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

ABSTRACT

Introduction

The South-East Asian (SEA) region and India are highly susceptible to antibiotic resistance, which is caused due to lack of antimicrobial stewardship (AMS) knowledge, uncontrolled use of antibiotics, and poor infection control. Nonadherence to national/local guidelines, developed to combat antimicrobial resistance, is a major concern. A virtual advisory board was conducted to understand the current AMS standards and challenges in its implementation in these regions.

Areas covered

Procalcitonin (PCT)-guided antibiotic use was discussed in various clinical conditions across initiation, management, and discontinuation stages. Most experts strongly recommended using PCT-driven antibiotic therapy among patients with lower respiratory tract infections, sepsis, and COVID-19. However, additional research is required to understand the optimal use of PCT in patients with organ transplantation and cancer patients with febrile neutropenia. Implementation of the solutions discussed in this review can help improve PCT utilization in guiding AMS in these regions and reducing challenges.

Expert opinion

Experts strongly support the inclusion of PCT in AMS. They believe that PCT in combination with other clinical data to guide antibiotic therapy may result in more personalized and precise targeted antibiotic treatment. The future of PCT in antibiotic treatment is promising and may result in effective utilization of this biomarker.

KEYWORDS:

• Antimicrobial stewardship
• COVID-19
• LRTI
• procalcitonin
• sepsis

1. Introduction

Antimicrobial resistance (AMR) is reported to be one of the major risks to modern development, global health, and food security [1,2]. The injudicious use of antibiotics, lack of knowledge/awareness of antimicrobial stewardship (AMS), lack of antibiotics auditing, and poor infection control in South-East Asian (SEA) countries and India seem to be some of the most common reasons for AMR.

The hospital-based AMS is an integrated strategy to improve the appropriate use of antimicrobials to decrease antimicrobial cost, augment patient-related outcomes, and minimize the side effects related to antimicrobial use [3–6]. Support of senior leadership, research and education, pharmaceutical knowledge, accountability, and prevention programs are some of the established principles contributing to a successful AMS [7]. The implementation of the AMS provides recommendations on saving healthcare-associated costs, interaction with the clinicians, and offers feedback to the prescribers. Further, successful AMS implementation also depends upon the assistance and cooperation between the hospital administration and medical leadership [8]. Toward this, the role of biomarkers and their inclusion in AMS has been gaining acceptance globally. The role of procalcitonin (PCT) has been widely analyzed [9] and can aid in improving the patient outcomes and reducing the burden of AMR worldwide [10]. PCT is a specific biomarker used in the diagnosis of bacterial infections, and various clinical settings comprising emergency department (ED), primary care, and intensive care [9]. It aids in ruling in or ruling out bacterial infections. Furthermore, the utilization of PCT has been reported at different stages of antibiotic therapy [11,12] namely, initiation, monitoring of antibiotic response, and early discontinuation of antibiotic therapy (Figure 1). However, PCT threshold values may fluctuate based on patient population at different institutions [13] and may be influenced by underlying comorbidities such as congestive heart failure and chronic kidney disease (CKD) [14].

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.

Nonadherence to national/local guidelines, developed to combat AMR, is a major concern, particularly in most of the SEA countries and India. Further, poor sanitation measures, excessive use of antimicrobials [2], over-the-counter availability of antibiotics, population overcrowding [15], insufficiency in terms of quality vaccines and diagnosis [2] have all contributed to high AMR. Hence, we convened a virtual advisory board meeting to understand the current standards of AMS and challenges in its implementation in these Asian countries. The purpose of this article is to highlight and discuss the clinical utility of PCT in guiding antibiotic therapy in clinical scenarios such as lower respiratory tract infections (LRTI), sepsis, COVID-19, febrile neutropenia in cancer, and organ transplantation. It further documents the comments from this panel, highlighting the challenges and plausible solutions in the implementation of PCT in AMS programs in these scenarios.

2. Methods

Experts from different SEA countries and India were selected to participate in the panel by a committee based on their extensive clinical experience in different medical fields and their publication track record in the field of infectious diseases. Our expert panel comprised a team of 10 experts from different clinical faculties, including critical care medicine, infectious diseases, pharmacy, clinical pathology, and respiratory medicine in the SEA countries and India.

