Cancer, Infection &Cancer, Infection &Palliative MedicinePalliative Medicine

Dr Tim CollynsDr Tim Collyns

Consultant MicrobiologistConsultant Microbiologist

LTHTLTHT

OverviewOverview

““Febrile neutropenia”Febrile neutropenia”

Site specific infectionsSite specific infections In era of increasing antimicrobial resistance In era of increasing antimicrobial resistance

Urinary tractUrinary tractRespiratory tractRespiratory tractSkin / soft tissueSkin / soft tissue

Clostridium difficileClostridium difficileFungalFungal

OverviewOverview

Presenter ignorance,…sucking eggs Presenter ignorance,…sucking eggs Hospice: “between” hospital & communityHospice: “between” hospital & communityRisk of “healthcare associated infections”Risk of “healthcare associated infections”

Meticillin resistant Meticillin resistant Staphylococcus aureus Staphylococcus aureus (MRSA)(MRSA)Clostridium difficileClostridium difficile

{Meticillin sensitive {Meticillin sensitive S aureus S aureus (MSSA)}(MSSA)}{Escherichia coli}{Escherichia coli}Multi-resistant Gram-negative bacilliMulti-resistant Gram-negative bacilli

Extended spectrum Extended spectrum ββ-lactamase (ESBL) producers-lactamase (ESBL) producers Plasmid: other antimicrobial classes. Plasmid: other antimicrobial classes.

Antimicrobial stewardship:Antimicrobial stewardship:1o compared to 2o care1o compared to 2o care

1o care:1o care:Judicious w.r.t starting antibioticsJudicious w.r.t starting antibiotics

““Viral” / (non-infectious) aetiologyViral” / (non-infectious) aetiology

““Simple” (if likely to be effective), short coursesSimple” (if likely to be effective), short coursesResisting patient pressure for “positive” actionResisting patient pressure for “positive” action

2o care2o care““Start Smart – then Focus” (DH ARHAI, 2011)Start Smart – then Focus” (DH ARHAI, 2011)

..Right drug, right dose, right time, right ..Right drug, right dose, right time, right duration…every patient.duration…every patient.

Start smartStart smartDon’t start antibiotics in absence of clinical Don’t start antibiotics in absence of clinical

evidence of bacterial infection.evidence of bacterial infection. If evidence: use local guidelines to initiate If evidence: use local guidelines to initiate

prompt effective antibiotic therapy.prompt effective antibiotic therapy.Document on Document on drug chart drug chart & in medical notes: & in medical notes:

clinical indication, duration or review date, clinical indication, duration or review date, route & doseroute & dose

Obtain cultures firstObtain cultures first

Then Focus:Then Focus:Review clinical diagnosis & continuing need Review clinical diagnosis & continuing need

for antibiotics by 48 hrs & make a clear plan for antibiotics by 48 hrs & make a clear plan of action – the “Antimicrobial Prescribing of action – the “Antimicrobial Prescribing Decision” [APD]Decision” [APD]

The 5 APD options areThe 5 APD options areStopStopSwitch iv to oralSwitch iv to oralChangeChangeContinueContinueOutpatient Parenteral Antibiotic Therapy (OPAT)Outpatient Parenteral Antibiotic Therapy (OPAT)

Clearly document the review & subsequent Clearly document the review & subsequent APD in medical notes. APD in medical notes.

Hospice / palliative medicine settingHospice / palliative medicine setting ““Specific” challenges, includeSpecific” challenges, include

Preceding / ongoing hospital involvementPreceding / ongoing hospital involvement Acquisition of multi-resistant pathogensAcquisition of multi-resistant pathogens

Debilitated / immunocompromisedDebilitated / immunocompromised More prone to clinical infection post acquisitionMore prone to clinical infection post acquisition

Lack of intravenous optionLack of intravenous option (Efficacy of enteral vs parenteral route)(Efficacy of enteral vs parenteral route) Limited choice (if any) - MR GNBs.Limited choice (if any) - MR GNBs.

