1. Management of Hospital-acquired and Ventilator-associated Pneumonia
Amanda Cantin, PharmD, BCCCP
Assistant Professor
Touro College of Pharmacy

2. Disclosures
I have no financial disclosures related to this presentation.

3. Objectives
Define hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP)
Describe diagnosis of HAP and VAP
Identify risk factors for infections with multi-drug resistant organisms (MDROs)
Differentiate empiric therapy recommendations for HAP and VAP
Discuss the role of short-course therapy, antibiotic de-escalation and use of local antibiograms in the treatment of HAP and VAP

4. Epidemiology of HAP and VAP
22% of all hospital-acquired infections (HAIs)
Mortality rates:
VAP range from 20 – 50%
Economic burden:
Prolonged mechanical ventilation
Prolonged hospital length of stay (LOS)
Excess cost $40,000 per patient
HAP and VAP together are the most commonly occurring hospital-acquired infections and make up about 22% of those infections
Mortality rates vary depending on the data that is utilized but in general for VAP the estimated mortality is anywhere from 20 to 50%
In HAP patients mortality can also range up to 50% and about 50% of patients experience some type of morbidity associates i.e.
Respiratory failure
Pleural effusions
Septic shock
Renal failure
Empyema
Pts with HAP admitted to the ICU have mortality rates similar to VAP
Economic burden
Prolonged mechanical ventilation: increased by 7.6 to 11.5 days
Prolonged LOS: increased by 11.5 to 13.1 days
Ref 2016 Guidelines
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5. Historical Perspective
1966:
ATS- Nosocomial Infections
2005:
ATS/ISDA-
HAP and VAP Guidelines
2016:
ATS/IDSA-
HAP and VAP
Guideline UPDATE
The American Thoracic Society first released a document addressing nosocomial infections including HAP and VAP in HAP and VAP have been public health concerts since the advent of hospitals and mechanical ventilators.
Several iterations of HAP and VAP guidelines have been published throughout the years.
In 1996 ATS published as consensus statement regarding management of hospital-acquired infections
In 2005 in collaboration with the Infectious Diseases Society of America, a new guideline addressing diagnosis and management of both HAP and VAP was published.
Because these two nosocomial infections are of such a great public health concern, the Society of Healthcare Epidemiology of America and IDSA published updated guidelines for the prevention of VAP in acute care hospitals
Due to a plethora of new research over the 11 years since the previous guidelines were published, ATS and IDSA released UPDATED guidelines for diagnosis and management of HAP and VAP
1996: ATS-
HAP Consensus
Statement
2014: SHEA/IDSA
VAP Prevention
Guidelines
Am J Respir Crit Care Med. 1996;153:1711–1725.
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6. Guideline Update: 2005 Versus 2016 What’s Different
Utilization of the GRADE methodology for evaluation of evidence
Strong versus weak recommendation
Quality of evidence
Removal of Health-care Associated Pneumonia (HCAP)
Emphasis on use of antibiograms
Hospital specific
Regional
Recommendations are rated as either ‘strong’ or ‘weak’
The words ‘we recommend’ indicate a strong recommendation
The words ‘we suggest’ indicate a weak recommendation
In general, a strong recommendation is on that most individuals would want that recommended course of therapy and only a small number would not
In a weak recommendation, the majority of individuals would want that recommended therapy but many would not.
This can be further broken down into clinicians:
Strong meaning most individuals should receive the therapy and adherence to the recommendation could be a quality criterion. In addition, decisional aids not likely to be needed to help individuals decide if the therapy is in line with their values
Weak meaning different approaches may be necessary based on the individual patient and decision aids may be helpful for them to decide.
Policy makers:
Strong recommendation could be adopted as policy in most situations
Weak recommendation requires debate and involvement of different stake-holders
HCAP removal
In 2005 guidelines, pts with exposure to the healthcare setting were assumed to be at a higher risk of MDROs
Less evidence to suggest these pts are at high risk of MDROs
Pt characteristics are more important risk factors than just exposure to the healthcare system
HCAP seen to be more closely related to CAP and will be addressed in future iterations of that guideline
Antibiograms
Emphasis placed on development and use of hospital specific antibiograms
Designed to limit the amount of empiric double gram-negative coverage and superfulous MRSA coverage used in pts with HAP/VAP
Benefit placed on minimizing exposure to these antibiotics
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7. Guideline Update: 2005 Versus 2016
Use of antibiograms
Recommend use of antibiogram directed empiric therapy
Recommend all hospitals generate/disseminate local antibiogram(s)
Specific for:
ICU population
VAP population
HAP population
Recommendations are rated as either ‘strong’ or ‘weak’
The words ‘we recommend’ indicate a strong recommendation
The words ‘we suggest’ indicate a weak recommendation
In general, a strong recommendation is on that most individuals would want that recommended course of therapy and only a small number would not
In a weak recommendation, the majority of individuals would want that recommended therapy but many would not.
This can be further broken down into clinicians:
Strong meaning most individuals should receive the therapy and adherence to the recommendation could be a quality criterion. In addition, decisional aids not likely to be needed to help individuals decide if the therapy is in line with their values
Weak meaning different approaches may be necessary based on the individual patient and decision aids may be helpful for them to decide.
Policy makers:
Strong recommendation could be adopted as policy in most situations
Weak recommendation requires debate and involvement of different stake-holders
HCAP removal
In 2005 guidelines, pts with exposure to the healthcare setting were assumed to be at a higher risk of MDROs
Less evidence to suggest these pts are at high risk of MDROs
Pt characteristics are more important risk factors than just exposure to the healthcare system
HCAP seen to be more closely related to CAP and will be addressed in future iterations of that guideline
Antibiograms
Emphasis placed on development and use of hospital specific antibiograms
Designed to limit the amount of empiric double gram-negative coverage and superfulous MRSA coverage used in pts with HAP/VAP
Benefit placed on minimizing exposure to these antibiotics
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8. Guideline Update: 2005 Versus 2016
Updates to local antibiogram based on:
Rate of change in resistance patterns
Resources
Data available for analysis
Recommendations are rated as either ‘strong’ or ‘weak’
The words ‘we recommend’ indicate a strong recommendation
The words ‘we suggest’ indicate a weak recommendation
In general, a strong recommendation is on that most individuals would want that recommended course of therapy and only a small number would not
In a weak recommendation, the majority of individuals would want that recommended therapy but many would not.
This can be further broken down into clinicians:
Strong meaning most individuals should receive the therapy and adherence to the recommendation could be a quality criterion. In addition, decisional aids not likely to be needed to help individuals decide if the therapy is in line with their values
Weak meaning different approaches may be necessary based on the individual patient and decision aids may be helpful for them to decide.
Policy makers:
Strong recommendation could be adopted as policy in most situations
Weak recommendation requires debate and involvement of different stake-holders
HCAP removal
In 2005 guidelines, pts with exposure to the healthcare setting were assumed to be at a higher risk of MDROs
Less evidence to suggest these pts are at high risk of MDROs
Pt characteristics are more important risk factors than just exposure to the healthcare system
HCAP seen to be more closely related to CAP and will be addressed in future iterations of that guideline
Antibiograms
Emphasis placed on development and use of hospital specific antibiograms
Designed to limit the amount of empiric double gram-negative coverage and superfulous MRSA coverage used in pts with HAP/VAP
Benefit placed on minimizing exposure to these antibiotics
Am J Respir Crit Care Med ; 171:
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9. Guideline Update: 2005 Versus 2016
Biomarkers to Diagnose HAP/VAP
Recommend using clinical criteria alone over:
Procalcitonin (PCT)
Soluble Triggering Receptor Expressed on Myeloid Cells (sTREM-1)
Strong recommendation; moderate quality evidence
Suggest using clinical criteria alone over:
C-reactive Protein (CRP)
Modified Clinical Pulmonary Infection Score (CPIS)
Weak recommendation; low-quality evidence
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10. Differentiating HAP and VAP
Nosocomial Pneumonia
Hospital-Acquired
Ventilator-Associated
Nosocomial pneumonia refers to all pneumonias that occur while the patient is within the healthcare system.
Nosocomial pneumonia can be further broken down into hospital-acquired and ventilator-associated based on more patient specific parameters.
The new 2016 HAP/VAP guidelines provide specific recommendations for each or these different conditions; therefore, we will address them separately.
Why is this important to differentiate?
Pathogen profile
Mortality/morbidity differences between the two

