Cancer, Infection

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Cancer, Infection Palliative Medicine

• Dr Tim Collyns
• Consultant Microbiologist
• LTHT

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• Overview
• Febrile neutropenia
• Site specific infections
• In era of increasing antimicrobial resistance
• Urinary tract
• Respiratory tract
• Skin / soft tissue
• Clostridium difficile
• Fungal

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• Overview
• Presenter ignorance,sucking eggs
• Hospice between hospital community
• Risk of healthcare associated infections
• Meticillin resistant Staphylococcus aureus (MRSA)
• Clostridium difficile
• Meticillin sensitive S aureus (MSSA)
• Escherichia coli
• Multi-resistant Gram-negative bacilli
• Extended spectrum ß-lactamase (ESBL) producers
• Plasmid other antimicrobial classes.

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• Antimicrobial stewardship
• 1o compared to 2o care
• 1o care
• Judicious w.r.t starting antibiotics
• Viral / (non-infectious) aetiology
• Simple (if likely to be effective), short
  courses
• Resisting patient pressure for positive action
• 2o care
• Start Smart then Focus (DH ARHAI, 2011)

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• ..Right drug, right dose, right time, right
  durationevery patient.
• Start smart
• Dont start antibiotics in absence of clinical
  evidence of bacterial infection.
• If evidence use local guidelines to initiate
  prompt effective antibiotic therapy.
• Document on drug chart in medical notes
  clinical indication, duration or review date,
  route dose
• Obtain cultures first

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• Then Focus
• Review clinical diagnosis continuing need for
  antibiotics by 48 hrs make a clear plan of
  action the Antimicrobial Prescribing Decision
  APD
• The 5 APD options are
• Stop
• Switch iv to oral
• Change
• Continue
• Outpatient Parenteral Antibiotic Therapy (OPAT)
• Clearly document the review subsequent APD in
  medical notes.

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• Hospice / palliative medicine setting
• Specific challenges, include
• Preceding / ongoing hospital involvement
• Acquisition of multi-resistant pathogens
• Debilitated / immunocompromised
• More prone to clinical infection post acquisition
• Lack of intravenous option
• (Efficacy of enteral vs parenteral route)
• Limited choice (if any) - MR GNBs.
• Clinical infection as the terminal event
• Infection prevention in end-of-life care
• Visitors, staff,

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• Guidelines
• Source
• International
• National
• Regional Yorkshire Cancer Network
• LTHT / NHS Leeds Leeds Health Pathways
• What
• Cancer-related
• Site-specific
• e.g. vascular catheter, urinary tract, pneumonia
• Organism specific
• e.g. MRSA, C difficile, Candidiasis,
  Aspergillosis
• (Setting 1o or 2o care)

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• Guidelines
• NCCN Prevention and treatment of cancer related
  infections - V.1.2012
• NCCN Clinical Practice Guidelines in Oncology
• www.nccn.org
• More traditional febrile neutropenia
• IDSA Clinical Practice Guideline for the use of
  antimicrobial agents in neutropenic patients with
  cancer 2010 Update by IDSA.
• Freifeld A, Clin Inf Dis 201152e56-e93.
• NICE Neutropenic sepsis prevention
  managementin cancer patients
• guidance.nice.org.uk/cg 151 issued Sep 2012

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• 1960s Increased sepsis risk with falling
  neutrophil count risk of bacteraemia
• Gram negative bacilli, esp Pseudomonas
  aeruginosa
• High mortality rate gt 50 lt 48hrs
• 1970s Empiric early iv therapy
• Schimpf 1971 carbenicillin gentamicin
• 1980s Broader spectrum ß - lactams
• Option Monotherapy vs dual therapy
• 1990s Risk stratification w.r.t oral / out
  patient Mx
• 000s Emerging infections / new agents..
• 010s (..too early ? more emergence fewer new
  agents)

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• NICE (2012)
• Treat neutropenic sepsis NS (2o / 3o care) as
  acute medical emergency, offer empiric antibiotic
  therapy immediately
• Offer ß-lactam monotherapy with
  piperacillin-tazobactam initially to patients who
  need intravenous treatment unless there are
  patient specific or local microbiological
  contraindications
• Do not offer an aminoglycoside, either as
  monotherapy or dual therapy, for initial empiric
  treatment of NS unless patient specific or
  local microbiological indications.

