Acute Medicine Training Day

3rd Apirl, 2014

Dr Julian SuttonConsultant in Infectious Diseases and Medical Microbiology

Case 1

• 30M, IT worker• PMH: Asthma & Severe eczema• Prednisolone 10mg OD & Methotrexate

• 2 days: Fever, chills, headache• 1 day: Vomiting, neck stiffness, worsening severity headache

• T38.2, P110, BP 115/75, Sats 97%

• Hb 156, Wbc 13.8, nø 12.8, lø 0.4, Plt 150• U+E normal, alb 35, bili 16, ALT 74, ALP 106, CRP341

Case 1

Case 1

• Blood cultures taken• Commenced on CNS dose Cefotaxime, Amoxicillin, Aciclovir• Urinalysis ++ protein, +++ ketones, +++ blood• CT brain without contrast…..

Case 1

• Small lateral and 3rd ventricles

• Global effacement of cerebral sulci

• Exaggerated grey/white matter differentiation c/w diffuse oedema

• Cerebellar tonsils extend into but not through the foramen magnum

• Conclusion: diffuse brain swelling c/w meningitis or meningoencephalitis

• D/w Neurosurgery if considering LP

Case 1• Admission blood cultures, gram positive cocci, both bottles at 24hrs • R/v by Infection team• Small ulcer on tongue• No splinters, possible vascultic lesion L hand, loud PSM• Alert and orientated, no meningism

• Imp: features c/w meningoencephalitis in IC’d host• Need to exclude Infective endocarditis (though headache and cerebral oedema

not explained by uncomplicated IE)

• Urgent echocardiogram• MRI brain w contrast• Neurology r/v re ability to perform LP• BC, EDTA blood for pneumococcal & meningococcal PCR, urine pneumococcal ag,

serum CrAg, HIV test

Case 1• Echocardiogram

– 1.2cm x 1cm mobile structure on post MV leaflet– Mild / Moderate MR– Normal bi-ventricular function

• Following day BCs confirmed as S. aureus (MSSA)• CNS dose cefotaxime continued• Amoxicillin and Aciclovir stopped• MR brain w contrast awaited….

• Pneumococcal & meningococcal PCR on blood negative• HSV, VZV and Enterovirus PCR on mouth ulcer negative• HIV negative, serum CrAg negative

Case 1

Case 1

Case 1

• lesions in the left side of the corpus callosum.

• right parietal white matter

• both lesions show modest peripheral enhancement

• no additional parenchymal, meningeal or dural enhancement

• cerebellar tonsils not low lying, cortical sulci not effaced

Case 1• Rifampicin 600mg BD added day 10• Minimum of 4 weeks iv antibiotics

• LP performed day 14 admission• N opening pressure, • CSF WBC 222 (44% polymorphs, 56% mononuclear) • CSF RBC 17• CSF/serum Glucose 4.2/6.0• CSF protein 984 mg/L (0-500)

• Diagnosis: MSSA MV IE with meningoencephalitis and embolic cerebral abscesses

• MV repair after 4 weeks iv antibiotics• Excellent recovery. Completed 6weekss antibiotics

The ARREST trial

Adjunctive Rifampicin to Reduce Early mortality from STaphylococcus aureus

bacteraemia: a multi-centre, randomised, blinded, placebo controlled trial

United Kingdom Clinical Infection Research Group

UKCIRG

Hypotheses:

1) There is a population of bacteria, in blood and/or infected tissues, which is relatively ‘resistant’ to killing by standard antibiotics (beta-lactams/glycopeptides).

2) Antibiotics with enhanced penetration and activity within cells, tissues and biofilms, will enhance killing of S. aureus early in the course of antibiotic treatment, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death.

