Expert Review of Anti-infective Therapy

ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/ierz20

Clinical utility of procalcitonin in implementation

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

Andrea Lay-Hoon Kwa, Brigitte Rina Aninda Sidharta, Do Ngoc Son, Kapil
Zirpe, Petrick Periyasamy, Rongpong Plongla, Subramanian Swaminathan,
Tonny Loho, Vu Van Giap & Anucha Apisarnthanarak

To cite this article: Andrea Lay-Hoon Kwa, Brigitte Rina Aninda Sidharta, Do Ngoc Son, Kapil
Zirpe, Petrick Periyasamy, Rongpong Plongla, Subramanian Swaminathan, Tonny Loho, Vu
Van Giap & Anucha Apisarnthanarak (2024) Clinical utility of procalcitonin in implementation
of procalcitonin-guided antibiotic stewardship in the South-East Asia and India: evidence and
consensus-based recommendations, Expert Review of Anti-infective Therapy, 22:1-3, 45-58,
DOI: 10.1080/14787210.2023.2296066

To link to this article: https://doi.org/10.1080/14787210.2023.2296066

© 2023 The Author(s). Published by Informa

UK Limited, trading as Taylor & Francis
Group.

Published online: 20 Dec 2023.

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EXPERT REVIEW OF ANTI-INFECTIVE THERAPY
2024, VOL. 22, NOS. 1–3, 45–58
https://doi.org/10.1080/14787210.2023.2296066

REVIEW

Clinical utility of procalcitonin in implementation of procalcitonin-guided antibiotic

stewardship in the South-East Asia and India: evidence and consensus-based
recommendations
Andrea Lay-Hoon Kwaa, Brigitte Rina Aninda Sidhartab, Do Ngoc Sonc, Kapil Zirped, Petrick Periyasamye,
Rongpong Plonglaf, Subramanian Swaminathang, Tonny Lohoh, Vu Van Giapi and Anucha Apisarnthanarakj
a
Department of Pharmacy, Singapore General Hospital; Emerging Infectious Diseases Program, Duke-National University of Singapore Medical
School, Singapore, Singapore; bClinical Pathology Laboratory, RSUD Dr. Moewardi Hospital, Central Java, Indonesia; cCenter for Critical Care
Medicine, Bach Mai Hospital; Hanoi Medical University; School of Medicine and Pharmacy, Hanoi National University, Hanoi, Vietnam; dDepartment
of Neurocritical Care, Ruby Hall Clinic, Grant Medical Foundation, Pune, India; eInfectious Diseases Unit, Medical Department, Hospital Canselor
Tuanku Muhriz UKM, Kuala Lumpur, Malaysia; fDivision of Infectious Diseases, Department of Medicine and Center of Excellence in Antimicrobial
Resistance and Stewardship; Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand; gInfectious Diseases,
Gleneagles Global Hospitals, Bengaluru, India; hDepartment of Clinical Pathology, Medistra Hospital; Medicine and Health Sciences, Universitas
Kristen Krida Wacana, Jakarta, Indonesia; iTraining and Direction of Healthcare Activities Center; Internal Medicine Department, Hanoi Medical
University; Vietnam Respiratory Society; Vietnam Society of Sleep Medicine; Respiratory Center, Bach Mai Hospital, Hanoi, Vietnam; jDivision of
Infectious Diseases, Thammasat University Hospital, Pratum Thani, Thailand

ABSTRACT ARTICLE HISTORY

Introduction: The South-East Asian (SEA) region and India are highly susceptible to antibiotic resis­ Received 29 May 2023
tance, which is caused due to lack of antimicrobial stewardship (AMS) knowledge, uncontrolled use of Accepted 13 December 2023
antibiotics, and poor infection control. Nonadherence to national/local guidelines, developed to combat KEYWORDS
antimicrobial resistance, is a major concern. A virtual advisory board was conducted to understand the Antimicrobial stewardship;
current AMS standards and challenges in its implementation in these regions. COVID-19; LRTI;
Areas covered: Procalcitonin (PCT)-guided antibiotic use was discussed in various clinical conditions across procalcitonin; sepsis
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 combina­
tion 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.

1. Introduction between the hospital administration and medical leadership [8].

Toward this, the role of biomarkers and their inclusion in AMS has
Antimicrobial resistance (AMR) is reported to be one of the major
been gaining acceptance globally. The role of procalcitonin (PCT)
risks to modern development, global health, and food security
has been widely analyzed [9] and can aid in improving the patient
[1,2]. The injudicious use of antibiotics, lack of knowledge/aware­
outcomes and reducing the burden of AMR worldwide [10]. PCT
ness of antimicrobial stewardship (AMS), lack of antibiotics audit­
ing, and poor infection control in South-East Asian (SEA) countries is a specific biomarker used in the diagnosis of bacterial infec­
and India seem to be some of the most common reasons for AMR. tions, and various clinical settings comprising emergency depart­
The hospital-based AMS is an integrated strategy to improve ment (ED), primary care, and intensive care [9]. It aids in ruling in
the appropriate use of antimicrobials to decrease antimicrobial or ruling out bacterial infections. Furthermore, the utilization of
cost, augment patient-related outcomes, and minimize the side PCT has been reported at different stages of antibiotic therapy
effects related to antimicrobial use [3–6]. Support of senior lea­ [11,12] namely, initiation, monitoring of antibiotic response, and
dership, research and education, pharmaceutical knowledge, early discontinuation of antibiotic therapy (Figure 1). However,
accountability, and prevention programs are some of the estab­ PCT threshold values may fluctuate based on patient population
lished principles contributing to a successful AMS [7]. The imple­ at different institutions [13] and may be influenced by underlying
mentation of the AMS provides recommendations on saving comorbidities such as congestive heart failure and chronic kidney
healthcare-associated costs, interaction with the clinicians, and disease (CKD) [14].
offers feedback to the prescribers. Further, successful AMS imple­ Nonadherence to national/local guidelines, developed to
mentation also depends upon the assistance and cooperation combat AMR, is a major concern, particularly in most of the SEA

