Population pharmacokinetics, dosing optimization and clinical outcomes of biapenem in patients with sepsis.

Introduction: Biapenem is a carbapenem antibiotic widely used in Asia, can be used for the treatment of adults and children with infections due to susceptible bacteria. Although biapenem is utilized in the treatment of a diverse range of bacterial infections, current pharmacokinetic data in the context of septic populations remain limited. Consequently, our research aims to evaluate the pharmacokinetics and efficacy of biapenem within a septic population to optimize biapenem therapy. Methods: In this study, we characterized the pharmacokinetics of biapenem in septic patients using a population pharmacokinetic (PPK) approach. The clinical PK data to develop the PPK model were obtained from 317 septic patients admitted to Nanjing Drum Tower Hospital between 2018 and 2022. All patients were randomized to the modeling and validation cohorts at a 3:1 ratio, with PPK modeling and validation performed utilizing the NONMEM software. Results: The model found to best describe the available data was a two-compartment PPK model with first-order elimination characterized by the parameters clearance (CL), central volume (V1), peripheral volume (V2), and intercompartmental clearance (Q). A covariate analysis identified that creatinine clearance (CLCR) was a significant covariate influencing biapenem CL, while blood urea nitrogen (BUN) was a significant covariate influencing biapenem Q. Accoding to the clinical outcome analyses, 70% of the time that the free antimicrobial drug concentration exceeds the MIC (fT >MIC) is associated with favourable clinical outcomes. The PPK model was then used to perform Monte Carlo simulations to evaluate the probability of attaining 70% fT >MIC. Conclusions: A final PPK model of biapenem was established for patients with sepsis. The current daily dosage regimen of 1.2 g may insufficient to achieve 70% fT >MIC in septic patients. The dosage regimen of 600 mg every 6 h appears to be the optimal choice.

Biapenem, a Carbapenem Antibiotic, Elicits Mycobacteria Specific Immune Responses and Reduces the Recurrence of Tuberculosis.

Tuberculosis (TB) still tops the list of global health burdens even after COVID-19. However, it will sooner transcend the current pandemic due to the prevailing risk of reactivation of latent TB in immunocompromised individuals. The indiscriminate misuse and overuse of antibiotics have resulted in the emergence of deadly drug-resistant variants of Mycobacterium tuberculosis (M.tb). This study aims to characterize the functionality of the carbapenem antibiotic-Biapenem (BPM) in generating long-lasting immunity against TB. BPM treatment significantly boosted the activation status of the innate immune arm-macrophages by augmenting p38 signaling. Macrophages further primed and activated the adaptive immune cells CD4+ and CD8+ T-cells in the lung and spleen of the infected mice model. Furthermore, BPM treatment significantly amplified the polarization of T lymphocytes toward inflammatory subsets, such as Th1 and Th17. The treatment also helped generate a long-lived central memory T-cell subset. The generation of central memory T lymphocyte subset upon BPM treatment in the murine model led to a significant curtailing in the recurrence of TB due to reactivation and reinfection. These results suggest the potentiality of BPM as a potent adjunct immunomodulator to improve host defense against M.tb by enriching long-term protective memory cells. IMPORTANCE Tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) tops the list of infectious killers around the globe. The emergence of drug-resistant variants of M.tb has been a major hindrance toward realizing the "END TB" goal. Drug resistance has amplified the global burden toward the quest for novel drug molecules targeting M.tb. Host-directed therapy (HDT) offers a lucrative alternative to tackle emerging drug resistance and disease relapse by strengthening the host's immunity. Through our present study, we have tried to characterize the functionality of the carbapenem antibiotic-Biapenem (BPM). BPM treatment significantly augmented long-lasting immunity against TB by boosting the innate and adaptive immune arms. The generation of long-lived central memory T lymphocyte subset significantly improved the disease outcome and provided sterilizing immunity in the murine model of TB. The present investigation's encouraging results have helped us depict BPM as a potent adjunct immunomodulator for treating TB.

