Febrile
Neutropenia
Welcome to the module on
Febrile Neutropenia!!
• Please take this brief pre-module quiz
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“presentation” mode
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Outline
Click to jump to a section
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•
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General principles and importance of FN
Diagnostic work-up of a patient with FN
Microbiology of FN
Selecting anti-microbials
Stopping anti-microbials
Practice cases
Outline
Click to jump to a section
•
•
•
•
•
•
General principles and importance of FN
Diagnostic work-up of a patient with FN
Microbiology of FN
Selecting anti-microbials
Stopping anti-microbials
Practice cases
Febrile Neutropenia: definitions
• Fever:
– The Infectious Diseases Society of America (IDSA) has
defined fever in a neutropenic patient as:
• oral temperature of ≥38.3°C (101°F), or
• oral temperature of ≥38.0°C (100.4°F) sustained over one hour
• Neutropenia
– Absolute Neutrophil Count (ANC) <500 cells/µL, or
– ANC < 1000 neutrophils/µl and predicted to decline to
<500 in the next 48 hrs (i.e. recent chemotherapy)
Importance
• Common
– Over 90% of patients treated
for leukemia will get FN
• Deadly
– 9.5% in hospital mortality (24fold-higher than average
medical inpatients)
• 14.3% if pt has leukemia
– Even worse if you find a
specific cause:
• GNR Bacteremia: 33% in hospital
mortality1
• Invasive Candidiasis: 37%
• Invasive Aspergillosis: 39%
• Disseminated Mucormycosis: 96%
mortality2
1)
Cancer 2006
2)
Clinical Infectious Disease 2005
100 patients with Leukemia
Importance
100 patients with Leukemia
• Common
– Over 90% of patients treated
for leukemia will get FN
• Deadly
– 9.5% in hospital mortality (24fold-higher than average
medical inpatients)
• 14.3% if pt has leukemia
– Even worse if you find a
specific cause:
• GNR Bacteremia: 33% in hospital
mortality1
• Invasive Candidiasis: 37%
• Invasive Aspergillosis: 39%
• Disseminated Mucormycosis: 96%
mortality2
1)
Cancer 2006
2)
Clinical Infectious Disease 2005
Febrile Neutropenia
No Febrile Neutropenia
90 will get FN!
Importance
100 patients with Leukemia
• Common
– Over 90% of patients treated
for leukemia will get FN
• Deadly
– 9.5% in hospital mortality (24fold-higher than average
medical inpatients)
• 14.3% if pt has leukemia
– Even worse if you find a
specific cause:
• GNR Bacteremia: 33% in hospital
mortality1
• Invasive Candidiasis: 37%
• Invasive Aspergillosis: 39%
• Disseminated Mucormycosis: 96%
mortality2
1)
Cancer 2006
2)
Clinical Infectious Disease 2005
Febrile Neutropenia
No Febrile Neutropenia
Death
14 will die
related to FN!
General Principles
• Asymptomatic is not reassuring
– Specific symptoms are rare
– A source is only found in 20-30% of febrile neutropenic
episodes1
• Duration of Treatment is Different
– In non-neutropenic patients, if all cultures and
diagnostic tests came back negative and the patient
became afebrile/asymptomatic, likely stop antibiotics
– In febrile neutropenia this is not the case
• The stakes are too high to stop early!
• If a source if found, treat per the standard of care for that type of
infection
• If no source is found, antibiotics should generally be continued until
fevers have resolved and neutropenia has resolved (more on this later)
1) Clin Infect Dis 2011
General Principles
• “Neutropenics don’t make pus”
– No Neutrophils in the blood means no neutrophils
elsewhere
– UA: no Pyuria, negative Leukocyte Esterase
– CSF analysis: no/few PMN’s
– Abscesses are rare
• Broader Bugs
– Pseudomonas is particularly deadly, which is why all febrile
neutropenic patients need to have it empirically covered
• More on specific antibiotics later
– Gram negative bacteremia is much more deadly than gram
positive, although less common
General Principles
• Consider central lines
– Common source of infection
– Common in patients receiving
chemotherapy
• Early Empiric Coverage Saves Lives
– Only blood cultures should
precede antibiotics. CXR and
other diagnostic considerations
can wait until after.