CONTACT Anucha Apisarnthanarak [email protected] Division of Infectious Diseases, Thammasat University Hospital, Pratum Thani 12120, Thailand
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
46 A. L-H. KWA ET AL.

implementation in these Asian countries. The purpose of this

Article highlights article is to highlight and discuss the clinical utility of PCT in
● The clinical utility of PCT in guiding antibiotic therapy among
guiding antibiotic therapy in clinical scenarios such as lower
patients with LRTI, sepsis, COVID-19, febrile neutropenia in cancer, respiratory tract infections (LRTI), sepsis, COVID-19, febrile neu­
and organ transplantation are discussed in this article. tropenia in cancer, and organ transplantation. It further docu­
● The experts strongly recommended the use of PCT; however, eviden­
tial gaps still exist in clinical scenarios like febrile neutropenia with
ments the comments from this panel, highlighting the
cancer and organ transplantation. challenges and plausible solutions in the implementation of
● Moreover, challenges such as absence of set protocol, non-adherence PCT in AMS programs in these scenarios.
to treatment, etc. and their plausible solutions will aid in the imple­
mentation of PCT in antimicrobial stewardship.
● Further research is warranted for the ideal use of PCT and patient
care in SEA countries and India.
2. Methods
Experts from different SEA countries and India were selected
to participate in the panel by a committee based on their
countries and India. Further, poor sanitation measures, excessive extensive clinical experience in different medical fields and
use of antimicrobials [2], over-the-counter availability of antibio­ their publication track record in the field of infectious dis­
tics, population overcrowding [15], insufficiency in terms of qual­ eases. Our expert panel comprised a team of 10 experts
ity vaccines and diagnosis [2] have all contributed to high AMR. from different clinical faculties, including critical care med­
Hence, we convened a virtual advisory board meeting to under­ icine, infectious diseases, pharmacy, clinical pathology, and
stand the current standards of AMS and challenges in its respiratory medicine in the SEA countries and India.

Sepsis LRTI
PCT-based algorithm is reported to have high safety Use of PCT reduces antibiotic prescription rates and
quotient for reduction in antibiotic therapy duration in patients with LRTI

Initiation: PCT-guided algorithm development for the initiation of antibiotics Initiation: Assists in reducing antibiotic usage during initiation
may reduce unnecessary antibiotic administration without increasing adverse
outcomes Ongoing: Management of LRTI

Ongoing: Managing critically ill patients with sepsis Discontinuation: Assists in reducing antibiotic usage during discontinuation
of antibiotic treatment in patients
Discontinuation: Patients with sepsis showing clinical signs of improvement
Cut-off values: PCT >0.25 µg/L (initiation of antibiotics is encouraged) and
Cut-off values: PCT <0.5 µg/L (discontinuation of antibiotics) discouraged if PCT <0.1 µg/L

Level of recommendation: Strong Level of recommendation: Strong

Patient Treatment Strategy

COVID-19 Febrile neutropenia in cancer Organ transplantation

PCT acts as a severity marker to risk stratify PCT may be a useful tool in assessing the PCT can possibly be used for AMS in
patients with COVID-19 and decreases potential efficacy and duration of treatment in severely transplant-related immunosuppressed patients
burden of unnecessary use of antibiotics immunocompromised patients

Initiation: Used in deciding antibiotics in Initiation: Inadequate evidence Initiation: Inadequate data
patients with COVID-19 suspected of a
secondary infection Ongoing: Inadequate evidence Ongoing: Inadequate data

Ongoing: Antibiotics continued for 10–14 Discontinuation: PCT is recommended in Discontinuation: PCT can be used in post-
days if PCT level high patients with malignancies and persistent organ transplantation patients, following
neutropenia treatment for transplant-related infection and
Discontinuation: Patients showing signs of with clinical signs of improvement
improvement Cut-off values: PCT <1 μg/L (antibiotics can
be initiated), PCT 1.5–2 μg/L in metastatic Level of recommendation: Weak
Cut-off values: PCT <0.1 μg/L (antibiotics patients (antibiotics discontinues)
strongly discouraged) and PCT ≥0.5 μg/L
(antibiotics strongly encouraged) Level of recommendation: Weak

Level of recommendation: Strong

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.
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 47

To understand the role of PCT in clinical conditions (LRTI, mentioned above. In the case of different opinions obtained
sepsis, COVID-19, febrile neutropenia in cancer, and organ trans­ from the experts, a question on febrile neutropenia in can­
plantation), a literature search was performed using PubMed cer was slightly modified to reach the final opinion of the
database before the expert panel meeting. The terms used for experts. The voting was conducted employing an electronic
the literature search were ‘procalcitonin,’ ‘PCT,’ ‘antibiotics,’ ‘anti­ online polling software, using a modified Delphi process
microbial resistance,’ ‘LRTI’ OR ‘lower respiratory tract infections,’ (Figure 2), wherein ≥ 50% was considered as strongly recom­
‘sepsis,’ ‘COVID-19,’ ‘organ transplantation,’ ‘febrile neutropenia mended. The recommendations included in this article are
in cancer,’ ‘antimicrobial stewardship,’ ‘antimicrobial stewardship intended to highlight the use of PCT across different clinical
programs,’ ‘Asia-Pacific.’ Meta-analysis, review articles, rando­ conditions based on the literature findings, levels of evi­
mized controlled trials (RCTs), observational studies (prospective dence, and the experts’ opinion and experience.
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, 3. Clinical utility of PCT
wherein an electronic survey questionnaire was used and 3.1. Clinical utility of PCT in guiding antibiotic therapy in
discussed by the group of experts to obtain their opinions LRTI
regarding the use of PCT in different clinical conditions.
Following these discussions, all experts voted on their pre­ PCT utilization for empirical use of antibiotics at:
ference to provide strong, moderate, weak, and no recom­ a. presentation stage in patients with LRTI
mendation in relation to PCT-guided antibiotic use in b. management of patients during ongoing treatment
empirical therapy, ongoing treatment stage, and for de- stage
escalating the antibiotic therapy in the clinical scenarios c. discontinuation of antibiotics stage in patients with LRTI
stage
Pilot