Optimal dosing regimen of biapenem based on population pharmacokinetic/pharmacodynamic modelling and Monte Carlo simulation in patients with febrile neutropenia and haematological malignancies.

In the current study, a population pharmacokinetic (PPK) model was developed for biapenem in patients with febrile neutropenia (FN) and haematological malignancies. Through Monte Carlo simulation, optimal administration regimens were suggested based on the developed PPK model. In a prospective, single-centre, open-label study, 174 plasma samples from 120 Chinese patients with FN and haematological malignancies were analysed by chromatography, and PK parameters were analysed by NONMEM. The drug clearance process was influenced by crucial covariates, namely creatinine clearance (CLCR) and concomitant posaconazole (POS). The ultimate PPK model was as follows: CL (L/h)=29.81 × (CLCR/121.38)0.806 × (1-POS × 0.297); volume of distribution (L)=114. For the target of ≥40% fT>minimum inhibitory concentration (MIC) (duration that the plasma level exceeds the MIC of the causative pathogen) and achieving the probability of target attainment ≥90%, the PK/pharmacodynamic breakpoint was 2 mg/L for the 2.4 g/day dosing regimen consisting of 600 mg q6h and 800 mg q8h. The breakpoint was 1 mg/L for the 1.2 g/day dosing regimen consisting of 300 mg q6h and 600 mg q12h. Empirical therapy would benefit from utilizing higher dosages and extended infusion durations. Therefore, it is suggested that patients with symptoms that are strongly suggestive of Pseudomonas aeruginosa or Acinetobacter baumannii infection may be suitable for combined treatment with other antibacterial drugs.

Efficacy of Omadacycline-Containing Regimen in a Mouse Model of Pulmonary Mycobacteroides abscessus Disease.

Mycobacteroides abscessus is an opportunistic pathogen in people with structural lung conditions such as bronchiectasis, chronic obstructive pulmonary disease, and cystic fibrosis. Pulmonary M. abscessus infection causes progressive symptomatic and functional decline as well as diminished lung function and is often incurable with existing antibiotics. We investigated the efficacy of a new tetracycline, omadacycline, in combination with existing antibiotics recommended to treat this indication, in a mouse model of M. abscessus lung disease. Amikacin, azithromycin, bedaquiline, biapenem, cefoxitin, clofazimine, imipenem, linezolid, and rifabutin were selected as companions to omadacycline. M. abscessus burden in the lungs of mice over a 4-week treatment duration was considered the endpoint. Omadacycline in combination with linezolid, imipenem, cefoxitin, biapenem, or rifabutin exhibited early bactericidal activity compared to any single drug. Using three M. abscessus isolates, we also determined the in vitro frequency of spontaneous resistance against omadacycline to be between 1.9 × 10-10 and 6.2 × 10-10 and the frequency of persistence against omadacycline to be between 5.3 × 10-6 and 1.3 × 10-5. Based on these findings, the combination of omadacycline and select drugs that are included in the recent treatment guidelines may exhibit improved potency to treat M. abscessus lung disease. IMPORTANCE M. abscessus disease incidence is increasing in the United States. This disease is difficult to cure with existing antibiotics. In this study, we describe the efficacy of a new tetracycline antibiotic, omadacycline, in combination with an existing antibiotic to treat this disease. A mouse model of M. abscessus lung disease was used to assess the efficacies of these experimental treatment regimens. Omadacycline in combination with select existing antibiotics exhibited bactericidal activity during the early phase of treatment.

