Abstract
- Antimicrobial resistance has emerged as a critical global health challenge. Significant variability in antibiotic prescribing practices underscores the urgent need for high-quality evidence to inform optimal antibiotic prescribing policies. The ideal duration of antimicrobial therapy remains uncertain, and a one-size-fits-all approach is far from ideal. In this review, we examine bacterial growth kinetics and antibiotic pharmacodynamics and explore various strategies for determining the duration of antibiotic therapy: fixed duration, biomarker-guided, clinical course–based, and the more recent double-trigger approach.
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Key Words: antibiotic duration; antibiotic therapy; biomarkers; double-trigger approach
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INTRODUCTION
Antibiotic use and overuse has risen dramatically during recent decades and been paralleled by a concerning surge in multidrug-resistant (MDR) pathogens [1]. Antimicrobial resistance (AMR) has emerged as a critical global health challenge. In 2019 alone, an estimated 4.95 million deaths were associated with bacterial AMR, including approximately 1.27 million deaths directly attributable to it [2]. In response, intensive care specialists are increasingly being urged to adopt a more judicious and targeted approach to antibiotic prescribing.
Significant variability in antibiotic prescribing practices has been demonstrated by Corona et al. A survey performed in 254 intensive care units (ICUs) revealed a wide range of non-evidence-based strategies for managing bloodstream infections (BSIs), from short-course (≤5 days) treatments with narrow-spectrum antibiotics to long-course (≥10 days) therapies involving broad-spectrum combinations [3]. These findings highlight the urgent need for high-quality evidence to guide optimal antibiotic prescribing policies for BSIs and other infections in critically ill patients.
Even when antibiotics are appropriately prescribed—considering indication, dosage, route of administration, timing, and with concomitant source control—re-evaluation at 48–72 hours remains crucial. Antibiotics carry inherent risks that are exacerbated by the unnecessary use of broad-spectrum drugs and needlessly long treatment durations. The optimal duration of antimicrobial therapy remains uncertain, but it is clear that a one-size-fits-all approach is inadequate. Physicians commonly prescribe antibiotic courses of round-numbered days (e.g., 10, 20, 30) or multiples of weeks, but that practice lacks scientific rationale; bacteria do not adhere to such temporal patterns, and biological cycles are not aligned with the human calendar (Figure 1). Nevertheless, short courses have been increasingly adopted to mitigate the adverse consequences of overuse without compromising clinical outcomes.
When prescribing antibiotics for infections, clinicians must consider two important questions: (1) What is the minimal duration needed to eradicate the causative pathogen? (2) Is a microbiological cure necessary, or is a clinical cure sufficient? Antibiotics are primarily intended to eliminate bacteria; however, they do not directly address organ dysfunction—which is often driven not only by the bacterial insult itself but also by the host’s inflammatory response. Sole reliance on microbiological criteria to determine treatment duration is thus problematic because microbiological eradication is not always necessary for clinical recovery [4]. This is particularly relevant for infections caused by pathogens such as Pseudomonas aeruginosa and Enterobacterales, where a clinical cure can occur despite persistent colonization [5]. Recent efforts to define the optimal duration of therapy have increasingly embraced multimodal strategies. These approaches integrate clinical assessment with biomarker-guided decision-making and are supported by interdisciplinary collaboration among physicians, pharmacists, and microbiologists. This shift has led to a growing trend toward short antibiotic courses that do not compromise patient outcomes [1].
Nonetheless, certain clinical scenarios continue to require prolonged therapy. Infections such as endocarditis, osteomyelitis, empyema, lung abscesses, and other deep-seated or anatomically complex infections can require extended antibiotic durations due to challenges in achieving sufficient drug penetration and ensuring effective source control. In immunocompromised patients, therapeutic decisions become even more nuanced. Most randomized controlled trials (RCTs) exclude patients with significant immunosuppression—such as those with malignancies or solid organ transplants—thus limiting the generalizability of current evidence to those populations. However, immunosuppression encompasses a broad and heterogeneous spectrum of patients. In selected, clinically stable immunocompromised patients, short antibiotic regimens have been used successfully, with favorable outcomes.
For infections caused by MDR organisms, current guidelines for empirical therapy generally do not advocate for prolonged durations based solely on resistance profiles. The evidence suggesting that MDR pathogens require extended treatment is insufficient, provided that the selected antimicrobial agent is appropriate and effective. Similarly, the need for combination therapy should be determined based on the clinical context rather than resistance alone [6].
