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Treatment of Hospital- Acquired and Ventilator- Associated Pneumonia TAYLOR D. STEUBER, PHARM.D., BCPS ASSISTANT CLINICAL PROFESSOR AUBURN UNIVERSITY HARRISON SCHOOL OF PHARMACY UAB SCHOOL OF MEDICINE-HUNTSVILLE CAMPUS Disclosures No

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SLIDE 1

Treatment of Hospital- Acquired and Ventilator- Associated Pneumonia

TAYLOR D. STEUBER, PHARM.D., BCPS ASSISTANT CLINICAL PROFESSOR AUBURN UNIVERSITY HARRISON SCHOOL OF PHARMACY UAB SCHOOL OF MEDICINE-HUNTSVILLE CAMPUS

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SLIDE 2

Disclosures

  • No actual or potential conflicts of interest in relation to

this presentation

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SLIDE 3

Learning Objectives

Pharmacists

1. Define hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) 2. Describe three updates from the 2005 guidelines for treatment of nosocomial pneumonia 3. Select appropriate first-line antimicrobials for empiric treatment of HAP and VAP

Technicians

1. Identify symptoms associated with HAP and VAP 2. Define a hospital antibiogram and its role in treatment of HAP and VAP 3. List antimicrobials used in the treatment of HAP and VAP

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SLIDE 4

Terms

  • HAP: Hospital-acquired pneumonia
  • VAP: Ventilator-associated pneumonia
  • CAP: Community-acquired pneumonia
  • HCAP: Healthcare-associated pneumonia
  • HAI: Hospital-acquired infection
  • ICU: Intensive care unit
  • IDSA: Infectious Diseases Society of

America

  • ATS: American Thoracic Society
  • MDR: Multi-drug resistant
  • BAL: Bronchoalveolar lavage
  • PSB: Protected specimen brush
  • PCT: Procalcitonin
  • sTREM-1: Soluble triggering receptor

expressed on myeloid cells

  • CRP: C-reactive protein
  • CPIS: Clinical pulmonary infection score
  • MRSA: Methicillin Resistant S. aureus
  • MSSA: Methicillin Susceptible S. aureus
  • PK: Pharmacokinetic
  • PD: Pharmacodynamic
  • ESBL: extended-spectrum beta-lactamase
  • GNR: gram negative rod
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SLIDE 5

Background

  • Account for 21.8% of HAIs
  • VAP
  • 10% of patients who require mechanical ventilation
  • Attributable mortality estimated at 13%
  • Increases mechanical ventilation, hospitalization, cost
  • HAP
  • HAP in ICU has similar mortality rate as VAP
  • Complications occur in 50% of patients

Magill SS, et al. N Engl J Med 2014;370(13):1198-1208. Wang Y, et al. N Engl J Med 2014;370:341-351. Melsen WG, et al. Lancet Infect Dis 2013;13(8):665-671. Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 6

Background

  • IDSA/ATS Clinical Practice Guidelines
  • 2005: Management of Adults with HAP, VAP, and HCAP
  • 2016: Management of Adults with HAP and VAP
  • Where did HCAP go?
  • Patients with “HCAP” NOT high risk for MDR pathogens
  • Patient characteristics are important determinants
  • Coverage for MDR pathogens among community-dwelling patients
  • Validated risk factors for MDR pathogens
  • Spring 2018 CAP Guidelines

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111. ATS/IDSA. Am J Respir Crit Care Med 2005;171:388-416

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SLIDE 7

Definitions

  • Pneumonia
  • Presence of new lung infiltrate
  • Clinical evidence the infiltrate is of an infectious origin
  • New onset fever, purulent sputum, leukocytosis, decline in oxygenation
  • HAP
  • Not incubating at the time of hospital admission
  • Occurring 48 hours or more after admission
  • VAP
  • Occurring >48 hours after endotracheal intubation

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111. ATS/IDSA. Am J Respir Crit Care Med 2005;171:388-416.

