HAP/VAP: New guidelines from

ERS, ESICM, ESCMID and

ALAT

Antoni Torres Conflicts of interest: Consulting or

Lecture fees:

– Bayer, Medimmune-AstraZeneca, Pfizer,

Arsanis, Cubist-Merck, Basilea, Aridis

1. ATS/IDSA Guidelines for the Management of

Adults with HAP, VAP and HCAP, 2005

2. Association of Medical Microbiology and

Infectious Diseases of Canada, 2008

3. British Society for Antimicrobial Chemotherapy,

2008

HAP/VAP: New guidelines from

ERS, ESICM, ESCMID and ALAT

1. New studies

2. Bacteriology of HAP (non-intubated)

3. De-escalation studies

4. Use of biomarkers to promote reduced therapy duration

5. MRSA, Acinetobacter

6. Aerosolized antibiotics

7. Prevention: SDD, zero VAP

8. New diseases: Ventilator associated tracheobronchitis

9. FDA/EMEA Guidance for HAP trials

Knowledge Has Advanced In a

Number of Areas

1. European Respiratory Society (ERS)

2. European Society of Clinical Microbiology and

Infectious Diseases (ESCMID)

3. European Society of Intensive Care Medicine

(ESICM)

4. Latino-American Society of Thorax (ALAT)

Participating Societies

1. ERS: S.Ewig, T.Welte, T.Tonia, A.Torres

2. ESCMID: J.Chastre, H.Hanberger, R.Read

3. ESICM: M.Bonten, A Paiva, JF Timsit

4. ALAT: C.Luna

5. USA Experts: M.Niederman, M.Kollef, R

Wunderink

Participating “Experts”

Using the GRADE approach in

Guideline Development

• A short guide

• Thomy Tonia, MSc, ERS Methodologist

Why do we need such an

approach?

• For clinicians and patients to be confident that following these

recommendations will do more good than harm, guidelines

need to be evidence based, transparent, and explicit about

whose values and preferences were taken into account.

• Systematic approach, transparency, and explicitness also

facilitate implementation, adaptation to local circumstances,

and updating of guidelines.

• A systematic approach to grading the strength of

recommendations can minimize bias.

Formulating questions

Ask an answerable question! Formulate the questions/ outcomes in a way that facilitates your search and the management of your results. Use the PICO format

• Population

• Intervention

• Comparison

• Outcome

Turning a question into PICO

• Are antibiotics effective in patients with

COPD?

• In patients with stable COPD should

antibiotics, as compared to usal care, be used

to prevent exacerbations?

Population

Inte

rven

tion

Com

paris

on

Outcome

Selecting outcomes and rating

their importance - Extremely important!

- Importance should be rated before

searching and evaluating the

studies!

- It should be primarily guided by

patients’ needs

- Outcome importance may be

changed after evidence collection,

under certain circumstances

Rating outcome importance-

example

Searching and selecting studies

• Think about which databases to

search

• Develop and test search

strategy

• Screen results (title & abstract

screening, full-text screening),

according to predefined

inclusion and exclusion criteria

• Document everything!

The GRADE approach

• Estimate of effect per outcome

• Quality of evidence per outcome

• RCTs start from high quality,

observational studies from low

• 5 factors that need to be assessed and might

result in rating quality down (risk of bias,

inconsistency, indirectness, imprecision,

publication bias)

• Three factors that might result in rating up

observational studies (very rare, be

cautious)

• Rate overall quality of evidence across

outcomes

Risk of bias

• Lack of allocation concealment

• Lack of blinding

• Large loss to follow-up

• Not adhering to Intention To Treat principle

• Stopping early for benefit

• Selective outcome reporting

Inconsistency

• Variability/ heterogeneity of results:

• Widely different estimates of effect across

studies suggest a true difference of the

underlying effect

Try to identify possible reasons for this (i.e.

differences in populations across studies,

differences in outcome definitions etc)

If no plausible reasons are identified, quality

decreases

Indirectness

• Indirect Comparison

• We want to study the effect of drug A versus drug B

• The available studies examine only the effect of drug A versus placebo and the effect of drug B versus placebo

• In this case we can indirectly compare drug A and drug B; however, the quality will decrease

• Other sources of indirectness

• Differences in

population/

intervention/ alternative

intervention/ outcomes

of interest between the

available studies and to

those that the

recommendation refers

to

Imprecision

When the estimate of the effect has wide CIs, that

include both important benefits or no important

benefits (or even important harms)

Uncertainty in the effect

Quality decreases

22

Publication Bias

• Refers to failure of reporting studies that

were undertaken; very often these are the ones

showing a negative effect

• Difficult to estimate the risk for publication

bias

• Risk is higher when only a few small studies

are available

GRADE Evidene Profile (using the GRADEPro software)

25

From evidence to

recommendations

o In intubated patients suspected of having

VAP should distal quantitative samples be

obtained instead of proximal qualitative

samples to focus and narrow initial empiric

antibiotic therapy?

PICO question #1

PICO question #1

OUTCOMES

28/30-day mortality CRITICAL

90-day mortality CRITICAL

Length of ICU stay IMPORTANT

Length of MV (or ventilator free days) IMPORTANT

Antibiotic free days CRITICAL

Antibiotic de-escalation IMPORTANT

Sepsis free days IMPORTANT

Extensively resistant bacteria infection IMPORTANT

Extensively resistant bacteria colonization IMPORTANT

Extensively resistant bacteria carriage IMPORTANT

o Can patients suspected of having nosocomial

pneumonia (HAP and VAP), who have early

onset infection and no risk factors for MDR

pathogens, be treated appropriately if they

receive a different, and narrower spectrum

empiric therapy than patients with late onset

infection and/or the presence of MDR risk

factors?