11. ≥ 48 hours after admission Hospital-acquired Pneumonia
Definition of HAP
Unchanged from 2005 guidelines
Development of symptoms ≥ 48 hours after hospital admission
Radiographic infiltrate
Clinical criteria:
Fever
Leukocytosis
Purulent sputum
Decline in oxygenation
Time zero = Admission
≥ 48 hours after admission
Symptom Development
The definition of HAP is unchanged from the 2005 guidelines.
HAP is development of pneumonia that was not ‘incubating’ at the time of admission and is apparent on chest x-ray with clinical criteria ≥ 48 hours after hospital admission.
Patients who are intubated can have HAP; however, they must have developed the pneumonia before intubation or <48 hours after intubation.
Hospital-acquired Pneumonia
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12. Diagnosis of HAP Microbiologic cultures
Sputum and blood
Non-invasive sampling preferred:
Spontaneous expectoration
Sputum induction
Nasotracheal suctioning
Endotracheal aspiration
Weak recommendation, very low-quality evidence
In terms of obtaining cultures; there is a general paucity of data for which type of culture should be obtained and much of the HAP data is derived from actual studies of VAP patients. However, there is a high likelihood that pts with HAP can develop bacteremia; therefore, guidelines still recommend obtaining sputum and blood cultures in all HAP pts. This is unchanged from the 2005 guidelines.
Endotracheal aspiration would be performed in a patient with HAP who subsequently requires mechanical ventilation.
In general, although the evidence for obtaining respiratory samples in this pt population is poor, obtaining cultures provides the opportunity to de-escalate antibiotics therapy and use targeted therapy. The guidelines are placing high value on identifying potential pathogens accurately and de-escalating antibiotic therapy
Consider adding use of biomarkers and CPIS scoring in the diagnosis of these conditions.
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13. Etiology of HAP Bacteria Gram (+) Gram (-) Gram (-) bacilli S. aureus
P. aeruginosa
The most common organisms for HAP are listed above.
These overlap with VAP with the exception of acinetobacter.
Based on a meta-analysis of 24 studies that provided relevant data regarding HAP
Gram-positive organisms
16% of isolates S. aureus (10% MRSA and 6% MSSA)
Gram-negative organisms
13% of isolates Pseudomonas
22% of isolates Gram-negative bacilli
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14. Etiology of HAP and Impact of Appropriate Therapy
Organism
Definitive
Possible
Total (%)
S. pneumoniae 14 2
16 (9.7)
L. pneumophilia 7
7 (4.2)
Enterobacteria 4
8 (4.8)
Aspergillus 3
P. aeruginosa 5
Acinetobacter
5 (4.2)
S. aureus 1
4 (3)
H. influenza
Other
Unknown
105 (63.6)
Total (n=165)
31 (18.8)
29 (17.6)
60 (36.4)
The meta-analysis conducted by the authors is supported by another multicenter trial conducted in 12 hospitals from 1999 to 2000.
This was a prospective trial focused on prospectively screening non-ICU patients for HAP and determining the microbial etiology of HAP using sputum/blood cultures and urine antigen testing for S. pneumo and Legionella.
Patients were diagnosed with HAP based on 1) new infiltrate; 2) clinical criteria: WBC >12,000, fever >38 C, cough and purulent expectoration; 3) PNA onset >72 hours after admission
Mortality was also evaluated as attributable to nosocomial pneumonia if it was the primary cause of death or contributed to it.
Microbiologic tests used were: urine legionella and strep antigen testing; blood and sputum cultures or tracheal aspirate cultures
Definitive: isolation of a primary pathogen in the blood, pleural fluid, lower respiratory tract, sputum or via positive urine
antigen testing
Possible: isolation of a nonprimary pathogen in adequate sputum samples in pure or predominant culture which correlated with the predominant morphology on gram stain
An etiologic diagnosis was obtained for on 60 of 165 patients with HAP.
Of those who had an etiologic diagnosis determined 95% received what was deemed appropriate antibiotic therapy by the authors.
The 5% of patients who did not receive appropriate antibiotic therapy had a significant difference in both crude and attributable mortality.
This study emphasizes the need for appropriate initial therapy to cover all likely organisms in HAP and highlights the difficulty in determining an actual etiologic diagnosis in patients with this condition.
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15. Etiology of HAP and Impact of Appropriate Therapy
Outcome
Appropriate Antibiotics
N=152
Inappropriate Antibiotics
N=8
P-value,
95% CI
Crude Mortality
34 (22.4%)
6 (75%)
p=0.003,
Attributable Mortality
23 (15.1%)
4 (50%)
p=0.02,
Based on the observations from this trial, inappropriate choice of antibiotic at the beginning of therapy was associated with increased rates of both crude and attributable mortality.
Although this is a small prospective trial, this data emphasizes the importance of choosing the appropriate antimicrobial therapy. The writing committee for the guidelines used this trial as indirect data to suggest the increased risk of mortality associated with these organisms (S. aureus, pseudomonas and gram (-) bacilli) and justify use of broad coverage especially because it can be difficult to achieve actual microbiologic diagnosis of HAP
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16. Etiology of HAP