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SLIDE 8

Risk Factors for MDR Pathogens

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

Risk Factors for MDR VAP

  • Prior intravenous antibiotic use within 90 days
  • Septic shock at time of VAP onset
  • ARDS preceding VAP
  • ≥ 5 days of hospitalization prior to VAP onset
  • Acute renal replacement therapy prior to VAP onset
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SLIDE 9

Risk Factors for MDR Pathogens

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

Risk Factors for MDR HAP

  • Prior intravenous antibiotic use within 90 days

Risk Factors for MRSA HAP/VAP

  • Prior intravenous antibiotic use within 90 days

Risk Factors for Pseudomonas HAP/VAP

  • Prior intravenous antibiotic use within 90 days

Note: structural lung disease (cystic fibrosis and bronchiectasis) also important factor

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SLIDE 10

IDSA/ATS Diagnostic Recommendations

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SLIDE 11

Diagnostic Methods

  • Blood Cultures: all patients with suspected HAP/VAP
  • Microbiologic Methods
  • VAP
  • Non-invasive sampling with semiquantitative cultures preferred
  • Endotracheal aspiration
  • Invasive quantitative culture cutoffs
  • BAL: 104 CFU/mL
  • PSB: 103 CFU/mL

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 12

Diagnostic Methods

  • Microbiologic Methods [cont.]
  • HAP
  • Non-invasive sputum sampling preferred over empiric treatment
  • Spontaneous expectoration
  • Sputum induction
  • Nasotracheal suctioning
  • Endotracheal aspiration if requiring mechanical ventilation

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 13

Diagnostic Methods

  • Biomarkers to diagnose along with clinical criteria
  • PCT – not recommended
  • sTREM-1 – not recommended
  • CRP – not suggested
  • Clinical Pulmonary Infection Score (CPIS)
  • Semi-objective scoring tool for VAP (0-12)
  • Not recommended

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111. Zilberberg MD, et al. Clin Infect Dis 2010;51(S1):S131–S135.

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SLIDE 14

IDSA/ATS Treatment Recommendations – VAP

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VAP – Empiric Treatment

  • Antibiograms
  • Local (hospital-specific, unit specific)
  • Population-specific ideal (ie. VAP patients)
  • “Regularly” update and disseminate
  • Empiric treatment informed by:
  • Local distribution of pathogens and their susceptibilities

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 16

VAP – Empiric Treatment

  • Empiric regimens should cover:
  • Staphylococcus aureus
  • Pseudomonas aeruginosa

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111. Sievert DM, et al. Infect Control Hosp Epidemiol 2013;34:1-14.

Organisms Associated with VAP Organism Prevalence

  • S. aureus

20-30%

  • P. aeruginosa

10-20% Enteric Gram Negative Bacilli 20-40% Acinetobacter baumannii 5-10%

  • Other gram-negative bacilli
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SLIDE 17

VAP – Empiric Treatment

  • Staphylococcus aureus coverage
  • MRSA if one of the following:
  • IV antibiotics in last 90 days (risk factor for MRSA VAP)
  • Risk factor for MDR VAP
  • Local MRSA prevalence >10-20%
  • Local MRSA prevalence unknown
  • MSSA coverage if none present

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 18

VAP – Empiric Treatment

  • Pseudomonas aeruginosa/gram-negative coverage
  • 2 agents if one of the following:
  • Risk factor for MDR VAP
  • Local gram-negative resistance >10% for single agent used
  • Local gram-negative resistance unknown
  • Structural lung disease (cystic fibrosis, bronchiectasis)
  • 1 agent if none present

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 19

Empiric T Empiric Treatment R eatment Regimens f gimens for V r VAP

MRSA MRSA Agents ents AP Beta Lact AP Beta Lactams ams AP Non-Be P Non-Beta Lactams ta Lactams Glycopeptide Vancomycin Antipseudomonal Penicillins Piperacillin-tazobactam Fluoroquinolones Ciprofloxacin Levofloxacin Oxazolidinones Linezolid Cephalosporins Cefepime Ceftazidime Aminoglycosides Amikacin Gentamicin Tobramycin Carbapenems Imipenem Meropenem Polymyxins (not preferred) preferred) Colistin Polymyxin B Monobactams Aztreonam

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 20

VAP – Empiric Treatment

  • No MRSA empiric coverage indicated
  • Include antipseudomonal with MSSA activity
  • Piperacillin-tazobactam, Cefepime, Levofloxacin,

Imipenem, Meropenem

  • Avoid aminoglycosides if possible
  • Avoid colistin if possible

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 21

IDSA/ATS Treatment Recommendations – HAP

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SLIDE 22

HAP – Empiric Treatment

  • Antibiograms
  • Local (hospital-specific, unit specific)
  • Population-specific ideal (ie. HAP patients)
  • “Regularly” update and disseminate
  • Empiric treatment informed by:
  • Local distribution of pathogens and their susceptibilities

