Age-Related Differences in Vancomycin-Associated Nephrotoxicity and Efficacy in Methicillin-Resistant Staphylococcus aureus Infection: A Comparative Study between Elderly and Adult Patients.

Elderly patients (age ≥ 65 years) are susceptible to methicillin-resistant Staphylococcus aureus (MRSA) infections, with potential for more adverse treatment outcomes or complications compared to younger adults (18-64 years). This study compared vancomycin-associated nephrotoxicity and efficacy in elderly and adult patients and investigated the correlation between vancomycin pharmacokinetic/pharmacodynamic (PK/PD) indices and clinical outcomes. A prospective study was conducted in 10 hospitals in Shanghai from October 2012 to November 2019. A total of 164 patients with MRSA infections were enrolled, including 83 elderly and 81 adult patients. Vancomycin therapeutic drug monitoring (TDM) was performed in all patients, indicating significantly higher vancomycin trough concentrations (Ctrough), 24-h area under the curve (AUC24) values, and AUC24/minimum inhibitory concentration (AUC24/MIC) values in elderly patients compared to adult patients. The incidence of vancomycin-associated nephrotoxicity was nearly three times higher in elderly patients (18.1% vs. 6.2%, p = 0.020), despite similar clinical and microbiological efficacy. Of particular importance, a Ctrough > 20 mg/L was found as an independent factor of nephrotoxicity in elderly patients. Further analysis of patients with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 also revealed that elderly patients had significantly higher vancomycin-related PK/PD indices and more nephrotoxicity than adult patients. In conclusion, elderly patients receiving vancomycin therapy face a higher risk of nephrotoxicity, which requires close vancomycin TDM, especially when the Ctrough exceeds 20 mg/L.

In vitro pharmacokinetics/pharmacodynamics of FL058 (a novel beta-lactamase inhibitor) combined with meropenem against carbapenemase-producing Enterobacterales.

Objective: FL058 is a novel beta-lactamase inhibitor with a broad spectrum of activity and a favorable safety profile. The objective of this study was to evaluate pharmacokinetic/pharmacodynamic (PK/PD) relationships for the combination of FL058 and meropenem in an in vitro infection model. Methods: By simulating human concentration-time profiles in the in vitro model, meropenem combined with FL058 when administered 1 g/0.5 g, 1 g/1 g, 2 g/1 g, and 2 g/2 g q8h by 3-h infusion achieved approximately 2- and 4-log10 kill to KPC/OXA-producing Klebsiella pneumoniae and Escherichia coli; the combination therapy could not inhibit NDM-producing K. pneumoniae but could maintain NDM-producing E. coli around a baseline. Results: The PK/PD indexes that best described the bacterial killing from baseline in log10 CFU/mL at 24 h were the percent time of free drug above the minimal inhibitory concentration (MIC) (%fT > MIC, MIC with FL058 at 4 mg/L) for meropenem and the percent time of free drug above 1 mg/L (%fT > 1 mg/L) for FL058. The targets for achieving a static effect and the 1- and 2-log10 kill were 74, 83, and 99 for %fT > MIC of meropenem and 40, 48, and 64 for %fT > 1 mg/L of FL058, respectively. The PK/PD index of %fT > 1 mg/L can provide a basis for evaluating clinical dosing regimens for FL058 combined with meropenem. Conclusion: FL058 combined with meropenem might be a potential treatment for KPC- and/or OXA-48-producing Enterobacterales infection.

A combination of genomics and transcriptomics provides insights into the distribution and differential mRNA expression of type VI secretion system in clinical Klebsiella pneumoniae.