– Delay in antibiotics associated
with longer hospital stays,1
increased mortality
• Time to antibiotics (TTA) <30 min:
3.0% mortality
• TTA 31-60 minutes: 18.1%
mortality2
1) BMC Health Services Research 2014
2) Antimicrobial Agents and Chemotherapy 2014
Neutrophil Count Determines
Infectious Risk
•
•
•
As neutrophil count drops <500,
susceptibility to infection
increases
Frequency and severity of
infection inversely proportional to
neutrophil count
Risk of severe infection and blood
stream infection greatest at ANC
<100/µL
Old School
paper
showing this
Adapted from Carolyn Alonso MD
Bodey GP et all Ann Intern Med. 1966 Feb;64(2):328-40
Outline
Click to jump to a section
•
•
•
•
•
•
General principles and importance of FN
Diagnostic work-up of a patient with FN
Microbiology of FN
Selecting anti-microbials
Stopping anti-microbials
Practice cases
Let’s see our first patient!
Time is of the
essence!
Anti-Pseudomonal
Antibiotic
Blood cultures
Oral exam
1. Mucositis
2. Oral
Candidiasis
3. HSV
reactivation
Assess for
Rhino-Sinusitis
1. Viral
2. Bacterial
3.
BellyFungal
Exam
Skin
Including
Peri-rectal area
Look, don’t
touch!
No digital rectal
exam in
New
Neutropenia
murmur or
lung
findings?
Initial Evaluation: H+P
• Perform site specific H&P including evaluation of:
–
–
–
–
–
–
–
Intravascular access device (port, PICC, peripheral IV)
Skin
Lungs/Sinus
GI tract/esophagus
Perirectal area
Urological
Neurological
• Key Questions to Consider:
–
–
–
–
–
–
Underlying disease; when was last chemo?
Prior infections?
Recent antibiotic prophylaxis: patient on it, taking it?
Meds (including immunosuppressants)
Exposures: sick contacts, pets, travel, TB exposures, blood products
Chart review: these are complex patients who often don’t know many specifics
Initial Evaluation: Labs and Workup
•
•
Labs
Radiology:
– CXR (or chest CT as sensitivity may be diminished in
patients with neutropenia)
•
Microbial assessment:
– Blood cultures: from each site of central venous
access and one peripheral vein
– Urinalysis and Urine Culture
– If diarrhea: C.diff
•
•
Consider norovirus (in season)
Consider stool culture, O+P (if concerning travel history)
– If skin lesions: if vesicular, consider DFA for
VZV/HSV, or skin biopsy if atypical appearing
Viral Culture and DFA for VZV/HSV
Step 1:
Select a clear vesicle and remove the
roof. Lift back the cap of the blister,
and remove excess fluid by gently
blotting with a swab. Place the swab
into the viral transport media for viral
culture.
Step 2:Scrape the base of the lesion
thoroughly with the scalpel blade to
collect basal cells.
Step 3:
Spread the cellular material collected
on the edge of the blade thinly over the
well area of the slide. Air dry for
several minutes.
https://portal.bidmc.org/Intranets/Clinical/Pathology/LabManual/SpecCollect/VZVDirect.aspx
Initial Evaluation: Labs and Workup
If respiratory symptoms:
• Nasal swab (screens for Influenza A/B, parainfluenza,
RSV, adenovirus)
• Urine Legionella Antigen, Strep pneumo urine
antigen
• Consider sputum culture if coughing (yield is highest
if obtained before antibiotics, but not a reason to
delay antibiotics)
• Bronchoscopy? More on this later
Culture and image anything with
symptoms
• Why so many CT scans?
– Pre-test probabilities for bad
things are much higher than
in immunocompetent
patients
– Plain films often unrevealing
• In one study of patients
with normal CXR, chest CT
demonstrated pneumonia
in more than one-half of
persistently febrile
neutropenic patients1
– Long term risk of radiation
exposure is minimal
compared to very high
immediate risk of death
1) Journal of Clinical Oncology 1999
A word on Blood Cultures
• 2 sets of blood cultures should be obtained
• 2 blood culture sets should detect 80-90% of BSI; ≥ 3
sets are needed to achieve > 96% detection
• Collect BC from all central catheters, and 1 peripheral
vein
• If persistent fever after empirical antibiotics, collect 2
sets of BC x 48hrs
– Beyond that, most experts would not continue daily
BC for persistent fever unless there is a clinical change
– Re-culture if recrudescent fever after initial
improvement
Adapted from Carolyn Alonso MD
Friefield A et al. CID 2011;52(4):e56–e93
Lee A et al. Detection of bloodstream infections in adults: how many blood cultures are needed? J Clin Microbiol 2007; 45:3546–8.
Cockerill FR 3rd, Wilson JW, Vetter EA, et al. Optimal testing parameters for blood cultures. Clin Infect Dis 2004; 38:1724–30.
