Introduction
Empirical antibiotics remain essential when sepsis or another serious bacterial infection is suspected, because delaying effective treatment may expose patients to rapid deterioration and preventable mortality.1 However, diagnostic uncertainty also contributes to the unnecessary continuation of broad-spectrum therapy after the initial clinical risk has declined. Procalcitonin has therefore attracted considerable interest as a biomarker for antibiotic stewardship. In critically ill patients, randomized trials and meta-analyses have shown that serial procalcitonin-guided strategies can support earlier antibiotic discontinuation.2–4 A phase-specific meta-analysis further demonstrated that the evidence was more favorable for cessation strategies than for initiation strategies.5 This distinction is clinically important because sepsis management is time-sensitive, microbiological confirmation is frequently unavailable, and a meta-analysis of 22,655 patients with sepsis or septic shock found that only 40.1% had culture-positive infection.6 Clinicians are therefore understandably reluctant to withhold empirical antibiotics at the point of initial presentation.1,7
The clinical role of procalcitonin has evolved substantially over the past three decades. Early studies demonstrated markedly elevated serum procalcitonin concentrations in severe bacterial infections and septic conditions, with concentrations appearing to increase with the severity of microbial invasion.8 Randomized trials subsequently evaluated PCT as a tool to guide antibiotic decision-making in lower respiratory tract infections,9 and this approach was later extended to critically ill patients.10 Further randomized evidence evaluated PCT-guided antibiotic discontinuation after empirical therapy had begun, using changes in PCT concentration to support decisions on earlier treatment cessation.11 Expert consensus subsequently incorporated PCT into structured antimicrobial-stewardship algorithms and emphasized interpreting PCT alongside clinical severity and the probability of bacterial infection rather than as an isolated prescribing rule.12 More recent meta-analytic evidence indicates that the effects of PCT-guided strategies differ across the antibiotic-treatment pathway, including initiation, cessation, and mixed strategies.5 Consensus guidance also emphasizes integration with clinical assessment, stewardship algorithms, education, and feedback.12 Selected key milestones in this evolution are summarized in Table 1. Table 1Key Milestones in the Evolution of Procalcitonin-Guided Antibiotic StewardshipYearMilestoneContribution to PCT Stewardship1993Early clinical PCT studyDemonstrated marked PCT elevation in severe bacterial infection and septic conditions82004Randomized LRTI trialExtended PCT into antibiotic decision-making in respiratory infection92010PRORATAEvaluated PCT-guided antibiotic decisions in critically ill patients102016de Jong ICU trialStrengthened evidence for serial PCT-guided antibiotic discontinuation112018Phase-specific meta-analysisShowed different effects for initiation versus cessation strategies52019International expert consensusPositioned PCT within structured stewardship and clinical assessment122023AACC guidanceConsolidated contemporary clinical indications and limitations132025ADAPT-SepsisConfirmed a modest reduction in antibiotic duration with daily PCT-guided review4Notes: Selected milestones are presented to illustrate the evolution of PCT from an infection-related biomarker to an antibiotic-stewardship tool; this is not intended as an exhaustive chronology.Abbreviations: ICU, intensive care unit; LRTI, lower respiratory tract infection; PCT, procalcitonin.
Consequently, procalcitonin is better positioned as a stewardship checkpoint than as an antibiotic gatekeeper. Contemporary reviews, expert consensus statements, and sepsis-focused analyses indicate that procalcitonin levels provide greater value in decisions concerning antibiotic duration than in determining whether treatment should be initiated, particularly when the pretest probability of bacterial infection is high or the patient is hemodynamically unstable.5,7 In clinically stable patients with lower-risk respiratory syndromes and a lower probability of bacterial infection, an admission procalcitonin result may contribute to reducing unnecessary antibiotic initiation. Nevertheless, evidence from these populations cannot be transferred uncritically to patients with suspected sepsis or critical illness, in whom a falsely low or prematurely obtained result could encourage inappropriate withholding of necessary treatment.7,14
This distinction is particularly relevant in resource-limited hospitals. Procalcitonin testing carries financial and operational demands, including assay availability, timely reporting, repeated measurements, and clinicians who are prepared to act on the results. Its availability alone does not ensure improved prescribing; meaningful stewardship effects depend on whether testing is integrated into structured clinical reassessment and supported by education, protocols, and feedback.12,15 In resource-constrained settings, including Somalia as an illustrative context, the central question is not simply whether procalcitonin is clinically useful, but where along the antibiotic treatment pathway its value is sufficient to justify limited laboratory and stewardship resources.