Clinical infection as the “terminal” eventClinical infection as the “terminal” event

Infection prevention in end-of-life careInfection prevention in end-of-life care Visitors, staff, Visitors, staff,

GuidelinesGuidelinesSourceSource

““International”International”NationalNationalRegional – Yorkshire Cancer NetworkRegional – Yorkshire Cancer NetworkLTHT / NHS Leeds – Leeds Health PathwaysLTHT / NHS Leeds – Leeds Health Pathways

WhatWhatCancer-relatedCancer-relatedSite-specificSite-specific

e.ge.g. vascular catheter, urinary tract, pneumonia. vascular catheter, urinary tract, pneumonia

Organism specificOrganism specific e.ge.g. MRSA, . MRSA, C difficile, C difficile, Candidiasis, AspergillosisCandidiasis, Aspergillosis

(Setting: 1o or 2o care)(Setting: 1o or 2o care)

Guidelines:Guidelines: NCCN: Prevention and treatment of cancer related NCCN: Prevention and treatment of cancer related

infections - V.1.2012infections - V.1.2012 NCCN Clinical Practice Guidelines in OncologyNCCN Clinical Practice Guidelines in Oncology www.nccn.org

More traditional – “febrile neutropenia”More traditional – “febrile neutropenia”IDSA: Clinical Practice Guideline for the use of IDSA: Clinical Practice Guideline for the use of

antimicrobial agents in neutropenic patients with antimicrobial agents in neutropenic patients with cancer: 2010 Update by [IDSA].cancer: 2010 Update by [IDSA].

Freifeld A, Clin Inf Dis 2011:52:e56-e93.Freifeld A, Clin Inf Dis 2011:52:e56-e93.

NICE: Neutropenic sepsis: prevention & NICE: Neutropenic sepsis: prevention & management…in cancer patients management…in cancer patients

guidance.nice.org.uk/cg 151 [issued Sep 2012]guidance.nice.org.uk/cg 151 [issued Sep 2012]

1960s:1960s: Increased sepsis risk with falling neutrophil count – risk Increased sepsis risk with falling neutrophil count – risk of of bacteraemia:bacteraemia:

Gram negative bacilli, esp Gram negative bacilli, esp Pseudomonas aeruginosaPseudomonas aeruginosaHigh mortality rate: > 50% < 48hrsHigh mortality rate: > 50% < 48hrs

1970s:1970s: Empiric early iv therapyEmpiric early iv therapySchimpf 1971: carbenicillin + gentamicinSchimpf 1971: carbenicillin + gentamicin

1980s:1980s: Broader spectrum Broader spectrum ββ - lactams- lactamsOption: Monotherapy vs “dual” therapyOption: Monotherapy vs “dual” therapy

1990s:1990s: Risk stratification w.r.t oral / out patient MxRisk stratification w.r.t oral / out patient Mx 000s: 000s: Emerging infections / new agents..Emerging infections / new agents..

010s:010s: (..too early ?: more emergence…& fewer new agents)(..too early ?: more emergence…& fewer new agents)

NICE (2012):NICE (2012):Treat neutropenic sepsis [NS] (2o / 3o care) Treat neutropenic sepsis [NS] (2o / 3o care)

as acute medical emergency, offer empiric as acute medical emergency, offer empiric antibiotic therapy immediatelyantibiotic therapy immediatelyOffer β-lactam monotherapy with piperacillin-Offer β-lactam monotherapy with piperacillin-

tazobactam initially to patients tazobactam initially to patients who need who need intravenous treatmentintravenous treatment – unless there are – unless there are patient patient specificspecific or local microbiological contraindications or local microbiological contraindications

Do not offer an aminoglycoside, either as Do not offer an aminoglycoside, either as monotherapy or dual therapy, for initial empiric monotherapy or dual therapy, for initial empiric treatment of [NS] unless treatment of [NS] unless patient specificpatient specific or local or local microbiological indications. microbiological indications.

Diagnosis of neutropenic sepsis in patients Diagnosis of neutropenic sepsis in patients having anticancer treatment having anticancer treatment with with neutrophil count < 0.5 x10neutrophil count < 0.5 x1099 / L, & / L, &

Temperature > 38Temperature > 3800 C or C or

OtherOther signs / symptoms consistent with signs / symptoms consistent with clinically significant sepsis. clinically significant sepsis.

…”…”Getting it right first time”Getting it right first time”

Kumar 2006: Septic shock patients, Kumar 2006: Septic shock patients, duration of hypotension prior to initiation of duration of hypotension prior to initiation of effective antimicrobial therapy – link to effective antimicrobial therapy – link to survival.survival.

