This document discusses infections in cancer patients, with a focus on febrile neutropenia. It describes how the mortality rate from infection in febrile neutropenic patients has dropped dramatically to under 10% due to early empirical antibiotic therapy and the addition of empirical antifungal therapy. It provides guidelines for evaluating and managing low-risk versus high-risk febrile neutropenic patients, including recommended antimicrobial regimens. It also discusses specific infections like pulmonary infections and their diagnosis.

1. Infections in cancer patients
particular focus on
Febrile Neutropenia
Contributers: Seyed Ali Mousavi Aghdas
Harrison's Principles of Internal Medicine: Chapter 104
Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with
Cancer: 2010 Update by the Infectious Diseases Society of America

2. INTRODUCTION
Autopsy studies show that most deaths from acute leukemia and half of deaths from
lymphoma are caused directly by infection. With more intensive chemotherapy,
patients with solid tumors have also become more likely to die of infection.
Fortunately, an evolving approach to prevention and treatment of infectious
complications of cancer has decreased infection-associated mortality rates and will
probably continue to do so. This accomplishment has resulted from three major
steps:
• 1. The practice of using “early empirical” antibiotics reduced mortality rates among
patients with leukemia and bacteremia from 84% in 1965 to 44% in 1972. Recent
studies suggest that the mortality rate due to infection in febrile neutropenic
patients dropped to <10% by 2013. This dramatic improvement is attributed to
early intervention with appropriate antimicrobial therapy.
• 2. “Empirical” antifungal therapy has also lowered the incidence of disseminated
fungal infection, with dramatic decreases in mortality rates. An antifungal agent is
administered—on the basis of likely fungal infection—to neutropenic patients who,
after 4–7 days of antibiotic therapy, remain febrile but have no positive cultures.
• 3. Use of antibiotics for febrile neutropenic patients as broad- spectrum
prophylaxis against infections has decreased both mortality and morbidity even
further. The current approach to treatment of severely neutropenic patients (e.g.,
those receiving high-dose chemotherapy for leukemia or high-grade lymphoma) is
based on initial prophylactic therapy at the onset of neutropenia, subsequent
“empirical” antibacterial therapy targeting the organisms whose involvement is
likely in light of physical findings (most often fever alone), and finally “empirical”
antifungal therapy based on the known likelihood that fungal infection will become
a serious issue after 4–7 days of broad-spectrum antibacterial therapy.

3. • Neutropenia is defined as an absolute neutrophil count (ANC) of
less than 500/µL, or less than 1000/µL with an anticipated decline
to less than 500/µL in the next 48-hour period. Neutropenic fever
is a single oral temperature of 38.3º C (101º F) or a temperature of
greater than 38.0º C ( 100.4º F) sustained for more than 1 hour in a
patient with neutropenia.
Note: Fever—generally a sign of infection in normal hosts—continues
to be a reliable indicator in neutropenic patients. In contrast,
patients receiving glucocorticoids and agents that impair T cell
function and cytokine secretion may have serious infections in the
absence of fever. The elderly, neonates, alcoholics and patients with
renal or liver failure are also in risk of severe infections in absence
of fever.
Major risk factors:
• Induction-remission for AML 70-90%
• Elderly patients receiving CHOP 35-45%
• Solid tumors 10-50%
Mortality from febrile neutropenia:
• Hematological malignancies 11%
• Gram + bacteremia 5%
• Gram – bacteremia 18%

4. • Pathogens: Coagulase – staphylocci are the most common blood isolates in
most centers. Enterobacteriacea (eg, Enterobacter, E.coli , Klebsiella) and
nonfermenting gram – rods (eg, pseudomonas aeruginosa)

5. Initial evaluation:

7. Low-risk patients are those with the following:
MASCC score ≥21 OR
• Anticipated brief (<7-d duration) period of neutropenia
• ANC greater than 100/µL and absolute monocyte count greater
than 100/µL
• Normal findings on chest radiograph
• Outpatient status at the time of fever onset
• No associated acute comorbid illness
• No hepatic or renal insufficiency
• Early evidence of bone marrow recovery
Low-risk patients may be candidates for oral empiric therapy and
may qualify for outpatient management. However, these patients
require very close outpatient monitoring and assessment. They
should be seen in the office daily for at least 72 hours.