To understand the role of PCT in clinical conditions (LRTI, sepsis, COVID-19, febrile neutropenia in cancer, and organ transplantation), a literature search was performed using PubMed database before the expert panel meeting. The terms used for the literature search were ‘procalcitonin,’ ‘PCT,’ ‘antibiotics,’ ‘antimicrobial resistance,’ ‘LRTI’ OR ‘lower respiratory tract infections,’ ‘sepsis,’ ‘COVID-19,’ ‘organ transplantation,’ ‘febrile neutropenia in cancer,’ ‘antimicrobial stewardship,’ ‘antimicrobial stewardship programs,’ ‘Asia-Pacific.’ Meta-analysis, review articles, randomized controlled trials (RCTs), observational studies (prospective and retrospective), and guidelines/consensus papers on PCT and respective clinical conditions published in English between 1997 and 2023 were selected.

Furthermore, a modified Delphi method was applied, wherein an electronic survey questionnaire was used and discussed by the group of experts to obtain their opinions regarding the use of PCT in different clinical conditions. Following these discussions, all experts voted on their preference to provide strong, moderate, weak, and no recommendation in relation to PCT-guided antibiotic use in empirical therapy, ongoing treatment stage, and for de-escalating the antibiotic therapy in the clinical scenarios mentioned above. In the case of different opinions obtained from the experts, a question on febrile neutropenia in cancer was slightly modified to reach the final opinion of the experts. The voting was conducted employing an electronic online polling software, using a modified Delphi process (Figure 2), wherein ≥ 50% was considered as strongly recommended. The recommendations included in this article are intended to highlight the use of PCT across different clinical conditions based on the literature findings, levels of evidence, and the experts’ opinion and experience.

Figure 2. Modified Delphi process flow chart.

3. Clinical utility of PCT

3.1. Clinical utility of PCT in guiding antibiotic therapy in LRTI

PCT utilization for empirical use of antibiotics at:

1. presentation stage in patients with LRTI

2. management of patients during ongoing treatment stage

3. discontinuation of antibiotics stage in patients with LRTI

3.1.1. Poll outcomes

Majority of the experts recommended that PCT can be utilized in decision-making for empirical treatment (at presentation in a patient with clinical signs of LRTI, 80% experts) and monitoring of antibiotic response in LRTI patients (during the ongoing treatment stage, 90%). Most of the experts (80%) agreed that PCT is a valuable biomarker for discontinuation of antibiotics in patients with LRTI showing clinical signs of improvement.

3.1.2. Commentary from experts

Similar observations, as that of the poll, were noted in the supporting evidence (such as 12 meta-analyses, 47 reviews, 26 RCTs, 6 observational studies, and 6 guideline papers) and consensus (Table 1).

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.

3.1.1.1. Initiation

LRTIs comprise acute bronchitis, pneumonia, and chronic obstructive pulmonary disease, which result in morbidity and mortality across all age groups [16]. According to an observational, prospective study, 75% of patients with acute LRTI were treated with antibiotics, despite the viral origin of their infection [17,18]. In the discussions that ensued, the experts opined that presence of mixed infections (bacterial and viral together) affects the performance of PCT; thus, the efficacy of PCT in such atypical conditions should be assessed. They commented that some studies in literature report the use of PCT as a diagnostic module demonstrating a wide range (40% to 90%) of sensitivity. The benefit of PCT, when compared to other biomarkers, is reported to demonstrate sensitivity of 89% and specificity of 94% for bacterial infection [19]. Additionally, a meta-analysis reported that initiation of antibiotics by the physicians with the help of PCT in patients with community-acquired pneumonia, was significantly low (p < 0.0001) [20]. PCT cutoff values depend on the type of LRTI, ward type (ED, intensive care unit [ICU], and respiratory department), and patient’s condition [21]. Currently, antibiotic initiation is strongly encouraged at PCT >0.5 µg/L and encouraged if PCT levels were between 0.25 µg/L and 0.5 µg/L [21]. Additionally, antibiotic treatment initiation is discouraged, if the PCT levels are <0.1 µg/L [22]. In the current study, experts from SEA countries and India opined that PCT is utilized only for initiation of antibiotic therapy among patients with LRTI due to irreclaimable costs in clinical practice. Furthermore, in addition to the use of PCT, clinical judgment also plays a significant role.