The type VI secretion system (T6SS) serves as a crucial molecular weapon in interbacterial competition and significantly influences the adaptability of bacteria in their ecological niche. However, the distribution and function of T6SS in clinical Klebsiella pneumoniae, a common opportunistic nosocomial pathogen, have not been fully elucidated. Here, we conducted a genomic analysis of 65 clinical K. pneumoniae isolates obtained from patients with varying infections. Genes encoding a T6SS cluster present in all analyzed strains of K. pneumoniae, and strains with identical sequence type carried structurally and numerically identical T6SS. Our study also highlights the importance of selecting conserved regions within essential T6SS genes for PCR-based identification of T6SS in bacteria. Afterward, we utilized the predominant sequence type 11 (ST11) K. pneumoniae HS11286 to investigate the effect of knocking out T6SS marker genes hcp or vgrG. Transcriptome analysis identified a total of 1,298 co-upregulated and 1,752 co-downregulated differentially expressed genes in both mutants. Pathway analysis showed that only Δhcp mutant exhibited alterations in transport, establishment of localization, localization, and cell processes. The absence of hcp or vgrG gene suppressed the expression of other T6SS-related genes within the locus I cluster. Additionally, interbacterial competition experiments showed that hcp and vgrG are essential for competitive ability of ST11 K. pneumoniae HS11286. This study furthers our understanding of the genomic characteristics of T6SS in clinical K. pneumoniae and suggests the involvement of multiple genes in T6SS of strain HS11286. IMPORTANCE: Gram-negative bacteria use type VI secretion system (T6SS) to deliver effectors that interact with neighboring cells for niche advantage. Klebsiella pneumoniae is an opportunistic nosocomial pathogen that often carries multiple T6SS loci, the function of which has not yet been elucidated. We performed a genomic analysis of 65 clinical K. pneumoniae strains isolated from various sources, confirming that all strains contained T6SS. We then used transcriptomics to further study changes in gene expression and its effect on interbacterial competition following the knockout of key T6SS genes in sequence type 11 (ST11) K. pneumoniae HS11286. Our findings revealed the distribution and genomic characteristics of T6SS in clinical K. pneumoniae. This study also described the overall transcriptional changes in the predominant Chinese ST11 strain HS11286 upon deletion of crucial T6SS genes. Additionally, this work provides a reference for future research on the identification of T6SS in bacteria.

In vitro pharmacodynamics of nemonoxacin and other antimicrobial agents against Mycoplasma pneumoniae.

IMPORTANCE: This study first reported the in vitro effector kinetics of the new non-fluorinated quinolone, nemonoxacin, against macrolide-resistant M. pneumoniae (MRMP) and macrolide susceptible M. pneumoniae (MSMP) strains along with other antimicrobial agents. The time-kill assays and pharmacodynamic analysis showed that nemonoxacin has significant mycoplasmacidal activity against MRMP and MSMP. This study paves the road to establish appropriate dosing protocols of a new antimicrobial drug for children infected with M. pneumoniae.

Pharmacokinetic, Pharmacokinetic/Pharmacodynamic, and Safety Investigations of Lefamulin in Healthy Chinese Subjects.

This study aimed to explore the pharmacokinetics (PK) and safety of oral (PO) and intravenous (IV) lefamulin in healthy Chinese subjects and to evaluate the efficacy of the intravenous administration regimen using pharmacokinetic/pharmacodynamic (PK/PD) analysis. This study was a randomized, open-label, single- and multiple-dose, intravenous and oral administration study. PK parameters were calculated, and the probability of target attainment (PTA) and the cumulative fraction of response (CFR) after IV administration of lefamulin 150 mg 1 h q12 h were analyzed with Monte Carlo simulations. Lefamulin exhibited extensive distribution. The mean steady-state AUC0-24 h of 150 mg lefamulin IV and 600 mg lefamulin PO were 10.03 and 13.96 µg·h/mL, respectively. For Streptococcus pneumoniae and Staphylococcus aureus, based on the free-drug AUC over MIC ratio (fAUC/MIC) target of 1-log10 cfu reduction, the PK/PD breakpoints were 0.25 and 0.125 mg/L, respectively. The CFR was over 90% for both types of strains with 95% protein binding rate, suggesting that the regimen was microbiologically effective. Lefamulin was safe and well-tolerated. The PK of lefamulin in healthy Chinese subjects were consistent with that in foreign countries. Lefamulin demonstrated the microbiological effectiveness against Streptococcus pneumoniae and Staphylococcus aureus.

Pharmacokinetics and Pharmacodynamics of a Novel Vancomycin Derivative LYSC98 in a Murine Thigh Infection Model Against Staphylococcus aureus.