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 23

HAP – Empiric Treatment

  • Empiric regimens should cover:
  • Staphylococcus aureus
  • Pseudomonas aeruginosa

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

Organisms Associated with VAP Organism Prevalence

  • S. aureus

16%

  • P. aeruginosa

13% Enteric Gram Negative Bacilli 19% Acinetobacter baumannii 6%

  • Other gram-negative bacilli
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SLIDE 24

HAP – Empiric Treatment

  • Staphylococcus aureus coverage
  • MRSA if one of the following:
  • IV antibiotics in last 90 days (risk factor for MRSA HAP)
  • Local MRSA prevalence >20%
  • Local MRSA prevalence unknown
  • High risk of mortality
  • Ventilatory support due to HAP or septic shock
  • MSSA coverage if none present

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 25

HAP – Empiric Treatment

  • Pseudomonas aeruginosa/gram-negative coverage
  • 2 agents if one of the following:
  • Risk factor for MDR HAP (IV antibiotics within 90 days)
  • High risk of mortality
  • Ventilatory support due to HAP or septic shock
  • Structural lung disease (cystic fibrosis, bronchiectasis)
  • Numerous and predominant gram-negative bacilli on gram stain
  • 1 agent if none present

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 26

Empiric T Empiric Treatment R eatment Regimens f gimens for HAP r HAP

Not high risk f Not high risk for mor r mortality ality No MRS No MRSA risk risk fact factor

  • rs

Not high risk f Not high risk for mor r mortality ality MRS MRSA risk risk fact factor

  • rs

High risk High risk of

  • f mor

mortality ality IV antibiotics IV antibiotics within ithin 90 da 90 days ys One of the following: One of the following: Two of the following:

  • Piperacillin-tazobactam
  • Cefepime
  • Levofloxacin
  • Imipenem
  • Meropenem
  • Piperacillin-tazobactam
  • Cefepime
  • Ceftazidime
  • Levofloxacin
  • Ciprofloxacin
  • Imipenem
  • Meropenem
  • Aztreonam
  • Piperacillin-

tazobactam

  • Cefepime
  • Ceftazidime
  • Imipenem
  • Meropenem
  • Aztreonam
  • Levofloxacin
  • Ciprofloxacin
  • Amikacin
  • Gentamicin
  • Tobramycin

Plus one of the following: Plus one of the following:

  • Vancomycin
  • Linezolid
  • Vancomycin
  • Linezolid

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 27

HAP – Empiric Treatment

  • No MRSA empiric coverage indicated
  • Include antipseudomonal with MSSA activity
  • Piperacillin-tazobactam, Cefepime, Levofloxacin,

Imipenem, Meropenem

  • Avoid aminoglycoside monotherapy
  • Avoid colistin if possible

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 28

IDSA/ATS Additional Recommendations – HAP/VAP

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SLIDE 29

PK/PD Dosing

  • Utilize PK/PD data for antibiotic dosing
  • Examples
  • Antibiotic blood concentrations: Vancomycin
  • Extended and continuous infusions: β-Lactams
  • Penicillins, cephalosporins, carbapenems
  • Weight-based dosing: Aminoglycosides
  • Reduced mortality, ICU length of stay
  • Improved clinical cure rate

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 30

Inhaled Antibiotics

  • Both inhaled and systemic antibiotics
  • VAP due to gram negative bacilli
  • Susceptible ONLY to aminoglycosides/polymyxins
  • Not responding to IV antibiotics alone
  • Tobramycin, gentamicin, and colistin
  • Improves clinical cure rate
  • No effect on mortality, adverse drug reactions

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

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SLIDE 31

HAP/VAP – Directed Treatment

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111. Tsai HY, et al. Diagn Microbiol Infect Dis 2014; 80:222–6. Nguyen HM, et al. J Antimicrob Chemother 2014; 69:871–80.

