Transcript Document

Cancer, Infection &
Palliative Medicine
Dr Tim Collyns
Consultant Microbiologist
LTHT

Overview

“Febrile neutropenia”

Site specific infections

In era of increasing antimicrobial resistance
 Urinary
tract
 Respiratory tract
 Skin / soft tissue
Clostridium difficile
 Fungal


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 β-lactamase (ESBL) producers
 Plasmid: other antimicrobial classes.

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)

..Right drug, right dose, right time, right
duration…every patient.

Start smart
Don’t 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


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.

Hospice / palliative medicine setting

“Specific” challenges, include
 Preceding

Acquisition of multi-resistant pathogens
 Debilitated


of intravenous option
(Efficacy of enteral vs parenteral route)
Limited choice (if any) - MR GNBs.
 Clinical
infection as the “terminal” event
 Infection

/ immunocompromised
More prone to clinical infection post acquisition
 Lack

/ ongoing hospital involvement
prevention in end-of-life care
Visitors, staff,

Guidelines

Source
 “International”
 National
– Yorkshire Cancer Network
 LTHT / NHS Leeds – Leeds Health Pathways
 Regional

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)

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 2011:52:e56-e93.
 NICE:
Neutropenic sepsis: prevention &
management…in cancer patients

guidance.nice.org.uk/cg 151 [issued Sep 2012]
1960s: Increased sepsis risk with falling neutrophil count – risk of
bacteraemia:
Gram negative bacilli, esp Pseudomonas aeruginosa
High mortality rate: > 50% < 48hrs
1970s: Empiric early iv therapy
Schimpf 1971: carbenicillin + gentamicin
1980s: Broader spectrum β - 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)

NICE (2012):

Treat neutropenic sepsis [NS] (2o / 3o care)
as acute medical emergency, offer empiric
antibiotic therapy immediately
 Offer
β-lactam monotherapy with piperacillintazobactam 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.

Diagnosis of neutropenic sepsis in patients
having anticancer treatment with
neutrophil count < 0.5 x109 / L, &

Temperature > 380 C or

Other signs / symptoms consistent with
clinically significant sepsis.

…”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%

“Low risk” of complications
Oral therapy.
(Initial / sequential)

Oral vs intravenous

Meta-analysis: Vidal 2004


15 trials, mortality rate: 0 – 8.8%


RR: 0.91 (95% CI 0.51 – 1.62)
Treatment failure rates:




Initial; or sequential (iv then PO)
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.

MASCC risk index score (Klastersky 2000)
Characteristic
 Extent of illness









No symptoms
Mild
Moderate
No hypotension
No COPD
Solid tumour or no IFI
No dehydration
Outpatient at onset of fever
Age < 60 [>16]
Score
5
5
3
5
4
4
3
3
2
>/ 21 = low risk complications / morbidity
PPV 91%, specificity 68%, sensitivity 71%

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 G+ve: eg co-amoxiclav.
Japanese guidelines: Quinolone alone

Unless mucositis / skin lesions: then eg with co-amoxiclav
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
…potential fly in the ointment –
prophylactic strategy


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

Bucaneve NEJM 2005 353:977-87


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)

Cullen 2005 NEJM 2005 353:988-98


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% (p<0.001)
Over entire course: 10.8 % vs 15.2% (p=0.01)
Hospitalisation 15.7 vs 21.6% (p=0.004)
Severe infection 1 vs 2.0 % (NS)

Each group: four infection related deaths.




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)


Antibiotic resistance

Infecting organisms




Individual patient
Unit / Hospital
Community
“Collateral”

MRSA, C difficile
(Reduced use of other antibiotics)

(Cost)

Treatment strategy: oral regimens

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:
of fibronectin – binding proteins
 Increased adhesion by quinolone resistant S
aureus
 Induction
Bisognano 2000, Paterson 2004,
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
<0.001
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

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

Fever & Neutropenic risk category: Intermediate
/ High
Prophylaxis:
Bacterial: Consider FQ prophylaxis

CG151:

Adult patients with acute leukaemias, stem
cell transplants or solid tumours in whom
significant neutropenia (\< 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]


…CG151 still being assessed LTHT / YCN

β-lactam resistance in Enterobacteriaceae:

Enzyme mediated: β-lactamases
 (Ancient

Serine residue active site; or metalloenzymes (Zinc ion)
 Inherent

heritage: > 2 billion years old)
– 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 β-lactams:
 Some
drug structures more resilient than others.
 Some blocked by β-lactamase inhibitors


clavulanic acid (co-amoxiclav), tazobactam (with
piperacillin)
Various classifications / name derivations

3 letter monikers for families:
 SHV (>50): Variable response to sulfhydryl inhibitors
 TEM (>130): After patient (Temoneira)
 CTX-M (>40), OXA, IMP:
 Ability to hydrolyse cefotaxime, oxacillin, imipenem

VIM: Verona integron encoded metallo-β-lactamase
KPC: Klebsiella pneumoniae carbapenemase
 New York / US.

