Download Management of Specific Infectious Complications in Children with

Management of Specific
Infectious Complications in
Children with Leukemias and
lymphomas
Speaker:林育成 藥師
Introduction (1)
Childhood cancer is the secondary cause of
death in children <15 years old
 Leukemia and lymphoma constitute
approximately 50% of new diagnosed
childhood cancer
 Maintenance regimens may last 1-3 years,
prolonging the period of
immunosuppression and continuing the risk
for infection

Introduction (2)
The magnitude of risk of infection varies
closely with the depth and duration of
granulocytopenia
 Low-risk acute lymphocytic leukemia
 high-risk acute lymphocytic leukemia

Introduction (3)
Patients who receive
chemotherapy
Fever
evidence of
infection
Neutropenia<1 week
Fewer
than 30%
Fewer than
30%
Neutropenia>1week
Almost
100%
Almost
100%
fever
Fever : the most important indicator of
infection in children with cancer
 Infectious and noninfectious cause
 Child’s underlying malignancy (Ewing
sarcoma)
 The production of pyrogens (e.g.. Certain
lymphoma)
 Most fevers in children with cancer are
associated with granulocytopenia and
infection.

Granulocytopenia
Important risk factor associated with
infection.
 The depth and duration of granulocytopenia
is directly related to the frequency of
serious infections
 Defects in chemotaxis, generation of
superoxide, phagocytosis, and bactericidal
activity in vitro.

Granulocytopenia
Abnormally reduced number of
granulocytes circulating in peripheral blood
 Absolute neutrophil count (ANC)<1,000
cells/mm ^3 indicates a reduction sufficient
to predispose patients to infection
 ANC: absolute numbers of both mature
neutrophils and immature neutrophils

(PMN, also called “polys” or “seg”)
“bands”
Absolute neutrophil count
ANC
500~1,000 <500
(cell/mm^3)
<100
Risk of
infection
and death
+++
+
++
Important risk factors for
infections (1)
Rate of neutrophil decline
 Duration of neutrpenia

Important risk factors for
infections (2)
ANCs falling rapidly, <500/mm^3 within 24
hours severe neutropenia
 Severe neutropenia > 7~10 days’ duration
high risk
 Leukemia patient with relapsing disease are
at increased risk of infection, even in the
absence of neutropenia

Factors contributing to the risk of
infection (1)
Abnormalities in mucosal and
integumentary physical defense
 Decreases in phagocyte numbers and
functions
 Profound alterations in cellular and humoral
immune defenses
 Alterations in innate recognition immunity
 Alterations in endogenous microbial flora

Factors contributing to the risk of
infection (2)
Exposure to new potential pathogens
secondary to treatment with cytotoxic and
antimicrobial agents
 Intravascular devices
 Hospitalization
 Alteration of nutrition

Glucocorticosteroids
Decrease neutrophil migration,
phagocytosis, and intracellular microbicidal
activity
 Alter macrophage function, diminishing
host defenses against tissue-invasive fungi
and other pathogens, including intracellular
bacteria, protozoan, and virus.

Glucocorticosteroids
Aggrevated cell-mediated immunity defects,
making patients even more susceptible to
infections
 Varicella-zoster virus [VZV];Herpes
simplex virus [HSV];Cytomegalovirus
[CMV]
 fungal [pneumocystosis, cryptococcosis,
histoplasmosis]

Antineoplastic agents that
decrease phagocytic and
bactericidal activity
Vinca alkoids
 L-asparaginase
 6-mercaptopurine
 methotrexate
 anthracyclines

Cytotoxic chemotherapy and
radiation therapy
Diminish B-cell functions,
 Leading to decreased immunoglobulin
concentrations
 Lowered opsonic activity
 Inadequate agglutination and lysis of
bacteria
 Deficient neutralization of bacterial toxins.

