although beyond the scope of this chapter, select vaccinations have also been
recommended for both autologous and allogeneic HSCT recipients (primarily caused
by a decline in antibody titers to many vaccine-preventable diseases).
(but are not limited to) administration of pneumococcal, influenza virus and H.
influenzae vaccines. Live vaccinations should be avoided in this population.
However, because immune response may be altered immediately after transplant,
delays of up to 3 months after cessation of immunosuppressive chemotherapy are
recommended for many vaccines. In addition, serologic testing of antibody response
is recommended in selected settings.
Although data to support use are sparse, IV immunoglobulins have been
recommended for HSCT recipients with severe hypogammaglobulinemia (i.e., serum
immunoglobulin G level <400 mg/dL) and recurrent infections.
immunoglobulins (IVIG) have been used as adjuncts in the prevention and treatment
of CMV infections. In contrast, granulocyte transfusions have not been proven to be
effective in either prevention or treatment of infection in the neutropenic cancer
INFECTIONS IN NEUTROPENIC CANCER
CASE 75-1, QUESTION 4: Seven days after completing chemotherapy, B.C. experienced a fever of 102°F
WBC count, 1,400 cells/μL, with 3% polymorphonuclear leukocytes (PMNs), 1% band forms, 70%
lymphocytes, and 22% monocytes
Platelet count, 17,000 cells/L
Serum creatinine (SCr), 1.1 mg/dL
Blood urea nitrogen (BUN), 24 mg/dL
What are the signs and symptoms of infection in B.C.? What are the most common sites and sources of
infection in patients such as B.C.?
B.C. has an ANC of 48 cells/μL (1,400 WBCs/μL × [0.03 PMNs + 0.01 bands])
and is therefore at high risk for infection.
Fever in neutropenic patients is defined as a single oral temperature of at least
38.3°C (101°F) or a temperature of at least 38.0°C (100.4°F) for more than 1 hour in
the absence of an obvious cause.
It is the earliest (and often the only) sign of
infection in neutropenic patients, because typical signs can be modified or absent in
4 However, only 48% to 60% of patients with febrile
neutropenia have occult or documented infections.
3 Noninfectious sources of fever in
the neutropenic cancer patient include inflammation, tumor progression, tumor lysis,
adverse drug reactions, and transfusion reactions.
consistent with a diagnosis of infection without fever should be considered to be
infection in the neutropenic host until proven otherwise.
In patients with documented infections, the most common sites are skin, mouth,
throat, esophagus, sinuses, abdomen, rectum, liver, vascular access, lungs, and
92 Although the lung is the most common site of serious infection in
neutropenic cancer patients, fever and dry cough are often the only presenting signs of
92 The impaired inflammatory response results in scant sputum production,
and sputum Gram stains often contain few PMNs. Radiologic evidence of a
pulmonary infection can be minimal or absent, and the chest examination is frequently
93 Pneumonia is associated with high mortality in neutropenic patients,
particularly in the setting of bacteremia. In the presence of shock, a mortality rate of
approximately 80% has been observed in these patients.
Invasive procedures such as venipuncture, central IV catheter placement (e.g.,
Hickman catheter), and skin biopsies are associated with cellulitis and systemic
infections. However, the typical signs and symptoms of infection (e.g., pain, heat,
erythema, swelling) are often absent in part owing to inadequate granulocytes.
Colonization of these lesions may result in local infection and the potential for
systemic dissemination of bacteria and fungi. Bacteremia occurs primarily from entry
of bacteria through the skin or through unrecognized ulcerations in the GI and
Because of the frequent lack of physical signs and symptoms of infection, the
clinician must obtain an accurate history (including the cancer type and treatment
regimen, new signs of infection, antimicrobial prophylaxis, prior infections, and
comorbidities) and conduct a careful physical examination at the first sign of fever. A
detailed search for subtle signs and symptoms of inflammation at the most common
sites, such as the oropharynx, bone marrow aspiration sites, lung, periodontium, skin,
vascular catheter access sites, nail beds, and perineum (including the anus) is
necessary. Before antibiotics are initiated, two sets of blood cultures (with
each set consisting of two culture bottles) should be obtained.
indwelling central venous catheters, one of the two sets of blood cultures should be
obtained from the catheter to help rule out catheter-related infection.
stools may be tested for the presence of C. difficile. Additional Gram stain and
cultures (e.g., stool, urine, skin, IV site, respiratory specimens) should be obtained
depending on signs and symptoms.
4 The yield from such cultures, however, may be
affected by the prior or concurrent administration of prophylaxis.
and oximetry should be obtained in the presence of respiratory symptoms.
Respiratory virus testing should take place for patients with upper respiratory tract
infection symptoms (i.e., coryza) or cough.
In settings in which pulmonary
aspergillosis is suspected, further radiologic evaluations (such as computed
tomography scans) should be considered.
29 A complete blood count, serum
electrolytes, coagulation, C-reactive protein, urinalysis, and assessment of organ
function (e.g., liver and kidney function) should be obtained to assist in drug dosing
and monitoring for treatment-related toxicities.
Recent advances have been made in nonculture-based diagnostic tests that help
support (or in some cases eliminate) the diagnosis of infection in these patients.
Such studies include C-reactive protein
tests are not routinely ordered, and their role in the treatment of the neutropenic
cancer patient has not yet been established.