17. Etiology of HAP

18. Etiology of HAP

19. Risk Factors for MDROs in HAP
2005 HAP/VAP Guidelines
Antimicrobial therapy in preceding 90 days
Current hospitalization ≥ 5 days
High frequency antibiotic resistance in the community of specific hospital unit
Presence or RF for HCAP
Hospitalization ≥ 2 days in last 90 days
Residence in NH or LTC
Home infusion therapy
Chronic dialysis within 30 days
Family member with MDRO
Immunosuppressive disease or therapy
2016 HAP Guidelines
MDR HAP
Prior use of IV antibiotics within 90 days
MRSA
Pseudomonas
Risk factors for MDROs have been updated in this version of the guidelines to reflect a more select patient population.
Base on a meta-analysis of data from the panel, only the 5 RF listed under MDR VAP are now considered.
IV antibiotic use is a direct risk factor for both MRSA and pseudomonas. This was the primary risk factor identified for pts with HAP. Notice how these recommendations are much less stringent than those in patients with suspected VAP.
This was delineated to help decrease use of superfulous broad spectrum antibiotic coverage.
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20. Empiric Therapy HAP All regimens should include coverage for:
S. aureus
Strong recommendation, low-quality evidence
Gram negative bacilli
P. aeruginosa
Strong recommendation, very low-quality evidence
Approximately 10% of cases of HAP are associated with MRSA and 6% with MSSA; therefore, panel recommends covering S. aureus in all empiric HAP regimens. Inadequate therapy for S. aureus may have risks for increased total mortality an increased risk of mortality associated with PNA.
Gram (-) bacilli and pseudomonas are also common causes and are therefore recommended in empiric regimens.
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21. Empiric Gram (+) Coverage HAP
Methicillin-susceptible S. aureus (MSSA)
No RF for antimicrobial resistance
Not at high-risk for mortality
Septic shock
Need for mechanical ventilation
Drug(s) of choice:
Piperacillin-tazobactam
Cefepime
Levofloxacin
Imipenem
Meropenem
Weak recommendation, very low-quality evidence
Similar to the VAP suggestions, if the pt has no RF for antimicrobial resistance, MRSA does not need to be covered empirically. Coverage for MSSA is adequate. In addition to MDRO RF, pt specific factors should be considered. Septic shock and need for mechanical ventialtion 2/2 PNA place pts at higher risk of mortality which may warrant more broad empiric coverage.
But in general HAP pts are less severely ill and because microbiologic cultures may be more difficult to obtain in these pts it is important to give conservative coverage because otherwise empiric coverage is likely to be continued for the duration of therapy.
Why not doripenem??
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22. Empiric Gram (+) Coverage HAP
Methicillin-resistant S. aureus (MRSA)
RF for antimicrobial resistance
Treated in ICU where MRSA rates >20%
Units where MRSA rates unknown
High risk for mortality
Drug(s) of choice:
Vancomycin
Linezolid
Weak recommendation, very low-quality evidence
The >20% rate was chosen by the panel in an effort to manage the risks/benefits in appropriately treating pts who may have MRSA infection but judiciously withholding MRSA coverage from pts who are not likely to need it.
The same MDR risk factors apply along with the criteria for high risk of mortality
No differences between MRSA agents have been found; therefore, either vancomycin or linezolid can be used but pt specific factors should be considered.
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23. MRSA Treatment: Vancomycin or Linezolid?
2011 Meta-analysis
Inclusion:
Randomized-controlled trials
Compared linezolid to a glycopeptide antibiotic
Pneumonia
Hospitalized patients
Primary outcome:
Clinical success at test-of-cure (TOC)
Glycopeptide antibiotics include vancomycin and teicoplanin
Meta-analysis of randomized controlled trials
Inclusion:
Randomized controlled trial
Compared linezolid to a glycopeptide (vancomycin or teicoplanin)
Pneumonia as source of infection
Hospitalized patients (could have been HAP or VAP)
Primary outcome:
Clinical success at test-of-cure (TOC) study follow-up visit for clinically evaluable patients (TOC visits ranged from 5 to 28 days after abx completion and success defined as clinical resolution of signs/symptoms from baseline)
Secondary outcome:
Clinical success at EOT
Microbiologic success (sputum pathogen eradication)
All-cause mortality
Drug related Aes
Pre-specified sub-group analysis of MRSA vs non-MRSA pneumonias
Studies compared linezolid 600 mg IV q 12 hours to vanco or teicoplanin (drug levels NOT assessed in trials for efficacy or toxicity)
