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Should  we  go  “All  In”  with  Procalcitonin?

 
Examining  the  Utility  of  the  New  Biomarker  
 
 

 
  http://www.amctv.com/shows/breaking-­‐bad/  
 
 
Residency  Rounds  
Justin  Gonzalez,  PharmD  
PGY1  Pharmacy  Resident  
Department  of  Pharmacy,  North  Austin  Medical  Center,  Austin,  TX  
The  University  of  Texas  at  Austin  College  of  Pharmacy  
 
November  1,  2013  
 
 
 
 
 
 
 
 
 
 
Learning  Objectives:  
 
1. Describe  the  implications  of  inappropriate  antibiotic  use  
2. Discuss  procalcitonin,  sepsis,  and  ventilator  associated  pneumonia  
3. Interpret  the  literature  examining  the  use  of  procalcitonin  in  clinical  practice  
4. Recommend  a  strategy  for  procalcitonin’s  utility  in  guiding  antibiotic  therapy  
 

I. Inappropriate  Antibiotic  Use  and  its  Implications  1-­‐3  
a. Up  to  50%  of  all  antibiotics  (abx)  prescribed  for  people  are  not  needed  or  are  not  optimally  
effective  as  prescribed  
i. Acute  bronchitis  (usually  viral)  à  antibiotics  prescribed  80%  of  the  time  
ii. Length  of  treatment  for  some  infections  has  been  poorly  studied  and  it  is  likely  that  
treatment  durations  are  inappropriately  long  
b. Implications  
i. Adverse  events  due  to  antibiotics  
1. Estimated  142,505  emergency  department  visits  annually  
ii. Multi-­‐drug  resistant  organisms  (Appendix  A)  
1. Methicillin  Resistant  Staph  Aureus  (MRSA),  S.  pneumoniae,  Extended  
Spectrum  β-­‐Lactamases  (ESBLs),  Vancomycin-­‐resistant  Enterococcus  (VRE),  
Carbapenem-­‐resistant  Enterobacteriaceae  (CRE),  etc.  
2. Annual  cases  à  2,049,442  
3. Annual  deaths  à  23,488  
iii. Clostridium  difficile  infections  
1. Annual  cases  à  250,000  
2. Annual  deaths  à  14,000  
iv. Cost  
1. Estimated  $20  billion  a  year  in  excess  direct  healthcare  cost  
2. Estimated  $35  billion  a  year  (2008  dollars)  
c. Four  Core  Actions  to  Prevent  Antibiotic  Resistance  as  Recommended  by  CDC  
i. Preventing  infections  and  preventing  spread  of  resistance  
ii. Tracking  resistant  bacteria  
iii. Improving  antibiotic  stewardship  
iv. Promoting  the  development  of  new  antibiotics  
d. Challenges  of  curbing  antibiotic  use  
i. Patient  expectations  
ii. Differentiating  a  true  infection  from  an  inflammatory  non-­‐infectious  cause  
iii. Differentiating  bacterial  vs  viral  infective  sources  
iv. Physician  hesitation  to  discontinue  antibiotics  earlier  than  guideline  
recommendations,  especially  in  critically  ill  patients  
 
II. Procalcitonin  3-­‐8  
a. What  is  procalcitonin  (PCT)?  
i. A  116  amino  acid  polypeptide  precursor  to  the  calcium  regulatory  hormone  
calcitonin  
ii. Synthesis  regulated  by  the  Calc-­‐1  gene  located  on  chromosome  11  
1. Stimulus  for  gene  transcription  and  subsequent  PCT  secretion  
a. Directly  à  microbial  toxins  
b. Indirectly  à  pro-­‐inflammatory  cytokines  [interleukin  (IL)-­‐1,  IL-­‐6,  and  
tumor  necrosis  factor-­‐α  (TNF-­‐α)]  
2. Induction  attenuation  
a. Interferon-­‐γ  à  cytokine  released  during  a  viral  infection  
iii. Production  
1. Healthy  individuals-­‐  restricted  to  neuroendocrine  thyroid  C-­‐cells  
a. Concentration  <0.05  mcg/L  
2. Infection-­‐  ubiquitously  from  extra-­‐thyroidal  tissues  throughout  the  body  
(liver,  kidney,  pancreas,  adipose,  and  white  blood  cells)  
a. Concentration  up  to  1000  mcg/L  
Gonzalez         2  

Patients  w/  acute  malaria  and  certain  types  of  invasive  fungal   infections   2. Early  course  of  infections   b. Assays   1.  Brahms  Diagnostics  (Berlin.  Brahms  Diagnostics  (Berlin. Other  factors  that  affect  PCT  levels   1. Detectable  in  the  blood  within  2-­‐4  hrs  and  peaks  within  6-­‐24  hrs   2.  Germany)   a.   b. Localized  infections   c.  Germany)   a. Levels  remain  low  during:   a. Neonates  (aged  less  than  48hrs)   b. First  day(s)  after  a  major  trauma/surgery. Patients  w/  prolonged  or  severe  cardiogenic  shock  and  prolonged   severe  organ  perfusion  abnormalities   d. Half  life  of  25-­‐30hrs   v. Kinetics   1. Detection  limit  à  0. Older  –  LUMI  test. Significant  elevations   a. Subacute  endocarditis   3. Levels  correlate  with  severity  of  bacterial  infection  (Figure  1)           Figure  1:  Procalcitonin  levels  associated  with  degree  of  bacterial  infection7       iv. Newer  –  Kryptor. Levels  are  NOT  attenuated  by  NSAIDS  or  steroids  (unlike  CRP)   vi.5  mcg/L   b.   treatment  w/  mono/polyclonal  antibodies   c. Not  approved  for  clinical  use   2.06  mcg/L                   Gonzalez         3   . Patients  w/  small-­‐cell  lung  cancer  and/or  medullary  C-­‐cell  carcinoma   of  the  thyroid   e.  severe  burns/heat  stroke. Detection  limit  à  0.

Table  1:  Comparison  of  procalcitonin  and  C-­‐reactive  protein  7. Systemic  inflammatory  response  syndrome  (SIRS)  –  a  clinical  response  arising  from   a  nonspecific  insult  manifested  by  ≥2  of  the  following:   1.  Enterococcus.  aeruginosa.   Gonzalez         4   . Society  Critical  Care  Medicine  Surviving  Sepsis  Campaign  2012:   Antibiotic  Recommendations   i. Intra-­‐abdominal   iii. Empiric  antibiotic  should  not  be  administered  for  more  than  3-­‐5  days.  P. Gram  (-­‐)  –  common.8     Procalcitonin  (PCT)   C-­‐Reactive  Protein  (CRP)   Normal  physiologic  levels   <  0. Urinary  tract   iv. Severe  sepsis-­‐  sepsis  +  organ  dysfunction. American  College  of  Chest  Physicians  (ACCP)/Society  of  Critical  Care  Medicine  (SCCM)   Definitions   i.  aureus. Bloodstream  infections  (catheter-­‐related)   d. Microbiology   i. Respiratory   ii.  aureus. Candida  albicans  >  non-­‐albicans  Candida  >>  other  fungi   iv. Other  –  less  common   1. Temp  ≥38°C  (100.8°F)   2.  and  Enterobacter   iii.  sepsis  induced  tissue  hypoperfusion  or   organ  dysfunction   iv.10   a. Fungal  –  on  the  rise   1.  coli.  Proteus. HR  ≥90  beats/min   3.  Coagulase  (-­‐)  Staph.  including  neutropenia  (grade  2C).  with  a  slow  clinical   response. WBC  count  ≥12K/mL  or  ≤4K/mL  or  >10%  bands   ii. Duration  of  therapy  typically  7-­‐10  days.  De-­‐escalation   to  the  most  appropriate  single  therapy  should  be  performed  as  soon  as   susceptibilities  are  known  (grade  2B)   iii.  undrainable  foci  of  infection. S.4°F)  or  ≤36°C  (96. E.05  mcg/L   <  10  mg/L   Type  of  infection  that  cause  levels   Bacterial   All  types   to  significantly  increase   Detectable  within   2-­‐4  hrs   12-­‐24  hrs   Peaks   6-­‐24  hrs   48  hrs   Time  it  takes  for  levels  to  fall  once   24hr  (∼50%  reduction  per  day)   3-­‐7  days   infection  has  been  controlled     III.  Serratia. Use  of  low  procalcitonin  or  similar  biomarkers  to  assist  the  clinician  in  the   discontinuation  of  empiric  abx  in  patients  who  initially  appeared  infected  but  has  no   subsequent  evidence  of  infection  (grade  2C)   ii.  S. Septic  shock-­‐  severe  sepsis  with  persistent  hypotension  despite  adequate  fluid   resuscitation   b. Sepsis9.  some  fungal  and   viral  infections  or  immunologic  deficiencies. Respirations  ≥20/min  or  PaCO2<  32mmHg   4.  longer  courses  for  pt. Sepsis-­‐  ≥2  SIRS  criteria  +  suspected  or  proven  infection   iii.  anaerobes   c.  Klebsiella.  bacteremia  with  S.  Group  A  Strep   Viridans   ii. Most  Common  Infection  Sources  of  Sepsis   i.  higher  mortality   1. Viruses.  pneumoniae. Gram  (+)  –  most  common   1.

