Unresolved sepsis

Unresolved sepsis and antibiotic treatment failure

Reviewed and revised 17 December 2015


  • When a ‘septic’ patient fails to improve despite initial therapy, it is important to ‘stop and think’ and systematically consider the multiple possible reasons why ‘the antibiotic is not working’
  • The mnemonic CCDHB (i.e. ‘Capital Coast District Health Board’) is a useful checklist of the possible reasons
  • Antibiotic treatment failure is more common with empiric therapy (e.g. too narrow coverage) than with directed therapy


  • no consensus definition exists
  • rates vary from 6 to 60%, depending on the study and the type of infection (e.g. pneumonia vs serious soft tissue infection vs intra-abdominal infection)
  • various criteria may be used to indicate antibiotic treatment failure
    • patient based (e.g. early death, physical manifestations of sepsis, organ dysfunction)
    • treatment based (e.g. change/ addition of antibiotics, ICU admission, additional organ support, operative intervention)
    • test based (e.g. in vitro resistance, persistent elevation of septic biomarkers, non-resolving/ worsening CXR infiltrates)
  • the time point of assessment is also undefined; 48 to 72h is commonly used for antibiotic treatment failure in pneumonia
  • antibiotic treatment failure, in various infections, is associated with:
    • increased mortality
    • increased hospital LOS
    • increased duration of antibiotic therapy
    • increased cost



  • Is the diagnosis correct?
  • Consider non-infectious causes of fever (e.g. due to drugs, VTE, malignancy, autoimmune condition and hyperthermia)
  • Inadequate source control? (e.g. abscess drainage, debridement)
  • Toxin production? (e.g. patient may remain sick even after the organism has been destroyed, due to the persistent effects of previously produced toxins)


  • e.g. metastatic sepsis, collection, secondary nosocomial infection?


  • wrong antibiotic, route, timing, dose or inadequate blood levels? (e.g. impaired oral absorption)
  • drug antagonism/ interaction?
  • decreased penetration to site? (e.g. ischaemic toe with poor blood supply, IV vancomycin for C. difficile instead of the oral form)


  • immunodeficient or compromised?
  • foreign body or prosthesis present?
  • hidden places: sinusitis, endocarditis, retroperitoneum, neuroaxial infection?


  • multi-resistant organism?
  • unusual organism? (e.g. fungi)
  • polymicrobial infection?
  • infectious agent not amenable to antimicrobials? (e.g. virus, prion)


Consider the following sources of secondary nosocomial infections

  • lines
  • lungs and thoracic cavity
  • urine (e.g. IDC)
  • wounds and invasive procedures
  • prostheses
  • gastrointestinal (e.g. C. difficile, norovirus)
  • respiratory viruses (e.g. influenza)

References and links


Journal articles

  • Garrod LP. Causes of failure in antibiotic treatment. British medical journal. 4(5838):473-6. 1972. [pubmed] [free full text]
  • Sánchez García M. Early antibiotic treatment failure. International journal of antimicrobial agents. 34 Suppl 3:S14-9. 2009. [pubmed] [free full text]

CCC 700 6

Critical Care


Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of three amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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