NDM: New Delhi metallo-β-lactamase

Jacoby 2005;

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


ESBLs:


carbapenem
Carbapenemase producing
Tigecycline
 Polymyxin (colistin)
?

Possible local choices outside the box
Yorkshire & Humber: E coli surveillance data, 2010 -2012
792 isolates, 14 hospital trusts (courtesy of HPA)

8% = ESβL producers

0.1% = carbapenemase producer

“Other” options
(Co-trimoxazole)
 Intramuscular gentamicin

 Urinary

catheter change
“usually” sensitive in vitro:
 Nitrofurantoin
 Pivmecillinam
(lower UTI, eGFR > 60ml/m)

Mecillinam

Beta lactam (6-β-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

Uses: Urinary tract infections




Advantages:



Lower
(Upper – step down oral therapy).
((Other MDR coliforms: e.g. Biliary))
High % still susceptible (> 90% global)
Low C difficile propensity
“Avoid” if penicillin allergy

(tho’ hypersensitivity reactions uncommon)

…NB: Avoid treating “asymptomatic
bacteriuria” (catheterised or noncatheterised) in adults.

Increase resistance
 Loss

of oral options.
“Good” bacteria
 Enterococci

Respiratory tract bacterial pathogens
AWARE 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
>99.9
N/A
N/A

..?.. Doxycycline may also protect against
development of C difficile infection

US study comparing ceftriaxone +/- doxycycline

> 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

..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.
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
Long-term intravascular catheters

Long term catheters should be removed
for patients with CRBSI associated
with:
Severe sepsis
 Suppurative thrombophlebitis
 Endocarditis
 BSI that continues despite > 72 hours
suitable antimicrobial therapy
 Infections due to S. aureus, P aeruginosa,
fungi or mycobacteria

IDSA, Mermel 2009
S aureus ; removal, unless major contraindications; 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.

Uncomplicated CRBSI involving longterm catheters due to [other] pathogens

Attempt treatment without catheter
removal:
Systemic and antimicrobial lock therapy
Administer both for 7 – 14 days

..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)

Other locks

Gentamicin

Taurolidine (TauroLock®)
 Broad
spectrum antimicrobial
 Unique site of action / no cross resistance
 Spontaneously breaks down.

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
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 >15, AKI
(Fidaxomycin)
Infection Prevention:
Hand washing with soap & water

..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 (< 12
hours), [EUCAST].

Fungal:

Prophylaxis

Empiric
 Fever
in neutropenic patient unresponsive to broad
spectrum antibiotics

“Pre-emptive”: suspicion of IFI

Targeted treatment – proven / probable

Candida
Candida albicans
 Non C albicans: C krusei
C glabrata


Aspergillus spp


Aspergillus fumigatus
Zygomycetes

Mucor, Rhizopus,

Amphotericin B


Azoles





Lipid formulations – ambisome, (abelcet, amphocil)
Fluconazole
Itraconazole
Voriconazole
Posaconazole
Echinocandins



Caspofungin
Micafungin
Anidulafungin


Changing criteria for diagnosis
De Pauw 2008: EORTC / MSG revised definitions of Invasive
Fungal Disease [for trial use]

Host factors:




Recent neutropaenia (<0.5 for > 10 days)
Allogeneic stem cell transplant receipt
Prolonged use corticosteroid (mean minimum: equivalent 0.3mg/kg/d, >
3 weeks)
Other recognised T cell immunosuppressants:


Clinical criteria


Lower respiratory tract disease: 1 out of 3 defined HRCT signs.
Sinonasal infection


Sinusitis on imaging + > 1 sign of eg acute localised pain, nasal ulcer + black
eshar
Mycological criteria:



eg cyclosporin, alemtuzumab (CamPath)
Direct tests: microscopy / culture,
Indirect tests: Aspergillus antigen
“Proven”, “probable”, “possible”

Pre-emptive

(“Suggestive”) Evidence of IFI:
 Galactomannan

Blood
BAL.

Β – glucan

 High



- Aspergillus
Resolution chest CT
Dense, well-circumscribed lesion(s) +/- halo sign
Air-crescent sign
Cavity.
Halo sign
Air crescent sign
Aspergillus microscopy
Colonies of Aspergillus fumigatus

Treatment – ongoing – azoles

Aspergillosis: voriconazole

More exotic moulds: posaconazole

…trough levels.
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.