3.1.1.2. Management

PCT has been reported to reduce antibiotic prescription rates and duration in patients with LRTI. According to a multicentric, non-inferiority, randomized controlled ProHosp trial (n = 1359), the overall duration of antibiotic exposure significantly reduced by 34.8% in the PCT group as compared to the standard-of-care group for all patients with LRTI, without compromising on clinical outcomes [18]. In addition, the decrease in the antibiotic prescription rates from 87.7% to 75.4% was also reported for all patients with LRTI [18]. Several guidelines for the management of adult LRTI state that biomarkers (such as PCT) can aid in shorter treatment duration [23].

A meta-analysis demonstrated significant reduction in the total exposure (p < 0.0001) and duration of the use of antibiotics (p < 0.0001) with the use of PCT [20]. A single-center, retrospective cohort study highlighted the importance of PCT in improving antibiotic management when there is lack of clarity on the diagnosis and treatment regime in patients suspected of infection. Antibiotics can be modified if the initial PCT values do not decrease upon administration of the initial treatment [24].

3.1.1.3. Discontinuation

The cutoff value of PCT for the discontinuation of antibiotics in patients with LRTI proposed by the expert panel was 0.25 µg/L or 80% reduction from the highest value. A follow-up PCT after 48 or 72 hours for possible decisions on discontinuation of the antibiotic treatment is recommended. This is in-line with another meta-analysis of 13 RCTs wherein, <0.25 µg/L was indicated as the cutoff for discontinuation of antibiotic treatment among patients in ED/medical ward and <0.5 µg/L among patients in ICU [25].

3.2. Clinical utility of PCT in guiding antibiotic therapy in sepsis

The need for PCT utilization among patients with sepsis in:

1. empirical stage of antibiotics treatment

2. ongoing treatment stage of antibiotics treatment

3. discontinuation stage of antibiotics treatment

3.2.1. Poll outcomes

The majority of experts (70%) suggest the use of PCT, along with clinical judgment, in deciding the antibiotic initiation among patients with sepsis or septic shock. Furthermore, all the experts recommended and agreed that PCT is a valuable biomarker for monitoring the response of critically ill patients with sepsis during the ongoing treatment stage. About 90% of the experts recommended using PCT (in addition to culture and sensitivity results) for discontinuation of antibiotics in patients with sepsis showing clinical signs of improvement.

3.2.2. Commentary from experts

The advisors’ recommendation is corroborated by evidence (11 meta-analyses, 12 reviews, 20 RCTs, and 4 guideline papers) suggesting PCT, in conjunction with clinical judgment, is useful in guiding the antibiotic therapy in patients with sepsis across all stages (Table 1).

3.2.2.1. Initiation

Based on the discussion with experts, the proposed cutoff value for sepsis diagnosis via PCT is 0.5 µg/L. The expert panel also suggested using PCT in antibiotic treatment initiation in sepsis if the turnaround time of the PCT test is faster as compared to other tests.

3.2.2.2. Management

PCT is evidently useful in estimating antibiotic therapy duration in diverse settings, including the ICU [26,27]. PCT is usually performed when there is uncertainty about bacterial infections, especially in pneumonia or unspecified sepsis cases. A prospective, multicenter RCT conducted for assessing the safety and efficacy of PCT in critically ill patients (sepsis, severe sepsis, or septic shock) demonstrated that PCT guidance aids in the reduction of treatment duration (5 days [3–9]) and daily antibiotic doses (7.5 daily doses) versus the standard-of-care group. A significant reduction in mortality (PCT group: 20% versus standard-of-care group: 25% at 28 days) was also observed [28]. Similar results were obtained in the PROGRESS randomized trial, wherein PCT guidance could effectively reduce the 28-day mortality, cost of hospitalization, and infection-related adverse events in patients with sepsis [29]. In a single-center before-and-after-intervention cohort-designed study, an approved PCT protocol was followed to effectively manage antibiotic use in adult sepsis patients within the ICU [30]. Another multicenter, prospective, parallel-group, open-label trial reported that a PCT-based strategy for the treatment of suspected bacterial infections among nonsurgical patients in ICUs might be effective in decreasing the antibiotic exposure without adverse outcomes [31]. A PCT-based algorithm is reported to have high safety quotient for the reduction in antibiotic therapy among patients with respiratory tract infections as well as sepsis [32,33]. Another study, assessing the role of PCT in newborns, revealed that patients in the PCT group experienced shortening of antibiotic therapy versus the standard group [34].

