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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
Recommended