PICO question #2

PICO question #2

OUTCOMES

Use of appropriate antibiotic therapy CRITICAL

28/30-day mortality CRITICAL

90-day mortality CRITICAL

Length of Stay IMPORTANT

Duration of therapy IMPORTANT

Treatment failure CRITICAL

Duration of mechanical ventilation IMPORTANT

Antibiotic therapy complications IMPORTANT

C. difficile colitis IMPORTANT

Emergence of AB-resistant bacteria during therapy CRITICAL

Quality of life scores IMPORTANT

o In patients with initial broad spectrum empiric

therapy for HAP/VAP does an initial regimen

combining two antibiotics targeting Gram-

negative bacteria improve outcomes and when

culture data are available, does combination

therapy need to be continued as definitive

therapy, compared to single antimicrobial agent

therapy?

PICO question #3

PICO question #3

OUTCOMES

All-cause 28/30-day mortality CRITICAL

All-cause 90-day mortality CRITICAL

Improvement in daily organ failure score, including a respiratory organ failure

subscore and/or PaO2/FIO2

IMPORTANT

Number of patients with relapse and/or secondary infection CRITICAL

Clinical and microbiological treatment response CRITICAL

Intervention-free days with a ventilator, vasopressor, dialysis, or antibiotic after the

diagnosis of VAP/HAP IMPORTANT

Duration of MV after the diagnosis of VAP/HAP IMPORTANT

Duration of ICU and hospital stay after the diagnosis of VAP/HAP IMPORTANT

Number of patients with adverse events, including nephrotoxicity CRITICAL

Emergence of antibiotic-resistant bacteria CRITICAL

Velocity of CRP or PCT decrease IMPORTANT

• In patients with HAP/VAP can duration of

antimicrobial therapy be shortened to 7-10 days

for certain populations as compared to 14 days

without increasing rates of relapsing infections

or decreasing clinical cure?

PICO question #4

PICO question #4

OUTCOMES

All-cause 28/30-day mortality CRITICAL

All-cause 90-day mortality CRITICAL

Number of patients with relapse and/or secondary infection CRITICAL

Improvement in daily organ failure score, including a respiratory organ

failure subscore and/or PaO2/FIO2 IMPORTANT

Intervention-free days with a ventilator, vasopressor, dialysis after the

diagnosis of VAP/HAP IMPORTANT

Antibiotic exposure after the diagnosis of VAP/HAP IMPORTANT

Duration of MV after the diagnosis of VAP/HAP IMPORTANT

ICU and hospital stay duration after VAP/HAP diagnosis IMPORTANT

Emergence of antibiotic-resistant bacteria CRITICAL

Number of patients with adverse events, including nephrotoxicity CRITICAL

Clinical and microbiological treatment response IMPORTANT

• In patients receiving AB treatment for VAP or

HAP, is bedside clinical assessment equivalent to

the detection of serial biomarkers to predict

adverse outcomes/clinical response at 72-96h?

PICO question #5

PICO question #5

OUTCOMES

28/30-day mortality CRITICAL

90-day mortality CRITICAL

Organ failure (shock, worse oxygenation, acute kidney

injury, thrombocytopenia, etc) CRITICAL

Subsequent antibiotic-resistant infections IMPORTANT

• In patients with HAP with severe sepsis or VAP,

can serum procalcitonin be used to reduce the

duration of antibiotic therapy, compared to care

that is not guided by serial biomarker

measurements?

PICO question #6

PICO question #6

OUTCOMES

Duration of antibiotic therapy CRITICAL

28/30-day mortality CRITICAL

All-cause 90-day mortality CRITICAL

Subsequent emergence of antibiotic resistance CRITICAL

Organ failure (shock, worse oxygenation, acute kidney

injury, thrombocytopenia, etc) IMPORTANT

• In patients requiring MV for ≥48 hours, does

topical application of non-absorbable antibiotics

(SOD) or chlorhexidine in the oropharynx or in

the oropharynx and intestinal tract along with

intravenous antibiotics (SDD) reduce the risk of

VAP occurrence and/or improve patient

outcome compared to standard care?

PICO question #7

PICO question #7 OUTCOMES

28/30-day mortality CRITICAL

90-day mortality CRITICAL

Development of VA-tracheobronchitis IMPORTANT

Development of VAP CRITICAL

Emergence of colonization with AB-resistant bacteria CRITICAL

Hospital length of stay IMPORTANT

Development of C. difficile-associated diarrhea IMPORTANT

Development of other nosocomial infections (e.g., catheter-

associated, BSI, UTI, IAI) IMPORTANT

Antibiotic use CRITICAL

1. Optimal timing for starting antibiotics

2. Risk factors for MDR

3. Initial single agent therapy vs. bitherapy

4. MRSA coverage

5. PK/PD optimized therapy

6. De-escalation

7. Duration of therapy

8. Therapy for specific pathogens

9. Aerosolized antibiotics

10. Ventilator-associated tracheobronchitis

Antimicrobial Treatment of

HAP/VAP