Ventilator  Associated  Pneumonia  (VAP)12.  efforts  should  be  made   to  shorten  the  duration  of  therapy  from  the  traditional  14  to  21  days  to  periods  as   short  as  7  days. Potential  uses  of  procalcitonin  in  sepsis   i. Prognosis   1.13   a. ProVAP  study15                             Gonzalez         5   .000mcL   ii. P.   Enterobacter  spp. Difficult  due  to  nonspecific  signs  and  symptoms  that  often  overlap  with  other   non-­‐infectious  causes  of  systemic  inflammation   ii.  MRSA   c.000mcL  or  <3. Decreasing  duration  of  antibiotic  therapy   1.  pneumoniae. Decreasing  duration  of  antibiotic  therapy   1.  optimal  approach  remains  to  be  defined   ii. Used  to  increase  sensitivity  and  specificity  of  VAP  diagnostic  criteria   b. S.)   ii. Diagnosis   1..  aeruginosa. Procalcitonin  not  mentioned   d.coli. Clinical  Diagnosis  [American  Thoracic  Society  (ATS)]   i. e. Late-­‐Onset  VAP  (≥5  days)  +/-­‐  MDR  Risk  Factors   1. Potential  uses  of  procalcitonin  in  VAP   i. Purulent  tracheal  secretions   2. Physician  hesitation  to  discontinue  antibiotics  due  to  fragile  state  of  patient     IV. Microbiology   i. If  patients  receive  an  initially  appropriate  antibiotic  regimen. Temp  >38°C   3. No  gold  standard. ATS  Guidelines  –  Antibiotic  Duration  Recommendation   i. Early-­‐onset  pathogens  +  MDR  pathogens   a. Diagnosis   1. Trending  of  levels  has  shown  correlation  with  severity  and  mortality   iii.  Klebsiella  (ESBL+).  Acinetobacter  spp. Leukocyte  count  >11.  provided  that  the  etiologic  pathogen  is  not  P. After  48hrs  of  intubation  à  New  or  persistent  infiltrate  on  chest  radiography   associated  with  at  least  two  of  the  following:   1.  aeruginosa. Clinical  pulmonary  infection  score  (CPIS)  [Appendix  B]   1.  Klebsiella.  MSSA.  and  that   the  patient  has  a  good  clinical  response  with  resolution  of  clinical  features  of   infection  (Level  I)   ii. Early-­‐Onset  VAP  (≤4  days)   1.  H.  influenzae.  Enterobacteriaceae  (E.

Four  studies  examining  procalcitonin’s  utility  in  the  intensive  care  unit  (ICU)  setting  and  1   meta-­‐analysis   i..  2011  à  meta-­‐analysis.  discontinue  abx  when:   § PCT  <  0.  discontinue  abx  when:   § PCT  dropped  more  than  90%  from  baseline  peak  level   § Absolute  value  <0.  Use  of  procalcitonin  to  shorten  antibiotic  treatment  duration  in  septic  patients  (ProSEP  trial):  a   randomized  trial.  HIV  pt. Heyland  et  al.  primary  infection   relapse  rate.   Listeria  spp. Stolz  et  al.  [n=27]).  2010  (ProRATA)  à  initiation  and  cessation  of  antibiotics  in  a  mixed   medical/surgical  cohort  of  630  patients   v. Nobre  et  al.  and  does  not  result  in  more  adverse  outcomes  in  patients   with  severe  sepsis  and  septic  shock.   deep  abscesses)   • Antibiotic  therapy  started  48hrs  or  more  before  enrollment   • Chronic. Hochreiter  et  al.  in-­‐hospital  mortality.  2009  (ProSICU)  à  duration  of  antibiotic  therapy  in  110  surgical   ICU  patients   iii.  chronic  osteomyelitis)   • Severely  immunocompromised  patients  (e.g.   Design   • Single  center. V.  controlled.  2009  (ProVAP)  à  duration  of  antibiotic  therapy  in  101  patients  w/   ventilator  associated  pneumonia  (VAP)   iv.  CD4<200.  and  patients  on   immunosuppressive  therapy  after  solid  organ  transplant)   • Withholding  of  life  support   • Absence  of  antimicrobial  treatment  despite  clinical  suspicion  of  sepsis   Methods/   • Randomization  performed  by  computer-­‐based  random  number  generation   Intervention   • All  patients  received  abx  therapy  according  to  guidelines  and  susceptibility  patterns. Literature  Evaluation  14-­‐19   a.  randomized.  Pneumocystitis  jiroveci.  hemorrhagic  fever.  open  interventional  trial   Inclusion   • Patients  w/  suspected  severe  sepsis  or  septic  shock  admitted  to  the  ICU   Exclusion   • Microbiologically  documented  infections  caused  by  Pseudomonas  aeruginosa.  brain  abscess.177(5):498-­‐505.  length  of  stay  (LOS)  in  the  ICU  and  hospital   Gonzalez         6   .  sepsis-­‐related  death.1  mcg/L.  Am  J  Respir  Crit  Care  Med.g.  includes  an  economic  evaluation     Appendix  C  offers  explanations  of  the  intensive  care  unit  (ICU)  assessment  scores  used  in  these  trials   -­‐  Simplified  Acute  Physiology  Score  (SAPS)   -­‐  Sepsis-­‐related  Organ  Failure  Assessment  (SOFA)  Score   -­‐  Organ  Dysfunction  and/or  Infection  (ODIN)  Score     Table  3:  Nobre  et  al. Bouadma  et  al.  according  to  the   treating  physician  who  was  unaware  of  the  patient’s  initial  PCT  levels   • Patients  w/  positive  blood  cultures  received  at  least  5  full  days  of  abx  therapy   • PCT  group  (PCT  daily  for  7  days.  malaria)   • Infectious  conditions  requiring  prolonged  antibiotic  therapy  (e.  aggregated  results  of  all  4  trials  plus  one  small   separate  trial  (Schroeder  et  al.  28-­‐day  mortality.  2008  (ProSEP)  trial  à  duration  of  antibiotic  therapy  in  79  patients  w/   sepsis  and  septic  shock   ii.25  mcg/L   o Baseline  PCT  ≤  1  mcg/L  reevaluated  at  day  3.g.  or  Mycobacterium  tuberculosis   • Severe  infections  due  to  viruses  or  parasites  (e.   Objective   To  test  if  an  algorithm  based  on  serial  measurements  of  procalcitonin  (PCT)  allows  reduction  in  the  duration  of   antibiotic  therapy  compared  with  empirical  rules.  Legionella  pneumophila.  2008.  then  at  5  day  intervals)à  used  predefined  “stopping  rules”  based  on   circulating  PCT  levels   o Baseline  PCT  ≥  1  mcg/L  reevaluated  at  day  5.  Acinetobacter  baumanni.  and  clinical  evaluation  rules  out  severe  infection   • Control   o Treated  according  to  standard  practice   • Final  decision  concerning  duration  of  antibiotic  therapy  was  left  to  the  discretion  of  the  physician  in  charge     Outcomes   • Primary  –  duration  of  antibiotics   • Secondary  –  Clinical  cure.  neutropenic  patients.  bacterial  endocarditis.  localized  infections  (e.g.

