BACKGROUND:We aimed to explore the population pharmacokinetics and pharmacodynamics (popPK/PD) of ciprofol in paediatric patients and to provide references for dose optimisation of ciprofol as initiation and maintenance dosages in paediatric patients. METHODS:Anaesthesia was induced with ciprofol at doses of 0.6 mg kg-1 or 0.9 mg kg-1 in paediatric patients (n=88; 0.08-15 yr; weight, 4.2-71.0 kg) undergoing cardiac or thoracic surgery. Blood samples were collected using opportunistic blood sampling, and ciprofol concentration was determined by a validated analytical method. A popPK/PD model of ciprofol was developed. The relationship between bispectral index (BIS) and drug concentration was characterised by an effect compartment model in children younger than 3 yr of age. RESULTS:A two-compartment model with body weight and an empirical maturation process as covariates optimally characterised ciprofol PK. The recommended induction dose was 0.6 mg kg-1. Maintenance of anaesthesia which targeted an optimal BIS range of 40-60 using simulation-based, weight-stratified infusion regimens was recommended as follows: 1.4 mg kg-1 h-1 for patients weighing 0-5 kg, 1.2 mg kg-1 h-1 for those weighing 5-30 kg, and 1.0 mg kg-1 h-1 for patients weighing >30 kg, with escalation to higher doses only under continuous BIS monitoring to avoid oversedation. CONCLUSIONS:A ciprofol induction dose of 0.6 mg kg-1 followed by a weight-stratified maintenance infusion of 1.0-1.4 mg kg-1 h-1 is recommended for paediatric anaesthesia. Extrapolation to children 3 yr of age and older assumed similarity in PD response, and potential inaccuracy in this age group is cautioned. CLINICAL TRIAL REGISTRATION:ChiCTR2600118090.

PURPOSE: This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model for aztreonam and amoxicillin/clavulanate to optimize pediatric dosing regimens against multidrug-resistant Gram-negative bacteria, particularly Escherichia coli and Klebsiella pneumoniae, while addressing gaps in tissue-specific drug exposure data. METHODS: PBPK models for aztreonam, amoxicillin, and clavulanate were developed and scaled to pediatric populations. Virtual pediatric subjects aged 2 to < 18 years were simulated and stratified by age group and dosing strategy. Drug concentrations were predicted in plasma, lung, skin, and brain tissues. Model performance was evaluated using published clinical pharmacokinetic data, with mean fold errors for Cmax and AUC within 0.5-2.0. Multiple clinically relevant dosing regimens were assessed, including standard q8h dosing, shortened dosing intervals (q6h), and prolonged infusion durations (up to 3 h). Probability of target attainment (PTA) was calculated based on predefined pharmacodynamic targets and reported MIC distributions. RESULTS: PBPK simulations demonstrated that dosing interval, infusion duration, and age group substantially influenced tissue exposure and PTA. Compared with q8h regimens, q6h dosing increased systemic and tissue exposure for aztreonam and amoxicillin, leading to improved PTA in plasma, lung, and skin tissues. Prolonged infusion further increased fT > MIC and PTA in peripheral tissues, whereas brain exposure and target attainment remained limited across regimens. Adolescents receiving adult fixed doses achieved higher PTA than younger children receiving weight-based dosing. Clavulanate showed consistently lower PTA, with effective target attainment restricted to low MIC ranges. CONCLUSION: A pediatric PBPK model for aztreonam-amoxicillin/clavulanate combination allows for an evaluation of tissue-specific target attainment in multidrug-resistant infection condition. These findings underscore the utility of PBPK modeling in guiding pediatric antibiotic stewardship and combating antimicrobial resistance.

