Chien-Chang Lee , Andrea Lay Hoon Kwa , Anucha Apisarnthanarak , Jia-Yih Feng , Eric Howard Gluck , Akihiro Ito , Anis Karuniawati , Petrick Periyasamy , Busadee Pratumvinit , Jeetendra Sharma , Rontgene Solante , Subramanian Swaminathan , Niraj Tyagi , Dien Minh Vu , Kapil Zirpe and Philipp Schuetz

Procalcitonin (PCT)-guided antibiotic stewardship in Asia-Pacific countries: adaptation based on an expert consensus meeting

De Gruyter | Published online: January 13, 2020

Abstract

Introduction

Recently, an expert consensus on optimal use of procalcitonin (PCT)-guided antibiotic stewardship was published focusing mainly on Europe and the United States. However, for Asia-Pacific countries, recommendations may need adaptation due to differences in types of infections, available resources and standard of clinical care.

Methods

Practical experience with PCT-guided antibiotic stewardship was discussed among experts from different countries, reflecting on the applicability of the proposed Berlin consensus algorithms for Asia-Pacific. Using a Delphi process, the group reached consensus on two PCT algorithms for the critically ill and the non-critically ill patient populations.

Results

The group agreed that the existing evidence for PCT-guided antibiotic stewardship in patients with acute respiratory infections and sepsis is generally valid also for Asia-Pacific countries, in regard to proposed PCT cut-offs, emphasis on diagnosis, prognosis and antibiotic stewardship, overruling criteria and inevitable adaptations to clinical settings. However, the group noted an insufficient database on patients with tropical diseases currently limiting the clinical utility in these patients. Also, due to lower resource availabilities, biomarker levels may be measured less frequently and only when changes in treatment are highly likely.

Conclusions

Use of PCT to guide antibiotic stewardship in conjunction with continuous education and regular feedback to all stakeholders has high potential to improve the utilization of antibiotic treatment also in Asia-Pacific countries. However, there is need for adaptations of existing algorithms due to differences in types of infections and routine clinical care. Further research is needed to understand the optimal use of PCT in patients with tropical diseases.

Introduction

Individualizing the antibiotic treatment approach to patients by use of procalcitonin (PCT), a blood biomarker of bacterial infection, is an increasingly accepted concept particularly in the setting of respiratory infections and sepsis [1], [2]. As a marker with both diagnostic and prognostic properties, several trials found that PCT-guided antibiotic stewardship leads to a reduction in antibiotic consumption and better clinical patient outcomes [3], [4], [5], [6].

However, PCT protocols used in previous trials had some differences in regard to PCT cut-off, frequency of PCT measurement and overruling criteria limiting the clinical implementation of this marker in routine care [7]. For the purpose of harmonization of the use of PCT across different clinical settings and diagnoses, a consensus conference took place in Berlin in 2018, where, based on the analysis of available trials and studies, experts agreed on three different PCT algorithms for antibiotic stewardship in patients with mild, moderate and severe disease [8].

In brief, these algorithms proposed that for optimal use, PCT levels should be put into the context of the clinical assessment in regard to severity of illness and probability of bacterial infection (uncertainty vs. bacterial infection highly suspected) to make reasonable and safe recommendations. The group also agreed on PCT cut-offs indicating low likelihood of bacterial infection of <0.25 μg/L in non-intensive care unit (non-ICU) patients and <0.5 μg/L in ICU patients. Emphasis was laid on serial testing of PCT levels to monitor the response to antibiotic therapy, and control of infection with a decrease in PCT from the peak by ≥80% and/or fall below the cut-off indicates resolution of illness and earlier discontinuation of antibiotics is recommended. However, most trials were done in European and US health care settings and also most experts participating in the meeting came from these countries. Due to differences in types of infections, patient populations, available resources and standard of clinical care, however, these recommendations and algorithms may need adaptations before they can be broadly implemented in other geographic regions such as Asia-Pacific countries [9].

Herein, our aim was to discuss within a group of experts from different Asia-Pacific countries, the necessary modifications of the Berlin consensus algorithm and to derive adapted algorithms on optimal use of PCT for the purpose of antibiotic stewardship in the Asia-Pacific region.

Materials and methods

The consensus process took place during a 1-day workshop in Bangkok on September 21, 2019. The consensus was developed by a multidisciplinary team of 16 experts on clinical use of PCT from 12 Asia-Pacific countries each representing different functional stakeholders in antibiotic stewardship, including physicians from medical and surgical critical care medicine, emergency medicine, respiratory medicine, clinical microbiology, infectious diseases, pharmacy and laboratory medicine. Table 1 gives an overview of the participants and their clinical and geographic background.

Table 1:

List of participating experts.

