1. Journal Club
Fraser Morton

2. Journal Club
De-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized non-inferiority trial
Leone, M et al
Intensive Care Med, Aug 2014

3. Conflicts of Interest
None

4. Current Concepts
De-escalation of antibiotics involves switching to a more appropriate narrow-spectrum antimicrobial regime once the causative pathogen is identified
Aims to prevent super infection and drug resistance in the community, improve patient safety and reduce costs
Excessive use of broad spectrum antibiotics promotes emergence of antibiotic- resistant bacterial pathogens in ICUs and poorer patient outcomes2
Surviving Sepsis Guidelines (2012)3 recommends daily re-assessment for potential de-escalation
Infectious Disease Society of America systemic review of antimicrobial stewardship (2013)4
Recommends de-escalation, but recognises this is based on moderate quality evidence from clinical studies with a lack of prospective RCTs

5. Current Concepts Two relevant studies:
Ganarcho-Montero et al., Intensive Care Med, 20135
Prospective observational study of 628 patients with severe sepsis or septic shock of which 35% had antimicrobial de-escalation
De-escalation had improved mortality (OR 0.58) even with adjustment for baseline severity and risk factors
Mokart et al., Intensive Care Med, 20136
Prospective observational study of 101 patients with neutropaenic sepsis of which 44% had de-escalation
No change in mortality hazard ratio with de-escalation out to 1 year after discharge (with multivariate logistic regression)

6. Current Concepts
Both studies recognised approximately only 50% of potential cases of sepsis with known microbiology had de-escalation
Significant potential for improvement
Cochrane Review of de-escalation of antimicrobial treatment for adults with sepsis, severe sepsis or septic shock (2013)7
Found no adequate direct evidence of RCTs assessing anti- microbial de-escalation efficacy or safety
Significant clinical question with a lack of relevant evidence

7. Null Hypothesis
De-escalation of empirical antimicrobial therapy in patients with severe sepsis or septic shock is inferior to continuation of empirical antimicrobial therapy
Aim is to prove non-inferiority
Primary outcome as length of ICU stay
Secondary aims of comparing the two strategies on:
Mortality
Number of super-infections
Organ failure
C.difficile infection
Vasopressor use
Duration antimicrobial therapy
Duration mechanical ventilation

8. Study Design
Non-inferiority trial – aims to demonstrate intervention is not worse than comparator by a specified non-inferiority margin (delta)
95% Confidence Interval must be within margin to satisfy non-inferiority

9. Non-Inferiority Studies
Common non-inferiority study design concerns8:
determining non-inferiority margin – who and why
not demonstrating any superiority, therefore not actually asking a significant clinical question
ethical issues with assigning acceptable mortality or failure margins
Susceptible to favourable bias with high discontinuation rates and intention-to-treat analysis
Calculation of adequate statistical power

10. Study Design Multicenter non-blinded randomized non-inferiority trial
Enrolled patients from 9 ICUs from Feb 2012 to April 2013
Centralised list by principal investigator with inclusion criteria assessed prior to enrollment and randomisation
Ethics approved and consent from patients or relatives
Patients enrolled once causative organism identified ?with sensitivities
1:1 blocked random assignment to de-escalation or continuation group
No mention of stratified randomisation within centres
At risk of selection bias (exacerbated by high non-inclusion)
No attempts at blinding

11. Inclusion Criteria
Presence of severe sepsis requiring empirical antimicrobial treatment
Defined as SIRS and suspected infection with evidence of at least one organ failure (conventional definition)
Appropriate use of empirical antimicrobial agents related to suspected source as per International Guidelines

12. Inclusion Flow Chart

13. Enrollment Issues
Significant exclusion (504) – only enrolled 19% of those screened
Majority lost due to logistic issues (poor documentation, consent, early discharge)
101 did not meet inclusion criteria or managed under another protocol – questions validity with current practice
Only 2 excluded due to carbapenemase production (0.3%) – a very low incidence representing an abnormal and potentially more well population
Incidence found between 3-70% depending on organism and geographical location9,10
Minimal loss to follow-up

