case 5 Facilitator version

Admission 66 year-old man Admitted for 2nd cycle chemotherapy Chronic myelomonocytic leukaemia Diagnosed 6/12 previously Skin and lymph node involvement 1st cycle complicated by right lower lobe pneumonia Empiric treated with meropenem and gentamicin x 8/7 No pathogen identified. Empiric treatment with meropenem, gentamicin. Settled.

Admission - history PMHx COPD Osteoarthritis MI - 20 years ago Allergic to penicillin – throat swelling Medications Valaciclovir Pantoprazole Nicotine patch Aqueous cream Throat swelling with penicillin

Admission - examination Dry flaky skin rash PICC – right arm (in situ x 2/12) Otherwise no abnormal findings Creatinine 112 (normal range 62-106) WCC 6.5 (normal range 3.5-11)

Days 2-6 Bone marrow aspirate Chemotherapy Fludarabine Cytarabine gCSF Well throughout Weekend leave Bone marrow aspirate – hypercellular, appearance consistent with remission from CMML

Day 9 Returned from weekend leave Neutropenic WCC 0.6 Neuts 0.6 Hb 8.3 Plts 177 Afebrile, no complaints Platelets 117

Days 10-11 Day 10 Afebrile Diarrhoea x 1 – sample sent for C. difficile PCR Day 11 Diarrhoea x 2 C. difficile PCR positive Contact precautions Oral metronidazole In single room accomodation

Days 12-13 3-4 episodes diarrhoea per day Afebrile Continued on metronidazole

Day 14 (Saturday) WCC 0.1 10.25 Patient complained of rigors Temp 39.4°C BP 143/83 HR 95 RR 19 O2 sats 95% (on room air) EWS 4 Neut count not routinely reported on call, was 0.0 on day 13

Irish national early warning score

Irish national EWS – escalation protocol

What’s wrong with the patient?

What’s wrong with the patient? Neutropenic fever Single oral temperature > 38.3°C or Temperature > 38.0°C sustained for > 1 hour

Day 14 10.30 Blood cultures drawn (PICC and peripheral) Medical review requested 10.50 Seen by haematology registrar on call

What are the potential sources of fever?

What are the potential sources of fever? C. difficile colitis Neutropenic enterocolitis PICC line Pneumonia Skin and mucous membranes Oral infection Perianal infection Bone marrow aspirate site

Day 14 10.50 Seen by haematology registrar on call No abdominal pain Diarrhoea settling No sore throat No cough, no SOB No urinary symptoms No change in rash PICC working

Day 14 Examination Throat – no erythema, no exudate PICC site – no erythema, clean Chest – clear to auscultation Abdomen – soft, non-tender Plan Blood cultures, MSU CXR Antibiotics

What do you need to consider when choosing antibiotic therapy?

What do you need to consider when choosing antibiotic therapy? Patient history Antibiotic allergies Symptoms Signs Recent antibiotic therapy Culture results Institutional resistance patterns/pathogens

Our patient Current C. difficile infection Penicillin allergy – throat swelling No localising symptoms or signs Antibiotic x 1/12 ago for pneumonia No antibiotic prophylaxis No recent isolates Not known to be colonised with MDRO (admission and weekly screens for MRSA, VRE, ESBL and CRE negative) Admission and weekly screens for MRSA, VRE, ESBL and CRE negative

Antibiotics prescribed Meropenem 1g iv 8-hourly – first dose given at 11.30 Gentamicin 300mg iv – first dose given at 11.28 (weight 62kg, creatinine 101)

What do you think of the antibiotic choice?

What do you think of the antibiotic choice? Monotherapy versus combination therapy Penicillin allergy and use of carbapenem

Recommendations for empiric antibiotics in neutropenic sepsis IDSA, 2010 (Freifeld et al, CID, 2011:52) Monotherapy with piptazobactam or carbapenem or ceftazidime or cefipime Penicillin hypersensitivity – clindamycin and ciprofloxacin or vancomycin and aztreonam NICE clinical guideline, 2012 (CG 151) Monotherapy with piptazobactam No specific recommendation for penicillin allergy

Carbapenem use in penicillin allergy Systematic review (Kula et al, CID, 2014) Cross-reactivity between penicillins and carbapenems for IgE-mediated reactions is very low – caution advised Cross-reactivity between cephalosporins and carbapenems may be higher – minimal data available

What about the timing of the antibiotics?

What about the timing of the antibiotics? Febrile neutropenia = medical emergency Empiric antibiotics should be given within one hour of presentation1, 2 Fever recorded at 10.25 Seen by registrar at 10.50 Antibiotics given at 11.28 and 11.30 1NI Cancer Network neutropenic sepsis guidelines, 2010 2NICE Clinical Guidelines 151, 2012

Day 14 Day 15 10.25 12.55 13.10 13.45 14.50 15.50 16.50 17.50 06.00 09.30 11.30

Day 15 Blood cultures (day 14) Line – both bottles – Gram negative bacilli Peripheral – sterile to date 11.45 Haematology registrar phoned by microbiology registrar Patient afebrile since 17.50 on day 14 Advised continue meropenem and gentamicin, repeat blood cultures Gentamicin 300mg given (no gentamicin level done, creatinine 103) No gentamicin level done, creatinine 101 – in normal range

CXR – day 15

Day 16 Blood cultures (day 14) Line – Klebsiella pneumoniae (MALDI-TOF) Direct susceptibilty test –susceptible to coamoxiclav, ciprofloxacin, gentamicin, cefuroxime Peripheral - sterile to date Blood cultures (day 15) Line and peripheral – sterile to date Trough gentamicin level 2.4 – dose held Patient remains afebrile, diarrhoea resolved ID by MALDI-TOF. Direct sens – looks susceptible to cefpodoxime, cipro, gent, cefoxitin, cefuroxime, coamox. Target gentamicin level <1.0; gentamicin held

Day 17 Blood cultures (day 14) Line – Klebsiella pneumoniae – resistant to amoxicillin only Peripheral - sterile to date Blood cultures (day 15) Line – sterile to date MSU (day 14) – WCC < 1, no growth Patient remains afebrile

What do you advise now?

What do you advise now? Antibiotic options with penicillin allergy Continue meropenem Change to ciprofloxacin – C. difficile infection Change to aztreonam Remove PICC? Line cultures positive No other source found VIP (visual infusion phlebitis) scores recorded daily = 0 Care bundle for PICC – completed daily – no signs infection recorded during admission

IV catheter removal IDSA, 2010 (Freifeld et al, CID, 2011:52) If CRBSI in neutropenic patient, remove catheter if: - S. aureus, P. aeruginosa, fungi or mycobacteria tunnel infection or port pocket site infection septic thrombosis infective endocarditis sepsis with haemodynamic instability BSI persisting for > 72 hours despite appropriate antibiotics

Day 17 Seen by consultant microbiologist Afebrile No diarrhoea WCC 0.1 EWS 0 Advice Consider removal of PICC Change meropenem to aztreonam Give one more dose of gentamicin (level = 0.5)

Progress PICC not removed Changed to aztreonam on day 17 Gentamicin stopped on day 18 (4 days in total) Metronidazole stopped on day 24 (14 days in total) Aztreonam stopped on day 28 (15 days mero/azt) Remained afebrile Discharged home on day 29 - WCC 1.8, neut 1.3 Line remains in situ, blood cultures sterile