ABSTRACT Multidrug-resistant Escherichia coli poses a significant threat to the healthcare system by causing treatment failure in infected patients. The use of a beta-lactam in combination with a beta-lactamase inhibitor has been shown to be an effective strategy to solve this problem. In vitro antimicrobial susceptibility experiments have demonstrated the antimicrobial activity of aztreonam and clavulanate. In this investigation, we conducted a transcriptomic analysis to reveal the downstream differential gene expression in E. coli ymmD45 (a strain newly isolated and found to carry the New Delhi metallo-β-lactamase gene) following exposure to aztreonam and clavulanate separately, as well as their combination. Differential gene expression, pathway enrichment, and gene network analyses demonstrated the polygenic nature of the response to the combination treatment, which suppressed the expression of pivotal virulence genes, disrupted two-component regulatory systems for bacteria to resist external stress, and interfered with the formation of the cellular membrane. Results from single-step mutant selection combined with deep whole-genome sequencing also revealed the spontaneous origin of the resistance mutations and confirmed action mechanisms during the combination treatment. Our study contributes valuable insights into the impact of antibiotic exposure on gene expression, laying the groundwork for understanding antibiotic resistance development in the treatment of multi-drug resistant infections through in vitro studies.IMPORTANCEMultidrug-resistant Escherichia coli is a major challenge in treating infections effectively. Aztreonam and clavulanate combination is promising in combating these resistant bacteria. By investigating the antimicrobial activity of aztreonam and clavulanate using transcriptomic analysis and mutant selection, this research sheds light on the mechanisms underlying antibiotic resistance and the effectiveness of combination therapies. The findings highlight how this particular antibiotic combination suppresses virulence genes, disrupts bacterial regulatory systems, and interferes with cellular functions critical for resistance. Moreover, the study lays the groundwork for understanding antibiotic resistance development in the treatment of multi-drug resistant infections through in vitro studies, offering insights that could inform future strategies in clinical settings. Ultimately, our findings could guide the development of better treatment strategies for multidrug-resistant infections, improving patient outcomes and helping to manage antibiotic resistance in healthcare.

Objective:In this study, a highly selective and sensitive LC-MS/MS method was developed to comprehensively analyze the distribution of astaxanthin across various tissues of Litopenaeus vannamei, as well as its variations in the hepatopancreas and ovary throughout ovarian development. Methods:The separation was performed on a BEH C8 column (1.7 μm, 2.1 × 50 mm) using a a gradient elution. The initial mobile phase composition was 0.1% formic acid in 3 mM ammonium acetate in water (solvent A) and methanol (solvent B) at a ratio of 15:85 (v/v), with a flow rate of 0.20 mL/min. Results:The assay demonstrated linearity over a concentration range of 20 to 10,000 ng/mL, with accuracy varying from -0.1 to 1.7% and precision within 2.1%. Using the established methodology, astaxanthin concentrations were quantitatively analyzed and comparatively assessed across various tissues of L. vannamei. Analytical results demonstrated that the ventral nerve cord and hepatopancreas exhibited the highest astaxanthin concentrations among all examined tissues, with values of 351 μg/g and 116 μg/g, respectively. During the ovarian developmental stages, astaxanthin was predominantly sequestered in the hepatopancreas during early phases, with concentrations ranging from 21.3 μg/g to 29.1 μg/g, representing a 43- to 59-fold increase compared to ovarian concentrations. However, a significant redistribution of astaxanthin was observed during the post-developmental stage, characterized by a substantial decrease to 5.74 μg/g in the hepatopancreas, concomitant with an increase to 7.47 μg/g in ovarian tissue. Conclusion:This validated LC-MS/MS method effectively quantified astaxanthin in various tissues of Litopenaeus vannamei, providing new insights into its tissue-specific distribution and potential role during ovarian development.