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• Diagnosis of neutropenic sepsis in patients
  having anticancer treatment with neutrophil count
  lt 0.5 x109 / L,
• Temperature gt 380 C or
• Other signs / symptoms consistent with clinically
  significant sepsis.

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• Getting it right first time
• Kumar 2006 Septic shock patients, duration of
  hypotension prior to initiation of effective
  antimicrobial therapy link to survival.
• Within first hour Survival 79.9
• Each subsequent hour delay average drop in
  survival 7.6

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• Low risk of complications
• Oral therapy.
• (Initial / sequential)

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• Oral vs intravenous
• Meta-analysis Vidal 2004
• Initial or sequential (iv then PO)
• 15 trials, mortality rate 0 8.8
• RR 0.91 (95 CI 0.51 1.62)
• Treatment failure rates
• Overall RR 0.94 (0.84-1.05)
• Initial oral 0.89 (0.77 1.03)
• Sequential 1.03 (0.86 1.24)
• Adverse events
• No death / permanent damage attributed to oral
  Rx.
• Higher rate of GI side effects in oral regime.

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• MASCC risk index score (Klastersky 2000)
• Characteristic Score
• Extent of illness
• No symptoms 5
• Mild 5
• Moderate 3
• No hypotension 5
• No COPD 4
• Solid tumour or no IFI 4
• No dehydration 3
• Outpatient at onset of fever 3
• Age lt 60 gt16 2
• gt/ 21 low risk complications / morbidity
• PPV 91, specificity 68, sensitivity 71

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• Commonest Quinolone co-amoxiclav
• 6 trials quinolone alone
• (No difference shown between above post
  protocol analysis).
• Oral antibiotic therapy
• safely offered to neutropenic children / adults,
  haemodynamically stable, have no organ failure,
  can take PO medications,
• Do not have pneumonia, central line infection,
  severe SSTI
• Not acute leukaemics
• (Or use MASCC scoring system).
• Prudent FQ 2nd drug active vs Gve eg
  co-amoxiclav.
• Japanese guidelines Quinolone alone
• Unless mucositis / skin lesions then eg with
  co-amoxiclav

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Ciprofloxacin susceptibilities (bacteraemias,
Haematology)
Organism Ciprofloxacin resistant (Total)
All Gram negative bacilli 31 (132) 24
Coliforms 8 (70) E coli 5 11
NLFs, incl P aeruginosa 7 (45) P aer 2 16
S maltophilia 16 (17) 94
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• potential fly in the ointment
• prophylactic strategy

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• Antibiotic prophylaxis
• Afebrile neutropenic patients
• Reduce frequency of febrile episodes by
  administration of (broad spectrum) Ax
• But potential deleterious effects
• Toxicity
• Emergence of antibiotic resistant bacteria (FQ)
• Fungal overgrowth

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• Bucaneve NEJM 2005 353977-87
• 760 adult patients
• 500 mg Levofloxacin vs placebo for neutropenia
• Febrile episode
• All treated 65 vs 85 (ADR -0.20 -0.26 to
  -0.14)
• Acute leukaemia 67 vs 85 (ADR -0.19 -0.27 to
  -0.10)
• Solid tumours / lymphoma 62 vs 84, (-0.22,
  -0.29 to -0.12)
• Death
• All treated 3 vs 5 (ADR -0.02, -0.05 to
  0.005)
• Acute leukaemia 5 vs 7 (ADR -0.02, -0.07 to
  0.02)
• Solid tumours / lymphoma 1 vs 3, (-0.02 -0.05
  to 0.004)

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• Cullen 2005 NEJM 2005 353988-98
• 1565 patients, cyclic chemotherapy for solid
  tumours / lymphoma (13)
• 500 mg Levofloxacin vs placebo for 7 days
• Febrile episode first cycle 3.5 vs 7.5
  (plt0.001)
• Over entire course 10.8 vs 15.2 (p0.01)
• Hospitalisation 15.7 vs 21.6 (p0.004)
• Severe infection 1 vs 2.0 (NS)
• Each group four infection related deaths.