Immunoglobulin deficiency
Susceptibility of encapsulated bacteria
 Markedly increased risk for Haemophilus
influenzae type B and pneumococcal blood
stream infections

Cytocotoxic chemotherapy v.s.
Vaccine

Depressed the responses to common
antiviral and antibacterial vaccines:
both primary and booster challenges
Defective antibody production (for up to 5
years after completion of anticancer therapy)
 Depending on underlying malignancy, doseintensity of antineoplastic chemotherapy,
and the vaccine used

Spleen

If spleen is infiltrated by leukemia and
lymphoma or removed for diagnostic or
therapeutic reasons, the risk of fulminant
infection from such encapsulated bacteria as
Streptococcus pneumoniae, H. influenzae,
and Neisseria meningitidis is consideralby
increased.
Candida spp.

Colonization by Candida spp.is also
common, in particular in patients receiving
broad -spectrum antibiotics .
Management of specific infectious
complications (1)
Prompt use of appropriate antimicrobial
therapy
 Modifications of antimicrobial therapy
 Adding anaerobic coverage for necrotizing
gingivitis or perirectal cellulitis
 Adding vancomycin for G(+) infections
caused by coagulase-negative staphylococci

Management of specific infectious
complications (2)

In patients with prolonged neutropenia:
addition of antifungal therapy
Bloodstream infections
Between 10%~20% of febrile and
neutropenic cancer patients have a
bacteremia.
 Sources of bacteremia

lung (25%),
perioral cellulitis (10%),
gastrointestinal tract (5%),
indwelling intravascular devices (increasing
frequency)
Common antibacterial agents (1)

Piperacillin: Broad G(-) spectrum
(particularly, Pseudomonas aeruginosa);
active against anaerobe, enterococci. In
neutropenic patients, use only in
combination with an aminoglycoside
Daily dose: 200-300 mg/kg in 4-6 divided
doses (max. 21g)
Common antibacterial agents (2)

Ceftazidime : Broad G(-) spectrum, including P.
aeruginosa; limited G(+) spectrum; no activity
against anaerobes. Combination with an
aminoglycoside recommended for G(-) bacteremia
 Daily doses:60-100 mg/kg in 3 divided doses (max.6g)

Ceftriaxone: option for empiric therapy in nonneutropenic patients with an indwelling central
vvenous catheter; no coverage of P. aeruginosa
 Daily doses :75-100 mg/kg in 1 single dose
Common antibacterial agents (3)

Imipenem: Broad G(-) and G(+) spectrum,
including P. aeruginosa; broad antianaerobic
activity. Combination with an animoglycoside is
recommended for treatment of P. aeruginosa
infections
 ( Daily dose: 50 mg/kg in 4 divided doses , max. 4g)

Aztreonam: Exclusive G(-) spectrum including
many strains of P. aeruginosa. Options for
combination therapy with vamcomycin
(±aminoglycoside) in patients with -lactam
allergy.
 (Daily dose: 100-150 mg/kg in 4 divided dose, max. 6g)
Common antibacterial agents (4)

Vancomcycin: Spectrum limited to G(+)
bacteria. Monitoring of serum levels
required with vancomycin
(Daily dose: 40 mg/kg in 2-4 divided doses,
max. 2g)

Gentamicin: Combinatory agent for empiric
therapy and for treatment of documented
G(-) infections, monitoring of serum levels
required.
(Daily dose: 5 mg/kg in 1 or 3 divided doses)
Common antibacterial agents (5)

Metronidazole: active against anaerobes
(abdominal/perirectal processes); first
choice for treatment of Clostridum difficlile
infection (PO)
(Daily dose: 30mg/kg in 4 divided doses, max.
4g)

Erythromcyin: Therapy for
proven/suspected infections by Chlamydia,
Mycoplasma, and Legionella
(30-50 mg/kg in 4 divided doses, max. 4g)
Catheter-Associated Bloodstream
Infections
Transiently placed and permanent central
venous catheters led to an increase in
catheter-associated bacteremias
 Diagnosis: blood cultures from both a
catheter lumen (+); a peripheral venous site
(+)

When is catheter removal required?
Blood cultures remain positive for more
than 24 to 48 hours after antibiotics have
been started
 A “tunnel infection” ( tenderness or
induration along the subcutaneous track of
the catheter) exists
 Detection of Candida spp. and other yeasts
in blood cultures

