THE ANTIMICROBIAL ARMS RACE

GETTING THE LAUNCH CODES RIGHT

Department of

Intensive Care MedicineRoyal Brisbane Hospital University of Queensland

Professor Jeffrey Lipman

Duration of hypotension prior to effective antimicrobial therapy: impact

on survival in septic shock

Kumar et al. Crit Care Med 2006;34:1589–96

Time of first dose of antibiotics after the onset of shock (hours)

0–30′

100

80

60

40

20

0

Mor

tailt

y (%

)

30′–1h 1–2 2–3 3–4 4–5 5–6 6–9 9–12 12–24 24–36 >36

GETTING THE LAUNCH CODES RIGHT

STRUCTURE The “BAD” effects of antibiotics

ie collateral damageLack of good infection definitions

eg Diagnosis of line related infection (amongst others)

Lack of sensitive biomarker ie how do you know when to start

BOWEL BACTERIAL LOAD

MORE BACTERIA IN/ON OUR BODY THAN CELLS

10 quadrillion cells 100 quadrillion bacterial

cells

ANTIBIOTICS KILL BACTERIA, BUT NOT ALL

The main risk factor for IR-GNB colonization was prior imipenem exposure. The odds ratio for colonization was already as high as 5.9 (95% confidence interval [95% CI], 1.5 to 25.7) after 1 to 3 days of exposure and increased to 7.8 (95% CI, 2.4 to 29.8). In conclusion, even brief exposure to imipenem is a major risk factor for IR-GNB carriage.

after 1 to 3 days of exposure

Kritsotakis et al J Antimicrob Chemother 2011;66:1383-91

DURATION OF THERAPY

CASE STUDY

52 YR OLD FEMALE WITH 60% TBSA BURNSGM-NEG ANTIBIOTICSD7 pre-op piptazD11 pre-op meropenem + gentD12 pre-op meropenem – plus 1 dose post opD14 pre-op meropenem – plus 1 dose post op

plus pre-op gentD14 Cultures taken Stenotrophomonas

CPIS< 6 : “std” vs 3 days cipro

MAIN RESULTS: ICU Mortality – same, BUT: ICU LOS LESS, 30 DAY MORTALITY LESS Resistance 15% vs 35%,

COMMENTS: Small study, low risk pts, a start

Some other OPD trials

AJRCCM 2000:162: 505-11

Basic resistance to disease that a species possesses

First line of defence against infection. The characteristics include the following:

Responses are broad and non-specific No memory or lasting protective immunity There is a limited repertoire of recognition

molecules The responses are phylogenetically ancient

INNATE (NONSPECIFIC) IMMUNITY

IMPORTANT TO REALISE THAT ONLY THIS PART NEEDS (and in fact responds to) ANTIBIOTICS

COMMON ICU INFECTIONS• VAP• LINE RELATED INFECTIONS• INTRA-ABDOMINAL INFECTIONS• NEUROSURGICAL – VENTRICULITIS• BURNS• UTI probably less so

BLOOD STREAM INFECTIONS EASIER TO DIAGNOSE

VAPDefinitions include many subjective components such as chest radiography, respiratory secretion assessment and chest auscultation findings. As a consequence, interobserver discordance for detecting VAP is high

The correlation between VAP defined using NHSN/CDC criteria and histological pneumonia is poor given that clinical signs have low specificity for VAP

VAP

• Despite keeping VAP fixed at 10%, the apparent rate of VAP varied between 6.0% and 31.6%

Variation in the apparent prevalence of VAP, depending on the frequency of other diseases in an ICU population.

Variation in the apparent prevalence of VAP, depending on the frequency of other diseases in an ICU population.

Not surprising then that 1.Attributable mortality varies from paper to paper2.What one person diagnoses and treats as VAP differs from the next consultant3.Therefore outcome of antibiotic therapy and duration thereof is fraught with difficulty

VAP

Published March 22, 2011

VAC was defined as ≥2 days of stable or decreasing daily minimum PEEP or FiO2 followed by a rise in daily minimum PEEP by ≥2.5 cm H2O lasting ≥2 days or a rise in daily minimum FiO2 by ≥15% lasting ≥2 days

“…..Our study shows that VAC is a simple and objectively defined parameter…......VAC's simplicity, objectivity, and consistent association with adverse outcomes make it a promising metric to succeed VAP for measuring quality and safety of care in ventilated patients.”

Critical Care Medicine March 2014

Some hospitals rated 0% of cases as having pneumonia; others

classified 100% as having pneumonia (median, 50%; interquartile range, 33–66%).