Existing evidence suggests that its greatest contribution occurs after initial stabilization, when serial biomarker changes can be interpreted alongside clinical trajectory, microbiological findings, source control adequacy, and emerging alternative diagnoses.1,7 Accordingly, This Perspective examines the different roles of procalcitonin from antibiotic initiation to discontinuation and considers how its use can be translated responsibly into resource-limited hospital practice.
From Antibiotic Initiation to Discontinuation: Different Decisions, Different Roles
The evidence supporting procalcitonin-guided antibiotic initiation and discontinuation is asymmetrical. Meta-analyses restricted to critically ill adults indicate that procalcitonin-guided discontinuation can reduce antibiotic exposure by approximately one to two days, whereas initiation-focused strategies have produced little or no consistent benefit in mortality or total antibiotic exposure within intensive care populations.5 A 2026 rapid systematic review of 19 trials evaluating procalcitonin-guided discontinuation among critically ill patients with sepsis reported an average reduction of approximately 2.0 antibiotic days without evidence of increased mortality.16 Similarly, a 2024 network meta-analysis found that procalcitonin-guided discontinuation shortened antibiotic treatment by 1.89 days. Greater effects were observed in procalcitonin protocols combining an absolute threshold of 0.5 μg/L with an 80% decline from peak concentration; importantly, little benefit was observed when monitoring intervals were too infrequent to capture meaningful biomarker kinetics.17
The evidence for discontinuation is strongest when procalcitonin is measured serially and interpreted alongside clinical stability. Reviews and consensus documents consistently emphasize changes over time rather than isolated values, because declining concentrations may support the resolution of bacterial infection in pneumonia and sepsis, while a single measurement cannot adequately account for disease timing, inadequate source control, or non-infectious inflammatory states.14,18 Successful ICU discontinuation algorithms have commonly recommended considering antibiotic cessation when procalcitonin falls to 0.5 μg/L or lower, or decreases by at least 80% from its peak value, generally after several days of treatment and only when the patient demonstrates clear clinical improvement.13,17 These thresholds should therefore be understood as decision-support criteria rather than automatic stopping rules.
Recent large, randomized trials have refined rather than challenged this interpretation. ADAPT-Sepsis, conducted across 41 intensive care units in the United Kingdom, found that daily procalcitonin-guided review reduced antibiotic duration by 0.88 days compared with standard care and met the prespecified noninferiority criterion for 28-day mortality, although mortality was numerically higher in the procalcitonin group than in the standard-care group (20.9% versus 19.4%; absolute difference, 1.57 percentage points; 95% CI, −2.18 to 5.32). C-reactive protein-guided care did not significantly shorten antibiotic treatment.4 Although this reduction was smaller than that reported in several earlier trials, the difference may reflect shorter contemporary treatment courses and stronger baseline stewardship practices; nevertheless, the study continues to support procalcitonin’s greatest value during reassessment and discontinuation rather than at treatment initiation.19 A similar pattern emerged in a 2024 non-ICU pneumonia trial, in which both CRP- and procalcitonin-guided algorithms shortened antibiotic treatment, although the study was not powered to establish the safety of shorter courses and the reduction was numerically greater with CRP.20