Introduction: LYSC98 is a novel vancomycin derivative used for gram-positive bacterial infections. Here we compared the antibacterial activity of LYSC98 with vancomycin and linezolid in vitro and in vivo. Besides, we also reported the pharmacokinetic/pharmacodynamic (PK/PD) index and efficacy-target values of LYSC98. Methods: The MIC values of LYSC98 were identified through broth microdilution method. A mice sepsis model was established to investigate the protective effect of LYSC98 in vivo. Single-dose pharmacokinetics of LYSC98 was studied in thigh-infected mice and liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to determine LYSC98 concentration in plasma. Dose fractionation studies were performed to evaluate different PK/PD indices. Two methicillin-resistant Staphylococcus aureus (MRSA) clinical strains were used in the dose ranging studies to determine the efficacy-target values. Results: LYSC98 showed a universal antibacterial effect in Staphylococcus aureus with a MIC range of 2-4 µg/mL. In vivo, LYSC98 demonstrated distinctive mortality protection in mice sepsis model with an ED50 value of 0.41-1.86 mg/kg. The pharmacokinetics results displayed maximum plasma concentration (Cmax) 11,466.67-48,866.67 ng/mL, area under the concentration-time curve from 0 to 24 h (AUC0-24) 14,788.42-91,885.93 ng/mL·h, and elimination half-life (T1/2) 1.70-2.64 h, respectively. Cmax/MIC (R 2 0.8941) was proved to be the most suitable PK/PD index for LYSC98 to predict its antibacterial efficacy. The magnitude of LYSC98 Cmax/MIC associated with net stasis, 1, 2, 3 and 4 - log 10 kill were 5.78, 8.17, 11.14, 15.85 and 30.58, respectively. Conclusion: Our study demonstrates that LYSC98 is more effective than vancomycin either in killing vancomycin-resistant Staphylococcus aureus (VRSA) in vitro or treating S. aureus infections in vivo, making it a novel and promising antibiotic. The PK/PD analysis will also contribute to the LYSC98 Phase I dose design.

Highly selective electrocatalytic reduction of nitrate to nitrogen in a chloride ion-free system by promoting kinetic mass transfer of intermediate products in a novel Pd-Cu adsorption confined cathode.

The mass transfer on the catalyst surface has a great influence on the selectivity of electrocatalytic nitrate reduction to nitrogen. In this study, a Pd-Cu adsorption confined nickel foam cathode is designed in the absence of both proton exchange membranes and chloride ions. The repulsion of the cathode enables intermediate products such as nitrite to accumulate in the confined region, resulting in an increase in the possibility of a second-order reaction to form nitrogen. The system can obtain more than 92% continuous N2 selectivity when it is used to treat 200 mg L-1 NO3--N under a current density of 8 mA cm-2, which is not only higher than those of semiconfined and nonconfined systems but also significantly better than the results obtained by Pd-Cu directly modified cathodes prepared by electrodeposition or impregnation. It is found that a high initial nitrate concentration and low current density are more beneficial for the accumulation of intermediates on Pd-Cu catalysts, thus improving the formation of nitrogen. A mechanism study reveals that the intermediates can completely occupy the active sites on the surface of Pd, avoiding the generation of active hydrogen, and therefore inhibiting the first-order reaction to produce ammonia. Moreover, the reducibility of Pd-Cu can also be gradually improved under the function of the cathode so that the system exhibits good stability. This study demonstrates an environmentally friendly and promising method for total nitrogen removal from industrial wastewater with high conductivity.

Identification and Comparative Genomic Analysis of Type VI Secretion Systems and Effectors in Klebsiella pneumoniae.

