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IDSA Guidelines on Pneumonia

Overview of Changes to 2016 vs. 2005 IDSA HAP and VAP Guidelines

Objectives

  • 2007 Community Acquired Pneumonia (CAP) guideline.
  • Adoption of GRADE methodology to evaluate evidence
  • To examine the evidence behind using the term healthcare associated pneumonia (HCAP) and rationale for its removal.

Update to align recommendations between IDSA and American Thoracics Society (ATS) projected to be published in Summer 2017.

  • Removal of "healthcare-associated pneumonia" (HCAP)

  • Address use of specific diagnostic tools
  • To review the evidence and current recommendation of specific diagnostic tools in HAP/VAP.
  • Risk factors for multidrug-resistant organisms (MDROs)
  • Prior HAP and VAP guidelines published in 2005 by IDSA and American Thoracics Society (ATS).
  • To determine whether antimicrobial activity against MRSA or Pseudomonas is warranted based on presence of risk factors for multidrug-resistant organisms.
  • Emphasis on use of antibiograms

Recently updated in May 2016.

  • Duration of treatment
  • To review the evidence behind the updated recommended duration of treatment of HAP/VAP.

Quick Review of Definitions...

Treatment of HAP & VAP

Hospital-Acquired Pneumonia (HAP)

In suspected HAP/VAP, recommend coverage for S. aureus, Pseudomonas aeruginosa, and other gram-negative bacilli in empiric regimens:

Impact of HAP & VAP

  • Occurs 48 hours or more after hospitalization and not incubating at the time of admission

Ventilator-Associated Pneumonia (VAP)

  • Develops more than 48 to 72 hours after endotracheal intubation
  • HAP and VAP together account for 22% of all hospital-acquired infections.

Am J Respir Crit Care Med. 2005;171(4):388.

Healthcare-Associated Pneumonia (HCAP)

  • Hospitalized in acute care hospital for 2 or more days within 90 days
  • Resided in nursing home or long term care
  • Recent IV antibiotics, chemotherapy,or wound care within past 30 days
  • Attended a hospital or hemodialysis clinic within past 30 days
  • Approximately 10% of patients requiring mechanical ventilation develop VAP, which can prolong hospitalization by 11.5 to 13.1 days.

Note: mostly based on weak recommendation, low quality evidence

Am J Respir Crit Care Med. 2005;171(4):388.

Summary

  • Recommended duration of treatment no longer specific to type of pathogen and virulence but set as 7 days for all HAP/VAP. Extended duration may be warranted and should take into account of patient's clinical status.
  • HAP alone is associated with overall mortality rates as high as 27 to 51%.
  • Antibiotic regimens should be tailored using local antibiotic-resistance data. All hospitals are recommended to routinely generate and distribute local antibiogram, especially for ICU.
  • Antibiotic dosing should be based on pharmacokinetic and pharmacodynamic data when available rather than manufacturer recommendations.

N Engl J Med 2014; 370:2542–3.

Clin Infect Dis 2010; 51(suppl 1):S120–5.

Am J Infect Control 2008; 36:S93–S100.

Eur Respir J 2011; 37:1332–1339.

Duration of Treatment

Why Dual

Antipseudomonal Coverage?

Summary

  • Systematic review of 41 trials that compared monotherapy to combination therapy in treatment of VAP reported no mortality benefit beyond monotherapy (RR=0.94; 95% CI: 0.76-1.16).

Traditionally, longer duration of treatment preferred for non-fermenting gram-negative bacilli (e.g. Pseudomonas).

  • 5 RCTs found similar clinical outcomes in monotherapy vs. combination antipseudomonal therapy including:
  • "HCAP" removed. However, some individual criteria still valid risk factors for MDROs. Potentially revised definition coming with new CAP guidelines.

- clinical treatment success

- microbiological treatment success

- ICU and hospital length of stay

- mortality

For patients with VAP or HAP, recommend a 7-day course of antimicrobial therapy rather than a longer duration.