In contrast, procalcitonin should not independently delay or prevent initial antibiotic therapy in suspected sepsis. Sepsis-focused reviews emphasize that empirical antibiotics remain necessary when the clinical probability of bacterial infection is high or the patient is physiologically unstable, irrespective of an initially low biomarker value.1,7 ICU stewardship reviews similarly conclude that biomarkers have limited value for reducing initial antimicrobial treatment outside selected non-severe respiratory infections because they do not reliably distinguish infectious from non-infectious inflammatory syndromes in critically ill patients.21 In the PRORATA trial, physicians administered antibiotics at inclusion to 65 patients despite a procalcitonin concentration below 0.5 μg/L, whereas antibiotics were withheld in only 28 patients with values below this threshold. The between-group difference in the proportion receiving antibiotics was consequently only 5.6% on day 1, illustrating the limited influence of procalcitonin on initial prescribing when clinicians suspected serious infection.10 ProACT likewise found that providing clinicians with real-time procalcitonin results and interpretive guidance for suspected lower respiratory tract infection did not reduce total antibiotic-days compared with usual care across 14 hospitals in the United States.22
The difference between initiation and discontinuation reflects fundamentally different clinical risks. Delaying effective treatment in sepsis can result in rapid deterioration and preventable harm,1 whereas stopping antibiotics somewhat earlier after stabilization is a more controlled decision that can be assessed against microbiological results, imaging findings, adequacy of source control, organ recovery, and the patient’s overall clinical trajectory.4,17 Procalcitonin-guided stewardship is therefore most credible when it supports the second decision, namely, whether empirical treatment can now be safely narrowed or stopped, rather than attempting to make the first decision in isolation. The stage-specific role of procalcitonin across the antibiotic treatment pathway is summarized in Table 2.
Table 2Stage-Specific Role of Procalcitonin Across the Antibiotic Treatment PathwayAntibiotic StageAppropriate Role of ProcalcitoninEvidence that Must Accompany PCTRecommended ActionMain CautionInitial presentationSupport diagnostic assessment but not independently determine initiation1,7,21Clinical severity, suspected source, organ dysfunction, cultures and imaging1,7Start empirical antibiotics promptly when sepsis probability is high1,7A low early PCT cannot safely exclude bacterial infection7,13Early reassessment, 24–72 hoursInterpret serial change rather than one isolated result12,13,17Clinical trajectory, culture results, imaging, organ recovery and source control12,13Continue, narrow, switch or reconsider antibiotics12,13Delayed or single testing may provide little stewardship value17,23De-escalationSupport narrowing or stopping unnecessary combination therapy12,13Microbiological findings, susceptibility results and clinical improvement12,13Reduce spectrum where appropriate12,13PCT does not identify the organism or antimicrobial susceptibility13DiscontinuationSupport shorter treatment when PCT is low or substantially declining4,11,13,17Clinical stability, adequate source control and infection-specific treatment requirements12,13Consider earlier discontinuation4,11,17Thresholds are decision-support criteria, not automatic stopping rules12,13Discordant or special situationsPrompt further clinical reassessment13,24,25Timing of testing, renal dysfunction, trauma, surgery, immunosuppression and infection type13,24,25Investigate alternative diagnoses, complications or inadequate source control13,24Avoid routine PCT-guided stopping in infections requiring prolonged therapy10,11,13Notes: PCT should be interpreted alongside clinical assessment, microbiological findings, imaging, source-control evaluation, and infection-specific treatment recommendations. Thresholds and serial changes should support, rather than independently determine, antibiotic initiation, de-escalation, or discontinuation.Abbreviation: PCT, procalcitonin.