Literature review and initial framework

Identifying key experts

Expert panel

Expert solicitation
selection

12 experts were
approached based on their
Finalization of experts (n=10) professional experience

Development of a questionnaire
Round 1

Participation of the experts in the online

survey (n=10)

Virtual advisory board meeting to

analyze and discuss the questionnaire
results
Summary of the results
circulated to the panel

Virtual advisory board 2 to discuss and

highlight the role of PCT in different
Round 2

clinical scenarios

Rating process via electronic survey Final collated results

polling based on the questionnaire circulated to the panel

Figure 2. Modified Delphi process flow chart.

48 A. L-H. KWA ET AL.

3.1.1. Poll outcomes is discouraged, if the PCT levels are <0.1 µg/L [22]. In the
Majority of the experts recommended that PCT can be utilized current study, experts from SEA countries and India opined
in decision-making for empirical treatment (at presentation in that PCT is utilized only for initiation of antibiotic therapy
a patient with clinical signs of LRTI, 80% experts) and monitor­ among patients with LRTI due to irreclaimable costs in clinical
ing of antibiotic response in LRTI patients (during the ongoing practice. Furthermore, in addition to the use of PCT, clinical
treatment stage, 90%). Most of the experts (80%) agreed that judgment also plays a significant role.
PCT is a valuable biomarker for discontinuation of antibiotics
in patients with LRTI showing clinical signs of improvement. 3.1.1.2. Management. PCT has been reported to reduce
antibiotic prescription rates and duration in patients with
3.1.2. Commentary from experts LRTI. According to a multicentric, non-inferiority, randomized
Similar observations, as that of the poll, were noted in the controlled ProHosp trial (n = 1359), the overall duration of
supporting evidence (such as 12 meta-analyses, 47 reviews, 26 antibiotic exposure significantly reduced by 34.8% in the PCT
RCTs, 6 observational studies, and 6 guideline papers) and group as compared to the standard-of-care group for all
consensus (Table 1). patients with LRTI, without compromising on clinical out­
comes [18]. In addition, the decrease in the antibiotic prescrip­
3.1.1.1. Initiation. LRTIs comprise acute bronchitis, pneumo­ tion rates from 87.7% to 75.4% was also reported for all
nia, and chronic obstructive pulmonary disease, which result patients with LRTI [18]. Several guidelines for the management
in morbidity and mortality across all age groups [16]. of adult LRTI state that biomarkers (such as PCT) can aid in
According to an observational, prospective study, 75% of shorter treatment duration [23].
patients with acute LRTI were treated with antibiotics, despite A meta-analysis demonstrated significant reduction in the
the viral origin of their infection [17,18]. In the discussions that total exposure (p < 0.0001) and duration of the use of antibio­
ensued, the experts opined that presence of mixed infections tics (p < 0.0001) with the use of PCT [20]. A single-center,
(bacterial and viral together) affects the performance of PCT; retrospective cohort study highlighted the importance of
thus, the efficacy of PCT in such atypical conditions should be PCT in improving antibiotic management when there is lack
assessed. They commented that some studies in literature of clarity on the diagnosis and treatment regime in patients
report the use of PCT as a diagnostic module demonstrating suspected of infection. Antibiotics can be modified if the initial
a wide range (40% to 90%) of sensitivity. The benefit of PCT, PCT values do not decrease upon administration of the initial
when compared to other biomarkers, is reported to demon­ treatment [24].
strate sensitivity of 89% and specificity of 94% for bacterial
infection [19]. Additionally, a meta-analysis reported that 3.1.1.3. Discontinuation. The cutoff value of PCT for the
initiation of antibiotics by the physicians with the help of discontinuation of antibiotics in patients with LRTI proposed
PCT in patients with community-acquired pneumonia, was by the expert panel was 0.25 µg/L or 80% reduction from the
significantly low (p < 0.0001) [20]. PCT cutoff values depend highest value. A follow-up PCT after 48 or 72 hours for possible
on the type of LRTI, ward type (ED, intensive care unit [ICU], decisions on discontinuation of the antibiotic treatment is
and respiratory department), and patient’s condition [21]. recommended. This is in-line with another meta-analysis of
Currently, antibiotic initiation is strongly encouraged at PCT 13 RCTs wherein, <0.25 µg/L was indicated as the cutoff for
>0.5 µg/L and encouraged if PCT levels were between 0.25 µg/ discontinuation of antibiotic treatment among patients in ED/
L and 0.5 µg/L [21]. Additionally, antibiotic treatment initiation medical ward and <0.5 µg/L among patients in ICU [25].