8. Empiric antimicrobial therapy:
• Amoxicillin-clavulanate 500 mg/125 mg PO q8h plus ciprofloxacin 500 mg
PO q12h
• Moxifloxacin 400 mg PO daily
Note: If penicillin allergic, substitute clindamycin 300 mg PO q6h for
amoxicillin-clavulanate

9. High-risk patients are those patients with any
one of the following:
MASCC <21 OR
• Anticipated, prolonged (>7-d duration), and profound neutropenia (ANC
<100/µL) following cytotoxic chemotherapy
• Significant medical co-morbidities, including hypotension, pneumonia,
new-onset abdominal pain, or neurologic changes
WARNING: High-risk patients should be admitted to the hospital for empiric
therapy and close observation.

11. Empirical antimicrobial therapy
•First-line monotherapy: This must include an agent with
antipseudomonal activity. Quinolones and aminoglycosides are not
acceptable as monotherapy. The following antibiotics are
appropriate as monotherapy:
• Piperacillin-tazobactam 4.5 g IV q6h or
• Cefepime 2 g IV q8h or
• Meropenem 1 g IV q8h or
• Imipenem-cilastatin 500 mg IV q6h
• No single agent has shown superiority in the empiric treatment of
febrile neutropenia.
Literature Note: According to a large RCT (219 individual patients)
conducted by Harter et al 2006; Single-agent therapy with
piperacillin/tazobactam is as effective as ceftazidime (2g IV q8h) in
the treatment of neutropenic fever among patients with acute
leukemia and is well tolerated. Direct and indirect costs of both
treatment regimes are equivalent.

12. Second-line dual therapy: The use of dual therapy in high-risk patients is indicated for
complicated cases (hypotension or pneumonia) or suspected or proven
antimicrobial resistance. Appropriate antibiotic regimens in this setting include the
following:
• Piperacillin-tazobactam 4.5 g IV q6h plus an aminoglycoside (see below)or
• Cefepime 2 g IV q8h plus an aminoglycoside (see below) or
• Meropenem 1 g IV q8h plus an aminoglycoside (see below) or
• Imipenem-cilastatin 500 mg IV q6h plus an aminoglycoside (see below)
• Aminoglycoside options:
• Gentamicin 2 mg/kg IV q8h or 5 mg/kg q24h or
• Amikacin 15 mg/kg/day or
• Tobramycin 2 mg/kg q8h
Literature Note: Aminoglycoside-related toxicity occasionally makes this regimen
difficult to use as the first-line drug therapy. Note that their ototoxic effect
increases when used with Cisplatin or Furosemide (lazix). A study by Takeuchi et al
2003 chose aztreonam as the alternative to aminoglycoside in combination with
piperacillin for neutropenic fever in pediatric patients and evaluated its
effectiveness (31 febrile episodes in 16 patients / Piperacillin 200 mg/kg per day
plus aztreonam150 mg/kg per day). The overall response rate was 67%. The
response rate when neutrophil count was less than 100/mm3 was 63%. The side
effects were mild and rare.

13. Indications for the empiric addition of vancomycin (15 mg/kg IV q12h) to drug regimens
listed above:
•Clinically suspected serious catheter-related infections (eg, bacteremia, cellulitis)
•Known colonization with penicillin- and cephalosporin-resistant pneumococci or
methicillin-resistant Staphylococcus aureus (MRSA)
•Blood culture positive for gram-positive bacteria
•Hypotension
•Severe mucositis
•prior fluoroquinolone prophylaxis provided
Additions to initial empirical therapy that may be considered for patients at risk for
infection with antibiotic-resistant organisms:
•MRSA – Vancomycin, linezolid, or daptomycin
•Vancomycin-resistant enterococcus (VRE) – Linezolid or daptomycin
•Extended-spectrum beta-lactamase (ESBL)–producing gram-negative bacteria – A
carbepenem (eg, imipenem, meropenem)
•Carbapenemase-producing organisms (eg, Klebsiella pneumoniaecarbapenemase) –
polymyxin-colistin or tigecycline

