Clinical utility of procalcitonin in implementation of procalcitonin-guided antibiotic stewardship in the South-East Asia and India: evidence and consensus-based recommendations

Figures & data

Figure 1. Importance and role of PCT in antibiotic stewardship at different stages of the patient with varied clinical conditions.

PCT:Procalcitonin; LRTI: Lower respiratory tract infections; AMS: Antimicrobial stewardship.

Figure 2. Modified Delphi process flow chart.

Table 1. Recommendations for the use of PCT test in different clinical scenarios.

Stages of Antibiotic Therapy	Type of Recommendation	Strength of Recommendation
LRTI
Initiation	Evidence/Consensus	Strong
Management	Evidence/Consensus	Strong
Discontinuation	Evidence/Consensus	Strong
Sepsis
Initiation	Evidence/Consensus	Strong
Management	Evidence/Consensus	Strong
Discontinuation	Evidence/Consensus	Strong
COVID-19
Initiation	Evidence/Consensus	Strong
Management	Evidence/Consensus	Strong
Discontinuation	Evidence/Consensus	Strong
Febrile Neutropenia in Cancer
Initiation	Evidence/Consensus	No recommendation
Management	Evidence/Consensus	Weak
Discontinuation	Evidence/Consensus	Weak
Organ Transplantation
Initiation	Evidence/Consensus	Weak
Management	Evidence/Consensus	Weak
Discontinuation	Evidence/Consensus	Weak

PCT: Procalcitonin; LRTI: Lower respiratory tract infections.

Note: ≥50% has been considered as strongly recommended. For strongly recommended, both the values (%) from strong recommendation and recommendation graphs (voting results) have been collated together.

Table 2. Key clinical studies highlighting the role of PCT in various clinical conditions.

Reference	Study Design/Type	Sample Size	Key Findings
COVID-19
Initiation Stage
Huttner et al., 2019 [63]	Commentary	—	Biomarkers like PCT might help in deciding for which COVID-19 patients antibiotics can be withdrawn
Monitoring the Response
Wolfisberg et al., 2021 [64]	Review	—	Decreased antibiotic usage with no negative effect on the outcomes PCT (>0.5 µg/L) might be an important prognostic indicator for hyperinflammation and the cytokine storm (characteristics observed in patients with severe COVID-19 progression)
Discontinuation Stage
Hughes et al., 2021 [65]	Retrospective observational	N = 730	Potential role of PCT in excluding bacterial co-infections assay in the first 48 h) Low PCT (<0.25 pg/mL) may help in deciding discontinuation of antibiotics at the 48–72 h review
Sepsis
Initiation Stage
Schuetz et al., 2011 [66]	Review article	14 RCTs	Measuring PCT levels can assist in making decisions pertaining to antibiotics treatment and thus reduce exposure to antibiotics Further, periodic examination of PCT levels after initiation of antibiotics will aid in cessation of antibiotics in patients showing clinical improvement
Monitoring the Response
Evans et al., 2016 [67]	Consensus statement	3 RCTs	The panel suggests against using PCT plus clinical evaluation to decide when to start antimicrobials, as compared to clinical evaluation alone for adults with suspected sepsis or septic shock.
Discontinuation Stage
Pepper et al., 2019 [68]	Systematic Review and Meta-analysis	>2500 articles examined and included 16 RCTs	PCT-guided antibiotic discontinuation appears to reduce antibiotic exposure
LRTI
Initiation Stage
Lee et al., 2020 [51]	Opinion paper	16 experts from 12 Asia-Pacific countries	For optimal use of PCT in Asia-Pacific countries, the two adapted algorithms will be able to reduce complexity in clinical routine An initial PCT value was observed to be helpful in predicting the chance of bacterial infection and need of antibiotic treatment, especially in low-risk and low-probability patients like those with bronchitis-type infection In patients with respiratory illnesses, diagnostic and therapeutic management of patients can be improved using PCT-based algorithms
Monitoring the Response
Cole et al., 2018 [69]	Single-center quasi-experimental before and after study	—	Based on low PCT values, PCT providers were inclined toward de-escalation of antibiotics but not toward discontinuation
Discontinuation Stage
Mathioudakis et al., 2016 [70]	Systematic review and meta-analysis	Eight trials evaluating 1062 patients with AECOPD	The clinical effectiveness and safety of PCT-based protocols is suggested in the study; thus, these PCT-based protocols can be utilized in discontinuation of antibiotics in patients presenting with AECOPD

AECOPD: Acute exacerbation of chronic obstructive pulmonary disease; PCT: Procalcitonin; RCT: Randomized controlled trials.