Within first hour: Survival 79.9%Within first hour: Survival 79.9%Each subsequent hour delay: average Each subsequent hour delay: average

drop in survival 7.6%drop in survival 7.6%

““Low risk” of complicationsLow risk” of complications

Oral therapy.Oral therapy.

(Initial / sequential)(Initial / sequential)

Oral vs intravenousOral vs intravenous Meta-analysis: Vidal 2004Meta-analysis: Vidal 2004

Initial; or sequential (iv then PO)Initial; or sequential (iv then PO)

15 trials, mortality rate: 0 – 8.8%15 trials, mortality rate: 0 – 8.8% RR: 0.91 (95% CI 0.51 – 1.62)RR: 0.91 (95% CI 0.51 – 1.62)

Treatment failure rates:Treatment failure rates: Overall: RR 0.94 (0.84-1.05)Overall: RR 0.94 (0.84-1.05) Initial oral: 0.89 (0.77 – 1.03)Initial oral: 0.89 (0.77 – 1.03) Sequential: 1.03 (0.86 – 1.24)Sequential: 1.03 (0.86 – 1.24)

Adverse eventsAdverse events No death / permanent damage attributed to oral Rx.No death / permanent damage attributed to oral Rx. Higher rate of GI side effects in oral regime.Higher rate of GI side effects in oral regime.

MASCC risk index score (Klastersky 2000)MASCC risk index score (Klastersky 2000)

CharacteristicCharacteristic ScoreScore Extent of illnessExtent of illness

No symptomsNo symptoms 55 MildMild 55 ModerateModerate 33

No hypotensionNo hypotension 55 No COPDNo COPD 44 Solid tumour or no IFISolid tumour or no IFI 44 No dehydrationNo dehydration 33 Outpatient at onset of feverOutpatient at onset of fever 33 Age < 60 [>16]Age < 60 [>16] 22

>/ 21 = low risk complications / morbidity>/ 21 = low risk complications / morbidityPPV 91%, specificity 68%, sensitivity 71%PPV 91%, specificity 68%, sensitivity 71%

Commonest: Quinolone + co-amoxiclavCommonest: Quinolone + co-amoxiclav 6 trials: quinolone alone6 trials: quinolone alone (No difference shown between above – ‘post – (No difference shown between above – ‘post –

protocol’ analysis).protocol’ analysis). Oral antibiotic therapy : Oral antibiotic therapy :

safely offered to neutropenic children / adults, safely offered to neutropenic children / adults, haemodynamically stable, have no organ failure, can haemodynamically stable, have no organ failure, can take PO medications,take PO medications,

Do not have pneumonia, central line infection, severe Do not have pneumonia, central line infection, severe SSTISSTI

Not acute leukaemicsNot acute leukaemics (Or use MASCC scoring system).(Or use MASCC scoring system).

Prudent: FQ + 2Prudent: FQ + 2ndnd drug active vs G+ve: eg co-amoxiclav. drug active vs G+ve: eg co-amoxiclav. Japanese guidelines: Quinolone alone Japanese guidelines: Quinolone alone

Unless mucositis / skin lesions: then eg with co-amoxiclav Unless mucositis / skin lesions: then eg with co-amoxiclav

Ciprofloxacin susceptibilities (bacteraemias, Haematology)Ciprofloxacin susceptibilities (bacteraemias, Haematology)

OrganismOrganism Ciprofloxacin resistant Ciprofloxacin resistant (Total)(Total)

%%

All Gram negative All Gram negative bacillibacilli

31 (132)31 (132) 2424

““Coliforms” Coliforms” 8 (70)8 (70)E coli E coli 55

1111

NLFs, incl NLFs, incl P P aeruginosa aeruginosa

7 (45)7 (45)P aerP aer: 2: 2

1616

S maltophiliaS maltophilia 16 (17)16 (17) 9494

……potential fly in the ointment – potential fly in the ointment –

prophylactic strategyprophylactic strategy

Antibiotic prophylaxisAntibiotic prophylaxisAfebrile neutropenic patientsAfebrile neutropenic patientsReduce frequency of febrile episodes by Reduce frequency of febrile episodes by

administration of (broad spectrum) Ax:administration of (broad spectrum) Ax:

But potential deleterious effects:But potential deleterious effects:ToxicityToxicityEmergence of antibiotic resistant bacteria Emergence of antibiotic resistant bacteria