Co-primary outcome measures

1. All-cause mortality up to 14 days

2. Death or microbiologically confirmed treatment failure or disease recurrence up to 12 weeks from randomisation

Microbiologically confirmed treatment failure is:(1)symptoms and signs of infection ongoing for longer than 14 days from randomisation AND (2) the isolation of same strain of S. aureus (confirmed by genotyping) from either blood or another sterile site (e.g. joint fluid, pus from tissue) indicating blood-born dissemination of the bacteria

Microbiologically confirmed disease recurrence:

the isolation of the same strain of S. aureus from a sterile site after >7 days of apparent clinical improvement

Study design

Parallel group, randomised (1:1), blinded, placebo-controlled multi-centre trial

Standard IV antibiotic ‘backbone’ + 14 days placebo

VsStandard IV antibiotic ‘backbone’

+ 14 days rifampicin

12-week follow-up• Doses

<60kg: 600mg rifampicin OD for 14 days≥60kg: 900mg rifampicin OD for 14 days

Inclusion criteria

• Adults (18 years or older) • Staphylococcus aureus (meticillin-susceptible or resistant)

grown from at least one blood culture

• Less than 96 hours of active* antibiotic therapy for the current infection, not including rifampicin

• Patient or legal representative (LR) provides written informed consent

* Defined by in vitro susceptibility testing

Exclusion criteria• Infection not caused by S. aureus alone in the opinion of the infection

specialist (e.g. S. aureus is considered a blood culture contaminant, or polymicrobial culture with another organism likely to be contributing clinically to the current infection)

• Sensitivity results already available and demonstrate rifampicin resistant S. aureus

• Infection specialist, in consultation with the treating physician, considers rifampicin is contraindicated for any reason

• Infection specialist, in consultation with the treating physician, considers rifampicin treatment is mandatory for any reason

• Infection specialist suspects active infection with Mycobacterium tuberculosis• Previously been randomised in ARREST for a prior episode of S. aureus

bacteraemia

The aim

Screen Consent Randomise Start study drug

11.00hrs 1400hrs 15.00hrs 16.00hrs

Complete within 6 hours

Lab result:

S. aureus in

Blood cultureVisit patient

< 96 hours of active treatment

S. aureus bacteraemia at Southampton,2006-2012

  COMMUNITY HOSPITAL

Year Resistant SensitiveTotal Community Acquired Isolates

% of Community

Isolates Resistant to Rifampicin

Resistant SensitiveTotal Hospital

Acquired Isolates

% of Hospital Acquired Isolates

Resistant to Rifampicin

MRSA

2006 0 18 18 0% 2 51 53 4%

2007 0 10 10 0% 0 30 30 0%

2008 0 3 3 0% 0 13 13 0%

2009 0 4 4 0% 0 4 4 0%

2010 0 4 4 0% 0 7 7 0%

2011 0 6 6 0% 1 2 3 33%

2012 0 4 4 0% 0 1 1 0%

Mean Resistance         0%       5%

MSSA

2006 0 40 40 0% 0 68 68 0%

2007 1 47 48 2% 0 53 53 0%

2008 0 44 44 0% 0 40 40 0%

2009 0 37 37 0% 0 22 22 0%

2010 1 50 51 2% 0 25 25 0%

2011 0 56 56 0% 0 23 23 0%

2012 1 55 56 2% 0 31 31 0%

Mean Resistance         1%       0%

Combined MRSA & MSSA

2006 0 58 58 0% 2 119 121 2%

2007 1 57 58 2% 0 83 83 0%

2008 0 47 47 0% 0 53 53 0%

2009 0 41 41 0% 0 26 26 0%

2010 1 54 55 2% 0 32 32 0%

2011 0 62 62 0% 1 25 26 4%

2012 1 59 60 2% 0 32 32 0%

Mean Resistance       

1%       1%

2012: n=92 S. aureus bacteraemias

64% were community-acquired, 87 MSSA, 5 MRSA

Trial duration

• 4 years funding. July 1st 2012 to June 31st 2016

• Expected recruitment duration: 3 years• October/November 2012 to November 2015• Approval for UHS to begin recruitment due April 2014• UHS Consultant for patient will be contacted for permission to

approach patient to gain consent for entry into the trial

Acute sepsis

Each hour of delay in antimicrobial administration over the 6 hrs following onset of hypotension was associated with an average decrease in survival of 7.6%.

Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596

Acute sepsis

Is there sepsis, severe sepsis or septic shock?

• Systemic Inflammatory Response Syndrome (SIRS). 2 or more = SIRS

– Temp >38°C or < 36°C– Heart Rate > 90 bpm– Respiratory Rate > 20 breaths/min– WBC > 12 or < 4x109/L– Acutely altered mental status– Hyperglycaemia (glucose >6.6 mmol/L) (unless diabetic)

– Are there symptoms or signs suggestive of new infection?– SIRS + evidence of infection = sepsis

Is there sepsis, severe sepsis or septic shock?