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.
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 49

3.2. Clinical utility of PCT in guiding antibiotic therapy in study, assessing the role of PCT in newborns, revealed that
sepsis patients in the PCT group experienced shortening of antibiotic
therapy versus the standard group [34].
The need for PCT utilization among patients with sepsis in:
a. empirical stage of antibiotics treatment
b. ongoing treatment stage of antibiotics treatment 3.2.2.3. Discontinuation. A meta-analysis reports that using
c. discontinuation stage of antibiotics treatment 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
3.2.1. Poll outcomes
Antibiotic Treatments in Acutely ill patients (PRORATA) trial,
The majority of experts (70%) suggest the use of PCT, along
discontinuation of antibiotics was encouraged in patients with
with clinical judgment, in deciding the antibiotic initiation
suspected or confirmed sepsis, where PCT levels were <0.5 µg/
among patients with sepsis or septic shock. Furthermore, all
L, or reduced by ≥ 80% from the previous peak value, respec­
the experts recommended and agreed that PCT is a valuable
tively [31]. Further, the panel revealed that in many hospitals
biomarker for monitoring the response of critically ill patients
in Vietnam and Indonesia, the diagnosis and management of
with sepsis during the ongoing treatment stage. About 90% of
patients with sepsis and septic shock in the ICU and ED mainly
the experts recommended using PCT (in addition to culture
depends on clinical judgment, although PCT may be included
and sensitivity results) for discontinuation of antibiotics in
for monitoring the response during the ongoing treatment
patients with sepsis showing clinical signs of improvement.
stage and for discontinuation.
Experts from India suggested that PCT was useful for the
3.2.2. Commentary from experts
detection of bacterial sepsis among critical and complicated
The advisors’ recommendation is corroborated by evidence
cases of COVID-19. PCT helped to exclude the possibility of
(11 meta-analyses, 12 reviews, 20 RCTs, and 4 guideline
bacterial sepsis, especially due to immunosuppressant use.
papers) suggesting PCT, in conjunction with clinical judgment,
However, after identification of the causative microorganisms,
is useful in guiding the antibiotic therapy in patients with
the serum PCT levels are found to be greater in patients with
sepsis across all stages (Table 1).
Gram-negative sepsis when compared to those with Gram-
positive or fungal sepsis, except in patients with severe sepsis.
3.2.2.1. Initiation. Based on the discussion with experts, the Therefore, PCT test is more sensitive to the Gram-negative
proposed cutoff value for sepsis diagnosis via PCT is 0.5 µg/L. bacterial infections [36].
The expert panel also suggested using PCT in antibiotic treat­
ment initiation in sepsis if the turnaround time of the PCT test
is faster as compared to other tests. 3.3. Clinical utility of PCT in guiding antibiotic therapy in
COVID-19
3.2.2.2. Management. PCT is evidently useful in estimating
PCT is a beneficial tool in the evaluation of patients with
antibiotic therapy duration in diverse settings, including the
COVID-19, safely decreasing the potential burden of unneces­
ICU [26,27]. PCT is usually performed when there is uncertainty
sary use of antibiotics.
about bacterial infections, especially in pneumonia or unspe­
cified sepsis cases. A prospective, multicenter RCT conducted
for assessing the safety and efficacy of PCT in critically ill 3.3.1. Poll outcomes
patients (sepsis, severe sepsis, or septic shock) demonstrated The majority of experts (70%) recommended PCT utilization in
that PCT guidance aids in the reduction of treatment duration the initiation of empirical antibiotics among patients with
(5 days [3–9]) and daily antibiotic doses (7.5 daily doses) versus COVID-19 suspected of a secondary bacterial infection. All
the standard-of-care group. A significant reduction in mortality the experts strongly recommended PCT in monitoring patients
(PCT group: 20% versus standard-of-care group: 25% at 28 when antibiotic is started during the ongoing treatment stage
days) was also observed [28]. Similar results were obtained in and in the consideration of discontinuation of antibiotics
the PROGRESS randomized trial, wherein PCT guidance could when there is a clinical improvement.
effectively reduce the 28-day mortality, cost of hospitalization,
and infection-related adverse events in patients with sepsis 3.3.2. Commentary from experts
[29]. In a single-center before-and-after-intervention cohort- The poll outcomes are consistent with published evidence (2
designed study, an approved PCT protocol was followed to reviews, 9 observational studies) and the current study con­
effectively manage antibiotic use in adult sepsis patients sensus (Table 1).
within the ICU [30]. Another multicenter, prospective, parallel-
group, open-label trial reported that a PCT-based strategy for 3.3.2.1. Initiation. PCT reduces the potential burden of
the treatment of suspected bacterial infections among non­ unnecessary use of antibiotics in COVID-19. PCT is recom­
surgical patients in ICUs might be effective in decreasing the mended at admission (day 1) in COVID-19; experts believe
antibiotic exposure without adverse outcomes [31]. A PCT- that administering antibiotics without PCT guidance is not
based algorithm is reported to have high safety quotient for the right clinical practice and may not be favorable for the
the reduction in antibiotic therapy among patients with patient. The utility of PCT and clinical pulmonary infection
respiratory tract infections as well as sepsis [32,33]. Another score (CPIS) has been stated to be very useful in critically ill
50 A. L-H. KWA ET AL.

