1. 1st
Asia Pacific Summit
Grand Hyatt, SingaporeGrand Hyatt, Singapore
44thth
-5-5thth
MarchMarch

2. Pneumonia Treatment Guidelines
Hospital-acquired Pneumonia (HAP)
Robert G MastertonRobert G Masterton
NHS Ayrshire and Arran, UKNHS Ayrshire and Arran, UK

3. 3
Why Guidelines?Why Guidelines?
• Evidence-based practiceEvidence-based practice
– Best outcome for patientsBest outcome for patients
– Best use of resourceBest use of resource
– Constrains idiosyncratic behaviourConstrains idiosyncratic behaviour
• Legal protectionLegal protection
• Identify research needsIdentify research needs
• A tool for educationA tool for education
• Gain public confidenceGain public confidence

4. 4
Why Guidelines for HAP?Why Guidelines for HAP?
• Second commonest hospital-acquired infection (15%)Second commonest hospital-acquired infection (15%)
• 0.5–1% of hospital admissions0.5–1% of hospital admissions
• Ventilator-associated pneumonia (VAP) 5–50% ofVentilator-associated pneumonia (VAP) 5–50% of
ventilated patientsventilated patients
• About 50% is E-VAPAbout 50% is E-VAP
• Hazard rateHazard rate
– 3% per day Week 13% per day Week 1
– 2% per day Week 22% per day Week 2
– 1% per day Week 31% per day Week 3
Am J Respir Crit Care Med. 2005;171:388–416.

5. 5
Why Guidelines for HAP?Why Guidelines for HAP?
• MortalityMortality
– Crude rate = 20–50%Crude rate = 20–50%
– Attributable rate = 30–33% for non-ventilatedAttributable rate = 30–33% for non-ventilated
– Attributable rate = 27–43% for ventilatedAttributable rate = 27–43% for ventilated
– Relative factor of x2 to x10 in ICURelative factor of x2 to x10 in ICU
• MorbidityMorbidity
– >Intubation = 18–22 days for VAP>Intubation = 18–22 days for VAP
– >Length of stay x2–3 = circa 13 days for VAP>Length of stay x2–3 = circa 13 days for VAP
– USA 1997: 1.75 million hospital bed daysUSA 1997: 1.75 million hospital bed days
– Cost USA 1997: $5,800 per case = $1.5 billion in totalCost USA 1997: $5,800 per case = $1.5 billion in total
Adapted from Am J Respir Crit Care Med. 2005;171:388–416.

6. 6
The Microbiology of HAPThe Microbiology of HAP
• Gram-negative = 48%Gram-negative = 48%
• PseudomonasPseudomonas spp.spp.
• AcinetobacterAcinetobacter spp.spp.
• Klebsiella spp.Klebsiella spp.
• E.coliE.coli
• Gram-positive = 43%Gram-positive = 43%
• S. aureusS. aureus
• S. pneumoniaeS. pneumoniae
• Others = 9% (viruses 1%)Others = 9% (viruses 1%)
Adapted from Am J Respir Crit Care Med. 2005;171:388–416.

7. 7
Early-onsetEarly-onset Late-onsetLate-onset
pneumoniapneumonia pneumoniapneumonia Others based onOthers based on
(<5 days)(<5 days) (>5 days)(>5 days) specific risksspecific risks
S. pneumoniaeS. pneumoniae P. aeruginosaP. aeruginosa Anaerobic bacteriaAnaerobic bacteria
H. influenzaeH. influenzae EnterobacterEnterobacter spp.spp. Legionella pneumophilaLegionella pneumophila
S. aureusS. aureus AcinetobacterAcinetobacter spp.spp.
EnterobacteriaceaeEnterobacteriaceae K. pneumoniaeK. pneumoniae
S. marcescensS. marcescens Influenza A and BInfluenza A and B
E. coliE. coli Respiratory syncytialRespiratory syncytial
Other GNBOther GNB virusvirus
S. aureusS. aureus (MRSA)(MRSA)
FungiFungi
The Microbiology of HAPThe Microbiology of HAP
GNB, Gram-negative bacilli; MRSA, methicillin-resistant S.aureus
Adapted from Am J Respir Crit Care Med. 2005;171:388–416.

