Neutropenic Sepsis Guideline

Neutropenic Sepsis Guideline Neutropenic Sepsis Guideline - definitions Suspected or proven infection in a neutropenic patient is a MEDICAL EMERGENCY and is an indication for immediate assessment and prompt treatment with intravenous (IV) antibiotics IMMEDIATELY ON PRESENTATION to anywhere within the hospital. Patients who are neutropenic following anti-cancer treatment may initially appear well. However, infections may progress rapidly to shock or death, especially when due to gram-negative bacilli. This guideline exists to provide assistance to admitting clinicians when faced with a case of suspected infection and neutropenia in both solid tumour oncology and haemato-oncology. If there is clinical suspicion of neutropenic sepsis in existing inpatients, they should be treated within 1 hour of clinical onset, as defined by baseline observations, Early Warning Score (EWS) or clinical suspicion. Neutropenic Sepsis Neutropenic sepsis can be diagnosed in patients who present with a neutrophil count of 1.0x10 9 /L and/or a fever. NB fever may not be present in some infected neutropenic patients. Infection should be suspected in any patient who is feeling generally unwell following chemotherapy. Fever Fever is a single oral temperature of 38⁰C. Diagnose neutropenic sepsis in patients having anti-cancer treatment whose neutrophil count is 1.0x10 9 /L and who have a temperature 38⁰C, a temperature of 37.5⁰C on two occasions recorded 1 hour apart, or other signs or symptoms consistent with clinically significant sepsis. NB fever may not be present in some infected neutropenic patients. Infection should be suspected in any patient who is feeling generally unwell following chemotherapy. Sepsis in non-neutropenic haem-oncology patients Patients who are severely immunocompromised due to primary haematological disorders or recent chemotherapy (e.g. bone marrow transplant / conditioning) may not have a neutrophils 1.0x10 9 /L at time of testing. These patients are at risk of similar infective complications and should be managed under the supervision of haematology / oncology team. There is a 24 hour on call service These guidelines may be used to treat septic episodes in this group with all cases discussed with the haematology / oncology team. These guidelines are designed to complement the pan-london neutropenic sepsis management guidelines available online

Neutropenic Sepsis Guideline Suspected or proven infection in a neutropenic patient is a medical emergency and is an indication for immediate assessment and immediate treatment with intravenous (IV) (within 1 hour of presentation) Inclusion: Patients with a) Suspected/confirmed neutropenic sepsis, b) Patient receiving chemotherapy in last 3 months or has bone marrow failure due to primary haematological disorder [Do not wait for FBC before initiating treatment] Check if the patient has: - Penicillin allergy - if severe IgE mediated reaction (e.g. anaphylaxis, angioedema or urticarial) discuss treatment with microbiology No 1 st Line therapy: Piperacillin /tazobactam IV 4.5g QDS plus Amikacin IV 15mg/kg stat* (*7.5mg/kg stat if known CrCl <40ml/min or AKI present) Do not delay dosing waiting for exact body wt / CrCl Yes Alternative therapy: Meropenem IV 1g TDS (penicillin allergy cross sensitivity reported at 1%; avoid in anaphylaxis) Or Beta-Lactam Free option: Discuss with microbiology If a patient has: - recent history of MRSA - a long line present (e.g. PICC/Hickman) - severe mucositis Add a glycopeptide: e.g. Vancomycin IV or Teicoplanin IV (dosing guide) Common Modifications To Initial Empirical Treatment In Neutropenic Patients Head, ear, eye, nose and throat Vesicular or ulcerative lesions consider HSV and VZV treatment Sinus tenderness or nasal ulcerative lesions suspect fungal infection e.g. aspergillus or zygomycetes such as mucor. Gastrointestinal Retrosternal symptoms consider endoscopy likely organisms include candida or HSV. In severely immunocompromised patients CMV should be considered Acute abdominal pains seek surgical advice Diarrhoea consider Clostridium difficile (refer to local guidelines) Respiratory Community acquired pneumonia with atypical presentation consider Azithromycin PO / clarithromycin IV Viral symptoms - Send nose and throat swabs for respiratory virus PCR / consider treatment Investigate for PCR / CMV / mycobacteria / PCP anyone who is neutropenic post transplant / chemo needs consideration of PCP. Central nervous system infections Suspected meningitis/encephalitis: Meropenem 2g IV TDS and consider adding Aciclovir 10mg/kg TDS IV Discuss all cases with microbiology Known Carbapenem resistant organism (CRO) / Vancomycin resistant enterococcus (VRE) colonised Discuss with microbiology