Two studies did not measure TOC results and one of those studies (Wunderink trial) was a negative trial showing linezolid was superior to vancomycin. These studies utilized end-of-therapy (EOT) outcome assessment
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24. Test-of-Cure Results 0.2 0.5 1 2 5 Favors Glycopeptide
Study
Linezolid
Glycopeptide
RR (95% CI)
Rubenstein, 2001
71/107
62/91
0.97 (0.80, 1.18)
Stevens, 2002
20/39
16/32
1.03 (0.65, 1.63)
Wunderink, 2003
114/168
111/171
1.05 (0.90, 1.22)
Cepeda, 2004
23/43
30/55
0.98 (0.68, 1.42)
Wilcox, 2004
51/53
52/56
1.04 (0.95, 1.13)
Kohno, 2007
11/34
6/19
1.02 (0.45, 2.33)
Wunderink, 2008
13/23
9/19
1.19 (0.66, 2.16)
Lin, 2008
19/26
18/33
1.34 (0.91, 1.98)
Total
322/493
304/476
1.04 (0.97, 1.11)
#success/total
The primary outcome of clinical success (TOC) was not different between antibiotic classes in the ITT population.
There was also no difference in the EOT end point. In addition, sensitivity analyses looking at blinded vs un-blinded and vanco vs teicoplanin compared to linezolid did not result in a difference in outcome.
Based on this and other meta-analyses, either vancomycin or linezolid can be used. The practitioner should consider pt specific factors (plt count, end organ function), available resources and cost when choosing an agent.
0.2
0.5 1 2 5
Favors Glycopeptide
Favors Linezolid
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25. Empiric Gram (-) Coverage HAP
Coverage of gram (-) bacilli
Use of 1 anti-pseudomonal agent
No RF for antimicrobial resistance
Not at high-risk for mortality
Weak recommendation, low-quality evidence
Approximately 35% of HAP cases are caused by GNB; therefore, empiric therapy with an agent active against these and pseudomonas is warranted.
Withholding appropriate therapy increases the risk of mortality.
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26. Empiric Gram (-) Coverage HAP
Coverage of gram (-) bacilli
Use of 2 anti-pseudomonal agents
RF for antimicrobial resistance
High risk for mortality
Weak recommendation, very low-quality evidence
Decision to recommend 2 anti-pseudomonal agents in pts with HAP and the above risk factors is based on the VAP data.
High risk of mortality is defined in the same manner: septic shock or need for mechanical ventilation 2/2 PNA
This balances the competing goals of providing early and appropriate antibiotic therapy to avoid risk of mortality but also avoiding superfluous treatment that may lead to abx resistance, side effects and increased cost.
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27. Other Recommendations for Empiric Therapy
Avoid use of aminoglycosides
Weak recommendation, low-quality evidence
Consider use of 2 anti-pseudomonal drugs:
Structural lung disease
The panel provides other recommendations in regard to empiric therapy.
Due to poor lung penetration, low drug levels and increased risk for nephrotoxicity and ototoxicity the panel recommends against using aminoglycoside monotherapy. There have also been no studies that support improved clinical outcomes when using aminoglycosides in the HAP population.
Pts with structural lung disease such as COPD and CF have an increased risk for colonization and infection with pseudomonas; therefore, the panel recommends considering 2 anti-pseudomonal drugs when empirically treating this pt population.
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28. Designing an Empiric HAP Regimen
No MRSA RF and NOT High-Risk Mortality
MRSA RF and NOT High-Risk Mortality
MDR RF and/or High-Risk Mortality
Piperacillin-tazobactam OR
Cefepime OR
Levofloxacin OR
Imipenem OR
Meropenem
Meropenem OR
Aztreonam
Amikacin OR
Gentamicin OR
Tobramycin OR
PLUS
Vancomycin OR
Linezolid
Based on pt specific RF for MDROs and risk of mortality, select antibiotics within the appropriate column.
For pts at High risk of mortality and with RF for MDRs, choose two antipseudomonal agents from column 3 that are in different classes.

29. Case #1
JZ is a 73 year old African American male admitted 4/24/17 with acute ischemic stroke.
PMH: HTN, HLD, DM
Current Medications:
Aspirin 81 mg PO daily
Atorvastatin 80 mg PO daily
Metformin 1000 mg PO daily
Amlodipine 10 mg PO daily
Lisinopril 20 mg PO daily

30. Case #1
Today (4/27) JZ is coughing up purulent sputum, has decreasing O2Sat and altered mental status. The primary team decides to intubated JZ.
Vital Signs:
HR 101; RR 22; BP 104/69mmHg; Temp 100.6⁰F; O2Sat 89% on 2L
Anthropometrics:
75 kg; 170 cm
Labs:
134 | 100 | 24 / \ 10.4 / 213
3.7 | 22 | / 31.6 \
Chest X-Ray:
Endotracheal tube present, terminating 3 cm above the carina.
Left lower lobe infiltrate suggestive of pneumonia vs atelectasis.