Klebsiella pneumoniae is a nosocomial opportunistic pathogen that can cause pneumonia, liver abscesses, and infections of the bloodstream. The resistance and pathogenicity of K. pneumoniae pose major challenges to clinical practice. However, the ecology and pathogenic mechanisms of K. pneumoniae have not been fully elucidated. Among these mechanisms, the secretion systems encoded by strains of the bacteria confer adaptive advantages depending on the niche occupied. The type VI secretion system (T6SS) is a multi-protein complex that delivers effector proteins to the extracellular environment or directly to eukaryotic or prokaryotic cells. T6SSs are widely distributed in Gram-negative bacteria and play an important role in bacterial virulence and the interactions between bacteria and other microorganisms or the environment. This study aimed to enhance the understanding of the characteristics of T6SSs in K. pneumoniae through an in-depth comparative genomic analysis of the T6SS in 241 sequenced strains of K. pneumoniae. We identified the T6SS loci, the synteny of the loci in different species, as well as the effectors and core T6SS-related genes in K. pneumoniae. The presence of a T6SS was a common occurrence in K. pneumoniae, and two T6SS clusters are the most prevalent. The variable region downstream of the gene vgrG usually encodes effector proteins. Conserved domain analysis indicated that the identified putative effectors in K. pneumoniae had the functions of lipase, ribonuclease, deoxyribonuclease, and polysaccharide hydrolase. However, some effectors did not contain predicted functional domains, and their specific functions have yet to be elucidated. This in silico study represents a detailed analysis of T6SS-associated genes in K. pneumoniae and provides a foundation for future studies on the mechanism(s) of T6SSs, especially effectors, which may generate new insights into pathogenicity and lead to the identification of proteins with novel antimicrobial properties.

Proteomic Response Revealed Signaling Pathways Involving in the Mechanism of Polymyxin B-Induced Melanogenesis.

Polymyxin B is a last-line antibiotic for extensively resistant Gram-negative bacterial infection. Skin hyperpigmentation is a serious side effect induced by polymyxin B that severely compromises the psychological health and compliance of patients. The literature lacks mechanistic studies that explain how hyperpigmentation occurs, and this substantially hinders the development of intervention strategies and improved compliance. SK-MEL-2 cells were used for the polymyxin B-induced hyperpigmentation mechanism study. Melanin content and tyrosinase activity were measured after polymyxin B treatment. Tandem mass tag (TMT)-labeling quantitative proteomics was employed to investigate the response of SK-MEL-2 cells to polymyxin B treatment. Real-time quantitative PCR and Western blot were applied to validate the mRNA and protein levels of related genes and proteins. The melanin content and tyrosinase activity were significantly upregulated after polymyxin B treatment in SK-MEL-2 cells at 48 h and 72 h. Quantitative proteomics showed that 237 proteins were upregulated and 153 proteins were downregulated in the 48 h group, and 49 proteins were upregulated and 49 proteins were downregulated in the 72 h group. The differentially expressed proteins were involved in pathways such as lysosome, PI3K/Akt signaling pathway, and calcium signaling pathway. The upregulation of melanogenic enzymes and microphthalmia-associated transcription factor (MITF) was validated by qPCR and Western blot. Meanwhile, phosphorylation of PI3K, ß-catenin, and cyclic-AMP response binding protein (CREB) in response to polymyxin B treatment was observed. The present study reveals the proteomic response of polymyxin B-induced melanogenesis in SK-MEL-2 cells for the first time. Signaling pathways, including melanin biosynthesis, PI3K/Akt, and calcium signaling pathways may be involved in the mechanism of melanogenesis. IMPORTANCE Polymyxin B-induced skin hyperpigmentation seriously affects the psychological health and compliance of patients. This study provides a proteomic clue to the mechanism at the cellular level for understanding polymyxin B-induced hyperpigmentation, contributing to a follow-up investigation of the corresponding PI3K/Akt signaling transduction pathway and calcium signaling pathway. The elucidation of its underlying mechanism is of great significance for patients' compliance improvement, intervention strategy, and new drug development.

Pharmacokinetics and pharmacodynamics of peptide antibiotics.

Antimicrobial resistance is a major global health challenge. As few new efficacious antibiotics will become available in the near future, peptide antibiotics continue to be major therapeutic options for treating infections caused by multidrug-resistant pathogens. Rational use of antibiotics requires optimisation of the pharmacokinetics and pharmacodynamics for the treatment of different types of infections. Toxicodynamics must also be considered to improve the safety of antibiotic use and, where appropriate, to guide therapeutic drug monitoring. This review focuses on the pharmacokinetics/pharmacodynamics/toxicodynamics of peptide antibiotics against multidrug-resistant Gram-negative and Gram-positive pathogens. Optimising antibiotic exposure at the infection site is essential for improving their efficacy and minimising emergence of resistance.