1. Continuing assessment The patient should be assessed at least every 2 hours in the initial period and daily with daily FBC and U&E. LFT and CRP tested at least three times weekly. If there is any change in clinical condition or rising early warning scores then prompt reassessment should take place. Fluid balance and urine output need to be monitored hourly Reassessment Daily Day 2 (48 hours) If white cell counts are improving, neutrophils are greater than 0.5 x 10 9 /l, and no microbiology evidence of infection then complete a five day course of antibiotics. Consider IV-to-PO switch / stopping aminoglycoside No clinical deterioration: The current antibiotic regimen should be continued for a further 24 hours then review antibiotics. Continue amikacin therapy (if part of empiric prescription - see TDM/dosing in local guidelines) Clinical deterioration: A full clinical assessment should take place and further clinical investigation, including repeat blood and urine cultures, should be arranged as indicated. Continue amikacin therapy (if part of empiric prescription - see TDM/dosing in local guidelines) Consider non-bacterial causes. A senior physician should decide if initiation of antifungal or antiviral treatment may be appropriate at this stage. Review antibiotic therapy to consider including a glycopeptide. Day 3 (72 hours) Review Sensitivities (if available) note: amikacin may be de-escalated to gentamicin where sensitivities known If white cell counts are improving, neutrophils are greater than 0.5 x 10 9 /l, and no microbiology evidence of infection then complete course of antibiotics. Consider IV-to-PO switch / stopping aminoglycoside A full clinical assessment should take place and further clinical investigation, including repeat blood and urine cultures, should be arranged as indicated. Consider non bacterial causes. A senior physician should decide if initiation of antifungal or antiviral treatment may be appropriate at this stage. Review antibiotic therapy to consider including a glycopeptide. Second line antimicrobials (carbapenem) plus a glycopeptide may be considered.

Day 4 (96 hours) If white cell counts are improving and neutrophils are greater than 0.5 x 10 9 /l then consider switching to IV antibiotics to oral antibiotics to complete course / and stopping aminoglycoside If the patient remains febrile and neutropenic after four days of appropriate antibacterial therapy then an antifungal drug should be considered at this stage (see below for dosing of antifungal therapy). Arrange imaging CT chest, liver and spleen. Consider CT of other regions including the CNS as symptoms/signs dictate. Consider galactomannan and B-D-Glucan testing for fungal infection. An antiviral should usually only be considered if there is microbiological evidence or in the case of cutaneous Herpes or Varicella infections. Day 5+ If afebrile for more than 48 hours, the physician can consider changing to broad spectrum oral therapy especially if the neutrophil count is recovering (>0.5 x 10 9 /l). Consider an antifungal if not already commenced. Continue to repeat cultures and consider further imaging of chest and abdomen as clinically indicated. Consider galactomannan and B-D-Glucan for fungal infection. Possible Cytomegalovirus (CMV) infection / reactivation should also be considered send quantitative CMV PCR and discuss with micro- virology or HIV consultant Duration of Antibiotics (IV / PO) Patients with neutrophil count 0.5 x 10 9 /l After review may stop antibiotics if patient has been apyrexial for 3 days if: a) cultures indicate organism eradicated b) all sites of infection have resolved c) patient free of signs and symptoms d) falling acute phase reactants e.g. CRP On discussion with the relevant consultant Patients with neutrophil count <0.5 x 10 9 /l Low risk and above factors a) to d) met, Stop antibiotics when patient has been afebrile for 5 days High risk (e.g. if patient has mucositis, ulcers, bleeding points, iv-catheter site infection present or if invasive procedures or ablative chemotherapy pending) Continue antibiotics so that patient receives at least 10 days treatment in total or until neutrophils 0.5 x 10 9 /l