Clinical Limitations and the Risk of Biomarker-Led Prescribing
Procalcitonin is not a stand-alone diagnostic test, and biomarker-led prescribing becomes unsafe when this is overlooked. Multiple reviews note suboptimal sensitivity and specificity, especially outside respiratory infection, and emphasize that procalcitonin must be interpreted in its clinical context rather than treated as a binary rule-out test.7,13 Localized infection can produce falsely low values, particularly when infection remains compartmentalized, as in empyema or other poorly disseminated processes; early sampling may also be misleading because procalcitonin rises several hours after infection onset.13,24
Conversely, non-infectious inflammatory states can elevate procalcitonin levels and erode specificity. Reviews have identified major surgery, severe trauma, shock, and other systemic inflammatory conditions as situations where interpretation becomes difficult, especially if clinicians rely on a single measurement instead of the trajectory.13,24 Renal dysfunction is another important challenge because baseline procalcitonin concentrations may be elevated, while renal replacement therapy can further alter measured values and reduce the reliability of standard cutoffs. Interpretation should therefore emphasize clinical context and serial trends rather than a fixed universal threshold.13,26
Immunosuppressed populations remain an evidence gap. Regional expert consensus recommendations from Southeast Asia and India note that further research is needed in transplant recipients and cancer patients with febrile neutropenia.25 The recent Pro-Can trial in critically ill cancer patients with sepsis found no reduction in time to antibiotic cessation despite daily testing, illustrating that efficacy in mainstream ICU populations does not guarantee the same value in high-risk immunocompromised subgroups.27 In that study, clinicians were explicitly allowed to override the algorithm, underscoring how competing concerns about host defense, atypical infection, and prolonged treatment needs can dilute biomarker impact.27
Infections that intrinsically require prolonged therapy are another boundary condition. Earlier ICU discontinuation trials often excluded infections or organisms requiring prolonged courses, and this exclusion remains conceptually appropriate because the biomarker cannot substitute for syndrome-specific standards, deep-focus eradication, or source control adequacy.10,11 A falling procalcitonin level does not justify truncating therapy for endocarditis, osteomyelitis, undrained abscesses, device infection, or other settings where treatment duration is driven by microbiology and anatomy more than systemic inflammatory resolution. The same caution applies when source control has not been achieved, because persistent but partially treated infection may coexist with biomarker decline.13,24
Safety signals are also not perfectly uniform. Although several meta-analyses report lower mortality with discontinuation strategies, certainty is limited by open-label designs, incomplete adherence, heterogeneous algorithms, and inconsistent background stewardship.3 One 2023 meta-analysis found reduced antibiotic duration and lower 28-day mortality but also higher recurrent infection odds, reminding clinicians that benefits are not cost-free and recurrence deserves closer study.28 Other analyses found no clear mortality advantage overall or only in less severely ill subgroups.29 Overall, procalcitonin should be interpreted as supportive evidence whose reliability varies according to timing, clinical context, host factors, and infection type.
Translating Procalcitonin-Guided Stewardship to Resource-Limited Hospitals
Whether procalcitonin improves antibiotic stewardship in resource-limited hospitals depends not only on its clinical efficacy but also on whether it can be implemented reliably. Stewardship interventions in low- and middle-income countries remain heterogeneous, frequently carry moderate or high risks of bias, and include relatively little evidence from low-income settings, limiting direct generalization across health systems.30 Nevertheless, procalcitonin-guided treatment was the most frequently evaluated structural intervention among the randomized trials included in that review and was associated with lower antibiotic use, indicating that biomarker-supported stewardship may be feasible in selected middle-income hospital settings.30
Direct evidence from resource-limited settings remains limited but is emerging. A systematic review of hospital antimicrobial stewardship interventions in low- and middle-income countries identified PCT-guided treatment among the most frequently evaluated structural interventions, although the underlying studies were heterogeneous and unevenly distributed across settings.30 Studies from Bangladesh, South Africa, and India have also evaluated PCT-guided de-escalation or discontinuation in patients with sepsis or critical illness.31–33 These studies provide more directly relevant evidence for resource-constrained hospitals, but differences in study design, patient populations, and health system context limit broad generalization across resource-limited settings. The clinical and geographical context of this evidence is summarized in Table 3.