14. ESMO

16. Recommendations if fever resolves in 3-5 days
Organism identified:
• Adjust antibiotics based on specific organism and site of infection.
• Continue therapy for at least 7 days until cultures are negative and clinical
recovery is noted.
No organism identified and ANC greater than 500/µL for 2 consecutive days:
• Change therapy to amoxicillin-clavulanate 500 mg/125 mg PO q8h plus
ciprofloxacin 500-750 mg PO q12h.
• Antibiotic therapy may be discontinued after 5-7 days once patient is afebrile
for 2 consecutive days.
No organism identified and ANC less than 500/µL:
• Continue current antibiotic regimen until day 7.
• If patient is initially low risk and clinically stable by day 7, then antibiotics can
be discontinued.
• If patient is initially high risk then continue antibiotic therapy for 2 weeks or
until resolution of neutropenia.
• Change to a prophylactic antibiotic regimen may be considered.

17. If fever persists after 3-5 days:
ANC greater than 500/µL:
•Continue current empiric antibiotic regimen.
•Stop regimen 4-5 days after ANC has reached >500/µL.
•Reassess for undiagnosed fungal infection.
ANC less than 500/µL:
•If patient is not on vancomycin, add vancomycin if criteria are met.
•If patient is already on vancomycin, consider discontinuation if cultures are
negative for MRSA.
•Consider adding empiric antifungal therapy (see below)

18. Antifungal agents can be withheld in a specific subset of high-risk febrile neutropenic patients.
These patients include those who remain febrile after 4-7 days of broad-spectrum antibiotics but
are clinically stable and without clinical or radiographic signs of fungal infection. In low-risk
patients, the risk of fungal infection is low; therefore, empiric antifungal agents should not be used
routinely.
• Empiric antifungal therapy:
• Amphotericin B liposomal complex 3 mg/kg q24h or
• Voriconazole 6 mg/kg q12h X 2 doses, then 4 mg/kg q12 h or
• Posaconazole 200 mg PO q6h for 7d, then 400 mg PO q12h or
• Itraconazole 200 mg IV q12h for 2d, then 200 mg IV or PO q24h for 7d, then 400 mg PO q24h
thereafter or
• Caspofungin 70 mg IV for 1 dose, then 50 mg IV q24h or
• Micafungin 100-150 mg IV q24h or
• Anidulafungin 200 mg IV for 1 dose, then 100 mg IV q24h
• Patients already on antifungal prophylaxis should be switched to a different class if fever persists.
• Continue therapy for 2 weeks if patient has stabilized and no infectious nidus is identified
Literature note: Safety, tolerability and efficacy of itraconazole and amphotericin B (AMB) are
compared for empirical antifungal treatment of febrile neutropenic cancer patients, by Schuler et al
2007. Significantly fewer itraconazole patients discontinued treatment due to any adverse event
(22.2 vs. 56.8% AMB; p < 0.0001). The main reason for discontinuation was a rise in serum
creatinine (1.2% itraconazole vs. 23.5% AMB). Renal toxicity was significantly higher and more drug-
related adverse events occurred in the AMB group. Intention-to-treat (ITT) analysis showed
favourable efficacy for itraconazole: response and success rate were both significantly higher than
for AMB (61.7 vs. 42% and 70.4 vs. 49.3%, both p < 0.0001). Treatment failure was markedly
reduced in itraconazole patients (25.9 vs. 43.2%), largely due to the better tolerability. Itraconazole
was tolerated significantly better than conventional AMB and also showed advantages regarding
efficacy.