31. What type of pneumonia does JZ have?
Ventilator-associated pneumonia
Healthcare-associated pneumonia
Aspiration pneumonia
Hospital-acquired pneumonia
Answer D
JZ has been present in the hospital for >48 hours. Although he requires mechanical ventilation for management of his respiratory status and pneumonia. He did not develop the pneumonia while he was on mechanical ventilation.
Health-care associated pneumonia is no longer included in the 2016 guidelines
Although JZ may have aspirated, there is no indication that he suffered and aspiration event

32. Vancomycin and piperacillin-tazobactam Meropenem and levofloxacin
The medical team asks for your recommendation on empiric antibiotic therapy for JZ. MRSA resistance rates are unknown in this institution. Which of the following is an appropriate empiric regimen for JZ?
Vancomycin and piperacillin-tazobactam
Meropenem and levofloxacin
Vancomycin, cefepime and levofloxacin
Linezolid and amikacin
Answer C
JZ is being treated for HAP.
He is considered to be a high risk of mortality because he is requiring mechanical ventilation as part of management for his HAP.
He does not have any other risk factors for MDROs.
Due to RF for mortality JZ is indicated to empirically receive:
MRSA coverage
Dual anti-pseudomonal coverage

33. > 48 hours after intubation Ventilator-associated Pneumonia
Definition of VAP
Unchanged from 2005 guidelines
Development of symptoms > 48 hours after endotracheal intubation
Radiographic infiltrate
Clinical criteria:
Fever
Leukocytosis
Purulent sputum
Decline in oxygenation
Admission
Time zero =
Intubation and Mechanical Ventilation
> 48 hours after intubation
Symptom Development
Definition of VAP is unchanged from the 2005 guidelines. Panel recognized that this definition is generally accepted and useful
VAP is development of pneumonia 48 hours after endotracheal intubation occurs. Therefore, time zero is the point at which the pt is intubated.
Pneumonia is a new infiltrate on chest x-ray with evidence to suggest the infiltrate is of an infectious origin, this can be delineated by the clinical criteria listed here:
-fever
-leukocytosis
-purulent sputum
-decline in oxygenation
Ventilator-associated Pneumonia
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34. Diagnosis of VAP Microbiologic cultures recommended
Sputum
Blood
Sampling via the non-invasive route preferred
Invasive route
Bronchoscopy
Blind bronchial sampling
Non-invasive route
Endotracheal aspiration (ETA)
Weak recommendation, low quality evidence
Due to the increasing risk of MDR pathogens and the risk of initial ineffective antibiotic therapy in patient’s with VAP, it is recommended to obtain sputum cultures in all patients with suspected VAP.
Although there is not clear evidence to support use of blood cultures in patients with VAP, approximately 15% of these patients will be bacteremic which in itself is a risk factor for increased morbidity and mortality; therefore, guidelines are recommending to obtain both sputum and blood cultures in these patients.
Sputum samples can be taken in a variety of ways from patients who are intubated and mechanically ventilated. The invasive route refers to sampling from a bronchoscopy or use of blind bronchial sampling. Non-invasive sampling would be those taken via aspiration from an endotracheal tube.
The use of the non-invasive route is preferred as there have been no studies proving that invasive sampling with quantitative cultures have improved clinical outcomes. Rather use of non-invasive samples decreases risk of complications and resource use allocated to each patient.
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35. Microbiologic Diagnosis of VAP
Semi-quantitative results preferred
Quantitative
Semi-quantitative
Weak recommendation, low quality evidence
Quantitative cultures results provide a direct number of cfu/mL bacteria grown from that particular sample
Semi-quantitative cultures provide a more subjective description of bacterial load within a sample (i.e. high vs moderate growth)
Use of quantitative vs non-quantitative results has been a debate.
Panelists summarized the available data for use of invasive vs non-invasive sampling techniques along with quantitative vs semi-quantitative data
Overall, semi-quantitative cultures taken from ETAs were the most sensitive but least specific in terms of diagnosis.
When reviewed together, patients who had antibiotics withheld due to cultures below the diagnostic threshold for VAP have similar clinical outcomes, less antibiotic use and better microbiologic outcome to patients who had antibiotics continued based on these quantitative cultures.
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36. Etiology of VAP Bacteria Gram (+) Gram (-) S. aureus Gram (-) bacilli
P. aeruginosa
Acinetobacter
The most common organisms known to cause VAP in the U.S. are listed here. These organisms also correspond with international surveillance programs albeit with a higher emphasis on P. aeruginosa and acinetobacter.
Gram-positive organisms
20 – 30% of isolates S. aureus
Gram-negative organisms
10 – 20% of isolates Pseudomonas
20 – 40% of isolates Gram-negative bacilli
5 – 10% of isolates Acinetobacter
Many of these organisms are also resistant to common antibiotics.
Ex ~50% of S. aureus are resistant to methicillin; 19-29% of P. aeruginos are resistant to piperacillin/tazobactam
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37. Etiology of VAP

38. Risk Factors for MDROs in VAP
2005 HAP/VAP Guidelines
Antimicrobial therapy in preceding 90 days
Current hospitalization ≥ 5 days
High frequency antibiotic resistance in the community of specific hospital unit
Presence or RF for HCAP
Hospitalization ≥ 2 days in last 90 days
Residence in NH or LTC
Home infusion therapy
Chronic dialysis within 30 days
Family member with MDRO
Immunosuppressive disease or therapy
2016 VAP Guidelines
MDR VAP
Prior use of IV antibiotics within 90 days
Septic shock at time of VAP
ARDS preceding VAP
≥ 5 days of hospitalization prior to VAP
Acute RRT prior to VAP
MRSA
Pseudomonas
Risk factors for MDROs have been updated in this version of the guidelines to reflect a more select patient population (HAP vs VAP).
Many studies have addressed potential risk factors for MDROs associated with VAP.
15 RF were included in a meta-analysis of the data.
Based on a meta-analysis of data from the panel, only the 5 RF listed under MDR VAP are now considered. IV antibiotic use is a direct risk factor for both MRSA and pseudomonas.
Question regarding early vs late onset of VAP and if that predisposes pts to MDRO PNA. Based on current evidence, the greatest risk factor for MDRO pneumonia is duration of admission. So, if pt has been in hospital >5 days plus other clinical factors, that is greater risk for MDROs rather than teasing out if the PNA developed 4 vs 7 days into the admit.
Table 2 from the guidelines
Discuss how this was determined using clinical evidence
More narrow definition
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39. Empiric Therapy VAP All regimens should include coverage for:
S. aureus
P. aeruginosa
Gram negative bacilli
Strong recommendation, low-quality evidence
S. aurues, P. aeruginosa and gram (-) bacilli are the most common pathogens associated with VAP. Delay of appropriate antimicrobial therapy for these pathogens is associated with an increased risk of mortality.
The guidelines will further delineate how to cover possible MDROs.
CID ; 63: 1-51.