(FQ)(FQ)Fungal overgrowthFungal overgrowth

Bucaneve NEJM 2005 353:977-87Bucaneve NEJM 2005 353:977-87

760 adult patients760 adult patients 500 mg Levofloxacin vs placebo for neutropenia500 mg Levofloxacin vs placebo for neutropenia

Febrile episode Febrile episode

All treated: 65 vs 85% (ADR -0.20; -0.26 to -0.14)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)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)Solid tumours / lymphoma: 62 vs 84%, (-0.22, -0.29 to -0.12)

Death Death

All treated: 3 vs 5 % (ADR -0.02, -0.05 to 0.005)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)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)Solid tumours / lymphoma: 1 vs 3%, (-0.02; -0.05 to 0.004)

Cullen 2005 NEJM 2005 353:988-98Cullen 2005 NEJM 2005 353:988-98

1565 patients, cyclic chemotherapy for solid tumours / 1565 patients, cyclic chemotherapy for solid tumours / lymphoma (13%)lymphoma (13%)

500 mg Levofloxacin vs placebo for 7 days 500 mg Levofloxacin vs placebo for 7 days

Febrile episode first cycle: 3.5% vs 7.5% (p<0.001)Febrile episode first cycle: 3.5% vs 7.5% (p<0.001) Over entire course: 10.8 % vs 15.2% (p=0.01)Over entire course: 10.8 % vs 15.2% (p=0.01) Hospitalisation 15.7 vs 21.6% (p=0.004)Hospitalisation 15.7 vs 21.6% (p=0.004) Severe infection 1 vs 2.0 % (NS)Severe infection 1 vs 2.0 % (NS)

Each group: four infection related deaths.Each group: four infection related deaths.

Gafter-Gvili 2006, Cochrane reviewGafter-Gvili 2006, Cochrane review

101 trials, 12599 patients: 1973-2005101 trials, 12599 patients: 1973-2005

Infection related deathsInfection related deathsRR 0.59 (0.47-0.75)RR 0.59 (0.47-0.75)

Fever occurrenceFever occurrenceRR 0.77 (0.74 – 0.81)RR 0.77 (0.74 – 0.81)

All cause mortality (quinolone)All cause mortality (quinolone)RR 0.52 (0.37 – 0.74)RR 0.52 (0.37 – 0.74)

Antibiotic resistanceAntibiotic resistance

Infecting organismsInfecting organisms Individual patientIndividual patient Unit / HospitalUnit / Hospital CommunityCommunity

““Collateral” Collateral” MRSA, MRSA, C difficileC difficile

(Reduced use of other antibiotics)(Reduced use of other antibiotics)

(Cost)(Cost)

Treatment strategy: oral regimensTreatment strategy: oral regimens

MRSAMRSARisk with fluoroquinolones.Risk with fluoroquinolones.

MRSA usually resistant to fluoroquinolonesMRSA usually resistant to fluoroquinolonesGood skin tissue penetration / excreted in human Good skin tissue penetration / excreted in human

sweat: sweat: Loss of colonisation resistance by normal skin floraLoss of colonisation resistance by normal skin flora

In vitro: In vitro: Induction of fibronectin – binding proteinsInduction of fibronectin – binding proteinsIncreased adhesion by quinolone resistant Increased adhesion by quinolone resistant S aureusS aureus

Bisognano 2000, Paterson 2004Bisognano 2000, Paterson 2004, ,

Multiple logistic regression analysis, factors associated with Multiple logistic regression analysis, factors associated with MRSA infectionMRSA infection

Graffunder 2002Graffunder 2002

Risk factorRisk factor OROR 95% CIs95% CIs P valueP value

LevofloxacinLevofloxacin 8.018.01 3.15, 20.33.15, 20.3 <0.001<0.001

MacrolidesMacrolides 4.064.06 1.15, 14.41.15, 14.4 0.030.03

Enteral feedingEnteral feeding 2.552.55 1.37, 4.721.37, 4.72 0.0030.003

SurgerySurgery 2.242.24 1.19, 4.221.19, 4.22 0.010.01

Previous Previous hospitalisationhospitalisation

1.951.95 1.02, 3.761.02, 3.76 0.040.04

LOS before LOS before cultureculture

1.031.03 1.0, 1.071.0, 1.07 0.050.05

NCCN 2012:NCCN 2012: Fever & Neutropenic risk category: LOWFever & Neutropenic risk category: LOW Standard chemotherapy regimens for most solid Standard chemotherapy regimens for most solid

tumourstumours Anticipated neutropenia less than 7 daysAnticipated neutropenia less than 7 days