3.2.2.3. Discontinuation

A meta-analysis reports that using PCT for antibiotic discontinuation alone can reduce not only antibiotic exposure, but also short-term mortality in the ICU setting among patients with sepsis [35]. As per an open-label, prospective, parallel-group, PROcalcitonin to Reduce Antibiotic Treatments in Acutely ill patients (PRORATA) trial, discontinuation of antibiotics was encouraged in patients with suspected or confirmed sepsis, where PCT levels were <0.5 µg/L, or reduced by ≥ 80% from the previous peak value, respectively [31]. Further, the panel revealed that in many hospitals in Vietnam and Indonesia, the diagnosis and management of patients with sepsis and septic shock in the ICU and ED mainly depends on clinical judgment, although PCT may be included for monitoring the response during the ongoing treatment stage and for discontinuation.

Experts from India suggested that PCT was useful for the detection of bacterial sepsis among critical and complicated cases of COVID-19. PCT helped to exclude the possibility of bacterial sepsis, especially due to immunosuppressant use. However, after identification of the causative microorganisms, the serum PCT levels are found to be greater in patients with Gram-negative sepsis when compared to those with Gram-positive or fungal sepsis, except in patients with severe sepsis. Therefore, PCT test is more sensitive to the Gram-negative bacterial infections [36].

3.3. Clinical utility of PCT in guiding antibiotic therapy in COVID-19

PCT is a beneficial tool in the evaluation of patients with COVID-19, safely decreasing the potential burden of unnecessary use of antibiotics.

3.3.1. Poll outcomes

The majority of experts (70%) recommended PCT utilization in the initiation of empirical antibiotics among patients with COVID-19 suspected of a secondary bacterial infection. All the experts strongly recommended PCT in monitoring patients when antibiotic is started during the ongoing treatment stage and in the consideration of discontinuation of antibiotics when there is a clinical improvement.

3.3.2. Commentary from experts

The poll outcomes are consistent with published evidence (2 reviews, 9 observational studies) and the current study consensus (Table 1).

3.3.2.1. Initiation

PCT reduces the potential burden of unnecessary use of antibiotics in COVID-19. PCT is recommended at admission (day 1) in COVID-19; experts believe that administering antibiotics without PCT guidance is not the right clinical practice and may not be favorable for the patient. The utility of PCT and clinical pulmonary infection score (CPIS) has been stated to be very useful in critically ill COVID-19 patients. The utilization of PCT-CPIS successfully decreased inappropriate use of antibiotics among severe-critically ill COVID-19 pneumonia patients [37,38]; as per the study protocol, antibiotics were not initiated if CPIS was ≤ 6 and PCT was <0.5 µg/L [38]. Antibiotics were initiated and reevaluated on day 3 for patients in the ICU, if CPIS was ≥ 6 and PCT was >0.5 µg/L. Antibiotics were continued, if the PCT levels were still high. However, the antibiotics were discontinued, if the PCT levels were low at <0.5 µg/L, or dropped by ≥ 80% [38]. PCT guidance is suggested for the antibiotic initiation in patients with COVID-19. However, specific criteria have been enforced for their prescription (such as empirical use of antibiotics until COVID-19 confirmation, clinical symptoms, bacterial complications, or PCT ≥0.5 ng/mL), to avoid unnecessary antibiotic use and facilitate discontinuation where antibiotics may not be required [39].

3.3.2.2. Discontinuation

It is observed that both, clinical judgment and the use of biomarkers, guide the discontinuation of the antibiotics in patients with COVID-19. In a prospective, single-center, cohort study, reduction in duration of antibiotic by 2 days was observed after the usage of PCT in patients with COVID-19. Determination of the chances of bacterial infection as well as its clinical judgment is considered using a PCT level of 0.5 μg/L as the higher limit [40]. However, a multicenter randomized controlled trial conducted in France demonstrated the inefficiency of PCT-guided strategy with respect to antibiotics exposure in patients with COVID-19 [41].

3.4. Clinical utility of PCT in guiding antibiotic therapy in febrile neutropenia in cancer

There are inadequate data available on the use of PCT among patients with febrile neutropenia in cancer; thus, more trials should be encouraged.

