Procalcitonin-Guided Antibiotic Therapy

1
Procalcitonin-Guided Antibiotic Therapy

• Prepared for
• Agency for Healthcare Research and Quality (AHRQ)
• www.ahrq.gov

2
Outline of Material

• Introduction to procalcitonin and its role in
  guiding antibiotic therapy in adult and pediatric
  patients with suspected infections
• Systematic review methods
• The clinical questions addressed by the
  comparative effectiveness review
• Results of studies and evidence-based conclusions
  about the effects of using procalcitonin versus
  clinical criteria to guide antibiotic therapy in
  adult and pediatric patients with suspected local
  or systemic infections
• Gaps in knowledge and future research needs
• What to discuss with patients and their
  caregivers

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.

3
Background The Need for Biomarkers To Guide
Antibiotic Therapy for Bacterial Infections

• The early initiation and appropriate use of
  antibiotics are important factors in managing
• Critically ill patients with suspected bacterial
  infections such as sepsis
• Patients with bacterial upper and lower
  respiratory tract infections in the ambulatory
  care or hospital setting
• Pediatric patients with suspected bacterial
  infections, including neonates with suspected
  sepsis
• Patients in the postoperative setting with
  suspected infections
• A key challenge associated with antibiotic
  therapy is the overuse and misuse of antibiotics,
  which can result in adverse effects and add to
  the increasing problem of antibiotic resistance.
• However, the duration of antibiotic therapy that
  is appropriate for these patients is often
  undefined, and clinical features offer limited
  guidance.

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
  Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.
• Pierrakos C, Vincent JL. Crit Care
  201014(1)R15. PMID 20144219.

4
Background Procalcitonin and Its Role as a
Biomarker of Bacterial Infections

• Several serum biomarkers have been identified
  with the potential to help diagnose local and
  systemic infections and guide their clinical
  management, particularly antibiotic therapy.
• Procalcitonin is the most extensively studied
  biomarker among these.
• Procalcitonin is the precursor of the hormone
  calcitonin its levels have been found to
  increase during infections and different degrees
  of inflammation.
• The primary utility of procalcitonin is suggested
  to be in establishing the presence of local or
  systemic bacterial infections and in guiding
  their management.
• Procalcitonin is often used with algorithms to
  guide care in association with clinical
  impressions.

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
  Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.
• Jones AE, Fiechtl JF, Brown MD, et al. Ann Emerg
  Med 2007 Jul50(1)34- 41. PMID 17161501.
• Pierrakos C, Vincent JL. Crit Care
  201014(1)R15. PMID 20144219.
• Tang H, Huang T, Jing J, et al. Infection 2009
  Dec37(6)497-507. PMID19826761.

5
Background Cutoffs for Procalcitonin Used in
Clinical Practice

• In healthy people, the levels of procalcitonin
  are very low.
• In systemic bacterial infections, including
  sepsis, the level of procalcitonin is generally
  0.5 ng/mL, with higher levels being associated
  with severe disease.
• In patients with suspected respiratory tract
  infection, a cutoff gt0.25 ng/mL is predictive of
  a bacterial infection.
• A level lt0.25 ng/mL signals resolution of the
  infection.
• In neonates, a nomogram accounting for the time
  from birth in hours is recommended for assessing
  procalcitonin cutoffs.
• The cutoff level of procalcitonin to identify
  postoperative patients with infection may be
  higher than that used for other patient groups
  due to cytokine release during surgery.

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
  Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.
• Chiesa C, Panero A, Rossi N, et al. Clin Infect
  Dis 1998 Mar26(3)664-72. PMID 9524841.
• Christ-Crain M, Muller B. Eur Respir J 2007
  Sep30(3)556-73. PMID 17766633.
• Luyt CE, Guerin V, Combes A, et al. Am J Respir
  Crit Care Med 2005 Jan 1171(1)48-53. PMID
  15447947.
• Simon L, Gauvin F, Amre DK, et al. Clin Infect
  Dis 2004 Jul 1539(2)206-17. PMID 15307030.

6
Uncertainties Related to the Use of Procalcitonin
To Guide Antibiotic Therapy

• Earlier studies have investigated the potential
  roles of procalcitonin in diagnosing and managing
  local and systemic infections.
• Some evidence indicates that procalcitonin, when
  compared with other markers, is more specific for
  bacterial infections.
• However, its clinical utility in diagnosing and
  managing patients with suspected infections
  remains unclear.
• This review focused on the clinical utility of
  procalcitonin in managing patients with suspected
  infections.
• Although questions about the clinical utility of
  procalcitonin in the diagnosis of patients with
  suspected infections persist, they were not
  addressed in this review.