Research progress in pharmacokinetics/pharmacodynamics and therapeutic drug monitoring of biapenem / 中国药房

Biapenem is a carbapenem antibiotic， and can be used for the treatment of sepsis， pneumonia， lung abscess， chronic respiratory lesions secondary infection， complex urinary tract infection and pyelonephritis， etc. This article reviewed the studies on the pharmacokinetics， pharmacodynamics and therapeutic drug monitoring （TDM） of biapenem. The pharmacokinetic parameters of biapenem are not significantly different in healthy subjects， and there is no accumulation after multiple doses of biapenem. However， there are large differences in pharmacokinetic parameters in patients with severe disease and patients with abnormal renal function compared with healthy subjects， which leads to conventional treatment regimens not achieving the desired outcome. In terms of pharmacodynamics， biapenem can improve the rate of reaching the target value by increasing the frequency of administration and prolonging the infusion time. For patients with anuria in end-stage renal disease， dosing intervals can be extended to avoid drug accumulation. However, for patients with severe infection, a daily dose of 1.2 g still can not control infections caused by Acinetobacter baumannii or Pseudomonas aeruginosa, which limits its use in patients with severe disease. It is recommended to implement TDM in severe patients and patients with abnormal renal function， and explore the best dosing regimen for biapenem in combination with pharmacokinetic models to ensure that the time that the free blood concentration of biapenem remains above minimum inhibitory concentration as a percentage of the time between doses （%fT＞MIC） is within the effective range，so that biapenem can exert a greater efficacy in severe patients and patients with abnormal renal function. For medical institutions that cannot carry out TDM， the efficacy of biapenem can be maximized by increasing the frequency of administration and prolonging the infusion time. For infections caused by P. aeruginosa， A. baumannii and Serratia marcescens with high drug resistance rates， it is recommended to combine or replace other antibiotics.

Real-world Biapenem vs. Meropenem in the treatment of severe community-acquired pneumonia in children: A propensity score matching analysis.

Objective: To compare the real-world efficacy and safety of Biapenem and Meropenem for treating severe community-acquired pneumonia (SCAP) in children. Methods: We retrospectively evaluated 915 children with SCAP who were treated with Biapenem or Meropenem from August 2018 to June 2022. A 1:1 propensity score matching (PSM) analysis was used to reduce the actual baseline difference between groups. Results: 416 patients participated in the analysis after PSM (Biapenem: Meropenem = 1:1). For the Biapenem group and Meropenem group, the effective rates were 90.4% and 90.9%, respectively (p = 1.0) and the incidence of adverse reactions were 7.7% and 7.2%, respectively (p = 1.0). There were no statistical differences between Biapenem and Meropenem. Conclusion: In general, the efficacy and safety of Biapenem are comparable to Meropenem in the treatment of children with SCAP.

Mutation and evolution of metallo-beta-lactamase CphA under the selective pressure of biapenem continuous concentration gradient.

One of the resistance mechanisms of superbugs is to hydrolyze antibiotics by producing metallo-ß-lactamases (MßLs). To verify how MßLs evolved to increase in activity in response to various ß-lactam antibiotics, the mutation and evolution of CphA from Aeromonas hydrophila (Zn2+-dependent MßL) was investigated in a medium with a continuous biapenem (BIA) concentration gradient. The results showed that a single-base mutation M1 and two frameshift mutations M3 and M4 were observed. Furthermore, a nonsense mutation M2 was observed. Compared with wild-type (WT), the minimum inhibitory concentrations (MICs) of the M3 and M4 increased by more than 128 times, and the catalytic efficiency of BIA by the M3 and M4 increased by 752% and 376% respectively. In the mutants, the carbon skeleton migration caused by the outward motion of the loop3 near the entrance of the binding pocket increased the cavity volume of the binding pocket and was more conducive to the entry and expulsion of BIA and its hydrolytic product in the binding pocket. The conformational change effect originated from mutations is transmitted to the binding pocket through the interactions between the side chain amino acid residues of the C-terminal and those of the loop3, thus affecting the binding and hydrolysis capability of the mutants to BIA in the binding pocket. All these indicated that during the repeated drug-endurance and -resistance, the CphA completed its mutation and conformational change and evolved to the mutants with a more delicate structure and stronger hydrolysis ability by a genetic mutation.

Studies on the Reactions of Biapenem with VIM Metallo ß-Lactamases and the Serine ß-Lactamase KPC-2.