COVID-19 patients. The utilization of PCT-CPIS successfully inadequate evidence for the initiation and monitoring of treat­
decreased inappropriate use of antibiotics among severe- ment. However, few experts recommended the use of PCT for
critically ill COVID-19 pneumonia patients [37,38]; as per the de-escalation or cessation of antibiotics in patients with cancer
study protocol, antibiotics were not initiated if CPIS was ≤ 6 who are treated for febrile neutropenia; PCT levels are ana­
and PCT was <0.5 µg/L [38]. Antibiotics were initiated and lyzed within 48 hours of antibiotic administration to decide on
reevaluated on day 3 for patients in the ICU, if CPIS was ≥ 6 antibiotics discontinuation. Experts recommended that in case
and PCT was >0.5 µg/L. Antibiotics were continued, if the PCT of high PCT levels, continuation of treatment with the same
levels were still high. However, the antibiotics were discontin­ antibiotics should be avoided and patient’s condition should
ued, if the PCT levels were low at <0.5 µg/L, or dropped by ≥ be reassessed. They further suggested that the antibiotics can
80% [38]. PCT guidance is suggested for the antibiotic initia­ be stopped if the patient remained with PCT <0.5 µg/L, with
tion in patients with COVID-19. However, specific criteria have close monitoring. A post-hoc analysis of a prospective, obser­
been enforced for their prescription (such as empirical use of vational cohort conducted among patients with cancer and
antibiotics until COVID-19 confirmation, clinical symptoms, febrile neutropenia reported that PCT can be an adjunctive
bacterial complications, or PCT ≥0.5 ng/mL), to avoid unneces­ biomarker for identifying cancer patients. Further, its guided
sary antibiotic use and facilitate discontinuation where anti­ algorithm can limit antibiotic duration, reduce adverse events,
biotics may not be required [39]. and prevent antimicrobial resistance emergence [42].
According to a retrospective review, PCT of <0.5 µg/L was
3.3.2.2. Discontinuation. It is observed that both, clinical recommended to guide the discontinuation of antibiotics in
judgment and the use of biomarkers, guide the discontinuation patients with malignancies and persistent neutropenia after 1
of the antibiotics in patients with COVID-19. In a prospective, week of antibiotic treatment. A reduction in the duration of
single-center, cohort study, reduction in duration of antibiotic antibiotic carbapenem (after 1 week of treatment) was
by 2 days was observed after the usage of PCT in patients with observed in the group, wherein physicians accepted AMS [43].
COVID-19. Determination of the chances of bacterial infection Similarly, PCT could be a useful tool in augmenting the AMS in
as well as its clinical judgment is considered using a PCT level of cancer patients with COVID-19 by decreasing the time period of
0.5 μg/L as the higher limit [40]. However, a multicenter rando­ antimicrobial therapy till the PCT results are available (after the
mized controlled trial conducted in France demonstrated the initial 72 hours). Furthermore, PCT levels of >0.25 μg/L are
inefficiency of PCT-guided strategy with respect to antibiotics reported to correlate with documented bacterial infection [44].
exposure in patients with COVID-19 [41]. The experts here opined that antibiotics can be initiated
with PCT levels of <1 μg/L in patients with nonfebrile neutro­
penic cancer, and discontinuation of the antibiotic treatment is
3.4. Clinical utility of PCT in guiding antibiotic therapy in
preferred among patients with metastatic cancer demonstrat­
febrile neutropenia in cancer
ing PCT levels from 1.5 to 2 μg/L.
There are inadequate data available on the use of PCT among
patients with febrile neutropenia in cancer; thus, more trials
3.5. Clinical utility of PCT in guiding antibiotic therapy in
should be encouraged.
organ transplantation
3.4.1. Poll outcomes There is a need for more research and published evidence on
Few experts (20%) agreed and recommended (weak) that PCT the use of PCT among patients with organ transplantation.
can be applied for the initiation of antibiotics among patients
presenting with febrile neutropenia or other signs of infection. 3.5.1. Poll outcomes
Further, all the experts provided weak recommendations for All the experts provided a weak recommendation for PCT use
the utility of PCT in monitoring the antibiotic response of in the initiation and monitoring response of antibiotic therapy
cancer patients with febrile neutropenia during the ongoing in organ transplantation. Very few experts (13%) recom­
treatment stage. For discontinuation of antibiotics in cancer mended the use of PCT in discontinuation of antibiotics in
patients who are being treated for febrile neutropenia or other post-organ transplantation patients, following treatment for
infections and exhibit clinical signs of improvement, the transplant-related infection and with clinical signs of improve­
recommendation was provided by only 40% of the experts. ment. Their recommendation was supported by the sparsely
This is due to the scarcity of published evidence (only 3 available published evidence (1 observational study) (Table 1).
observational studies) to provide recommendation on using
PCT in febrile neutropenia cases (Table 1). 3.5.2. Commentary from experts
The utilization of PCT has been reported as a sensitive marker
3.4.2. Commentary from experts to distinguish between systemic bacterial infections and organ
PCT may be used to guide if the clinical fever (often a reason transplantation-related complications [45]. According to
to initiate antibiotics) is due to infectious or noninfectious a systematic review and meta-analysis, PCT can be a useful
causes (malignancies and drugs can cause fever too) in febrile, marker in liver transplant recipients to help in distinguishing
non-neutropenic, cancer patients, so as to discontinue their infection complications from acute rejections [46]. Another
antibiotics safely [42]. retrospective data analysis reported that PCT can possibly be
Febrile neutropenia is critical in cancer; thus, most experts used for AMS in transplant-related immunosuppressed
are reluctant to use PCT in these patients mainly due to patients [47].
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 51