50])   o Vasopressors  (62%  control.  median  days   2.  36%  PCT  group  [p=0.3  PCT  group  [p=0.003   abx  therapy.  median  (5.  clinical.2  (1.89])   o Mechanical  ventilation  (81%  control.6  (-­‐0.  Duration  of   10  (3-­‐33)   6  (4-­‐16)   Mean  difference:   0.  median  days   [n=37]   [n=31]   3.4)   (range)   Secondary  Outcomes   No  statistically  significant  difference  between  groups  for  any  secondary  outcome.3)   NS   days/1000     Per  Protocol.  median   7  (1-­‐91)   4  (1-­‐21)   Mean  difference:   0.  43.  7.1  to  5.1  (0.  71%  PCT  [p=0.  Duration  of  abx   9.Statistics   • Intention  to  treat  (ITT)  analysis  for  primary  endpoints   • Power  analysis  –  needed  66  patients  to  meet  90%  power  to  detect  a  33%  (4  day)  difference  in  duration  of   antibiotic  therapy   • Comparability  of  the  two  groups  was  analyzed  by  the  χ2  test.5)   (range)   ITT.52])   o Positive  blood  culture  (30%  control.  chronic  localized  infections.  Total  abx  exposure   644   541   1.2)   Author’s   • Observed  a  significant  reduction  in  antibiotic  use.02     days  (range)   4.96])   o Septic  shock  (42%  control.  and  neutropenic  patients)                               Gonzalez         7   .76])   • Algorithm  overruling  by  physicians  occurred  w/  19%  of  the  patients  in  PCT  group   Outcomes   Control   PCT  Group   RR  or  Mean   P  Value   Group   (n=39)   Difference  (95%)   (n=40)   Primary  outcomes   ITT.9  to  1.  52%  PCT  group  [p=0.3  to  5.  and  laboratory  baseline  characteristics   o Sepsis  of  pulmonary  origin  predominated  both  groups  (68%  control.  two-­‐sample  t  test.5  (2-­‐33)   6  (3-­‐34)   Mean  difference:   NS   therapy.  without  apparent  harm  in  patients  with  severe  sepsis   Conclusions   and  septic  shock  when  PCT  algorithm  was  followed   • These  patients  also  happened  to  have  a  shorter  ICU  stay   Strengths   • ITT  analysis  used  for  primary  outcomes   • Attrition  described   • Compliance  to  PCT  algorithm  stated   Weaknesses   • Single  center   • Small  study   • Algorithm  overruled  in  19%  of  PCT  group   • High  exclusion  rate    [72%]  (difficult  to  treat  microorganisms.0  to  8.6%  PCT  group  [p=0.  84%  PCT  group  [p=0.  and  Mann-­‐Whitney  U  test   • Cox  proportional  hazards  regression  analysis  used  to  estimate  the  rate  of  abx  treatment  discontinuation   Results   • Randomized  39  to  PCT  group  and  40  to  control  group   • Excluded  72%   • Similar  demographic.80])   o Baseline  PCT  level  mcg/L.  except  for   ICU  length  of  stay.6  (1.  severely   immunocompromised.4  control.

5)   17.5)   <0.  Crit  Care  2009.  randomized  prospective  controlled.   • Also  had  a  favorable  effect  on  the  length  of  the  intensive  care  stay.   • This  may  contribute  to  an  optimized  antibiotic  regimen  with  beneficial  effects  on  microbial  resistance   and  costs  in  intensive  care  medicine.Table  4:  Hochreiter  M.   Design   • Single  center.  diagnosis.9  (+/-­‐  1.046     Deceased   14  (25%)   15  (28%)   NS   Author’s   • Procalcitonin  assessment  is  a  helpful  tool  to  decide  on  the  duration  of  antibiotic  treatment  in  surgical   Conclusions   ICU  patients.  open  label  trial   Inclusion   • All  patients  admitted  to  the  surgical  intensive  care  unit  (SICU)  requiring  antibiotic  therapy  based  on   confirmed  or  highly  suspected  bacterial  infections  and  at  least  two  concomitant  SIRS  criteria   Exclusion   • Refused  consent   • Antibiotic  treatment  initiated  before  intensive  care  admission   • Had  therapy  limitations  (did  not  specify)   Methods/   • Randomization  method  not  defined   Interventions   • PCT  group  (assay  measured  daily)   o Antibiotic  therapy  was  discontinued  if:   § Clinical  signs  and  symptoms  of  infection  improved  AND   § PCT  decreased  to  <  1  mcg/L  OR   § Initial  PCT  value  was  >  1  mcg/L.  gender  distribution.13:R83.  the  physician  in  charge  had  the  option  to  proceed   with  or  adjust  the  abx  treatment   Outcomes   • Primary  -­‐  duration  of  antibiotics   • Secondary  -­‐  intensive  care  days.1)   0.  et  al.   Strengths   • Did  not  exclude  immunosuppressed  or  difficult  to  treat  microorganisms   • Encouraged  8  day  antibiotic  therapy  in  control  group   Weaknesses   • Small  study   • Used  less  sensitive  LUMI  test  assay   • High  exclusion  rate   • Type  of  surgery  performed  not  reported   • Randomization  method  not  described   • Attrition  not  reported   • Did  not  report  if  any  patients  were  immunosuppressed   • Did  not  report  microorganism  culture  data   • Adherence  to  PCT  guidance  not  reported   • Obscure  exclusion  criteria  “had  therapy  limitations”       Gonzalez         8   .5  (+/-­‐  12.  Schweiger  AM.  diagnoses.  antibiotic  substance  classes.  Procalcitonin  to  guide  duration  of  antibiotic  therapy  in  intensive  care   patients  (ProSICU):  a  randomized  prospective  controlled  trial.   survival/death)   Results   • Randomized  57  to  PCT  group  and  53  to  control  group   • Exclusion  rate  72%   • Both  groups  were  comparable  in  terms  of  age.9  (+/-­‐  0.  Kohler  T.  and   outcome   o Peritonitis  à  54%   o Pneumonia  à  39%   Outcomes   PCT  Group   Control  Group   P  Value   (n=57)   (n=53)   Primary  Outcomes   Length  of  abx  therapy   5.  mortality   Statistics   • Mann-­‐Whitney-­‐Wilcoxon  U  test  for  comparative  statistics   • Chi-­‐squared  test  for  comparison  of  proportions  (gender.001   (days)   Secondary  Outcomes   Intensive  care  (days)   15.  disease  severity.7)   7.7  (+/-­‐  10.   Objective   To  investigate  the  clinical  usefulness  of  PCT  for  guiding  antibiotic  therapy  in  surgical  intensive  care  patients.  but  had  dropped  to  25-­‐35%  of  the  initial  value  over   three  days   • Control  group   o Antibiotic  treatment  was  applied  as  standard  regimen  over  eight  days   • Irrespective  of  study  group  and  at  any  time  point.