Carbapenems are important antibacterials and are both substrates and inhibitors of some ß-lactamases. We report studies on the reaction of the unusual carbapenem biapenem, with the subclass B1 metallo-ß-lactamases VIM-1 and VIM-2 and the class A serine-ß-lactamase KPC-2. X-ray diffraction studies with VIM-2 crystals treated with biapenem reveal the opening of the ß-lactam ring to form a mixture of the (2S)-imine and enamine complexed at the active site. NMR studies on the reactions of biapenem with VIM-1, VIM-2, and KPC-2 reveal the formation of hydrolysed enamine and (2R)- and (2S)-imine products. The combined results support the proposal that SBL/MBL-mediated carbapenem hydrolysis results in a mixture of tautomerizing enamine and (2R)- and (2S)-imine products, with the thermodynamically favoured (2S)-imine being the major observed species over a relatively long-time scale. The results suggest that prolonging the lifetimes of ß-lactamase carbapenem complexes by optimising tautomerisation of the nascently formed enamine to the (2R)-imine and likely more stable (2S)-imine tautomer is of interest in developing improved carbapenems.

Moxifloxacin combined with biapenem for severe pneumonia in 65 older adult patients / 中国基层医药

Objective:To investigate the clinical effects of moxifloxacin combined with biapenem on controlling inflammatory responses and improving immune function in older adult patients with severe pneumonia.Methods:120 older adult patients with severe pneumonia, who received treatment in the Second People's Hospital of Lishui from February 2017 to March 2020, were included in this study. They were randomly assigned to receive either biapenem (control group, n = 55) or moxifloxacin combined with biapenem (observation group, n = 65) for 7 days. Inflammatory response control, immune function improvement, and adverse reactions were assessed in each group after treatment. Results:After treatment, levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP) and procalcitonin (PCT) in the observation group were (24.51 ± 4.24) ng/L, (12.51 ± 3.15) mg/L and (4.62 ± 1.05) μg/L, respectively, which were significantly lower than those in the control group [(48.74 ± 4.67) ng/L, (26.80 ± 4.24) mg/L, (8.92 ± 1.10) μg/L, t = 29.77, 21.14, 21.87, all P < 0.001). The proportion of CD 3+ and CD 4+ cells and CD 4+ / CD 8+ ratio in the observation group were (63.27 ± 3.72)%, (39.97 ± 2.18)%, 1.79 ± 0.16, respectively, which were significantly higher than those in the control group [(55.58 ± 2.28)%, (35.18 ± 2.62)%, 1.41 ± 0.15, t = 17.08, 10.93, 13.34, all P < 0.001). Total effective rate was significantly higher in the observation group than in the control group [96.92% (63/65) vs. 83.64% (46/55), χ2 = 6.32, P < 0.05]. There was no significant difference in the incidence of adverse reactions between observation and control groups [10.77% (7/65) vs. 9.09% (5/55), χ2 = 0.09, P > 0.05]. Conclusion:Moxifloxacin combined with biapenem based on routine treatment for severe pneumonia in older adult patients can greatly strengthen anti-inflammatory effects, improve immune function, and enhance clinical efficacy without increasing adverse drug reactions.

In vitro effectiveness of biapenem against IMP-producing Enterobacteriaceae.

The options available for treating infections with carbapenemase-producing Enterobacteriaceae (CPE) are limited; with the increasing threat of these infections, new treatments are urgently needed. Biapenem (BIPM) is a carbapenem, and limited data confirming its in vitro killing effect against CPE are available. In this study, we examined the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of BIPM for 14 IMP-1-producing Enterobacteriaceae strains isolated from the Okayama region in Japan. The MICs against almost all the isolates were lower than 0.5 µg ml-1, indicating susceptibility to BIPM, while approximately half of the isolates were confirmed to be bacteriostatic to BIPM. However, initial killing to a 99.9 % reduction was observed in seven out of eight strains in a time-kill assay. Despite the small data set, we concluded that the in vitro efficacy of BIPM suggests that the drug could be a new therapeutic option against infection with IMP-producing CPE.