8. 8
HAP GuidelinesHAP Guidelines
• Pulmonary guidelines are increasingly published inPulmonary guidelines are increasingly published in
peer-reviewed journals, but few are tested clinically inpeer-reviewed journals, but few are tested clinically in
randomised controlled trials (RCTs).randomised controlled trials (RCTs).
– There is continued reliance on consensus statements andThere is continued reliance on consensus statements and
expert opinion.expert opinion.
– Pulmonary guideline publications have continued toPulmonary guideline publications have continued to
increase dramatically in number and in importance sinceincrease dramatically in number and in importance since
1974, both on the local level and internationally (13.3% are1974, both on the local level and internationally (13.3% are
about pneumonia)about pneumonia)
Hackner et al. Chest 1999;116:1046–1062

9. 9
HAP GuidelinesHAP Guidelines
• SwedenSweden
– Patients treated at medical institutions with home-like conditionsPatients treated at medical institutions with home-like conditions
– Patients hospitalised in acute somatic departmentsPatients hospitalised in acute somatic departments
– Post-operative patientsPost-operative patients
• France — VAP onlyFrance — VAP only
– Early onset — no prior antibioticsEarly onset — no prior antibiotics
– Early onset — prior antibioticsEarly onset — prior antibiotics
• OROR
– Late onset — no prior antibioticsLate onset — no prior antibiotics
– Late onset — prior antibioticsLate onset — prior antibiotics
Mandell et al. Chest 1998;113:188S–193S
29 countries surveyed
5 with HAP guidelines
2 in Europe

10. 10
Which Guideline Is best?Which Guideline Is best?
VariableVariable ATS (1996)ATS (1996) Trouillet (1998)Trouillet (1998)
Predictive accuracy forPredictive accuracy for
organismorganism
91%91% 83%83%
Adequacy of treatmentAdequacy of treatment
recommendationsrecommendations
79%79% 80%80%
Problem organismsProblem organisms PseudomonasPseudomonas spp.,spp.,
AcinetobacterAcinetobacter spp.,spp.,
StenotrophomonasStenotrophomonas
spp., MRSAspp., MRSA
PseudomonasPseudomonas spp.spp.
Ioanas et al. Eur Respir J 2003;22:876–82

11. 11
HAP GuidelinesHAP Guidelines
NameName YearYear CountryCountry TreatmentTreatment PreventionPrevention DiagnosisDiagnosis
BSACBSAC 20062006 UKUK   
ATSATS 20052005 USAUSA   
GALANNGALANN 20052005 Lat/AmLat/Am 
CCCSCCCS 20042004 CanadaCanada 
HICPACHICPAC 20042004 USAUSA 
GEIH, etc.GEIH, etc. 20042004 SpainSpain (severe)(severe)
CoronaCorona 20032003 ItalyItaly 
CollardCollard 20032003 USAUSA 
ICCCICCC 20022002 GlobalGlobal   
RelloRello 20012001 SpainSpain  

12. 12
BSAC Work StreamsBSAC Work Streams
Sub-groupSub-group Citations reviewedCitations reviewed Articles reviewedArticles reviewed
PreventionPrevention 971971 350350
DiagnosisDiagnosis 17531753 8585
TreatmentTreatment 38683868 308308

13. 13
Classification of EvidenceClassification of Evidence
• Systematic reviews and meta-analyses of RCTsSystematic reviews and meta-analyses of RCTs
• Prospective RCTsProspective RCTs
• Non-randomised intervention studiesNon-randomised intervention studies
• Cohort studiesCohort studies
• Diagnostic studiesDiagnostic studies
• Expert opinionExpert opinion

14. 14
BSAC Data QualityBSAC Data Quality
0
10
20
30
40
50
60
70
Prevention Diagnosis Treatment
Syst rev
RCT
Cohort
Case con
Diagnostic
Expert opinion
Percentage of papers reviewed

