Biapenem (BPM) is a carbapenem antibiotic, employed in the combat against bacterial infections (Brismar et al., 1996). It exhibits its antibacterial prowess by inhibiting bacterial cell wall synthesis. Comparable to the in vitro potency of imipenem and meropenem, BPM possesses a broad-spectrum efficacy, spanning Gram-negative and Gram-positive bacteria, and extending to anaerobic bacteria (Dong et al., 2016). Demonstrations of both clinical and bacteriological effectiveness have been evident in the management of diverse bacterial infections - pneumonia, complicated urinary tract infections, pyelonephritis, peritonitis, and others (Perry and Ibbotson, 2002). Over the past decades, BPM has ascended to become a choice in treating infections precipitated by extended-spectrum β-lactamase-producing Gram-negative bacteria (Alonso et al., 2006).

Alterations in the volume of distribution (Vd) and clearance of antibiotics have been observed in sepsis (van der Poll, 2001; Roberts and Lipman, 2006). Endotoxins induce the synthesis of various endogenous mediators, including cytokines, interleukins, and platelet-activating factor, can influence the vascular endothelium, leading to vasodilation, along with an aberrant distribution of blood flow, endothelial damage, and heightened capillary permeability. This syndrome results in fluid translocation from the intravascular compartment to the interstitial space, consequently increasing the Vd of water-soluble drugs, including carbapenems, and diminishing their serum concentrations (Murínová et al., 2022). It was reported that bipenem has a relatively short elimination half-life of approximately 1 hour. Additionally, it manifests a significant inter-individual variability in its pharmacokinetic characteristics, which leads to substantial disparities in the blood drug concentration amongst patients. Consequently, identical dosing regimens can produce disparate clinical outcomes in different patients. Sole dependence on the suggested dosing regimen outlined in the product label is inadequate for dose adjustments in diverse patient populations, particularly in cases involving sepsis (Evans et al., 2021). Therefore, exploration into the pharmacokinetic profiles of BPM within the septic patient populace is crucial in order to predict the pharmacokinetic parameters of this specific populace, and to effectively enhance or refine the dosage for improved patient outcomes.

BPM exhibits a time-dependent bactericidal action, where its antimicrobial effectiveness is contingent upon the duration for which serum drug levels surpass the minimal inhibitory concentration (MIC). In the current clinical practice, BPM is commonly administered twice or three times a day, with a dose of 300mg–600 mg per administration (Griffith et al., 2023). However, due to its relatively brief elimination half-life and time-dependent nature, achieving the pharmacokinetics/pharmacodynamics (PK/PD) target remains challenging with dosing intervals of either 8 or 12 h (Ikawa et al., 2008a; Ikawa et al., 2008b; Rao et al., 2023).

Currently, there is a notable gap in the literature, as population pharmacokinetic studies focusing on BPM in septic patients are lacking. This is particularly significant considering the frequent prescription of BPM within this patient population. Thus, the primary objective of this study is to investigate the pharmacokinetics of BPM in septic individuals utilizing a population pharmacokinetic (PPK) approach. This investigation is intended to facilitate dosing optimization, thereby enhancing the achievement of the PK/PD target in this patient cohort.

Life-threatening sepsis and severe nosocomial bacterial infections in hospitalized patients represent a significant clinical challenge (Evans et al., 2021). A robust correlation exists between the fT _>MIC of carbapenems and their clinical efficacy (Zhanel et al., 2007). Deviations from optimal dosage, whether insufficient or excessive, can lead to adverse effects, consequently influencing the overall clinical efficacy of these antimicrobial agents (Boonpeng et al., 2022; Dinh et al., 2022). Consequently, this research endeavors to develop a BPM PPK model specifically for adult patients suffering from sepsis. This initiative is intended to furnish empirical support for the optimization of clinical administration strategies of this antimicrobial agent.

