# 08 - 79 Infections in Patients with Cancer

### 79 Infections in Patients with Cancer

■
■DIARRHEA
Similar to the vomiting syndromes, chemotherapy-induced diarrhea 
may be immediate or can occur in a delayed fashion up to 48–72 h 
after the drugs. Careful attention to maintained hydration and elec­
trolyte repletion, intravenously if necessary, along with antimotility 
treatments such as “high-dose” loperamide (4 mg at the first occur­
rence of diarrhea, with 2 mg repeated every 2 h until 12 h without 
loose stools, not to exceed a total daily dose of 16 mg), are appropriate. 
Octreotide (100–150 μg), a somatostatin analogue, or intralumenally 
acting opiate-based preparations may be considered for patients not 
responding to loperamide.

■
■MUCOSITIS
Irritation and inflammation of the mucous membranes (mucositis) 
particularly afflicting the oral and anal mucosa, but potentially involv­
ing the entire gastrointestinal tract, may accompany cytotoxic chemo­
therapy. Topical therapies, including anesthetics and barrier-creating 
preparations, may provide symptomatic relief in mild cases.
■
■ALOPECIA
Chemotherapeutic agents vary widely in causing alopecia, with anthra­
cyclines, alkylating agents, and topoisomerase inhibitors reliably 
causing near-total alopecia when given at therapeutic doses. Antime­
tabolites are more variably associated with alopecia. Psychological sup­
port and the use of cosmetic resources are to be encouraged. “Chemo 
caps” that reduce scalp temperature to decrease the degree of alopecia 
are controversial during treatment with curative intent of neoplasms, 
such as leukemia or lymphoma, or in adjuvant breast cancer therapy. 
The richly vascularized scalp can certainly harbor micrometastatic or 
disseminated disease.
PART 4
Oncology and Hematology
■
■GONADAL DYSFUNCTION AND PREGNANCY
All cancer treatments described in this chapter should be regarded 
as potentially injurious to the developing fetus and to newborns via 
lactation. However, there are gradations to the degree of reproductive 
harm. All agents tend to have increased risk of adverse outcomes when 
administered during the first trimester, and strategies to delay chemo­
therapy, if possible, until after this milestone should be considered if 
the pregnancy is to continue to term. Patients in their second or third 
trimester can be treated with most regimens for the common neo­
plasms afflicting women in their childbearing years, with the excep­
tion of antimetabolites, particularly antifolates, which have notable 
teratogenic or fetotoxic effects throughout pregnancy. The need for 
anticancer chemotherapy per se is infrequently a clear basis to recom­
mend termination of a concurrent pregnancy, although each treatment 
strategy in this circumstance must be tailored to the individual needs 
of the patient.
Cessation of ovulation and azoospermia reliably result from regi­
mens that contain alkylating agents and topoisomerase poison. The 
duration of these effects varies with age and sex. Sperm banking before 
treatment may be considered. Females experience amenorrhea with 
anovulation after alkylating agent therapy; egg preservation may be 
considered but may delay inception of urgent treatment. Recovery of 
normal menses is frequent if treatment is completed before age 30, but 
patients are unlikely to recover menses after age 35. Even those who 
regain menses usually experience premature menopause. Because the 
magnitude and extent of decreased fertility can be difficult to predict, 
patients should be counseled to maintain effective contraception, 
preferably by barrier means, during and after therapy. Resumption of 
efforts to conceive should be considered in the context of the patient’s 
likely prognosis. Hormone replacement therapy should be undertaken 
in women who do not have a hormonally responsive tumor. For 
patients who have had a hormone-sensitive tumor primarily treated by 
a local modality, conventional practice would counsel against hormone 
replacement, but this issue is under investigation.
■
■PALLIATIVE AND SUPPORTIVE CARE
An important perspective the primary care provider may bring to patients 
and their families facing incurable cancer is that, given the limited value 
of chemotherapeutic approaches at some point in the natural history of 

most metastatic cancers, palliative care or hospice-based approaches, with 
meticulous and ongoing attention to symptom relief and with family, 
psychological, and spiritual support, should receive prominent attention 
as a valuable therapeutic plan (Chaps. 13 and 73). Optimizing the quality 
of life rather than attempting to extend it becomes a valued intervention. 
Patients facing the impending progression of disease in a life-threatening 
way frequently choose to undertake toxic treatments of little to no poten­
tial value, and support provided by the primary caregiver in accessing 
palliative and hospice-based options in contrast to receiving toxic and 
ineffective regimens can be critical in providing a basis for patients to 
make sensible choices.
Late effects of cancer and its treatment are reviewed in Chap. 100.
■
■FURTHER READING
Ascione L et al: Predicting response to antibody drug conjugates: A 
focus on antigens’ targetability. Oncologist 28:944, 2023.
Chabner BA, Longo DL: Cancer Chemotherapy, Immunotherapy, 
and Biotherapy; Principles and Practice, 7th ed. Philadelphia, Wolters 
Kluwer, 2025.
Emadi A, Karp JE: Cancer Pharmacology: An Illustrated Manual of 
Anticancer Drugs, 2nd ed. New York, Springer Publishing Co., 2024.
Federman N: Molecular pathogenesis of desmoid tumor and the role 
of γ-secretase inhibition. NPJ Precis Oncol 6:62, 2022.
Hesketh PJ et al: Antiemetics: American Society of Clinical Oncology 
clinical practice update. J Clin Oncol 35:3240, 2017.
Kaelin WG Jr: Von Hippel-Lindau disease: Insights into oxygen sens­
ing, protein degradation, and cancer J Clin Invest 132:e162480, 2022.
Morad G et al: Hallmarks of response, resistance, and toxicity to 
immune checkpoint blockade. Cell 184:5309, 2021.
Nikanjam M et al: Liquid biopsy: Current technology and clinical 
applications. J Hematol Oncol 15:131, 2022.
Puzanov I et al: Managing toxicities associated with immune check­
point inhibitors: Consensus recommendations from the Society for 
Immunotherapy of Cancer (SITC) Toxicity Management Working 
Group. J Immunother Cancer 5:95, 2017.
Rosen N, Longo DL: Targeting oncogenic RAS protein. N Engl J Med 
387:184, 2022.
Sartor O et al: Lutetium-177–PSMA-617 for metastatic castrationresistant prostate cancer. N Engl J Med 385:1091, 2021.
Brahm H. Segal, Juan C. Gea-Banacloche

Infections in Patients 

with Cancer
GENERAL CONCEPTS
Infection is an important complication of cancer and cancer therapy 
and drives excess hospitalization and mortality. Prevention, diagnosis, 
and treatment of infection increases survival and improves quality 
of life. In this regard, the infectious diseases consultant works col­
laboratively with multiple stakeholders to prevent infection and to 
effectively diagnose and treat infections when they occur. Cornerstones 
of infection prevention are compliance with standard infection control 
guidelines, limiting exposure to pathogens, vaccination of patients and 
caregivers, and targeted use of antimicrobial prophylaxis. Although 
there have been substantial improvements in diagnostic modalities 
for infection including molecular and antigen-based diagnostics, the 
infectious diseases physician is frequently confronted with patients 
with suspected infection (e.g., neutropenic fever, lung lesions observed 
by imaging) without a definitive diagnosis. In addition, infectious and 
noninfectious disorders may have overlapping manifestations, such as