40. Empiric Gram (+) Coverage VAP
Methicillin-susceptible S. aureus (MSSA)
No RF for antimicrobial resistance
Treated in ICU where MRSA rates <10 – 20%
Drug(s) of choice:
Piperacillin-tazobactam
Cefepime
Levofloxacin
Imipenem
Meropenem
Weak recommendation, very low-quality evidence
Not all patients require maximal empiric coverage. Decision to give most aggressive and broad-spectrum coverage is based on pt specific factors.
There is no specific evidence to pin-point threshold for give MSSA vs MRSA coverage.
The panel chose these particular values to try and minimize probability of inappropriate antibiotic coverage while recognizing indiscriminate coverage of all organisms in this setting is not necessary.
To arrive at these thresholds the panel considered the number of patients that would need to be treated to benefit 1 individual.
Example: ~25% of VAP is caused by MRSA. Using a prevalence rate of 10 to 20% means only 2.5 to 5% of VAP will be caused by MRSA and the majority of patients will not benefit from receiving MRSA coverage.
No evidence to specifically recommend one MSSA agent over the other. Use of an agent with MSSA and pseudomonal coverage may be appropriate empiric therapy in many pts. So use of a single agent, like those above, is possible.
CID ; 63: 1-51.

41. Empiric Gram (+) Coverage VAP
Methicillin-resistant S. aureus (MRSA)
RF for antimicrobial resistance
Treated in ICU where MRSA rates >10 – 20%
Units where MRSA rates unknown
Drug(s) of choice:
Vancomycin
Linezolid
Weak recommendation, very low-quality evidence
In deciding on empiric MRSA coverage, the panel suggests either vancomycin or linezolid can be used. Evidence does not clearly delineate that one agent is more effective than the other. Therefore, choice should be based on pt specific factors such as renal function, blood cell counts and concomitant therapies.
CID ; 63: 1-51.

42. Empiric Gram (-) Coverage VAP
Coverage of gram (-) bacilli
Use of 1 anti-pseudomonal agent
No RF for antimicrobial resistance
<10% of gram (-) isolates are resistant to an agent being considered for monotherapy
Weak recommendation, low-quality evidence
Due to the higher prevalence of gram (-)s causing VAP, the panel has suggested a lower threshold for empiric treatment with 1 vs 2 anti-pseudomonal agents. The higher prevalence means there is a higher risk of potential inappropriate empiric therapy.
CID ; 63: 1-51.

43. Empiric Gram (-) Coverage VAP
Coverage of gram (-) bacilli
Use of 2 anti-pseudomonal agents from 2 different classes
RF for antimicrobial resistance
>10% of gram (-) isolates are resistant to an agent being considered for monotherapy
ICU where local antimicrobial susceptibility rates are unknown
Weak recommendation, low-quality evidence
The panel made the recommendation to use 2 anti-pseudomonal agents in the pt population above despite their meta-analysis showing no difference in mortality, clinical response, adverse effect or acquired resistance rates with mono vs dual therapy. The recommendation was made because the panel was concerned that the data specifically excluded pts with hx of MDROs.
The data does suggest however that therapy can be de-escalated once organisms and susceptibilities are known.
CID ; 63: 1-51.

44. Summary of Meta-Analyses Comparing Different Classes of Gram-Negative Agents for Empiric Treatment of VAP
Comparison
Mortality
RR (95% CI)
Clinical Response
Acquired Resistance
Adverse Events
Combination vs monotherapy
1.11
(0.9, 1.38)
0.89
(0.75, 1.07)
1.13
(0.42, 3.00)
0.90
(0.69, 1.18)
Cephalosporin vs non-cephalosporin
0.97
(0.74, 1.27)
0.92
(0.78, 1.09)
2.36
(0.63, 8.86)
1.01
(0.82, 1.25)
Quinolone vs non-quinolone
(0.92, 1.39)
1.05
(0.91, 1.20)
0.77
(0.59, 1.01)
0.88
(0.78, 0.99)
Anti-Pseudomonal PCN vs non-anti-Pseudomonal PCN
1.12
(0.76, 1.66)
1.10
(0.80, 1.52)
Not Reported
0.96
(0.77, 1.20)
Aminoglycoside vs non-aminoglycoside
1.15
(0.88, 1.50)
0.82
(0.71, 0.95)
(0.70, 1.33)
Carbapenem vs non-carbapenem
0.78
(0.65, 0.94)
1.02
(0.93, 1.12)
1.16
(0.53, 2.55)
1.08
(0.90, 1.28)
Authors of the guidelines do not make specific recommendations on which gram (-) and anti-pseudomonal agent to use for treatment of VAP/HAP.
This is based on a meta-analysis of trial data conducted by them. In general there are no differences in mortality, clinical response, acquired resistance and AEs between agents used empirically.
Carbapenems are the exception to this observation as they showed lower rates of mortality BUT no difference in clinical response, acquired resistance or AEs. Trials also did not address C. diff rates associated with carbapenem use. Based on these data, author’s did not feel there was sufficient evidence to suggest carbapenem based regimens over any other abx. Also, doripenem is not recommended as it was shown to have higher mortality rates compared to meropenem and imipenem.
Reference: Supplemental Data tables and Figures for the IDSA-ATS management of Adults with aHAP and VAP: 2016 Clinical Practice Guidelines
Page 24 of guidelines for further explanation of why panel made recommendations
CID ; 63: 1-51.