15. 15 Am J Respir Crit Care Med. 2005;171:388–416
HAP, VAP and Healthcare-associatedHAP, VAP and Healthcare-associated
pneumonia (HCAP) Guidelinepneumonia (HCAP) Guideline

16. 16
HAP, VAP or HCAP suspected
Obtain lower respiratory tract (LRT) sample for culture
(quantitative or semi-quantitative) and microscopy
Clinical improvement at 48–72 hours
De-escalate antibiotics,
if possible.
Treat selected patients
for 7–8 days
and reassess
Search for other
pathogens,
complications, other
diagnoses or other
sites of infection
Days 2 and 3: Check cultures and assess clinical response:
(temperature, WBC, chest X-ray, oxygenation, purulent sputum,
haemodynamic changes and organ function)
YESYESNONO
Unless there Is both a low clinical suspicion for pneumonia and
negative microscopy of LRT sample, begin empiric antimicrobial
therapy using algorithm in Figure 2 and local microbiologic data
Cultures -
Consider
stopping
antibiotics
Adjust antibiotic therapy,
search for other
pathogens,
complications, other
diagnoses or other
sites of infection
Cultures +Cultures +Cultures -
Am J Respir Crit Care Med. 2005;171:388–416

17. 17
Questions for Treatment PracticeQuestions for Treatment Practice
• What are the optimal empiric and definitive antibioticWhat are the optimal empiric and definitive antibiotic
therapies for patients with HAP?therapies for patients with HAP?
• Do pharmacodynamic and pharmacokinetic profilesDo pharmacodynamic and pharmacokinetic profiles
influence outcomes?influence outcomes?
• Do outcomes depend on whether monotherapy orDo outcomes depend on whether monotherapy or
combination therapy is used?combination therapy is used?
• Are data available to support the efficacy of instilled orAre data available to support the efficacy of instilled or
nebulised therapy?nebulised therapy?
• Are there clear criteria available for the initiation ofAre there clear criteria available for the initiation of
step-down therapy, eg intravenous to oral?step-down therapy, eg intravenous to oral?

18. 18
Treatment — Volume of Evidence (1)Treatment — Volume of Evidence (1)
• There is a large body of evidence from RCTs over theThere is a large body of evidence from RCTs over the
past three decadespast three decades
• Earlier studies evaluated antibiotics that are no longerEarlier studies evaluated antibiotics that are no longer
regarded as appropriate empiric therapy for HAPregarded as appropriate empiric therapy for HAP
particularly late-onset — due to dramatic changes inparticularly late-onset — due to dramatic changes in
the nature and susceptibility patterns of the pathogensthe nature and susceptibility patterns of the pathogens
• No well-conducted studies for pharmacoeconomic orNo well-conducted studies for pharmacoeconomic or
health economic evaluationshealth economic evaluations
www.bsac.org.uk

19. 19
Treatment — Volume of Evidence (2)Treatment — Volume of Evidence (2)
• Only four studies were randomised double-blindOnly four studies were randomised double-blind
studiesstudies
• In several studies so few patients were enrolled thatIn several studies so few patients were enrolled that
the likelihood of a type II error is highthe likelihood of a type II error is high
• No studies addressed patient demography and riskNo studies addressed patient demography and risk
factors or assessed empiric or definitive treatment infactors or assessed empiric or definitive treatment in
relation to severity of illness or duration ofrelation to severity of illness or duration of
hospitalisationhospitalisation
• Limited data concerning the influence of appropriateLimited data concerning the influence of appropriate
therapy on duration of hospital stay, particularly lengththerapy on duration of hospital stay, particularly length
of time on a ventilator, and costof time on a ventilator, and cost
www.bsac.org.uk