Critical Care Medicine March 2014

Conclusions: “In this nationally representative study of hospitals, assignment of VAP is extremely variable, enough to render comparisons between hospitals worthless, even when standardized cases eliminate variability in clinical data abstraction………

VAP IS DYINGIn its place will be

IVAC (Infection associated Ventilator Associated Complications)

HAP • Pipes in patient • Temperature• WCC• Atelectasis

I put it to you we over treat here tooI put it to you we over treat here too

Basic resistance to disease that a species possesses

First line of defence against infection. The characteristics include the following: Responses are broad and non-specific No memory or lasting protective immunity There is a limited repertoire of recognition

molecules The responses are phylogenetically ancient

INNATE (NONSPECIFIC) IMMUNITY

OTHER DEFINITIONS

Line related sepsisVentriculitis

Infections associated with conditions such as •Pancreatitis•Burns

CASE STUDY

52 YR OLD FEMALE WITH 60% TBSA BURNSGM-NEG ANTIBIOTICSD7 pre-op piptazD11 pre-op meropenem + gentD12 pre-op meropenem – plus 1 dose post opD14 pre-op meropenem – plus 1 dose post op

plus pre-op gentD14 Cultures taken Stenotrophomonas

CASE STUDY 52 YR OLD FEMALE WITH 60% TBSA BURNS

D14 Cultures taken StenotrophomonasNo clinical alteration in vital signs but given Bactrim 3 weeks later Ps. grown from burn wounds, sputum and blood cultures No clinical alteration in vital signs but given cefepimeArbitrarily 7 days and stopped with no alteration

before cefepime and after cefepime

OTHER DEFINITIONS

Line related sepsisVentriculitis

Infections associated with conditions such as •Pancreatitis•Burns

BIOMARKERS?

“An ideal biomarker should distinguish between various stages of bacterial infection, inform further diagnostic tests, help to time treatment, and provide information about prognosis…….”

Lancet Infect Dis. 2013 May;13(5):382-4

Crit Care Med 2012; 40: 2304–2309

Conclusions: Procalcitonin measuring for the initiation of antimicrobials did not appear to be helpful in a strategy aiming at decreasing the antibiotic consumption in intensive care unit patients.

Our analysis found a significant association between the presence of shock and elevation in PCT which was evident in the infected and noninfected cohort. This finding is particularly relevant in understanding the role of PCT in the critically ill where shock is common.

Crit Care Med 2012;40:2781-7

Prevalent infections demonstrated a trend toward a higher PCT peak than did incident infections.…….. the capacity to produce a PCT response in the face of a new infection may be blunted in those who are already critical ill

Crit Care Med 2012;40:2781-7

Conclusions: …..Shock had an association with higher procalcitonin values independent of the presence of infection. Trends in differences in procalcitonin values were seen in patients who had incident vs. prevalent infections.

Crit Care Med 2012;40:2781-7

SEPTICYTE

BIOMARKERS Certainly they haven’t been shown to help us in burns and pancreatitis.

BNP goes up in SEPSIS

Early work from us Anesth Analgesia Case reports Nov 2013Crit Care Med Accepted Feb 2014

0

1

2

3

4

5

6

7

12 24 36 48 72 96 120 144 168

CIl/

m2

0

500

1000

1500

2000

2500

3000

3500

SV

RI

Cardiac index

Systemic vascular resistance index

* * *

* * *

*=p<0.01

Myocardial function in burns

Sepsis

Normal burn

55yo M TBSA 22% Sepsis Day 3

0

1

2

3

4

5

6

7

12 24 36 48 72 96 120 144 168

CIl/

m2

0

500

1000

1500

2000

2500

3000

3500

SV

RI

BNP 1,347ng/L at this point

55yo M TBSA 22% Sepsis Day 3

Cardiac index

BNP 30pg/L0-48 hours Systemic vascular

resistance index

MeasureMeasure

BNPBNP PCTPCT SISI SVRISVRI

SensitivitySensitivity 88%88% 47 %47 % 63 %63 % 82%82%

SpecificitySpecificity 100%100% 47 %47 % 74 %74 % 86%86%

PPVPPV 100%100% 55 %55 % 78 %78 % 88 %88 %

NPVNPV 86%86% 39 %39 % 59 %59 % 77 %77 %

Sensitivity & Specificity

BNP 97%

SVRI 85%

SI 80%

PCT 56%

GETTING THE LAUNCH CODES RIGHT

STRUCTURE The “BAD” effects of antibiotics

ie collateral damageLack of good infection definitions

eg Diagnosis of line related infection (amongst others)

Lack of sensitive biomarker ie how do you know when to start

Kritsotakis et al J Antimicrob Chemother 2011;66:1383-91

DURATION OF THERAPY

IMPORTANT TO REALISE THAT ONLY THIS PART NEEDS (and in fact responds to) ANTIBIOTICS

“An ideal biomarker should distinguish between various stages of bacterial infection, inform further diagnostic tests, help to time treatment, and provide information about prognosis. Procalcitonin is not a perfect biomarker but it is the best available means for making individualised treatment decisions to reduce duration of antibiotic treatment or withhold antibiotics for non-life-threatening respiratory tract infections”

Lancet Infect Dis. 2013 May;13(5):382-4

Duration of hypotension prior to effective antimicrobial therapy: impact

on survival in septic shock

Kumar et al. Crit Care Med 2006;34:1589–96

Time of first dose of antibiotics after the onset of shock (hours)

0–30′

100

80

60

40

20

0

Mor

tailt

y (%

)

30′–1h 1–2 2–3 3–4 4–5 5–6 6–9 9–12 12–24 24–36 >36

GET YOUR LAUNCH CODES CORRECT

Kumar et al. Crit Care Med 2006;34:1589–96

THE END !

j.lipman@uq.edu.au

www.som.uq.edu.au/btccrc