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• Gafter-Gvili 2006, Cochrane review
• 101 trials, 12599 patients 1973-2005
• Infection related deaths
• RR 0.59 (0.47-0.75)
• Fever occurrence
• RR 0.77 (0.74 0.81)
• All cause mortality (quinolone)
• RR 0.52 (0.37 0.74)

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• Antibiotic resistance
• Infecting organisms
• Individual patient
• Unit / Hospital
• Community
• Collateral
• MRSA, C difficile
• (Reduced use of other antibiotics)
• (Cost)
• Treatment strategy oral regimens

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• MRSA
• Risk with fluoroquinolones.
• MRSA usually resistant to fluoroquinolones
• Good skin tissue penetration / excreted in human
  sweat
• Loss of colonisation resistance by normal skin
  flora
• In vitro
• Induction of fibronectin binding proteins
• Increased adhesion by quinolone resistant S
  aureus
• Bisognano 2000, Paterson 2004,

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Multiple logistic regression analysis, factors
associated with MRSA infection Graffunder
2002
Risk factor OR 95 CIs P value
Levofloxacin 8.01 3.15, 20.3 lt0.001
Macrolides 4.06 1.15, 14.4 0.03
Enteral feeding 2.55 1.37, 4.72 0.003
Surgery 2.24 1.19, 4.22 0.01
Previous hospitalisation 1.95 1.02, 3.76 0.04
LOS before culture 1.03 1.0, 1.07 0.05
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• NCCN 2012
• Fever Neutropenic risk category LOW
• Standard chemotherapy regimens for most solid
  tumours
• Anticipated neutropenia less than 7 days
• Prophylaxis
• Bacterial NONE
• Fungal None
• Viral None unless prior HSV episode

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• Fever Neutropenic risk category Intermediate /
  High
• Prophylaxis
• Bacterial Consider FQ prophylaxis

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• CG151
• Adult patients with acute leukaemias, stem cell
  transplants or solid tumours in whom significant
  neutropenia (\lt 0.5x109 /L) is an anticipated
  consequence of chemotherapy
• Offer prophylaxis with fluoroquinolone during
  expected period of neutropenia only.
• No mention of any different action if known FQ
  resistant, or FQ contra-indicated.
• No mention of specific oral options for FNE
  whilst on FQ prophylaxis initial or s/down

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• CG151 still being assessed LTHT / YCN

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• ß-lactam resistance in Enterobacteriaceae
• Enzyme mediated ß-lactamases
• (Ancient heritage gt 2 billion years old)
• Serine residue active site or metalloenzymes
  (Zinc ion)
• Inherent gene carried on bacterial chromosome
• De-repressed e.g. Enterobacter, Citrobacter
  species
• Acquired transmissible genetic elements
  plasmids
• E.g. Klebsiella pneumoniae, E coli
• Vary in ability to hydrolyse different ß-lactams
• Some drug structures more resilient than others.
• Some blocked by ß-lactamase inhibitors
• clavulanic acid (co-amoxiclav), tazobactam (with
  piperacillin)
• Various classifications / name derivations

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• 3 letter monikers for families
• SHV (gt50) Variable response to sulfhydryl
  inhibitors
• TEM (gt130) After patient (Temoneira)
• CTX-M (gt40), OXA, IMP
• Ability to hydrolyse cefotaxime, oxacillin,
  imipenem
• VIM Verona integron encoded metallo-ß-lactamase
• KPC Klebsiella pneumoniae carbapenemase
• New York / US.
• NDM New Delhi metallo-ß-lactamase
• Jacoby 2005

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• NDM-1
• First detected United Kingdom January 2008.
• Now predominant carbapenem-hydrolysing enzyme in
  Enterobacteriaceae in UK (44 2009)
• 2008 2009 37 isolates
• K pneumoniae (21), E coli (7), Enterobacter spp
  (5), Citrobacter freundii (2), Morganella (1),
  Providencia (1)
• 29 patients 15 in urine
• ESBLs widespread in India,
• NDM-1 also in isolates in north south India
• Links between many of the UK patients and
  India Kumaraswamy 2010 HPA

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• ESBLs
• carbapenem
• Carbapenemase producing
• Tigecycline
• Polymyxin (colistin)
• ?