 2009.25-­‐0.  Smyrnios  N.  the  VAP-­‐related  clinical  deterioration  rate.5  mcg/L  or  a  decrease  of  ≥80%  compared  with  day  0  à  discontinuation  of   antibiotics  encouraged   o Level  ≥0.  and  overall   mortality  at  28  days   Statistics   • Power  analysis:  84  patients  (42  per  group)  needed  to  detect  a  significant  difference  in  antibiotic-­‐free   days  alive  between  groups  with  a  power  of  90%  and  α  error  of  0.  et  al.   Objective   To  determine  if  procalcitonin  serum  evaluation  reduces  antibiotic  exposure  in  patients  with  clinically   diagnosed  ventilator-­‐associated  pneumonia  (VAP)  with  a  similar  clinical  and  laboratory  outcome.  the  number  of  ICU-­‐free  days.038   Antibiotic  duration  in  pt  w/   7  (0-­‐13.5  mcg/L  or  decrease  by  <80%  compared  with  day  0  à  discontinuation  of  antibiotics   discouraged   o Level  >1  mcg/L  à  discontinuation  of  antibiotics  strongly  discouraged   • Control  group   o Standard  antibiotic  duration  w/  an  emphasis  on  ATS  guideline  recommendations   • Irrespective  of  study  group  and  at  any  time  point.Table  5:  Stolz  D.  the  evolution  of   disease  severity  scores.5  mg/kg/day  for  >  1  month)   • Were  severely  immunosuppressed  (including  AIDS)   • Coexisting  extrapulmonary  infection  diagnosed  between  day  1  and  3  requiring  abx  therapy  for  >3  days   Methods/   • Randomization  through  arbitrary  allocation  to  one  of  the  groups  based  on  sealed  envelopes   Interventions   • In  both  groups.  which  was  slightly  higher  for  the   control  group  (p=0.34:1364-­‐1375.049    Antibiotic  duration  days  (range)   10  (6-­‐16)   15  (10-­‐23)   0.  randomized.  Eur  Respir  J.  the  physician  in  charge  had  the  option  to  proceed   with  or  adjust  the  abx  treatment   Outcomes   • Primary  -­‐  Number  of  antibiotic-­‐free  days  alive  assessed  28  days  after  enrollment  in  the  study   • Secondary  -­‐  Number  of  mechanical  ventilation-­‐free  days.042)   • Algorithm  overruling  in  16%  of  PCT  group   • Appropriate  initial  empiric  antibiotic  therapy  in  86%  of  cases  (no  differences  between  groups)       Outcomes   PCT  Group   Control  Group   P  Value   (n=51)   (n=50)   Primary  Outcomes   Antibiotic-­‐free  days  alive  (range)   13  (2-­‐21)   9.5)   14  (1-­‐21)   0.5  (1.  physician  was  unaware  of  PCT  levels  on  initiation   • Educational  sessions  provided  to  physicians  emphasizing  current  standard  antibiotic  de-­‐escalation   strategy  according  to  American  Thoracic  Society  guidelines   • PCT  group  (after  72hr)   o Daily  procalcitonin  levels  were  notified  to  the  physicians  for  10  days   o Level  <  0.   Design   • Multinational.  controlled  open  interventional  trial   Inclusion   • Patients  intubated  for  mechanical  ventilation  for  ≥48hrs  if  they:   o >18yrs   o Clinically  diagnosed  VAP  (American  Thoracic  Society  criteria)   Exclusion   • Pregnant   • Enrolled  in  another  trial   • Received  immunosuppressants  or  corticosteroid  therapy  (≥0.25  mcg/L  à  discontinuation  of  antibiotics  strongly  encouraged   o Level  0.017   microbiologically  diagnosed  VAP   Secondary  Outcomes     No  statistically  significant  difference  between  groups  for  any  secondary  outcome   Gonzalez         9   .  Eggimann  P.  Procalcitonin  for  reduced  antibiotic  exposure  in  ventilator-­‐associated   pneumonia  (ProVAP):  a  randomized  study.  Control=51   • Exclusion  rate  of  38%   • Clinical  characteristics  similar  between  groups  except  for  ODIN  score.5-­‐17)   0.  length  of  hospital  stay.05  using  a  two-­‐tailed  test   • Intention  to  treat  analysis   • Categorical  variables  à  Chi-­‐squared  or  Fisher’s  exact  test   • Continuous  variables  à  Non-­‐parametric  Mann-­‐Whitney  U-­‐test  or  unpaired  t-­‐test   • Cumulative  events  curves  à  Kaplan-­‐Meier   • Time  to  discontinuation  of  abx  à  Log-­‐rank  test   • Occurrence  of  events  on  day  28  à  Cox  proportional  hazards  regression  analysis   Results   • 101  patients  randomized.  PCT=  50.

  • Serum  procalcitonin  reduces  antibiotic  exposure  in  critically  ill  patients  treated  for  VAP.   • The  absence  of  differences  in  secondary  outcomes  suggests  procalcitonin-­‐guided  antibiotic  reduction  is   not  associated  with  a  worse  outcome  in  VAP.Author’s   • We  observed  a  benefit  of  incorporating  procalcitonin  into  the  antibiotic  reduction  strategy  suggested  by   Conclusions   current  ATS/IDSA  guidelines.   Strengths   • Similar  baseline  characteristics  (including  taking  into  account  causative  microorganisms)   • No  attrition   • Met  90%  power  to  detect  a  significant  difference  between  the  groups  for  the  primary  outcome   • Measured  and  took  into  account  appropriate  empiric  antibiotics  between  groups   Weaknesses   • Small  study   • Focused  only  on  critically  ill  VAP  patients   • Excluded  immunocompromised  patients  and  patients  on  large  amounts  of  corticosteroids   • Algorithm  overruling  in  16%   • High  rate  of  exclusion  (38%)                                                                               Gonzalez         10   .

 student’s  t  test.  at  each  infectious  episode  until  day  28.   Design   • Multicenter.  Sepsis  related  organ  failure  assessment  (SOFA)  score.  ≥0.  Lancet.25  and  <0.  septic  shock..  or  Toxoplasma   gondii).05  (assumed  mean  12  days  without  antibiotics)   • Non-­‐inferiority  mortality  comparison:  300  patients  per  group  to  exclude  a  10%  difference  in  mortality   w/  80%  power   • Comparisons  –  chi  squared.g.  number  of  days  without  mechanical   ventilation.  and  conc.  and  laboratory  baseline  characteristics   • Medical  admission  à  90%  PCT  group.  Control-­‐  6%   o Skin  and  soft  tissue  à  PCT-­‐  2%.  Tubach  F.  infective  endocarditis.   Objective   To  establish  the  effectiveness  of  an  algorithm  based  on  the  biomarker  procalcitonin  to  reduce  antibiotic   exposure  in  intensive  care  units.  p<0.5  mcg/L  à  continuing  of  abx   encouraged   § Increase  of  conc.e.  <0.  89%  control  group   • Surgical  admission  à  10%  PCT  group.  poor  chance  of  survival  (SAPS  II  score  of  more  than  65  points).  ≥0.  2010.  Control-­‐  4%   Gonzalez         11   .  open-­‐label  trial   • Setting  -­‐  eight  ICUs  at  university-­‐affiliated  hospitals  in  France  (five  medical.  anterior  mediastinitis  after  cardiac  surgery.  compared  w/  peak  conc.  length  of  stay  in  the  ICU  and  hospital.375(9713):463-­‐474.  ≥0.  Luyt  CE.  Kaplan  Meier   Results   • Randomized  307  to  PCT  group  and  314  to  control  group  (52%  rate  of  exclusion)   • Similar  demographic.  ≥0.   days  of  antibiotic  exposure  per  1000  inpatient  days   Statistics   • Power  analysis:  133  patients  per  group  to  detect  a  3  day  increase  in  days  without  antibiotics  w/  90%   power.  Control-­‐  2%   o Intra-­‐abdominal  à  PCT-­‐  5%.5  and  <1  mcg/L  à  abx  encouraged   § Conc.  ≥0.Table  6:  Bouadma  L.  hepatic  or  cerebral  abscesses.  or  conc.  and  conc.25  mcg/L  à  abx  strongly  discouraged   § Conc.  three  surgical)   Inclusion   • Admitted  to  the  ICU  with  suspected  infections   • Not  receiving  antibiotics  before  inclusion   • Patients  who  developed  sepsis  during  their  ICU  stay   Exclusion   • Under  18  years  of  age   • Known  pregnancy   • Expected  stay  in  ICU  of  <  3  days   • Bone-­‐marrow  transplant  or  chemotherapy-­‐induced  neutropenia  (<500  neutrophils/mL)   • Infections  for  which  long-­‐term  antibiotic  treatment  is  recommended  (i.   osteoarticular  infections.5  mcg/L  à  changing  of  abx   strongly  encouraged   o Final  decision  was  at  the  discretion  of  the  patients’  physician   • Control  group   o Antibiotics  given  for  standard  duration   *Excludes  situations  requiring  immediate  abx  treatment  (e.  Control-­‐  1%   o Primary  blood  stream  à  PCT  3%.  or  infection  with  Mycobacterium  tuberculosis.  et  al.  <0.  ≥1  mcg/L  à  abx  strongly  encouraged   o Guidelines  for  continuing  or  stopping  of  antibiotics   § Conc.  every  day  while  on  abx)   o Guidelines  for  starting  antibiotics*   § Conc.5  mcg/L  à  abx  discouraged   § Conc.  Control-­‐  2%   o Catheter  related  à  PCT-­‐  2%.25  and  <0.  do  not  resuscitate  (DNR)  orders   Methods/   • Computer  generated  randomization   Interventions   • PCT  group  (blood  samples  at  inclusion.25  mcg/L  à  stopping  abx  strongly  encouraged   § Decrease  by  ≥80%  from  peak  conc.  clinical.  purulent  meningitis)   Outcomes   • Primary   o Death  from  any  cause  by  days  28  and  60  (non-­‐inferiority)   o Number  of  days  without  antibiotics  at  28  days  after  inclusion   • Secondary  –  percentage  of  patients  with  relapse  or  superinfection.  11%  control  group   • Infection  site   o Pulmonary  à  PCT-­‐  71%.5  mcg/L  à  stopping  abx   encouraged   § Decrease  by  <80%  from  peak  conc.  Use  of  procalcitonin  to  reduce  patients’  exposure  to  antibiotics  in  intensive  care   units  (ProRATA  trial):  a  multicenter  randomized  controlled  trial.  parallel-­‐group.  Control-­‐  7%   o CNS  à  PCT-­‐  3%.  Pneumocystis  jirovecii.   chronic  prostatitis.  randomized  prospective.  Control-­‐  74%   o Urinary  tract  à  PCT-­‐  9%.