BACTERIAL GROWTH KINETICS AND KILLING DYNAMICS
Understanding bacterial growth dynamics is essential for optimizing antibiotic use. Bacteria are prokaryotic organisms that typically reproduce asexually via binary fission. Under optimal conditions—such as an appropriate availability of nutrients, temperature, oxygen level, moisture, pressure, and pH—they proliferate rapidly, following a predictable growth pattern known as the bacterial growth curve, which consists of four distinct phases: lag, exponential (log), stationary, and death (Figure 2).
(1) Lag phase: in this initial phase, bacteria adapt to their new environment by synthesizing RNA, enzymes, and other molecules necessary for growth. Although they are metabolically active, the cells do not divide immediately. (2) Exponential (log) phase: during this phase, bacteria divide rapidly, resulting in exponential population growth. Metabolic activity is at its peak, and the cells are most vulnerable to antibiotics that target processes such as cell wall synthesis or protein production. The rapid turnover of bacterial cells contributes to genetic variation and phenotypic heterogeneity within populations. (3) The number of new cells produced equals the number of cells dying, resulting in stabilization of the overall population. (4) Death phase: continued nutrient depletion and the accumulation of toxic byproducts lead to an exponential decline in the number of viable cells.
Although the bacterial growth curve offers a theoretical framework for understanding, it is seldom observed in natural environments, where conditions are rarely ideal. In laboratory settings, however, controlled closed culture systems allow researchers to replicate optimal conditions and observe these growth phases.
Persistence
Persistence is a prime example of phenotypic heterogeneity. When a bacterial culture is exposed to an antibiotic, a small subpopulation of cells—known as persisters—survives the treatment because this phenotype is not actively dividing or proliferating. Once the antibiotic is removed, this surviving fraction begins to regrow. Notably, the regrown culture remains susceptible to the same antibiotic, except for the recurring presence of a small fraction of persister cells.
In contrast to resistance, which involves heritable genetic changes, persistence is a non-heritable, phenotypic adaptation. It does not involve genetic mutation or selection but arises from transient physiological states within the bacterial population. Studies have shown that persister cells that are present before the antibiotic exposure tend to grow more slowly than their non-persister counterparts, suggesting that persistence confers a survival advantage under stress at the cost of reduced fitness in optimal, unstressed conditions (Figure 3) [7].
Antibiotic-Induced Bacterial Killing Dynamics
Pharmacodynamics (PD) describes the relationship between antibiotic concentration and bacterial killing. Antibiotics are traditionally classified as either time-dependent or concentration-dependent, depending on how efficacy is best achieved. These classifications primarily rely on the minimum inhibitory concentration (MIC), defined as the lowest antibiotic concentration that inhibits visible bacterial growth in vitro. However, MIC values are determined under standardized conditions that do not accurately reflect the complex and dynamic environments encountered in infected patients. Several additional PD factors—such as bacterial density, growth rate, metabolic byproducts, phenotypic heterogeneity (e.g., persisters and biofilm-associated cells), and variable drug exposures—can critically influence treatment outcomes [8,9].
Given a basic understanding of bacterial persistence, one would theoretically expect to observe a biphasic decay pattern in bacterial populations following antibiotic administration. Initially, a rapid decline in bacterial load would reflect the deaths of actively growing, susceptible cells, and that would be followed by a slower phase attributable to the killing—or persistence—of the refractory subpopulation (Figure 4). This biphasic dynamic supports the rationale for treatment durations that are sufficient to eliminate susceptible bacteria but do not need to be long enough to sterilize persisters, especially when host immunity and source control are adequate.
To better characterize those dynamics, continuous culture systems that maintain bacterial populations in controlled growth conditions have been used for real-time monitoring of drug effects. Unlike traditional batch cultures, continuous systems can simulate fluctuating antibiotic exposures and help researchers assess the activity of both bacteriostatic and bactericidal agents, as well as the impact of refractory subpopulations, including persisters, biofilm-associated cells, and post-antibiotic effects. However, although they are more informative than static models, continuous cultures still do not replicate the complexity of the human immune system.