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• Possible local choices outside the box

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Yorkshire Humber E coli surveillance data,
2010 -2012792 isolates, 14 hospital trusts
(courtesy of HPA)
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• 8 ESßL producers
• 0.1 carbapenemase producer

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• Other options
• (Co-trimoxazole)
• Intramuscular gentamicin
• Urinary catheter change
• usually sensitive in vitro
• Nitrofurantoin (lower UTI, eGFR gt 60ml/m)
• Pivmecillinam

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• Mecillinam
• Beta lactam (6-ß-amidinopenicillanic acid)
• Pivmecillinam Pivaloyloxymethyl ester
• Much more active vs Gram negatives
• (Enterococci resistant, S saprophyticus may be
  inhibited)
• Enterobacteriaceae
• Usual suspects more tricky
• P aeruginosa, Acinetobacter spp, anaerobes
  resistant
• Serratia marcescens usually resistant
• M morganii, Providencia spp may be sensitive
• (Paradoxical effect with P stuartii)
• P mirabilis, P vulgaris usually sensitive

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• Uses Urinary tract infections
• Lower
• (Upper step down oral therapy).
• ((Other MDR coliforms e.g. Biliary))
• Advantages
• High still susceptible (gt 90 global)
• Low C difficile propensity
• Avoid if penicillin allergy
• (tho hypersensitivity reactions uncommon)

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• NB Avoid treating asymptomatic bacteriuria
  (catheterised or non-catheterised) in adults.
• Increase resistance
• Loss of oral options.
• Good bacteria
• Enterococci

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Respiratory tract bacterial pathogensAWARE
surveillance, US, 2008-10 Adapted
from Pfaller 2012
susceptible S pneumoniae H influenzae M catarrhalis
Amoxicillin 83 73
Co-amoxiclav 83 99.9 100
Erythro/clarithro 60 76 99.5
Tetracycline 75 99 99.8
Co-trimoxazole 66 77 94.4

Levofloxacin 99 100 100
Linezolid gt99.9 N/A N/A
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• ..?.. Doxycycline may also protect against
  development of C difficile infection
• US study comparing ceftriaxone /- doxycycline
• gt 2300 patients studied
• 1.67 / 10000 patient days vs 8.11 / 10000
• Rate of CDI 27 lower for each day of receipt
• HR 0.73, 95 CI 0.56 0-.96
• Doernberg 2012

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• ..NB these organisms (and S aureus et al) can be
  normal upper respiratory tract commensal flora.
• Adjudge positive microbiology results in
  conjunction with current clinical / radiological
  findings.

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S aureus, AWARE surveillance, US, 2008-10
Adapted from Farrell 2012
susceptible MSSA MRSA
Penicillin (amoxicillin) 23 (0)
Flucloxacillin (100) (0)
Erythromycin 66 8
Clindamycin 94 66
Tetracycline 96 95
Co-trimoxazole 99 99
Levofloxacin 89 29
Linezolid 100 99.8
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• Long-term intravascular catheters

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• Long term catheters should be removed for
  patients with CRBSI associated with
• Severe sepsis
• Suppurative thrombophlebitis
• Endocarditis
• BSI that continues despite gt 72 hours suitable
  antimicrobial therapy
• Infections due to S. aureus, P aeruginosa, fungi
  or mycobacteria
• IDSA, Mermel 2009

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• S aureus removal, unless major
  contra-indications e.g.
• No alternative venous access
• Significant bleeding diathesis
• Quality of life issues take priority over need
  for re-insertion of a new catheter at a different
  site
• If retain four weeks therapy, systemic lock
  therapy.