pneumonia versus drug-related pneumonitis and fever from infection 
versus cancer-associated fever. Given the broad differential diagnosis, 
aggressive diagnostic evaluation including biopsies may be required. 
Sometimes, empirical therapy must be administered based on the most 
likely or dangerous infections; these situations are common in patients 
with hematologic malignancies in whom an invasive tissue diagnosis 
may be unsafe due to thrombocytopenia.
We provide recommendations for therapy of both documented and 
suspected infections. Specific treatment plans should consider several 
factors, such as evidence of clearance of infection, whether a persistent 
nidus exists (e.g., abscess or infectious phlebitis), the specific pathogen, 
and the immune status of the patient. A general principle of therapy is 
that longer courses are required in patients with persistent and severe 
immunocompromise (e.g., prolonged neutropenia in patients with acute 
leukemia or myelodysplastic syndrome). An individualized approach to 
the diagnosis and management of infections that is tailored to overall 
goals of care is recommended. For example, in the setting of uncon­
trolled malignancy (e.g., recurrent cholangitis from obstructive pan­
creatic or biliary cancers or secondary infections of tumor from bowel 
fistulization), source control by surgery or catheter drainage may not be 
feasible, and antibiotics may be used palliatively for patient comfort and 
to avoid unnecessary hospitalizations rather than to cure an infection.
We will address the risk factors for infections and the preventive 
measures that may be adopted based on those risk factors. Most spe­
cific infections have dedicated chapters, and readers are advised to 
access those for in-depth discussions. We will focus here on infections 
associated with (or caused by) the treatment of cancer. Chemotherapyinduced neutropenia is the most important etiology, and the manage­
ment of neutropenic fever will be discussed in detail. We will also 
discuss infections associated with new treatment modalities, including 
biologics, immunotherapy, and cellular therapies. Infections related to 
hematopoietic stem cell transplant (HCT) are discussed in Chap. 148.
RISK FACTORS FOR INFECTION IN 
PATIENTS WITH CANCER
When evaluating patients with cancer and suspected infection, it is 
important to consider the major factors—both intrinsic and treatmentassociated—that predispose to infection. This knowledge, in turn, 
guides the differential diagnosis, diagnostic evaluation, and initial 
therapy.
■
■RISK FACTORS INTRINSIC TO THE CANCER
These are the direct consequence of the cancer. In the case of solid 
tumors, the most obvious risk factor for infection relates to obstruc­
tion. As examples, lung tumors that obstruct the airway predispose to 
postobstructive pneumonia, obstructive pancreatic and biliary tumors 
predispose to cholangitis, and tumors that result in obstructive uropa­
thy predispose to urinary tract infections. Tumors of the head and neck 
increase the risk of local infection and aspiration pneumonia. Gastro­
intestinal tumors can present with obstruction and local abscess pro­
duction by enteric flora and bloodstream infection (e.g., bloodstream 
infection by Streptococcus gallolyticus or Clostridium septicum in colon 
cancer). Direct invasion through the colonic mucosa is associated with 
local abscess formation and sepsis by enteric flora.
Some hematologic malignancies are associated with specific immune 
deficits. Acute leukemia and myelodysplastic syndrome can manifest 
with pancytopenia at diagnosis. Patients may have a high burden of 
circulating leukemic cells and lack normal circulating neutrophils. 
Some patients with myelodysplastic syndrome or acute myelogenous 
leukemia (AML) have mutations that are associated marrow failure and 
immunodeficiency. For example GATA2 deficiency is associated with 
major viral, bacterial, and fungal infections as well as hematological 
malignancies and solid tumors. Multiple myeloma and chronic lym­
phocytic leukemia are associated with impaired immunoglobulin pro­
duction that can manifest with recurrent sinopulmonary infections and 
poor antibody responses to both prior infections and vaccination. Case 
series suggest that patients with hairy cell leukemia are at increased risk 
of nontuberculous mycobacterial infections. T cell–associated leuke­
mias and lymphomas can be associated with human T lymphotropic 

virus 1 (HTLV1) and have T cell impairment and opportunistic infec­
tions by Pneumocystis jirovecii, Cryptococcus neoformans, tuberculosis, 
or disseminated strongyloidiasis.

■
■RISK FACTORS ASSOCIATED WITH 

CANCER THERAPY
There has been a dramatic expansion in cancer therapeutics, most of 
which influence host defense against infections (Table 79-1). Broadly 
speaking, cancer therapy can compromise either or both the physical 
barriers and immune responses that protect from infection. Examples 
of physical barrier disruption include central venous catheters, surgical 
wounds that can be a portal of entry for skin microbes, and disruption 
of the lymphatic drainage after mastectomy and lymphadenectomy for 
breast cancer.
The mucosal lining of the gastrointestinal tract, respiratory tract, 
and other luminal surfaces constitutes the first line of host defense, 
both as a physical barrier and by secretion of a variety of antimicrobial 
products, such as immunoglobulin A (IgA), lactoferrin, and anti­
microbial peptides. Standard nonselective cytotoxic agents have the 
combined effect of both pancytopenia and mucosal disruption that 
predispose to infection. Radiation is sometimes administered concur­
rently with chemotherapy and, depending on the location of the radia­
tion field, can cause significant mucosal injury. Antineoplastic agents 
that inhibit specific pathway(s) that drive tumor cell progression are 
considered targeted, but they also impair specific components of the 
immune system whose function relies on these same pathways. For 
example, the anti-tumor activity of Bruton tyrosine kinase inhibitors 
against B-cell malignancies is by inhibiting the B-cell receptor signaling 
cascade, but this property can have broad immune effects that increase 
the risk of viral and fungal infections.
CHAPTER 79
Infections in Patients with Cancer 
Chemotherapy-Induced Neutropenia 
It has been recognized 
for more than 50 years that the duration and degree of neutropenia 
drive susceptibility to infections in patients with cancer. Cytotoxic regi­
mens that result in prolonged neutropenia also deplete other immune 
cells (e.g., circulating monocytes and lymphocytes) and commonly 
cause mucosal injury. The risk of infection is proportional to the degree 
of neutropenia once the absolute neutrophil count (ANC) becomes 
<1000/µL. For example, standard induction chemotherapy with 
anthracycline plus cytarabine for AML causes prolonged neutropenia 
and severe mucositis. The combination of prolonged neutropenia and 
mucositis predisposes these patients to gastrointestinal tract infections 
that include ulcerations of the oral mucosa, neutropenic enterocolitis 
(typhlitis), and perirectal infections, as well as bloodstream infec­
tions by gastrointestinal flora such as viridians group streptococci, 
enterococci, and Enterobacterales. Reactivation of oral mucosal herpes 
simplex virus (HSV) is another common complication of leukemia 
therapy. Reflecting the fact that Candida species are endogenous 
gastrointestinal flora, these patients are also at risk for candidemia 
and chronic disseminated candidiasis. Patients with more prolonged 
neutropenia (e.g., ANC <500/µL for ≥2 weeks) are at risk for invasive 
aspergillosis and other molds. Refractory and relapsed acute leukemia 
further increase the risk of invasive fungal disease (Table 79-1).
Antimicrobial prophylaxis tailored to the underlying immune 
defects has been shown to be effective in several settings, and it 
should be used with knowledge of the proven benefits and the direct 
and indirect toxicities (prevention of fever differs from prevention of 
infection and prolongation of survival), as well as the limitations of the 
available evidence. As an example, prophylaxis with a fluoroquinolone 
like levofloxacin should be considered in adults with prolonged neu­
tropenia (e.g., ANC <500/µL for ≥7 days). Multiple studies have shown 
decreased frequency of neutropenic fever and fewer documented infec­
tions, and meta-analyses suggest a survival benefit. In patients with 
AML receiving induction chemotherapy, prophylaxis with posacon­
azole was associated with less invasive fungal disease (IFD) and a 
survival benefit, so posaconazole is frequently recommended as 
prophylaxis in patients with profound, prolonged neutropenia. It is 
plausible that isavuconazole may be equally effective, but its efficacy in 
this setting has not been demonstrated.

TABLE 79-1  Immune Defects and Associated Infections in Cancer Patients
HOST DEFENSE 
DEFECT
PREDOMINANT PATHOGENS
PATIENTS WITH CANCER AT GREATEST RISK
Neutropenia (ANC 
<500/µL)
Gram-negative and gram-positive bacteria
Cytotoxic chemotherapy, underlying hematologic malignancy 