Outline
Click to jump to a section
•
•
•
•
•
•
General principles and importance of FN
Diagnostic work-up of a patient with FN
Microbiology of FN
Selecting anti-microbials
Stopping anti-microbials
Practice cases
Sources of Infection
• An infectious source is identified in only 2030% of febrile neutropenia
• Bacteremia is found in 10-25% of patients
• It is thought that a patient’s endogenous flora
is the source in ~80% of patients
• Mostly from translocation of GI flora that are
no longer held in check by the immune system
Gut flora (mostly GNR’s)
translocation is the usual source
Skin Flora (GPC’s like Strep/Staph) are
increasingly more common, given
prevalence of indwelling lines these days
Sources of Infection
• Gram Negative infection carries higher risk in
FN than GPC infection
• Anaerobes: Possible, but rare; no need to
empirically cover these
• Fungi, Viruses, TB all need to be considered as
well, though not typically covered up front
Organisms
G(+) = Increasingly common
Gram Positives
• Staph epidermidis (most
common gram positive)
• Staph aureus
• Streptococcus
• Less common:
–
–
–
–
–
–
Corynebacterium,
Bacillus spp
Lactobacillus spp
Propionibacterium acnes
Listeria
Clostridium
G(-) = Most deadly
Gram Negatives
•
•
•
•
•
Escherichia coli
Pseudomonas aeruginosa
Klebsiella spp
Enterobacter spp
Less common:
– Citrobacter spp
– Acinetobacter spp
– Stenotrophomonas maltophila
Other Organisms to Consider
Viruses
• Herpesvirus family
– HSV1, HSV2, VZV, EBV, CMV,
HHV-6
• Enterovirus
• Respiratory viruses
–
–
–
–
RSV
Influenza
Parainfluenza
Adenovirus
Fungi and Mycobacteria
• Fungi
– Rarely identified as cause of
initial fever
– More common to be cause of
persistent or recurrent fever
– Candida spp and Aspergillus spp
account for most invasive fungal
infections during neutropenia
• TB reactivation
– considered if epidemiologic risk
(travel, glucocorticoid use)
– Other non-TB mycobacteria
For BMT patients, timing from transplant matters!
Engraftment
Day 15-45 to Day 100
GNR’s
Late Phase
Day 100+
Encapsulated
bacteria
GPC’s
Herpes Simplex Virus (HSV)
Cytomegalovirus (CMV)
Viral
Bacterial
Pre-Engraftment
Day 0 to Day 15-45
EBV post-transplant lymphoproliferative disease (PTLD)
Respiratory and enteric viruse
Fungal
HHV6
Aspergillus
Candida
Pneumocystis (PCP)
For BMT patients, timing from transplant matters!
GNR’s
GPC’s
Viral
Bacterial
Pre-Engraftment
Day 0 to Day 15-45
Engraftment
Day 15-45 to Day 100
Late Phase
Day 100+
Encapsulated
Prebacteria
engraftment,
Herpes Simplex
Virus (HSV)
infection
Cytomegalovirus (CMV)
mostly
Respiratory and enteric viruse
related to
line
Aspergillus
infections!
EBV post-transplant lymphoproliferative disease (PTLD)
Fungal
HHV6
Candida
Pneumocystis (PCP)
For BMT patients, timing from transplant matters!
Viral
Bacterial
Pre-Engraftment
Day 0 to Day 15-45
Engraftment
Day 15-45 to Day 100
Late Phase
Day 100+
GNR’s
Encapsulated
During/after
bacteria
GPC’s
engraftment,
opportunistic Herpes Simplex Virus (HSV)
Cytomegalovirus (CMV)
infection risk
Respiratory and enteric viruse
rises
EBV post-transplant lymphoproliferative disease (PTLD)
Fungal
HHV6
Aspergillus
Candida
Pneumocystis (PCP)
Pneumonia is common and good
expectorated sputum samples are
sometimes hard to get.
So what about bronchoscopy to workup Febrile Neutropenia?
Utility of Early vs. Late
Bronchoscopy in Evaluation of
Infiltrates in HSCT
• Pulmonary infiltrates frequently complicate HSCT –
optimal timing of when to perform bronchoscopy
has been unclear.
• MD Anderson study 2010:
– Retrospectively reviewed 501 consecutive,
adult, non-intubated patients who underwent
BAL for evaluation of new pulmonary infiltrate
in first 100 days following HSCT
– Aim was to determine diagnostic yields, need
for treatment modifications, and patient
outcomes following early ( ≤ 4 days ) vs. late (≥
5 days) bronchoscopy
Adapted from Carolyn Alonso MD
Shannon VR, et al.. Bone Marrow
Transplant. 2010 Apr;45(4):647-55.