• Severe sepsis screen:– Any of the following present and new to the patient?

– SBP <90 or mean < 65mmHg

– New or increased O2 requirement to maintain SpO2 >90%

– Creatinine >180 umol/L or UO <0.5ml/kg/hour for 2 hours– Bilirubin >34 umol/L – Platelets <100 x109/L– Lactate > 2 mmol/L– Coagulopathy: INR >1.5 or APTT>60s

Is there sepsis, severe sepsis or septic shock?

• Severe sepsis diagnosed – Sepsis 6:– 1. Oxygen 100%

– 2. Blood Cultures– 3. IV antibiotics– 4. Fluids– 5. Measure lactate and Hb– 6. Urinary catheter and monitor UO

– Must check all relevant past Microbiology results – e.g. previous ESBL infection, MRSA colonisation

– Consult specialist in Infection - Microbiology/Infectious Diseases– Piperacillin/tazobactam 4.5g qds– Meropenem if non-severe penicillin allergy– Add Vancomycin if high risk for invasive MRSA infection

Is there sepsis, severe sepsis or septic shock?

• Septic shock screen:– Severe Sepsis with Hypotension, despite adequate

fluid resuscitation or lactate >4 mmol/L

– Sepsis 6 PLUS….– Add Gentamicin 3-5mg/kg– Consider antifungal– Refer for vasopressor support

Is there sepsis, severe sepsis or septic shock?

To diagnose Severe Sepsis patients must reach all three of the following criteria. Follow top of guideline overleaf.

1. Known infection or clinical evidence suggestive of infection

2. Meet 2 or more of SIRS criteria?

Tachycardia ≥90

RR> 20 or PaCO2 <4.3

WCC >10 or <4

Temp ≤36 or ≥38

3. Evidence of end organ hypo-perfusion

Systolic BP <90 or MAP <65

Cr >180 or U/O <0.5ml/kg for 2 hours

Lactate >2

Bili > 35, Plt < 100, SpO2 <90%, Acute confusion

If your patients meets all three criteria they have Severe Sepsis.

If they are fluid therapy resistant, then they have Septic Shock

To diagnose Severe Sepsis patients must reach all three of the following criteria. Follow top of guideline overleaf.

1. Known infection or clinical evidence suggestive of infection

2. Meet 2 or more of SIRS criteria?

Tachycardia ≥90

RR> 20 or PaCO2 <4.3

WCC >10 or <4

Temp ≤36 or ≥38

3. Evidence of end organ hypo-perfusion

Systolic BP <90 or MAP <65

Cr >180 or U/O <0.5ml/kg for 2 hours

Lactate >2

Bili > 35, Plt < 100, SpO2 <90%, Acute confusion

If your patients meets all three criteria they have Severe Sepsis.

If they are fluid therapy resistant, then they have Septic Shock

Audit of implementation of the sepsis 6 at UHS Mamadou Jallow, Pre-registration Pharmacist

Kieran Hand, Consultant Pharmacist

• Aim to identify patients with severe sepsis and septic shock and evaluate whether sepsis six interventions are implemented in a timely manner

• CCOT database searched from October 2011 to September 2012 for patients with a systolic blood pressure (≤90mmHg) and a body temperature of >38.3C or <36C to identify patients with potential severe sepsis

• Case notes reviewed

Audit of implementation of the sepsis 6 at UHS

% of patients given IV Antibiotics

< 1 hour

79%

21%

Implemented < 1hour

Implementedbetween 1-6 hoursafter onset

Audit of implementation of the sepsis 6 at UHS

Audit of implementation of the sepsis 6 at UHS

E. coli resistance rates in UHS inpatient urine samples 2008 – 2013

Initial Empiric antibiotic therapy

• Is there severe sepsis or septic shock?