3.4.1. Poll outcomes

Few experts (20%) agreed and recommended (weak) that PCT can be applied for the initiation of antibiotics among patients presenting with febrile neutropenia or other signs of infection. Further, all the experts provided weak recommendations for the utility of PCT in monitoring the antibiotic response of cancer patients with febrile neutropenia during the ongoing treatment stage. For discontinuation of antibiotics in cancer patients who are being treated for febrile neutropenia or other infections and exhibit clinical signs of improvement, the recommendation was provided by only 40% of the experts. This is due to the scarcity of published evidence (only 3 observational studies) to provide recommendation on using PCT in febrile neutropenia cases (Table 1).

3.4.2. Commentary from experts

PCT may be used to guide if the clinical fever (often a reason to initiate antibiotics) is due to infectious or noninfectious causes (malignancies and drugs can cause fever too) in febrile, non-neutropenic, cancer patients, so as to discontinue their antibiotics safely [42].

Febrile neutropenia is critical in cancer; thus, most experts are reluctant to use PCT in these patients mainly due to inadequate evidence for the initiation and monitoring of treatment. However, few experts recommended the use of PCT for de-escalation or cessation of antibiotics in patients with cancer who are treated for febrile neutropenia; PCT levels are analyzed within 48 hours of antibiotic administration to decide on antibiotics discontinuation. Experts recommended that in case of high PCT levels, continuation of treatment with the same antibiotics should be avoided and patient’s condition should be reassessed. They further suggested that the antibiotics can be stopped if the patient remained with PCT <0.5 µg/L, with close monitoring. A post-hoc analysis of a prospective, observational cohort conducted among patients with cancer and febrile neutropenia reported that PCT can be an adjunctive biomarker for identifying cancer patients. Further, its guided algorithm can limit antibiotic duration, reduce adverse events, and prevent antimicrobial resistance emergence [42].

According to a retrospective review, PCT of <0.5 µg/L was recommended to guide the discontinuation of antibiotics in patients with malignancies and persistent neutropenia after 1 week of antibiotic treatment. A reduction in the duration of antibiotic carbapenem (after 1 week of treatment) was observed in the group, wherein physicians accepted AMS [43]. Similarly, PCT could be a useful tool in augmenting the AMS in cancer patients with COVID-19 by decreasing the time period of antimicrobial therapy till the PCT results are available (after the initial 72 hours). Furthermore, PCT levels of >0.25 μg/L are reported to correlate with documented bacterial infection [44].

The experts here opined that antibiotics can be initiated with PCT levels of <1 μg/L in patients with nonfebrile neutropenic cancer, and discontinuation of the antibiotic treatment is preferred among patients with metastatic cancer demonstrating PCT levels from 1.5 to 2 μg/L.

3.5. Clinical utility of PCT in guiding antibiotic therapy in organ transplantation

There is a need for more research and published evidence on the use of PCT among patients with organ transplantation.

3.5.1. Poll outcomes

All the experts provided a weak recommendation for PCT use in the initiation and monitoring response of antibiotic therapy in organ transplantation. Very few experts (13%) recommended the use of PCT in discontinuation of antibiotics in post-organ transplantation patients, following treatment for transplant-related infection and with clinical signs of improvement. Their recommendation was supported by the sparsely available published evidence (1 observational study) (Table 1).

3.5.2. Commentary from experts

The utilization of PCT has been reported as a sensitive marker to distinguish between systemic bacterial infections and organ transplantation-related complications [45]. According to a systematic review and meta-analysis, PCT can be a useful marker in liver transplant recipients to help in distinguishing infection complications from acute rejections [46]. Another retrospective data analysis reported that PCT can possibly be used for AMS in transplant-related immunosuppressed patients [47].

PCT is not recommended to guide antibiotic initiation for early post-transplant sepsis. However, one expert from India opined that PCT kinetics played an important role in deciding the therapy duration. A reduction in the average duration of antibiotic therapy was found based on the kinetics data among liver and kidney transplant recipients. However, more research and data concerning the use of PCT in transplant is required. Another expert from India stated that rather than considering the data unavailability, a collated decision and overall experience might be preferred if an improvement is observed while managing the patient.

However, a critical challenge in utilization of PCT in organ transplantation is the lack of published data. The data currently available are only from single-centered experiences, mainly retrospective (not prospective); good quality systematic review data are also unavailable.