Ulinastatin plus biapenem for severe pneumonia in the elderly and its influence on pulmonary function and inflammatory cytokines.

To estimate the efficacy of ulinastatin (UTI) plus biapenem (BIPM) in the treatment of severe pneumonia in the elderly and its influence on pulmonary function (PF) and inflammatory cytokines. METHODS: We included 97 elderly patients with severe pneumonia in the present study. Patients in control group (n=47) were given BIPM, and those in research group (n=50) were treated with BIPM plus UTI. The clinical efficacy, adverse reactions, arterial blood gas (ABG) indices, PF and inflammatory cytokines were recorded. RESULTS: Patients in the research group had earlier fever clearance, inflammation absorption and cough disappearance than those in control group, as well as better clinical efficacy. In addition, no significant differences were found in the incidence of adverse reactions between the two groups during treatment. Monitoring changes in ABG indices, PF, and inflammatory cytokines revealed increased levels of PaO2, pH, FEV1, FVC, FEV1/FVC after treatment, but levels of PaCO2, IL-1ß, IL-6, TNF-α, and hs-CRP decreased compared to before treatment. Levels of indices that increased after treatment in the research group were higher than those in the control group, whereas the levels of other indices that decreased after treatment were lower. CONCLUSION: The combination of UTI and BIPM shortens the time of symptom disappearance, enhances PF, and inhibits inflammation, achieving higher efficacy in the treatment of severe pneumonia in the elderly.

Role of organic anion transporter 3 in the renal excretion of biapenem and potential drug-drug interactions.

Biapenem is a carbapenem antibiotic. It is excreted predominantly through the kidney as unchanged forms. However, the molecular mechanism of renal excretion of biapenem and potential drug-drug interactions (DDIs) were still unknown. In the present study, the role of organic anion transporters (OAT) 1/3 and organic cation transporters (OCT) 2 in the renal excretion of biapenem, and the potential DDIs between biapenem and six clinical commonly prescribed antibiotics and antiviral drugs that acted as substrates or inhibitors of OAT3 were evaluated in vitro. Further, the effect of probenecid on the pharmacokinetics of biapenem was explored in the rats. We observed that biapenem could not inhibit the transport activities of OAT1 or OCT2, while mildly inhibited OAT3 (IC50 >500 µM). Among the tested antibiotics and antiviral drugs, the relatively high DDI index values (maximal unbound plasma concentration over IC50, Imax,u/IC50) were found for piperacillin, linezolid and benzylpenicillin, which were 2.84, 1.7 and 0.62, respectively. Although probenecid had the highest DDI index (27.1) in vitro, no significant impact of it on the pharmacokinetics of biapenem was observed in the rats. Our results indicated that biapenem was primarily eliminated by the glomerular filtration, while OAT3-mediated renal tubular secretion was a minor route. Biapenem is not a clinically relevant substrate or inhibitor because of its low affinity to OAT3. According to current results, it would be safe to use biapenem with other antibiotics and antiviral drugs that acted as substrates or inhibitors of OAT3.

Biapenem reduces sepsis mortality via barrier protective pathways against HMGB1-mediated septic responses.