Name Affiliation Field of expertise
Anucha Apisarnthanarak Thammasart University Hospital, Division of Infectious Diseases, Bangkok Thailand Infectious Diseases

Antibiotic Stewardship
Jia-Yih Feng Taipei Veterans General Hospital, Department of Chest Medicine, Taipei, Taiwan Pneumology
Eric Howard Gluck Swedish Covenant Hospital, Critical Care Services, Chicago, IL, USA Critical Care Medicine
Akihiro Ito Ohara Healthcare Foundation, Kurashiki Central Hospital, Department of Respiratory Medicine, Okayama, Japan Pneumology
Anis Karuniawati Department of Microbiology, Faculty of Medicine, Universitas Indonesia; Cipto Mangunkusumo Hospital, Jakarta, Indonesia Clinical Microbiology
Andrea Lay Hoon Kwa Singapore General Hospital, Singapore, Singapore; Emerging Infectious Diseases Program, Duke-National University of Singapore Medical School, Singapore, Singapore Pharmacotherapy

Infectious Diseases

Antibiotic Stewardship
Chien-Chang Lee National Taiwan University Hospital, Emergency Medicine Department and Health Data Science Research Group, Taipei, Taiwan Emergency Medicine
Petrick Periyasamy PPUKM (HCTM), Hospital Canselor Tuanku Muhriz UKM (HCTM), Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Kuala Lumpur, Malaysia Infectious Disease
Busadee Pratumvinit Mahidol University, Faculty of Medicine Siriraj Hospital, Department of Clinical Pathology, Bangkok, Thailand Laboratory Medicine
Jeetendra Sharma Artemis Hospital Critical Care Medicine, Gurgaon, India Critical Care Medicine
Rontgene Solante San Lazaro Hospital, Adult Infectious Diseases and Tropical Medicine, Manila, Philippines Infectious Diseases
Subramanian Swaminathan Gleneagles Global Hospitals, Infectious Diseases, Chennai and Bengaluru, India Infectious Diseases
Niraj Tyagi Sir Ganga Ram Hospital, Institute of Critical Care & Emergency Medicine, Delhi, India Critical Care Medicine
Dien Minh Vu National Hospital of Tropical Diseases, Critical Care Dept., Hanoi, Vietnam Critical Care Medicine
Kapil Zirpe Ruby Hall Clinic, Dept. of Neuro Critical Care, Grant Medical Foundation, Pune, India Critical Care Medicine
Philipp Schuetz Department of Internal Medicine, Kantonsspital Aarau, Aarau, Switzerland; and University of Basel, Basel, Switzerland Internal Medicine

Consensus process

In the first step, the expert group reviewed the current evidence from previous trials on PCT-guided stewardship discussing the different algorithms that were previously used and the differences in PCT across clinical settings in regard to PCT cut-offs and emphasis on initiation or early stopping of antibiotics [10], [11], [12], [13]. There was particular emphasis on the Berlin algorithms and how these could be applied to Asia-Pacific countries considering the differences in patient populations, types of infections and differences in resources available for diagnostic tests [8], [14].

Experts also exchanged experiences in routine clinical practice where PCT use for differential diagnosis and prognostication still prevails over its use for antibiotic stewardship in most hospitals of the region. Also, the limitations of these approaches as well as the barriers for broader PCT implementation for antibiotic stewardship in these health care systems were discussed. All controversial issues were openly debated and the algorithms were further edited during several feedback rounds by incorporating adjustments until consensus was found. All delegates who attended the meeting then voted to: (1) agree, (2) disagree or (3) abstain, on the adaptations to the algorithm on the same day using a modified Delphi process [15].

Results

Overall, the expert group agreed that the existing evidence for PCT-guided antibiotic stewardship in patients with acute respiratory infections and sepsis is valid also for Asia-Pacific countries in regard to proposed PCT cut-offs, emphasis on diagnosis, prognosis and antibiotic stewardship, overruling criteria and adaptations to clinical settings (outpatients, emergency department, clinical wards and intensive care). The trial data have shown most promising results for PCT to guide the initiation of antibiotics in patients with bronchitis and COPD exacerbation, and to guide duration in patients with CAP [4], [8].

The group also noted an important lack of trials focusing on some specific patient populations important to Asia-Pacific countries, such as tropical diseases [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. Because of the lack of strong trial data currently limiting the clinical utility in these patients, there is need for adaptation of the proposed algorithms. Also, due to lower resource availabilities, not all critically ill patients may be treated in an ICU, and biomarker levels may be measured less frequently and particularly for the purpose of stopping the antibiotic treatment. The experts decided that two adapted algorithms, one for the critically ill and one for the non-critically ill patient population would be best to reduce complexity in clinical routine for optimal PCT use in Asia-Pacific countries (Figures 1 and 2).