Fungal pneumonia
Aspergillus spp. : The most frequent
primary respiratory fungal pathogens in
cancer patient
 C. albicans and non-albicans Candida
species: The most common yeast like
pathogens in pediatric cancer patients and
can cause primary pneumonia

Upper Respiratory tract
infections
Otitis
 sinusitis
 epiglottitis

Lower Respiratory Tract
Infections
Patch infiltrates in non-neutropneic children
 Patch infiltrates in neutropenic children
 Diffuse infiltrates in neutropenic children
 Diffuse infiltrates in non-neutropenic
children

Nocardia Infection
Nocardia species ( Nocardia asteroides and
Nocardia brasiliensis)
 main portal entry: respiratory tract
 Main clinical manifestation: focal
pulmonary infection
 30 % of patients with Nocardia pneumonia
have subcutaneous abscess and brain
abscesses

Treatment of Norcardia infection
Sulfadiazine or TMP/SMX
 Combination of imipenem-cilastatin
 If the patient is unable to tolerate or does
not respond to sulfonamide: amoxicillinclavulanic acid plus amikacin

Fungal pneumonias
Infections by Histoplasma capsulatum,
Coccidioides immitis, and Blastomyces
dermatitidis
 In severely immunocomprosmised cancer
patients: cause invasive and often
dissemianated diseases that are lifethreatening

Approaches to antifungal therapy
for fungal pneumonias
Amphotericin B deoxycholate : all mycoses;
0.5~1.0 mg/kg/day
 Itraconazole : histoplasmosis and
blastomycosis; 5~12 mg/kg/day
 Fluconazole: coccidioidomycosis; 8~12
mg/kg/day

Pneumocystis carinii and
Protozoal Pneumonia
P. carinii and the protozoal organism
Toxoplasmosis gondii and S. steroralis can
cause diffuse infiltrates in both neutropenic
and non-neutropenic patients.
 PCP has decreased with the introduction of
prophylactic TMP/SMX

Pneumocystis carinii and
Protozoal Pneumonia
Children with hematologic malignanies who
are receiving dose-intensive antineoplastic
chemotherapy are at high risk for
development of life-threatening
Pneumocysitis carnii pneumonia
 Prophylactic TMP/SMX

Viral pneumonias (1)
Adenovirus
 measles
 RSV
 Parainfluenza
 CMV
 Varicella

Viral pneumonias (2)
Ganciclovir: does not appear to improve the
outcome of fully developed CMV
pneumonia in allogeneic bone marrow
transplantation patients, although some
what better responses have been obtained
with a combination of ganciclovir and
intravenous anti-CMV immunoglobulin.
 Daily dose: 10mg/kg in 2 divided doses

Viral pneumonias (3)
CMV: found in the urine or saliva of 27% of
children with leukemia
 CMV: cause gastrointestinal, hepatosplenic,
chorioretinal, CNS, pulmonary, and
disseminated disease
 Pneumonitis: the most common
manifestation of CMV disease in the cancer
setting

Viral pneumonias (4)
Primary varicella in the child with cancer
has a natural mortality rate of 7% to 20% if
untreated
 Acyclovir 500mg/square meter of body area
every 8 hours
 Acyclovir therapy appeared to be effective
even in children with varicella who has
already developed pulmonary infiltrated
when treatment as initiated.

Infections of Orointestinal Tract
S-phase specific chemotherapeutic agents:
e.g. methotrexate, cytosine arabinoside, 5fluorouracil
 Mucositis

Oral Mucositis
Associated with chemotherapy
 Sometimes be exceedingly severe,
requiring TPN and patient-directed
continuous analgesia with morphine
derivatives
 Mouth-cleansing solutions help decrease
the discomfort and control superinfection

Treatment of oral candidiasis
Oral clotrimazole troches: 50mg five times
daily
 fluconazole :3-6mg /kg/day
 cyclodextrin-itraconazole: 5 day/kg/day
 intrvaenous amphotericin B: 0.5mg /kg or
less per day for 5days

Oral HSV infection
Acyclovir orally (for patient can reliably
swallow these pills)
 Acyclovir intravenous

Chronic Disseminated
(“Hepatosplenic”) Candidiasis
Chronic disseminated candidiasis (CDC)
 CDC is an uncommon but potentially lifethreatening condition in patients with cancer
 Develops during prolonged
granulocytopenia but usually becomes
apparent only on recovery from
granulocytopenia.