Limitations:

  • Diagnosis shifting towards greater reliance on clinical criteria alone due to poor performance characteristics or lack of clinical difference in emerging clinical tools or biomarkers.
  • Many trials were unblinded
  • Trials enrolled HAP/VAP due to any pathogen (only 6-23% were due to Pseudomonas)
  • Most trials conducted a decade ago
  • Prevalence of multidrug-resistant or difficult-to-treat organisms were low in majority of studies.

IDSA noted: Shorter or longer duration may be indicated depending on improvement in clinical, radiologic, and laboratory parameters.

Crit Care Med 2008; 36: 108–17.

Crit Care Med 1997; 25:1663–70.

Crit Care Med 2008; 36:737–44.

BMC Infectious Diseases 2012, 12:308

  • Evidence to support dual pseudomonal coverage is very weak. Consider reserving for high risk MDROs. Decision to use dual coverage should still consider clinical status of patient.

Questions?

Is there an Increased Risk for Recurrent Pneumonia?

2 systematic reviews of RCTs compared short course (7-8 days) vs. long course (10-15 days) antibiotics in VAP and found reduced recurrent VAP due to MDR pathogens and increased antibiotic free days (mean of 4.2 days).

  • No differences in mortality, recurrent pneumonia, treatment failure, length of stay or duration of mechanical ventilation.
  • In 1 review, subgroup analysis of VAP secondary to non-glucose fermenting gram-negative bacillus including Pseudomonas and Acinectobacter (33% of group) found short courses associated with recurrent infection.

IDSA conducted own meta-analysis using same trials and found no difference for pneumonia recurrence in the same subgroup.

IDSA panel noted weak evidence suggests combination therapy is beneficial for initial empiric therapy but once susceptibilities known, no differences in outcome.

Small observational study (n=154) that examined VAP due to non-glucose fermenting gram-negative bacilli compared short course (3-8 days) vs. long course (≥ 9 days) antibiotics, also found no difference in recurrence or mortality.

  • Based on 2 observational studies.
  • 1 study showed association that initial combination therapy reduced likelihood of inappropriate empiric treatment (antibiotic not covering pathogen). Inappropriate initial therapy known to be associated with increased mortality.

Cochrane Database Syst Rev 2015; 8:Cd007577.

Chest 2013; 144:1759–67.

Surg Infect (Larchmt) 2007; 8:589–97.

  • Other study was subgroup analysis that found decreased all-cause 28 day mortality associated with combination therapy in patients with bacteremic pseudomonas pneumonia (OR= 0.05; 95% CI: 0.01-0.34).

Evidence is very weak. Consider reserving dual coverage for high risk of drug-resistant Pseudomonas.

Crit Care Med 2007; 35:1888–95.

BMC Infectious Diseases 2012, 12:308

Risk Factors for MDROs

Clinical Pulmonary Index Score (CPIS)

  • Emerging tool based on 5 to 7 variables (e.g. temperature, WBC, PaO2/FiO2 ratio) to assist in deciding whether to initiate antibiotics for suspected VAP.
  • CPIS score > 6 at baseline or at 72 h considered suggestive of pneumonia.
  • Meta-analysis of performance characteristics of CPIS demonstrated low accuracy with sensitivity of 65% and specificity of 64% and studies had serious risk of bias.
  • Sensitivity and specificity did not meet IDSA requirements of >90%.
  • Prior IV antibiotic use most significantly associated with both MDROs HAP (OR=5.17; 95% CI: 2.11-12.67) and MDROs VAP (OR=12.3; 95% CI: 6.48-23.35).
  • Risk factors for MDROs HAP rarely studied. Other risk factors may be relevant but evidence is lacking.

Am J Respir Crit Care Med 2003; 168:173–9.

Eur Respir J 2006; 27:158–64.

Respir Care 2011;56:1087–94.

