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Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial.

Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial.



2016年5月 Lancet Inf Dis に報告された、オランダ15施設による重症患者に対してプロカルを用いて抗菌薬投与期間を検討したRCT。



P : 

Critically ill patients aged at least 18 years, admitted to the ICU, and who received their first dose of antibiotics no longer than 24 h before inclusion in the study for an assumed or proven infection were eligible to participate


Critically ill ; [ie, sepsis, severe sepsis, or septic shock])


E :  n= 538

In the procalcitonin-guided group, a non-binding advice to discontinue antibiotics was provided if procalcitonin concentration had decreased by 80% or more of its peak value or to 0·5 μg/L or lower. 


C :  n=457

In the standard-of-care group, patients were treated according to local antibiotic protocols. 


O : 

Primary endpoints were antibiotic daily defined doses and duration of antibiotic treatment.


Median consumption of antibiotics was 7·5 daily defined doses (IQR 4·0-12·7) in the procalcitonin-guided group versus 9·3 daily defined doses (5·0-16·6) in the standard-of-care group (between-group absolute difference 2·69, 95% CI 1·26-4·12, p<0·0001).


Median duration of treatment was 5 days (3-9) in the procalcitonin-guided group and 7 days (4-11) in the standard-of-care group (between-group absolute difference 1·22, 0·65-1·78, p<0·0001).


T :  prospective, multicentre, randomised, controlled, open-label










First, about 30% of patients randomly assigned to the procalcitonin-guided strategy were discharged from the ICU before the algorithm recommended to stop antibiotic treatment. This figure was higher than the 20% we had anticipated when designing this study. Further reduction of antibiotics might have been achieved if procalcitonin guidance had been continued on the wards. However, this study was designed for patients during ICU stay and continuation of the protocol on the ward was not deemed possible for logistical reasons. 
Second, physicians did not adhere to the stopping advice in more than half of the patients. The patients in whom antibiotic treatment was continued did differ in some baseline characteristics from those who actually stopped antibiotics (appendix). Apparently, physicians use procalcitonin concentrations to show that antibiotics can be safely stopped in stable patients. They are, however, hesitant to stop use if patients are not yet stable. Clearly, use of procalcitonin concentrations cannot convince them in such cases.32 Whether discontinuation of antibiotics in these subjectively unstable patients would have led to increased mortality cannot be established by this study. Procalcitonin measurements can be used to support decision making in stable patients, but does not abolish proper clinical reasoning. Despite this limitation overall antibiotic consumption was reduced, indicating that especially inappropriate antibiotics were the first to be discontinued, which might turn out to be a major contributor to antibiotic stewardship.

Third, specific patients who were immunocompromised or treated for illnesses needing long durations of antibiotic treatment were excluded. These exclusions were chosen for safety and pragmatic reasons. Advice to stop antibiotic use in these patients was often ignored and therefore regarded as not useful. However, we are not aware of any reasons why measuring procalcitonin would not be useful in reducing duration of treatment in these infections too, albeit over longer timescales or with other thresholds. Particularly in these patient groups, early termination of antibiotic treatment might affect the overall consumption of antibiotics. 


Fourth, clinicians were aware of the study group assignments and not all co-interventions that might have been affected by this knowledge could be assessed. 


Fifth, we did not collect data for antibiotic resistance and, therefore, we are unaware of the appropriateness of the empirical antibiotic strategy. Additionally, in many patients cultures were negative or contained bacteria or fungi that were not thought of as true pathogens (eg, candida colonisation in sputum cultures). The patients who did not reach a stopping rule might be the patients for whom the initial therapy was inappropriate or inadequate. Such patients might be detected earlier in the procalcitonin-guided group than in the standard-of-care group, leading to an earlier antibiotic switch. 









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