Figure 1: PCT use in non-critically ill patients in Asia-Pacific countries.

Figure 1:

PCT use in non-critically ill patients in Asia-Pacific countries.

Figure 2: PCT use in critically ill patients in Asia-Pacific countries.

Figure 2:

PCT use in critically ill patients in Asia-Pacific countries.

Use of PCT-guided stewardship in critically ill and non-critically ill patients

Similar to the proposed algorithms from the Berlin conference, the group agreed that PCT levels should be put into the context of the clinical assessment in regard to severity of illness and probability of bacterial infection to make safe and efficient recommendations. To reduce complexity, however, we decided on only two algorithms, for non-critically ill (mild to moderate severity of disease) and critically ill (severe disease) patients. Again, in a first step, patients need to be stratified according to clinical criteria and based on the probability of bacterial infection (uncertainty vs. bacterial infection highly suspected). PCT should then be added to the assessment of patients with PCT cut-offs of <0.25 μg/L in non-critically ill patients, and <0.5 μg/L in critically ill patients indicating low likelihood of bacterial infection. While in non-critically ill patients and low probability of bacterial infection a low PCT level should advise physicians against the use of antibiotic, for critically ill patients empiric therapy is mandatory with retesting of PCT after 6–24 h to re-evaluate the need for antibiotic therapy. Thus, for critically ill patients, the main purpose of PCT is to discontinue antibiotics but not for decision regarding initiation. Further, for patients where empiric antibiotic therapy was started, serial testing of PCT levels is recommended to monitor the response to antibiotic therapy and control of infection. A drop in PCT from the peak by ≥80% and/or fall below the cut-off was taken as a strong indicator for resolution of illness, and earlier discontinuation of antibiotics is recommended when the patient is clinically stable.

Discussing the application of the algorithms in the context of the Asia-Pacific patient population, it was emphasized that for patients with clinical suspicion of tropical diseases such as malaria, Dengue fever or hemorrhagic fever, and other diseases with high prevalence in the region, such as tuberculosis or typhus, there is a lack of systematic PCT studies in general and of antibiotic stewardship studies in particular [16], [17], [18], [19], [20], [21], [22]. There are some studies suggesting that PCT may help to risk-stratify these patients and provide prognostic information, but more research is needed to understand the role of PCT in these clinical conditions before applying PCT-guided antibiotic stewardship to them. The group thus decided that, at this time point, these PCT algorithms cannot be used to guide any antibiotic decisions in these patients and management should be based on clinical grounds and international recommendations. This was reflected in the proposed modified algorithms.

For the outpatient and emergency department settings, an initial PCT value was found to be helpful in estimating the likelihood for bacterial infection and thus the need for antibiotic treatment – particularly for the low-risk and low-probability patient population (e.g. a patient with a bronchitis-type infection). A high-sensitive point-of-care device with a fast turn-around time would be helpful to enable rapid decision-making. Clinical trials have shown that for inpatient treatment in the ward and the ICU, measuring a baseline level within the first 24 h is helpful with repeated levels within 24–72 h depending on the clinical situation. Importantly, however, experts felt that – in case of resource limitations – measurement of PCT may be prioritized for patient populations and time points where antibiotic decision-making is directly influenced, thus at a time point where either a physician considers stopping antibiotic treatment (but needs reassurance) or where a patient is clinically deteriorating (and physicians need additional information about resolution of infection).

Barriers to the use of PCT in Asia-Pacific countries

During the meeting, we also discussed major barriers for the more widespread use of PCT in Asia-Pacific countries. It was discussed that in Asia-Pacific countries, both cultural and health care-related aspects play a role, but also some medical aspects are important. Culturally, many patients expect antibiotic treatment and a doctor’s decision to withhold antibiotic in a case with low probability of bacterial infection may be not accepted, particularly as patients may buy the drugs over the counter. Changing this mindset requires national educational programs addressed to the entire population. A lack of education and deeper understanding regarding PCT use for antibiotic stewardship also plays a role at the level of healthcare providers. Importantly, several studies have proven overall cost-savings of PCT-guided stewardship at the hospital level when considering expenses in the laboratory but lower costs for antibiotics at the pharmacy [5], [6]. This overall cost saving potential is often not understood at the level of hospital administration or health care authorities leading to hospitals and health insurances limiting the use in PCT to seemingly reduce costs for diagnostic tests. When local data on the clinical and health economic impact of PCT are available and are communicated to the respective functions, PCT can often better be implemented as part of the antibiotic stewardship program. Another implementation barrier relates to the fact that a majority of antimicrobial prescribing and PCT result interpretation are done by individuals who are not infection specialists. As the laboratory reports usually provide a reference cut-off value of 0.5 ng/mL for PCT test results, misinterpretation with resulting inappropriate antibiotics use is likely. From the medical standpoint, the biggest hurdle for wider implementation in Asia-Pacific countries is a lack of scientific data for tropical diseases (Table 2), which are highly prevalent in the region and require additional consideration when interpreting the PCT results in the clinical context.