19. Physical predisposition to infection in patients with cancer:
• Break in the skin------- SCC of the skin
• The artificial closure of a normally patent orifice
• Lymph node dissection ------------- radical mastectomy, cellulitis (streptococci or staphylococci)
• Splenectomy ----------- hairy cell leukemia, chronic lymphocytic leukemia (CLL), and chronic
myelogenous leukemia (CML) and in Hodgkin’s disease (encapsulated bacteria S.pneumonia ,
H.influenza, N.meningitidis / protozoan Babesia / Capnocytophaga canimorsus, a bacterium carried
in the mouths of animals)
Note: Many clinicians recommend giving splenectomized patients a small supply of antibiotics effective
against S. pneumoniae, N. meningitidis, and H. influenzae to avert rapid, overwhelming sepsis in
the event that they cannot present for medical attention immediately after the onset of fever or
other signs or symptoms of bacterial infection. A few tablets of amoxicillin/clavulanic acid (or
levofloxacin if resistant strains of S. pneumoniae are prevalent locally) are a reasonable choice for
this purpose.
• Neutropenia-----------Acute myeloid and acute lymphocytic leukemias, hairy cell leukemia
(Staphylococci, streptococci, enteric organisms, fungi)
• Lack of antibody---------Chronic lymphocytic leukemia, multiple myeloma (S. pneumoniae, H.
influenzae, N. meningitides)
• Lack of T cell-----------Hodgkin’s disease, leukemia, T cell lymphoma (Mycobacterium tuberculosis,
Listeria, herpesviruses, fungi, intracellular parasites)
Note: Patients with acute lymphocytic leukemia (ALL), patients with non-Hodgkin’s lymphoma, and all
cancer patients treated with high-dose glucocorticoids (or glucocorticoid-containing chemotherapy
regimens) should receive TMP-SMX prophylaxis for Pneumocystis infection for the duration of their
chemotherapy.

20. Pulmonary infections:
• Bleomycin is the most common cause of chemotherapy-induced
lung disease. Other causes include alkylating agents (such as cyclo-
phosphamide, chlorambucil, and melphalan), nitrosoureas
(carmustine [BCNU], lomustine [CCNU], and methyl-CCNU),
busulfan, procarbazine, methotrexate, and hydroxyurea. Both
infectious and noninfectious (drug- and/or radiation-induced)
pneumonitis can cause fever and abnormalities on chest x-ray; thus,
the differential diagnosis of an infiltrate in a patient receiving
chemotherapy encompasses a broad range of conditions.
• Bacterial pneumonia in neutropenic patients may present without
purulent sputum—or, in fact, without any sputum at all—and may
not produce physical findings suggestive of chest consolidation
(rales or egophony). In granulocytopenic patients with persistent or
recurrent fever, the chest x-ray pattern may help to localize an
infection and thus to deter-mine which investigative tests and
procedures should be undertaken and which therapeutic options
should be considered. In this setting, a simple chest x-ray is a
screening tool; because the impaired host response results in less
evidence of consolidation or infiltration, high-resolution CT is
recommended for the diagnosis of pulmonary infections.

21. •Microscopic and microbiologic evaluation of the fluid obtained by endoscopic
bronchial lavage is often diagnostic. Lavage fluid should be cultured for
Mycoplasma, Chlamydia, Legionella, Nocardia, more common bacterial
pathogens, fungi, and viruses. In addition, the possibility of Pneumocystis
pneumonia should be considered, especially in patients with ALL or lymphoma
who have not received prophylactic trimethoprim-sulfamethoxazole (TMP-SMX).
The characteristics of the infiltrate may be helpful in decisions about further
diagnostic and therapeutic maneuvers. Nodular infiltrates suggest fungal
pneumonia (e.g., that caused by Aspergillus or Mucor).

