Download Febrile Neutropenia

Definition:
Fever: > 38.3 degrees on one occasion. > 38 degrees
sustained over 1 hour. A+RMC guidelines: >37.5 in
patient with risk factors.
2. Neutropenia: <0.5 or < 1 and expected to fall. < 0.1
represents high risk.
3. Elderly and pts on corticosteroids may not mount a
fever; if there are clinical features of a new infection
AND neutropenic, treat as febrile neutropenia.
1.
High Risk: any of...
 Nature of the neutropenia:
 Severe: < 0.1
 Expected to be prolonged > 7 days (usually applies to
haematological malignancies)
 Clinically unstable:
 Hypotensive
 Pneumonia or pulmonary infiltrates
 Neurological or mental state changes
 Severe mucositis or diarrhea
 Intravascular device infection
 GI: abdo pain, nausea, vomiting
 Biochemical abnormalities:
 Renal impairment: CrCl < 30mLs / min
 Liver impairment: ALT > 5 x normal
 Patient factor:
 ECOG > 2
 > 60
 On steroids
 Co-morbitidies: eg COPD, uncontrolled cancer.
 Would always be managed as inpatient with IV
antibiotics.
Low Risk:
 None of the high risk features. Otherwise well pt,
usually with a solid organ malignancy (less aggressive
chemotherapy) where neutropenic duration is
expected to be < 7 days.
 Can be treated as outpatient with daily review, but
currently this is not being practiced in Bendigo.
Common infections:
Historical context
 1960 -1970s: Gram negative infections predominated
 Since 1980s – 1990s: Gram positive infections have
predominated because of central venous catheters, use
of prophylactic ciprofloxacin which has mostly Gcoverage, and antibiotics designed to cover
pseudomonas.
 Coagulase negative staph are most common organism
isolated on blood cultures.
General points:
 Only 25% of patients will have a bacteraemia (ie:
positive blood cultures)
 80% of infections arise from endogenous flora of the
patient.
 G- infections have a high mortality and are more likely
to cause infections outside of bloodstream (ie: biliary,
respiratory, urinary etc).
 Anaerobes only involved in 3.4% of infections, often
polymicrobial. Don’t need to routinely cover for them.
Mortality: G- highest:
 A prospective study of > 2000 pts revealed:
 23% of febrile neutropenic episodes associated with
bacteraemia.
 G+ 57%, G- 34%, polymicrobial 9%
 Mortality: G+ 5%, G- 18%
Klastersky J et al; Int J Antimicrob
Agents; 2007; 30 (suppl 1).
Bacteremia and mortality
Klastersky J et al; Int J Antimicrob
Agents; 2007; 30 (suppl 1).
Fungal infections:
 Rarely seen early on in the course of neutropenia.
 More common after the 1st week of prolonged
neutropenia.
 Candida:
 CVC infection
 Oral candidiasis, esophagitis.
 Systemic infection: hepatosplenic disease, endocarditis
less common.
 Aspergillus: more common after > 2/52 of
neutropenia. Sinusitis, pneumonia
General principles:
 Signs and symptoms of infection often attenuated in
neutropenic patients, for eg:
 Lack of pulmonary infiltrate with pneumonia
 Lack of pyuria with UTI
 Fever is often the only sign of a serious infection.
 Symptoms and signs of infection can become apparent
as neutrophils recover.
 Daily review of symptoms and new signs of infection.
History:
 Enquire about:
 Focal symptoms (often absent)
 Exposure to infections
 Prophylactic antibiotics
 Prior infections
 Evidence of colonisation eg MRSA.
 Co-morbidities
Physical examination:
 Focus on:
1. Skin: evidence of cellulitis, viral rash eg HSV
2. Central line: cellulitis, fluctuance, dysfunction of line
can be indicative of an infected clot.
3. Oropharynx: mucositis, candidiasis, dental abscess
4. Peri-anal region: abscess. Do not perform PR as this
can cause bacteraemia
Blood tests:
 FBE with differential leucocyte count.
 UEC and LFTs
 ? CRP: studies have demonstrated inconsistant
results. Routine testing not recommended.
X-rays:
 CXR routine.
 CT as clinically indicated: eg CT sinuses for suspected
sinusitis, CT chest for respiratory symptoms despite
normal CXR etc.
Blood cultures:
 2 sets of blood cultures recommended.
 Studies have demonstrated that 2 sets of blood cultures
detects 80 – 90% of bloodstream pathogens in critically ill
patients, whereas 3 sets only increases this to 96% 1 – 2.
 Pt with CVC: One set from CVC (both lumens if 2 are
present) AND peripheral blood cultures. Peripheral set is
important to help distinguish a line infection from
contamination.
 Pt without CVC: 2 peripheral sets of blood cultures from
different venepuncture sites.
1. Lee A et al; J Clin Microbiol 2007; 45;3546
2. Cockerill F et al; Clin Infect Dis 2004; 38; 1724
 Ongoing fevers:
 2 sets of blood cultures per day for 2 days then stop.
 Fevers beyond 2 days:
 Only perform Blood cultures if there is a clinical
deterioration.
Other microbiological tests:
 According to symptoms, signs:
1. Stool: pt has diarrhoea. CDT most important
2.
3.
4.
5.
test
Urine: symptoms or indwelling catheter.
CSF: if meningitis suspected. Platelet
transfusion may be required.
Sputum: for productive cough.
Bronchoscopy: infiltrate on CXR or CT if pt
worsens after 24 – 48 hrs of empirical
antibiotics.
Backbone of treatment: Antipseudomonal β Lactam:
 Options:
1. Penicillin: Tazocin: ticarcillin / tazobactam:
2. Cephalosporin: Cefipime:
3. Carbapenem: Meropenem:

Currently cefipime 2g TDS is the regimen used at
Bendigo Health.
Backbone (continued...).




These cover MSSA, most G+ infections, common Ginfections, pseudomonas.
Goal is to cover most infections and the most
virulent infections.
Lack coverage for MRSA. Cefipime lacks anaerobe
cover.
All are considered to be acceptable options in
published guidelines.
Infectious Diseases: A Clinical approach;
3rd edition
Principles:
 Hypersensitivity to penicillin occurs in 10% of pts.
 2 types of hypersensitivity:
Type I (anaphylaxis): angio-oedema, hypotension,
bronchospasm
2. Type II: delayed, rash and fever
 Cross reactivity to cephalosporins: 3 – 6%
 Result: for type I reaction, don’t use any β lactam
(cephalosporin, penicillin, carbapenem). For
type II can use a different β lactam.
1.
Regimen for β lactam anaphylaxis:
 CIPROFLOXACIN1 400mg IV 12 hourly2 PLUS
 VANCOMYCIN1 IV loading dose (according to patient
actual body weight):
 <60kg = 1g; 60-90kg = 1.5g; >90kg = 2g
 Then continue maintenance dose according to
therapeutic guidelines. Aim for trough of 15 –
20mcg/mL.
 Ciprofloxacin alone is inadequate because of limited
G+ cover including strep viridans.
Routine use?
 Randomized studies have failed to demonstrate any
advantage in routine use of vancomycin.
 Most common G+ organism cultures is coagulase
negative staph which is not very virulent. This may
account for lack of benefit.
 Overuse can increase MRSA and VRE.
Indications for initial vancomycin:
Suspected CVC infection:
1.



Surrounding cellulitis
Blocked port or PICC
Fever precipitated by flushing line.
G+ cocci on gram stain (until susceptibility known).
Known colonisation with MRSA or cephalosporinresistant pneumococci (not on A+RMC protocol).
4. Septic shock or clinically unstable (eg: hypoxia,
tachycardia).
 Discontinue after 3 days if cultures negative for
relevant organims.
2.
3.
Antibiotics:
1. Cefipime: 2g TDS:
 A-RMC guidelines: are to give meropenem instead
1g 8 hourly
2. Vancomycin
3. Gentimicin: (Both A+RMC and Petermac
guidelines.)
 Cefipime lacks anaerobe cover, although tazocin and
meropenem have anaerobe cover.
 If pt has abdominal pain, peri-anal abscess or severe
diarrhoea, then need to add metronidazole 500mg
IV BD.
1. Persistant fever: stable clinically
 Median time to defervescence:
 Solid organ tumour: 2 days
 Haematological malignancies including autologous
stem cell transplant: 5 days
 Therefore: ongoing fevers in an otherwise stable pt in
1st 48 hours is not an indication to change antibiotics.
2. Documented infection:
 An infection can be identified either clinically or
microbiologically (ie: positive culture results).
 Treat according to the infection identified with the
appropriate duration of antibiotics:
 Eg: Staph Aureus: needs > 2 weeks of antibiotics. 4
weeks if deep seated infection eg: endocarditis,
osteomyelitis, septic thrombophlebitis.
 Eg 2: Pseudomonas: 2 weeks of IV antibiotics.
 G- sepsis generally requires 2 weeks of antibiotics
3. Where initial vancomycin used:
 If cultures do not reveal a G+ infection, then stop after
48 – 72 hours.
4. Persistant fever > 72 hours or
new fever:
 Search for a new infection, with repeat septic work up.
 Symptom directed diagnostic tests, but consider:
 Clostridium difficile diarrhoea: faeces cdt
 Neutropenic enterocolitis: CT abdomen
 CT sinuses: fungal infection.
 Consider non infectious causes:
 Drug related fever
 Disease related fevers
 Non uncommonly fevers persist with no cause but pt
defervesces once neutrophils recover.