PCT is not recommended to guide antibiotic initiation for reduced risk for systemic infection [54], clinical reevaluation is
early post-transplant sepsis. However, one expert from India required and PCT tests are repeated [9,18].
opined that PCT kinetics played an important role in decid­ According to a Singapore General Hospital-based prospec­
ing the therapy duration. A reduction in the average dura­ tive observational cohort study, the use of PCT for antibiotic
tion of antibiotic therapy was found based on the kinetics discontinuation under AMS did not compromise the patients’
data among liver and kidney transplant recipients. However, outcome and was helpful in reducing the antibiotic use [55].
more research and data concerning the use of PCT in A hospital-based AMS is present and implemented among
transplant is required. Another expert from India stated hospitals/institutions in Singapore (2011), Thailand (2012)
that rather than considering the data unavailability, [56], Malaysia (2014), and Vietnam (2016, updated in 2020)
a collated decision and overall experience might be pre­ [57]. Currently, hospitals in Indonesia follow the national pro­
ferred if an improvement is observed while managing the gram for implementation of AMR control, national guidelines
patient. for AMS by the Ministry of Health (MoH) using antibiotic
However, a critical challenge in utilization of PCT in organ guidelines (access, watch, and reserve of antibiotic therapy)
transplantation is the lack of published data. The data cur­ similar to the WHO to control AMR [58]. Similarly, in Thailand,
rently available are only from single-centered experiences, the National Strategic Plan on AMR and Antibiotics Smart Use
mainly retrospective (not prospective); good quality systema­ project has been implemented [59]. One Health strategy
tic review data are also unavailable. (Singapore) [60] and ABS prevention and infection control
(ASPIC) program (India) [61] are other examples of national
programs for preventing AMR.
4. Implementation of PCT in AMS program:
According to experts, PCT utilization in the antibiotic treat­
challenges and probable solutions
ment initiation can help in LRTI and sepsis. In COVID-19, PCT
The development and application of AMS is reported to differ helps in reducing the potential burden of unnecessary usage
among various countries [48]. AMS has been implemented in of antibiotics [62]. PCT may differentiate the causative reason
Singapore and Indonesia. Meanwhile, in countries such as (bacterial infections versus malignancies versus drugs) for
Thailand and Vietnam, there is a lack of implementation of a clinical fever in febrile, non-neutropenic cancer patients
AMS despite its availability in hospitals. In India, the concept [42]. Moreover, PCT has been reported as a useful marker to
of AMS is subjective and limited to the guidelines on using distinguish between systemic bacterial infections and organ
antimicrobials for empiric therapy rather than on discontinua­ transplantation-related complications [45]. Additionally, key
tion or de-escalation of therapy. Currently, despite the pre­ clinical studies also highlight the importance of PCT in these
sence of AMS, there are challenges in the implementation of conditions (Table 3). No recommendation was made on the
AMS in SEA countries and India. These challenges include lack utilization of PCT for initiating antibiotics in patients with
of willingness of hospital management and inadequate enfor­ febrile neutropenia. However, weak recommendation was pro­
cement from the regulatory authorities, admission of patients vided by the experts for the use of PCT in managing and de-
infected with multidrug-resistant pathogen or previous anti­ escalating antibiotics among febrile neutropenic patients, and
biotic use, absence of set protocol, difficulty in controlling in the management of antibiotic therapy across all the stages
prescriptions provided by the senior doctors, and COVID-19, in patients with organ transplantation.
in addition to the various challenges described in Table 2 Further, although PCT demonstrates promising outcomes
[49]. Adequate inventory management systems driven by in many conditions, there are some limitations that should
pharmacists are required for sustainable administration of be considered before the integration of PCT in routine
antimicrobials and to implement AMS programs success­ clinical practice [52]. Infection site and bacterial type may
fully [50]. 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
5. Discussion
diagnostic accuracy to predict bacteremia [72]. A RCT study­
PCT-guided AMS has been reported to guide the initiation and ing the PCT-based strategy failed to demonstrate that it
duration of antibiotic treatment in patients with clinical con­ reduces the antibiotic exposure and might not be efficient
ditions without compromising (and possibly improving) on in differentiating between infectious and noninfectious
the clinical outcomes [20,51]. It is possible to detect PCT 3 to causes of acute chronic obstructive pulmonary disease
4 hours after an infection, therefore making it a suitable test (ACOPD). Further, irrespective of the origin of acute exacer­
for diagnosis. Further, it peaks at 6 to 12 hours, meaning it will bation of chronic obstructive pulmonary disease (AECOPD),
be easily detectable at this time point after the onset of an patients with AECOPD benefit from antibiotic therapy and
infection [9]. Post initiation of antibiotics, PCT values should be a delay in the antibiotic prescription may result in unfavor­
reassessed every 1 or 2 days for adequate monitoring and able outcomes such as increased mortality [73].
once the PCT levels fall below 0.1 ng/mL (or 80 to 90% Additionally, AMS programs must ascertain that PCT diag­
below initial measurement), antibiotics can be stopped. If the nostic test has exhibited adequate sensitivity within the
PCT levels still remain high, alternative therapies must be patient cohort of interest prior to incorporating the test
considered [52,53]. Further, in the instance where antibiotics into treatment guidelines based on a high negative predic­
are withheld, such as in patients with acute bronchitis or tive value [74]. Moreover, the 2019 Infectious Diseases
exacerbation of chronic obstructive pulmonary disease with Society of America guidelines for the management of
 52

Table 2. Key clinical studies highlighting the role of PCT in various clinical conditions.
Reference Study Design/Type Sample Size Key Findings
A. L-H. KWA ET AL.