Utility of Early vs. Late Bronchoscopy
in Evaluation of Infiltrates in HSCT:
Diagnostic Yield
• BAL was successful in identifying clinically significant pathogens in 55%
of patients
• Early BAL was more than 2x as likely to yield a diagnosis of infection
compared with late BAL (73% vs. 31%; P<0.0001)
• Diagnosis of infection was highest when BAL was performed in the
first 24hrs of presentation (75%)
– Yield at 5 days declined to 40%
– Yield at 10+ days declined to 14%
• Non-diagnostic exams threefold higher in late BAL compared with
early BAL (68% vs. 16 %; P< 0.0001)
Adapted from Carolyn Alonso MD
Shannon VR, et al.. Bone Marrow
Transplant. 2010 Apr;45(4):647-55.
Outline
Click to jump to a section
•
•
•
•
•
•
General principles and importance of FN
Diagnostic work-up of a patient with FN
Microbiology of FN
Selecting anti-microbials
Stopping anti-microbials
Practice cases
Antibiotic Selection
Need an antibiotics
refresher?
See the “Antibiotics”
module on
IDmodules.com for a
thorough review!
Initial Regimen?
• All initial regimens should primarily target gram
negative rods, particularly Pseudomonas aeruginosa
Initial Empiric Therapy
• The goal of initial empiric therapy is to prevent serious
morbidity/mortality until culture data is available
• Relative frequency of bacteremia (prospective study of 2142
cancer pts with FN):
– Gram positive 57% = Mortality rate 5%
– Gram negative 34%= Mortality rate 18%
– Polymicrobial 10%= Mortality rate 13%
• Of the single gram negative pathogens, the most common
pathogens:
– E.coli (41%), associated with mortality rate 18%
– Klebsiella (11%), associated with a mortality rate 10%
– Pseudomonas (24%), associated with a mortality rate of 31%
• Therefore, initial therapy should target Pseudomonas
– Anti-Pseudomonal drugs have coverage of E coli and other GN’s
Klastersky J et al. Bacteraemia in febrile neutropenic cancer
patients. Int J Antimicrob Agents. 2007 Nov;30 Suppl 1:S51-9. Epub 2007 Aug 8.
Antibiotic
Pseudomonas
MRSA
Anaerobes Enterococci ESBL
CPE
Cefepime
yes
no
no
no
no
no
Ceftazidime
yes
no
no
no
no
no
Gram(+)
coverage is
spotty
PiperacillinTazobactam
yes
no
Yes, but
not c-diff
usually, but
rarely VRE
no
no
False (+) fungal
markers
Carbapenems yes
no
Yes, but
not c-diff
sometimes, Yes
but rarely
VRE
no
Less
alternatives
once Resistant
no
no
no
no
A weaker
agent. Should
be used in
combination
Downsides
2nd Line
Aztreonam
Yes
(though
less so)
no
If there is nothing localizing,
what do you do?
• An agent that covers gram positives and gram negatives
including pseudomonas is the preferred initial therapy.
• Cefepime, Ceftazidime, a carbapenem (like meropenem), or
Piperacillin-Tazobactam are all first line choices
– Note that ertapenem does NOT cover pseudomonas and would not be
used
– You might think that carbapenems and or piperacillin-tazobactam
would be preferred over the cephalosporins, since they also cover
anaerobes
– However in RCTs they perform equivalently1
– This is because anaerobes are relatively rare pathogens in neutropenic
fever, ~3%2
– The exceptions are neutropenic enterocolitis (aka typhlitis) as well as a
few other situations (i.e. periodontal cellulitis). Consider adding
metronidazole in anyone with abdominal symptoms, like diarrhea.
1)
2)
Uygun. Ped Blood Cancer 2009
Support Care Cancer 1993
What about MRSA?
None of those agents cover MRSA… Shouldn’t
everyone get Vancomycin?
• This strategy has been suggested
• However multiple RCTs and a meta-analysis all
showed that routine addition of Vancomycin to initial
empiric coverage does not improve outcomes.1
– But does lead to increased renal toxicity
• Mortality from untreated staphylococcal infections is
~4% in first 48 hours (compared to ~90% for gram
negative bacteremia). Thus you can wait for cultures
for Staph in patients who look well and have no
obvious source, but you can’t wait to cover gram
negatives
• So, when should we add Vancomycin?