(e.g., myelodysplasia, acute leukemia)
Prolonged (≥10 days), 
profound neutropenia 
(ANC <100/µL)
Increased risk of bacterial infections
Candidemia
Invasive aspergillosis and other molds
HSV reactivation
Respiratory viral infections
T cell 
immunodeficiency
Common bacterial infections
Intracellular bacteria (e.g., Listeria monocytogenes, Salmonella 
species)
Nocardia species
Tuberculosis and NTM
Respiratory viral infections
Reactivation of herpes viruses (HSV, VZV); with severe impairment: 
CMV, EBV-associated lymphoproliferative disease; HHV-6-associated 
marrow suppression or encephalopathy, and HHV-8-associated 
malignancies)
Mucosal candidiasis
Pneumocystis jirovecii
Dimorphic fungal infections (e.g., histoplasmosis, 
coccidioidomycosis)
Cryptococcus neoformans
Invasive aspergillosis and other molds
Toxoplasmosis
Strongyloides hyperinfection
PART 4
Oncology and Hematology
B cell 
immunodeficiency
Encapsulated bacteria (Streptococcus pneumoniae, Haemophilus 
influenzae, Neisseria meningitidis)
Respiratory viral infections
Reactivation of HSV and VZV
Reactivation of HBV
PML (reactivation of JC virus)
Splenectomy and 
functional asplenia
Encapsulated bacteria (can result in life-threating sepsis)
Malaria, babesiosis
Mucosal injury
Localized infections by oral and GI flora (e.g., dental infections, 
neutropenic enterocolitis, perianal infection)
Bacteremia (coliforms, oral streptococci, enterococci, anaerobes; 
can be polymicrobial)
Systemic 
corticosteroids
Broad suppressive effect on innate and adaptive immunity related to 
dose and duration of treatment
Increased risk of common bacterial and viral infections
Prolonged high-dose corticosteroids (e.g., prednisone equivalent 
to ≥20 mg/day for ≥28 days) increases risk of multiple opportunistic 
pathogens associated with impaired T cell immunity (e.g., 
Pneumocystis jirovecii)
Abbreviations: AIDS, acquired immunodeficiency syndrome; ANC, absolute neutrophil count; BTK, Bruton tyrosine kinase; CAR, chimeric antigen receptor; CMV, 
cytomegalovirus; EBV, Epstein-Barr virus; GVHD, graft-versus-host disease; HBV, hepatitis B virus; HHV, human herpes virus; HSV, herpes simplex virus; MDS, 
myelodysplastic syndrome; NTM, nontuberculous mycobacteria; PML, progressive multifocal leukoencephalopathy; TNF, tumor necrosis factor; VZV, varicella-zoster virus.
Corticosteroids 
Corticosteroids are part of several chemotherapy 
regimens used in hematologic malignancies, such as in acute lymphoid 
leukemias, lymphomas, and multiple myeloma. Patients with brain 
tumors, both primary and metastatic, are treated with corticoste­
roids to control edema. In addition, corticosteroids are a mainstay of 
therapy to control inflammatory complications of cancer therapy. For 
example, immune checkpoint inhibitors are associated with pneumo­
nitis, colitis, and autoimmune endocrinopathies that are treated with 
corticosteroids, and additional agents such as tumor necrosis factor α 
blockade when corticosteroids alone are insufficient. Corticosteroids 
are also used as therapy for graft-versus-host disease (GVHD) fol­
lowing allogeneic stem cell transplantation and for cytokine release 
syndrome (CRS) following bispecific antibody therapy and adoptive 
cellular therapy.

Induction/reinduction therapy for acute leukemia; pancytopenia 
from underlying hematologic malignancy; myeloablative conditioning 
regimens for stem cell transplantation and lymphodepletion for adoptive 
cellular therapy
Underlying hematologic malignancy including primary T cell 
malignancies
AIDS-associated malignancies
Corticosteroids, TNF-α blockade
Janus kinase inhibitors
Purine analogues
Alemtuzumab
GVHD
Lymphodepletion for adoptive cellular therapy
Lymphoid malignancies (e.g., chronic lymphocytic leukemia, multiple 
myeloma)
B cell–depleting agents (e.g., rituximab, BTK inhibitors)
Stem cell transplantation, particularly with chronic GVHD
Bispecific antibodies and adoptive cellular therapy targeted against B 
cell antigens (e.g., CD19-directed CAR T cell regimens)
Functional asplenia in chronic GVHD
Cytotoxic chemotherapy that results in both neutropenia and mucosal 
injury
Radiation (e.g., for head and neck tumors or rectal cancer) predisposes 
to local tissue damage, impaired blood flow, and secondary bacterial 
infection
Corticosteroids are common components of antineoplastic regimens 
for hematologic cancers (e.g., for acute lymphoblastic leukemia, 
lymphomas, and multiple myeloma) and are administered concurrently 
with other immunosuppressive therapies
Other common indications for corticosteroids are to reduce 
inflammation from central nervous system tumors and as therapy for 
immune-related toxicities
High-dose corticosteroids have inhibitory effects on multiple com­
ponents of innate and adaptive immunity. The risk of infections is 
related to their dose and duration, the underlying malignancy, and 
other immunosuppressive agents that are used concurrently. For exam­
ple, induction therapy for acute lymphoblastic leukemia includes both 
cytotoxic agents that result in pancytopenia and corticosteroids that 
cumulatively increase infection risk. Corticosteroids can also decrease 
signs of infection such as fever and abdominal tenderness. The inhibi­
tory effect of corticosteroids on T cell immunity increases the risk of 
infections by viruses (e.g., HSV, varicella-zoster virus [VZV]), myco­
bacteria, Nocardia species, and fungal infections, including mucosal 
candidiasis, dimorphic fungi, and Pneumocystis jirovecii pneumonia 
(PJP) (Table 79-1). Prophylaxis against Pneumocystis jirovecii with 
trimethoprim sulfamethoxazole (TMP-SMX) (or an alternative agent if

intolerant) is recommended in patients receiving the adult equivalent 
of prednisone ≥20 mg per day for at least 4 weeks.
Radiation 
Radiation causes direct tissue damage (including dam­
age to the vasculature) and impairs wound healing. Infectious com­
plications of radiation include local infection and fistulization. As an 
example, neoadjuvant radiation therapy for rectal tumors increases the 
risk of surgical site infections. Radiation to the head and neck increases 
the risk of infections related to the tumor and as a surgical complica­
tion. Osteoradionecrosis of the jaw predisposes to secondary infections 
of the soft tissue and bone that may require combined prolonged anti­
biotics and surgical removal of dead bone and reconstruction.
Splenectomy 
Splenectomy may be performed for diagnosis or 
treatment of cancer. The spleen has several key immune functions 
including removing of bacteria from blood, antigen presentation to 
T cells, and housing B cells that are activated and produce antibodies. 
Functional asplenia is present after splenic irradiation and with chronic 
GVHD. Asplenic patients are principally at risk for overwhelming sepsis 
by encapsulated bacteria like Streptococcus pneumoniae, Haemophilus 
influenzae, and Neisseria meningitidis. Patients should be vaccinated 
against these pathogens prior to planned splenectomy. Antibiotic pro­
phylaxis (e.g., with penicillin) should be considered for the first 2 years after 
splenectomy, especially in patients with active malignancy or receiv­
ing immunosuppressive therapy. Asplenic patients with fever should 
be started promptly on antibiotics active against S. pneumoniae (e.g., 
ceftriaxone or levofloxacin or moxifloxacin). Vancomycin should be 
added in areas where high-level penicillin or cephalosporin resistance 
is common. Asplenic individuals also have increased risk of babesiosis, 
malaria, and infection with Capnocytophaga canimorsus (associated 
with animal bites or scratches) and Salmonella spp.
B Cell–Depleting Agents 
B cell–depleting agents are used as 
therapy for patients with B cell malignancies, such as B cell lymphomas 
and chronic lymphocytic leukemia. They are commonly used in com­
bination with other antineoplastic agents. Antibody-based drugs such 
as rituximab result in prolonged B cell depletion, while Bruton tyrosine 
kinase (BTK) inhibitors (e.g., ibrutinib) interrupt a key enzyme and 
B cell activation but have shorter-acting effects. The effects of B cell 
depletion include increased risk of encapsulated bacteria and respi­
ratory viral infections. Importantly, these patients are likely to have 
reduced immune responses to vaccination against bacteria and viruses, 
including influenza, SARS-CoV-2, and hepatitis B. The risk of severe 
COVID-19 is substantially increased in patients with hematologic 
malignancies compared with patients with solid tumors, and B cell–
depleting agents are associated with increased COVID-19 severity and 
lack of serologic responses to SARS-CoV-2 infection and vaccination. 
All patients who will receive B cell–depleting agents should be screened 
for hepatitis B infection and receive therapy for hepatitis B (e.g., with 
entecavir or tenofovir alafenamide) for active or prior hepatitis B 
infection (see Chaps. 350 and 352 on hepatitis viruses and Chap. 208 
on human immunodeficiency virus [HIV] infections). Rituximab and 
other B cell–depleting agents have been associated with progressive 
multifocal leukoencephalopathy (PML) and PJP, but the magnitude of 
the effect is difficult to ascertain. In addition, BTK inhibitors can have 
off-target effects on innate immune cells and increase the risk of other 
infections, including invasive aspergillosis, particularly when com­
bined with other immunosuppressive agents, such as corticosteroids.
Bispecific Antibodies 
Bispecific antibodies are engineered to 
have dual specificity for a T cell antigen (e.g., CD3, a component of 
the T cell receptor complex) and a tumor antigen with the goal of 
stimulating T cell killing of tumor cells. When bispecific antibody con­
structs directed against B cell antigens (e.g., blinatumomab, a bispecific 
antibody against CD3 and the B cell antigen CD19) are used against B 
cell malignancies, the overall effect is a nonselective depletion of both 
tumor cells and normal B cells. Importantly, bispecific antibodies are 
commonly used in patients with refractory hematologic malignancies 
who already are at high risk for infection based on the underlying can­
cer and prior therapy. Bispecific antibody therapy can result in CRS, 

characterized by fever and inflammatory organ damage. Treatment of 
CRS involves high-dose corticosteroids and interleukin 6 (IL-6) block­
ade, which further increases the risk of infections.