Melatonin supplements have been widely used to improve sleep quality and overcome sleep disorders, with melatonin and vitamin B6 serving as the primary active ingredients. This study developed a novel analytical method for the simultaneous quantification of melatonin and vitamin B6 using 1H-NMR spectroscopy. The characteristic signals of melatonin and vitamin B6 hydrochloride at δ 7.09 ppm and δ 8.12 ppm were selected for quantitative analysis, with maleic acid used as the internal standard. The method was validated for specificity, precision, and stability. The results demonstrate that the method exhibits high precision and complies with the guidelines established by the China Food and Drug Administration (CFDA). Furthermore, this method has been successfully applied to commercially available formulations. Compared to conventional methods, the 1H-NMR technique offers a more efficient and simpler alternative, making it suitable for the simultaneous quantitative determination of melatonin and vitamin B6 hydrochloride. This approach ensures the quality, stability, and safety of commercial melatonin products.

Guided by the principles of Analytical Quality by Design (AQbD), a highly selective and sensitive LC-MS/MS method was established for the simultaneous quantification of 15 compounds in Shouhui Tongbian capsules, enabling their effective quality control. The separation was carried out on a BEH C18 column (1.7 μm, 2.1 × 100 mm) with a mobile phase comprising 0.1% formic acid in 3 mM ammonium acetate aqueous solution and methanol (60 : 40, v/v) at a flow rate of 0.30 mL min-1. The method exhibited good linearity within a certain concentration range (R2 > 0.9906) depending on the compound; the precision ranged from 0.6% to 14.7% and accuracy was within 11.2%. Among the 15 detected compounds, aloin had the highest content in the Shouhui Tongbian capsules, reaching 227.3780 mg g-1, followed by betaine and L-hydroxyproline, with concentrations of 1.3204 mg g-1 and 1.2929 mg g-1, respectively. This method simultaneously detected the content of 15 compounds in five batches of Shouhui Tongbian capsules.

Antibody–drug conjugates (ADCs) are intricate compounds that pose significant challenges in bioanalytical characterization. Therefore, multiple bioanalytical methods are required to comprehensively elucidate their pharmacokinetic (PK) profiles. In this study, we investigated DS001, an ADC consisting of a humanized monoclonal antibody (hRS7), a cleavable chemical linker, and the microtubule inhibitor monomethyl auristatin E (MMAE), with a drug-to-antibody ratio (DAR) of 8. This study established a rapid and sensitive hybrid immunoaffinity liquid-chromatography-tandem-mass-spectrometry (LC–MS/MS) approach for the simultaneous quantification of the total antibody and the enzymatically cleavable conjugated payload of DS001. This method is capable of monitoring fluctuations in average DAR values during PK assessments. The sample preparation procedure involved immunocapture, denaturation, trypsin digestion, papain digestion, and termination, all completed within a total processing time of less than 4 h. The method demonstrated linearity for the total antibody in the range of 100 ng/mL (lower-limit-of-quantification, LLOQ) to 100,000 ng/mL, and for the conjugated payload from 3.495 ng/mL (LLOQ) to 3495 ng/mL in rat serum. Both analytes exhibited standard curve correlation coefficients (r) greater than 0.990 within their respective linear ranges. The precision and accuracy of the method were within ± 15

Renshen Guben oral liquid, a traditional Chinese medicine derived from Liuwei Dihuang Pill, is widely used for symptoms associated with Qi and Yin deficiency. However, its complex multi-herbal composition complicates quality assessment; existing methods relying on limited marker compounds are insufficient to reflect its pharmacological basis. This study developed a robust and sensitive UHPLC-MS/MS method for the simultaneous determination of 11 representative active constituents, including ginsenosides, paeonol, and catalpol. Guided by Analytical Quality by Design principles, chromatographic conditions, and MS parameters were optimized to ensure selectivity and sensitivity. The method achieved complete separation within 15 min of run time and exhibited excellent linearity (R-2 >= 0.9899), low quantification limits (1-50 ng/mL), and acceptable precision and accuracy (relative standard deviations <= 15%; recoveries 87.5%-113.7%). Evaluation using Analytical Eco-Scale and AGREE tools yielded favorable green chemistry scores. The method was successfully applied to five batches of samples, revealing batch-to-batch variability, particularly in ginsenosides and paeonol content, suggesting that raw material source and processing may impact consistency. This UHPLC-MS/MS method provides a comprehensive tool for quality control of complex herbal preparations and supports further pharmacological and pharmacokinetic investigations.