BACKGROUND: As a late mediator of sepsis, the role of high mobility group box 1 (HMGB1) has been recognized as important, and suppression of HMGB1 release and restoration of vascular barrier integrity are regarded as potentially promising therapeutic strategies for sepsis. For repositioning of previously FDA-approved drugs to develop new therapies for human diseases, screening of chemical compound libraries, biological active, is an efficient method. Our study illustrates an example of drug repositioning of Biapenem (BIPM), a carbapenem antibiotic, for the modulation of HMGB1-induced septic responses. METHODS: We tested our hypothesis that BIPM inhibits HMGB1-induced vascular hyperpermeability and thereby increases the survival of septic mouse model from suppression of HMGB1 release upon lipopolysaccharide (LPS)-stimulation. In LPS-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model, antiseptic activity of BIPM was investigated from suppression of vascular permeability, pro-inflammatory proteins, and markers for tissue injury. RESULTS: BIPM significantly suppressed release of HMGB1 both in LPS-activated HUVECs (upto 60%) and the CLP-induced sepsis mouse model (upto 54%). BIPM inhibited hyperpermeability (upto 59%) and reduced HMGB1-mediated vascular disruptions (upto 62%), mortality (upto 50%), and also tissue injury including lung, liver, and kidney in mice. CONCLUSION: Reduction of HMGB1 release and septic mortality by BIPM (in vitro, from 5 to 15 µM for 6 h; in vivo, from 0.37 to 1.1 mg/kg, 24 h) indicate a possibility of successful repositioning of BIPM for the treatment of sepsis.

Metabolomic Insights Into the Synergistic Effect of Biapenem in Combination With Xuebijing Injection Against Sepsis.

The drug combination of biapenem (BIPM) and xuebijing injection (XBJ) is commonly applied for the treatment of sepsis in China. However, the potential synergistic mechanism is still enigmatic. There have been no studies focused on the plasma metabolome alterations in sepsis after the intervention of this combination. In this work, an untargeted metabolomics approach was performed by liquid chromatography-mass spectrometry coupled with multivariate statistical analysis to provide new insights into the synergistic effect of BIPM in combination with XBJ. We characterized the metabolic phenotype of sepsis and described metabolic footprint changes in septic rats responding to XBJ and BIPM individually and in combination, in addition to histopathological and survival evaluation. A total of 91 potential biomarkers of sepsis were identified and 32 disturbed metabolic pathways were constructed. Among these biomarkers, 36 metabolites were reversely regulated by XBJ, mainly including glycerophospholipids, sphingolipids, free fatty acids (FFAs), bile acids and acylcarnitines; 42 metabolites were regulated by BIPM, mainly including amino acids, glycerophospholipids, and acylcarnitines; 72 metabolites were regulated after XBJ-BIPM combination treatment, including most of the 91 potential biomarkers. The results showed that the interaction between XBJ and BIPM indeed exhibited a synergistic effect by affecting some key endogenous metabolites, 15 metabolites of which could not be regulated when XBJ or BIPM was used alone. Compared with Model group, 13, 22, and 27 metabolic pathways were regulated by XBJ, BIPM, and XBJ-BIPM combination, respectively. It suggested that many more endogenous metabolites and metabolic pathways were significantly regulated after combination treatment compared with XBJ or BIPM monotherapy. Metabolisms of lipids, amino acids, acylcarnitines, and bile acids were common pathways involved in the synergistic action of XBJ and BIPM. This study was the first to employ metabolomics to elucidate the synergistic effect and decipher the underlying mechanisms of BIPM in combination with XBJ against sepsis. The results provide some support for clinical application of antibiotics in combination with traditional Chinese medicines and have important implications for the treatment of sepsis in clinic.

Biapenem as a Novel Insight into Drug Repositioning against Particulate Matter-Induced Lung Injury.