45. Designing an Empiric VAP Regimen
Gram (+) Antibiotics with MRSA Activity
MSSA, Gram (-) and Antipseudomonal Antibiotics
Gram (-) Antibiotics with Antipseudomonal activity: Non-β-Lactam
Vancomycin OR
Piperacillin-tazobactam
Ciprofloxacin
Levofloxacin
Linezolid
Cefepime
Ceftazidime
Amikacin
Gentamicin
Tobramycin
Imipenem
Meropenem
Colistin
Polymyxin B
Aztreonam
When designing and empiric regimen for VAP, consider pt specific risk factors for MDROs and the institutional antibiogram.
In pts with risk factors for MRSA such as IV antibiotic use or the institution has >10-20% prevalence of MRSA, chose an antibiotic from the first column. Use vanco or linezolid based on pt specific factors
Then choose an agent from the second column to cover pseudomonas and gram (-) organisms. If resistance rates to one of the antibiotics in the 2nd column is >10% or the pt has other risk factors for MDRs also choose and antibiotic from the 3rd column. The pt will be on 3 empiric antibiotics total.
If the pt does not have RF for MRSA and rates of resistance rates to antipseudomonal agents are <10%, choose an antibiotic from the second column. The pt will only be on 1 empiric antibiotic

46. Emerging Therapies Generic Name Brand Name FDA Indications
Ceftolozane/Tazobactam
Ceftazidime/Avibactam
Brand Name
Zerbaxa
Avycaz
FDA Indications
cIAI (with metronidazole)
cUTI (incl. pyelonephritis)
In vivo Gram-negative Activity
Enterobacter cloacae
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumonia
Proteus mirabilis
Pseudomonas aeruginosa
Citrobacter freundii
Citrobacter koseri
In vivo Gram-positive Activity
Streptococcus anginosus
Streptococcus constellatus
Streptococcus salivarius
N/A
In vivo Anaerobic Activity
Bacteroides fragilis
ESBL Activity
Class A, C, D
Carbapenemases (KPC)
Avycaz [package insert]. Irvine, CA. Allergan USA, Inc
Zerbaxa [package insert]. Whitehouse Station, NJ. Merck & Co., Inc

47. Clinical Trials Ceftolozane/Tazobactam Ceftazidime/Avibactam
Phase III Trial (ASPECT-NP) currently enrolling patients
Comparing ceftolozane/tazobactam to meropenem for VAP and HAP requiring ventilation
Ceftazidime/Avibactam
Phase III Trial completed January 2016
Comparing ceftazidime/avibactam to meropenem in patients with nosocomial pneumonia
Nosocomial pneumonia includes VAP

48. Case #2
EK is a 26 year old Caucasian male admitted to the trauma ICU on 4/23/17 with multiple fractures and bilateral pneumothoraces requiring chest tube placement s/p ATV accident. EK is currently mechanically ventilated.
PMH: None
Current medications:
Enoxaparin 30 mg subcutaneously Q 12 hours
Fentanyl Infusion IV 250 mcg/hr
Propofol Infusion IV 22 mcg/kg/min
Famotidine 20 mg via OGT Q 12 hours

49. Case #2
Today (4/27) EK has new onset of fever and a change in his chest x-ray.
Vital Signs:
HR 97; RR 18; BP 120/71mmHg; Temp 101.7⁰F; O2Sat 94% on 40% FiO2
Anthropometrics:
87 kg; 182 cm
Labs:
140 | 99 | 17 / \ 12.4 / 178
3.7 | 21 | / 35.9 \
Chest X-Ray:
Endotracheal tube present, terminating 2 cm above the carina.
New right lower lobe opacity compared to previous studies. Representing pneumonia vs atelectasis, correlate clinically.

50. Based on the EK’s patient specific factors and the hospital’s antibiogram below. Which of the following is an appropriate empiric regimen for EK?
Organism
Oxacillin
Vancomycin
Piperacillin-tazobactam
Meropenem
Cefepime
Levofloxacin
S. aureus 91 99 87 89 93 86
E. coli -- 85 90 79
P. aeruginosa 78 84 81
P. mirabilis 96 83
Answer B
EK has no RF for MDR organisms (no IV abx, no shock, no ARDS, no HD, 4 days of admission)
MRSA rates in this hospital are <10%; therefore, MRSA coverage is not indicated
Dual anti-pseudomonal coverage is indicated b/c all anti-pseudomonal agents available at this institution have >10% resistance rates
Piperacillin-tazobactam plus levofloxacin
Linezolid plus cefepime
Meropenem
Vancomycin plus meropenem plus levofloxacin

51. De-escalation of Antibiotics
De-escalation therapy
Changing empiric broad-spectrum therapy to narrower spectrum regimen
Fixed therapy
Maintaining broad-spectrum therapy for the duration of treatment
Suggest antibiotic therapy be de-escalated rather than fixed
Weak recommendation, very low-quality evidence
It is generally accepted that de-escalation therapy is beneficial for pts and to prevent development of MDROs.
Data evaluated by the panel offered conflicting results regarding use of de-escalation strategies vs fixed therapy.
3 studies found a non-statistically significant reduction in mortality with de-escalation therapy vs 2 studies that found an increase in mortality with the same approach.
When all evidence is evaluated together:
Not difference in mortality or ICU LOS
Conflicting evidence regarding recurrent pneumonia
De-escalation may ↑ antimicrobial days, superinfection and emergence of MRSA
National guidelines recommend use of de-escalation strategy due to reduced antimicrobial resistance, side effects and costs. However, there is little evidence to support these claims. Still, authors felt the evidence regarding this subject is of such poor quality and there are so many variables influencing the outcomes of published trials that they would base recommendation on clinical experience and clinical rationale.
This area is identified as needing further well-designed RCTs to give better evidence.
CID ; 63: 1-51.