Table 2:

Barriers to the implementation of PCT in Asia-Pacific countries.

Topic Comment References
Lack of evidence for some patient populations
 Tropical disease Few studies have looked at tropical diseases (e.g. malaria, dengue fever, rickettsia, typhoid); current data have been inconclusive on whether PCT improves stewardship, PCT may provide prognostic information [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]
 Tuberculosis Few studies on tuberculosis, PCT remains low in patients with tuberculosis limited to the lung but increases in severe cases with systemic infection [27], [28]
 Hemorrhagic fever syndrome Few studies have looked at hemorrhagic fever syndromes, PCT has been reported to be increased in severe cases despite lack of bacterial infection, PCT seems to provide prognostic information [16], [17]
 Lack of research in Asia-Pacific countries There has been little research done in Asia-Pacific countries, particularly regarding interventional research; thus unclear how PCT impacts antibiotic use in clinical routine in the very different countries and health care environments in this region [29], [30]
Resources
 Cost to the hospital Added costs for PCT testing are often only compared to the very low antibiotic costs in some countries, without considering other potential cost savings like from shorter LOS, reduced adverse effects like C. diff. etc.

Also, fixed budget for the lab in some hospitals limit broader PCT implementation as costs and savings occur in different departments.

PCT testing often limited to —one to three tests per patient
[5], [6]
 Limitation for measurement by government Some countries restrict PCT reimbursement to certain indications and time points [31]
 Lack of high-quality (sensitive) POC technology For primary care and smaller emergency care institutions, POC devices may help to implement a PCT strategy

Currently available POC tests often have insufficient technical performance and are not validated to be used for antibiotic stewardship
[32]
Educational support
 Educational material on PCT Many physicians have no formal education for the use of PCT and educational material is scarce [33]
 General ASP education and resources Lack of well-established infectious disease clinical training for hospital pharmacists, and the paucity of infectious disease specialists to oversee ASPs [34]
Cultural differences
 Self-medication of patients with antibiotics In some countries, over-the-counter use of antibiotics may overrule physicians [26]
 Patient expectation for antibiotics Patients are demanding antibiotics for some conditions even if no bacterial infection is evident. Education of patients and relatives may be needed to make them understand the problems of antibiotic overuse

Discussion

Recently, it has been recognized that one of the biggest risks to human health comes in the form of antibiotic-resistant bacteria. Increasing emergence of multidrug-resistant pathogens is considered to be one of the most urgent threats to global health [35], [36]. This is particularly true for Asia-Pacific countries where antibiotic overuse has been a major problem, with multidrug-resistant pathogens on the rise [31], [37]. While several factors contribute to the problem of multidrug resistance including antibiotic usage in animals, self-medication of patients and poor hygiene standards, overuse of antibiotics in the in-hospital settings has been recognized as a main driver [36]. Accordingly, with support of the WHO, national antibiotic stewardship programs have been initiated over the last decade to facilitate a judicious use of antibiotics and reduction of antibiotic resistance rates in the Asian countries [34], [38], [39].

Herein, the use of a biomarker-guided treatment protocol aiming to provide the shortest possible duration of antibiotics only to patients truly in need of these drugs is one promising approach [29], [30]. Therefore, some of these antibiotic stewardship programs also included the integration of PCT to support clinical decision-making on the initiation or stop of antibiotic treatment in the individual patient [40]. Where consequently applied over a longer time period, the more judicious use of antibiotics led not only to reduced antibiotic exposure of patients, but was also accompanied by lower side effects, shorter length of stay and cost savings [4], [6], [41].

This, however, is currently still limited to certain segments in the hospital sector in Asia-Pacific countries. Besides health care system-related hurdles, there are also acceptance barriers to overcome. Thus, despite solid evidence from interventional trials including more than 10,000 patients [3], [4], there is still much heterogeneity regarding the optimal integration of PCT into clinical workflow. To improve PCT use in clinical practice, three algorithms for PCT use in mild, moderate and severe infections have been proposed during the Berlin conference [8]. These algorithms, however, may not unconditionally be transposed to other health care settings, such as Asia-Pacific countries due to differences in patient populations, types of infections, health care structure, resource use and cultural differences. To close this gap, we have now – during an Asia-Pacific experts meeting – modified the algorithms of the Berlin consensus and propose two algorithms for clinical practice that consider the specific regional situation and needs (Figures 1 and 2).