Proven Organism Agent(s) of Choice MSSA Oxacillin, Nafcillin, Cefazolin MRSA Vancomycin, Linezolid Pseudomonas spp. Based on susceptibilities*, avoid aminoglycosides ESBL-producing GNR Based on susceptibilities (Carbapenems?) Acinetobacter spp. Carbapenems, Ampicillin/Sulbactam, (Colistin IV/INH) Carbapenem-resitance Polymyxins IV + Colistin INH

*Consider 2 agents if in septic shock or high risk of death (>25%)

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SLIDE 32

HAP/VAP – Length of Therapy

  • 7-day course recommended for all patients
  • Reduced:
  • Antibiotic exposure
  • No difference:
  • Mortality
  • Recurrent pneumonia
  • Treatment failure

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111.

  • VAP due to MDR pathogens
  • Length of stay
  • Mechanical ventilation
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SLIDE 33

HAP/VAP – Final Recommendations

  • De-escalate when susceptibilities known
  • Discontinuation of antibiotics along with clinical criteria
  • PCT: suggested
  • If used, baseline PCT then daily
  • CPIS: not suggested

Kalil AC, et al. Clin Infect Dis 2016;63(5):e61-e111. Stolz D, et al. Eur Respir J 2009;34:1364–75. Bouadma L, et al. Lancet 2010; 375:463–74.

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SLIDE 34

Summary

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SLIDE 35

Yes

Pneumonia ≥ 48 hours after: Intubation (VAP) Hospitalization (HAP)

Any of the following?

  • IV antibiotics in last 90 days
  • Ventilator support
  • Septic shock

Any of the following?

  • IV antibiotics in last 90 days
  • Septic shock
  • ARDS preceding VAP
  • ≥ 5 days hospitalization
  • Acute RRT prior to VAP

No Treatment:

  • MRSA coverage plus
  • 2 anti-pseudomonal agents
  • Different classes

Are S . aureus isolates:

  • >10-20% MRSA? (VAP)
  • >20% MRSA? (HAP)
  • Unknown? (HAP/VAP)

Treatment:

  • MRSA coverage plus
  • Anti-pseudomonal agent(s)

Yes Any of the following?

  • Structural lung disease
  • >10% pseudomonal resistance to monotherapy (VAP)
  • Local susceptibilities unknown (VAP)
  • Numerous/predominant GN bacilli on gram stain (HAP)

No No Yes Treatment:

  • 2 anti-pseudomonal agents
  • 1 with MSSA activity (if no MRSA)
  • Different classes

Treatment:

  • 1 anti-pseudomonal agent
  • MSSA activity (if no MRSA)

Assessment Treatment (End) Treatment (Continue)

Step 1: Risk/Severity Step 2: GP Risk Step 3: GN Risk

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SLIDE 36

Takeaway Points

  • Removal of the term “HCAP”
  • Removal of the term “early-onset” and “late-onset”
  • Development of hospital/unit-specific antibiograms
  • Minimize unnecessary dual gram-negative coverage
  • Minimize unnecessary MRSA coverage
  • Risk factor assessment – see treatment algorithm
  • PK/PD dosing preferred
  • Directed therapy preferred
  • Short-course (7 days) preferred over longer course
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SLIDE 37

Assessment Question #1

Hospital acquired pneumonia (HAP) is defined as a pneumonia not incubating at the time of hospital admission and occurring 48 hours or more after hospital admission. True or False.

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SLIDE 38

Assessment Question #1

Hospital acquired pneumonia (HAP) is defined as a pneumonia not incubating at the time of hospital admission and occurring 48 hours or more after hospital admission. True or False.

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SLIDE 39

Assessment Question #2

Which of the following durations is appropriate for most patients treated for HAP or VAP?

  • a. 3 days
  • b. 7 days
  • c. 10 days
  • d. 14 days
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SLIDE 40

Assessment Question #2

Which of the following durations is appropriate for most patients treated for HAP or VAP?

  • a. 3 days
  • b. 7 days
  • c. 10 days
  • d. 14 days
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SLIDE 41

Assessment Question #3

Which of the following combinations represents the most appropriate empiric treatment regimen for hospital-acquired pneumonia (HAP) where the prevalence of MRSA is >20% and the patient has not had IV antibiotics in the last 90 days and is not at high risk of mortality?

  • a. Daptomycin + piperacillin-tazobactam
  • b. Linezolid + tobramycin
  • c. Vancomycin + cefepime
  • d. Vancomycin + cefepime + levofloxacin
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SLIDE 42

Assessment Question #3

Which of the following combinations represents the most appropriate empiric treatment regimen for hospital-acquired pneumonia (HAP) where the prevalence of MRSA is >20% and the patient has not had IV antibiotics in the last 90 days and is not at high risk of mortality?