52. Optimal Antibiotic Duration
VAP, a 7-day course of therapy recommended
No difference:
Mortality
Recurrent pneumonia
Treatment failure
Hospital LOS
Duration of mechanical ventilation
Includes non-glucose fermenting gram (-) bacilli
Strong recommendation; moderate quality evidence
Clinical debate regarding optimal antibiotic duration of VAP exists; in the 2005 guidelines it was recommended to limit abx course from the traditional days to 7 days only with the execption of pts being treated for a psuedomonal pneumonia. This was based primarily on the Chastre study published in 2003 that found no difference in 8 vs 15 day therapy for VAP pts; however, pts with pneumonia due to pseudomonas or acinetobacter had a higher likelihood of recurrence with a shorter duration of therapy.
Current meta-analysis done by authors of 2016 guidelines found no differences in short (7-8 day) course vs long (10-15 day) course of therapy in terms of mortality, clinical cure and recurrent pneumonia. Again, no differences were found in pts with infections due to non-glucose fermenting gram (-) bacilli. Although there may be an increase in recurrence, mortality and clinical cure rates to not appear to be affected.
CID ; 63: 1-51.

53. 8-Day vs 15-Day Course of Therapy
2003 Chastre, et al.
Prospective, randomized, double-blind, controlled study
Inclusion criteria:
Mechanical ventilation for ≥ 48 hours
≥ 18 years old
Clinical suspicion of VAP
Positive quantitative cultures from bronchoscopy
Initiation of appropriate antibiotics within 24 hours of bronchoscopy
JAMA ; 290(19):

54. 8-Day vs 15-Day Course of Therapy
Primary outcomes:
Event
8-Day Regimen
(n=197)
15-Day Regimen
(n=204)
Between-Group Risk Difference (90% CI)
Death from all causes
37/197 (18.8)
35/204 (17.2)
1.6 (-3.7 to 6.9)
Pulmonary infection recurrence
NF GNB
57/197 (28.9)
26/64 (40.6)
53/204 (26)
16/63 (25.4)
2.9 (-3.2 to 9.1)
15.2 (3.9 to 26.6)
Mean (SD)
Mean Difference
(95% CI)
No. Antibiotic-free days
13.1 (7.4)
8.7 (5.2)
4.4 (3.1 to 5.6)
JAMA ; 290(19):

55. Short vs Long Course Therapy
2015 Cochrane Systematic Review
Outcomes
Assumed Risk
Long-Course
Corresponding Risk
Short-Course
(95% CI)
Relative Effect
No. of Participants
(Studies)
Mortality
F/u: 28 days
175 per 1000
201 per 1000
(141 to 277)
OR 1.18
(0.77 to 1.8)
598
(3 studies)
NF-GNB
265 per 1000
255 per 1000
(123 to 450)
OR 0.95
(0.39 to 2.27)
179
(2 studies)
Systematic review included HAP and VAP patients together in the analysis because no evidence of existed for pts with high likelihood of HAP who were not mechanically ventilated.
Pugh R, Grant C, Cooke RPD, Dempsey G.
Cochrane Database of Systematic Reviews 2015, Issue 8. Art. No.: CD

56. Short vs Long Course Therapy
2015 Cochrane Systematic Review
Outcomes
Assumed Risk
Long-Course
Corresponding Risk
Short-Course
(95% CI)
Relative Effect
No. of Participants
(Studies)
Recurrence of PNA
180 per 1000
237 per 1000
(171 to 318)
OR 1.41
(0.94 to 2.12)
733
(19 studies)
Recurrence of PNA NF-GNB
247 per 1000
417 per 1000
(272 to 577)
OR 2.18
(1.14 to 4.16)
176
(2 studies)
28-Day Antibiotic-free Days
The mean 28-day antibiotic free days in the intervention group was 4.02 higher
(2.26 to 5.78 higher)
431
Systematic review included HAP and VAP patients together in the analysis because no evidence of existed for pts with high likelihood of HAP who were not mechanically ventilated.
Pugh R, Grant C, Cooke RPD, Dempsey G.
Cochrane Database of Systematic Reviews 2015, Issue 8. Art. No.: CD

57. Optimal Antibiotic Duration
HAP, a 7-day course of therapy recommended
No specific studies available for HAP
Data extrapolated from VAP
Increased 28-day antibiotic free days
Reduced recurrent VAP due to MDR pathogens
Strong recommendation; very-low quality evidence
There is a paucity of data regarding optimal duration of HAP therapy. Most information is extrapolated from the VAP populaiton and studies. In general, a short course of therapy is not associated with increased mortality, recurrent pneumonia, treatment failure, hospital LOS or duration of MV.
In addition, reducing the number of antibiotic days reduces risk of antibiotic associated side-effects including C. difficile infections, acquisition of antibiotic resistance and costs.
Based on these benefits, the panel recommends a short-course of therapy with 7 days or potentially less if indicated.
CID ; 63: 1-51.

58. Summary Definitions of HAP and VAP are unchanged from 2005 guidelines
Diagnosis of HAP and VAP should be based on clinical criteria and non-invasive semi-quantitative cultures
Risk factors for MDROs differ between HAP and VAP patients
Empiric therapy should be based on patient risk factors and local antimicrobial resistance patterns
Short-course therapy with de-escalation recommended

59. THANK YOU