Chronic Disseminated
(“Hepatosplenic”) Candidiasis
Preferentially affects the liver and spleen.
 Characteristics:

persistent fever despite granulocyte recovery
right upper quadrant abdominal pain
Serum alkaline phosphatase levels ( )
Approaches to management of
hepatosplenic candidiasis
Amphotericin B +flucytosine
 Amphotericin B lipid complex, followed by
long-term fluconazole for susceptible
isolates
 Fluconazole (intolerant or refractory to
amphotericin B)
 Antifungal therapy is recommended until
resolution or calcification of lesions (6
mon~1 year)

Perirectal cellulitis
Perirectal cellulitis:can be a problem in
children with prolonged, profound
granulocytopenia
 The risk of perirectal cellulitis increase if
perirectal mucositis, hemorrhoids, fissure,
or rectal manipulation has occurred.

Treatment of perirectal cellulitis

Begin early with antibiotics to cover aerobic
gram-negative bacilli, anaerobes, and group
D streptococci, stool softerners, and lowresidue diet
Genitourinary infections
Infections of the genitourinary tract are
uncommon in children with cancer unless
obstruction by tumor, catheterization,
neurologic dysfunction
 Pathogens: Gram-negative aerobic bacilli
and enterococci
 Treatment: amphotericin B plus flucytosine
or fluconazole for probable renal
candidiasis

Cutaneous infections
Bacterial skin infections include common
local gram(+) infections,
 Starting at sites of invasive devices or skin
breaks, wounds, radiation, burns, or
furuncles (especially in patients receiving
glucocorticosteroids)

Cutaneous infections
P. aeruginosa, can cause fulminant local
infection ,
 Embolic or vasculitic-appearing lesions can
be seen with bacteremia caused by P.
aeruginosa, Aeromonas hydrophilus,
Corynebacterium equi, or S. marcescens.

Cutaneous infections :VZV
Primary varicella: the most serious vesicular
eruption in children with cancer
 High rate of visceral dissemination and
considerable mortality
 If seronegative patient exposed to VZV,
immuoprophylaxis with VZV immune
globulin should be given intravenously no
later than 72 hours after the exposure

Cutaneous infections:VZV

The patient should not receive
immunosupressive therapy for
approxiamtely 21 days after exposure, and
not until scabs heal over if disease develop.
Central nervous system infections
Meningitis
 Encephalitis

Encephalitis
Encephalitis : generally rare
 Cause: usually caused by HSV, VZV, or
measles
 Differential diagnosis: neoplastic, toxic ,
metabolic cause

Encephalitis
If one or more enhancing lesion are seen in
the brain, Toxoplasma should be
condsidered.
 pyrimethamine and sulfadiazine or
TMP/SMX

本院目前使用中之抗黴菌藥物比較表
Diflucan
Cancidas
Fungizone
Ambisome
商品名
Fluconazole Caspofungin Amphotericin B Liposomal
成分
amphotericin B
yes
yes
yes
yes
注射劑
yes
No
No
No
口服劑
100mg
50mg
50mg inj:595
50mg inj :
健保價
inj:695
inj:12236
6641
150mg
tab:280
50mg tab:109
yes
yes
yes
抗菌活性 yes
Candida
Cryptocc yes
No
yes
yes
ocus
Aspergill No
yes
yes (not good ) yes ( high
us
dose)
Scedopori No
No
No
No
um
Fusarium No
No
No
No
595
19923~39846
平均每日 注射劑：9788 12236
藥價
口服劑：2808
Reference
Clinical management of infections in
immunocompromised infants and children.
Andreas H. Groll. Management of specific
infectious complications in children with
leukemias and lymphomas, 2001. P111-143
 Pharmacotherapy, a pathophysiologic
approach. Infection in
immunocompromised patients. Fifth edition,
Douglas N. Fish, Infections in
immunocompromised patients 2089-2109

Thanks for your attention!