Importantly, patients presenting with fever in Asia-Pacific countries may have tropical diseases, tuberculosis, hemorrhagic fever syndrome and other conditions where we currently have insufficient data on optimal use of PCT [16], [17], [18], [19], [20], [21], [22], [27], [28]. In our adapted algorithm, we therefore excluded such patients based on clinical suspicion from the PCT stewardship algorithm. Although it may be difficult to understand if a patient has tropical or non-tropical illness, after in-depth examination and history taking a physician may come up with a probability which directs him to further treat the patient. It is important that future studies also look at this important and large patient population regarding optimal use of PCT.

Importantly, also for the Asia-Pacific population, the proposed algorithms need to be used only in conjunction with a thorough clinical examination and caution should be used in patients with immunosuppression, autoimmune diseases, cystic fibrosis, pancreatitis, trauma, pregnancy and high-volume transfusion [42], [43], [44], [45]. As there are higher prevalence of chronic liver disease and chronic kidney disease in Asia-Pacific countries, interpretation of PCT results in these patient populations may warrant caution [46]. Evidence shows that PCT tests are sufficiently accurate in differentiating bacterial infection from other causes of febrile illness in patients with liver cirrhosis [47]. However, PCT in patients with chronic kidney disease may lack sensitivity [48]. In Asia-Pacific countries, patients often receive hemodialysis rather than peritoneal dialysis. There is a lack of data on the accuracy of PCT in patients undergoing hemodialysis [48]. Thus, the results of PCT in this patient population needs to be interpreted in the context of clinical findings. Also, the algorithm should be used in acute infections, but not in patients with chronic infections (e.g. abscess, osteomyelitis, endocarditis), and pretreatment with antibiotics may effect PCT levels [49], [50]. PCT measurements should be done with high-sensitive PCT assays with sufficient precision in the relevant cut-off levels [51], [52]. We recommend against the use of off-label assays with low quality because false-negative and false-positive PCT levels may affect treatment safety of patients [32].

Conclusions and outlook

Using a biomarker, such as PCT, may help to personalize treatment decisions, which translates into lower antibiotic exposure and better clinical outcomes through the decrease in antibiotic-associated side effects [4], [13]. PCT should always be implemented in antibiotic stewardship protocols which have shown to also have favorable effects on outcomes in patients with sepsis, and current sepsis guidelines recommend to implement strategies to reduce antibiotic exposure [53], [54], [55]. Knowledge of PCT kinetics also provides prognostic information which may influence decisions to obtain further samples for diagnostic testing or pursue other therapeutic strategies and the timing of patient discharge [56]. The herein proposed modified algorithm should enable easier clinical adoption in Asia-Pacific countries where differences exist. Yet, experience with PCT and education about its correct use remain essential prerequisites to optimize PCT-guided treatment [57]. A clinical decision support system or including several decision cut-offs of PCT in the laboratory reports may lower the barrier of PCT-guided treatment for non-experts [58]. More clinical trials and a broader knowledge of real-world data in these countries would be of interest to assess clinical and health economic impact in the different countries. Additional research should consider both less-understood indications or patient groups as well as patients in primary care and/or nursing homes where a major proportion of antibiotics are prescribed. Also, PCT cut-offs may need to be adapted to specific diseases and differences in patient populations seen in Asia-Pacific countries. Thus, we encourage further research efforts for this specific region for optimal patient care and use of PCT.

In conclusion, integration of PCT into algorithms for antibiotic stewardship has the potential to improve the diagnostic and therapeutic management of patients presenting with respiratory illnesses and sepsis, and holds great promise to mitigate the global bacterial resistance crisis and move from a default position of standardized care to more personalized treatment decisions. There is need for adaptation of existing PCT algorithms for Asia-Pacific countries and for further research.

    Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

    Research funding: The entire project received an unrestricted grant by Thermo Fisher Scientific, Funder Id: http://dx.doi.org/10.13039/100011033. P. Schuetz reported receiving support from BRAHMS GmbH and Biomérieux to attend meetings and fulfilling speaking engagements.

    Employment or leadership: None declared.

    Honorarium: None declared.

    Competing interests: 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.