A notable example of the use of these systems comes from Udekwu and Levin [8], who studied Staphylococcus aureus in continuous culture. Despite achieving their pharmacokinetic/pharmacodynamic targets and favorable antibiotic concentrations, they did not achieve complete bacterial eradication. Although initial reductions in viable counts were observed post-dosing, regrowth occurred before the next dose. This finding suggests that phenotypically resistant subpopulations—particularly biofilm-associated cells—can limit antibiotic efficacy, even in the best, most optimal conditions.
Further clinical evidence is provided by Dennesen et al. [5], who investigated treatment outcomes in patients with ventilator-associated pneumonia (VAP). Although all patients showed clinical improvement within 6 days of therapy, Gram-negative pathogens—especially Enterobacterales and P. aeruginosa—were frequently re-isolated from tracheal aspirates, despite their documented in vitro susceptibility and ongoing clinical improvement. These findings highlight a disconnect between microbiological eradication and clinical resolution. Notably, recurrent infections were more common in patients with persistent colonization, raising the question of whether treatment should prioritize clinical endpoints over complete microbial clearance [5].
This concept is increasingly relevant in conditions such as VAP, in which a clinical cure, defined by symptomatic improvement and biomarker trends, often occurs despite ongoing colonization. As such, it might represent a more meaningful and patient-centered endpoint than a microbiological cure alone. Taken together, these insights support the implementation of the double-trigger antibiotic stewardship strategy described below.
DURATION OF ANTIBIOTIC THERAPY
During the past three decades, recommendations for the duration of antibiotic therapy have changed significantly—from prolonged courses lasting several weeks to shorter regimens measured in days. The PneumoA trial was one of the first studies to demonstrate that a fixed 8-day course of appropriate antibiotics was as effective against late-onset VAP as the traditional 15-day regimen [10]. This finding marked a paradigm shift from a conservative play-it-safe strategy to an evidence-based, outcome-driven, decision-making approach.
Fixed Duration
Although relatively few studies have specifically evaluated how antibiotic stewardship interventions intended to reduce treatment duration affect clinical outcomes, evidence from systematic reviews and an RCT consistently demonstrates that short antibiotic courses yield clinical outcomes comparable to those of long regimens across a range of infections in both adult and pediatric populations [11]. A recent example is the 2024 BALANCE trial, which compared a strict 7-day fixed course to a 14-day regimen against BSIs. The study found that the shorter course showed no inferiority in terms of mortality and relapse, suggesting that fixed durations might be sufficient in treating even serious infections [12].
Notable exceptions are infections caused by Gram-negative bacteria, particularly P. aeruginosa. Some studies, such as the Doripenem trial by Kollef et al. [13], have raised concerns about the safety and effectiveness of short antibiotic courses in treating this pathogen. Others, such as the iDIAPASON study to evaluate the optimal duration of antibiotic therapy for VAP caused by non-fermenting Gram-negative bacilli, including P. aeruginosa, found no significant differences in either the composite outcome or the individual endpoints—90-day mortality and VAP recurrence—between the two treatment durations (8 vs. 15 days). However, the limited statistical power of that study restricts the strength and generalizability of its conclusions [14].
Biomarkers
Biomarkers are increasingly used in antimicrobial stewardship programs to shift antibiotic decision-making from a one-size-fits-all approach to personalized care. Host-response biomarkers—particularly procalcitonin (PCT) and C-reactive protein (CRP)—have been studied extensively as tools to support antibiotic discontinuation. Although the physiology of these markers is beyond the scope of this paper, their clinical applications merit attention.
Procalcitonin
Multiple studies have evaluated PCT as a tool to guide antibiotic duration: Nobre et al. [15] conducted an RCT and demonstrated that a serial PCT-based algorithm reduced antibiotic duration by 4 days in patients with severe sepsis and septic shock without increasing mortality or recurrence. ICU stays were also shortened by 2 days. Antibiotics were discontinued when the PCT levels decreased by ≥90% from baseline, but not before day 3 (if baseline PCT <1 µg/L) or day 5 (if ≥1 µg/L).
A meta-analysis of 26 RCTs involving 9,048 patients found that PCT-guided therapy reduced antibiotic duration (mean difference, −1.79 days; 95% CI, −2.65 to −0.92) and was associated with lower 28-day mortality (OR, 0.84; 95% CI, 0.74–0.95), compared with standard therapy. However, it was also linked to a higher rate of recurrent infection (OR, 1.36; 95% CI, 1.10–1.68), with no significant differences in the ICU or hospital length of stay [16]. These findings underscore the need for well-designed studies that can further clarify the role of PCT-guided antibiotic stewardship in critically ill patients.