4. Implementation of PCT in AMS program: challenges and probable solutions

The development and application of AMS is reported to differ among various countries [48]. AMS has been implemented in Singapore and Indonesia. Meanwhile, in countries such as Thailand and Vietnam, there is a lack of implementation of AMS despite its availability in hospitals. In India, the concept of AMS is subjective and limited to the guidelines on using antimicrobials for empiric therapy rather than on discontinuation or de-escalation of therapy. Currently, despite the presence of AMS, there are challenges in the implementation of AMS in SEA countries and India. These challenges include lack of willingness of hospital management and inadequate enforcement from the regulatory authorities, admission of patients infected with multidrug-resistant pathogen or previous antibiotic use, absence of set protocol, difficulty in controlling prescriptions provided by the senior doctors, and COVID-19, in addition to the various challenges described in Table 2 [49]. Adequate inventory management systems driven by pharmacists are required for sustainable administration of antimicrobials and to implement AMS programs successfully [50].

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.

5. Discussion

PCT-guided AMS has been reported to guide the initiation and duration of antibiotic treatment in patients with clinical conditions without compromising (and possibly improving) on the clinical outcomes [20,51]. It is possible to detect PCT 3 to 4 hours after an infection, therefore making it a suitable test for diagnosis. Further, it peaks at 6 to 12 hours, meaning it will be easily detectable at this time point after the onset of an infection [9]. Post initiation of antibiotics, PCT values should be reassessed every 1 or 2 days for adequate monitoring and once the PCT levels fall below 0.1 ng/mL (or 80 to 90% below initial measurement), antibiotics can be stopped. If the PCT levels still remain high, alternative therapies must be considered [52,53]. Further, in the instance where antibiotics are withheld, such as in patients with acute bronchitis or exacerbation of chronic obstructive pulmonary disease with reduced risk for systemic infection [54], clinical reevaluation is required and PCT tests are repeated [9,18].

According to a Singapore General Hospital-based prospective observational cohort study, the use of PCT for antibiotic discontinuation under AMS did not compromise the patients’ outcome and was helpful in reducing the antibiotic use [55]. A hospital-based AMS is present and implemented among hospitals/institutions in Singapore (2011), Thailand (2012) [56], Malaysia (2014), and Vietnam (2016, updated in 2020) [57]. Currently, hospitals in Indonesia follow the national program for implementation of AMR control, national guidelines for AMS by the Ministry of Health (MoH) using antibiotic guidelines (access, watch, and reserve of antibiotic therapy) similar to the WHO to control AMR [58]. Similarly, in Thailand, the National Strategic Plan on AMR and Antibiotics Smart Use project has been implemented [59]. One Health strategy (Singapore) [60] and ABS prevention and infection control (ASPIC) program (India) [61] are other examples of national programs for preventing AMR.

According to experts, PCT utilization in the antibiotic treatment initiation can help in LRTI and sepsis. In COVID-19, PCT helps in reducing the potential burden of unnecessary usage of antibiotics [62]. PCT may differentiate the causative reason (bacterial infections versus malignancies versus drugs) for a clinical fever in febrile, non-neutropenic cancer patients [42]. Moreover, PCT has been reported as a useful marker to distinguish between systemic bacterial infections and organ transplantation-related complications [45]. Additionally, key clinical studies also highlight the importance of PCT in these conditions (Table 3). No recommendation was made on the utilization of PCT for initiating antibiotics in patients with febrile neutropenia. However, weak recommendation was provided by the experts for the use of PCT in managing and de-escalating antibiotics among febrile neutropenic patients, and in the management of antibiotic therapy across all the stages in patients with organ transplantation.

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.

Further, although PCT demonstrates promising outcomes in many conditions, there are some limitations that should be considered before the integration of PCT in routine clinical practice [52]. Infection site and bacterial type may affect PCT values [71]. While low PCT levels can be used to detect bacteremia, as per a systematic review, widespread use of PCT is not recommended because of its moderate diagnostic accuracy to predict bacteremia [72]. A RCT studying the PCT-based strategy failed to demonstrate that it reduces the antibiotic exposure and might not be efficient in differentiating between infectious and noninfectious causes of acute chronic obstructive pulmonary disease (ACOPD). Further, irrespective of the origin of acute exacerbation of chronic obstructive pulmonary disease (AECOPD), patients with AECOPD benefit from antibiotic therapy and a delay in the antibiotic prescription may result in unfavorable outcomes such as increased mortality [73]. Additionally, AMS programs must ascertain that PCT diagnostic test has exhibited adequate sensitivity within the patient cohort of interest prior to incorporating the test into treatment guidelines based on a high negative predictive value [74]. Moreover, the 2019 Infectious Diseases Society of America guidelines for the management of community-acquired pneumonia (IDSA CAP) guideline recommends empiric antibiotic treatment in patients with suspected or radiologically confirmed CAP irrespective of initial PCT levels [75].

