1. No category

Complex and severe infection management of
immunocompromized patients – focus on oncooncohematology
Diseases associated with severe
immunocompromise
„Congenital immunodeficiency syndromes
„Cancer
„Chemo-, radiotherapy
„Stem cell and organ trancplantation
„HIV infection/AIDS
„Severe autoimmune diseases
„Long-lasting corticosteroid treatrment
Prof. Csongor Kiss
Other risk factors to develop severe
nosocomial infections
Multiple, overlapping risk factors of infections
render cancer patients particularly vulnerable
„ Diabetes mellitus
Childhood cancer is a rare disease
BUT
it represents a significant public health
problem!
(Morbidity, mortality, QoL
QoL,, social
segregation of pts and their families,
costs – for the involved families and for
the society)
„ Chronic liver/renal diseases
„ Alcohol/drug dependence
„ Excessive surgery/trauma
„ Long-lasting treatmant in ICU
(mechanical ventillation, i.v. lines)
„ Malnutrition
„ Low/high age
„ Splenectomy
Cancer and its treatment impairs barrier
function of the skin and mucosal surfaces
Natural and adaptive immunity
Defence
Barriers
Leukemic infiltration and bleeding
of the gingiva
UreteroUreterocutaneo-cutaneo
stoma
Natural
Mechanical integrity
Secretion
Mucociliar function
Phagocytes
Humoral factors
Lysosim
Lactoferrin
Interferons
Interleukins
Cellular factors
Phagocytes
NK cells
Adaptive
Immunoglobulins
Immunoglobulins
T lymphocytes
Severe oral mucositis due to
cytostatic chemotherapy
1
The most important host factor of both local and
systemic antimicrobial defence in cancer patients is:
is:
neutrophil polymorpho
polymorphonuclear
nuclear leukocytes
The most frequent and significant manifestation of
infection in the neutropenic cancer patient is FEVER
NeutroNeutropenia
Cancer
Chemo
Chemo-therapy
INFECTION
NeutroNeutropenia
FEVER
Impaired
barrier
function
Febrile Neutropenia (FN)
„ What is febrile neutropenia?
„ What to do with a patient with febrile
neutropenia?
„
„
Evaluation (patient and microbe) – risk
assessment
Treatment
„
„
„
„
„
Who should receive empirical Rx?
When should empirical Rx be started?
What is appropriate initial Rx?
How should initial Rx be modified?
How long should empirical Rx be continued?
Significance of FN in pediatric oncology
„ commonest cause of unplanned hospital
admissions for pediatric patients on therapy for
cancer
„ mortality
t lit rate
t ≅ 1% (90% iin 1962
1962, 27% iin 1978
and 7% in 1994)
„ significant morbidity
„ significant cost
NeutroNeutropenia
FN – what is it?
„ Many definitions of both fever and neutropenia
„ EG. Infectious Diseases Society of America Guidelines
„ fever :
single oral temperature ≥ 38.3°C
temperature ≥ 38.0°C for at least an hour
axillary
ill
t
temp
38 0 38 5oC 2x/24
38.0-38,5
2 /24 h or ≥ 38.5
38 5oC 1x
1
„ neutropenia: ANC /(J+Band+Se) x WBC/ < 0.5 x 109/L or
„ < 1.0 x 109/L with a predicted decrease to < 0.5 x 109/L
„ severe neutropenia: ANC < 0.2 x 109/L
„ neutropenic patients who are unwell but afebrile, and non-
neutropenic febrile patients expected
neutropenic, => treat as per FN Pt
to
become
Neutropenia: single most important risk factor
for infection in cancer patients
„ Most frequently - bacterial
infection
„ Risk of infection increases 10-
fold with declining neutrophil
counts < 500/mm3
„ 48-60% : occult infection
„ 16-20% with
neutropenia<100/mm3 have
bacteremia
2
Possible sites of infection
Evaluation
Should be thorough but quick!
Should include:
„ History (type and stage of cancer and its
treatment, previous infections, etc.)