Am J Respir Crit Care Med 2000; 162(2 pt 1):505–11.

Intensive Care Med 2006; 32:676–83.

  • Several potential risk factors for MRSA pneumonia (e.g. MRSA colonization) and pseudomonas aeruginosa (e.g. cystic fibrosis, bronchiectasis) but published evidence for most is scarce, of low quality or of mixed findings.

Intensive Care Med 2008; 34:675–82.

Intensive Care Med 2005; 31:1488–94.

Am J Respir Crit Care Med 1998; 157:531–9.

Removal of HCAP

Use of Biomarkers and Clinical Pulmonary Infection Score (CPIS) for diagnosis of HAP/VAP

Recommend use of clinical criteria alone to diagnose HAP or VAP and to determine whether to initiate antibiotics.

Do not support the following to be used along with clinical criteria for diagnosis:

Procalcitonin (PCT)

  • Procalcitonin (PCT)
  • Soluble Triggering Receptor Expressed on Myeloid Cells (sTREM-1)
  • C-Reactive Protein (CRP)
  • Clinical Pulmonary Infection Score (CPIS)
  • Peptide precursor of calcitonin that is constitutively released by thyroid gland and lungs.
  • Undetectable (<0.01 ng/mL) in healthy individuals but is rapidly produced when stimulated by endotoxin such as in bacterial infections.

  • May increase in response to sterile inflammation or viral infection but less common.
  • No studies examined clinical outcomes after initiating antibiotics based on PCT for suspected HAP/VAP.

Soluble Triggering Receptor Expressed on Myeloid Cells (sTREM-1)

Limitations:

Instead, conducted meta-analysis of 6 studies to explore performance characteristics for serum PCT for diagnosis of HAP/VAP.

  • Studies had varying thresholds for cut off to diagnose HAP/VAP, which ranged from 0.5 to 3.9 ng/mL and were not validated. Optimal PCT diagnostic threshold varied depending on severity, clinical setting, and assay used.

Meisner et al., Crit Care 1999, 3:45-50

Meisner M., J Lab Med 1999;23:263-72

  • Serum PCT and clinical criteria can diagnose HAP/VAP with only sensitivity of 67% (95% CI: 53%-79%) and specificity of 83% (95% CI, 43%–97%).

Failed to meet a priori clinical criteria of >90% sensitivity and specificity to use as diagnostic tool by IDSA panel.

  • Immunoglobulin expressed on neutrophils and monocytes infiltrating tissues invaded by bacteria and fungi.

Clin Infect Dis. 2016 Sep 1;63(5):575-82.

Infect Dis 2009; 9:49.

Chest 2010; 138:121–9.

Lancet 1993; 341:515–8.

  • Unclear role as several recent studies suggest may also be elevated in noninfectious inflammation.
  • Similar to procalcitonin, no studies available that explored clinical outcomes in HAP/VAP.
  • Instead, examined performance characteristics of sTREM-1 for diagnosing HAP or VAP and findings similar to procalcitonin.

Introduced in 2005 ATS/IDSA guidelines to stratify community patients at increased risk of multidrug-resistant organisms (MDROs).

C-Reactive Protein (CRP)

Failed to meet IDSA predetermined diagnostic threshold (>90%) with sensitivity of 84% (95% CI, 63%–94%) and specificity of 49% (95% CI, 18%–81%)

  • Nonspecific marker of inflammation synthesized by liver in response to factors released by macrophages and adipocytes.

J Immunol 2000; 164:4991–5.

Chin Crit Care Med 2006; 18:370–2.

Clin Infect Dis. 2016 Sep 1;63(5):575-82.

  • 3 studies that evaluated ability of CRP to identify patients with VAP. None were able to distinguish between patients with and without VAP.

Diagnosis of HAP &VAP

Microbiologic methods

Eur Respir J 2008;31:356–62.

Chin Crit Care Med 2006; 18:370–2.