Adoptive Cellular Therapy 
Adoptive cellular therapy (ACT) 
involves administration of genetically engineered cells targeted to 
tumor antigens. The most commonly used ACT is chimeric antigen 
receptor (CAR) T cells, in which autologous T cells are genetically engi­
neered to express a receptor directed against a tumor antigen. Engage­
ment of cells expressing this antigen results in the CAR T cell activation 
and tumor cell killing. In contrast to bispecific antibodies, current ACT 
involves lymphodepletion chemotherapy (usually with fludarabine and 
cyclophosphamide) to deplete immune cells and allow maximal expan­
sion of the engineered T cells. A major goal of immunotherapy is to 
make ACT more effective for a broad range of solid tumors; however, 
the current use of ACT largely involves refractory B cell malignancies: 
lymphoblastic leukemia, lymphomas, and multiple myeloma. Lym­
phodepletion regimens result in pancytopenia, and both neutropenia 
and lymphopenia can be prolonged (months to years). In the case of 
standard CD19-directed CAR T cells, B cell depletion is by design; the 
persistence of CAR T cells is required for antitumor immunity, but it 
is nonselective, and the duration of global B cell depletion can be for 
years. ACT can also be complicated by CRS and an immune effector 
cell–associated neurotoxicity syndrome that can be life-threatening 
and requires treatment with intensive high-dose corticosteroids often 
combined with IL-6 blockade. Additional hematologic complications 
can occur after ACT, such as hemophagocytic lymphohistiocytosis 
(HLH), which extends pancytopenia and entails additional immuno­
suppressive therapy.
CHAPTER 79
Infections in Patients with Cancer 
Recommendations regarding prophylaxis following ACT are based 
mainly on extrapolation and expert opinion. These include levofloxa­
cin during neutropenia, TMP-SMX while on systemic corticosteroids 
or while CD4 count is <200/µL, acyclovir, and perhaps mold-active 
prophylaxis (e.g., posaconazole) during periods of prolonged neutro­
penia. Recipients of CAR T cells constitute a heterogeneous population 
due to the effect of multiple previous courses of therapy, sometimes 
including allogeneic HCT, and prophylaxis should be tailored to the 
degree of immunosuppression.
Cancer and HIV Infection 
HIV-associated malignancies include 
Epstein-Barr virus–associated non-Hodgkin and Hodgkin lymphomas, 
HHV-8-associated Kaposi sarcoma and primary effusion lymphoma, 
and human papilloma virus–associated cervical and anal cancer. HIVpositive patients have higher risks of chronic hepatitis B and hepatitis 
C infections that increase the risk of hepatocellular carcinoma. Patients 
with HIV infection can also have cancers that are not HIV-associated. 
A mainstay of cancer management in patients who are HIV-positive is 
that the antineoplastic regimen must be concurrent with antiretroviral 
therapy and appropriate prophylactic antimicrobials. The goals of anti­
retroviral therapy are a nondetectable HIV viral load and tolerability 
of the regimen, which includes monitoring and avoiding drug–drug 
interactions with antineoplastic chemotherapy. In general, it is recom­
mended to test for HIV and hepatitis B and hepatitis C infection prior 
to starting antineoplastic therapy.
DIAGNOSIS AND MANAGEMENT OF 
INFECTIONS IN PATIENTS WITH 
NEUTROPENIA
Chemotherapy-induced neutropenia remains the major risk factor for 
infection in patients with cancer. However, patients with cancer fre­
quently have multiple risk factors for infection, both from the under­
lying malignancy and its treatment. When evaluating patients with 
neutropenia and suspected infection, it is important to consider these 
other risk factors in the diagnostic evaluation and therapy (Fig. 79-1).
■
■NEUTROPENIC FEVER
A high proportion of cancer patients who become neutropenic after 
receiving chemotherapy develop fever. The standard definition of neu­
tropenic fever (NF) is a single oral temperature ≥38.3°C or a tempera­
ture of ≥38.0°C sustained over 1 h, with an absolute neutrophil count

A
B
FIGURE 79-1  Multiple pulmonary infections in a patient with acute myelogenous 
leukemia (AML). A patient with AML in remission after reinduction therapy 
with cytarabine, granulocyte colony-stimulating factor, and fludarabine (FLAG) 
presented with fever and neutropenia. A chest CT demonstrated diffuse pulmonary 
infiltrates (A). Bronchoalveolar lavage (BAL) was unrevealing except for positive 
PCR for Pneumocystis jirovecii, and trimethoprim-sulfamethoxazole was instituted. 
After 11 days of appropriate treatment (B), a repeat CT showed resolution of the 
infiltrates but a conspicuous, dense, well-circumscribed pulmonary nodule that 
had not been appreciated initially. Targeted BAL of the left lower lobe was positive 
for galactomannan, providing the diagnosis of probable invasive aspergillosis. The 
initial BAL had been of the right middle lobe only. Immunocompromised patients 
may have several infections simultaneously, and cancer patients often accumulate 
risk factors for infection during their treatment.
PART 4
Oncology and Hematology
(ANC) of <500 cells/µL, or an ANC that is expected to decrease to 
<500 cells/µL over the next 48 h.
During neutropenia localizing signs and symptoms of infection 
may be subtle or altogether lacking, and infections may progress very 
quickly. These two basic features mandate early initiation of empiri­
cal antibacterial agents in neutropenic patients whenever infection is 
suspected. Although fever is the most common sign of infection, it is 
not the only one, and similar management should be used whenever 
infection is suspected in a neutropenic patient, such as in the presence 
of otherwise unexplained pain, tenderness, or erythema potentially 
secondary to infection.
NF is considered infectious in origin, but an infection is identified 
in only a minority of cases. An infection may be documented micro­
biologically (e.g., Pseudomonas aeruginosa bacteremia identified by 
positive blood cultures) or only clinically (e.g., abdominal pain and 
bloody diarrhea with negative blood cultures, presumed to represent 
neutropenic enterocolitis). Using standard diagnostic methods (i.e., 
routine cultures, serologic tests, and imaging studies) an infection is 
documented in approximately 40% of episodes of NF. However, newer 
diagnostic modalities using plasma cell–free DNA polymerase chain 
reaction (PCR) identify a potential bacterial etiology most of the time. 
Most bacteria identified by these studies are part of the normal flora 
of skin and bowel (as are the bacteria isolated by standard culture 
methods when these are positive), since these physical barriers are 
often disrupted by the cancer treatments that caused the neutropenia. 
Infections during neutropenia are typically caused by microorganisms 
carried by the patient as part of their microbiome.
■
■MANAGEMENT OF NEUTROPENIC FEVER
First Neutropenic Fever 
There is a wealth of good-quality evi­
dence to support standard-of-care guidelines for the management 
of the initial episode of NF. After a swift history and physical exam 
(focused on potential portals of entry like the vascular catheter exit site, 
mouth, and perianal area), blood cultures are obtained and empirical 
antibiotic therapy is initiated using a single agent (monotherapy) with 
broad-spectrum activity, including coverage of P. aeruginosa. Ideally, anti­
biotics should be given within 1 h of the onset of NF. The diagnostic 
utility of chest imaging in the absence of respiratory symptoms or signs 
has not been established.
Ceftazidime, cefepime, imipenem, meropenem, and piperacillintazobactam are the best-studied antibiotics used as monotherapy for 
NF. The specific choice will vary from institution to institution based 
on the local frequency of resistant bacteria. This “backbone regimen” 