COVID-19
Initiation Stage
Huttner et al., Commentary — ● Biomarkers like PCT might help in deciding for which COVID-19 patients antibiotics can be withdrawn
2019 [63]
Monitoring the Response
Wolfisberg et al., Review — ● Decreased antibiotic usage with no negative effect on the outcomes
2021 [64] ● 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., Retrospective observational N = 730 ● Potential role of PCT in excluding bacterial co-infections assay in the first 48 h)
2021 [65] ● 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., Review article 14 RCTs ● Measuring PCT levels can assist in making decisions pertaining to antibiotics treatment and thus reduce exposure to antibiotics
2011 [66] ● 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 Consensus statement 3 RCTs ● The panel suggests against using PCT plus clinical evaluation to decide when to start antimicrobials, as compared to clinical
[67] evaluation alone for adults with suspected sepsis or septic shock.
Discontinuation Stage
Pepper et al., Systematic Review and Meta- >2500 articles examined and ● PCT-guided antibiotic discontinuation appears to reduce antibiotic exposure
2019 [68] analysis included 16 RCTs
LRTI
Initiation Stage
Lee et al., 2020 Opinion paper 16 experts from 12 Asia-Pacific ● For optimal use of PCT in Asia-Pacific countries, the two adapted algorithms will be able to reduce complexity in clinical routine
[51] countries ● 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 Single-center quasi-experimental — ● Based on low PCT values, PCT providers were inclined toward de-escalation of antibiotics but not toward discontinuation
[69] before and after study
Discontinuation Stage
Mathioudakis Systematic review and meta- Eight trials evaluating 1062 ● The clinical effectiveness and safety of PCT-based protocols is suggested in the study; thus, these PCT-based protocols can be
et al., 2016 analysis patients with AECOPD utilized in discontinuation of antibiotics in patients presenting with AECOPD
[70]
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, Cost Making it affordable
and Indonesia ● Test not fully reimbursed by insurance agencies ● Crucial to have strong and extended health insurance coverage
● Expensive test ● Reduction in the cost of PCT to aid in its implementation in LMIC
● Lack of study on the cost-effectiveness of PCT in CAP ● Cost-effectiveness analysis: Assess the cost-effectiveness of PCT-guided antibiotic therapy for CAP
● Lack of funds 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, Lack of knowledge/trained staff Increasing awareness and knowledge
Malaysia, and ● Difficulty in using PCT test/PCT driven protocol: As a parameter to diagnose cause Guideline and training:
Indonesia of infection, to determine effectiveness of antibiotics, and understand its kinetics
● Guidelines: Incorporation of PCT into patient management nationwide, i.e. nationalized protocol is
● Interpretation of PCT test results: Adopting the same practices (indicating/inter­
preting PCT) among clinicians and AMS team required and setting up workshops/training/refresher training and update
● Heterogeneous knowledge among physicians on maximizing the use of PCT ● Outcome assessment/education: Education and training on PCT kinetics and easy-to-use cutoff for
● Knowledge and attitude gap in identifying and managing sepsis in ED and ICU
general physicians, surgeons, students, and clinical pharmacists
● Protocol: Creation of PCT protocol for day 0 and day 5 will help in PCT ordering
● Use of guidelines for patient management in national insurance policies
● Administrators should implement AMS as the first line of treatment in all the units of all hospitals
● Understanding and awareness among administrators about the concept of AMS
● PCT ordering

3 Indonesia, India, Lack of resources Improved resources

Malaysia, and ● Nonavailability of resources in hospitals ● Include PCT in all hospitals
Thailand ● Lack of clear guidelines for the use of antibiotics and using PCT upfront to prevent ● Clarity in guidance/new algorithms at the hospital/country level (need for written PCT algorithms
antibiotic use due to the current surviving sepsis guidelines and accurate PCT protocols in hospitals)
● TAT of RT-PCR test ● Obtain a prompt RT-PCR test result
● Lengthy TAT of PCT: Challenge to use it as an upfront diagnostic marker ● More research required on the use of PCT in tropical diseases
● Lack of evidence on the use of PCT in several settings (including AMS programs, ● Setting up more ID 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

4 Vietnam Reimbursement Reimbursement of PCT test

● Explaining the rationale to insurance auditors on a case-to-case basis ● Should be provided up to 1 time every 24 hours and 48 hours for septic shock and severe infection,
● SOFA score reimbursement policy limits the use of PCT respectively
5 Thailand and India Serial testing ● Could be improved through education
● Can help determine upward and downward trend of PCT values
● Lack of initial and serial testing

(Continued )
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY
53
54 A. L-H. KWA ET AL.

community-acquired pneumonia (IDSA CAP) guideline

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.
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:
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
recommends empiric antibiotic treatment in patients with

Transparency with respect to every investigation, drug use, and cost should be maintained
suspected or radiologically confirmed CAP irrespective of
initial PCT levels [75].

The hospital should be accountable for every decision taken by the concerned staff
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 infec­
tions, renal failure, and other conditions. Contrarily, false-
● Clinical audits can be useful for the consistency of the AMS program

Discontinuation of antibiotics, if PCT values are low after week one

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
Probable Solutions

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-
Transparency and accountability

19, resulting in inappropriate antibiotic therapy usage (in

terms of extended duration) [39].
Precise use of IT

5.1. Future research

Low PCT levels

Despite the utility of PCT in LRTI [18], sepsis [51], and COVID-
system)

19 [62], some evidential gaps exist in regards to guiding

Audits

antibiotic therapy in these various clinical conditions, particu­

●

●
●

larly in febrile neutropenia with cancer [78] and organ trans­

● Effectiveness of program is a problem as there is a doubt if there is documenta­

plantation [47]. More data are warranted to demonstrate the

utility of PCT in these settings by undertaking more rando­
mized controlled trials for studying the initiation [73], escala­
tion, de-escalation [27], oral switch [79], and discontinuation of
treatment [35].
Change of IT consultants every alternate or every year

Culture negative patients showing signs of high fever

● Consistency of AMS program is absent in institutes

6. Conclusion and outlook

Lack of consistency and effectiveness of AMS

tion, discussion, and audits of data collected

Challenges

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
Culture negative sepsis
Lack of PCT adoption

patients with sepsis, they suggest using PCT for initiation

and recommend the use of PCT in management and dis­
continuation of antibiotic therapy. However, further
Lack of IT

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 insur­

ance companies of every country should be aware of the
usefulness of PCT and extend the necessary support for the
Country

same. However, additional research should be considered in

Table 3. (Continued).

the SEA region and India for optimal utilization of PCT and
Malaysia

patient care. The establishment of lasting and mutually

India

beneficial partnerships between high-income and low and

Sr. No

middle-income countries (LMICs) must be rooted in the

6

principles of capacity building [80].