14. Treatment Arms De-escalation strategy Continuation strategy
Primary empirical antibiotic changed to narrowest spectrum possible once cultures known and based on guidelines and de-escalation hierarchy as specified
Companion antimicrobial ceased at day 3, MRSA agents ceased if not identified
Continuation strategy
Primary antibiotic continued for duration of treatment (provided it is active for microbe)
Potential for de-escalation after 8-15 days if continuing >15 days
Companion drug ceased day 3-5, MRSA agents continued as per guidelines

15. Data collection
Baseline characteristics and risk factors for multi- drug resistant bacteria collected at inclusion
Duration of ICU stay as primary outcome
Secondary outcomes as mentioned with follow-up to 90 days
“Monitored” for organ failure, although frequency not designated
Death during ICU stay reported as discharge – possible skewing of hospital stay if mortality increased

16. Data analysis
Differences between groups assessed using multiple sampling distribution testing (i.e.. chi squared)
Used linear regression modeling of ICU stay after adjustment for baseline SAPS II score
Cox models performed for adjustment on SAPS II of secondary outcomes
Appropriate forms of analysis for given data
Post-hoc analysis to subgroup of patients with VAP
Risk of Type I error

17. Non-inferiority margin
Used data from two previous observational studies to estimate mean duration ICU stay of 10 days
Using a non-inferiority margin of 2 days with 80% statistical power – calculated 51 patients would be required in each arm to establish non-inferiority (recruited 120 to allow for loss to follow-up)
Duration of ICU stay expressed as median and interquartile range, mean difference and 95% CI
Non-inferiority is present if upper confience bound of mean difference of ICU stay is less than 2 days

18. Baseline Characteristics
Unbalanced groups – favours de-escalation
Poor randomization (simple 1:1)
Possible selection bias (not blinded)
Risk of confounding bias
- requires adjustment of covariates
- other covariates likely to be unaccounted
Longer inclusion time – potentially longer duration empirical antibiotics
- weaken effect of de-escalation

19. Baseline Characteristics
Infection source was homogenous, although pneumonia over-represented in de-escalation group
- Potential selection bias – easier to identify organism and de-escalate
Initial antibiotic use did not differ apart from carbapenems
- Poor randomisation

20. Adherence to Protocol
Duration of companion antibiotics significantly less in de-escalation group (2.0 vs 3.0 days), consistent with strategy goals
De-escalation occurred at median day 3 [IQR 2-4], likely earliest possible availability of culture
Latest de-escalation day was 9 – weakens effect od intervention

21. Outcomes

22. Outcomes
Duration of ICU stay had a mean of 15.2±15.0 in the de-escalation group, and 11.8±12.6 in the empirical group (P = 0.71)
Higher than estimated 10 days for sample size calculation
The greater SD and IQR of de-escalation may recognise a subset in patients ineffectively treated
Antibiotic duration for initial episode was unchanged, however were used significantly more in the de- escalation over the entire admission (14.1 vs 9.9 days)
Potentially represents recurrent of incompletely treated infection, or super-infection as discovered (inconsistent with hypothesis)

23. Mortality
Insignificant difference in mortality with 31% and 23% in de-escalation and empirical groups at 90 days
Possible Type II error given small number and study not powered for mortality comparisons or superiority
Higher than Australian figures % absolute mortality in severe sepsis in Australian ICUs8, questioning validity although small number
No significant increase in Hazard Ratio of Cox regression following adjustment
Other secondary outcomes were not significantly different

24. Super Infection
Super infection episodes requiring antibiotics occurred significantly more in the de-escalation group, 27% vs 11%
Correlates with previous super-infection rates ie % in CORTICUS study9
This accounts for the significantly increased number of days of antibiotic use in de-escalation (14.1 vs 9.9), given same antibiotic duration for initial episode
No increase in mortality or organ failure despite super infection
May represent colonisation rather than super-infection (given high incidence)
Of the super infections, 56% were from new pathogens
Possible synergistic effect of empirical therapy, multiple causative microbes or incorrectly identified initial pathogen

25. Results Discussion
Mean difference between de-escalation group and continuation group was 3.4 (95% CI -1.7 to 8.5)
Therefore the de-escalation group was not found to be non- inferior for ICU length of stay than continuation of empirical antibiotics with a non-inferiority margin of 2 days
Significance of this result is debatable:
indirect nature of length of stay as measure of non-effectiveness
arbitrary selection of margin of 2 days
Larger duration of stay than calculated for sample size
Unbalance age and wellness of groups
Lack of blinding could influence decision to discharge