22. Skin Lesions:
•In the neutropenic host, a macule progresses rapidly to ecthyma
gangrenosum , a usually painless, round, necrotic lesion consisting of a
central black or gray-black eschar with surrounding erythema. Ecthyma
gangrenosum, which is located in nonpressure areas (as distinguished
from necrotic lesions associated with lack of circulation), is often
associated with Pseudomonas aeruginosa bacteremia but may be caused
by other bacteria. Candidemia is also associated with a variety of skin
conditions and commonly presents as a maculo-papular rash. Punch
biopsy of the skin may be the best method for diagnosis.
•Cellulitis, an acute spreading inflammation of the skin, is most often
caused by infection with group A Streptococcus or Staphylococcus aureus,
virulent organisms normally found on the skin. It is essential to recognize
cellulitis early and to treat it aggressively. Patients who are neutropenic or
who have previously received antibiotics for other reasons may develop
cellulitis with unusual organisms (e.g., Escherichia coli, Pseudomonas, or
fungi). Early treatment, even of innocent-looking lesions, is essential to
prevent necrosis and loss of tissue. Debridement to prevent spread may
sometimes be necessary early in the course of disease, but it can often be
performed after chemotherapy, when the PMN count increases.

23. Sweet syndrome, or febrile neutrophilic dermatosis, the
disease is characterized by the presence of leukocytes in
the lower dermis, with edema of the papillary body.
Ironically, this disease now is usually seen in neutropenic
patients with cancer, most often in association with acute
myeloid leukemia (AML) but also in association with a
variety of other malignancies. Sweet syndrome usually
presents as red or bluish-red papules or nodules that may
coalesce and form sharply bordered plaques. The edema
may suggest vesicles, but on palpation the lesions are solid,
and vesicles probably never arise in this disease. The
lesions are most common on the face, neck, and arms. On
the legs, they may be confused with erythema nodosum.
The development of lesions is often accompanied by high
fevers and an elevated erythrocyte sedimentation rate.
Both the lesions and the temperature elevation respond
dramatically to glucocorticoid administration. Treatment
begins with high doses of glucocorticoids (prednisone, 60
mg/d) followed by tapered doses over the next 2–3 weeks.

24. Oral cavity
• The oral cavity is rich in aerobic and anaerobic bacteria that normally live in a
commensal relationship with the host. The antimetabolic effects of chemotherapy
cause a breakdown of mucosal host defenses, leading to ulceration of the mouth
and the potential for invasion by resident bacteria. Mouth ulcerations afflict most
patients receiving cytotoxic chemotherapy and have been associated with viridans
streptococcal bacteremia. Candida infections of the mouth are very common.
Fluconazole is clearly effective in the treatment of both local infections (thrush)
and systemic infections (esophagitis) due to Candida albicans. Other azoles (e.g.,
voriconazole) as well as echinocandins offer similar efficacy as well as activity
against the fluconazole-resistant organisms that are associated with chronic
fluconazole treatment.
• Noma (cancrum oris), commonly seen in malnourished children, is a penetrating
disease of the soft and hard tissues of the mouth and adjacent sites, with resulting
necrosis and gangrene. It has a counterpart in immunocompromised patients and
is thought to be due to invasion of the tissues by Bacteroides, Fusobacterium, and
other normal inhabitants of the mouth. Noma is associated with debility, poor oral
hygiene, and immunosuppression.
• Viruses, particularly HSV, are a prominent cause of morbidity in
immunocompromised patients, in whom they are associated with severe
mucositis. The use of acyclovir, either prophylactically or therapeutically, is of
value.

25. Hepatic candidiasis
•Results from seeding of the liver (usually from a gastrointestinal source) in
neutropenic patients. It is most common among patients being treated for
AML and usually presents symptomatically around the time the
neutropenia resolves. The characteristic picture is that of persistent fever
unresponsive to antibiotics, abdominal pain and tenderness or nausea,
and elevated serum levels of alkaline phosphatase in a patient with
hematologic malignancy who has recently recovered from neutropenia.
The diagnosis of this disease (which may present in an indolent manner
and persist for several months) is based on the finding of yeasts or
pseudohyphae in granulomatous lesions. Hepatic ultrasound or CT may
reveal bull’s-eye lesions. MRIs reveal small lesions not visible by other
imaging modalities. The pathology (a granulomatous response) and the
timing (with resolution of neutropenia and an elevation in granulocyte
count) suggest that the host response to Candida is an important
component of the manifestations of disease. In many cases, although
organisms are visible, cultures of biopsied material may be negative. The
designation hepatosplenic candidiasis or hepatic candidiasis is a misnomer
because the disease often involves the kidneys and other tissues; the term
chronic disseminated candidiasis may be more appropriate. Because of
the risk of bleeding with liver biopsy, diagnosis is often based on imaging
studies (MRI, CT). Treatment should be directed to the causative agent
(usually C. albicans but sometimes Candida tropicalis or other less
common Candida species).