 difference  (95%  CI).)   • Explored  using  PCT  for  starting  antibiotic  therapy  as  well   Weaknesses   • Surgical  patients  represented  only  10%  of  the  study  population   • Excluded  difficult  to  treat  microorganisms  and  neutropenic  patients   • Algorithm  overruled  in  53%  of  patients  in  PCT  group                                                           Gonzalez         12   . • Non-­‐adherence  to  algorithm  à  53%  PCT  group   • For  initiation  of  abx  à  93  (30%)  had  initial  PCT  levels  <0.7)   <0.  (9%)   Outcomes   PCT  Group   Control  Group   Between  group   P  Value   (n=307)   (n=314)   absolute  difference   Primary  Outcomes   28-­‐day  mortality*   65  (21.8%  (-­‐2.3  (9.6  to  6.5  mcg/L  (the  cutoff  point  for  discouraging   antimicrobial  initiation)  à  Antibiotics  only  withheld  for  28  pts.2%)   64  (20.1)   11.7)   NA   Number  of  days  without   14.4  to  4.7  (1.0001   antibiotics   Secondary  Outcomes   No  differences  between  groups  for  any  of  the  safety  parameters   Duration  of  antibiotics   6.4%)   0.0001   (days  [SD])   Data  are  number  (%).1)   -­‐3.2)   2.   *Non-­‐inferiority  outcomes  -­‐  Difference  (90%  CI)   Author’s   • Procalcitonin  guided  antibiotic  therapy  substantially  lowers  antibiotic  exposure  and  is  non-­‐inferior  to   Conclusion   standard  care  with  respect  to  outcomes   Strengths   • Largest  RCT  to  date   • Powered  to  compare  mortality  differences   • Intention  to  treat  analysis   • Did  not  exclude  immunocompromised  (except  for  bone  marrow  transplant  and  neutropenic  pts.6  (8.  or  mean  (SD).1%)   3.0)   9.9  (7.1)   <0.8  to  -­‐2.2)   NA   60-­‐day  mortality*   92  (30%)   82  (26.8%  (-­‐4.1  (6.1  to  9.8  (-­‐4.

  • On  the  basis  of  no  effect  in  hospital  mortality  or  hospital  length  of  stay.  (2009)   o Bouadma  et  al.68-­‐2.04  to  +0.04.  p=0.  compared  to  surgical  admission   • Compliance  to  algorithm  varied  between  studies.  Costs   were  determined  from  the  literature  and  are  reported  in  2009  Canadian  dollars.  assuming  PCT  assay  price  of  $49.  et  al.06.   Table  7:  Heyland  DK.  -­‐2.  95%  CI  -­‐0.  p=0.78)  [p<0.  (2010)   Aggregated   • Effect  on  Antibiotic  Duration   Results   o Weighted  mean  difference  à  -­‐2.5  to  +1.  a  cost  minimization  analysis  was   conducted  using  the  costs  of  procalcitonin  testing  and  antibiotic  administration  and  acquisition.00001]   • Mortality   o No  effect  was  seen  of  a  PCT  guided  strategy  on  hospital  mortality  (risk  ratio  1.51  to  -­‐1.  physician  non-­‐compliance  was  >50%  in  two  of  the   studies   • All  studies  used  different  arbitrarily  derived  PCT  cut  off  values   • Meta-­‐analysis  dominated  by  one  large  trial  (Bouadma  n=621)                   Gonzalez         13   .  p=0.  2011.75  to  +1.(9)37:1792-­‐1799.86  (95%  CI  -­‐4.46)   • Cost  analysis   o Using  average  antibiotic  costs.  Procalcitonin  for  reduced  antibiotic  exposure  in  the  critical  care  setting:  A   systematic  review  and  an  economic  evaluation.30.  the  frequency  of  use  and  the  cost  of  the  PCT  assays.   • Five  articles  met  the  inclusion  criteria   o Nobre  et  al.   Design   • Included  randomized  controlled  trials  conducted  in  the  ICU  that  compared  procalcitonin-­‐guided   strategy  to  usual  care  and  reported  on  antibiotic  utilization  and  clinically  important  outcomes.61)   • Length  of  stay  (LOS)   o No  overall  effect  seen  in  ICU  or  hospital  LOS   § ICU  LOS  weighted  mean  difference  -­‐1.  (2008)   o Hochreiter  et  al.   Strengths   • Approximately  1000  patients  have  been  studied  in  these  five  randomized  controlled  trials   • Only  looked  at  randomized  controlled  trials   • Adjusted  for  methodologic  quality  of  the  studies   • Included  an  economic  analysis   Weaknesses   • Approximately  75%  of  studied  patients  had  a  medical.  Johnson  AP.07.86-­‐1.   • Results  were  qualitatively  and  quantitatively  summarized.01.  (2009)   o Stolz  et  al.5  (95%  CI  -­‐4.  p=0.26  (95%  CI  0.  Reynolds  SC.  p=0.14  (95%  CI.  and  2  days  less  of  abx  therapy   à  Cost  savings  of  $470  per  patient  episode  in  comparison  to  usual  care   o Using  more  expensive  antibiotic  costs  à  Cost  savings  of  $1134  per  patient  episode   Author’s   • PCT-­‐guided  therapy  is  associated  with  approximately  2  days  of  reduction  in  antibiotic  usage   Conclusions   o Reduction  due  to  early  discontinuation  of  antibiotics  rather  than  less  initiation  of  empirical   antibiotics   • No  difference  in  hospital  mortality   o Cannot  exclude  a  7%  risk  increase  (or  smaller)  in  hospital  mortality   • The  magnitude  of  cost  savings  associated  with  PCT  measurements  will  be  a  function  of  the  costs  of   antibiotics  commonly  used.  95%  CI   0.25)   § Hospital  LOS  weighted  mean  difference  -­‐1.35.  Crit  Care  Med.05.21)   • Recurrent  infections   o No  evidence  of  an  increase  for  the  PCT  guided  strategy   § Risk  ratio  1.  (2009)   o Schroeder  et  al.  risk  difference  0.  their  duration.   Objective   To  evaluate  the  effect  of  a  procalcitonin-­‐guided  antibiotic  strategy  on  clinical  and  economic  outcomes.59.