IntroductionThis study aimed to characterize time-dependent metabolic alterations and identify metabolites associated with treatment response in HER2-negative breast cancer patients undergoing neoadjuvant chemotherapy (NAC) with the TEC regimen (docetaxel, epirubicin, and cyclophosphamide).MethodsA total of 60 plasma samples were collected from 20 patients at three time points: baseline (T1), after three cycles of NAC (T2), and before surgery (T3). Pathological assessment classified patients into three response groups: pathologic complete response (pCR, n = 5), pathologic partial response (pPR, n = 7), and pathologic stable disease (pSD, n = 8).ResultsAfter three cycles of NAC, a greater decrease in glycochenodeoxycholate was associated with poorer treatment response, whereas a larger reduction in LysoPC(18:1) correlated with better response. Following six cycles, elevated epinephrine levels were positively associated with therapeutic efficacy, while increased cysteine levels were linked to unfavorable outcomes. Ursodeoxycholic acid showed an upward trend in pCR patients but declined in pPR and pSD groups. Combined analysis of ursodeoxycholic acid and cysteine improved the predictive performance for treatment response.DiscussionThese findings reveal dynamic metabolic reprogramming during NAC and suggest that ursodeoxycholic acid and cysteine may serve as potential predictive biomarkers of therapeutic efficacy in HER2-negative breast cancer patients treated with the TEC regimen.

Background:Fosfomycin combined with other antibiotics is often used to treat Pseudomonas aeruginosa infections. In this study, we investigated the effects of fosfomycin and azithromycin as monotherapy and combination therapy on the metabolic changes of multidrug-resistant P. aeruginosa. Methods:Multidrug-resistant P. aeruginosa was exposed to fosfomycin, azithromycin, or their combination. Non-targeted metabolomic profiling was performed using LC-MS/MS. Differential metabolites were identified statistically using Student's t-test, with significance defined as p < 0.05 and log2 fold change (log2FC) ≥ 1 or ≤ -1. Results:The minimum inhibitory concentration was 32/4 μg/mL for fosfomycin/azithromycin combination against the P. aeruginosa strain evaluated for metabolomic changes. Metabolomic analysis showed that the combination therapy resulted in greater disturbances affecting the abundance and content levels of metabolites of P. aeruginosa than monotherapies. The affected metabolic pathways were mainly amino acid metabolism, nucleotide metabolism, carbohydrate metabolism and lipid metabolism, among which nucleotide metabolism was most significantly disturbed. In the nucleotide metabolism, purine metabolism was affected more than pyrimidine metabolism. Conclusion:Fosfomycin-azithromycin combination therapy exerted stronger interference on the metabolic pathways of P. aeruginosa than either drug alone, indicating more substantial metabolic alterations at the cellular level. These findings provide mechanistic insights that may help inform the potential application of combination regimens against multidrug-resistant P. aeruginosa in the clinic.

Emerging pharmaceutical markets like Brazil, India, and China have seen significant growth due to rising medication demand, expanding middle-class access, and government support. However, this growth often focuses on cost-driven strategies like generic drug production rather than innovation. Challenges such as fragmented regulatory systems, limited infrastructure, low R&D budgets, and dependence on imported active pharmaceutical ingredients (APIs) limit global competitiveness in drug innovation. R&D investment in these markets rarely exceeds 5% of revenue, compared to 20% in established markets, widening the innovation gap. Advanced technologies such as physiologically based pharmacokinetic (PBPK) modeling, artificial intelligence (AI), and virtual bioequivalence studies present opportunities to overcome these barriers. These tools streamline drug development, lower costs, and improve regulatory processes. For instance, a case study on generic donepezil showed that a $150,000 investment in PBPK modeling software could yield returns of 113.7% when clinical studies are required and 1,120% if a biowaiver is granted. These results demonstrate the financial and operational advantages of adopting innovative technologies, enabling faster market entry and scalability across portfolios. By embracing advanced tools, companies in emerging markets can align with global regulatory trends, enhance sustainability through resource efficiency, and improve access to affordable medicines. This approach bridges the gap between economic growth and technological leadership, fostering global competitiveness and contributing to public health advancements.