The screening of biologically active chemical compound libraries can be an efficient way to reposition Food and Drug Adminstration (FDA)-approved drugs or to discover new therapies for human diseases. Particulate matter with an aerodynamic diameter equal to or less than 2.5 µm (PM2.5) is a form of air pollutant that causes significant lung damage when inhaled. This study illustrates drug repositioning with biapenem (BIPM) for the modulation of PM-induced lung injury. Biapenem was used for the treatment of severe infections. Mice were treated with BIPM via tail-vein injection after the intratracheal instillation of PM2.5. Alterations in the lung wet/dry weight, total protein/total cell count and lymphocyte count, inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were monitored in the PM2.5-treated mice. BIPM effectively reduced the pathological lung injury, lung wet/dry weight ratio, and hyperpermeability caused by PM2.5. Enhanced myeloperoxidase (MPO) activity by PM2.5 in the pulmonary tissue was inhibited by BIPM. Moreover, increased levels of inflammatory cytokines and total protein by PM2.5 in the BALF were also decreased by BIPM treatment. In addition, BIPM markedly suppressed PM2.5-induced increases in the number of lymphocytes in the BALF. Additionally, the activity of mammalian target of rapamycin (mTOR) was increased by BIPM. Administration of PM2.5 increased the expression levels of toll-like receptor 4 (TLR4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1, which were suppressed by BIPM. In conclusion, these findings indicate that BIPM has a critical anti-inflammatory effect due to its ability to regulate both the TLR4-MyD88 and mTOR-autophagy pathways, and may thus be a potential therapeutic agent against diesel PM2.5-induced pulmonary injury.

Analysis of Related Substances in Biapenam by Micellar Electrokinetic Capillary Chromatography / 中国药学杂志

OBJECTIVE: To establish a method for analysis of related substances in biapenem with micellar electrokinetic capillary chromatography(MEKC). METHODS: In order to improve the separation selectivity, a zwitterionic surfactant, 3-(N, N-dimethylhexadecylammonium)-propanesulfonate(PAPS) was used. The optimal separation conditions were as follows: the total length of the capillary was 48.5 cm (the effective length was 48 cm), the buffer was 90 mmol•L-1 tris(hydroxymethyl)aminomethane (tris)-phosphate buffer containing 17 mmol•L-1 PAPS and 3 mg•mL-1 polyoxyethylene 23 lauryl ether (Brij 35), the applied voltage was 22 kV, and the capillary temperature was controlled at 30℃. Further more, the specificity, linearity, precision, repeatability, stability and durability were studied. The contents of related substances in biapenem commercial samples were analyzed. RESULTS: The MEKC method, which was a comparable analysis method to HPLC, successfully separated the adjacent impurities of biapenem by using the zwitterionic surfactant PAPS. The specific test showed that this method was especially suitable for the detection of biapenem dimers A, B and open-ring compound. CONCLUSION: In this method, MEKC with zwitterionic surfactant is for the first time applied to the analysis of related substances in biapenem (amphoteric drugs). It provides a feasible analysis method with high sensitivity, good specificity and reproducibility for the quality control of biapenem.

Activities of Biapenem against Mycobacterium tuberculosis in Macrophages and Mice.

OBJECTIVE: To assess the activities of biapenem against multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis. METHODS: Biapenem/clavulanate (BP/CL) was evaluated for in vitro activity against Mycobacterium tuberculosis (Mtb) multidrug-resistant (MDR) isolates, extensively drug-resistant (XDR) isolates, and the H37RV strain. BP/CL activity against the H37Rv strain was assessed in liquid cultures, in macrophages, and in mice.. RESULTS: BP/CL exhibited activity against MDR and XDR Mtb isolates in liquid cultures. BP/CL treatment significantly reduced the number of colony forming units (CFU) of Mtb within macrophages compared with control untreated infected macrophages. Notably, BP/CL synergized in pairwise combinations with protionamide, aminosalicylate, and capreomycin to achieve a fractional inhibitory concentration for each pairing of 0.375 in vitro. In a mouse tuberculosis infection model, the efficacy of a cocktail of levofloxacin + pyrazinamide + protionamide + aminosalicylate against Mtb increased when the cocktail was combined with BP/CL, achieving efficacy similar to that of the positive control treatment (isoniazid + rifampin + pyrazinamide) after 2 months of treatment. CONCLUSION: BP/CL may provide a new option to clinically treat MDR tuberculosis.

Recognition and interaction of CphA from Aeromonas hydrophila with imipenem and biapenem by spectroscopic analysis in combination with molecular docking.