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• Uncomplicated CRBSI involving long-term catheters
  due to other pathogens
• Attempt treatment without catheter removal
• Systemic and antimicrobial lock therapy
• Administer both for 7 14 days

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• ..If multiple positive catheter-drawn blood
  cultures with coagulase negative staphylococci
  or Gram negative bacilli, but concurrent
  negative peripheral blood cultures can give lock
  therapy without systemic therapy for 10 14
  days.
• Vancomycin at least 1000x higher than organism
  MIC (e.g. 5 mg/ml)

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• Other locks
• Gentamicin
• Taurolidine (TauroLock)
• Broad spectrum antimicrobial
• Unique site of action / no cross resistance
• Spontaneously breaks down.

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• Lock therapy
• 14 days in total
• ?Alternating lumens 24 hourly in hospital
  access needed
• Dwell time up to one week
• Repeat luminal blood cultures post completion
• 48 72 hours

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• Clostridium difficile
• Diagnosis
• Now two stage testing process
• Initial GDH
• If positive toxin test.
• Treatment (..if indicated also review PPIs)
• Metronidazole non-severe
• Vancomycin severe colitis WCC gt15, AKI
• (Fidaxomycin)
• Infection Prevention
• Hand washing with soap water

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• ..Improve speeds of other diagnoses
• Aetiology in vitro susceptibilities
• Bacteriological methods long-standing, but
• Direct to specimens PCR / NAAT
• blood, sterile sites
• Organism identification MALDI-TOF
• Matrix-Assisted Laser Desorption Ionisation Time
  of Flight Mass Spectroscopy bacteria / yeasts
• expect more unheard of species names
• Rapid automated sensitivity testing (lt 12 hours),
  EUCAST.

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• Fungal
• Prophylaxis
• Empiric
• Fever in neutropenic patient unresponsive to
  broad spectrum antibiotics
• Pre-emptive suspicion of IFI
• Targeted treatment proven / probable

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• Candida
• Candida albicans
• Non C albicans C krusei
• C glabrata
• Aspergillus spp
• Aspergillus fumigatus
• Zygomycetes
• Mucor, Rhizopus,

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• Amphotericin B
• Lipid formulations ambisome, (abelcet,
  amphocil)
• Azoles
• Fluconazole
• Itraconazole
• Voriconazole
• Posaconazole
• Echinocandins
• Caspofungin
• Micafungin
• Anidulafungin

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• Changing criteria for diagnosis
• De Pauw 2008 EORTC / MSG revised definitions of
  Invasive Fungal Disease for trial use
• Host factors
• Recent neutropaenia (lt0.5 for gt 10 days)
• Allogeneic stem cell transplant receipt
• Prolonged use corticosteroid (mean minimum
  equivalent 0.3mg/kg/d, gt 3 weeks)
• Other recognised T cell immunosuppressants
• eg cyclosporin, alemtuzumab (CamPath)
• Clinical criteria
• Lower respiratory tract disease 1 out of 3
  defined HRCT signs.
• Sinonasal infection
• Sinusitis on imaging gt 1 sign of eg acute
  localised pain, nasal ulcer black eshar
• Mycological criteria
• Direct tests microscopy / culture,
• Indirect tests Aspergillus antigen

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• Pre-emptive
• (Suggestive) Evidence of IFI
• Galactomannan - Aspergillus
• Blood
• BAL.
• ? glucan
• High Resolution chest CT
• Dense, well-circumscribed lesion(s) /- halo sign
• Air-crescent sign
• Cavity.

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Halo sign
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Air crescent sign
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Aspergillus microscopy
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Colonies of Aspergillus fumigatus
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• Treatment ongoing azoles
• Aspergillosis voriconazole
• More exotic moulds posaconazole
• trough levels.

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• Conclusions
• Antimicrobial stewardship
• Start Smart then Focus.
• Increasing antimicrobial resistance Gram
  negatives.
• Review Microbiology results in conjunction with
  other current information.
• Antimicrobial guidelines on intranet individual
  cases - Microbiology advice.

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