„ Physical examination: respect minimal signs!
„ Risk assessment
„ Investigations (lab, culture, imaging)
Preantibiotic Investigations
„ Blood C/S : central line & peripheral
„ Chest X-Ray
„ Urine C/S
„ URTI
„ Dental sepsis
„ Mouth ulcers
„ Skin sores
„ Exit site of central venous catheters
„ Anal fissures
„ GI
Febrile Neutropenia
Bacterial causes (EORTC)
(60-70%)
„ Gram-negative bacilli (30-40%)
„ Gram-positive bacteria
„ Stool C/S
„ Biopsy cultures
„ Viral studies
Gram--positive Bacteria
Gram
Gram--negative Bacteria
Gram
„ Staphylococcus spp :
„ Escherichia coli
MSSA,MRSA,
„ Streptococcus spp : viridans
„ Enterococcus faecalis/faecium
„ Corynebacterium spp
„ Bacillus spp
„ Stomatococcus mucilaginosus
„ Klebsiella spp : ESBL
„ Pseudomonas aeruginosa
„ Enterobacter spp
„ Acinetobacter spp
„ Citrobacter spp
„ Stenotrophomonas maltophilia
3
Anerobic Bacteria
„ Bacteroides spp
„ Clostridium spp
„ Fusobacterium spp
„ Propionibacterium spp
„ Peptococcus spp
„ Veillonella spp
„ Peptostreptococcus spp
Low Risk Patients
in remission receiving conventional
chemother., i.e. patients w/o AML or ALL/NHL in
induction
„ expected duration of neutropenia ≤ 7 days
„ clinically
clinicall and hemodynamically
hemod namicall stable
„ unexplained or simple infection
„ no other significant comorbidities
„ no system involvement
„ absolute monocyte count > 150/mm3
„ C-reactive protein < 90mg/L
„ select good candidates for outpatient therapy
High Risk Patients
Need parenteral antibiotics + close monitoring
„ Hematological malignancies
„ Severe and prolonged neutropenia
„ Evidence of cardiovascular instability, shock /
„
„
„
„
„
„
dehydration
d
h d ti
Mucositis preventing oral hydration
Complex focal infection eg CVL site infection
Respiratory / gastrointestinal involvement
Need for blood products
Renal / hepatic insufficiency
Change in mental status
Immediate Introduction of Initial
Empiric Antibiotics - Rationale
„ tumors
Initial Empiric Antibiotics
Considerations
„ Severe risk of bacterial sepsis
„ Insensitivity of diagnostic tests
„ Delays in identification of pathogens
Initial Empiric Antibiotics
Recommended choices
„ Broad spectrum of bactericidal activity
„ Local prevalence, susceptibility pattern
„ Monotherapy
„ Antibiotic toxicity : well-tolerated, allergy
„ Duotherapy without vancomycin
„ Host factors : severity of presentation
„ Vancomycin
V
i plus
l one or ttwo d
drugs
„ Prior antibiotic usage
„ Antibiotic costs
„ Ease of administration
4
Combination Therapy
Advantages
Combination Therapy
Disadvantages
„ Increased bactericidal activity
„ Drug toxicities
„ Potential synergistic effects
„ Drug interactions
„ Broader antibacterial spectrum
p
„ Potential cost increase
„ Limits emergence of resistance
„ Administration time
Start Empiric Ab Therapy – e.g. According to
Infectious Diseases Society of America
Guidelines
monotherapy with ceftazidime, cefepime,
imipenem or meropenem,
„ Or aminoglycoside + antipseudomonal penicillin,
cephalosporin or carbapenem
„ Initial Vancomycin + added antibiotics only if;
„ suspected catheter related infection
„ potential for severe mucositis
„ known
colonization
with
penicillin
and
cephalosporin-resistant pneumococci or MRSA
„ gram positive organisms awaiting sensitivity
„ cardiovascular compromise
guidelines continued …
„ Initial
Outpatient FN therapy –
Low--risk Patients only!