Coenzyme Q10 and vitamin E are among the most widely consumed nutritional supplements in China owing to their antioxidant and other health-promoting properties. This study aimed to establish an accurate and efficient analytical method for the simultaneous determination of these two compounds in commercial softgel capsules, which is essential for rigorous quality control. Herein, a proton nuclear magnetic resonance (1H NMR) method was developed and validated using coumarin as an internal standard. Characteristic signals at 3.997 ppm for coenzyme Q10 and 2.621 ppm for vitamin E were selected for quantification. The method demonstrated excellent performance in terms of precision (relative standard deviation <2%), specificity (resolution >1.5), and stability (24-h variation <3%). The validation results complied with the China Food and Drug Administration guidelines, demonstrating high accuracy. Application to products from four different manufacturers showed compound contents ranging from 98.2% to 102.4% of label amounts. These findings support 1H NMR spectroscopy as a rapid, precise, and reliable approach for the simultaneous quality assessment of coenzyme Q10 and vitamin E formulations.

Hirudo nipponica Whitman has been utilized in traditional medicine for centuries for its bioactive components. In this study, a novel polysaccharide, which was called SZ, was isolated from H. nipponica Whitman through enzymatic hydrolysis, alkaline extraction, and chromatographic purification. The structure of SZ was characterized using high-performance liquid chromatography (HPLC), Fourier-transform infrared spectroscopy (FT-IR), gas chromatography-mass spectrometry (GC-MS), and nuclear magnetic resonance (NMR) spectroscopy. The results revealed that SZ has a prevalent component monosaccharide of glucose (Glc) and a backbone of →4-)α-D-Glcp-(1 → residues, with branches attached at O-3 and O-6 positions. The molecular weight of SZ was determined to be 221.28 kDa. SZ exhibited potent immune-enhancing activity in vitro, as demonstrated by its ability to modulate the expression of inflammatory cytokines in RAW264.7 macrophages. Real-time quantitative PCR analysis further confirmed the immunomodulatory effects of SZ on RAW264.7 cells, showing significant upregulation of iNOS, TNF-α, and IL-6 mRNA expression. This study suggests that SZ has the potential to serve as an immunomodulatory agent.

BackgroundThe combination antimicrobial therapy consisting of amikacin, polymyxin-B, and sulbactam demonstrated in vitro synergy against multi-drug resistant Acinetobacter baumannii.ObjectivesThe objectives were to predict drug disposition and extrapolate their efficacy in the blood, lung, heart, muscle and skin tissues using a physiologically-based pharmacokinetic (PBPK) modeling approach and to evaluate achievement of target pharmacodynamic (PD) indices against A. baumannii.MethodsA PBPK model was initially developed for amikacin, polymyxin-B, and sulbactam in adult subjects, and then scaled to pediatrics, accounting for both renal and non-renal clearances. The simulated plasma and tissue drug exposures were compared to the observed data from humans and rats. Efficacy was inferred using joint probability of target attainment of target PD indices.ResultsThe simulated plasma drug exposures in adults and pediatrics were within the 0.5 to 2 boundary of the mean fold error for the ratio between simulated and observed means. Simulated drug exposures in blood, skin, lung, and heart were consistent with reported penetration ratio between tissue and plasma drug exposure. In a virtual pediatric population from 2 to <18 years of age using pediatric dosing regimens, the interpretive breakpoints were achieved in 85–90% of the population.ConclusionThe utility of PBPK to predict and simulate the amount of antibacterial drug exposure in tissue is a practical approach to overcome the difficulty of obtaining tissue drug concentrations in pediatric population. As combination therapy, amikacin/polymyxin-B/sulbactam drug concentrations in the tissues exhibited sufficient penetration to combat extremely drug resistant A. baumannii clinical isolates.