References

1. Sager R, Kutz A, Mueller B, Schuetz P. Procalcitonin-guided diagnosis and antibiotic stewardship revisited. BMC Med 2017;15:15. Search in Google Scholar

2. Muller B, Schuetz P, Trampuz A. Circulating biomarkers as surrogates for bloodstream infections. Int J Antimicrob Agents 2007;30(Suppl 1):S16–23. Search in Google Scholar

3. Schuetz P, Wirz Y, Sager R, Christ-Crain M, Stolz D, Tamm M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev 2017;10:CD007498. Search in Google Scholar

4. Schuetz P, Wirz Y, Sager R, Christ-Crain M, Stolz D, Tamm M, et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis. Lancet Infect Dis 2018;18:95–107. Search in Google Scholar

5. Schuetz P, Balk R, Briel M, Kutz A, Christ-Crain M, Stolz D, et al. Economic evaluation of procalcitonin-guided antibiotic therapy in acute respiratory infections: a US health system perspective. Clin Chem Lab Med 2015;534:583–92. Search in Google Scholar

6. Stojanovic I, Schneider JE, Wei L, Hong Z, Keane C, Schuetz P. Economic evaluation of procalcitonin-guided antibiotic therapy in acute respiratory infections: a Chinese hospital system perspective. Clin Chem Lab Med 2017;55:561–70. Search in Google Scholar

7. Schuetz P, Bolliger R, Merker M, Christ-Crain M, Stolz D, Tamm M, et al. Procalcitonin-guided antibiotic therapy algorithms for different types of acute respiratory infections based on previous trials. Expert Rev Anti Infect Ther 2018;16:555–64. Search in Google Scholar

8. Schuetz P, Beishuizen A, Broyles M, Ferrer R, Gavazzi G, Gluck EH, et al. Procalcitonin (PCT)-guided antibiotic stewardship: an international experts consensus on optimized clinical use. Clin Chem Lab Med 2019;57:1308–18. Search in Google Scholar

9. Kuo YT, Liou JM, El-Omar EM, Wu JY, Leow AH, Goh KL, et al. Primary antibiotic resistance in Helicobacter pylori in the Asia-Pacific region: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2017;2:707–15. Search in Google Scholar

10. Briel M, Schuetz P, Mueller B, Young J, Schild U, Nusbaumer C, et al. Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care. Arch Intern Med 2008;168:2000–7; discussion 7–8. Search in Google Scholar

11. Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. J Am Med Assoc 2009;302:1059–66. Search in Google Scholar

12. Bouadma L, Luyt CE, Tubach F, Cracco C, Alvarez A, Schwebel C, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010;375:463–74. Search in Google Scholar

13. de Jong E, van Oers JA, Beishuizen A, Vos P, Vermeijden WJ, Haas LE, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis 2016;16:819–27. Search in Google Scholar

14. Schuetz P, Koller M, Christ-Crain M, Steyerberg E, Stolz D, Muller C, et al. Predicting mortality with pneumonia severity scores: importance of model recalibration to local settings. Epidemiol Infect 2008;136:1628–37. Search in Google Scholar

15. Memtsoudis SG, Hargett M, Russell LA, Parvizi J, Cats-Baril WL, Stundner O, et al. Consensus statement from the consensus conference on bilateral total knee arthroplasty group. Clin Orthop Relat Res 2013;471:2649–57. Search in Google Scholar

16. Wangrangsimakul T, Althaus T, Mukaka M, Kantipong P, Wuthiekanun V, Chierakul W, et al. Causes of acute undifferentiated fever and the utility of biomarkers in Chiangrai, northern Thailand. PLoS Negl Trop Dis 2018;12:e0006477. Search in Google Scholar

17. Trunfio M, Savoldi A, Vigano O, d’Arminio Monforte A. Bacterial coinfections in dengue virus disease: what we know and what is still obscure about an emerging concern. Infection 2017;45:1–10. Search in Google Scholar

18. Naderi M, Hashemi M, Kouhpayeh H, Ahmadi R. The status of serum procalcitonin in pulmonary tuberculosis and nontuberculosis pulmonary disease. J Pak Med Assoc 2009;59:647–8. Search in Google Scholar

19. Chen CM, Chan KS, Chao HC, Lai CC. Diagnostic performance of procalcitonin for bacteremia in patients with severe dengue infection in the intensive care unit. J Infect 2016;73:93–5. Search in Google Scholar

20. Lubell Y, Blacksell SD, Dunachie S, Tanganuchitcharnchai A, Althaus T, Watthanaworawit W, et al. Performance of C-reactive protein and procalcitonin to distinguish viral from bacterial and malarial causes of fever in Southeast Asia. BMC Infect Dis 2015;15:511. Search in Google Scholar

21. Righi E, Merelli M, Arzese A, Siega PD, Scarparo C, Bassetti M. Determination of PCT on admission is a useful tool for the assessment of disease severity in travelers with imported Plasmodium falciparum malaria. Acta Parasitol 2016;61:412–8. Search in Google Scholar

22. Akech SO, Kinuthia DW, Macharia W. Serum procalcitonin levels in children with clinical syndromes for targeting antibiotic use at an emergency Department of a Kenyan Hospital. J Trop Pediatr 2019. Search in Google Scholar