Polymyxin B Combined with Minocycline: A Potentially Effective Combination against blaOXA-23-harboring CRAB in In Vitro PK/PD Model.

Polymyxin-based combination therapy is commonly used to treat carbapenem-resistant Acinetobacter baumannii (CRAB) infections. In the present study, the bactericidal effect of polymyxin B and minocycline combination was tested in three CRAB strains containing blaOXA-23 by the checkerboard assay and in vitro dynamic pharmacokinetics/pharmacodynamics (PK/PD) model. The combination showed synergistic or partial synergistic effect (fractional inhibitory concentration index ≤0.56) on the tested strains in checkboard assays. The antibacterial activity was enhanced in the combination group compared with either monotherapy in in vitro PK/PD model. The combination regimen (simultaneous infusion of 0.75 mg/kg polymyxin B and 100 mg minocycline via 2 h infusion) reduced bacterial colony counts by 0.9-3.5 log10 colony forming units per milliliter (CFU/mL) compared with either drug alone at 24 h. In conclusion, 0.75 mg/kg polymyxin B combined with 100 mg minocycline via 2 h infusion could be a promising treatment option for CRAB bloodstream infections.

Regulatory utility of pharmacometrics in the development and evaluation of antimicrobial agents and its recent progress in China.

Pharmacometrics is an emerging science that interprets drug, disease, and trial information in a mathematical fashion to inform and facilitate efficient drug development and/or regulatory decisions. Pharmacometrics study is increasingly adopted in the regulatory review of new antimicrobial agents. We summarized the 31 antimicrobial agents approved by the US Food and Drug Administration (FDA) and the 26 antimicrobial agents approved by European Medicines Agency (EMA) from January 2001 to May 2019. We also reviewed recent examples of utilizing pharmacometrics to support antimicrobial agent's registration in China, including modeling and simulation methods, effects of internal/external factors on pharmacokinetic (PK) parameters, safety and efficacy evaluation in terms of exposure-response analysis, refinement of the wording of product labeling and package leaflet, and possible postmarketing clinical trial. Ongoing communication among regulator, academia, and industry regarding pharmacometrics is encouraged to streamline and facilitate the development of new antimicrobial agents. The industry can maximize its benefit in drug development through continued pharmacometrics education/training.

Epidemiological and genomic characteristics of Acinetobacter baumannii from different infection sites using comparative genomics.

BACKGROUND: Acinetobacter baumannii is a common nosocomial pathogen that poses a huge threat to global health. Owing to the severity of A. baumannii infections, it became necessary to investigate the epidemiological characteristics of A. baumannii in Chinese hospitals and find the reasons for the high antibiotic resistance rate and mortality. This study aimed to investigate the epidemiologic and genetic characteristics of A. baumannii isolated from patients with hospital acquired pneumonia (HAP), bloodstream infection (BSI) and urinary tract infection (UTI) in China and uncover potential mechanisms for multi-drug resistance and virulence characteristics of A. baumannii isolates. RESULTS: All isolates were classified into two primary clades in core gene-based phylogenetic relationship. Clonal complex 208 (CC208) mainly consisted of ST195 (32 %) and ST208 (24.6 %). CC208 and non-CC208 isolates had carbapenem resistance rates of 96.2 and 9.1 %, respectively. Core genes were enriched in 'Amino acid transport and metabolism', 'Translation', 'Energy production and conversion', 'Transcription', 'Inorganic ion transport and metabolism' and 'Cell wall/membrane/envelope synthesis'. Most isolates possessed virulence factors related to polysaccharide biosynthesis, capsular polysaccharide synthesis and motility. Eleven isolates belong to ST369 or ST191 (oxford scheme) all had the virulence factor cap8E and it had a higher positive rate in UTI (35.3 %) than in BSI (18.9 %) and HAP (12.9 %). ABGRI1 antibiotic resistance islands were responsible for streptomycin, tetracycline and sulfonate resistance. The blaOXA-23 gene was the most probable cause for carbapenem resistance, although the blaOXA-66 gene with nonsynonymous SNPs (F82L, I129L) was not. CONCLUSIONS: A. baumannii is a genomically variable pathogen that has the potential to cause a range of infectious diseases. There is high proportion of carbapenem resistance in isolates from all three infection sites (HAP, BSI and UTI), which can be attributed to the blaOXA-23 gene. CC208 is the predominant clone in blaOXA-23-carrying A. baumannii that should be monitored. Virulence factors involving bacteria motility and polysaccharide biosynthesis which are widespread in clinical A. baumannii strains deserve our attention.