C-reactive protein
CRP is another biomarker that has been widely studied for guiding antibiotic therapy: a meta-analysis of three studies (n=727) showed that CRP-guided therapy significantly reduced antibiotic duration (−1.82 days; 95% CI, −3.23 to −0.40), without affecting the mortality (OR, 1.19; 95% CI, 0.67–2.12) or relapse rates (OR, 3.21; 95% CI, 0.85–12.05), compared with standard therapy [17].
In a Brazilian RCT, 130 critically ill patients were randomized to CRP-guided or standard antibiotic therapy. The CRP group followed a protocol combining daily CRP monitoring with clinical assessment. Although the median antibiotic duration was similar (7.0 days), cumulative antibiotic exposure was significantly lower in the CRP group (P=0.007). These findings suggest that CRP monitoring could enable earlier discontinuation in selected patients without increasing overall antibiotic use [18].
PCT or CRP?
Kubo et al. [19] conducted a meta-analysis of 18 studies with 5,023 participants to compare PCT- and CRP-guided strategies with standard care in patients with sepsis. Both approaches significantly reduced antibiotic duration (PCT, −1.89 days; CRP, −2.56 days). Only PCT-guided strategies were associated with reduced mortality—27 fewer deaths per 1,000 participants—particularly among patients meeting the Sepsis-3 criteria. Neither approach was associated with an increased risk of infection recurrence, although the certainty of that evidence was rated as low.
Oliveira et al. [20] directly compared PCT- and CRP-guided antibiotic discontinuation strategies that were both implemented following a fixed 7-day minimum course and clinical stabilization based on Sequential Organ Failure Assessment (SOFA) scores. Although no significant difference in antibiotic duration was observed between the groups, the study underscores the feasibility and safety of biomarker-guided discontinuation. Its findings support a double-trigger approach that aligns biomarker kinetics with clinical recovery criteria.
As fixed-duration regimens gain broader validation and acceptance—exemplified by the BALANCE trial [12] and similar studies—the marginal benefit of biomarker-guided strategies might diminish in standard practice. Nonetheless, biomarkers could still be valuable in selected high-risk populations, in cases of diagnostic uncertainty, or as a means to reinforce clinical decisions to safely shorten antibiotic courses, particularly when the biomarkers show a clear downward trajectory. Ultimately, aligning biomarker kinetics with clinical recovery could help to optimize stewardship efforts while minimizing unnecessary exposure.
Economic impact
When considering the use of biomarkers, it is also essential to weigh their clinical utility against their financial cost, which is often higher than clinical judgment alone. Economic evaluations indicate that the cost-effectiveness of biomarker-guided strategies varies substantially depending on local factors, including the price of PCT and CRP assays, daily hospital or ICU costs, and antibiotic pricing.
A Dutch study assessing PCT-guided therapy in patients with lower respiratory tract infections reported a reduction in in-hospital costs of approximately €65 per patient, with an incremental cost-utility ratio of €57,400 per quality-adjusted life year gained—suggesting moderate cost-effectiveness within accepted European thresholds [21]. Similarly, in Switzerland, a study in primary care settings found that PCT testing—whether used alone or combined with point-of-care lung ultrasound—was associated with an incremental cost-effectiveness ratio of CHF 2.2 per percentage point reduction in antibiotic prescribing, indicating good value for the money [22].
Given those findings, it is recommended that healthcare institutions adopt a local decision-analytic framework to assess the cost-effectiveness of biomarker use in their specific context. This framework should account for region-specific variables such as assay pricing, hospital bed per day costs, patterns of antibiotic use, and local AMR profiles.
Clinical Course-Based Strategies
Another approach to guide antibiotic discontinuation relies on clinical course assessment. The REGARD-VAP trial compared individualized short-course antibiotic therapy (3–7 days) with standard long-course therapy (≥8 days) in patients with VAP [23]. Among 461 patients, the median treatment duration was 6 days in the short-course group versus 14 days in the control group. Individualized discontinuation based on clinical response was non-inferior to standard care in terms of 60-day mortality and pneumonia recurrence, and it significantly reduced antibiotic exposure and adverse events. Clinical response criteria included the resolution of fever for 48 hours and hemodynamic stability, which are not pneumonia-specific criteria.
Fixed Duration, Biomarker-guided, or Clinical Evaluation?