5  mcg/L  or  decrease  by  <80%   -­‐  Exclusion  rate  –  38%   compared  with  day  0  à  discontinuation   -­‐  Algorithm  overruling  – of  antibiotics  discouraged   16%   -­‐  Level  >1  mcg/L  à  discontinuation  of   antibiotics  strongly  discouraged   Bouadma   -­‐  ICU  patients  w/  suspected   63%  pneumonia   -­‐  Conc.25-­‐0.   and  2  SIRS  criteria   39%  pneumonia   PCT  decreased  to  <  1  mcg/L  OR   abx   (ProSICU)   -­‐  100%  surgical   If  initial  PCT  value  was  >  1  mcg/L..   i. General  limitations  of  the  trials  include  high  rate  of  patients’  exclusion.  infx  requiring   encouraged   long  term  abx   -­‐  Increase  of  conc.5  mcg/L  à  stopping   compromised   abx  encouraged   -­‐  Excluded  bone-­‐marrow   -­‐  Decrease  by  <80%  from  peak  conc.  high  rate  of   algorithm  overruling.   -­‐  Mechanically  ventilated   100%  VAP   -­‐  Level  <  0.1  mcg/L.  in  patients  with  sepsis  predominantly  of  pulmonary  origin  and/or  VAP.   Gonzalez         14   .  and  clinical  evaluation   -­‐Algorithm  overruling  –   rules  out  severe  infection   19%   Hochreiter   -­‐  SICU  patients  w/  infection   54%  peritonitis   Discontinue  abx  when:   20%  ↓  in   et  al.  w/  “therapy   dropped  to  25-­‐35%  of  the  initial  value   limitations”   over  three  days   -­‐  Exclusion  rate  –  72%   -­‐  Algorithm  overruling  not   reported   Stolz  et  al.   -­‐  24%  surgical   day  5.  discontinue  abx  when:   abx   (ProSEP)   -­‐  Excluded  difficult  to  treat   -­‐PCT  dropped  by  90%  from  baseline   exposure   (79)   organisms. Heyland  et  al.  but  had   exposure   (28)   -­‐  Excluded  pt. In  the  ICU. Table  8:  Summary  of  randomized  controlled  trials  of  procalcitonin  use  in  the  ICU   Studies   Population/Exclusions/   Infection   PCT  Algorithm   Antibiotic   (n)   Algorithm  Overruling   Exposure   Nobre  et   -­‐  Sepsis  and  septic  shock     69%  pneumonia   -­‐Baseline  PCT  ≥  1  mcg/L  reevaluated  at   37%  ↓  in   al.  and  long  duration  of  antibiotic  therapy  in  the  control  group. Conclusions   a. Procalcitonin  has  shown  to  be  most  effective  when  serial  level  measurements  are  used  as  a   follow  up  tool  to  assist  clinicians  in  deciding  when  it  is  most  appropriate  to  discontinue   antibiotics  on  a  patient-­‐by-­‐patient  basis.25  and  <0.5  mcg/L  or  a  decrease  of   -­‐  90%  medical   ≥80%  compared  with  day  0  à   -­‐  Excluded   discontinuation  of  antibiotics  encouraged   immunosuppressed   -­‐  Level  ≥0.  compared  w/  peak   -­‐  Exclusion  rate  –  52%   conc.25  mcg/L  à  stopping  abx   33%  ↓  in   et  al.   procalcitonin-­‐guided  antimicrobial  therapy  has  shown  on  average  to  reduce  the  duration  of   antibiotic  therapy  by  2-­‐3  days. Only  one  study  powered  to  detect  this  difference   ii.  chemo  induced   conc.   bacterial  infection     strongly  encouraged   abx   (ProRATA)   -­‐  90%  medical   -­‐  Decrease  by  ≥80%  from  peak  conc.5  mcg/L  à  changing  of   -­‐  Algorithm  overruling  – abx  strongly  encouraged   53%       VI.  and   transplant.   -­‐Absolute  value  <0.  or   exposure   (621)   -­‐  16%  immuno-­‐ conc.   b.  ≥0.5  mcg/L  à  continuing  of  abx   neutropenia.25  mcg/L  à  discontinuation  of   27%  ↑  abx   (ProVAP)   patients  w/  ventilator   antibiotics  strongly  encouraged   free  days   (101)   associated  pneumonia   -­‐  Level  0.25  mcg/L   immunosuppressed. No  statistically  detectable  adverse  outcomes  have  been  associated  with  the  shorter   duration  of  antibiotics.  and  conc.   d.  meta-­‐analysis  cannot  exclude  a  7%  risk  increase  in  hospital  mortality   c.  discontinue  abx  when:   -­‐  Exclusion  rate  –  72%   -­‐PCT  <  0.  and   Baseline  PCT  ≤  1  mcg/L  reevaluated  at   neutropenic   day  3.  ≥0.  <0.  ≥0.

 respectively22.  ECOPD. Emergency  department  and  primary  care  settings  for  patients  w/  upper  and  lower   respiratory  tract  infections. Most  robust  data  from  Bouadma  et  al. Gaps  in  Knowledge  and  Future  Research  Needs   a. Initial  PCT  level  <0. Factors  to  consider   1.2%  prescription  rates20   b.  cut  off  values   iii. Initial  PCT  level  >1  mcg/mL  in  29%  of  no  confirmed  infection   2. At  baseline  when  antibiotics  are  initiated   2. Ninety  three  (30%)  had  initial  PCT  levels  <0. Discontinue  antibiotics  if  procalcitonin  level  is  <0. If  patient  is  not  immunocompromised   2. Use  in  immunocompromised. For  patients  with  sepsis  of  pulmonary  origin  and/or  VAP   i.  neutropenic. Conditions  that  may  falsely  elevate  PCT  levels   3. Appropriate  procalcitonin  cutoff  levels  in  different  populations           Gonzalez         15   .  every  1-­‐2  days   b.  Briel  et  al. Recommendations  for  Procalcitonin  Use  in  the  ICU   a.25  mcg/mL  in  28%  of  confirmed  infections   c. Other  potential  areas  of  use  for  procalcitonin20-­‐24   a. As  a  follow-­‐up  tool  to  assist  clinician’s  decision  of  knowing  when  it  is  appropriate  to   discontinue  antibiotics   ii. If  patient  is  not  pregnant   4.  given  antimicrobials  (PCT  group:   88%  and  Control:  87%)  and  of  ICU  days  during  which  antimicrobials   were  given  (PCT  group:  64%  and  Control:  60%)   b.29   a. NOT  recommended  for  use  in  antibiotic  initiation  in  the  ICU   i. Layios  et  al. No  difference  in  proportion  of  pts. Conditions  that  may  keep  PCT  levels  low   2.  (9%)     VIII.   VII.  consider  further  diagnostic  evaluation   v.  showed  reduction  in  antibiotic   prescription  rates  by  72%  and  42%. Two  RCTs  looking  at  this  question  show  PCT  based  strategies  for  initiation  are   relatively  ineffective   1.5  mcg/L  or  has  dropped  by   80%  or  more  from  baseline   iv.23     IX.  12.  and  Burkhardt  et  al.  and  pediatric  populations   b. If  the  patient  is  clinically  improving   5.18   a.  relative  reduction-­‐  35%  antibiotic  duration. If  patient  has  not  had  surgery  in  the  past  24hrs   3. PCT  value  which  is  rising  or  not  declining  is  a  poor  prognostic  indicator  and   suggests  infection  is  not  controlled. Algorithm   1. Once  patient  begins  to  improve  clinically. Non-­‐ICU  inpatient  –  ProHOSP  trial  showed  reduced  antibiotic  initiation  and  promoted  early   antibiotic  de-­‐escalation  in  patients  with  respiratory  tract  infections  (CAP.5  mcg/L  (the  cutoff  point   for  discouraging  antimicrobial  initiation)  à  Abx  only  withheld  for  28   pts.  acute   bronchitis). Bouadma  et  al. When  to  order  levels   1.

X. Stop  Antibiotics  on  guidance  of  Procalcitonin  Study  (SAPS):  a  randomized  prospective   multicenter  investigator-­‐initiated  trial  to  analyse  whether  daily  measurements  of   procalcitonin  versus  a  standard-­‐of-­‐care  approach  can  safely  shorten  antibiotic  duration  in   intensive  care  unit  patients-­‐-­‐calculated  sample  size:  1816  patients                                                                                                               Gonzalez         16   . Study  in  pipeline25   a.