Pharmacokinetics and Pharmacodynamics of Nemonoxacin in a Neutropenic Murine Lung Infection Model Against Streptococcus Pneumoniae.

Nemonoxacin, a novel nonfluorinated quinolone for the treatment of community-acquired pneumonia. We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets and PK/PD breakpoints of nemonoxacin against Streptococcus pneumoniae using a neutropenic murine lung infection model. Single-dose PK analysis after subcutaneous administration of nemonoxacin at doses from 2.5 to 80 mg/kg showed maximum plasma concentration (Cmax) 0.56-7.32 mg/L, area under the concentration-time curve from 0 to 24 h (AUC0-24) 0.67-26.10 mg·h/L, and elimination half-life (T1/2) 0.8-1.4 h. The epithelial lining fluid (ELF) penetration ratio of total drug was 1.40. Dose fractionation (1.25-80 mg/kg/day, every 24, 12, 8, and 6 h) and dose escalation studies (1.25-160 mg/kg, every 24 h) were conducted. The sigmoid Emax Hill equation was used to describe the dose-response data. The free-drug plasma fAUC0-24/MIC ratio was considered the PK/PD index most closely associated with efficacy (R2 0.9268). Median fAUC0-24/MIC associated with static, 1-log10 and 2-log10 CFU reduction from baseline were 8.6, 23.2 and 44.4, respectively. Monte Carlo simulation showed 500 mg qd and 750 mg qd oral doses of nemonoxacin were able to achieve 90% probability of target attainment (PTA) against bacteria with MIC of 0.5 mg/L and 1 mg/L. We recommended susceptibility (S) ≤ 0.5 mg/L, intermediate (I) = 1 mg/L and resistant (R) ≥ 2 mg/L as the PK/PD breakpoints for nemonoxacin against S. pneumoniae.

Pharmacokinetics of Levornidazole Tablet in Healthy Chinese Subjects and Proposed Dosing Regimen Based on Pharmacokinetic/Pharmacodynamic Analysis.

INTRODUCTION: Levornidazole is a novel nitroimidazole antimicrobial agent active against anaerobes. We aimed to investigate the pharmacokinetic (PK) profile of levornidazole after single and multiple oral doses of levornidazole tablets in healthy Chinese subjects and propose the dosing regimen based on pharmacokinetic/pharmacodynamic (PK/PD) analysis. METHODS: A single-center, randomized, double-blind, placebo-controlled study was conducted with a single ascending dose (250, 500, 1000, and 1500 mg) and multiple doses of 500 mg levornidazole q12h for 7 days. Food effect on PK and absolute bioavailability were investigated at the 500 mg dose level. Blood and urine samples were collected to determine the PK parameters of levornidazole. The probability of target attainment (PTA) and cumulative fraction of response (CFR) were calculated by Monte Carlo simulation to predict the clinical efficacy of levornidazole tablets. RESULTS: Plasma concentration reached peak about 0.5 h after single dose (250-1500 mg) of levornidazole tablets. The maximal concentration (Cmax) and exposure (AUC0-∞) of levornidazole increased linearly with dose. High-fat diet did not affect the absorption extent of levornidazole tablets. The absolute oral bioavailability of levornidazole tablets was 98.3% ± 7.6%, associated with large apparent volume of distribution (48.68 ± 4.92 l) and long half-life (11.93 ± 1.28 h). The urinary excretion of levornidazole was 7.99%. Levornidazole, administered at either 500 mg q12h or 750 mg q24h, achieved a CFR > 95.4% and PTA > 99% for B. fragilis (minimum inhibitory concentration ≤ 1.0 mg/l) infections. CONCLUSION: Levornidazole tablets are absorbed rapidly and completely and distributed extensively with a long half-life and low urinary excretion after a single dose or multiple doses in healthy Chinese subjects. Levornidazole tablets can be taken with or without food. Levornidazole tablets 500 mg q12h and 750 mg q24h are expected to achieve the desired efficacy in B. fragilis infections. CLINICAL TRAIL REGISTRATION: Trial registration number CTR20160786 at http://www.chinadrugtrials.org.cn/ .