Prophylaxis: Prophylaxis:

Bacterial: Bacterial: NONENONE

Fungal:Fungal: NoneNone

Viral:Viral: None unless prior HSV None unless prior HSV episodeepisode

Fever & Neutropenic risk category: Fever & Neutropenic risk category: Intermediate / HighIntermediate / High

Prophylaxis: Prophylaxis:

Bacterial: Bacterial: ConsiderConsider FQ prophylaxis FQ prophylaxis

CG151:CG151:Adult patients with acute leukaemias, stem Adult patients with acute leukaemias, stem

cell transplants or solid tumours in whom cell transplants or solid tumours in whom significant neutropenia (\< 0.5x10significant neutropenia (\< 0.5x109 9 /L) is an /L) is an anticipated consequence of chemotherapyanticipated consequence of chemotherapy

Offer prophylaxis with fluoroquinolone during Offer prophylaxis with fluoroquinolone during expected period of neutropenia only.expected period of neutropenia only.

[No mention of any different action if known [No mention of any different action if known FQ resistant, or FQ contra-indicated].FQ resistant, or FQ contra-indicated].

[No mention of specific oral options for FNE [No mention of specific oral options for FNE whilst on FQ prophylaxis – initial or s/down] whilst on FQ prophylaxis – initial or s/down]

……CG151 still being assessed LTHT / YCNCG151 still being assessed LTHT / YCN

β-lactam resistance in Enterobacteriaceae:β-lactam resistance in Enterobacteriaceae:Enzyme mediated: β-lactamasesEnzyme mediated: β-lactamases

(Ancient heritage: > 2 billion years old)(Ancient heritage: > 2 billion years old) Serine residue active site; or metalloenzymes (Zinc ion) Serine residue active site; or metalloenzymes (Zinc ion)

Inherent – gene carried on bacterial chromosomeInherent – gene carried on bacterial chromosome ““De-repressed”: e.g. De-repressed”: e.g. Enterobacter, Citrobacter Enterobacter, Citrobacter speciesspecies

Acquired – transmissible genetic elements: plasmidsAcquired – transmissible genetic elements: plasmids E.g. E.g. Klebsiella pneumoniae, E coliKlebsiella pneumoniae, E coli

Vary in ability to hydrolyse different β-lactams:Vary in ability to hydrolyse different β-lactams:Some drug structures more resilient than others.Some drug structures more resilient than others.Some blocked by β-lactamase inhibitors Some blocked by β-lactamase inhibitors

clavulanic acid (co-amoxiclav), tazobactam (with clavulanic acid (co-amoxiclav), tazobactam (with piperacillin)piperacillin)

Various classifications / name derivations Various classifications / name derivations

3 letter monikers for families:3 letter monikers for families: SHV (>50): Variable response to sulfhydryl inhibitorsSHV (>50): Variable response to sulfhydryl inhibitors TEM (>130): After patient (Temoneira)TEM (>130): After patient (Temoneira) CTX-M (>40), OXA, IMP:CTX-M (>40), OXA, IMP:

Ability to hydrolyse cefotaxime, oxacillin, imipenem Ability to hydrolyse cefotaxime, oxacillin, imipenem

VIM: Verona integron encoded metallo-VIM: Verona integron encoded metallo-ββ-lactamase-lactamase KPC: KPC: Klebsiella pneumoniae Klebsiella pneumoniae carbapenemasecarbapenemase

New York / US.New York / US.

NDM: New Delhi metallo-NDM: New Delhi metallo-ββ-lactamase-lactamaseJacoby Jacoby

2005; 2005;

NDM-1:NDM-1:First detected United Kingdom January 2008.First detected United Kingdom January 2008.Now predominant carbapenem-hydrolysing enzyme in Now predominant carbapenem-hydrolysing enzyme in

Enterobacteriaceae in UK (44% 2009)Enterobacteriaceae in UK (44% 2009)2008 – 2009: 37 isolates2008 – 2009: 37 isolates

K pneumoniae K pneumoniae (21)(21), E coli , E coli (7)(7), Enterobacter , Enterobacter spp spp (5)(5), , Citrobacter freundii Citrobacter freundii (2(2), Morganella ), Morganella (1)(1), Providencia , Providencia (1)(1)

29 patients – 15 in urine 29 patients – 15 in urine

ESBLs widespread in India,ESBLs widespread in India,NDM-1 also in isolates in north & south IndiaNDM-1 also in isolates in north & south IndiaLinks between many of the UK patients and IndiaLinks between many of the UK patients and India

Kumaraswamy 2010; HPAKumaraswamy 2010; HPA

ESBLs: ESBLs: carbapenemcarbapenem

Carbapenemase producingCarbapenemase producingTigecyclineTigecyclinePolymyxin (colistin)Polymyxin (colistin)??

