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Cancer, Infection

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Title: Cancer, Infection


1
Cancer, Infection Palliative Medicine
  • Dr Tim Collyns
  • Consultant Microbiologist
  • LTHT

2
  • Overview
  • Febrile neutropenia
  • Site specific infections
  • In era of increasing antimicrobial resistance
  • Urinary tract
  • Respiratory tract
  • Skin / soft tissue
  • Clostridium difficile
  • Fungal

3
  • 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.

4
  • 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)

5
  • ..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

6
  • 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.

7
  • 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,

8
  • 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)

9
  • 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

10
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11
  • 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)

12
  • 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.

13
  • 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.

14
  • 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

15
  • Low risk of complications
  • Oral therapy.
  • (Initial / sequential)

16
  • 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.

17
  • 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

18
  • 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

19
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
20
  • potential fly in the ointment
  • prophylactic strategy

21
  • 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

22
  • 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)

23
  • 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.

24
  • 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)

25
  • Antibiotic resistance
  • Infecting organisms
  • Individual patient
  • Unit / Hospital
  • Community
  • Collateral
  • MRSA, C difficile
  • (Reduced use of other antibiotics)
  • (Cost)
  • Treatment strategy oral regimens

26
  • 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,

27
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
28
  • 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

29
  • Fever Neutropenic risk category Intermediate /
    High
  • Prophylaxis
  • Bacterial Consider FQ prophylaxis

30
  • 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

31
  • CG151 still being assessed LTHT / YCN

32
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33
  • 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

34
  • 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

35
  • 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

36
  • ESBLs
  • carbapenem
  • Carbapenemase producing
  • Tigecycline
  • Polymyxin (colistin)
  • ?

37
  • Possible local choices outside the box

38
Yorkshire Humber E coli surveillance data,
2010 -2012792 isolates, 14 hospital trusts
(courtesy of HPA)
39
  • 8 ESßL producers
  • 0.1 carbapenemase producer

40
  • Other options
  • (Co-trimoxazole)
  • Intramuscular gentamicin
  • Urinary catheter change
  • usually sensitive in vitro
  • Nitrofurantoin (lower UTI, eGFR gt 60ml/m)
  • Pivmecillinam

41
  • 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

42
  • 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)

43
  • NB Avoid treating asymptomatic bacteriuria
    (catheterised or non-catheterised) in adults.
  • Increase resistance
  • Loss of oral options.
  • Good bacteria
  • Enterococci

44
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
45
  • ..?.. 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

46
  • ..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.

47
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
48
  • Long-term intravascular catheters

49
  • 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

50
  • 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.

51
  • 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

52
  • ..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)

53
  • Other locks
  • Gentamicin
  • Taurolidine (TauroLock)
  • Broad spectrum antimicrobial
  • Unique site of action / no cross resistance
  • Spontaneously breaks down.

54
  • 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

55
  • 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

56
  • ..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.

57
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58
  • Fungal
  • Prophylaxis
  • Empiric
  • Fever in neutropenic patient unresponsive to
    broad spectrum antibiotics
  • Pre-emptive suspicion of IFI
  • Targeted treatment proven / probable

59
  • Candida
  • Candida albicans
  • Non C albicans C krusei
  • C glabrata
  • Aspergillus spp
  • Aspergillus fumigatus
  • Zygomycetes
  • Mucor, Rhizopus,

60
  • Amphotericin B
  • Lipid formulations ambisome, (abelcet,
    amphocil)
  • Azoles
  • Fluconazole
  • Itraconazole
  • Voriconazole
  • Posaconazole
  • Echinocandins
  • Caspofungin
  • Micafungin
  • Anidulafungin

61
  • 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

62
  • 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.

63
Halo sign
64
Air crescent sign
65
Aspergillus microscopy
66
Colonies of Aspergillus fumigatus
67
  • Treatment ongoing azoles
  • Aspergillosis voriconazole
  • More exotic moulds posaconazole
  • trough levels.

68
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69
  • 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.

70
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