may be complemented with a second agent against resistant gramnegative or gram-positive bacteria depending on clinical features, 
prior history of resistant pathogens, or local trends of antimicrobial 
resistance.
It should be emphasized that standard empirical monotherapy 
regimens for NF apply to clinically stable patients with NF of unclear 
etiology. Management of neutropenic patients with localized signs of 
infection (e.g., respiratory, intra-abdominal, intravascular catheter–
associated) are discussed below. In patients who are clinically unstable, 
such as those with hypotension or signs of organ injury raising con­
cern for sepsis (e.g., impaired mental status, pulmonary edema, acute 
renal injury), a broader-spectrum antimicrobial regimen is warranted. 
Although the specific regimen for presumed or documented septic 
shock varies based on the patient’s prior history of resistant infection 
and local susceptibility patterns, an example of an initial regimen is 
vancomycin, meropenem, and possibly an aminoglycoside; in patients 
at risk for candidiasis, an echinocandin may be added.
The standard monotherapy regimens lack activity against specific 
gram-positive pathogens. Gram-positive coverage with a glycopeptide 
antibiotic (vancomycin in the United States) is not routinely part of 
the initial regimen. Instead, the addition of a glycopeptide is reserved 
for clinical situations in which a gram-positive pathogen resistant to 
the standard regimen (e.g., methicillin-resistant Staphylococcus aureus 
[MRSA]) is more likely. The Infectious Diseases Society of America 
(IDSA) guidelines recommend empirical gram-positive coverage with 
sepsis, clinically evident soft tissue infection, clinically suspected cath­
eter exit site infection, pneumonia, severe mucositis (only if ceftazi­
dime is used as empirical regimen, because mucositis is a risk factor 
for viridans group streptococci), and known carrier status of MRSA or 
penicillin-resistant pneumococcus. Meta-analysis has shown that the 
routine inclusion of vancomycin in the initial regimen is not associated 
with better outcomes but does result in more nephrotoxicity.
After starting antibiotics, fever usually resolves in 24–72 h. If an 
infection was diagnosed, antibiotics are continued for the appropriate 
amount of time for that specific infection. When a specific microbe is 
isolated (e.g., from blood cultures), experts disagree regarding the need 
for continuing the broad-spectrum coverage versus narrowing based 
on susceptibility results.
If no microorganism is isolated and no source is identified, the 
optimal strategy for antibiotic management of NF that resolves with 
antibiotics is debated. In the past, empirical antibiotics were continued 
until resolution of neutropenia. However, recent studies have suggested 
that de-escalation from empiric therapy to prophylaxis or discontinua­
tion are safe if specific criteria are met, including clinical stability. The 
advantage of such de-escalation or early discontinuation strategies 
relates to reduced antibiotic exposure and lower risk of selection of 
resistant pathogens; these benefits must be balanced against the poten­
tial for inadequately treated infection. Large, randomized, multicenter 
trials are required to evaluate the benefits and safety of antibiotic deescalation or discontinuation of empirical antibiotic therapy in patients 
with persistent neutropenia.
Persistent Fever 
If the fever continues while receiving empirical 
antibiotic therapy without a diagnosis, evidence supports and guide­
lines recommend continuing the same antibiotic without addition or 
modification in the absence of clinical changes or new microbiologic 
data. The antibacterial regimen should be modified only if new clinical 
features arise (e.g., hypotension) of if new microbiologic data become 
available (e.g., a positive culture), and not just because of persistent 
fever. Although there is agreement on this issue between different 
guidelines, persistent, stable fever is a common reason why the anti­
bacterial regimen is modified in clinical practice. The longer the neu­
tropenic fever persists during the administration of broad-spectrum 
antibiotics, the higher the likelihood of IFD. Depending on prior his­
tory, use of antifungal prophylaxis, and local practices, one may choose 
to initiate empirical antifungal treatment after 5 days of fever (this was 
standard of care for decades and is called empirical antifungal therapy) 
or to perform tests focused on diagnosing an occult fungal infec­
tion and initiate antifungals only if these additional tests support the

possibility of IFD. This more recent approach has been named preemp­
tive antifungal strategy and seems to result in similar patient outcomes 
with less use of antifungals. The empirical antifungal of choice will vary 
depending on the antifungal prophylaxis used (if any). Caspofungin 
and liposomal amphotericin B are the best-studied empirical antifun­
gal treatment of NF, but expert recommendations vary. A frequently 
used approach is to administer posaconazole as antifungal prophylaxis 
in high-risk patients with neutropenia (e.g., those receiving induc­
tion or reinduction regimens for acute myeloid leukemia) and to not 
modify the antifungal regimen based solely on persistent or recurrent 
neutropenic fever.
Recrudescent Fever and Fever at the Time of Neutrophil 
Recovery 
In addition to the initial episode of fever and persistent 
fever, there are two other NF scenarios that have been less well stud­
ied: recrudescent fever and fever at the time of neutrophil recovery. 
Recrudescent fever refers to the situation in which the initial episode 
of fever resolves without a diagnosis, neutropenia persists, the antibi­
otic regimen is continued unmodified, and fever reappears after the 
patient has been afebrile for 48–96 h. This is not uncommon during 
prolonged neutropenia during induction or reinduction therapy in 
acute leukemia. In this case (as opposed to the first episode of NF), an 
infection is identified most of the time (bacterial, fungal, or viral), and 
the recommended approach is to empirically modify the antimicrobial 
regimen that had successfully controlled the fever up to this point, 
aiming for coverage of resistant bacteria and fungi. Intensive diagnos­
tic procedures, including CT imaging, should be undertaken. Where 
available, CT combined with positron emission tomography (CT-PET) 
may be considered.
Finally, fever at the time of neutrophil recovery may be infectious 
in origin: either a preexisting infection that was silent due to lack of 
neutrophils (sometimes this is considered analogous to the immune 
reconstitution inflammatory syndrome [IRIS] seen after initiation of 
antiretroviral therapy in AIDS) or, less likely, a superinfection. How­
ever, fever is frequently noninfectious at this time and is related to 
myeloid engraftment. In any case, the recommended response to fever 
that occurs simultaneously with resolution of neutropenia is not any 
specific empirical antimicrobial regimen, but to pursue a thorough 
diagnostic evaluation.
■
■OUTPATIENT THERAPY FOR NEUTROPENIC 
FEVER
Outpatient therapy for neutropenic fever should be considered in 
patients at lower risk for infectious complications from neutropenia. 
These patients typically have solid rather than hematologic tumors 
with a short expected duration of neutropenia, usually 7 days or less. 
Criteria for candidates for outpatient empirical therapy include clinical 
stability, no localizing symptoms or signs of infection, ability to eat and 
drink without difficulty, absence of significant comorbidities such as 
chronic lung or cardiovascular disease, normal renal and liver function, 
and easy access to a hospital and a caregiver at home. Outpatient oral 
antibiotic therapy in adults typically involves a quinolone (e.g., levo­
floxacin or ciprofloxacin) plus amoxicillin-clavulanate; such regimens 
are appropriate only for patients who have not received a quinolone as 
prophylaxis.
DOCUMENTED INFECTIONS DURING 
NEUTROPENIA
■
■BACTEREMIA
Bacteremia is the most common microbiologically documented infec­
tion in neutropenic patients with fever. NF is associated with bacte­
remia in only 10% of cases, but this subgroup of patients has much 
higher mortality than the general group of neutropenic patients 
with fever, particularly with gram-negative bacteremia. Most recent 
series show similar proportions of gram-positive (coagulase-negative 
Staphylococcus, Streptococcus species, Enterococcus species including 
vancomycin-resistant Enterococcus [VRE]) and gram-negative bacteria 
(Enterobacterales and P. aeruginosa).

Bacteremia in neutropenic patients may be secondary to another site 
of infection (e.g., pneumonia, neutropenic enterocolitis, cellulitis) or, 
most commonly, to mucosal barrier injury (MBI) caused by the anti­
neoplastic treatment. The chemotherapy and/or radiation frequently 
damages the mucosa of the gastrointestinal tract, facilitating translo­
cation of commensal bacteria during neutropenia. Clinically, one may 
question whether the bacteremia may be a central line–associated blood­
stream infection (CLABSI). If the isolate is an intestinal bacterium, it 
is considered related to MBI in the absence of local signs of infection 
involving the venous catheter. If the isolate is part of the skin flora, like 
coagulase-negative Staphylococcus, it is more likely to be a CLABSI, 
but it may also represent a contaminant or colonization of the catheter. 
Colonization or contamination should be presumed when only one of 
several blood culture bottles is positive for normal skin flora, especially 
if the culture takes more than 24 h to turn positive. When a blood 
culture becomes positive for a gram-positive organism, it is important 
to repeat blood cultures, ideally from both central and peripheral 
sites, to determine whether the blood culture isolate is recovered from 
more than one bottle and at different time points. Skin flora growing 
from blood drawn from the catheter with negative peripheral blood 
cultures can reflect catheter colonization (i.e., not a true bloodstream 
infection) or CLABSI with low levels of bacteria in blood resulting in 
negative peripheral cultures. When both the peripheral and the central 
blood cultures are positive for the same organism, bacteremia is con­
firmed, and the differential time to positivity may allow establishing 
the diagnosis of catheter-related bacteremia if the central line culture 
grows at least 2 h earlier than the peripheral. However, the practice of 
always obtaining a peripheral blood culture may not be practical on an 
oncology ward, where patients may be febrile daily and are frequently 
thrombocytopenic.