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.

7
Agency for Healthcare Research and Quality (AHRQ)
Comparative Effectiveness Review (CER) Development

• Topics are nominated through a public process,
  which includes submissions from health care
  professionals, professional organizations, the
  private sector, policymakers, members of the
  public, and others.
• A systematic review of all relevant clinical
  studies is conducted by independent researchers,
  funded by AHRQ, to synthesize the evidence in a
  report summarizing what is known and not known
  about the select clinical issue. The research
  questions and the results of the report are
  subject to expert input, peer review, and public
  comment.
• The results of these reviews are summarized into
  Clinician Research Summaries and Consumer
  Research Summaries for use in decisionmaking and
  in discussions with patients. The Research
  Summaries and the full report, with references
  for included and excluded studies, are available
  at www.effectivehealthcare.ahrq.gov/procalcitonin.
  cfm.

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.

8
Rating the Strength of Evidence From the
Comparative Effectiveness Review

• The strength of evidence was classified into four
  broad categories

High Further research is very unlikely to change the confidence in the estimate of effect.
Moderate Further research may change the confidence in the estimate of effect and may change the estimate.
Low Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.
Insufficient Evidence either is unavailable or does not permit estimation of an effect.

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.

9
The Clinical Question Addressed by This
Comparative Effectiveness Review

• Key Question In selected populations of patients
  with suspected local or systemic infection, what
  are the effects of using procalcitonin
  measurement plus clinical criteria for infection
  to guide initiation, discontinuation, or a change
  of antibiotic therapy when compared with clinical
  criteria for infection alone on
• Intermediate outcomes, such as initiation,
  discontinuation or change of antibiotic therapy,
  antibiotic usage, and length of stay?
• Health outcomes, such as morbidity, mortality,
  function, quality of life, and adverse events of
  antibiotic therapy (persistent or recurrent
  infection and antibiotic resistance)?

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.

10
Effects of Using Procalcitonin To Guide
AntibioticTherapy in Critically Ill Adult
Patients in the ICU (1 of 2)

• In the studies that used procalcitonin-based
  algorithms , physicians could consider other
  clinical information and over-ride algorithms
  based on their judgment.
• Procalcitonin guidance reduced antibiotic
  usage.Strength of Evidence High
• Using procalcitonin guidance to discontinue
  antibiotic therapy did not increase morbidity, as
  indicated by length of stay in the ICU.Strength
  of Evidence Moderate
• Using procalcitonin guidance to discontinue
  antibiotic therapy did not increase mortality
  (in-hospital, 28-day, or overall mortality).
• Evidence for this finding was rated low due to
  disagreement on the appropriate noninferiority
  margin.Strength of Evidence Low

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.

11
Effects of Using Procalcitonin To Guide
AntibioticTherapy in Critically Ill Adult
Patients in the ICU (2 of 2)

• In this review, antibiotic intensification
  included a change in the antibiotic regimen or
  broadening the spectrum of antibiotic therapy.
• Procalcitonin-guided intensification of
  antibiotic therapy was associated with greater
  duration of use and increased total exposure to
  antibiotics.Strength of Evidence Moderate
• Procalcitonin-guided intensification of
  antibiotic therapy was associated with increased
  morbidity, including increase in intensive care
  unit (ICU) length of stay, days on mechanical
  ventilation, and days with abnormal renal
  function.Strength of Evidence Moderate

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.

12
Effects of Using Procalcitonin To Guide
Antibiotic Therapy in Patients With RTIs in the
Ambulatory Care or Hospital Setting (1 of 2)

• Patient populations with respiratory tract
  infections (RTIs) included those with acute
  exacerbations of chronic obstructive pulmonary
  disease, community-acquired pneumonia,
  bronchitis, sinusitis, tonsillitis, or
  pharyngitis.
• In the studies that used procalcitonin-based
  algorithms , physicians could consider other
  clinical information and over-ride algorithms
  based on their judgment.
• Procalcitonin guidance reduced duration of use of
  and prescription rates of antibiotics.Strength
  of Evidence High
• Procalcitonin guidance reduced total antibiotic
  exposure.Strength of Evidence Moderate

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.