101 and β-D-glucan testing may assist in the diagnosis of fungal
103 Serial galactomannan testing has also been used preemptively to
initiate antifungal therapy before overt signs and symptoms of invasive fungal
In addition to other issues regarding sensitivity and specificity of
these assays, both galactomannan and β-D-glucan are affected by prior or current
29 At present, the use of these tests should be restricted to
persistent fever despite other etiologic investigations.
CASE 75-1, QUESTION 5: How can an infection be confirmed in patients such as B.C.?
Several factors influence the colonization and subsequent infection by
microorganisms in cancer patients. Organisms isolated from infected patients can be
found in endogenous flora or acquired during hospitalization.
colonization include staff-to-staff and patient-to-patient transmission (e.g., lack of
frequent and adequate hand hygiene), direct transmission from the environment (e.g.,
inadequately disinfected bathtubs, sinks, toilet bowls), foods (e.g., raw fruits and
vegetables), inhalation from contaminated fomites (e.g., respirators, ventilating
systems), and IV access devices. In addition to immunosuppression, the underlying
malignancy and associated chemotherapy diminish the cancer patient’s resistance to
The acquisition of and subsequent colonization by potentially pathogenic microbes
may be detected by serial surveillance cultures of specimens obtained from various
body sites such as the nasopharynx, axilla, urine, and rectum. Such surveillance
cultures may be useful for infection control purposes. However, little clinically
useful information is gained in the absence of infection. Therefore, surveillance
cultures are generally restricted to select patients for infection control purposes. In
such cases, culture of the anterior nares (for MRSA) or rectal samples (for VRE or
multidrug-resistant gram-negative bacilli) may be performed.
In summary, B.C.’s surveillance culture results indicate that she is colonized with
several potential pathogens associated with infection in the immunocompromised
host, but these results are probably not useful in selecting empiric antibiotics for her
be performed in patients such as B.C.?
Neutropenic cancer patient with fever and/or other signs and symptoms of
infection should undergo prompt risk assessment and initiation of antibiotic therapy.
obtained. Early studies confirmed high mortality in neutropenic patients with
untreated gram-negative infections up to 24 to 48 hours after the onset of fever. Crude
mortality rates secondary to P. aeruginosa bacteremia approached 91%.
of empiric, broad-spectrum antibiotics has resulted in significant reductions in
Initial Empiric Antibiotic Regimens
of the fact that neither the source of her fever nor the pathogen has been established?
Practice guidelines prepared by the National Comprehensive Cancer Network,
Infectious Diseases Society of America,
4 and the European Society of Medical
identify antimicrobial options for the treatment of fever in the neutropenic
cancer patient. The ideal antibiotic regimen for empiric management in this setting
(i.e., those without evidence of site- or pathogen-specific infections) remains
controversial. High-risk patients requiring IV therapy are often candidates for
monotherapy regimens, including an antipseudomonal third-generation cephalosporin
(e.g., ceftazidime), a fourth-generation cephalosporin (e.g., cefepime), or an
antipseudomonal carbapenem (e.g., imipenem–cilastatin or meropenem).
Initial, empiric use of additional antibiotics (such as fluoroquinolones,
aminoglycosides, and vancomycin) may be added to patients who are clinically
4 Alternative initial empiric parenteral regimens (excluding those containing
vancomycin) have been investigated in this patient population.
because no significant differences exist among any of these empiric approaches,
monotherapy is employed in most patients.
Optimal Antibacterial Spectrum
Despite continued development in antibacterial drugs, the empiric management of
febrile neutropenic patients is complicated by the changing spectrum of bacterial
pathogens and their antimicrobial susceptibilities. Empiric antibiotic regimens
should provide broad-spectrum coverage against the potential gram-negative bacilli
most commonly isolated from neutropenic cancer patients (e.g., E. coli, K.
pneumoniae, P. aeruginosa), staphylococci, and viridans streptococci.
mortality from untreated bacteremia caused by P. aeruginosa is so high,
empiric regimens have traditionally included antimicrobials with antipseudomonal
Selecting an initial empiric regimen for a given patient should take into account the
patient’s risk of infection, likely pathogens, infection site-specific antibiotic efficacy,
and institutional susceptibility patterns. This point is especially true in areas
experiencing a growing frequency of multidrug-resistant organisms, such as MRSA,
VRE, and extended-spectrum β-lactamase (ESBL)-producing organisms (such as K.
18 Patient-related considerations should include medical
stability, allergies, prior and concomitant antimicrobials, and organ dysfunction (e.g.,
renal or hepatic). Attempts should be made to identify low-risk patients for whom
oral antimicrobial therapy may be an option. Finally, dosing schedules, acquisition
costs, and the potential for significant toxicities should be considered. In addition to
broad-spectrum activity, antibacterial regimens should be bactericidal against the
infecting pathogen. However, no adequately controlled comparative trials of
bacteriostatic versus bactericidal antibiotics have been conducted in humans.
In summary, many organisms, including those recovered from surveillance
cultures, may be pathogens in B.C. Those associated with a high mortality rate during
the first 48 hours should be empirically treated pending culture and sensitivity
results. Therefore, an empiric regimen with optimal activity against commonly
isolated gram-negative bacilli (including P. aeruginosa) should be promptly
Carefully selected (i.e., low risk) adult febrile neutropenic patients may be
candidates for oral antibiotic therapy, either as initial therapy or as follow-up to IV
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