CHAPTER 79
Infections in Patients with Cancer 
More important than whether blood cultures are collected from the 
central catheter alone or from central and peripheral venous sources 
is ensuring that an adequate volume of blood (as determined by the 
specific blood culture platform) is collected. The optimal frequency 
of blood cultures in NF has not been established. Similarly, the use 
of surveillance blood cultures in neutropenic patients has not been 
adequately studied. The amplification by PCR of plasma cell–free 
DNA, with its superior yield compared with blood cultures, is still 
investigational, and its place in the routine management of NF remains 
to be defined.
If CLABSI is diagnosed, the preferred treatment is to remove 
the catheter. Again, this may not always be practical in the case of 
thrombocytopenic patients with limited access, and an attempt to 
salvage a permanent catheter (i.e., tunneled catheter or port) may be 
appropriate as long as the patient remains hemodynamically stable and 

the blood cultures become negative upon initiating appropriate anti­
biotics. Antibiotic lock therapy should be considered, if feasible. The 
likelihood of success when a catheter is colonized with S. aureus, 
mycobacteria, or Candida species is low, and these catheters should 
be removed as soon as possible. It is customary to provide some time 
without central access (e.g., a 48-h “line holiday”) before replacing the 
central venous catheter, although the evidence supporting this practice 
is scant. Patients may require continuous central IV access, and in this 
case it is reasonable to use nonsurgically placed lines (e.g., a peripher­
ally inserted central catheter) and to place a new surgically implanted 
port (e.g., mediport) only when there is clear evidence of blood culture 
clearance.
Endocarditis is rare during neutropenia, but it should be suspected 
with persistently positive blood cultures or with clinical findings like 
a new murmur or embolic phenomena. Routine echocardiogram in 
every case of bacteremia in neutropenic patients is not recommended, 
but patients with S. aureus bacteremia do require one.
■
■RESPIRATORY INFECTIONS
Sinusitis 
Sinusitis may manifest by pressure, facial pain, rhinor­
rhea, and postnasal drip but occasionally has very mild symptoms 
that will be elicited only by targeted questioning during the physical 
exam. Symptomatic sinusitis in neutropenic patients may be caused by

pathogens relatively uncommon in immunocompetent people, includ­
ing S. aureus, P. aeruginosa, and other gram-negative bacilli. Evaluation 
by CT and consultation by otolaryngology to examine the integrity of 
the mucosa and obtain samples for culture is recommended. Invasive 
fungal sinusitis may be caused by Aspergillus species, agents of mucor­
mycosis, Fusarium species, and relatively less virulent dematiaceous 
molds like Alternaria, Bipolaris, or Curvularia. CT findings sugges­
tive of fungal etiology include marked asymmetry, heterogeneous 
radiodensity of the contents of the sinuses, and, later in the disease, 
bony erosions. The endoscopic exam may show pale, devitalized 
mucosa and, sometimes, necrotic ulceration of a turbinate caused by 
the angioinvasive process. Invasive fungal sinusitis during neutropenia 
mandates surgical resection. Repeated visits to the operating room 
in conjunction with optimal antifungal therapy are necessary to save 
the patient’s life. The empirical antifungal agent may vary depending 
on the preexisting antifungal prophylaxis, but, given the possibility of 
mucormycosis and fusariosis, many experts would recommend a lipid 
formulation of amphotericin B, often considered the antifungal of 
choice for mucormycosis, together with posaconazole, which is nonin­
ferior to voriconazole for Aspergillus species and has superior activity 
in vitro against dematiaceous molds.

Pneumonia 
Pulmonary infiltrates are a common diagnostic chal­
lenge in immunocompromised hosts. A systematic approach to the 
differential, which includes infections and noninfectious etiologies, is 
mandatory. Some important noninfectious conditions to be consid­
ered include heart failure, fluid overload, transfusion reactions like 
transfusion-associated circulatory overload (TACO) and transfusionassociated lung injury (TRALI), chemotherapy-associated pneumoni­
tis, organizing pneumonia, and diffuse alveolar hemorrhage, as well as 
dissemination of the cancer itself. The radiologic appearance is useful 
to separate unilateral focal processes (suggestive of bacterial or mold 
infection) from multifocal or diffuse infections, which may be caused 
in addition by viruses, atypical bacteria, and PJP. Single or multiple 
dense, well-circumscribed nodules suggest IFD in high-risk patients 
(e.g., those with leukemia and allogeneic stem cell transplant recipi­
ents), but Nocardia species may have the same appearance and other 
bacteria like P. aeruginosa and Stenotrophomonas maltophilia may 
cause angioinvasive infection and result in similar radiology. Unfor­
tunately, characteristic radiologic differences may not hold true in an 
individual case, and every attempt should be made to obtain a respira­
tory sample for microbiologic diagnosis.
PART 4
Oncology and Hematology
Early bronchoscopy with bronchoalveolar lavage (BAL) in neutro­
penic patients with pneumonia is recommended. The yield of BAL is 
highest for diffuse and multifocal processes. In the case of pulmonary 
nodules accessible to percutaneous or endobronchial biopsy, the choice 
of diagnostic procedure will often depend on institutional expertise, 
clinical status, and comorbidities. The empirical antimicrobial regi­
men may vary slightly depending on the radiology and the individual 
risk factors but should always provide optimal antibacterial coverage 
by combining one of the antipseudomonal β-lactams together with 
vancomycin and an agent active against Legionella, like azithromycin, 
a fluoroquinolone, or doxycycline. If the patient has risk factors for 

S. maltophilia (high prevalence in the institution, previous exposure 
to carbapenems), the addition of TMP-SMX or levofloxacin should be 
considered.
The empirical addition of TMP-SMX for PJP depends on the clinical 
scenario and risk factors. If the only immune defect of the patient is 
neutropenia, the main concerns are bacteria and molds, the likelihood 
of PJP is low, and empirical anti-Pneumocystis coverage seems unnec­
essary. However, patients with hematologic malignancies often have 
received corticosteroids or other agents that decrease cellular immu­
nity and put them at risk for PJP. In this case, empirical coverage until 
PJP has been ruled out is reasonable. The current gold standard for the 
diagnosis of PJP is PCR of respiratory secretions, which occasionally 
may detect patients who are merely colonized. Serum β-d-glucan is 
typically elevated in patients with PJP, and a positive result increases 
the likelihood of PJP in a patient with appropriate risk factors and 
radiologic findings. However, false-positive and -negative β-d-glucan 