• What is the source of infection?– Respiratory tract / urinary tract / SSTI / intra-abdominal / CNS /

uncertain

• For sepsis of uncertain chest and/or urinary origin, combine treatments for RTI and UTI, and if meets criteria for severe sepsis, ensure gentamicin is included, if no renal failure

• Empiric therapy must take account of relevant recent Microbiology results

Initial Empiric antibiotic therapy

• Have relevant urgent investigations been done?– Blood culture– Urine culture

– EDTA blood for meningococcal/pneumococcal PCR– CSF– Sputum / bacterial throat swab / viral throat swab– Wound swabs if appropriate

• Guidelines are there to help promote patient safety but use intelligently – If in doubt consult with an Infection specialist

Case 2: ‘A case of urinary sepsis’

• 76M NH resident, COPD, AF, schizophrenia• Previous CAUTIs• Dysuria and constipation• Hb 124, WBC 20, Plts 87, U 20.2, Creat 181, CRP 181,

lactate 1.3• Afebrile, nomotensive

• Commenced on empiric iv gentamicin

• Blood cultures – not done on admission• 1st Urine culture – not processed• Severe sepsis not recognised• Previous gentamicin – resistant E. coli in urine within the last

6 months

• Delayed (day 3 of admission) blood culture – Group B Streptococcus

Case 2: ‘A case of urinary sepsis’

Potential harm caused by antimicrobials…

• Adverse drug reaction

• Selection pressure for resistant organisms– Particularly within the hospital environment

• Risk factor for C. difficile infection (CDI)

Antimicrobial stewardship – ‘start smart then focus’

UHS: monthly C. difficile cases 2007 - 2010

SUHT Number of C. difficile Cases (>2 Yrs) Including SHA Trajectory

1410

56

13

6361

64

57

46

56

38

31

3734

9

29

2023

2725 25

28

15

2219

2225

38

1713

8 8 712 10

0

10

20

30

40

50

60

70

Ap

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7

Ma

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7

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7

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7

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8

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SUHT SHA Trajectory

UHS: monthly C. difficile cases 2012 - 2013

SUHT C.diff cases 2012/13 (As per HPA Definition)

30

5

1

44

6

332

33

0

2

4

6

8

10

12

14

16

April May June July August September October November December January February March

No

of C

ases

SUHT Target

Community C.diff cases 2012/13 (As per HPA Definition)

45

3

98

13

16

10

4

11

5

0

2

4

6

8

10

12

14

16

April May June July August September October November December January February March

No

of C

ases

Community

2012/13 Qtr 1 Qtr 2 Qtr 3 Qtr 4Target 15 12 8 11Actual 8 12 11 6

• Section A – intended for use by frontline staff in acute healthcare settings.

• Section B – intended for use and consideration during the planning and implementation phases at board / executive level.

• Section C – intended for risk assessment and public information

• Section D – Glossary

Antimicrobial stewardship – ‘start smart then focus’

Countries and regions with reported high prevalence of healthcare-associated carbapenemase-producing

Enterobacteriaceae

UK NRL-confirmed carbapenemase producing Enterobacteriaceae

43AMRHAI unpublished data

Early cases often imported

Imported & ‘home grown’

No.

of

isol

ates

No. of labs referring carbapenemase-producing Enterobacteriaceae to AMRHAI

AMRHAI unpublished data

Occurrence of carbapenemase-producing Enterobacteriaceae (CPE) (all types of isolates) based on self-assessment by national experts, EuSCAPE project, 38

European countries, March 2013

http://www.ecdc.europa.eu/en/eaad/Documents/EuSCAPE-summary-CPE-CRA.pdf

Acute trust – patient admission flow chart for infection prevention and control (IP&C) of carbepenemase-producing Enterobacteriaceae

Early recognition of individuals who may be colonised / have an infection.

• IN THE LAST 12 MONTHS HAS THE PATIENT: • Been an inpatient in a hospital abroad • OR • Been an inpatient in a UK hospital known to have had problems with spread of

carbapenemase-producing Enterobacteriaceae • OR • Previously been colonised or had an infection with carbapenemase-producing

Enterobacteriaceae or close contact (see glossary) with a person who has, if known

• If one or more of above applies then: • The patient is considered to meet the criteria for being a suspected case of

carbapenemase-producing Enterobacteriaceae colonisation or infection (as applicable)

• AND REQUIRES IMMEDIATE ISOLATION, PLUS: • instigation of strict standard precautions to prevent possible spread • screening to assess current status for colonisation or infection• assessment for appropriate treatment (applies to infection only)

Risk Assessment

Summary

• Good antimicrobial stewardship is part of the process to optimise patient care and reduce risk of harm requiring….

– Clinical judgment– Sending appropriate diagnostic tests– Review of relevant previous information – Microbiology results

• There are signifiant threats to our ability to Rx serious infectons including CPE