We conducted a prospective, two-period crossover case-controlled, interventional study in the trauma ICU at Charlotte Maxeke hospital, Johannesburg, South Africa. Eighty patients were recruited from April 2014 to July 2015. Adult patients in the trauma ICU with suspected sepsis that were either not on antibiotics or had been on antibiotic therapy for less than 48 hours were approached for consent. Patients were recruited consecutively until the sample size was achieved.
All patients in the PCT group had a serum procalcitonin done at study recruitment and then every 48 hours until antibiotics were discontinued. Procalcitonin was not used to guide antibiotic treatment in the control group.
The research protocol was approved by the Human Research Ethics Committee (HREC) of the University of the Witwatersrand, Johannesburg, South Africa.
Patients above the age of 18 years admitted to the trauma ICU with suspected or confirmed bacterial sepsis with written consent and who survived more than 48 hours after study inclusion.
Exclusions included patients in whom consent could not be obtained, pregnancy, patients requiring prolonged antibiotic therapy and those who had severe co-morbidities e.g. congestive cardiac failure, cirrhosis, insulin dependent diabetes, renal failure requiring dialysis, and advanced HIV infection with CD4 ˂100 cells/µL. Patients who had received more than 48 hours of antibiotics before study enrolment and those with poor chance of survival (ISS score ≥45, injury critical or untreatable at screening) were also excluded.
Prior to the study antibiotics were given empirically according to the site-specific ICU algorithm and always covering at least the spectrum of previously prescribed antimicrobials as well as expected organisms. Piperacillin-tazobactam was commonly used as empiric treatment for nosocomial sepsis while amoxicillin-clavulanate was usual for community acquired infections. Antibiotics were changed to cover the spectrum of organisms cultured from the site of sepsis. The control period was between April 2014 and January 2015. Forty patients with suspected or confirmed sepsis were recruited consecutively into the control group. Antibiotics were given as per the ICU protocol above. Decisions regarding discontinuation of antibiotic treatment were left at the attending doctor’s discretion.
In the intervention period, 40 patients with confirmed or suspected sepsis were recruited consecutively into the intervention group between February 2015 and July 2015. The PCT level was measured at study recruitment and then on alternate days. Antibiotics were given as per the ICU protocol discussed above. If the PCT decreased to an absolute value of less than 0.5 µg /L or by ≥80% from the peak PCT concentration, clinicians were encouraged to stop antibiotics. Antibiotics were not stopped if there were ongoing signs of sepsis (e.g. temperature ≥ 38.3ºC) with an obvious source of sepsis. The PCT complemented but did not replace clinical decision making and clinicians were able to deviate from the PCT algorithm if the need arose. Although clinicians were encouraged to stop antibiotics according to this PCT algorithm the decision to stop was at the discretion of the attending clinician.
The procalcitonin (PCT) in patient serum was measured on the ADVIA Centaur ®BRAHMS PCT assay. The assay has a measurement range of 0.02 - 75µg/L and analytical sensitivity of 0.02µg/L.
Microbiological specimens were processed according to standard microbiological procedures. Identification and antimicrobial susceptibility testing (AST) of cultured organisms was performed on the Vitek®2 (bioMérieux) instrument. Alternatively, AST was performed by disc diffusion or E-test® (bioMérieux). All AST results were interpreted according to the current Clinical and Laboratory Standards Institute (CLSI) criteria.
Study definitions and data collection
Further information regarding data collection and study definitions can be found in the supplementary material.
The primary outcome was to determine if a procalcitonin based clinical algorithm would decrease total antibiotic days compared to standard antibiotic treatment in surgical trauma patients in an ICU setting. Secondary outcomes included antibiotic free days alive at 28 days from study inclusion, in-hospital mortality (death from any cause), ICU length of stay and recurrence or relapse of infection.
In calculating the sample size, a difference of 2 days’ antibiotic duration between the mean in one group and the mean in the other group (μ1- μ2) of 2 days would be significant. It was determined that 40 patients were needed in each group to detect a significant difference.
Comparisons were made between the two groups using mean (±standard deviation) and t-test for continuous variables. The p-value was determined by a chi square but if the number of items constituting a variable was less than 10 then the p value was calculated using the Fisher’s exact test. Statistical significance was considered for two-sided p ˂0.05. Categorical variables were compared using percentages.
Diversity between study groups was determined using chi square test and Fisher’s exact test as appropriate. Risk ratio for death and infectious complications (relapse) were calculated at the 95% confidence interval. Kaplan-Meier survival curves were evaluated by the log-rank test. A multivariate analysis was not undertaken due to the small number of study subjects. Data was analysed using Statistica™ version 13.2.