At present, there are many methods evaluating the influence of covariates on PK model parameters. In spite of the selected method, the intention of such evaluations is usually to describe inter- and intra-subject variability in PK parameters with patient factors. These factors may be those patient characteristics that are recorded for each subject at a baseline study visit and describe patient-specific factors such as the subject’s gender, age, weight, and height, for instance. Covariates that describe something about the current disease status and/or medical history for each patient may also be collected (Mould and Upton, 2013). In longer term studies, the extent to which a covariate, such as renal function, measured by creatinine clearance, may be changing could be particularly important to capture, especially BPM elimination is largely renal (Perry and Ibbotson, 2002). Other covariates that are sometimes studied as time-varying factors include laboratory measures of hepatic function, which may be measured at multiple study visits, as well as concomitant medications of interest with the potential to induce a drug–drug interaction. So the above covariates were introduced in the model building in this study.

The present study used a two-compartment model to describe the pharmacokinetic data of BPM, which is consistent with previous study (Ikawa et al., 2008b). To assess the pharmacokinetic characteristics of the adult patients with sepsis, we examined the impact of covariates on pharmacokinetic parameters. The previous study of Ikawa et al. found that the average CL of BPM in adult patients was 8.13 L/h for CLCr of 77.5 mL/min (Ikawa et al., 2008b). In this study, an average CL was observed, the mean CL of BPM in patients with sepsis was 8.33 L/h for CLCr of 78.2 mL/min. Hang et al. reported an average CL BPM in critically ill patients was 20.9 L/h, higher than the CL observed from this study (Hang et al., 2018). Although ALB was included as a covariate affecting CL during the model building process using forward inclusion method, it was eventually eliminated from the final model. Therefore, it was found through the study that CLCr was the most significant influencing factor on BPM CL. However, we speculate that a low ALB level may also have a potential impact on CL of BPM. Patients with lower level of ALB was often related with impaired renal or liver function. A previous study has also shown that, under the same renal function level, patients with decompensated cirrhosis have relatively lower meropenem trough concentrations, suggesting that alteration of pharmacokinetics was common in patients with impaired liver function, which could be similar in pharmacokinetics of BPM (Bastida et al., 2020).

Also, the volume of distribution of BPM differs significantly from previous studies. Ikawa et al. reported an average V (V₁+V₂) of 14.3 L in adult patients (Ikawa et al., 2008b) while Hang et al. found the V was 46.43 L in critically ill patients (Hang et al., 2018). In the current investigation, the V (V₁+V₂) of BPM was observed to reach a notable 73.8 L among patients suffering from sepsis, approximately four to five times higher than that observed in other patient populations in previous studies. Although only a few studies have investigated the population pharmacokinetics of carbapenems in septic patients, an increase in the volume of distribution is common. Fukumoto et al. revealed the volume of distribution of meropenem V (V₁+V₂) in patients with sepsis was 39.7L (Fukumoto et al., 2023), while Murínová et al. reported an average V of 55L in patients with serious infection (Murínová et al., 2022), respectively. Both studies reported higher V of meropenem in patients with sepsis comparing with other patients, which may be caused by the increase in V of hydrophilic drugs, which is quite common in critically ill patients (Roberts and Lipman, 2006). In this study, the observed elevation in the V of BPM among septic patients, also a hydrophilic drug, is consistent with the theory established in previous research.