False-positive PCT results are also a drawback associated with PCT test which can occur due to multiple organ failure, acute respiratory distress syndrome, systemic fungal infections, renal failure, and other conditions. Contrarily, false-negative results can occur due to early cause of infection, localized infection, and subacute endocarditis [76]. In patients with CKD, elevated baseline PCT levels are observed (regardless of renal replacement therapy) [9], thus making it crucial to differentiate between elevated baseline and infection-related PCT levels [77]. Elevated baseline PCT levels may result in extended durations of unnecessary antibiotic therapy [12]. As per a retrospective study, the PCT levels are high in the patients with COVID-19, resulting in inappropriate antibiotic therapy usage (in terms of extended duration) [39].

5.1. Future research

Despite the utility of PCT in LRTI [18], sepsis [51], and COVID-19 [62], some evidential gaps exist in regards to guiding antibiotic therapy in these various clinical conditions, particularly in febrile neutropenia with cancer [78] and organ transplantation [47]. More data are warranted to demonstrate the utility of PCT in these settings by undertaking more randomized controlled trials for studying the initiation [73], escalation, de-escalation [27], oral switch [79], and discontinuation of treatment [35].

6. Conclusion and outlook

PCT-guided AMS along with regular education possesses high potential to regulate the use of antibiotics in the SEA countries and India. Experts strongly recommended the use of PCT in guiding the antibiotic therapy across all the stages (initiation, management, and discontinuation) among patients with LRTI and COVID-19. Further, among patients with sepsis, they suggest using PCT for initiation and recommend the use of PCT in management and discontinuation of antibiotic therapy. However, further research is required to understand the optimal use of PCT in patients with organ transplantation and cancer patients with febrile neutropenia.

The experts also believe that the government and insurance companies of every country should be aware of the usefulness of PCT and extend the necessary support for the same. However, additional research should be considered in the SEA region and India for optimal utilization of PCT and patient care. The establishment of lasting and mutually beneficial partnerships between high-income and low and middle-income countries (LMICs) must be rooted in the principles of capacity building [80].

7. Expert opinion

The AMR rate is higher in the SEA region and India and is believed to be caused due to lack of AMS knowledge, uncontrolled antibiotic use, and poor infection control. In recent years, several national/local guidelines have been developed to combat AMR in these regions. However, non-adherence to these protocols/guidelines is a major concern in most SEA countries and India. This nonadherence to guidelines may be multifactorial, as underlying conditions and disease severity may result in patient’s noncompliance while prescriber non-adherence may be the result of lack of knowledge. These factors are however seen to differ across healthcare systems [81]. Further, noncompliance with guideline-recommended treatment can lead to an increased use of broad-spectrum empirical therapy [82].

PCT, although a valuable biomarker, may not always be a dependable prognostic marker and should be interpreted based on clinical practice [14]. A meta-analysis reported no difference in short-term mortality with the use of PCT-guided approach, however, a substantial reduction of duration of antibiotic treatment was observed with the PCT-guided strategy. These varied results may be the result of differences in follow-up period or non-adherence to protocol [83]. Contrarily, the ProACT study demonstrated that the PCT-guided approach did not result in a decreased exposure to antibiotics as compared with standard care protocol [84]. Therefore, the use of PCT must depend on individual needs of AMS programs and cannot be generalized. This, in turn, will minimize unnecessary PCT testing and result in associated cost-saving.