26. Limitations Relatively small sample size Lack of blinding of treatment
Potential weakening of effect due to heterogeneity of infective sources
Attempted post hoc analysis on VAP patients with too small a sample size
Not specified if de-escalation antibiotic choice made on organism alone, or culture sensitivities
No interim results analysis or provision for cessation of the study if unexpected harm or benefit (although unlikely, not possible with non-inferiority model and short study)

27. Improvements Superiority trial
Adaptive biased randomisation or at least stratified within centres
Strict criteria of choice of antibiotic and de-escalation decision, with further clarification of adherence to treatment guidelines
Repeat study with more narrow inclusion criteria of specific infective source
Use more direct measures of infection resolution
Confirm super-infection vs colonisation with same measures
Blinding

28. Discussion Relevance New information Research question
Clear relevance of topic forming major part of recommended antibiotic stewardship in sepsis management
New information
Paucity of evidence with no relevant RCTs identified by Cochrane Review
Extrapolation of findings limited by study design
Research question
Clear clinical question – is de-escalation as a strategy non- inferior to empirical antimicrobial management in severe sepsis
Weakened by ambiguity in definition of de-escalation and identification of suitable antibiotics, although attempted to rectify issue with development of antimicrobial hierarchy and use of international guidelines for management

29. Discussion Appropriateness Elimination of bias Protocol Adherence
Study design compromised by desire to establish non- inferiority by an ambiguous margin on an indirect measure rather than compare strengths of treatment
Elimination of bias
Many potential sources of bias in unbalanced randomisation, small study population and lack of blinding
Protocol Adherence
Appeared to adhere to protocol although large variation in population and not explicitly confirmed
Minimal loss to follow-up

30. Discussion Statistical analysis Supportive Data Conflicts of Interest
Attempted to adjust for unbalanced populations
Appropriate statistical analysis
Supportive Data
Data did justify conclusions although unable to extrapolate given design
Conflicts of Interest
Multiple authors had links to pharmaceutical companies, however would seem irrelevant given broad nature of trial

31. Summary
The study could not demonstrate non-inferiority of de- escalation of antibiotics, despite a favourable demographic of the treatment group
Primarily due to super infection of new pathogens for an unknown reason with no postulated cause, although mortality and other outcomes were unchanged – possibly represents colonisation
Multiple issues with study design weakening strength of conclusion and validity
Unclear whether this will alter current practice, as the large potential benefits of de-escalation are not patient specific and not assessed in this trial

32. References
Leone, M., et al., De-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial. Intensive Care Med, 2014.
Eliopoulos, G.M., D.L. Paterson, and L.B. Rice, Empirical antibiotic choice for the seriously ill patient: are minimization of selection of resistant organisms and maximization of individual outcome mutually exclusive? Clinical infectious diseases, (8): p
Dellinger, R.P., et al., Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, Intensive care medicine, (2): p
Dellit, T.H., et al., Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship. Clinical Infectious Diseases, (2): p
Garnacho-Montero, J., et al., De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Intensive Care Medicine, (1): p

33. References
Mokart, D., et al., De-escalation of antimicrobial treatment in neutropenic patients with severe sepsis: results from an observational study. Intensive Care Medicine, (1): p
Gomes Silva, B.N., et al., De-escalation of antimicrobial treatment for adults with sepsis, severe sepsis or septic shock. Cochrane Database Syst Rev,
Ricci, S., What Does ‘Non-Inferior to’ Really Mean? Cerebrovascular Diseases, (6): p
Gupta, N., et al., Carbapenem-Resistant Enterobacteriaceae: Epidemiology and Prevention. Clinical Infectious Diseases, (1): p
Kotsanas, D., et al., Down the drain”: carbapenem-resistant bacteria in intensive care unit patients and handwashing sinks. Med J Aust, (5): p
Finfer, Simon, et al. "Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units." Intensive care medicine 30.4 (2004):
Sprung, C.L., et al. "Hydrocortisone Therapy for Patients with Septic Shock", The New England journal of medicine, vol. 358, no. 2, pp