 Rogers  P.  Singh  N.  A  New  Simplified  Acute  Physiology  Score   (SAPS  II)  Based  on  a  European/North  American  Multicenter  Study.  et  al.   18.  Expert  Rev  Anti  Infect  Ther   2010.  Procalcitonin-­‐Guided  Antibiotic  Use  in  the  Critically  Ill.8:575-­‐587.  Procalcitonin  for  reduced  antibiotic  exposure  in  ventilator-­‐associated  pneumonia:  a   randomized  study.  Crit  Care  Med  2013  Feb.  The  SOFA  (Sepsis-­‐related  Organ  Failure  Assessment)  score  to  describe  organ   dysfunction/failure.   7.9:107.22(7):707-­‐10.  Nobre  V.   3.  et  al.  et  al.  JAMA   2009.  Heyland  DK.  Atwood  CW.cdc.  Eur  Respir  J  2010.  et  al.   22.  more  or  less?  Swiss  Med  Wkly  2005.  Crit  Care  Med  2011.  Takala  J.  <http://www.References:   1.  Novara  A.  et  al.  Muller  B.  Guidelines  for  the  management  of  adults  with  hospital-­‐acquired.  Schroeder  S.  ventilator-­‐associated.  (1993).  Moreno  R.  Sibbald  WJ.  Schweiger  AM.   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 infections:  the  Randomized-­‐Controlled  Multicenter  ProHOSP  Trial.  Assink-­‐de  Jong  E.  Stanley  Lemeshow.  Procalcitonin  in  bacterial  infections  –  hype.  Christ-­‐Crain  M.  Procalcitonin-­‐guided  interventions  against  infections  to  increase  early  appropriate  antibiotics  and  improve   survival  in  the  intensive  care  unit.  Johnson  AP.  Burkhardt  O.  et  al.302(10):1059-­‐1066.   present.  Am  J  Respir  Crit  Care  Med  2005.  Smyrnios  N.com/>   8.  Antibiotic  Resistance:  Threat  Report  2013.   5.  Christ-­‐Crain  M.  Stolz  D.  Schuetz  P.  Bone  RC.  Jean-­‐Roger  Le  Gall.  et  al.  Mueller  B.   10.(9)37:1792-­‐1799.  Strategies  for  reduction  in  duration  of  antibiotic  use  in  hospitalized  patients.  Levy  M.  PRORATA  trial  group.  Arch  Intern  Med  2008.  Wenzel  RP.  N  Engl  J  Med  2006.  20  Sept  2013.   15.  Haagen  U.  Brahms®:Procalcitonin  and  Sepsis.  Procalcitonin  (PCT)-­‐guided  algorithm  reduces  length  of  antibiotic  treatment  in   surgical  intensive  care  patients  with  severe  sepsis:  results  of  a  prospective  randomized  study.  controlled  trial   comparing  procalcitonin-­‐guidance  with  standard  therapy.   20.  hope.  Procalcitonin  Clinical  Utility  in  Diagnosing  Sepsis.  Procalcitonin  guidance  and  reductions  of  antibiotic  use  in  acute  respiratory  tract   infection.   21.  A  proposed  solution  for  indiscriminate  antibiotic  prescription.  Bouadma  L.  Langenbecks  Arch  Surg   2009.  Use  of  procalcitonin  to  reduce  patients’  exposure  to  antibiotics  in   intensive  care  units  (PRORATA  trial):  a  multicenter  randomized  controlled  trial.  Crit  Care  Med  2011.270:2957-­‐2963.  JAMA  1993.40:2304.  On  behalf  of  the  Working  Group  on  Sepsis-­‐Related  Problems  of  the  European  Society  of  Intensive  Care   Medicine.  IDSA  Guideline  Committee.19:137-­‐144.  Mueller  B.   4.36(3):601-­‐607.  Dellinger  R.131(1):9-­‐19.  Surviving  Sepsis  Campaign:  International  Guidelines  for  Management  of  Severe  Sepsis   and  Septic  Shock:  2012.  Use  of  procalcitonin  to  shorten  antibiotic  treatment  duration  in  septic  patients:  a   randomized  trial.  Koehler  T.  Procalcitonin  for  guidance  of  antibiotic  therapy.  et  al.gov/drugresistance/threat-­‐report-­‐2013/>   2.  Kohler  T.  Tubach  F.  Baumann  NA.  MD.  355:2125-­‐2130.  Fowler  AA.  Schachinger  H.   12.  U.35(7).  de  Lange  DW.34(6):1364-­‐1375.  Procalcitonin  to  guide  duration  of  antibiotic  therapy  in  intensive  care  patients:   a  randomized  prospective  controlled  trial.  Am  J  Respir  Crit  Care  Med  2008.  Schuetz  P.  Fagon  JY.  Luyt  C.13:178.  Layios  et  al.  Ewig  S.  Becker  K.  Hayashi  Y.   19.  Clinical  Laboratory  News.  Procalcitonin-­‐guided  antibiotic  use  vs  a  standard  approach  for  acute  respiratory  tract   infections  in  primary  care.  Wolbers  M.  MD.  Stop  Antibiotics  on  guidance  of  Procalcitonin  Study  (SAPS):  a  randomised   prospective  multicenter  investigator-­‐initiated  trial  to  analyse  whether  daily  measurements  of  procalcitonin  versus  a  standard-­‐ of-­‐care  approach  can  safely  shorten  antibiotic  duration  in  intensive  care  unit  patients-­‐-­‐calculated  sample  size:  1816  patients.  Hochreiter  M.   24.  Crit  Care  Med  2012.  Eggimann  P.  Chest  2007.  Hochreiter  M.  2009.  Characterization  of  intensive  care  unit  patients  using  a  model  based  on  the  presence  or   absence  of  organ  dysfunctions  and/or  infection:  The  ODIN  model.  Graf  J-­‐D.  PhD.  Lancet  2010.  and  future.  Antibiotic  treatment  of  exacerbations  of  COPD:  a  randomized.28(4):977-­‐983.  Harbarth  S.52:1232-­‐40.  Fabienne  Saulnier.  et  al.   17.  Clin  Infect  Dis   2011.  Schuetz  P.  Thermo  Scientific.   13.   25.  Werner  A.  and   healthcare-­‐associated  pneumonia.  16  Sept  2013.  Christ-­‐Crain  M.  van  Oers  JA.S.   29.  Sprung  CL.  Am  J  Respir  Crit  Care  Med  2000  Aug.  Chastre  J.   6.  Eur  Respir  J  2009.  et  al.   27.   Crit  Care  Med  2000.  Vincent  JL.  Short-­‐course  empiric  antibiotic  therapy  for  patients  with  pulmonary  infiltrates  in  the   intensive  care  unit.  Albrich  W.375(9713):463-­‐474.   26.  et  al.135:451-­‐460.  Calcitonin  precursors  are  reliable  marker  of  sepsis  in  a  medical  intensive  care  unit.13(3):R83.  Department  of   Health  and  Human  Services.  et  al.  et  al.  The  ACCP-­‐SCCM  consensus  conference  on  sepsis  and  organ  failure.41(2):580-­‐637.168(18):2000-­‐2007.   28.

7  to  <101.600   440   Summary  Totals  for  Antibiotic-­‐Resistant  Infections   2.000   11.Appendix  A1   Antibiotic  Resistant  Microorganism   Estimated  Annual   Estimated  Annual   Number  of  Cases   Number  of  Deaths   Carbapenem-­‐resistant  Enterobacteriaceae  (CRE)   9.700   440   classes)   Drug-­‐resistant  non-­‐typhoidal  Salmonella  (ceftriaxone.  mm3   >4000  to  <11000   <4000  or  >11000   <4000  or  >11000  +  bands   >50%   PaO2/FiO2   >240  or  ARDS   -­‐   <240  without  ARDS   CXR   No  infiltrate   Diffuse/patchy  infiltrate   Localized  infiltrate   CXR  progression   No  progression   -­‐   +  progression   Tracheal  secretions   Rare   Abundant   Abundant  +  purulent   Tracheal  aspirate  of   Rare/light  or  no  growth   Moderate  or  heavy   -­‐   pathogenic  bacteria   (semiquantitive)   Tracheal  aspirate  of   Rare/light  or  no  growth*   Moderate  or  heavy*   -­‐   pathogenic  bacteria   (semiquantitive)   *  +1  point  if  same  bacteria  seen  on  gram  stain   Total  score  >6  à  clinical  diagnosis  of  VAP   CPIS  ≤6  after  72h  à  consider  simplification/discontinuation  of  antibiotic  therapy           Gonzalez         18   .442   23.2  to  <102   <96.200.000   1.300   Multidrug-­‐resistant  Pseudomonas  aeruginosa  (three  or  more  drug   6.300   610   Drug-­‐resistant  Neisseria  gonorrhoeae  (any  drug)   246.700   (ESBLs)   Vancomycin-­‐resistant  Enterococcus  (VRE)   20.  F   97.000   28   Drug-­‐resistant  Candida  (fluconazole)   3.000   40   5  or  more  drug  classes)   Drug-­‐resistant  Shigella  (azithromycin  or  ciprofloxacin)   27.000   Drug-­‐resistant  tuberculosis   1.300   160   Clindamycin-­‐resistant  Group  B  Streptococcus   7.049.000   <5   Multidrug-­‐resistant  Acinetobacter  (three  or  more  drug  classes)   7.8  or  >102.400   220   Extended-­‐spectrum  β-­‐lactamase  producing  Enterobacteriaceae   26.1   101.000   <5   Methicillin-­‐resistant  Staphylococcus  aureus  (MRSA)   80.402   50   Vancomycin-­‐resistant  Staphylococcus  aureus  (VRSA)   <5   <5   Erythromycin-­‐resistant  Group  A  Streptococcus   1.000   1.300   500   Drug-­‐resistant  Campylobacter  (azithromycin  or  ciprofloxacin)   310.1   WBC.000   7.  ciprofloxacin.000   Streptococcus  pneumonia   1.488       Appendix  B:  Clinical  Pulmonary  Infection  Score  (CPIS)  criteria  and  interpretation12   Patient  Characteristic   0   1   2   Temp.   100.