In the present study, we found that the Q of BPM in septic patients is affected by the levels of BUN. It has been reported that BUN levels are significantly correlated with the prognosis of sepsis patients (Li et al., 2021; Harazim et al., 2023), with even a mild elevation in BUN being associated with an increased mortality in these patients. While the association between elevated BUN levels and neurohormonal response has predominantly been established within populations of patients experiencing cardio-renal issues, we contend that elevated BUN, irrespective of eGFR, may intricately signify intricate underlying pathological processes directly involved in the pathophysiology of sepsis. Although the link between elevated BUN and neurohormonal response has almost exclusively been derived from population of patients with cardio-renal problems we believe that elevated BUN independent of GFR may sensitively reflect complex underlying pathological processes directly implicated in the pathophysiology of sepsis. In the context of sepsis, arterial underfilling arising from systemic inflammation-induced arterial vasodilation serves as a robust trigger for the activation of the sympathetic nervous system (SNS), the renin–angiotensin–aldosterone axis (RAAS), and the non-osmotic release of vasopressin (AVP) (Gomes et al., 2020). While the SNS, RAAS and AVP all constitute pivotal adaptive responses to stress, there is a compelling inclination to hypothesize that excessive and prolonged activation during sepsis may transition into a maladaptive state, eliciting adverse effects. Moreover, sepsis is distinguished by a profound and frequently enduring catabolic state, culminating in the depletion of muscle mass and neuromuscular weakness. In this context, elevated BUN may additionally function as an indicator of severe catabolism in sepsis. Substantiating this concept, Haines et al. recently recognized the urea-to-creatinine ratio as a promising biomarker of catabolism associated with critical illness (Haines et al., 2019). The aforementioned alterations may signify the undiscovered prognostic value of BUN in the pathophysiology of sepsis, potentially entwined with systemic metabolism and inflammatory levels, which influence the pharmacokinetics of BPM.

According to our analyses, achieving a 70% fT _>MIC significantly enhances the likelihood of clinical cure in patients with sepsis treated with BPM. This finding underscores the critical role of optimizing antimicrobial exposure to improve therapeutic outcomes. Additionally, the analysis identified hypoalbuminemia as a significant risk factor for treatment failure. The implications of these findings are twofold. Firstly, they highlight the importance of individualized dosing strategies based on PK/PD principles to maximize the efficacy of BPM in treating septic patients. Secondly, the identification of hypoalbuminemia as a risk factor suggests that addressing underlying nutritional deficits or managing the protein distribution profiles may be crucial in enhancing treatment efficacy. These insights pave the way for targeted interventions and optimized therapeutic strategies in the management of sepsis, potentially improving patient outcomes through tailored therapeutic approaches.

Carbapenems demonstrate time-dependent antibacterial activity, wherein their efficacy is most closely associated with the % fT _>MIC. It is generally recommended that the %fT _>MIC of carbapenems should reach a threshold of 40%–50% to achieve optimal bactericidal effects, and the position paper of European Society of Intensive Care Medicine recommended a clinical PK/PD target for efficacy of 50%–100%fT _>MIC (Abdul-Aziz et al., 2020). In this study, we chose a target of 70% fT _>MIC. Although there are limited pharmacodynamic data of BPM beyond this study, a goal of 70% fT _>MIC would represent a more conservative endpoint. As shown in the results of Monte Carlo simulations, in the population of patients with sepsis, it appears that the recommended dosage as per the product label may not adequately achieve the clinical efficacy targets. Under the daily total dose regimen of 1.2 g, probability was lower than 80% to attain 70% fT _>MIC in patients with pathogens exhibiting a MIC of 1.0 mg/L. Only the 300 mg q6h regimen demonstrates a probability exceeding 60% for attaining 70% fT _>MIC in this microbial subset. The probability drop to less than 30% in patients with pathogens exhibiting a MIC of 2.0 mg/L under the daily total dose regimen of 1.2 g. This implies that a higher daily dosage of BPM is required in septic patients to achieve therapeutic goals. To improve PK/PD target attainment, an optimized dosing regimen of 600 mg q6h was required for pathogens with a MIC of 1.0 mg/L because of a higher PD parameter attainment (81.47%). In septic patients, the BPM regimen of 600 mg q8h appears to exhibit no significant increase in the probability of achieving PK/PD targets compared to the 300 mg q6h regimen. The difference in target attainment probabilities between the two dosage regimens exceeds 10% only when the MIC is 2 mg/L (41.08% vs. 27.32%). Currently, there are no recommendations published by CLSI and EUCAST regarding bacterial susceptibility breakpoints for BPM. According to the antimicrobial susceptibility report from the bacteriological laboratory in China, Escherichia coli and Enterobacter cloacae exhibited susceptibility to BPM, with MIC₉₀ values of 0.25 mg/L and 0.5 mg/L, respectively, while Klebsiella pneumoniae has an MIC₉₀ of 2 mg/L (Dong et al., 2016). Therefore, based on our research findings, it is suggested that BPM may necessitate a daily dosage higher than the current clinical standard (1.2 g per day) in septic patients to achieve sufficient clinical efficacy while infections are caused by Klebsiella pneumoniae. This calls for further exploration through meticulously designed prospective randomized controlled clinical studies.