Table 3. Challenges and probable solutions in the implementation of PCT in AMS program.

Sr. No	Country	Challenges	Probable Solutions
1	Thailand, India, Vietnam, and Indonesia	Cost Test not fully reimbursed by insurance agencies Expensive test Lack of study on the cost-effectiveness of PCT in CAP Lack of funds	Making it affordable Crucial to have strong and extended health insurance coverage Reduction in the cost of PCT to aid in its implementation in LMIC Cost-effectiveness analysis: Assess the cost-effectiveness of PCT-guided antibiotic therapy for CAP and LRTI management Cost comparison of using PCT as a marker of infection Pressure from regulatory bodies and tie-ups with insurance companies (might help in easier implementation)
2	Thailand, India, Vietnam, Malaysia, and Indonesia	Lack of knowledge/trained staff Difficulty in using PCT test/PCT driven protocol: As a parameter to diagnose cause of infection, to determine effectiveness of antibiotics, and understand its kinetics Interpretation of PCT test results: Adopting the same practices (indicating/interpreting PCT) among clinicians and AMS team Heterogeneous knowledge among physicians on maximizing the use of PCT Knowledge and attitude gap in identifying and managing sepsis in ED and ICU Use of guidelines for patient management in national insurance policies Understanding and awareness among administrators about the concept of AMS PCT ordering	Increasing awareness and knowledgeGuideline and training: Guidelines: Incorporation of PCT into patient management nationwide, i.e. nationalized protocol is required and setting up workshops/training/refresher training and update Outcome assessment/education: Education and training on PCT kinetics and easy-to-use cutoff for general physicians, surgeons, students, and clinical pharmacists Protocol: Creation of PCT protocol for day 0 and day 5 will help in PCT ordering Administrators should implement AMS as the first line of treatment in all the units of all hospitals
3	Indonesia, India, Malaysia, and Thailand	Lack of resources Nonavailability of resources in hospitals Lack of clear guidelines for the use of antibiotics and using PCT upfront to prevent antibiotic use due to the current surviving sepsis guidelines TAT of RT-PCR test Lengthy TAT of PCT: Challenge to use it as an upfront diagnostic marker Lack of evidence on the use of PCT in several settings (including AMS programs, in tropical disease, and other situations) Lack of good quality published data (e.g. lack of study in organ transplantation) Outsourcing of samples to different centers Not all stakeholders are involved in the AMS, such as emergency physicians and intensivists in the ICU Trained pharmacists and retained the same Nonavailability of resources for training physicians at the undergraduate or postgraduate level Lack of ID specialists in HIC committees	Improved resources Include PCT in all hospitals Clarity in guidance/new algorithms at the hospital/country level (need for written PCT algorithms and accurate PCT protocols in hospitals) Obtain a prompt RT-PCR test result More research required on the use of PCT in tropical diseases Setting up more ID programs
4	Vietnam	Reimbursement Explaining the rationale to insurance auditors on a case-to-case basis SOFA score reimbursement policy limits the use of PCT	Reimbursement of PCT test Should be provided up to 1 time every 24 hours and 48 hours for septic shock and severe infection, respectively
5	Thailand and India	Serial testing Lack of initial and serial testing	Could be improved through education Can help determine upward and downward trend of PCT values
6	India	Lack of consistency and effectiveness of AMS Consistency of AMS program is absent in institutes Effectiveness of program is a problem as there is a doubt if there is documentation, discussion, and audits of data collected Lack of IT Change of IT consultants every alternate or every year Lack of PCT adoption	Audits Clinical audits can be useful for the consistency of the AMS program Precise use of IT Appointing one IT specialist to cater to 5–6 hospitals or for hospitals within a range of 50 kms (instead of one/hospital) (e.g. telecommunication or telemedicine and implementation of EMR system) Transparency and accountability Transparency with respect to every investigation, drug use, and cost should be maintained The hospital should be accountable for every decision taken by the concerned staff
7	Malaysia	Culture negative sepsis Culture negative patients showing signs of high fever	Low PCT levels Discontinuation of antibiotics, if PCT values are low after week one

PCT: Procalcitonin; CAP: Community-acquired pneumonia; LMIC: Low-middle income countries; LRTI: Low respiratory tract infection; ED: Emergency department; ICU: Intensive care unit; AMS: Antimicrobial stewardship; TAT: Turnaround time; RT-PCR: Real-time-polymerase chain reaction; ID: Infectious diseases; HIC: Hospital infection control; SOFA: Sequential organ failure assessment; IT: Information technology; EMR: Electronic medical record.

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