1) Lancet Infect Dis 2005
When to add coverage for resistant
gram positives (like MRSA)
Hemodynamic or Clinical
Instability
Risk of further
myelosuppression
Pneumonia
MRSA colonization
Vancomycin (preferred)
or
Linezolid or Daptomycin
(if concern for VRE)
Mucositis, Cellulitis/SSTI
Culture positive for gram
positive bacteria
Should not be used in
pulmonary infection
(inactivated by lung
surfactant)
Catheter-related infection
Adapted from Carolyn Alonso MD
Friefield A et al. Clinical Infectious Diseases 2011;52(4):e56–e93
• If vancomycin was empirically added but all
cultures negative for 48 hours, and no clinical
signs of gram positive infection, you can stop
vancomycin
– Vancomycin overuse has been associated with the
development of resistance and drug toxicity
– Example of Vancomycin resistance?
VRE
If vancomycin was empirically added but all cultures negative
for 48 hours, and no clinical signs of gram positive infection,
can stop vancomycin…EVEN IF fevers continue to persist
Vancomycin overuse has been associated with the
development of resistance AND adverse drug reactions
Continued fevers should prompt serial re-examination
• But DOESN’T mean antibiotic regimen is failing, if thorough review is reassuring
Modifying Therapy
• Persistent fever in a stable asymptomatic patient who is culture
negative does not necessarily require addition of more antibiotics
(e.g empiric vancomycin without evidence suggesting gram positive
infection)
• Bacterial infections advance rapidly in neutropenic patients, so if a
patient has not clinically worsened in some way after several days
of not being covered for a particular bacteria, they are unlikely to
have that bacteria
• This is NOT true however for fungi, which tend to grow slower. For
this reason the IDSA recommends adding empiric antifungals if
persistent unexplained neutropenic fever > 4-7 days
– NOT initially on day 1 of neutropenic fever
Antifungals
• Empiric antifungals for persistent unexplained neutropenic
fever can be added after 4-7 days
– Yeasts (mostly candida species) start to appear when neutropenia
is longer than 4-7 days.
– Molds (especially aspergillus and mucor) tend to occur in patients
with durations of neutropenia lasting longer than 2 weeks.
– Delaying therapy too long is dangerous. A difference in starting
amphotericin of 6 days increased mortality in mucormycosis from
49% to 83% (CID 2008)2
– Alternative to empiric antifungals is to test fungal markers (Bglucan and galactomannan) and obtain of CT chest and sinuses
looking for evidence of fungal infection.
• Options:1
– Include Amphotericin, Caspofungin, Voriconazole, Itraconazole
– Pulmonary nodules -> Amphotericin or Voriconazole
– Suspect Mucormycosis? -> Amphotericin
1) Adopted from 2010 IDSA guidelines
Confused by anti-fungals?
• We have a module for that! Check out the
fungal infection and anti-fungal therapy
module on www.IDmodules.com
Fungal cell wall
• Galactomannan: A
polysaccharide that is a
major component of
Aspergillus cell walls; also
present in the cell walls of a
number of other fungal
species
– May be detected in the blood before
signs/symptoms
– False +s: certain B-lactam antibiotics (zosyn)
– Other fungi may have GM: Fusarium species,
Penicillium species, Histoplasma capsulatum
– False + results are more likely to occur during
the first 100 days following HSCT and in
patients with gastrointestinal tract mucositis
Adapted from Carolyn Alonso MD
Pic: Rev Iberoam Micol. 2010;27:155
Slide courtesy Carolyn Alonso
• 1,3-Beta-D-glucan, a cell wall
component of many fungi
• Not specific for Aspergillus
• Can be positive in:
– Candidiasis
– Pneumocystis jirovecii (PCP)
– Fusarium
• Typically negative in patients
with mucormycosis or
cryptococcosis
• False positives:
–
–
–
–
–
Hemodialysis with cellulose membranes
Intravenous immunoglobulin (IVIG)
Albumin
Gauze packing of serosal surfaces
Bloodstream infections with certain bacteria, such as
Pseudomonas aeruginosa
Adapted from Carolyn Alonso MD
Pic: Rev Iberoam Micol. 2010;27:155
Slide courtesy Carolyn Alonso
Outline
Click to jump to a section
•
•
•
•
•
•
General principles and importance of FN
Diagnostic work-up of a patient with FN
Microbiology of FN
Selecting anti-microbials
Stopping anti-microbials
Practice cases
So, when Can Antibiotics Be Stopped?