26. Meningitis
The presentation of meningitis in patients with lymphoma or CLL and in patients receiving
chemotherapy (particularly with glucocorticoids) for solid tumors suggests a diagnosis of
cryptococcal or listerial infection. As noted previously, splenectomized patients are
susceptible to rapid, overwhelming infection with encapsulated bacteria (including S.
pneumoniae, H. influenzae, and N. meningitidis). Central nervous system (CNS) tuberculosis
should be considered, especially in patients from countries where tuberculosis is highly
prevalent in the population.
• A predisposition to infections with intracellular organisms similar to those encountered in
patients with AIDS is seen in cancer patients receiving (1) high-dose cytotoxic chemotherapy,
(2) chemotherapy affecting T cell function (e.g., fludarabine), or (3) antibodies that eliminate
T cells (e.g., anti-CD3, alemtuzumab, anti-CD52) or cytokine activity (anti–tumor necrosis
factor agents or interleukin 1 receptor antagonists). Infection with varicella-zoster virus (VZV)
has been associated with encephalitis that may be caused by VZV-related vasculitis. Chronic
viral infections may also be associated with dementia and encephalitic presentations. A
diagnosis of progressive multifocal leukoencephalopathy should be considered when a
patient who has received chemotherapy (rituximab in particular) presents with dementia.
Other abnormalities of the CNS that may be confused with infection include normal-pressure
hydrocephalus and vasculitis resulting from CNS irradiation. It may be possible to
differentiate these conditions by MRI.
Brain Masses
Mass lesions of the brain most often present as head-ache with or without fever or neurologic
abnormalities. Infections associated with mass lesions may be caused by bacteria
(particularly Nocardia), fungi (particularly Cryptococcus or Aspergillus), or parasites
(Toxoplasma). Epstein-Barr virus (EBV)–associated lymphoma may also present as single—or
sometimes multiple—mass lesions of the brain. A biopsy may be required for a definitive
diagnosis.

28. CATHETER-RELATED INFECTIONS
• Because IV catheters are commonly used in cancer chemotherapy and are prone
to cause infection, they pose a major problem in the care of patients with cancer.
Some catheter-associated infections can be treated with antibiotics, whereas in
others the catheter must be removed. If the patient has a “tunneled” catheter
(which consists of an entrance site, a subcutaneous tunnel, and an exit site), a red
streak over the subcutaneous part of the line (the tunnel) is grounds for
immediate device removal. Failure to remove catheters under these circumstances
may result in extensive cellulitis and tissue necrosis. More common than tunnel
infections are exit-site infections, often with erythema around the area where the
line penetrates the skin. Most authorities recommend treatment (usually with
vancomycin) for an exit-site infection caused by coagulase-negative
Staphylococcus. Treatment of coagulase-positive staphylococcal infection is
associated with a poorer outcome, and it is advisable to remove the catheter if
possible. Similarly, most clinicians remove catheters associated with infections due
to P. aeruginosa and Candida species, because such infections are difficult to treat
and bloodstream infections with these organisms are likely to be deadly. Catheter
infections caused by Burkholderia cepacia, Stenotrophomonas species,
Agrobacterium species, Acinetobacter baumannii, Pseudomonas species other
than aeruginosa, and carbapenem-resistant Enterobacteriaceae are likely to be
very difficult to eradicate with antibiotics alone. Similarly, isolation of Bacillus,
Corynebacterium, and Mycobacterium species should prompt removal of the
catheter.