results occur, and this test is not specific for PJP; therefore, a positive 
serum β-d-glucan does not always obviate the need for BAL.
Invasive fungal disease (IFD) is suggested by single or multiple 
dense, well-circumscribed nodules, particularly larger than 2 cm. The 
halo sign (ground glass opacity surrounding a dense nodule) or the 
reverse halo sign (ground glass opacity seen inside a nodule, some­
times said to be more common in mucormycosis) may be present, 
but these are not diagnostic. Peripheral wedge-shaped infiltrates also 
may be seen. In patients at high risk for IFD, initiation or escalation of 
antifungal therapy is commonly begun prior to establishing a diagno­
sis. Such decisions must consider the antifungal prophylaxis that the 
patient is receiving. If the patient is on fluconazole or no antifungal 
prophylaxis, a mold-active azole (e.g., voriconazole, posaconazole, 
isavuconazole) as empirical therapy is reasonable pending a diagnosis, 
since Aspergillus is by far the most likely mold infection. If on the other 
hand, a suspected fungal infection occurs while receiving a mold-active 
azole, many experts would recommend switching the regimen to lipo­
somal amphotericin B, while aggressively pursuing a diagnosis.
Evaluation of suspected pneumonia involves sputum and blood 
cultures, nasopharyngeal swab for PCR for respiratory viruses, urine 
Legionella antigen, and in patients with neutropenia, evaluation for IFD 
(e.g., serum galactomannan, beta-glucan) should be included. If these 
studies are negative and the empirical antimicrobial regimen does not 
lead to improvement, early BAL or image-guided percutaneous lung 
biopsy should be considered. If non-invasive diagnostic studies identify 
a pathogen, it is important to consider the potential for concurrent or 
secondary infection by other pathogens. For example, respiratory viral 
infections can be complicated by secondary bacterial pneumonias, 
and cases of invasive pulmonary aspergillosis following COVID-19 
have been documented. It is therefore important to consider a broad 
differential diagnosis and to repeat imaging and diagnostic evaluation 
in patients with worsening pneumonia even when an initial diagnosis 
has been made.
■
■INTRA-ABDOMINAL INFECTIONS
Neutropenic Enterocolitis (Typhlitis) 
Sometimes bacteria 
invade the wall of the intestine and proliferate there, causing inflamma­
tion and even necrosis of segments of the bowel. The clinical syndrome 
includes fever, abdominal pain, and tenderness and diarrhea, which is 
occasionally bloody. The term typhlitis (inflammation of the cecum) 
is sometimes used, as the cecum is most commonly involved, but the 
terminal ileum, ascending colon, and other segments of the intestine 
also may be affected, so the more general term neutropenic enterocolitis 
is preferred. Blood cultures are frequently positive (with bowel flora), 
but not always. Plain films of the abdomen are not sensitive or specific, 
but a right lower quadrant soft tissue density, distended bowel loops, 
ileus, or “thumbprinting” suggesting mucosal edema may sometimes 
be seen. A CT scan of the abdomen and pelvis usually demonstrates 
a right lower quadrant inflammatory mass, with thickened bowel wall 
and stranding of the surrounding fat. Conservative management with 
broad-spectrum antibiotics, bowel rest, bowel decompression, and 
nutritional support is usually preferred. Surgery may be required if the 
patient deteriorates and intestinal perforation, peritonitis, and hemo­
dynamic instability ensue. Carbapenems and piperacillin-tazobactam are 
appropriate given their broader spectrum. If ceftazidime or cefepime is 
used, additional agents against anaerobic bacteria (e.g., metronidazole) 
must be added. In selecting an empirical regimen, it is important to 
note prior infections with antibiotic-resistant infections, such as VRE, 
and extended-spectrum β-lactamase (ESBL) of carbapenem-resistant 
(CRE) gram-negative infections.
Similar to intra-abdominal infections, perirectal and perianal infec­
tions are caused by gastrointestinal flora in the context of neutropenia 
and mucosal injury. CT imaging is helpful to assess the extent of infec­
tion. These infections typically respond to broad-spectrum antibiotic 
therapy without the need for surgery, but follow-up imaging after neu­
trophil recovery may be necessary if symptoms or fever persist.
Clostridioides difficile (C. difficile)–Associated Disease 
Cancer 
patients are at increased risk of C. difficile–associated disease (CDAD)

because of their frequent exposure to healthcare facilities, antibiotics, 
and chemotherapeutic drugs. Patients with a history of CDAD in the 
previous year are often treated prophylactically with oral vancomycin 
(125 mg daily) when empirical antibiotic therapy for neutropenic fever 
is begun. Every hospitalized neutropenic patient with diarrhea should 
be tested for C. difficile. It is unclear whether neutropenic patients 
with CDAD have worse outcomes, higher risk of complications, or 
increased frequency of neutropenic enterocolitis. First-line treatment is 
fidaxomicin, with oral vancomycin as an alternative. In case of ileus or 
overwhelming CDAD, combination of either oral fidaxomicin or van­
comycin with IV metronidazole (which is secreted into the intestinal 
lumen) is recommended.
Cholecystitis 
Cholecystitis is a rare infection during neutropenia, 
and most cases have been seen during treatment of acute leukemia. The 
presentation is like that in nonneutropenic individuals, but bacteremia 
is more common. At least half of the reported cases have been acal­
culous cholecystitis. Conservative management, frequently including 
cholecystostomy, is used until resolution of neutropenia when chole­
cystectomy can be performed more safely.
■
■CENTRAL NERVOUS SYSTEM INFECTIONS
Bacterial central nervous system (CNS) infections are uncommon 
during neutropenia and usually secondary to an episode of bacteremia 
(which may or may not have been detected) or to extension from the 
paranasal sinuses. Meningitis caused by gram-negative bacilli, includ­
ing P. aeruginosa, may occur in this setting. Two unexpected causes of 
CNS infections are worth mentioning. Rothia mucilaginosa, a grampositive coccus that is part of the oral flora, may seed the meninges 
during a transient bacteremia that seemed to be controlled easily with 
appropriate antibiotic treatment. This is a rare infection, and most 
cases treated successfully have received meropenem and vancomycin. 
Similarly, Bacillus cereus, a gram-positive bacillus ubiquitous in the 
environment, has been reported as a cause of difficult-to-treat men­
ingitis and brain abscess in neutropenic patients with acute leukemia. 
The combination of meropenem and vancomycin also has been used 
successfully. Listeria monocytogenes meningitis and bacteremia are 
most common in patients with impaired cellular immunity, includ­
ing patients with cancer receiving immunosuppressive regimens. 
Besides meningitis, L. monocytogenes can also cause rhombencephalitis 
(inflammation of the brainstem and cerebellum) and brain abscess. 
The combination of ampicillin and gentamicin is recommended. In 
cases of penicillin allergy TMP-SMX may be used. Listeria monocyto­
genes is susceptible in vitro to meropenem and linezolid, but clinical 
experience is limited.
In patients with hematologic cancers and prolonged neutropenia, 
brain lesions should raise the concern for opportunistic pathogens, 
usually fungi. Aspergillus and Candida brain abscesses are usually 
hematogenous; mucormycosis more frequently follows extension from 
the sinuses. Empirical treatment should be administered including 
antibacterial (typically meropenem plus vancomycin) and antifungal 
agents until the etiology is established. As mentioned for pulmonary 
infections, the choice of antifungal may be conditioned by preexisting 
antifungal prophylaxis. Voriconazole is the preferred agent for CNS 
aspergillosis and liposomal amphotericin B for mucormycosis. Echino­
candins do not achieve therapeutic levels in the brain or cerebrospinal 
fluid (CSF), and they should not be relied upon for the treatment of 
CNS infections.
Nocardia species and Toxoplasma gondii are important causes of 
brain abscess in immunocompromised patients. The major risk factor 
for these infections is suppressed T cell immunity. In patients with 
cancer, prolonged intensive corticosteroid therapy and use of purine 
analogues are examples of risk factors. TMP-SMX used as prophylaxis 
for PJP may also confer some protection against Listeria, Nocardia, and 
Toxoplasma.
Patients with cancer are at increased risk of viral encephali­
tis. Herpes simplex virus (HSV) encephalitis is characterized by 
fever and decreased level of consciousness. Imaging shows unilateral 

involvement of the temporal lobe. Abnormalities in the CSF may be 
altered by radiation therapy or corticosteroids. The diagnosis is by 
PCR of the CSF, which may be falsely negative early in the course of the 
disease. Herpes zoster encephalitis is a rare but devastating complica­
tion in patients with defective T cell immunity. Human herpesvirus 6 
(HHV-6) encephalitis is rare outside of allogeneic stem cell transplan­
tation (allo-HCT) (see Chap. 148). Finding a high level of HHV-6 in 
blood in any other setting brings up the possibility of HHV-6 chromo­
somal integration, which is present in around 1% of the population.