Anti-fungal agents The decision to commence antifungal treatment must be made on the clinical evidence. However there is rarely a positive microbiological confirmation of a fungal organism. Evidence suggests that up to one third of neutropenic patients who remain pyrexial for seven days may have a fungal infection. Any decision to start therapy should be made in consultation with a senior haematologist, usually the consultant. An attempt to establish a diagnosis may be made by high resolution CT scan of the chest and possibly liver and in selected patients bronchoscopy with lavage or nasal sinus washings. It is appropriate to consider these investigations when starting antifungal therapy. Invasive aspergillosis can occur in severely immunocompromised patients and empiric antifungal therapy should target aspergillus infection. Antifungal therapy should be based on the nature of the patient s illness, degree of immunosuppression, taking into account the potential side effects and interactions with other medication. 1.1. Empirical anti-fungal therapy Clinical / Patient risk factors for mould infections (e.g. aspergillosis) Low risk of mould infection (non-respiratory source / negative HRCT) Significant respiratory symptoms, other reason for high suspicion of moulds (e.g. aspergillosis), or prolonged neutropenia (>7 days) First line Review antifungal therapy based on imaging and antigen results Caspofungin IV 70mg stat then 50mg OD (<80kg) or 70mg ( 80kg) Note: Echinocandins are static against moulds (including aspergillis) and should only be used where mould infection is NOT suspected / a risk. Discuss with consultant Voriconazole IV / PO (see dosing below) Potent cytochrome P450 interactions; check for drug interactions Or AmBisome IV 3mg/kg daily OD (IV Test dose on initial infusion) 1.2. Targeted anti-fungal therapy Candida species Empiric Rx Blood cultures/deep Sites Alternative Rx Contra-indicated or failure of 1st line therapy Antifungal Route Dosing Duration Caspofungi n AmBisome (liposomal amphoteric in) Step down therapy for Candida sp sensitive strains / line tip positive and removed in stable patient Fluconazol e IV/PO* Aspergillosis - Proven invasive / high suspicion IV IV 70mg stat; then 50mg/day (<80kg) or 70mg/day ( 80kg) 3mg/kg OD (IV Test dose on initial infusion) 400mg OD Discuss with microbiology/ haematology Uncomplicated line infection, complete 14 days post line removal Note: The oral bioavailability of fluconazole and voriconazole is greater than 90%. Empiric Rx Voriconazole IV/PO* See dosing information below Alternative Rx AmBisome (liposomal amphotericin) Other (including moulds) IV 3mg/kg OD (IV Test dose on initial infusion) Discuss each case with microbiology Discuss with micro

1.3. Antifungal drug information 1.3.1. Liposomal amphotericin B AmBisome There is the largest base of evidence to show that amphotericin has activity against a broad range of fungi. However, amphotericin B has an unacceptable level of toxicity and therefore a lipid formulation should be used. It is licensed for empirical use in suspected fungal infections. It should be used as 1st line where liver involvement with fungi is proven or suspected. A test dose of 1mg (over 15 minutes) must be given as part of the first dose and patients observed for 30 minutes. Side effects: Hypokalaemia: Almost inevitable with treatment and potassium supplements should be considered. Magnesium levels should be monitored at least three times per week. Infusion related reactions: Include pyrexia and rigors. These usually diminish with continued therapy. Patients may require premedication with paracetamol 1g orally and chlorphenamine 10mg IV. Steroid cover should generally be avoided where possible in immunocompromised patients. The reactions may be so severe that a different agent is required. Contact microbiology to discuss alternative options. Nephrotoxicity: Well recognised and rises in serum creatinine may require a reduction in dose or changing to different antifungal therapy. Ensure the patient is well hydrated prior to infusion to reduce nephrotoxicity Abnormal liver function test: Usually mild and not clinically relevant. Severe disturbance may require discontinuation of therapy. 1.3.2. Echinocandins Caspofungin Dose: 70 mg stat dose, then continue daily at 70mg 80 kg or 50mg <80kg ONCE daily No dose adjustment for patients with renal failure of any degree (renal function should be monitored) Monitor liver function; Avoid in liver impairment where possible; a dose reduction to 35mg/day advised in Child-Pugh score C

1.3.3. Azoles Voriconazole Voriconazole can be used as a 1st line treatment for invasive aspergillosis. It is also licensed for the treatment of resistant Candida and Aspergillus infection so may be used where patients are intolerant of the above treatments (discuss with Consultant / microbiologist). It also has the advantage that it is available in an oral form and therefore treatment can be continued as an outpatient. IV dose: 6mg/kg 12 hourly for 2 doses then 4mg/kg bd Oral dose: >40kg 400mg 12 hourly for 2 doses then 200mg bd, <40kg 200mg bd then 100mg bd Side effects: The drug is metabolised by cytochrome P450 liver enzymes. Therefore it has a large number of drug interactions. Check on possible interactions before starting the drug. Visual disturbances: Common and usually clinically insignificant and transient. Abnormal liver function test: May require cessation of the drug GI disturbances: Common. Posaconazole Used on the advice of microbiology or consultant haematologist/oncologist for prevention / treatment of aspergillosis / moulds PO dose: 300mg tablets ONCE daily (liquid not recommended as 1 st line due to unpredictable absorption)