To integrate all the available evidence, Arulkumaran et al. [24] conducted a meta-analysis of 22 randomized trials involving 6,046 patients. The study compared PCT-guided therapy, clinical algorithm–guided therapy, and fixed-duration antibiotic regimens. PCT-guided therapy was associated with a significant reduction in antibiotic duration (mean difference, −1.23 days; 95% CI, −1.61 to −0.85; P<0.001), whereas clinical algorithm–guided therapy did not demonstrate a significant effect. Notably, fixed-duration strategies aimed for predefined reductions in antibiotic duration ranging from 3 to 7 days. Mortality outcomes were inconclusive based on both a meta-analysis and trial sequential analyses.
Biomarker-guided antibiotic stewardship has consistently shown reductions in antibiotic duration, but findings on mortality and relapse remain variable. Although PCT-guided strategies show potential benefits in selected critically ill populations, heterogeneity in study designs and populations limits definitive conclusions. Furthermore, the increasing adoption of fixed-duration antibiotic regimens could attenuate the incremental clinical benefit of biomarker guidance.
WHAT’S NEW?
ADAPT Trial and a Bayesian Analysis
As previously noted, high-quality research on biomarkers is essential to establish their optimal clinical use. The ADAPT trial, a recent multicenter, concealed intervention RCT involving 2,760 patients, sought to address limitations identified earlier [25]. The trial demonstrated that patients managed with a daily PCT-guided protocol saw a statistically significant reduction in antibiotic duration within 28 days, compared with those treated with standard care or a CRP-guided protocol. No significant difference in all-cause mortality up to 28 days was observed. Despite those findings, the trial received criticism for its potential biases: the standard care arm exhibited antibiotic durations much longer than are typical (>10 days when the protocol said that it should have been 7 days); the clinicians had access to CRP values across all groups, which potentially influenced their decisions; and the overall mortality rate exceeded anticipated levels.
A subsequent Bayesian analysis estimated the effects of PCT-guidance on antibiotic duration reduction as approximately half a day—indicating statistical significance but limited clinical relevance. This trial also demonstrated that, in isolation, biomarker-guided strategies could prolong antibiotic duration (mean total duration for PCT-guided protocol, 9.8 days [SD, 7.2]) compared with a short, fixed-duration approach. If a biomarker-guided strategy is used, it should be integrated into an algorithm that combines a fixed duration with the kinetics of biomarkers in a double trigger approach.
Double Trigger Approach
In an effort to combine the strengths of clinical assessment and biomarker monitoring, the double-trigger approach integrates both clinical and laboratory variables to guide antibiotic discontinuation. Rezende et al. [26] developed an algorithm that incorporates serial CRP levels alongside key clinical parameters—such as the SOFA score, presence of an unresolved infectious focus, and overall clinical improvement—to tailor antibiotic duration in hospitalized adult patients. The primary objective of their study was to assess whether their algorithm could safely reduce antibiotic treatment duration, compared with standard care guided by current best practices (Figure 5). Preliminary results showed no significant difference in overall antibiotic duration or rates of adverse events between groups. However, among the subgroup of patients discharged with continued oral antibiotic therapy at home, a modest reduction of one day in treatment duration was observed. Final results are pending, and definitive conclusions should await the full analysis.
In low-income settings, where daily biomarker monitoring could be impractical, simplified strategies remain promising. A feasible alternative involves measuring biomarkers at baseline (day 1) and again at 72 hours (day 3), while integrating clinical assessment and accounting for the expected kinetics of the chosen biomarker. In situations in which even limited biomarker testing is unavailable, a pragmatic approach is to implement a fixed minimum duration of antibiotic therapy, followed by clinical reassessment. If no clinical improvement is observed at the end of the fixed minimum period, treatment should be extended and microbiological cultures repeated. This stepwise approach aligns with recent recommendations for managing non-resolving pneumonia [27]. Importantly, each case must be evaluated individually, with particular attention to source control—a critical determinant of infection resolution.