Aztreonam/avibactam is effective against serious infections caused by Gram-negative bacteria including Enterobacterales harboring metallo-β-lactamases. While the utility of this combination has been established in vitro and in clinical trials, the purpose of this study is to enhance our understanding of the underlying mechanism responsible for their activities through metabolomic profiling of a multidrug-resistant Escherichia coli clinical isolate. Metabolomic analyses of time-dependent changes in endogenous bacterial metabolites in a clinical isolate of a multidrug-resistant E. coli treated with aztreonam and avibactam were performed. E. coli metabolomes were compared at 15 min, 1 h and 24 h following treatments with either avibactam (4 mg/L), aztreonam (4 mg/L), or aztreonam (4 mg/L) + avibactam (4 mg/L). Drug treatment affected 326 metabolites with magnitude changes of at least 2-fold, most of which are involved primarily in peptidoglycan biosynthesis, nucleotide metabolism, and lipid metabolism. The feedstocks for peptidoglycan synthesis were depleted by aztreonam/avibactam combination; a significant downstream increase in nucleotide metabolites and a release of lipids were observed at the three timepoints. The findings indicate that the aztreonam/avibactam combination accelerates structural damage to the bacterial membrane structure and their actions were immediate and sustained compared to aztreonam or avibactam alone. By inhibiting the production of crucial cell wall precursors, the combination may have inflicted damages on bacterial DNA.

Background: Levo-tetrahydropalmatine and low-dose naltrexone are used in association with reducing cocaine-related cravings, but there are no analytical methods for the quantitative simultaneous analysis of this drug combination. Objective: A highly selective and sensitive LC-MS/MS assay was developed and validated to simultaneously quantify l-THP and naltrexone. The analytical method for l-THP offers improved sensitivity compared to previously published methods. Methods: The product ion transitions of l-THP and naltrexone were 357.0→193.0 and 342.2→324.1, respectively. Chromatographic separations were performed using a BEH-C18 column by an isocratic elution mode with acetonitrile and 0.1% formic acid in water containing 3 mM ammonium acetate. L-THP and naltrexone were extracted from rat plasma using a liquidliquid extraction method. Results: For l-THP and naltrexone, the assay displayed good linear response over a concentration range of 0.5-1000 ng/mL and 0.25-500 ng/mL, respectively. The intra-day accuracy of the method for l-THP and naltrexone was 93.8-101% with a precision (%CV) of 2.43-8.15% and 93.4-108% with a precision of 3.47-8.22%. The inter-day accuracy for l-THP and naltrexone was 91.2-102% with a CV of 2.46–8.06% and 91.5–97.8% with a CV of 3.29–8.92%, respectively. Conclusion: The assay has been used for pharmacokinetic studies of l-THP and naltrexone in the rat.