The molecular recognition and interaction of CphA from Aeromonas hydrophila with imipenem (Imip) and biapenem (Biap) were studied by means of the combined use of fluorescence spectra and molecular docking. The results showed that both the fluorescence quenching of CphA by Imip and Biap were caused through the combined dynamic and static quenching, and the latter was dominating in the process; the microenvironment and conformational of CphA were altered upon the addition of Imip and Biap from synchronous and three-dimensional fluorescence. The binding of CphA with Imip or Biap caused a conformational change in the loop of CphA, and through the conformational change, the loop opened the binding pocket of CphA to allow for an induced fit of the newly introduced ligand. In the binding of CphA with Imip, the whole molecule entered into the active pocket of CphA. The binding was driven by enthalpy change, and the binding force between them was mainly hydrogen bonding and Van der Waals force; whereas in the binding of CphA with Biap, only the beta-lactam ring of Biap entered into the binding pocket of CphA while the side chain was located outside the active pocket. The binding was driven by the enthalpy change and entropy change together, and the binding force between them was mainly electrostatic interaction. This study provided an insight into the recognition and binding of CphA with antibiotics, which may be helpful for designing new substrate for beta-lactamase and developing new antibiotics resistant to superbugs.

Activities of Biapenem against Mycobacterium tuberculosis in Macrophages and Mice / 生物医学与环境科学（英文）

OBJECTIVE@#To assess the activities of biapenem against multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis.@*METHODS@#Biapenem/clavulanate (BP/CL) was evaluated for in vitro activity against Mycobacterium tuberculosis (Mtb) multidrug-resistant (MDR) isolates, extensively drug-resistant (XDR) isolates, and the H37RV strain. BP/CL activity against the H37Rv strain was assessed in liquid cultures, in macrophages, and in mice..@*RESULTS@#BP/CL exhibited activity against MDR and XDR Mtb isolates in liquid cultures. BP/CL treatment significantly reduced the number of colony forming units (CFU) of Mtb within macrophages compared with control untreated infected macrophages. Notably, BP/CL synergized in pairwise combinations with protionamide, aminosalicylate, and capreomycin to achieve a fractional inhibitory concentration for each pairing of 0.375 in vitro. In a mouse tuberculosis infection model, the efficacy of a cocktail of levofloxacin + pyrazinamide + protionamide + aminosalicylate against Mtb increased when the cocktail was combined with BP/CL, achieving efficacy similar to that of the positive control treatment (isoniazid + rifampin + pyrazinamide) after 2 months of treatment.@*CONCLUSION@#BP/CL may provide a new option to clinically treat MDR tuberculosis.

Evaluating biapenem dosage regimens in intensive care unit patients with Pseudomonas aeruginosa infections: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation.

This study was conducted to identify optimal dosage regimens and estimate pharmacokinetic/pharmacodynamic (PK/PD) characteristics of short-infusion (SI) versus extended-infusion (EI) biapenem against Pseudomonas aeruginosa infections in Chinese intensive care unit (ICU) patients. A total of 85 strains of P. aeruginosa were collected, and the minimum inhibitory concentration (MIC) of biapenem was measured by the serial two-fold agar dilution method. We designed four frequently used clinical regimens: biapenem 300 mg I.V. q12h, q8h, and q6h, and 600 mg q12h. The Monte Carlo Simulation (MCS) was performed using previously published pharmacokinetic data to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of these regimens as an SI (0.5 h) and an EI (1 h, 2 h, 3 h, and 4 h). For a target of 40%fT>MIC (serum drug concentration remains above the MIC for a dosing period), none of the regimens achieved any CFRs>90% for P. aeruginosa, multidrug-resistant P. aeruginosa (MDR-PA) and even non-MDR-PA. The traditional biapenem SI regimens most commonly seen in clinical practice were insufficient in treating both MDR and non-MDR P. aeruginosa in ICU patients. However, biapenem 600 mg q12h over 2-4 h EI regimens could achieve CFR>90% with 20%fT>MIC. Clinical trials should aim to validate the potentially greater PK/PD index with higher, more frequent doses and longer extended infusions.