Possible local choices outside the boxPossible local choices outside the box

Yorkshire & Humber: E coli surveillance data, 2010 -2012Yorkshire & Humber: E coli surveillance data, 2010 -2012792 isolates, 14 hospital trusts (courtesy of HPA)792 isolates, 14 hospital trusts (courtesy of HPA)

8% = ES8% = ESββL producersL producers

0.1% = carbapenemase producer0.1% = carbapenemase producer

““Other” optionsOther” options (Co-trimoxazole)(Co-trimoxazole) Intramuscular gentamicinIntramuscular gentamicin

Urinary catheter changeUrinary catheter change

““usually” sensitive usually” sensitive in vitroin vitro::

Nitrofurantoin (lower UTI, eGFR Nitrofurantoin (lower UTI, eGFR >> 60ml/m) 60ml/m)

Pivmecillinam Pivmecillinam

MecillinamMecillinam Beta lactam (6-Beta lactam (6-ββ-amidinopenicillanic acid)-amidinopenicillanic acid) Pivmecillinam Pivaloyloxymethyl ester: Pivmecillinam Pivaloyloxymethyl ester:

Much more active vs Gram negativesMuch more active vs Gram negatives (Enterococci resistant, (Enterococci resistant, S saprophyticus S saprophyticus may be inhibited)may be inhibited)

EnterobacteriaceaeEnterobacteriaceae

Usual suspects more tricky:Usual suspects more tricky: P aeruginosa, Acinetobacter P aeruginosa, Acinetobacter spp, anaerobes: resistantspp, anaerobes: resistant Serratia marcescensSerratia marcescens: usually resistant: usually resistant M morganiiM morganii, , Providencia Providencia spp may be sensitivespp may be sensitive

(Paradoxical effect with (Paradoxical effect with P stuartiiP stuartii))

P mirabilis, P vulgarisP mirabilis, P vulgaris: usually sensitive: usually sensitive

Uses: Urinary tract infectionsUses: Urinary tract infections LowerLower (Upper – step down oral therapy).(Upper – step down oral therapy). ((Other MDR coliforms: e.g. Biliary))((Other MDR coliforms: e.g. Biliary))

Advantages:Advantages: High % still susceptible (> 90% global)High % still susceptible (> 90% global) Low Low C difficile C difficile propensitypropensity

““Avoid” if penicillin allergyAvoid” if penicillin allergy (tho’ hypersensitivity reactions uncommon)(tho’ hypersensitivity reactions uncommon)

……NB: Avoid treating “asymptomatic NB: Avoid treating “asymptomatic bacteriuria” (catheterised or non-bacteriuria” (catheterised or non-catheterised) in adults.catheterised) in adults.

Increase resistanceIncrease resistanceLoss of oral options.Loss of oral options.

““Good” bacteriaGood” bacteriaEnterococciEnterococci

Respiratory tract bacterial pathogensRespiratory tract bacterial pathogensAWARE surveillance, US, 2008-10AWARE surveillance, US, 2008-10

Adapted from Pfaller 2012Adapted 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 Doxycycline may also protect against development of development of C difficileC difficile infection infection

US study comparing ceftriaxone +/- doxycyclineUS study comparing ceftriaxone +/- doxycycline > 2300 patients studied> 2300 patients studied

1.67 / 10000 patient days vs 8.11 / 100001.67 / 10000 patient days vs 8.11 / 10000Rate of CDI 27% lower for each day of receiptRate of CDI 27% lower for each day of receipt

HR 0.73, 95% CI 0.56 – 0-.96HR 0.73, 95% CI 0.56 – 0-.96

Doernberg 2012Doernberg 2012

..NB these organisms (and ..NB these organisms (and S aureus et alS aureus et al) ) can be normal upper respiratory tract can be normal upper respiratory tract commensal flora.commensal flora.