20. 20
Treatment — Volume of Evidence (3)Treatment — Volume of Evidence (3)
• Few studies compared >2 therapeutic optionsFew studies compared >2 therapeutic options
• Almost all studies had insufficient power toAlmost all studies had insufficient power to
demonstrate superiority of one regimen over anotherdemonstrate superiority of one regimen over another
• A limitation is that the primary microbiologicalA limitation is that the primary microbiological
evaluations are invariably related to pathogens that areevaluations are invariably related to pathogens that are
susceptible to the trial antibioticssusceptible to the trial antibiotics
• Only six studies recruited ≥200 patients to bothOnly six studies recruited ≥200 patients to both
treatment and comparator armstreatment and comparator arms
www.bsac.org.uk

21. 21
And the Evidence Shows …And the Evidence Shows …
• Whereas the pathogens and their susceptibility in late-Whereas the pathogens and their susceptibility in late-
onset HAP are highly variable, those in early-onsetonset HAP are highly variable, those in early-onset
HAP are limitedHAP are limited
Evidence grade = 2+Evidence grade = 2+
• Infections caused byInfections caused by P. aeruginosaP. aeruginosa are associatedare associated
with a significantly higher incidence of treatment failurewith a significantly higher incidence of treatment failure
than those caused by other organismsthan those caused by other organisms
Evidence grade = 1+Evidence grade = 1+
www.bsac.org.uk

22. 22
Treatment RecommendationTreatment Recommendation
• The choice of empiric antibiotic therapy for patientsThe choice of empiric antibiotic therapy for patients
with HAP in an individual unit should be based onwith HAP in an individual unit should be based on
knowledge of the nature and susceptibility patterns ofknowledge of the nature and susceptibility patterns of
the pathogens that are prevalent in that unit andthe pathogens that are prevalent in that unit and
– Should also take account of such variables as duration ofShould also take account of such variables as duration of
hospital stay (ie, early- or late-onset infection), recenthospital stay (ie, early- or late-onset infection), recent
administration of antibiotic therapy and co-morbidities.administration of antibiotic therapy and co-morbidities.
– Similarly, definitive therapy should be determined by cultureSimilarly, definitive therapy should be determined by culture
and susceptibility test resultsand susceptibility test results
Recommendation grade = ARecommendation grade = A
www.bsac.org.uk

23. 23
Treatment Recommendation (2)Treatment Recommendation (2)
• Treatment with an appropriate antibiotic should beTreatment with an appropriate antibiotic should be
started as soon as possible in order to reduce mortalitystarted as soon as possible in order to reduce mortality
Recommendation grade = ARecommendation grade = A
http://www.bsac.org.uk/

24. 24
Good Practice PointsGood Practice Points
• For patients with early-onset infections (For patients with early-onset infections (<5<5 days afterdays after
admission to hospital) who have not previouslyadmission to hospital) who have not previously
received antibiotics and in the absence of other riskreceived antibiotics and in the absence of other risk
factors, the use of amoxicillin/clavulanate orfactors, the use of amoxicillin/clavulanate or
cefuroxime would be appropriatecefuroxime would be appropriate
• For patients with early-onset infections (For patients with early-onset infections (<5<5 daysdays
following admission to hospital) who have recentlyfollowing admission to hospital) who have recently
received antibiotics and/or have other risk factors, areceived antibiotics and/or have other risk factors, a
third-generation cephalosporin (cefotaxime orthird-generation cephalosporin (cefotaxime or
ceftriaxone) or a fluoroquinolone, orceftriaxone) or a fluoroquinolone, or
piperacillin/tazobactam would be appropriatepiperacillin/tazobactam would be appropriate
www.bsac.org.uk

25. 25
ATS Treatment GuidanceATS Treatment Guidance
• Select empiric therapy based on the absence or presence of risk factors for
MDR pathogens.
• Choice of agents dictated by local microbiology, cost, availability, and
formulary restrictions.
• Patients with HCAP should be treated for potentially drug-resistant
organisms
• Inappropriate therapy is a major risk factor for excess mortality and length of
stay and antibiotic-resistance is most commonly associated with
inappropriate therapy.
• In empiric therapy where recent antibiotic used select from a different
antibiotic class.
• Initial antibiotic therapy should be given promptly because delays in
administration may add to excess mortality resulting from VAP.
• Initial empiric therapy is more likely to be appropriate if a protocol for
antibiotic selection is developed.
Am J Respir Crit Care Med. 2005;171:388–416.