13
Effects of Using Procalcitonin To Guide
Antibiotic Therapy in Patients With RTIs in the
Ambulatory Care or Hospital Setting (2 of 2)

• Procalcitonin guidance did not increase
  mortality, hospital length of stay, or intensive
  care unit admission rates.Strength of Evidence
  Moderate
• Evidence was insufficient to determine the effect
  of procalcitonin guidance on antibiotic-associated
  adverse events.Strength of Evidence
  Insufficient

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.

14
Effects of Using Procalcitonin To Guide
Antibiotic Therapy in Pediatric Patients

• Procalcitonin guidance reduced the use of
  antibiotic therapy for suspected early neonatal
  sepsis.Strength of Evidence Moderate
• The evidence was insufficient to determine if
  procalcitonin guidance reduced antibiotic usage
  in children aged 136 months with fever.Strength
  of Evidence Insufficient

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.

15
Effects of Using Procalcitonin To Guide
Antibiotic Therapy in Postoperative Patients

• Evidence was insufficient to determine if
  procalcitonin guidance can identify postoperative
  patients at risk of developing infections who
  might benefit from pre-emptive antibiotic
  therapy.Strength of Evidence Insufficient

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.

16
Conclusions (1 of 2)

• Procalcitonin guidance for antibiotic
  discontinuation reduced antibiotic usage in adult
  patients in intensive care units (ICUs) without
  increasing mortality.
• However, there was uncertainty related to the
  evidence on mortality.
• The use of procalcitonin to guide antibiotic
  intensification rather than discontinuation in
  adult patients in ICUs resulted in increased
  antibiotic usage, which was associated with
  increased morbidity.

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.

17
Conclusions (2 of 2)

• Procalcitonin guidance for initiating and
  discontinuing antibiotic therapy significantly
  reduced antibiotic prescription rates and
  duration of use in patients with acute
  respiratory tract infections (including acute
  exacerbations of chronic obstructive pulmonary
  disease, community-acquired pneumonia, and acute
  bronchitis) in the ambulatory care or hospital
  setting.
• Data to support a role for procalcitonin guidance
  in the pediatric population were lacking in the
  literature.
• However, there was moderate-strength evidence
  showing that procalcitonin guidance resulted in
  reduced antibiotic usage in neonates with
  suspected early sepsis.

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm. 

18
Applicability of the Findings of This Review

• This systematic review found that procalcitonin
  guidance for antibiotic discontinuation reduces
  antibiotic usage for adult patients in both
  medical and surgical intensive care units (ICUs)
  and, therefore, is applicable to clinical
  practice related to antibiotic discontinuation in
  the ICU settings.
• This systematic review found that procalcitonin
  guidance for initiating and discontinuing
  antibiotic therapy for patients with respiratory
  tract infections in the ambulatory care or
  hospital setting significantly reduced antibiotic
  prescription rates and duration of use and,
  hence, is applicable to these patient
  populations.
• Certain populations of interest were excluded
  from one or more studies of procalcitonin
  guidance reviewed in this report. Thus, findings
  from this review should not be extrapolated to
  these high-risk groups.

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.

19
Gaps in Knowledge and Future Research Needs (1 of
2)

• Assessing the effect of using procalcitonin
  guidance in patients who are immunocompromised is
  an important research need, as this patient
  population may gain significant clinical benefit
  from potentially reduced antibiotic usage.
• Future studies are needed to assess
  procalcitonin-guided initiation and
  discontinuation of antibiotics in pediatric
  populations in both inpatient and outpatient
  settings.
• Future studies are needed to assess the effects
  of procalcitonin-guided antibiotic usage and
  total exposure on antibiotic-associated adverse
  reactions, superinfections, or the development of
  antibiotic resistance.

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.

20
Gaps in Knowledge and Future Research Needs (2 of
2)

• More research is needed regarding the effect on
  mortality of reduced antibiotic usage resulting
  from procalcitonin-guided antibiotic therapy.
• For a more pertinent comparative effectiveness
  approach, different comparators should have been
  selected, such as antibiotic stewardship programs
  and structured implementation of practice
  guidelines.
• Additional future research needs include the
  determination of the appropriate procalcitonin
  cutoff level in different populations, and
  assessment of the cost-effectiveness of using
  procalcitonin to guide antibiotic therapy.

• Soni NJ, Samson DJ, Galaydick JL, et al. AHRQ
  Comparative Effectiveness Review No. 78.
• Available at www.effectivehealthcare.ahrq.gov/proc
  alcitonin.cfm.