Adjudge “positive” microbiology results in Adjudge “positive” microbiology results in conjunction with current clinical / conjunction with current clinical / radiological findings. radiological findings.

S aureusS aureus, AWARE surveillance, US, 2008-10, AWARE surveillance, US, 2008-10

Adapted from Farrell 2012Adapted 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 cathetersLong-term intravascular catheters

Long term catheters should be removed Long term catheters should be removed for patients with CRBSI associated for patients with CRBSI associated with:with:Severe sepsisSevere sepsisSuppurative thrombophlebitisSuppurative thrombophlebitisEndocarditisEndocarditisBSI that continues despite > 72 hours BSI that continues despite > 72 hours

suitable antimicrobial therapysuitable antimicrobial therapy Infections due to Infections due to S. aureus, P aeruginosaS. aureus, P aeruginosa, ,

fungi or mycobacteriafungi or mycobacteria

IDSA, Mermel 2009IDSA, Mermel 2009

S aureus S aureus ; removal, unless major contra-; removal, unless major contra-indications; e.g.indications; e.g.

No alternative venous accessNo alternative venous access

Significant bleeding diathesisSignificant bleeding diathesis

Quality of life issues take priority over Quality of life issues take priority over need for re-insertion of a new catheter need for re-insertion of a new catheter at a different siteat a different site

If retain: four weeks therapy, systemic + If retain: four weeks therapy, systemic + lock therapy.lock therapy.

Uncomplicated CRBSI involving long-Uncomplicated CRBSI involving long-term catheters due to [other] pathogensterm catheters due to [other] pathogens

Attempt treatment without catheter Attempt treatment without catheter removal:removal:Systemic and antimicrobial lock therapySystemic and antimicrobial lock therapy

Administer both for 7 – 14 daysAdminister both for 7 – 14 days

..If multiple positive catheter-drawn ..If multiple positive catheter-drawn blood cultures with coagulase – blood cultures with coagulase – negative staphylococci or Gram – negative staphylococci or Gram – negative bacilli, but concurrent negative negative bacilli, but concurrent negative peripheral blood cultures: can give lock peripheral blood cultures: can give lock therapy without systemic therapy for 10 therapy without systemic therapy for 10 – 14 days.– 14 days.

Vancomycin: at least 1000x higher than Vancomycin: at least 1000x higher than organism MIC (e.g. 5 mg/ml)organism MIC (e.g. 5 mg/ml)

Other locksOther locksGentamicinGentamicin

Taurolidine (TauroLockTaurolidine (TauroLock®®))Broad spectrum antimicrobialBroad spectrum antimicrobialUnique site of action / no cross resistanceUnique site of action / no cross resistanceSpontaneously breaks down.Spontaneously breaks down.

Lock therapy:Lock therapy:14 days in total14 days in total?Alternating lumens 24 hourly in hospital & ?Alternating lumens 24 hourly in hospital &

access neededaccess neededDwell time up to one weekDwell time up to one weekRepeat luminal blood cultures post completionRepeat luminal blood cultures post completion

48 – 72 hours48 – 72 hours

Clostridium difficileClostridium difficileDiagnosisDiagnosis

Now two stage testing process:Now two stage testing process:Initial: GDHInitial: GDHIf positive: toxin test.If positive: toxin test.

Treatment (..if indicated; also review PPIs)Treatment (..if indicated; also review PPIs)

Metronidazole: “non-severe”Metronidazole: “non-severe”

Vancomycin: “severe”: colitis; WCC >15, AKIVancomycin: “severe”: colitis; WCC >15, AKI

(Fidaxomycin)(Fidaxomycin)

Infection Prevention:Infection Prevention:

Hand washing with soap & waterHand washing with soap & water

..Improve speeds of other diagnoses..Improve speeds of other diagnosesAetiology; Aetiology; in vitroin vitro susceptibilities susceptibilities

Bacteriological methods long-standing, Bacteriological methods long-standing, but:but:Direct to specimens: PCR / NAAT Direct to specimens: PCR / NAAT

blood, sterile sitesblood, sterile sites

Organism identification: MALDI-TOFOrganism identification: MALDI-TOFMatrix-Assisted Laser Desorption Ionisation Time Matrix-Assisted Laser Desorption Ionisation Time

of Flight Mass Spectroscopy: bacteria / yeastsof Flight Mass Spectroscopy: bacteria / yeasts……expect more “unheard of” species names expect more “unheard of” species names

Rapid automated sensitivity testing (< 12 Rapid automated sensitivity testing (< 12 hours), [EUCAST]. hours), [EUCAST].