23. Thanachartwet V, Desakorn V, Sahassananda D, Jittmittraphap A, Oer-Areemitr N, Osothsomboon S, et al. Serum procalcitonin and peripheral venous lactate for predicting dengue shock and/or organ failure: a prospective observational study. PLoS Negl Trop Dis 2016;10:e0004961. Search in Google Scholar

24. Peter JV, Karthik G, Ramakrishna K, Griffith MF, Jude Prakash JA, Job V, et al. Elevated procalcitonin is associated with increased mortality in patients with scrub typhus infection needing intensive care admission. Ind J Crit Care Med 2013;17:174–7. Search in Google Scholar

25. Manegold C, Schmiedel S, Chiwakata CB, Dietrich M. Procalcitonin serum levels in tertian malaria. Malar J 2003;2:34. Search in Google Scholar

26. Apisarnthanarak A, Tunpornchai J, Tanawitt K, Mundy LM. Nonjudicious dispensing of antibiotics by drug stores in Pratumthani, Thailand. Infect Control Hosp Epidemiol 2008;29:572–5. Search in Google Scholar

27. Kim J, Kim SE, Park BS, Shin KJ, Ha SY, Park J, et al. Procalcitonin as a diagnostic and prognostic factor for tuberculosis meningitis. J Clin Neurol 2016;12:332–9. Search in Google Scholar

28. Ugajin M, Miwa S, Shirai M, Ohba H, Eifuku T, Nakamura H, et al. Usefulness of serum procalcitonin levels in pulmonary tuberculosis. Eur Respir J 2011;37:371–5. Search in Google Scholar

29. Cai Y, Ee J, Liew YX, Lee W, Chlebicki MP, Goh YC, et al. A procalcitonin-based guideline promotes shorter duration of antibiotic use safely in acute pancreatitis. J Infect 2014;69:412–5. Search in Google Scholar

30. Loo LW, Liew YX, Lee W, Lee LW, Chlebicki P, Kwa AL. Discontinuation of antibiotic therapy within 24 hours of treatment initiation for patients with no clinical evidence of bacterial infection: a 5-year safety and outcome study from Singapore General Hospital Antimicrobial Stewardship Program. Int J Antimicrob Agents 2019;53:606–11. Search in Google Scholar

31. Apisarnthanarak A, Kwa AL, Chiu CH, Kumar S, Thu LT, Tan BH, et al. Antimicrobial stewardship for acute-care hospitals: an Asian perspective. Infect Control Hosp Epidemiol 2018;39:1237–45. Search in Google Scholar

32. Lippi G, Salvagno GL, Gelati M, Pucci M, Lo Cascio C, Demonte D, et al. Two-center comparison of 10 fully-automated commercial procalcitonin (PCT) immunoassays. Clin Chem Lab Med 2019;58:77–84. Search in Google Scholar

33. Neeser O, Branche A, Mueller B, Schuetz P. How to: implement procalcitonin testing in my practice. Clin Microbiol Infect 2019;25:1226–30. Search in Google Scholar

34. Honda H, Ohmagari N, Tokuda Y, Mattar C, Warren DK. Antimicrobial stewardship in inpatient settings in the Asia Pacific region: a systematic review and meta-analysis. Clin Infect Dis 2017;64(suppl_2):S119–26. Search in Google Scholar

35. Jee Y, Carlson J, Rafai E, Musonda K, Huong TT, Daza P, et al. Antimicrobial resistance: a threat to global health. Lancet Infect Dis 2018;18:939–40. Search in Google Scholar

36. Spellberg B, Bartlett JG, Gilbert DN. The future of antibiotics and resistance. N Engl J Med 2013;368:299–302. Search in Google Scholar

37. Saito N, Takamura N, Retuerma GP, Frayco CH, Solano PS, Ubas CD, et al. Frequent community use of antibiotics among a low-economic status population in Manila, the Philippines: a prospective assessment using a urine antibiotic bioassay. Am J Trop Med Hyg 2018;98:1512–9. Search in Google Scholar

38. Lee CF, Cowling BJ, Feng S, Aso H, Wu P, Fukuda K, et al. Impact of antibiotic stewardship programmes in Asia: a systematic review and meta-analysis. J Antimicrob Chemother 2018;73:844–51. Search in Google Scholar

39. Parathon H, Kuntaman K, Widiastoety TH, Muliawan BT, Karuniawati A, Qibtiyah M, et al. Progress towards antimicrobial resistance containment and control in Indonesia. Br Med J 2017;358:j3808. Search in Google Scholar

40. Liew YX, Chlebicki MP, Lee W, Hsu LY, Kwa AL. Use of procalcitonin (PCT) to guide discontinuation of antibiotic use in an unspecified sepsis is an antimicrobial stewardship program (ASP). Eur J Clin Microbiol Infect Dis 2011;30:853–5. Search in Google Scholar

