Stop Antibiotics on guidance of Procalcitonin Study (SAPS)
De Jong et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients:a randomised, controlled, open-label trial. Lancet Infect Dis 2016. S1473-3099(16)00064-5.
Procalcitonin (PCT) guided antibiotic therapy has been shown to decrease the duration of antibiotic therapy. However, safety of this method is not backed up by robust evidence and physicians are understandably scared of ceasing antibiotics based on PCT.
Whether the PCT guided therapy is superior to the conventional approach in terms of antibiotic use and duration, hospital and ICU length of stay and cost effectiveness? This study also aimed to evaluate the non-inferiority of PCT guided antibiotic therapy in terms of recurrent infections and mortality at 28 days.
A prospective open-labelled trial was conducted over a period of almost four years in three university medical centers and 12 teaching hospitals in the Netherlands. The study-protocol was already published in BMC Infect Dis in 2013.
Patients (>18 years) admitted to intensive care unit (ICU) and had received first dose of antibiotic in less than 24 hours for a proven or suspected infection.
Patients on antibiotics for prophylaxis, selective digestive decontamination or chronic use (i.e. infective endocarditis) were excluded. Moreover, patients with an expected stay of <24 hours in ICU, with severe viral, parasitic or mycobacterial infections and immunocompromised patients were also excluded.
Stopping Antibiotic criteria in PCT group
A decrease in PCT value to 20% or less from initial or an absolute PCT value of 0.5mcg/L or less.
Reinstitution of antibiotics.
Recurrent inflammation measured by C-reactive protein (CRP) concentration.
Antibiotics consumed (Dose and number of 24 hour periods between start and cessation of antibiotics.
Primary safety outcome i.e 28 day and one-year mortality (assessed by modified intention-to-treat population.)
Percentage of recurrent infection.
Hospital and ICU length of stay.
Expenditure in antibiotics and PCT test.
A power of 90% was aimed for taking into consideration that approximately 20% of the enrolled population might deviate from protocol. The non-inferiority margin for PCT group was set at a mortality rate of 30% compared to 28% in the conventional group.
Total 4507 patients were screened in 15 ICUs, out of which 776 [538 (71%) of this group completed antibiotics in ICU] and 799 [457 (58%) of this group completed antibiotics in ICU] were included in the PCT and conventional group respectively. A stopping criteria was reached in 557 patients in PCT group. Cessation of antibiotics was done in 243 and 297 patients within 24 and 48 hours respectively. In 38 patients, antibiotics were stopped before reaching the criteria.
The following results were pertinent to 28 days -
Mortality rates were 20% and 25% (absolute difference was 5.4% (95% CI 1.2–9.5, p=0.012) in the PCT and conventional group respectively.
Median consumption of antibiotic were 7.5 and 9.3 defined daily doses respectively in PCT and conventional group respectively (p< 0.0001). Median duration of treatment was 5 and 7 days respectively in PCT and conventional group (p<0.0001). The median antibiotic free days were 7 and 5 days respectively in PCT and conventional group respectively (p=0.0016).
A higher number of patients received repeat antibiotic treatment [38(5%) vs 23(3%), p=0.049] in PCT group for reinfection (proven or suspected).
The median cost of antibiotics was 107 and 129 Euros, p=0.006) respectively in PCT and conventional group.
The ICU length of stay, hospital LOS and CRP level were nonsignificant in both the groups.
One-year mortality data were 35% and 41% (p=0.007) in PCt and conventional group respectively.
This study showed a reduction in antibiotic treatment duration and consumption. It was achieved with the addition of a procalcitonin-guided algorithm to aid clinical judgment. This reduction of antibiotic duration was achieved in a setting with a low background consumption of antibiotics without an increase in mortality.
limitations of the study
The investigators were aware of the assignment to the groups. So, it could not eliminate bias due to lack of blinding. Moreover, they might have been biased to think of reinfection and restart antibiotics in PCT group more promptly.
In more than 50% cases, physicians deviated from study protocol i.e. stopped antibiotics in patients who were stable and continued in others even if the cessation criteria was/were reached.
This study excluded the immune compromised patients. It didn’t include patients on long term antibiotics use. It would have been really interesting to see the outcome in these patients.
There was lack of data on antibiotic resistance. So the antibiotic therapy might have been inappropriate in few cases leading to alteration of result in terms of antibiotic use, duration, mortality and hospital stay.
Strengths of the study
This is the largest PCT study with a convincing evidence for non-inferiority and safety of PCT based antibiotic therapy.
It included heterogenous ICU-population which is more near reality.
It provided two distinct criteria (a decrease in PCT value to 20% or less from initial or an absolute PCT value of 0.5mcg/L) for stopping of antibiotics.
TAKE HOME MESSAGE
PCT should be used in monitoring in critically ill patients with proven or presumed bacterial infection to decrease the duration, dose and resistance of antibiotics.
Evidence prior to this study
Bouadma L, et al; PRORATA trial group. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet. 2010 Feb 6;375(9713):463-74.
PCT guided antibiotic therapy in severe sepsis and sepsis, led to significant increase in antibiotics free day. It also demonstrated a nonsignificant increase in 60-day mortality associated with PCT guided antibiotic therapy.
This study kept a low threshold (PCT less than or equal to 0.10 mcg/L for cessation of antibiotics therapy and demonstrated non-significant reduction in duration of antibiotic therapy.
An extensive meta-analysis that include a total of 16,514 patients, of whom 3420 suffered from bacteraemia. The overall area under the summary receiver-operating characteristic (SROC) curve was 0.79.
The authors concluded that the optimal and most widely used PCT cut-off value was 0.5 mcg/L. It had a sensitivity of 76% and specificity of 69%.
The lowest area under the SROC curve was found in immunocompromised /neutropenic patients (0.71) suggesting less accuracy of PCT in this group of patients.
The highest area under the SROC curve was found in intensive-care patients (0.88) suggesting a higher accuracy.
PCT was suggested to have a fair diagnostic accuracy for bacteraemia in adult patients suspected of infection or sepsis and a low PCT value can be used to rule out the presence of bacteraemia.
MD, FNB, FCCP,EDIC