Effects of Different Component Contents of Colistin Methanesulfonate on the Pharmacokinetics of Prodrug and Formed Colistin in Human.

PURPOSES: To evaluate the effects of component contents in different colistin methanesulfonate (CMS) formulas on their clinical pharmacokinetics of the prodrug CMS and the formed colistin. METHODS: Two CMS formulas (CTTQ and Parkedale) were investigated in a single dose, randomized, open-label, crossover study conducted in 18 healthy Chinese subjects. Both CMS formulas met the requirements of European Pharmacopoeia 9.2 with 12.1% difference in the two major active components (CMS A and CMS B). The PK parameters after a single intravenous infusion of CMS at 2.5 mg/kg were calculated and the steady-state plasma colistin concentrations (Css,avg) following multiple dosing, once every 12 h for 7 days, were simulated with the non-compartment model. RESULTS: The systemic exposure (AUC0-inf) of CMS were 59.49 ± 5.90 h·µg/mL and 51.09 ± 4.70 h·µg/mL, and the AUC0-inf of colistin were 15.39 ± 2.63 h·µg/mL and 12.36 ± 2.10 h·µg/mL for CTTQ and Parkedale, respectively. The ratios (90% CI) of geometric mean of AUC0-inf of CTTQ to Parkedale were 116.38% (112.95%, 119.91%) and 124.49% (120.76%, 128.35%) for CMS and colistin, respectively. The predicted Css,avg (95% CI) were 0.92 (0.85, 0.99) µg/mL and 0.74 (0.69, 0.79) µg/mL for CTTQ and Parkedale, respectively. CONCLUSION: The difference in component content in the two CMS formulas had a significant (P < 0.001) impact on the systemic exposure of colistin in human, thus, warranted essential considerations in clinical applications.

Acute toxicity is a dose-limiting factor for intravenous polymyxin B: A safety and pharmacokinetic study in healthy Chinese subjects.

OBJECTIVES: Polymyxin B is a last-line antibiotic for multidrug-resistant gram-negative bacterial infections. However, limited safety and pharmacokinetic information is available. We investigated the safety and pharmacokinetics of intravenous polymyxin B in healthy subjects. METHODS: An open-label, single-dose clinical trial was conducted in healthy Chinese subjects. Polymyxin B (sulphate) was administered intravenously at 0.75 or 1.5 mg/kg (n = 10 per dose, 5 males and 5 females) to examine the safety and pharmacokinetics. RESULTS: One female subject in the 1.5-mg/kg group discontinued due to abdominal pain during administration. The most frequently reported adverse events were perioral paraesthesia, dizziness, and numbness of extremities (7/10 subjects in the 0.75-mg/kg group, all subjects in the 1.5-mg/kg group). All neurotoxicity-related events dissipated without treatment within a maximum of 23 h. Notably, abdominal pain (3/5) and vulvar pruritus (2/5), colpitis (2/5) or abnormal uterine bleeding (1/5) were reported in female subjects receiving the 1.5-mg/kg dose. In the 0.75-mg/kg group, the total clearance, volume of distribution and half-life of polymyxin B were 0.028±0.002 L/h/kg, 0.219±0.023 L/kg and 5.44±0.741 h, respectively; similar values were observed in the 1.5-mg/kg group. Urinary recovery was 3.7 ±â€¯1.1% and 8.1 ±â€¯1.3% in the 0.75- and 1.5-mg/kg groups, respectively. Population pharmacokinetics of polymyxin B was consistent with a three-compartment model. The clearance and distribution of the central compartment were 0.027 L/h/kg and 0.071 L/kg, respectively. CONCLUSIONS: This study is the first to examine the safety and pharmacokinetics of polymyxin B in healthy subjects. Our results highlight that acute toxicity is a dose-limiting factor for intravenous polymyxin B.