Focus on Antibiotic-Associated Harms
Clinical investigation has also explored the harm associated with long antibiotic durations. A recent umbrella review analyzed 35 systematic reviews encompassing a total of 23,174 patients to assess the harms associated with short versus long antibiotic courses [28]. Among the studies, 46.8% focused on respiratory tract infections, 21.8% on urinary tract infections, and 15.6% on various infectious diseases. Most trials were conducted in community settings (54.9%). Adverse events occurred in 19.9% (n=4,039) of patients, superinfections in 4.8% (n=280), and AMR in 10.6% (n=246). Notably, each additional day of antibiotic therapy increased the odds of adverse events by 4% (OR, 1.04; 95% CI, 1.02–1.07) and the odds of severe adverse events by 9% (OR, 1.09; 95% CI, 1.00–1.19). No statistically significant daily increase was observed for superinfections or AMR.
Prescription patterns might differ from local guidelines because fluoroquinolones were the most studied antibiotic class (20 studies, 7,047 patients), followed by penicillins (13 studies, 5,470 patients) and cephalosporins (12 studies, 3,459 patients). Importantly, most RCTs had limited follow-up (generally ≤30 days), potentially underestimating late-onset harms such as Clostridioides difficile infection or colonization with resistant organisms. These findings underscore the importance of balancing treatment duration against potential harms and support antibiotic stewardship efforts to minimize unnecessary exposure.
Another study focused on the prevalence of antibiotic resistance in community-onset sepsis and the outcomes associated with inadequate and broad-spectrum empiric antibiotic therapy [29]. From the 17,430 adult patients included in that cohort study, 67.0% received empiric broad-spectrum antibiotics, but resistant Gram-positive organisms were isolated in only 13.6% of patients and resistant Gram-negative organisms in 13.2%. Both inappropriate and appropriate but overly broad antibiotics were associated with higher mortality during follow up after detailed risk adjustment (inadequate empiric antibiotics: OR, 1.19; 95% CI, 1.03–1.37; P =0.02; unnecessarily broad empiric antibiotics: OR, 1.22; 95% CI, 1.06–1.40; P=0.007). These findings highlight the urgent need for improved rapid diagnostic tests that can detect resistant pathogens and for more prudent use of broad-spectrum antibiotics.
CONCLUSION
Stopping antibiotic treatment is often perceived to be more challenging than initiating it, indicating that it is a critical opportunity for improvement. Although treatment durations are well established for several clinical conditions (VAP, community-acquired pneumonia, complicated intra-abdominal infections), they remain less clearly defined for others.
In critically ill patients, limiting antibiotic therapy to 7–8 days appears to be both safe and effective for most infectious diseases. Extending antibiotic courses beyond that duration does not confer additional benefit and is associated with increased risks of MDR bacterial emergence and drug-related toxicity. No optimal strategy for antibiotic discontinuation has been established, but biomarkers integrated into algorithms that consider both treatment duration and biomarker kinetics can enable individualized cessation of antibiotics that is safer and potentially earlier than standard protocols.
KEY MESSAGES
▪ In critically ill patients, limiting the duration of antibiotics to 7–8 days seems safe and efficacious in most acute bacterial infectious conditions.
▪ A double-trigger strategy combining the biomarker-guided and fixed duration approaches is the best way to determine when to stop antibiotic treatment.
▪ Prolonging antibiotic treatment is not beneficial and is associated with adverse events.
NOTES
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CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was reported.
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FUNDING
None.
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ACKNOWLEDGMENTS
The figures presented in this paper were AI-generated using DALL•E.
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AUTHOR CONTRIBUTIONS
Conceptualization: GSG, PP. Writing–original draft: GSG, JF. Writing–review & editing: GSG, PP. All authors read and agreed to the published version of the manuscript.
Figure 1.The bacterial lifecycle does not align with a normal week.
Figure 2.Different bacterial growth phases.
Figure 3.The effects of antibiotics on bacterial populations and persisters.
Figure 4.Biphasic decay pattern in bacterial populations following antibiotic administration.
Figure 5.Double-trigger approach concept. a) A relatively prolonged duration may be required when adequate drug penetration or source control is difficult to achieve (e.g., endocarditis, osteomyelitis, empyema, lung abscesses, and other deep-seated infections); b) Characterized by the resolution of septic shock or sepsis, or of the clinical signs that initially suggested the infection (e.g., expectoration, dysuria, local pain); c) Most studies assume that a 5–7 day course is sufficient for most infections; d) Biomarker values and timing vary across studies. Rezende et al. [26] used C-reactive protein (CRP) assessed on day 1 and day 3 (if initially <100 mg/L) or on day 5 (if >100 mg/L). Antibiotic therapy was discontinued if CRP was <35 mg/L on day 3 or had decreased by >50% on day 5.
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