Low
„ Increasingly, published trials are supporting
the efficacy of outpatient therapy
„ Less cost
„ Preferred by most families
„ Reduced nosocomial infection risk
„ Reduced administration of broad-spectrum
antibiotics and associated drug resistance
„ Reduced treatment-related toxicity
„ If used as initial therapy, Vancomycin should be
given with ceftazidime or cefepime, +/- an
aminoglycoside, or with carbapenem +// an
aminoglycoside, or with an anti-pseudomonal
penicillin and an aminoglycoside (Cave:
BREAKTHROUGH infections!)
„ Add antifungal at day 5
Out--patient Antibiotics – Conditions
Out
Allowing Administration
„ Adequate institutional and community
infrastructure
„ Trained health professionals 1) at discharge from
hospital and 2) at regular review in the home /
hospital setting
„ Detect early deterioration / lack of response to
minimize morbidity and mortality
„ Family selection; compliance, transportation,
geography
„ 24hr advice and emergency care
„ Antimicrobials chosen on patient condition, ease of
administration and local sensitivities
5
Initial Antibiotic Modifications
Considerations
Persistent Fever
Causes
„ Nonbacterial infection
„ Persistence of fever
„ Resistant bacteria
„ Clinical deterioration
„ Slow response to antibiotics
„ Culture results
„ Fungal sepsis
„ Drug intolerance/side effects
„ Inadequate serum & tissue levels
„ Drug fever
Persistent Fever >
Choices of Mx
5 Days
Duration of Antibiotic Therapy
When to stop?
„ Continue initial Rx
„ No infection identified after
„ Change or add antibiotics
„ ANC
3 days of Rx
> 500 for 2 consecutive days
„ Afebrile > 48 hr
„ Add an antifungal drug(Ampho B)
„ Clinically well
Algorithm for initial management of
febrile neutropenia
Fever (temperature ≥38.8ºC) + neutropenia (<500 neutrophils/mm3)
Low risk
Oral
Vancomycin
not needed
Monotherapy
Ciprofloxacin
+
Amoxicillin / clavulanate
(adults only)
Fever (temperature ≥38.8ºC) + neutropenia (<500 neutrophils/mm3)
Hypotension or other evidence of cardiovascular impairment
Potential severe Low
mucositis
risk
High risk
High risk
IV
• Cefepime,
• Ceftazidime
or
• Carbapenem
Two drugs
•
•
•
•
Aminoglycoside
+
Antipseudomonal
penicillin,
Cefepime,
Ceftazidime,
or
Carbapenem
Clinically suspected catheter infection
Algorithm
initial management
of febrile
Colonization byfor
penicillin/cephalosporin-resistant
pneumococci
or MRSA
neutropenia
Bacteremia by GPC
Vancomycin
needed
Oral
IV
Vancomycin +
Vancomycin
+
• Cefepime,
• Ceftazidime
or
• Carbapenem
± Aminoglycoside
Reassess after 3–5 days
Reproduced with permission from Hughes et al. Clin Infect Dis 2002;34:730–751
Vancomycin
not needed
Monotherapy
Ciprofloxacin
+
Amoxicillin / clavulanate
(adults only)
• Cefepime,
• Ceftazidime
or
• Carbapenem
Two drugs
•
•
•
•
Aminoglycoside
+
Antipseudomonal
penicillin,
Cefepime,
Ceftazidime,
or
Carbapenem
Vancomycin
needed
Vancomycin +
Vancomycin
+
• Cefepime,
• Ceftazidime
or
• Carbapenem
± Aminoglycoside
Reassess after 3–5 days
Reproduced with permission from Hughes et al. Clin Infect Dis 2002;34:730–751
6
Febrile Neutropenia
Conclusions
„ Significant morbidity & mortality
„ Choice of initial empiric therapy dependent on
epidemiologic & clinical factors
„ Monotherapy as efficacious as combination
Rx
„ Modifications upon reassessment
„ Duration dependent on ANC
7