PCT is a specific biomarker that helps in ruling in or ruling out bacterial infections. PCT-guided antibiotic treatment option has redefined the therapeutic measures to combat antimicrobial resistance by guiding PCT antibiotic therapy in various clinical scenarios like LRTI, sepsis, COVID-19, febrile neutropenia in cancer, and organ transplantation. Despite the utility of PCT in LRTI, sepsis, and COVID-19, some evidential gaps exist in the guiding of antibiotic therapy in these various clinical conditions, particularly in febrile neutropenia with cancer and organ transplantation. More data are warranted to demonstrate the utility of PCT in these settings. Moreover, the literature suggests that addition of PCT to AMS protocols can be helpful in saving the overall healthcare costs. Though there is a scarcity of available evidence in these conditions, experts strongly believe that PCT can be included in a guideline or in AMS.

According to the experts, the challenges in implementation of the PCT in the SEA region and India include cost of PCT (lack of funds, reimbursement concerns in some countries), as it incurs an additional cost compared to other laboratory assays, which remains a major barrier [85,86]. Comprehensive cost-effectiveness assessments are thus required to evaluate whether the health benefits and associated cost savings can offset the additional expenses of PCT testing [87], especially in the setting of an RCT. Further, the absence of set protocol, lack of trained staff, nonavailability or lack of resources, admission of patients infected with multidrug-resistant pathogen or previous antibiotic use, COVID-19, lack of willingness of hospital management, lack of consistency and effectiveness of AMS, difficulty in controlling prescriptions provided by the senior doctors and inadequate enforcement from the regulatory authorities are some of the complexities encountered. The solutions related to the challenges in implementation of PCT in AMS programs can be applied in clinical practice which can aid in overcoming the future challenges. The experts also believe that support and awareness regarding the utilization of PCT by the Government and insurance companies of every country will aid in sufficient utility of PCT. However, better and advanced research in the SEA region and India is needed for optimal utilization of PCT and patient care.

In the future, as per the experts, PCT may become a crucial tool in AMS programs. The cutoff values for PCT may become more refined since more data are being collected and analyzed, leading to more accurate and effective use of this biomarker. Furthermore, new technologies may develop that allow for even more rapid and accurate PCT testing, allowing more accessibility of this tool to healthcare providers. Currently, the Sepsis assay kit (PATHFAST™ B･R･A･H･M･S PCT), an immunoassay used in the early detection and differential diagnosis of bacterial infections, such as sepsis. Similarly, the IB10 sphingotest® PCT and AQT90 FLEX PCT assay are some point-of-care immunoassays enabling convenient measurement of PCT [88–90] Some of these technologies are already in existence, although costs may be prohibitive for SEA.

It is also possible that PCT may be used in combination with other clinical data to guide antibiotic therapy in a more personalized and precise way. This could lead to more targeted antibiotic treatment, further reducing the risk of antibiotic resistance and improving patient outcomes. Overall, the future of PCT in antibiotic treatment is promising, and continued research and development in this area will probably lead to even more effective utilization of this biomarker in the years to come.

Article highlights

• The clinical utility of PCT in guiding antibiotic therapy among patients with LRTI, sepsis, COVID-19, febrile neutropenia in cancer, and organ transplantation are discussed in this article.

• The experts strongly recommended the use of PCT; however, evidential gaps still exist in clinical scenarios like febrile neutropenia with cancer and organ transplantation.

• Moreover, challenges such as absence of set protocol, non-adherence to treatment, etc. and their plausible solutions will aid in the implementation of PCT in antimicrobial stewardship.

• Further research is warranted for the ideal use of PCT and patient care in SEA countries and India.

Declaration of interest

Andrea Lay-Hoon Kwa, Do Ngoc Son, Kapil Zirpe, Petrick Periyasamy, Rongpong Plongla, Subramanian Swaminathan, Vu Van Giap received funds from Thermo Fischer Scientific Pte Ltd to attend the advisory board meeting Anucha Apisarnthanarak has received funding for scientific advisory board meeting from Thermo Fisher Scientific Pte Ltd. Brigitte Rina Aninda Sidharta, Tonny Loho received honorarium from Abbott Laboratories Pte Ltd (Singapore) to attend the advisory board meeting.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors are thankful to Abbott Laboratories (Singapore) Pte. Ltd. and Thermo Fisher Scientific Pte. Ltd. for providing financial support to facilitate this advisory board meeting. The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication. The authors acknowledge Ms. Ankita Mistry (Turacoz Healthcare Solutions) for helping in the coverage of advisory board meetings and publication support.

Additional information

Funding

This work was supported by Abbott Laboratories (Singapore) Pte Ltd and Thermo Fisher Scientific Pte Ltd. The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.