 hematologic   dysfunction  and  the  presence  of  infection   • Prediction  of  outcome  is  found  using  logistic  regression  analysis   Variables   Coefficient   Odds-­‐ratio   p-­‐value   Constant   -­‐3.19   3.0001   Cardiovascular  dysfunction   1.1  or   norepinephrine  <0.18   3.9   2.  site  of  injury.2-­‐1.  acute  infection  at  ICU  admission.2-­‐1.   <400   <300   <200   <100   mmHg   Coagulation   <150   <100   <50   <20   Platelets  x  103/mm3   Liver   1.  hydrogen  ion  concentration.1   Central  Nervous  System   13-­‐14   10-­‐12   6-­‐9   <6   Glasgow  Coma  Score   Renal   1.  providing  a  daily  score  of  0-­‐24  points.Appendix  C  26-­‐28     Simplified  Acute  Physiology  Score  (SAPS  II)   • Designed  to  measure  the  severity  of  disease  for  patients  admitted  to  the  ICU  (>18  yr)  and  calculates  probability  of   hospital  mortality.  heart  rate.69   <0.36   0.99   2.1   norepinephrine  >0.  surgical)     SAPS  (III)   • Designed  to  provide  a  real-­‐life  predicted  mortality  for  a  patient  by  following  a  well  defined  procedure.59   -­‐   <0.  cardiovascular.25   <0.97   <0.4   3.  mg/dL   Cardiovascular   MAP<70   Dopamine  <5  or   Dopamine  >5  or   Dopamine  >15  or   Hypotension   dobutamine  (any  dose)   epinephrine  <0.1  or   epinephrine  >0.86   2.011   Hepatic  dysfunction   0.  AIDS)  15)  Type  of  admission  (medical.   use  of  therapeutic  options  before  ICU  admission  (vasoactive  drugs).9   2.28   <0.09   2.0001   Neurologic  dysfunction   0.53   1.  hepatic..  oxygenation     Sequential  Organ  Failure  Assessment  (SOFA)  Score   • SOFA  score  is  a  six-­‐organ  dysfunction/failure  score  measuring  multiple  organ  failure  daily.  systolic  blood  pressure.     • Mortality  rate  increases  as  number  of  organs  with  dysfunction  increases   Points   1   2   3   4   Respiration  PaO2/Fi02.   • Variables  used:  1)  age  2)  heart  rate  3)  SBP  4)  Body  temp  5)  If  on  mechanical  ventilation  –  PaO2/FiO2  6)  Urinary   output  7)  BUN  8)  WBC  count  9)  Potassium  10)  Sodium  11)  Bicarbonate  12)  Bilirubin  13)  Glasgow  Coma  Score  14)   Chronic  disease  (cancer.  leukocytes.9   >12   Bilirubin.  co-­‐morbidities.  surgical  status.055   Infection   0.0-­‐3.0-­‐11.  renal.  when  precise  diagnostic  evaluation  is  not  possible   • Less  subjectivity   • Discrimination  comparable  to  SAPS  II  &  APACHE  II   • Answer  yes/no  questions  on  variables  of  respiratory.   • Must  use  worst  corresponding  variables  upon  24hr  of  admission.  platelets.  based  on  a   statistical  mathematical  model  that  needs  calibration.  neurologic.  The  score  is  calculated  and  results  in  an  integer   between  0  –  163  and  a  predicted  mortality  between  0-­‐100%.  No  new  score  can  be  calculated  unless  the  patient  is   discharged  and  readmitted  to  the  ICU.5-­‐4.0001   Renal  dysfunction   1.  total  bilirubin.  estimated  GCS.  reason  for  ICU   admission.  planned  or  unplanned  admission.0001   Respiratory  dysfunction   1.70   0.9   6.9  or  <500   >5  or  <200  mL/day   Creatinine  mg/dL  or   mL/day   Urine  Output  mL/day     Organ  Dysfunction  and/or  Infection  (ODIN)  Score   • Easily  available  data  (within  the  first  24h  of  admission).  Each  organ  is  graded  from   0  (normal)  to  4  (most  abnormal).  length  of  stay  before  ICU  admission.   creatinine.0-­‐5.78   0.0001   Hematologic  dysfunction   0.   • Total  score  can  range  from  0  –  217.57   1.  body  temp.   • Twenty  Variables  used:  Age.002       Gonzalez         19   .  intra-­‐hospital  location  before  ICU.

1-­‐0.5   +   PCT  reduces  antibiotic   exposure  during  outbreak  of   viral  meningitis   Bronchitis   Randomized   0.25   ?   PCT  may  help  to  exclude   ischemia  and  necrosis  in  bowel   obstruction   Arthritis   0.5   +++   PCT  reduces  antibiotic   Controlled  Trials   exposure  in  the  ED  without   adverse  outcomes   COPD  exacerbation   0.5-­‐1.5   +   PCT  is  helpful  at  identifying   neutropenic  patients  with   systemic  bacterial  infection   Postoperative  fever   0.5   +++   PCT  reduces  antibiotic   exposure  in  the  ED  and   hospital  without  adverse   outcomes   Pneumonia   0.25-­‐0.5   +   PCT  differentiates  non-­‐ infectious  fever  from  post-­‐ operative  infections   Urinary  Tract  Infection   0.25-­‐0.  +++  strong  evidence       Gonzalez         20   .25   ++   PCT  reduces  antibiotic   pneumonia   exposure  without  adverse   outcomes   Severe  sepsis/  Shock   0.  ++  good  evidence.1-­‐0.1   ++   PCT  differentiates   (primary)   contamination  from  true   infection   Endocarditis   2.  80-­‐90%  ↓   +++   PCT  reduces  antibiotic   exposure  in  the  ICU  without   adverse  outcomes   +  moderate  evidence.  80-­‐90%  ↓   +++   PCT  reduces  antibiotic   exposure  in  the  hospital   without  adverse  outcomes   Postoperative   0.  75-­‐85%  ↓   ++   PCT  reduces  antibiotic   infections   exposure  in  the  surgical  ICU   without  adverse  outcomes   Ventilator-­‐associated   0.0.5.25   +   PCT  differentiates  non-­‐ infectious  (gout)  arthritis  from   true  infection   Bacteremic  infections   0.25   ++   Low  PCT  levels  help  to  rule  out     bacteremic  infections     Blood  stream  infection   0.1-­‐0.Appendix  D:  Overview  of  studies  investigating  the  use  of  PCT  in  different  types  of  infection13   Type  of  infection   Study  designs   PCT  cut-­‐off  (mcg/L)   Benefit  of   Main  conclusions   using  PCT?   Abdominal  infections   Observational   0.1-­‐0.1-­‐0.5   ?   PCT  correlates  with  severity   and  extent  of  infected   pancreatitis   Neutropenia   0.3   +   PCT  is  an  independent   predictor  for  acute   endocarditis  with  high   diagnostic  accuracy   Pancreatitis   0.1-­‐0.25   +   PCT  correlates  with  severity  of   urinary  tract  infections   Meningitis   0.5.1-­‐0.