Enhanced bacterial killing with colistin/sulbactam combination against carbapenem-resistant Acinetobacter baumannii.

AIMS: Polymyxin-based combination therapy is often used to treat carbapenem-resistant Acinetobacter baumannii (A. baumannii) infections. Although sulbactam is intrinsically active against A. baumannii, few studies have investigated colistin/sulbactam combinations against carbapenem-resistant A. baumannii. METHODS: Whole genome sequencing was undertaken on eight carbapenem-resistant (colistin-susceptible) isolates of A. baumannii from Chinese patients. Bacterial killing of colistin and sulbactam, alone and in combination, was examined with checkerboard (all isolates) and static and dynamic time-kill studies (three isolates). In the dynamic studies, antibiotics were administered in various clinically-relevant dosing regimens that mimicked patient pharmacokinetics. RESULTS: The eight isolates consisted of ST195, ST191 and ST208 belonging to clonal complex 208, which is the most epidemic clonal type of A. baumannii globally. All isolates possessed Acinetobacter-derived cephalosporinase (ADC-61 or ADC-78) and seven of eight isolates contained the carbapenem-resistance gene blaOXA-23. The colistin/sulbactam combination was synergistic against two of eight isolates in checkerboard studies. In time-kill studies, rapid bacterial killing of ca. 3-6 log10 CFU/mL was observed with colistin monotherapy, followed by steady regrowth. Sulbactam monotherapy was generally ineffective. Substantially enhanced bacterial killing was observed with colistin/sulbactam combinations in both static and dynamic models, especially with the higher sulbactam concentration (2 g) and/or longer sulbactam infusion time (2 hours) in the dynamic model. CONCLUSIONS: This study was the first to use a pharmacokinetics/pharmacodynamics model to investigate synergistic activity of colistin/sulbactam combinations against A. baumannii. It showed that clinically-relevant dosing regimens of colistin combined with sulbactam may substantially improve bacterial killing of multidrug-resistant and carbapenem-resistant A. baumannii.

Pharmacokinetic/Pharmacodynamic Based Breakpoints of Polymyxin B for Bloodstream Infections Caused by Multidrug-Resistant Gram-Negative Pathogens.

The latest PK/PD findings have demonstrated negligible efficacy of intravenous polymyxins against pulmonary infections. We investigated pharmacokinetic/pharmacodynamic (PK/PD)-based breakpoints of polymyxin B for bloodstream infections and the rationality of the recent withdrawal of polymyxin susceptibility breakpoints by the CLSI. Polymyxin B pharmacokinetic data were obtained from a phase I clinical trial in healthy Chinese subjects and population pharmacokinetic parameters were employed to determine the exposure of polymyxin B at steady state. MICs of 1,431 recent clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae collected from across China were determined. Monte-Carlo simulations were performed for various dosing regimens (0.42-1.5 mg/kg/12 h via 1 or 2-h infusion). The probability of target attainment, PK/PD breakpoints and cumulative fraction of response were determined for each bacterial species. MIC90 of polymyxin B was 1 mg/L for P. aeruginosa and 0.5 mg/L for A. baumannii and K. pneumoniae. With the recommended polymyxin B dose of 1.5-2.5 mg/kg/day, the PK/PD susceptible breakpoints for P. aeruginosa, A. baumannii and K. pneumoniae were 2, 1 and 1 mg/L respectively for bloodstream infection. For Chinese patients, polymyxin B dosing regimens of 0.75-1.5 mg/kg/12 h for P. aeruginosa and 1-1.5 mg/kg/12 h for A. baumannii and K. pneumoniae were appropriate. Breakpoint determination should consider the antimicrobial PK/PD at infection site and delivery route. The recent withdrawal of polymyxin susceptible breakpoint by CLSI primarily based on poor efficacy against lung infections needs to be reconsidered for bloodstream infections.