In patients who have had neurosurgery, including those with 
neurosurgical devices (e.g., shunts or reservoirs), infections by grampositive bacteria are most common, although gram-negative infections 
including coliforms and P. aeruginosa can occur. Risk factors include 
multiple neurosurgeries (e.g., for recurrent tumor), cranial irradiation, 
antiangiogenics (which disrupt blood supply), and use of immuno­
suppressives. Vancomycin plus an antipseudomonal cephalosporin 
(e.g., ceftazidime) is an appropriate initial regimen for postneuro­
surgical CNS infections, pending culture data. Surgical drainage and 
debridement of infected material and removal of hardware are usually 
required.
CHAPTER 79
■
■SKIN AND SOFT TISSUE INFECTIONS
As a rule, focal skin lesions in neutropenic, febrile patients should 
be biopsied, as the diagnostic possibilities are multiple, and some of 
the causes may be life-threatening and require immediate treatment. 
Cellulitis may be caused by streptococci or S. aureus, but also by 
gram-negative bacilli, and broad-spectrum coverage with an antip­
seudomonal β-lactam and vancomycin should be administered until 
an etiologic diagnosis is established. Multiple foci of erythematous 
tender plaques with underlying fasciitis and myositis are associated 
with bacteremia by Clostridium septicum, sometimes seen in patients 
with colorectal cancer. Ecthyma gangrenosum appears as a tender, 
erythematous papule that then becomes necrotic and ulcerated. It may 
be caused by local inoculation or by hematogenous seeding, typically of 

P. aeruginosa but sometimes other gram-negative bacteria or even 
molds like Fusarium species. Single or multiple lesions may be seen. 
Disseminated candidiasis with hematogenous cutaneous disease mani­
fests with fever and other signs of systemic infection and multiple 
raised cutaneous papules. Hemorrhagic bullae are described in cel­
lulitis caused by gram-negative bacteria (including Vibrio vulnificus, 
which may be suspected with a history of liver dysfunction and expo­
sure to shellfish).
Infections in Patients with Cancer 
Many noninfectious processes can cause skin lesions, but the pres­
ence of fever is unusual except in Sweet syndrome, also known as acute 
neutrophilic dermatosis (Fig. 79-2). This is characterized by fever and 
a variety of skin lesions including papules, nodules, plaques, and some­
times blisters. Skin lesions are often tender and may ulcerate. Sweet 
syndrome can have many causes, including underlying cancer, usually 
hematologic. Pathergy is characteristic, and lesions may appear at the 
insertion site of an intravascular catheter, mimicking infection 
(Fig. 79-2). Leukemia cutis may manifest as a variety of nontender 
papules, nodules, or plaques. Fever is unusual. Chemotherapeutic 
agents can cause a variety of skin reactions, including hyperpigmenta­
tion, hand-foot syndrome (erythema, edema, and blistering of palms 
and soles), and several rashes. Definitive diagnosis often requires 
biopsy of skin lesions with appropriate cultures and histopathology.
■
■URINARY TRACT INFECTIONS
It is common to obtain urine cultures in patients with NF regardless 
of urinary symptoms, and sometimes bacteriuria is detected. The 
question of whether it is just asymptomatic bacteriuria (common and 
increasing with age in both men and women), unrelated to the fever, 
or reflects true urinary tract infection (UTI) necessitating specific 
treatment may not be immediately answerable. It is appropriate to 
treat bacteriuria in patients with NF, and standard empirical antibiotic 
regimens used for NF will cover most urinary pathogens. If UTI is 
believed to be the source of NF, CT imaging should be considered to

A
B
C
D
PART 4
Oncology and Hematology
FIGURE 79-2  Sweet syndrome. A 47-year-old man admitted for acute myelogenous 
leukemia (AML) received a surgically implanted catheter and was started on 
idarubicin and cytosine arabinoside (Ara-C). He developed erythema and tenderness 
at the insertion site and the cuff site after 24 h, followed by fever. The catheter 
was removed and cultured (negative) and broad-spectrum antibiotics started, 
without effect. The catheter exit site worsened, with bullae formation (A). New 
skin nodules developed on his left thigh, both cheeks, and scalp. Tender induration 
of the sternocleidomastoid muscle was noticeable clinically and by CT (B). Skin 
biopsy showed a dense infiltrate of mature neutrophils consistent with Sweet 
syndrome (C, D). The lesions and the fever resolved promptly with oral prednisone.
evaluate for complicated UTI with potential etiologies including geni­
tourinary tract obstruction by tumor or kidney stones, pyelonephritis, 
and prostatitis.
PREVENTION OF INFECTIONS 

IN PATIENTS WITH CANCER
Prevention measures to avoid infections should be tailored to the 
immune status of the patient and consequent risk of infections. The 
most stringent measures apply to patients with hematologic malignan­
cies with prolonged neutropenia, to stem cell transplant and adop­
tive cellular therapy recipients, and to other patients who may have 
prolonged neutropenia for other reasons (e.g., aplastic anemia) or are 
receiving intensive systemic corticosteroid therapy. At the other end of 
the spectrum are patients with solid tumors who are in remission and 
not receiving active chemotherapy or only receiving hormonal agents, 
such as antiestrogen therapy for breast cancer. These patients should 
adhere to guidelines to prevent infection that apply to the general 
population such as hand hygiene, food safety, and guideline-based vac­
cines. This section is focused on prevention measures for patients with 
cancer at high risk for infections including opportunistic infection.
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■ENVIRONMENTAL PRECAUTIONS
Inpatient leukemia and transplant wards are typically engineered with 
HEPA filters and appropriate air exchanges, and individual patient 
rooms are under positive pressure relative to the outside. The principal 
rationale for these precautions is to reduce mold spore exposure; these 
structural precautions were in part driven by outbreaks of aspergillosis. 
For similar reasons, houseplants are restricted from these wards. Con­
struction, which can release mold spores, must be performed under 
stringent infection control precautions to minimize patient exposure. 
In addition to limiting mold exposure, these precautions may have 
additional benefits to limit airborne transmission of other infections.
The vast majority of chemotherapy regimens are administered 
to outpatients, including to patients with hematologic malignancies 

receiving intensive immunosuppressive regimens. The stringent envi­
ronmental precautions used for inpatients are not feasible in the out­
patient setting or in the home. Patients should not have construction 
done in their homes and should avoid exposure to construction sites 
during periods of significant immune compromise. Patients should 
also not be involved in gardening, mulching, or similar activities that 
result in spore exposure.
■
■PROTECTION FROM FOOD-BORNE INFECTIONS
The old practice of implementing “low-microbial diets” for neutrope­
nic patients did not show convincing benefit in well-designed studies 
and carries the disadvantages of limiting nutrition and affecting quality 
of life. Patients should be educated about food and water safety precau­
tions issued by the Centers for Disease Control and Prevention (www.
cdc.gov/food-safety/foods/weakened-immune-systems.html) and other 
authoritative bodies that are tailored to immunocompromised persons 
but are less restrictive than low-microbial diets. These guidelines stress 
hand hygiene, washing vegetables and fruits, not consuming raw or 
undercooked meat, poultry, or fish or unpasteurized dairy products, 
avoidance of waterborne infections, and awareness of food-borne 
outbreaks. Travel to regions where food and water safety is not reliable 
should be avoided.
Animals also are a potential source of infection, particularly via the 
fecal–oral route. Patients with cancer should avoid exposure to farm 
animals and wild animals (e.g., hunting and butchering). Acquiring 
a new pet while immunocompromised is not advisable. Existing pets 
can continue to live in the patient’s house, but the patient should avoid 
direct exposure to animal waste, such as cleaning a cat litter box or 
bird cage. Patients should avoid dogs recently vaccinated for kennel 
cough, if possible. Contact with more exotic pets (e.g., reptiles) should 
be avoided because they can harbor more unusual pathogens (e.g., 
Salmonella species).
■
■RESPIRATORY VIRAL INFECTIONS
Patients with cancer should avoid contact with persons with symp­
toms or signs of respiratory infection to the extent feasible. Risk of 
viral infection is increased in congregate settings that are indoors and 
involve large numbers of people in close proximity. Precautions to limit 
infection spread, such as choosing outdoor over indoor events and 
avoiding crowded settings, are advisable. For example, a dinner at a 
restaurant in which the table is limited to a few persons carries less risk 
of transmissible infections than a crowded buffet-style setting.
Patients with cancer should be aware of local patterns of viral 
infection. This point was amply demonstrated during the COVID-19 
pandemic and applies to other viral infections, such as influenza and 
respiratory syncytial virus (RSV). If local viral outbreaks occur, patients 
with cancer should use additional precautions to limit exposure. In 
addition to avoiding crowds, masking may provide an additional layer 
of protection, especially in settings of high levels of community spread 
of respiratory viral infections.
■
■SEXUAL INTIMACY
To avoid risk of sexually transmitted infections, it is recommended that 
sexual intercourse be in a monogamous relationship. During neutrope­
nia, sexual intercourse and oral–genital or rectal stimulation may cause 
injury and predispose to infection. Once the ANC recovers, sexual 
activity usually can be resumed.
■
■ANTIMICROBIAL PROPHYLAXIS
Antimicrobial prophylaxis should be tailored to infection risk. Most 
patients with solid tumors require no antimicrobial prophylaxis. In 
addition to side effects of antibiotics, increased risk of C. difficile, and 
selection of antibiotic-resistant flora, there is precedent for antibiotics 
diminishing the efficacy of immune checkpoint inhibitors by disrup­
tion of the microbiome.
As discussed above, prophylaxis with a quinolone should be con­
sidered in adults with prolonged neutropenia (e.g., ANC <500/µL 
for at least 7 days). Acyclovir prophylaxis to prevent HSV and VZV