41. Ito A, Ishida T, Tokumasu H, Washio Y, Yamazaki A, Ito Y, et al. Impact of procalcitonin-guided therapy for hospitalized community-acquired pneumonia on reducing antibiotic consumption and costs in Japan. J Infect Chemother 2017;23:142–7. Search in Google Scholar

42. Wu JY, Lee SH, Shen CJ, Hsieh YC, Yo PH, Cheng HY, et al. Use of serum procalcitonin to detect bacterial infection in patients with autoimmune diseases: a systematic review and meta-analysis. Arthritis Rheum 2012;64:3034–42. Search in Google Scholar

43. Wu CW, Wu JY, Chen CK, Huang SL, Hsu SC, Lee MT, et al. Does procalcitonin, C-reactive protein, or interleukin-6 test have a role in the diagnosis of severe infection in patients with febrile neutropenia? A systematic review and meta-analysis. Support Care Cancer 2015;23:2863–72. Search in Google Scholar

44. Schuetz P, Raad I, Amin DN. Using procalcitonin-guided algorithms to improve antimicrobial therapy in ICU patients with respiratory infections and sepsis. Curr Opin Crit Care 2013;19:453–60. Search in Google Scholar

45. Schuetz P, Kutz A, Grolimund E, Haubitz S, Demann D, Vogeli A, et al. Excluding infection through procalcitonin testing improves outcomes of congestive heart failure patients presenting with acute respiratory symptoms: results from the randomized ProHOSP trial. Int J Cardiol 2014;175:464–72. Search in Google Scholar

46. Prasad N, Jha V. Hemodialysis in Asia. Kidney Dis (Basel) 2015;1:165–77. Search in Google Scholar

47. Lin KH, Wang FL, Wu MS, Jiang BY, Kao WL, Chao HY, et al. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection in patients with liver cirrhosis: a systematic review and meta-analysis. Diagn Microbiol Infect Dis 2014;80:72–8. Search in Google Scholar

48. Lu XL, Xiao ZH, Yang MY, Zhu YM. Diagnostic value of serum procalcitonin in patients with chronic renal insufficiency: a systematic review and meta-analysis. Nephrol Dial Transplant 2013;28:122–9. Search in Google Scholar

49. Tessmer A, Welte T, Martus P, Schnoor M, Marre R, Suttorp N. Impact of intravenous {beta}-lactam/macrolide versus {beta}-lactam monotherapy on mortality in hospitalized patients with community-acquired pneumonia. J Antimicrob Chemother 2009;63:1025–33. Search in Google Scholar

50. Yu CW, Juan LI, Hsu SC, Chen CK, Wu CW, Lee CC, et al. Role of procalcitonin in the diagnosis of infective endocarditis: a meta-analysis. Am J Emerg Med 2013;31:935–41. Search in Google Scholar

51. Bartoletti M, Antonelli M, Bruno Blasi FA, Casagranda I, Chieregato A, Fumagalli R, et al. Procalcitonin-guided antibiotic therapy: an expert consensus. Clin Chem Lab Med 2018;56:1223–9. Search in Google Scholar

52. Schuetz P, Bretscher C, Bernasconi L, Mueller B. Overview of procalcitonin assays and procalcitonin-guided protocols for the management of patients with infections and sepsis. Expert Rev Mol Diagn 2017;17:593–601. Search in Google Scholar

53. Garnacho-Montero J, Gutierrez-Pizarraya A, Escoresca-Ortega A, Corcia-Palomo Y, Fernandez-Delgado E, Herrera-Melero I, et al. De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Int Care Med 2014;40:32–40. Search in Google Scholar

54. Schuetz P, Mueller B. Biomarker-guided de-escalation of empirical therapy is associated with lower risk for adverse outcomes. Int Care Med 2014;40:141. Search in Google Scholar

55. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Int Care Med 2017;43:304–77. Search in Google Scholar

56. Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med 2008;177:498–505. Search in Google Scholar

57. Broyles MR. Impact of procalcitonin-guided antibiotic management on antibiotic exposure and outcomes: real-world evidence. Open Forum Infect Dis 2017;4:ofx213. Search in Google Scholar

58. Rawson TM, Moore LSP, Hernandez B, Charani E, Castro-Sanchez E, Herrero P, et al. A systematic review of clinical decision support systems for antimicrobial management: are we failing to investigate these interventions appropriately? Clin Microbiol Infect 2017;23:524–32. Search in Google Scholar

Received: 2019-10-30
Accepted: 2019-12-03
Published Online: 2020-01-13
Published in Print: 2020-11-26

©2020 Philipp Schuetz et al., published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.