26. 26
ATS Guidance against Late HAPATS Guidance against Late HAP
Potential Pathogens Combination Antibiotic Therapy
Late HAP & MDR pathogens
Pseudomonas aeruginosa or
Klebsiella pneumoniae (ESBL)
Acinetobacter species
MRSA
Legionella pneumophila
Antipseudomonal cephalosporin (cefepime, ceftazidime)
Antipseudomonal carbepenem
(imipenem or meropenem)
or beta-Lactam/-lactamase inhibitor (piperacillin–tazobactam)
plus Antipseudomonal fluoroquinolone†
(ciprofloxacin or levofloxacin) or Aminoglycoside
(amikacin, gentamicin, or tobramycin)
plus
Linezolid or vancomycin
Am J Respir Crit Care Med. 2005;171:388–416.

27. 27
HAP Treatment ConsensusHAP Treatment Consensus
• Risk assessment approachRisk assessment approach
• Early versus late antibiotic selectionEarly versus late antibiotic selection
• Empiric late treatment driven by local surveillanceEmpiric late treatment driven by local surveillance
• Hit hard and hit earlyHit hard and hit early
• As short a duration as possibleAs short a duration as possible
• De-escalate when and where possibleDe-escalate when and where possible

28. 28
Do Great Minds Think Alike …?Do Great Minds Think Alike …?
BSACBSAC ATSATS
PreventionPrevention
SDDSDD
Effective, cost-Effective, cost-
effective, noeffective, no
resistance riskresistance risk
 HAP butHAP but
discourage use duediscourage use due
to resistanceto resistance
DiagnosisDiagnosis
MicrobiologyMicrobiology
Treat and testTreat and test Test and treatTest and treat
TreatmentTreatment
MRSA — linezolidMRSA — linezolid
No recommendationNo recommendation
can be madecan be made
Superiority needsSuperiority needs
validationvalidation
May be preferredMay be preferred

29. 29
VAP Guideline AdherenceVAP Guideline Adherence
• The overall non-adherence rate was 37.0%The overall non-adherence rate was 37.0%
• The non-adherence rate was 25.2% for clinical useThe non-adherence rate was 25.2% for clinical use
strategies, and 45.6% for less effective strategiesstrategies, and 45.6% for less effective strategies
• Pharmacological strategies had a higher degree of –Pharmacological strategies had a higher degree of –
non-adherence than non-pharmacological strategiesnon-adherence than non-pharmacological strategies
• Non-adherence to recommendations did not relate toNon-adherence to recommendations did not relate to
the weight of evidencethe weight of evidence
• Commonest reasons for non-adherence were:Commonest reasons for non-adherence were:
– Disagreement with interpretation of clinical trials (35%)Disagreement with interpretation of clinical trials (35%)
– Unavailability of resources (31.3%)Unavailability of resources (31.3%)
– Costs (16.9%)Costs (16.9%)
Rello et al. Chest 2002;122:656–661

30. 30
Do Guidelines Work in VAP?Do Guidelines Work in VAP?
• ICU imipenem-based regimenICU imipenem-based regimen
• After D3 therapy based on susceptibility resultsAfter D3 therapy based on susceptibility results
• Better empirical cover (81 vs 46%; p<0.01)Better empirical cover (81 vs 46%; p<0.01)
• No change in imipenem resistance ratesNo change in imipenem resistance rates
Soo Hoo et al. Chest 2005;128:2778-87

31. 31
The Future for HAP GuidelinesThe Future for HAP Guidelines
• Production of a guideline model for all to follow easilyProduction of a guideline model for all to follow easily
• Holistic guidelinesHolistic guidelines
• Production of care-path bundleProduction of care-path bundle
• Cost-effectiveness evaluationCost-effectiveness evaluation
• A single set of recommendationsA single set of recommendations

32. 32

33. 1st
Asia Pacific Summit
Grand Hyatt, SingaporeGrand Hyatt, Singapore
44thth
-5-5thth
MarchMarch