Table 3Clinical and Geographical Context of Procalcitonin-Guided Antibiotic Stewardship and Its Relevance to Resource-Limited HospitalsGeographical SettingClinical ContextMain Evidence PatternRelevance to Resource-Limited HospitalsEurope/United KingdomICU and sepsisMajor randomized trials support PCT-guided reassessment and shorter antibiotic duration, particularly during discontinuation.4,10,11Provides the main efficacy foundation, but evidence comes largely from well-resourced critical-care systems.United StatesLower respiratory tract infection and hospital stewardshipPCT guidance has not consistently reduced antibiotic exposure in routine practice.22,34Shows that PCT availability alone may not change prescribing without effective clinical integration.LMICs overallHospital antimicrobial stewardshipPCT has been evaluated within LMIC stewardship programs, but evidence is heterogeneous and unevenly distributed.30Directly relevant, but broad generalization across resource-limited health systems remains difficult.BangladeshAdults with suspected bacterial sepsisPCT-guided de-escalation has been evaluated directly in a resource-limited hospital setting.31Provides particularly relevant evidence for selective PCT-supported discontinuation.South AfricaSurgical/trauma ICU and sepsisSerial PCT-guided stopping has been evaluated in an African critical-care setting, with limited study size and generalizability.32Demonstrates feasibility while highlighting the limited African evidence base.South-East Asia & IndiaSepsis, respiratory infection, and hospital stewardshipRegional studies and consensus support clinically integrated and selective PCT use.25,33Supports adapting PCT use to local infrastructure, patient population, and stewardship capacity.ChinaHospital infection / ICUReal-world evidence shows that adherence to PCT stopping criteria can be limited.35Reinforces that clinician adherence and implementation determine whether testing changes antibiotic use.Notes: The table summarizes selected published evidence and guidance relevant to the clinical and geographical development of procalcitonin-guided antibiotic stewardship. It does not represent the prevalence or routine adoption of procalcitonin testing within individual countries or regions.Abbreviations: ICU, intensive care unit; LMICs, low- and middle-income countries; PCT, procalcitonin.
Nevertheless, much of the large multicenter randomized evidence supporting PCT-guided antibiotic discontinuation has been generated in adult critical care populations in comparatively well-resourced health systems.4,10,11 Accordingly, the framework proposed in this Perspective draws on both direct evidence from resource-limited settings and cautious extrapolation from studies conducted in better-resourced hospitals.
The feasibility of the test depends on laboratory logistics. Procalcitonin is clinically useful only when the assay is available, affordable, and reported in time to influence antibiotic review. Routine-care data from community hospitals also show that serial testing, which underpins most successful discontinuation algorithms, is often poorly implemented: 70% of patient data sets contained only one procalcitonin measurement, and only 23% of those tested repeatedly had measurements spaced within the recommended 24–72-hour interval.23 In hospitals with delayed reporting, reagent interruptions, or limited weekend laboratory services, serial monitoring may therefore be difficult to sustain.
Affordability must also be assessed in relation to the actual benefits of prescribing. Economic models from Europe and the United States suggest that procalcitonin may generate downstream savings by reducing antibiotic exposure, hospital stay, and treatment-related complications; however, these savings occur only when clinicians respond appropriately to the results.36,37 Real-world experience shows that assay procurement and staff costs may outweigh any benefits when implementation is weak. One small US hospital spent $63,274 on procalcitonin testing during the first year of implementation, while antibiotic purchasing costs did not decrease ($306,173 before versus $315,303 after) and average hospital length of stay remained unchanged (3.6 versus 3.7 days; P =0.75).34 Resource-limited hospitals should therefore avoid indiscriminate testing and prioritize clinical situations in which procalcitonin is most likely to change treatment duration or support discontinuation.
Clinician adherence is another major determinant of effectiveness. In BATCH, adherence to the procalcitonin recommendation was only 36% at the first review and 54% at any review, suggesting that limited familiarity and trust reduced the intervention’s effect.15 In community practice, only about one-third of eligible patients had antibiotics discontinued within 36 hours of meeting procalcitonin stopping criteria.23 Clinicians in another small hospital frequently preferred their own judgment over the biomarker result and remained reluctant to withhold or stop treatment.34 A 2026 multicenter Chinese retrospective study similarly reported low adherence to timely discontinuation; among patients meeting procalcitonin stopping criteria, earlier discontinuation was associated with lower antibiotic exposure and shorter intensive care stays, without a significant mortality difference.35
These findings support the integration of procalcitonin into a broader stewardship package that includes clear algorithms, clinician education, regular feedback, and structured antibiotic review rather than treating the test as an independent diagnostic answer.12,38 Pragmatic evidence reinforces this principle: among hospitalized adults with low procalcitonin or positive respiratory viral testing, stewardship-guided interpretation reduced in-hospital antibiotic use by 4.1 days compared with usual care and increased discontinuation of respiratory antibiotics within five days from 49% to 76%.39 In resource-limited settings, including Somalia as an illustrative context, the most defensible approach is selective use among adults already receiving empirical antibiotics for suspected sepsis or severe respiratory infection, particularly where daily reassessment and serial testing are feasible. This approach is more consistent with the evidence than using procalcitonin as a gatekeeper at the initial presentation.