 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 55

7. Expert opinion difficulty in controlling prescriptions provided by the senior

doctors and inadequate enforcement from the regulatory
The AMR rate is higher in the SEA region and India and is
authorities are some of the complexities encountered. The
believed to be caused due to lack of AMS knowledge, uncon­
solutions related to the challenges in implementation of PCT
trolled antibiotic use, and poor infection control. In recent
in AMS programs can be applied in clinical practice which can
years, several national/local guidelines have been developed
aid in overcoming the future challenges. The experts also
to combat AMR in these regions. However, non-adherence to
believe that support and awareness regarding the utilization
these protocols/guidelines is a major concern in most SEA
of PCT by the Government and insurance companies of every
countries and India. This nonadherence to guidelines may be
country will aid in sufficient utility of PCT. However, better and
multifactorial, as underlying conditions and disease severity
advanced research in the SEA region and India is needed for
may result in patient’s noncompliance while prescriber non-
optimal utilization of PCT and patient care.
adherence may be the result of lack of knowledge. These
In the future, as per the experts, PCT may become a crucial
factors are however seen to differ across healthcare systems
tool in AMS programs. The cutoff values for PCT may become
[81]. Further, noncompliance with guideline-recommended
more refined since more data are being collected and analyzed,
treatment can lead to an increased use of broad-spectrum
leading to more accurate and effective use of this biomarker.
empirical therapy [82].
Furthermore, new technologies may develop that allow for
PCT, although a valuable biomarker, may not always be
even more rapid and accurate PCT testing, allowing more
a dependable prognostic marker and should be interpreted
accessibility of this tool to healthcare providers. Currently, the
based on clinical practice [14]. A meta-analysis reported no
Sepsis assay kit (PATHFAST™ B･R･A･H･M･S PCT), an immu­
difference in short-term mortality with the use of PCT-guided
noassay used in the early detection and differential diagnosis
approach, however, a substantial reduction of duration of
of bacterial infections, such as sepsis. Similarly, the IB10 sphin­
antibiotic treatment was observed with the PCT-guided strat­
gotest® PCT and AQT90 FLEX PCT assay are some point-of-care
egy. These varied results may be the result of differences in
immunoassays enabling convenient measurement of PCT [88–
follow-up period or non-adherence to protocol [83]. Contrarily,
90] Some of these technologies are already in existence,
the ProACT study demonstrated that the PCT-guided
although costs may be prohibitive for SEA.
approach did not result in a decreased exposure to antibiotics
It is also possible that PCT may be used in combination with
as compared with standard care protocol [84]. Therefore, the
other clinical data to guide antibiotic therapy in a more perso­
use of PCT must depend on individual needs of AMS programs
nalized and precise way. This could lead to more targeted anti­
and cannot be generalized. This, in turn, will minimize unne­
biotic treatment, further reducing the risk of antibiotic resistance
cessary PCT testing and result in associated cost-saving.
and improving patient outcomes. Overall, the future of PCT in
PCT is a specific biomarker that helps in ruling in or ruling
antibiotic treatment is promising, and continued research and
out bacterial infections. PCT-guided antibiotic treatment
development in this area will probably lead to even more effec­
option has redefined the therapeutic measures to combat
tive utilization of this biomarker in the years to come.
antimicrobial resistance by guiding PCT antibiotic therapy in
various clinical scenarios like LRTI, sepsis, COVID-19, febrile
neutropenia in cancer, and organ transplantation. Despite Funding
the utility of PCT in LRTI, sepsis, and COVID-19, some eviden­ This work was supported by Abbott Laboratories (Singapore) Pte Ltd and
tial gaps exist in the guiding of antibiotic therapy in these Thermo Fisher Scientific Pte Ltd. The funding organization(s) played no
various clinical conditions, particularly in febrile neutropenia role in the study design; in the collection, analysis, and interpretation of
with cancer and organ transplantation. More data are war­ data; in the writing of the report; or in the decision to submit the report
for publication.
ranted 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 Declaration of interest
conditions, experts strongly believe that PCT can be included Andrea Lay-Hoon Kwa, Do Ngoc Son, Kapil Zirpe, Petrick Periyasamy,
in a guideline or in AMS. Rongpong Plongla, Subramanian Swaminathan, Vu Van Giap received
funds from Thermo Fischer Scientific Pte Ltd to attend the advisory
According to the experts, the challenges in implementation
board meeting Anucha Apisarnthanarak has received funding for scien­
of the PCT in the SEA region and India include cost of PCT tific advisory board meeting from Thermo Fisher Scientific Pte Ltd.
(lack of funds, reimbursement concerns in some countries), as Brigitte Rina Aninda Sidharta, Tonny Loho received honorarium from
it incurs an additional cost compared to other laboratory Abbott Laboratories Pte Ltd (Singapore) to attend the advisory board
assays, which remains a major barrier [85,86]. Comprehensive meeting.
The authors have no other relevant affiliations or financial involvement
cost-effectiveness assessments are thus required to evaluate
with any organization or entity with a financial interest in or financial
whether the health benefits and associated cost savings can conflict with the subject matter or materials discussed in the manuscript
offset the additional expenses of PCT testing [87], especially in apart from those disclosed.
the setting of an RCT. Further, the absence of set protocol, lack The authors have no relevant affiliations or financial involvement with
of trained staff, nonavailability or lack of resources, admission any organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript. This
of patients infected with multidrug-resistant pathogen or pre­
includes employment, consultancies, honoraria, stock ownership or
vious antibiotic use, COVID-19, lack of willingness of hospital options, expert testimony, grants or patents received or pending, or
management, lack of consistency and effectiveness of AMS, royalties.
56 A. L-H. KWA ET AL.

Reviewer disclosures 16. Hey J, Thompson-Leduc P, Kirson NY, et al. Procalcitonin guidance
in patients with lower respiratory tract infections: a systematic
Peer reviewers on this manuscript have no relevant financial or other review and meta-analysis. Clin Chem Lab Med. 2018;56
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