Objective: This study aimed to develop a population pharmacokinetic model of cefotaxime for early neonatal pneumonia patients (postnatal age ≤ 7 days) and optimize dosage regimens to guide personalized treatment. Methods: Opportunistic blood sampling was utilized to collect samples from newborns. The model was developed using nonlinear mixed effects modeling software, enabling the determination of pharmacokinetic parameters and the completion of dose simulations for practical application. Results: A total of 51 newborns were included, and 94 blood samples of cefotaxime were collected, with the concentration ranging from 6.9 to 383.2 μg/ml. The findings indicated that a two-compartment model was most appropriate for describing the pharmacokinetics of cefotaxime in this population. Covariate analysis revealed significant influences of current body weight and age on the pharmacokinetic parameters. The median (range) weight-normalized clearance of cefotaxime was 0.08 (0.04-0.15) L/h/kg, and the median (range) values for the central and peripheral compartment volumes were 0.13 (0.10-0.16) L/kg and 0.19 (0.16-0.24) L/kg, respectively. Monte Carlo simulation results indicated that for these neonates, when the MIC was 2 μg/mL, the original dosing regimen (50.0 mg/kg, every 12 hours) achieved 100% fT>MIC in over 90% of the neonates. Moreover, for neonates weighing ≤ 2.5 kg, reducing the dose to 25.0 mg/kg still met the target. Conclusion: The population pharmacokinetic model developed in this study provides valuable insights for the management of cefotaxime in neonates with pneumonia. This study supports the necessity of weight based personalized dosing regimens to achieve optimal treatment levels.

Introduction The emergence of multidrug-resistant (MDR) Acinetobacter baumannii prompts clinicians to consider treating these infections with polymyxin combination. Methods Metabolomic analysis was applied to investigate the synergistic effects of polymyxin-B, amikacin and sulbactam combination therapy against MDR A. baumannii harboring OXA-23 and other drug resistant genes. The drug concentrations tested were based on their clinical breakpoints: polymyxin-B (2 mg/L), amikacin (16 mg/L), polymyxin-B/amikacin (2/16 mg/L), and polymyxin-B/amikacin/sulbactam (2/16/4 mg/L). Results The triple antibiotic combination significantly disrupted levels of metabolites involved in cell outer membrane structure including fatty acids, glycerophospholipids, nucleotides, amino acids and peptides as early as 15 min after administration. Amikacin and polymyxin-B alone perturbed a large number of metabolites at 15 min and 1 h, respectively, but the changes in metabolites were short-lived lasting for less than 4 h. In contrast, the combination treatment disrupted a large amount of metabolites beyond 4 h. Compared to the double-combination, the addition of sulbactam to polymyxin-B/amikacin combination produce a greater disorder in A. baumannii metabolome that further confer susceptibility of bacteria to the antibiotics. Conclusion The metabolomic analysis identified mechanisms responsible for the synergistic activities of polymyxin-B/amikacin/sulbactam against MDR A. baumannii .

BACKGROUND:Carbapenem-resistant Acinetobacter baumannii (CRAB) is resistant to major antibiotics such as penicillin, cephalosporin, fluoroquinolone and aminoglycoside, and has become a significant nosocomial pathogen. The efficacy of rifampicin and colistin combination against CRAB could be dependent on the administration routes and drug concentrations at the site of infection.OBJECTIVE:The objective is to predict drug disposition in biological tissues. Treatment efficacy is extrapolated by assessing respective pharmacodynamic (PD) indices, as well as parameters associated with the emergence of resistance.METHODS:Physiologically-based pharmacokinetic models of rifampicin and colistin were utilized to predict tissue exposures. Dosing regimens and administration routes for combination therapy were evaluated in terms of in vitro antimicrobial susceptibility of A. baumannii associated with targeted PD indices and resistance parameters.RESULTS:Simulated exposures in blood, heart, lung, skin and brain were consistent with reported penetration rates. The results demonstrated that a combination of colistin and rifampicin using conventional intravenous (i.v.) doses could achieve effective exposures in the blood and skin. However, for lung infections, colistin by inhalation would be required due to low lung penetration from intravenous route. Inhaled colistin alone provided good PD coverage but this practice could encourage the emergence of additional resistance which may be overcome by a combination regimen that includes inhaled rifampicin.CONCLUSION:This in silico extrapolation provides valuable information on dosing regimens and routes of administration against CRAB infections in specific tissues. The PBPK modeling approach could be a non-invasive way to inform therapeutic benefits of combination antimicrobial therapy.