Definition: 1. 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.

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 s: Gram negative infections predominated Since 1980s – 1990s: Gram positive infections have predominated because of central venous catheters, use of prophylactic ciprofloxacin which has mostly G- coverage, 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 1 st 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; 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 test 2. Urine: symptoms or indwelling catheter. 3. CSF: if meningitis suspected. Platelet transfusion may be required. 4. Sputum: for productive cough. 5. Bronchoscopy: infiltrate on CXR or CT if pt worsens after 24 – 48 hrs of empirical antibiotics.

Backbone of treatment: Anti- pseudomonal 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 G- infections, 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; 3 rd edition

Principles: Hypersensitivity to penicillin occurs in 10% of pts. 2 types of hypersensitivity: 1. 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.

Regimen for β lactam anaphylaxis: C IPROFLOXACIN 1 400mg IV 12 hourly 2 PLUS V ANCOMYCIN 1 IV loading dose (according to patient actual body weight): 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: 1. Suspected CVC infection: Surrounding cellulitis Blocked port or PICC Fever precipitated by flushing line. 2. G+ cocci on gram stain (until susceptibility known). 3. Known colonisation with MRSA or cephalosporin- resistant 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.

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 1 st 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.