• If organism identified, duration of therapy is dictated by
the particular organism and site; eg 14 days for E.
coli bacteremia
• Appropriate antibiotics should also continue for at least
the duration of neutropenia (ANC <500)
• If initial fever was unexplained, it is recommended that
the initial regimen be continued until there are clear
signs of marrow recovery (ANC >500) and fever is
resolved
• Alternatively, if all signs and symptoms (including fever)
of a documented infection have resolved, patients who
remain neutropenic may start/resume oral
fluoroquinolone prophylaxis until marrow recovery.
Friefield A et al. Clinical Infectious Diseases 2011;52(4):e56–e93
Outline
Click to jump to a section
•
•
•
•
•
•
General principles and importance of FN
Diagnostic work-up of a patient with FN
Microbiology of FN
Selecting anti-microbials
Stopping anti-microbials
Practice cases
Case #1
You are admitting a 34 y/o male with a history
of AML, currently undergoing chemotherapy
via a right-sided chest port-a-cath
 He has no specific complaints and physical
exam is unremarkable, though he looks
unwell
 ANC = 250
 Temp = 101.1F
What would be the best empiric antibiotic
regimen?
•
•
•
•
•
A) Cefepime
B) Zosyn
C) Vancomycin
D) Cefepime and Vancomycin
E) Cefepime, Vancomycin, and Micafungin
What would be the best empiric antibiotic
regimen?
•
•
•
•
•
A) Cefepime
B) Zosyn
C) Vancomycin
D) Cefepime and Vancomycin
E) Cefepime, Vancomycin, and Micafungin
What would be the best empiric antibiotic
regimen?
• A) Cefepime –
you want pseudomonal coverage, but given a line is in
place, you will also want empiric GPC and MRSA coverage
• B) Zosyn – covers pseudomonas, but also anaerobes, which is
unnecessary for empiric coverage in this situation. Also, no MRSA coverage
• C) Vancomycin – covers gram positives and MRSA, but no gram
negative or pseudomonal coverage
• D) Cefepime and Vancomycin – Correct! Will cover gram
negatives including pseudomonas (cefepime), and MRSA
(vanco)
• E) Cefepime, Vancomycin, and Micafungin – too broad.
There is no clear indication for initial empiric anti-fungal coverage
(micafungin) in this case
Case #2
You are admitting the same 34 year old male with a
history of AML, currently undergoing chemotherapy via
Hickman.
- Again, he has no specific complaints and physical
exam is unremarkable, though he looks unwell
- ANC = 250
- Temp = 101.1F
- However, you learn he has allergies (hives and
anaphylaxis) to Penicillins and Cephalosporins
Antibiotic regimen?
What would be the best empiric antibiotic
regimen?
•
•
•
•
•
•
A) Cefepime and vancomycin
B) Zosyn and vancomycin
C) Aztreonam and vancomycin
D) Ciprofloxacin and vancomycin
E) Meropenem and vancomycin
F) Aztreonam, ciprofloxacin, and vancomycin
What would be the best empiric antibiotic
regimen?
•
•
•
•
•
•
A) Cefepime and vancomycin
B) Zosyn and vancomycin
C) Aztreonam and vancomycin
D) Ciprofloxacin and vancomycin
E) Meropenem and vancomycin
F) Aztreonam, ciprofloxacin, and vancomycin
What would be the best empiric antibiotic
regimen?
• A) Cefepime and vancomycin – allergy
• B) Zosyn and vancomycin – allergy
• C) Aztreonam and vancomycin – this could be used,
however aztreonam is not that strong a drug. It covers pseudomonas
variably; thus if the patient is ill, it is advisable to use a 2nd agent as
well
• D) Ciprofloxacin and vancomycin – ciprofloxacin alone
does not reliably provide empiric pseudomonas coverage
• E) Meropenem and vancomycin – there is some allergic
cross-reactivity between PCN/cephalosporin allergy and
carbapenems, so this could be risky
• F) Aztreonam, ciprofloxacin, and vancomycin –
Correct! Since cipro and aztreo don’t reliably cover
pseudomonas empirically, double cover up-front
Case #3
You are admitting a 42 year old female with a
history of AML, currently undergoing
chemotherapy
- She has no specific complaints and physical
exam is unremarkable, though looks ill
- ANC = 150
- Temp = 102.8F
- On chart review, no prior microbiologic culture
data of note, and no recent antibiotic use
- You appropriately start her on empiric
cefepime and vancomycin
Shortly thereafter, the micro lab calls…..
ESBL
(Extended-Spectrum Beta-Lactamase)
Next steps?