From Evidence to Action in Resource-Limited Hospitals
Resource-limited hospitals should not introduce procalcitonin as a routine screening test for every patient with suspected infection or as a mandatory threshold for starting antibiotics.1,7 Its use should be concentrated where the evidence is strongest: hospitalized adults who have already received empirical antibiotics for suspected sepsis or severe respiratory infection and whose need for continued treatment remains uncertain.4,17 In these patients, procalcitonin can support reassessment and earlier discontinuation, but only when interpreted alongside clinical improvement, microbiological findings, imaging, organ recovery, and adequacy of source control.12,13 Before introducing procalcitonin-guided stewardship, hospitals should ensure three minimum conditions: the results must be available in time to influence prescribing, repeat measurements must be feasible when clinically indicated, and a structured antibiotic review must exist to translate the results into action.12,15,23 Every procalcitonin request should therefore be linked to a planned reassessment within 24–72 hours, during which clinicians decide whether to continue, narrow, switch, or discontinue therapy. When the biomarker recommendation is not followed, the reason should be documented and reviewed, because testing without clinician adherence is unlikely to reduce antibiotic exposure and may simply increase laboratory expenditure.15,23,34
Implementation should begin selectively rather than through immediate hospital-wide expansion. Intensive care units, high-dependency units, and wards that already conduct regular antibiotic reviews may provide the most appropriate starting points. Pilot programs should measure whether procalcitonin reduces antibiotic days, broad-spectrum exposure, and time to discontinuation without increasing antibiotic restart, recurrent infection, mortality, or readmission.
Hospitals should also evaluate turnaround time, clinician adherence, and the cost per antibiotic day avoided before expanding testing.4,28,36 Where timely serial testing and structured reassessment cannot be provided, strengthening basic stewardship practices, including documentation of indication, culture collection, 48–72-hour review, de-escalation, intravenous-to-oral switching, and predefined treatment duration, may offer greater value than introducing procalcitonin prematurely.12,30
For Somalia and similarly constrained health systems, the immediate priority should therefore be a local feasibility assessment rather than unrestricted test adoption. Hospitals should first determine where procalcitonin is available, whether results are produced rapidly, whether repeated testing is affordable, and whether clinicians currently use the results to change antibiotic treatment. Procalcitonin should be expanded only when it can strengthen an existing stewardship decision, not merely because the assay can be performed.
Conclusion
Procalcitonin should not be used to independently determine antibiotic initiation in suspected sepsis, because a low initial result cannot safely exclude serious bacterial infection in high-risk or unstable patients. Its more defensible role begins after empirical treatment has been initiated, when serial measurements can support reassessment, de-escalation, shorter treatment duration, and earlier discontinuation alongside clinical stability, microbiological evidence, and adequate source control. Therefore, the central implementation question for resource-limited hospitals is not whether procalcitonin is available, but whether the results can be delivered repeatedly, interpreted correctly, and converted into a timely prescribing decision.
Hospitals unable to provide serial testing and structured antibiotic review may achieve greater stewardship benefit by first strengthening basic reassessment and de-escalation practices. Where these conditions are present, selective procalcitonin use among patients already receiving empirical antibiotics may increase clinicians’ confidence in stopping treatment earlier. Based on the published literature reviewed in this Perspective, we propose that procalcitonin be considered as a targeted discontinuation aid within an accountable stewardship process in resource-limited hospitals, rather than as an expensive substitute for clinical judgment.