  • a. Daptomycin + piperacillin-tazobactam
  • b. Linezolid + tobramycin
  • c. Vancomycin + cefepime
  • d. Vancomycin + cefepime + levofloxacin
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SLIDE 43

References

  • Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of health care–associated infections. N Engl J Med 2014;370(13):1198-1208.
  • Wang Y, Eldridge N, Metersky ML, et al. National trends in patient safety for four common conditions, 2005–2011. N Engl J Med 2014;370:341-351.
  • Melsen WG, Rovers MM, Groenwold RH, et al. Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from

randomised prevention studies. Lancet Infect Dis 2013;13(8):665-671.

  • Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines

by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 2016;63(5):e61-e111.

  • American Thoracic Society and Infectious Disease Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated,

and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171:388-416.

  • Zilberberg MD and Shorr AF. Ventilator-associated pneumonia: the clinical pulmonary infection score as a surrogate for diagnostics and outcome. Clin Infect

Dis 2010;51(S1):S131–S135.

  • Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the

National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010. Infect Control Hosp Epidemiol 2013;34:1-14.

  • Tsai HY, Chen YH, Tang HJ, et al. Carbapenems and piperacillin/tazobactam for the treatment of bacteremia caused by extended-spectrum beta-lactamase-

producing Proteus mirabilis. Diagn Microbiol Infect Dis 2014; 80:222–6.

  • Nguyen HM, Shier KL, Graber CJ. Determining a clinical framework for use of cefepime and beta-lactam/beta-lactamase inhibitors in the treatment of

infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother 2014; 69:871–80.

  • Stolz D, Smyrnios N, Eggimann P, et al. Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study. Eur Respir J

2009;34:1364–75.

  • Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicenter

randomised controlled trial. Lancet 2010; 375:463–74.

  • Navalkele B, Pogue JM, Nishan B, et al. Risk of acute kidney injury in patients on concomitant vancomycin and piperacillin–tazobactam compared to those
  • n vancomycin and cefepime Clin Infect Dis 2017;64(2):116-23.
  • Hammond DA, Smith MN, Li C, Hayes SM, Lusardi K, Bookstave PB. Systematic review and metaanalysis of acute kidney injury associated with

concomitant vancomycin and piperacillin/tazobactam Clin Infect Dis 2017;64(5):666-74.

  • Mousavi M, Zapolskaya T, Scipione MR, Louie E, Papadopoulos J, Dubrovskaya Y. Comparison of rates of nephrotoxicity associated with vancomycin in

combination with piperacillin-tazobactam administered as an extended versus standard infusion Pharmacother 2017;37(3):379-85.

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SLIDE 44

Questions?

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SLIDE 45

Supplemental Slides

Image from: Zilberberg MD, et al. Clin Infect Dis 2010;51(S1):S131–S135.

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SLIDE 46

Supplemental Slides

Image from: Bouadma L, et al. Lancet 2010; 375:463–74.

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SLIDE 47

Supplemental Slides

  • Piperacillin-tazobactam (PT) vs. cefepime (C) with concomitant vancomycin (V)
  • AKI in VPT vs. VC (retrospective, matched cohort); Navalkele et al. 2017
  • VPT 81/279 [29%] vs. VC 31/279 [11%] (HR 4.27, 95% CI 2.73-6.68)
  • VPT faster onset than VC (3 vs 5 days; p<0.0001)
  • AKI in V with PT vs. V without PT (meta-analysis); Hammond et al. 2017
  • VPT associated with AKI (OR 3.12, 95% CI 2.04-4.78)
  • AKI in VPT SI vs. VPT EI (retrospective, matched cohort); Mousavi et al. 2017
  • VPT SI 24/140 [17.1%] vs VPT EI 25/140 [17.9%] (p>0.99)
  • Median time to onset 4 (IQR 3-6) days, no difference

Navalkele B, et al. Clin Infect Dis 2017;64(2):116-23. Hammond DA, et al. Clin Infect Dis 2017;64(5):666-74. Mousavi M, et al. Pharmacother 2017;37(3):379-85. AKI: acute kindey injury SI: standard infusion HR: hazards ratio EI: extended infusion OR: odds ratio