At the same time, we must confess that the current study’s limitation to a single-center cohort restricts its external validity. Extending the future study to include multiple centers, especially those in different geographic locations, would not only enhance the robustness of the pharmacokinetic model but also improve its generalizability across broader patient populations. While the study effectively identifies creatinine clearance and blood urea nitrogen as significant predictors of biapenem clearance, these findings scratch the surface of the complex interplay of factors impacting drug metabolism in septic patients. Investigating additional covariates, such as genetic factors, could uncover nuances in pharmacokinetic parameters that standard analyses might overlook. The inclusion of a validation cohort in the study is commendable; however, validation through an independent cohort from diverse demographics or geographic areas would solidify the pharmacokinetic model’s utility and reliability. This approach would mitigate the cohort-specific bias and confirm the model’s efficacy across various clinical settings. The manuscript delineates the inter-individual variability observed in the pharmacokinetic parameters of biapenem. Identifying the sources of this variability is crucial for optimizing dosing strategies. Moreover, exploring inter-occasion variability, which accounts for changes in pharmacokinetic parameters between different visits of the same patient, could enhance the model’s accuracy. This variability might be attributed to changes in disease state, concomitant medications, or recovery phase, and its inclusion in the analysis could refine dose adjustments over the course of treatment. However, due to the retrospective nature of the study, we were not able to discover the variability more specifically. This study fail to integrate microbiological efficacy data, such as bacterial load dynamics and susceptibility changes, to enhance the pharmacokinetic model’s utility by linking drug exposure to microbial response. This approach should be utilized in future prospective study to provide a more holistic understanding of biapenem’s therapeutic impact, particularly in modifying treatment strategies based on microbiological feedback. Lastly, while the manuscript adeptly discusses pharmacokinetic-driven dose optimization using Monte Carlo simulations, and compare the clinical outcomes of the, integrating these theoretical dosing schemes with real-world clinical outcomes would vastly improve the practical value of the study. Prospective clinical trials designed to evaluate the correlation between optimized dosing regimens and patient-centric outcomes such as infection resolution and survival rates are essential for translating pharmacokinetic insights into clinical practice.

This study represents the first exploration of the PK parameters of BPM in septic patients. The considerable sample size included in this study can be attributed to the routine implementation of TDM in clinical practice for BPM therapy. There are limitations in our present study. The use of data collected during routine TDM limiting the number of BPM concentrations measured for each patient. Due to the substantial heterogeneity in microbiota among septic patients and the complexity of clinical conditions during treatment, integrating PPK models, actual clinical efficacy, and PK/PD index is challenging and complicated. Ultimately, the optimal dose regimen based on modeling and simulation should be evaluated in clinical practice to confirm its clinical benefits.

The PPK model of BPM was developed in patients with sepsis and elucidated the significant effects of CLCr and BUN on BPM pharmacokinetics. The target of 70%fT _>MIC is associated with favorable clinical outcomes_. The current daily dosage regimen of 1.2 g may potentially fall short of achieving sufficient clinical efficacy in septic patients when treating pathogens with MIC>1 g/L. To attaian 70%fT _>MIC, the dosage regimen of 600 mg every 6 h appears to be the optimal choice. These results better define the pharmacokinetics of BPM and help in the choice of the appropriate dosage regimens of BPM for patients with sepsis.