Crit Care Med 2011; 39:2048–58.

Kollef et al. in 2005 conducted a large retrospective study that found HCAP* associated with:

Suggest noninvasive sampling with semiquantitative cultures to diagnose VAP.

  • 2008 Cochrane Systematic Review: 5 randomized controlled trials (RCTs) compared invasive with quantitative cultures vs. non-invasive sampling with semiquantitative/quantitative cultures.

  • Higher MRSA rate (26.5%) vs. CAP (8.9%) p<0.01
  • Higher Pseudomonas rate (25.3%) vs. CAP (17.1%) p<0.01
  • Increased mortality rate (19.8%) vs. CAP (10%) p<0.0001
  • Longer length of stay

No significant differences in clinical outcomes such as 28 day mortality, overall mortality, length of ICU stay, duration of mechanical ventilation, or antibiotic change.

Invasive Sampling

Bronchoscopic techniques or mini-BAL:

  • Bronchoalveolar lavage (BAL)
  • Protected specimen brush (PSB)
  • Blind bronchial sampling (mini-BAL)

* defined as hospitalization in past 3 months, hemodialysis (HD), or from nursing facility.

Non-invasive Sampling

  • Endotracheal aspiration

2014 Large Retrospective US-based study:

Semiquantitative

  • Presence or absence of pathogenic germs in culture
  • Described growth as light, moderate or heavy
  • Requires no specialized microbiologic methods

MDROs not associated with HCAP classification (OR=2.95, 95% CI: 0.66-5.80, p=0.23) or with most of its individual components (HD, home infusion, home wound care and ≥ 48 hrs hospitalization in prior 90 days).

Quantitative

Independent risk factors for predictors of MDROs:

  • Threshold count of bacterial growth to differentiate between infection vs. colonization of lower airways.
  • Pseudomonas aeruginosa colonization/infection in the past year
  • Antimicrobial use in previous 90 days
  • Admission from a nursing home
  • Duration of hospitalization in previous 90 or 180 days

Emerging evidence: HCAP not associated with higher risk for MDROs or mortality

Systematic review of 24 studies (n=22,456):

Recommendations regarding MDROs should be based on validated risk factors and not just healthcare exposure.

Compared frequency of resistant pathogens (MRSA, Enterobacteriaceae, P. aeruginosa) in HCAP vs. CAP.

To be further addressed in upcoming CAP guidelines...

Antimicrob Agents Chemother. 2014 Sep;58(9):5262-8.

  • Increased risk of MDROs in HCAP but confounded by publication bias.

Cochrane Database Syst Rev. 2014 Oct 30;(10):CD006482.

Similarly, Micek et al. found that 28% of patients defined as HCAP received inappropriate initial empiric antibiotics (failed to target the infecting pathogen).

  • Discriminatory ability of HCAP for MDROs was low, especially in high-quality and prospective studies.
  • Among these patients, the pathogens that were most frequently associated with pneumonia were P. aeruginosa (28%), MRSA (27%), and Acinetobacter species (15%).
  • After adjustment for age and comorbities, mortality not increased in HCAP (p=0.30)

Clin Infect Dis 2014; 58:330–9.

Studies were interpreted as HCAP patients may be associated with excess mortality rate due to high frequency of resistant pathogens not covered by initial empiric antibiotics.

Therefore, suggested use of empiric broad-spectrum antibiotics in HCAP

However, studies that followed weren't able to consistently replicate the higher frequency of MDROs found in HCAP.

Clin Infect Dis 2011;53:107-13.

Ann Intern Med 2009;150:19-26.

Medicine 2011; 90(6): .390–5

Chest 2005;128:3854-62.

Update on Infectious Disease Society of America (IDSA) 2016 Hospital-Acquired Pneumonia (HAP) and Ventilator-Associated Pneumonia (VAP) Guidelines

Claudia Ho, BSc Pharm, ACPR

September 21st, 2016

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