• Start Meropenem
• Continue vancomycin and discontinue Pip-tazo
(zosyn)
• Evaluate for possible sources
What if…..
CPE
Antimicrobial options are
limited, but include:
Colistin
Tigecycline
Avitaz
Zyrbaxa
Call ID consult!
(carbapenemase producing enterobacteriaceae)
See IDmodules.com antibiotic module if these
are unfamiliar to you!
Case #4
• 75 F w/ refractory CLL p/w fever, watery diarrhea
• Treatment history:
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Diagnosis 2003, not treated until 2008
Rituxan x 6 (‘08)
Fludarabine, cyclophosphamide, Rituxan x8 (‘08-10)
Bendamustine, Rituxan (‘10)
CVP x 2 (1/11)
R-EPOCH x 2 (5/11)
Campath (8/11)
• Recent hospitalization for febrile neutropenia,
interstitial infiltrates on chest imaging, thought to
be Community Acquired Pneumonia (CAP)
– Discharged on PO Cefpodoxime
This case adapted from Carolyn Alonso MD
Case #4
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Presents today with 1 week of diarrhea, waking up from sleep, intermittent
fecal incontinence
Initially afebrile and “well appearing” in outpt clinic, sent home
Sxs worsened, new fever 101F & weakness
ROS: No nausea, vomiting, no sick contacts, no unusual foods
SH: unremarkable
FHx: non-contributory
Drug allergies: none
Exam:
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100.6F HR 122 (afib w/ RVR) BP 117/52 97%RA
Exam notable for hypoactive bowel, pain LLQ, distention. She has no indwelling lines in place
Labs:
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WBC: 183 (2% Neu, 96 Lym, 2 Mono)
Hct 20.4
Plt 27
BMP nl
LFTs nl except tbili 2.3
Lactate 0.9
Initial Workup?
• Blood cultures, UA/UCx, CXR
• CT Abdomen/Pelvis
• Image anything with symptoms!
• C-Diff testing
• Presents with diarrhea and recent antibiotic use
• Could consider stool culture, O+P if (+) travel history
Empiric Coverage?
• Cefepime
• Standard options for Neutropenic Fever
• Metronidazole
• For any Neutropenic fever with diarrhea
• ? PO Vancomycin
• Can’t be faulted for empirically covering C-Diff in high risk patients
Mural edema involving the entire colon extending to
the rectum compatible with pancolitis and proctitis
• C diff toxin PCR sent on
admission was positive
• What treatment would
you give?
• Given oral vancomycin
and intravenous
metronidazole 500 mg q
8 hours
• No need for cefepime!
Once cause of fever
identified, narrow
coverage to that
• You found C. dif, just
treat the C. dif!
• See IDmodules.com for
more information on
Clostridium difficile!
Case #5
• 53yoF s/p allogenic bone marrow transplant 2
years ago, now relapsed AML and receiving
chemotherapy. Also has a history of diabetes and
hypertension.
• 1 week ago she developed soreness of top of her
mouth, then 3 days ago developed swelling and
ulceration
• She reports low grade temps x 3 weeks
• Now febrile to 101.4F.
• ANC ~1000, but upon chart review it is trending
downward
This case adapted from Carolyn Alonso MD
On Exam of the Hard Palate
Management
How are you thinking about this case?
What is on your differential?
What would be your next steps in
management?
Differential Diagnosis for Oral
Lesions in Cancer Patients
• Viral:
– Herpes Simplex Virus and Varicella Zoster Virus (HSV/VZV)
• Bacterial:
– Acute necrotizing ulcerative gingivitis (“Trench mouth”)
– Bacteroides, Fusobacterium, syphilis
• Fungal:
– Mucor
– Aspergillus
– Endemic mycoses (histoplasma, coccidiomycosis)
• Malignancy-related
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Leukemic involvement
Kaposi’s
Chemotherapeutic effect
Apthous ulcers
Next steps:
• Empiric Coverage?
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Don’t forget the basics, it’s still neutropenic fever!
Pip-Tazo
Mucositis on exam
Vancomycin
clinical suspicion for fungi is high enough, no need to
? Amphotericin B Ifwait
4-7 days before starting empiric anti-fungal coverage
? Acyclovir
If high pretest probability of HSV
• Diagnostics?
– DFA for VZV/HSV (see ”Initial Evaluation” section earlier!)
– Swab and viral culture in “UTM” (Universal Transport Media)
tube
– CT imaging of sinuses
– ENT consult for palatal biopsy
Case 5, continued:
• CT of sinuses shows extensive involvement
• ENT performs palatal biopsy
Mucor!