Fungal:Fungal:

ProphylaxisProphylaxis

EmpiricEmpiricFever in neutropenic patient unresponsive to broad Fever in neutropenic patient unresponsive to broad

spectrum antibioticsspectrum antibiotics

““Pre-emptive”: suspicion of IFIPre-emptive”: suspicion of IFI

Targeted treatment – proven / probableTargeted treatment – proven / probable

CandidaCandidaCandida albicansCandida albicansNon Non C albicansC albicans:: C kruseiC krusei

C glabrataC glabrataAspergillus Aspergillus sppspp

Aspergillus fumigatusAspergillus fumigatus

ZygomycetesZygomycetesMucorMucor, , RhizopusRhizopus, ,

Amphotericin BAmphotericin B Lipid formulations – ambisome, (abelcet, amphocil)Lipid formulations – ambisome, (abelcet, amphocil)

AzolesAzoles FluconazoleFluconazole ItraconazoleItraconazole VoriconazoleVoriconazole PosaconazolePosaconazole

EchinocandinsEchinocandins CaspofunginCaspofungin MicafunginMicafungin AnidulafunginAnidulafungin

Changing criteria for diagnosisChanging criteria for diagnosis De Pauw 2008: EORTC / MSG revised definitions of Invasive De Pauw 2008: EORTC / MSG revised definitions of Invasive

Fungal Disease [for trial use]Fungal Disease [for trial use]

Host factors:Host factors: Recent neutropaenia (<0.5 for > 10 days)Recent neutropaenia (<0.5 for > 10 days) Allogeneic stem cell transplant receiptAllogeneic stem cell transplant receipt Prolonged use corticosteroid (mean minimum: equivalent 0.3mg/kg/d, > Prolonged use corticosteroid (mean minimum: equivalent 0.3mg/kg/d, >

3 weeks) 3 weeks) Other recognised T cell immunosuppressants:Other recognised T cell immunosuppressants:

eg cyclosporin, alemtuzumab (CamPath) eg cyclosporin, alemtuzumab (CamPath)

Clinical criteriaClinical criteria Lower respiratory tract disease: 1 out of 3 defined HRCT signs.Lower respiratory tract disease: 1 out of 3 defined HRCT signs. Sinonasal infectionSinonasal infection

Sinusitis on imaging + Sinusitis on imaging + > > 1 sign of eg acute localised pain, nasal ulcer + black 1 sign of eg acute localised pain, nasal ulcer + black eshareshar

Mycological criteria:Mycological criteria: Direct tests: microscopy / culture,Direct tests: microscopy / culture, Indirect tests: Aspergillus antigenIndirect tests: Aspergillus antigen

““Proven”, “probable”, “possible”Proven”, “probable”, “possible”

Pre-emptivePre-emptive (“Suggestive”) Evidence of IFI:(“Suggestive”) Evidence of IFI:

Galactomannan - Galactomannan - AspergillusAspergillus BloodBlood BAL.BAL.

ΒΒ – glucan – glucan

High Resolution chest CTHigh Resolution chest CT Dense, well-circumscribed lesion(s) +/- halo signDense, well-circumscribed lesion(s) +/- halo sign Air-crescent signAir-crescent sign Cavity.Cavity.

Halo signHalo sign

Air crescent signAir crescent sign

Aspergillus Aspergillus microscopymicroscopy

Colonies of Colonies of Aspergillus fumigatusAspergillus fumigatus

Treatment – ongoing – azolesTreatment – ongoing – azolesAspergillosis: voriconazoleAspergillosis: voriconazole

More exotic moulds: posaconazoleMore exotic moulds: posaconazole

……trough levels.trough levels.

Conclusions:Conclusions:Antimicrobial stewardshipAntimicrobial stewardship

Start Smart – then Focus.Start Smart – then Focus.

Increasing antimicrobial resistance – Gram Increasing antimicrobial resistance – Gram negatives.negatives.

Review Microbiology results in conjunction Review Microbiology results in conjunction with other current information.with other current information.

Antimicrobial guidelines on intranet individual Antimicrobial guidelines on intranet individual cases - Microbiology advice.cases - Microbiology advice.