• Started on ambisome and taken to the OR with ENT for debridement
Want more detail?
• IDSA Guidelines: on Febrile Neutropenia
https://www.idsociety.org/uploadedFiles/IDSA/GuidelinesPatient_Care/PDF_Library/FN.pdf
• Don’t forget to see IDmodules.com for:
– Antibiotics
– Antifungals
– Pneumonia
– Many more!
Congratulations!
• Please take the post-module quiz here
https://goo.gl/forms/94dRpJHN7uo4qb3v2
80
References
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Kuderer, N. M., Dale, D. C., Crawford, J., Cosler, L. E. and Lyman, G. H. (2006), Mortality,
morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer, 106:
2258–2266. doi:10.1002/cncr.21847
Stéphane Vigouroux, Odile Morin, Philippe Moreau, Françoise Méchinaud, Nadine Morineau,
Béatrice Mahé, Patrice Chevallier, Thierry Guillaume, Viviane Dubruille, Jean-Luc Harousseau,
Noël Milpied; Zygomycosis after Prolonged Use of Voriconazole in Immunocompromised
Patients with Hematologic Disease: Attention Required. Clin Infect Dis 2005; 40 (4): e35-e37.
doi: 10.1086/427752
Alison G. Freifeld, Eric J. Bow, Kent A. Sepkowitz, Michael J. Boeckh, James I. Ito, Craig A.
Mullen, Issam I. Raad, Kenneth V. Rolston, Jo-Anne H. Young, John R. Wingard; Clinical Practice
Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010
Update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52 (4): e56-e93. doi:
10.1093/cid/cir073
Perron T, Emara M, Ahmed S. Time to antibiotics and outcomes in cancer patients with febrile
neutropenia. BMC Health Services Research. 2014;14:162. doi:10.1186/1472-6963-14-162.
Rosa RG, Goldani LZ. Cohort Study of the Impact of Time to Antibiotic Administration on
Mortality in Patients with Febrile Neutropenia. Antimicrobial Agents and Chemotherapy.
2014;58(7):3799-3803. doi:10.1128/AAC.02561-14.
Heussel et al. Pneumonia in febrile neutropenic patients and in bone marrow and blood stemcell transplant recipients: use of high-resolution computed tomography. Journal of Clinical
Oncology. 1999 Mar;17(3):796-805.
Friefield A et al. Clinical Infectious Diseases 2011;52(4):e56–e93 Lee A et al. Detection of
bloodstream infections in adults: how many blood cultures are needed? J Clin Microbiol 2007;
45:3546–8.
Cockerill FR 3rd, Wilson JW, Vetter EA, et al. Optimal testing parameters for blood cultures. Clin
Infect Dis 2004; 38:1724–30.
References, cont.
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Klastersky J et al. Bacteraemia in febrile neutropenic cancer patients. Int J Antimicrob Agents.
2007 Nov;30 Suppl 1:S51-9. Epub 2007 Aug 8.
Coullioud et al. Prospective multicentric study of the etiology of 1051 bacteremic episodes in
782 cancer patients. CEMIC (French-Belgian Study Club of Infectious Diseases in Cancer).
Support Care Cancer 1993 Jan;1(1):34-46.
Vardakas, Konstantinos Z et al. Role of glycopeptides as part of initial empirical treatment of
febrile neutropenic patients: a meta-analysis of randomised controlled trials. The Lancet
Infectious Diseases, Volume 5 , Issue 7 , 431 – 439
Rev Iberoam Micol. 2010;27:155
uptodateonline.com; topic “Diagnosis of invasive aspergillosis”
Reed C, Bryant R, Ibrahim AS, et al. Combination Polyene-Caspofungin Treatment of RhinoOrbital-Cerebral Mucormycosis. Clinical infectious diseases : an official publication of the
Infectious Diseases Society of America. 2008;47(3):364-371. doi:10.1086/589857.
Shannon VR, et al.. Utility of early versus late fiberoptic bronchoscopy in the evaluation of new
pulmonary infiltrates following hematopoietic stem cell transplantation. Bone Marrow
Transplant. 2010 Apr;45(4):647-55.
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology:
Prevention and Treatment of cancer-related infections, version 1.2013
Bodey GP et all Ann Intern Med. 1966 Feb;64(2):328-40
Schindel C et al. J Clin Microbiol 2000;38:4294-95
Sopena N et al. Eur J Clin Microbiol Infect Dis 2002;21:845-8
Oren I et al. Bone Marrow Transpl 2002;30:175-9