Model-based dosing optimization and therapeutic drug monitoring practices of teicoplanin in patients with complicated or non-complicated methicillin-resistant staphylococcus aureus infection.

AIMS: This study aims to establish a population pharmacokinetic (PK) model of teicoplanin in Chinese adult patients to evaluate the dosing regimen in the label sheet and optimize it. METHODS: Nonlinear mixed-effects modelling was used to estimate PK parameters. Monte Carlo simulations were used to evaluate the attainment of various dosing regimens in achieving the target trough concentrations in patients with normal or decreased renal function. RESULTS: A total of 115 patients were enrolled in this retrospective study. Creatinine clearance (CrCL) and albumin (ALB) were identified as covariates on the clearance of teicoplanin. For the treatment of non-complicated methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with normal renal function and serum ALB concentration, the recommended dosing regimen was 600 mg q12h with five administrations as the loading dose followed by 600 mg qd as the maintenance dose; for the treatment of serious and/or complicated MRSA infections, the recommended dosing regimen was 800 mg q12h with five administrations as the loading dose followed by 800 mg qd as the maintenance dose. It is worth noting that both the loading and maintenance doses ought to be modified based on the patient's renal function and serum ALB concentration. In addition, trough concentrations of teicoplanin were significantly increased every other week. CONCLUSIONS: Both loading dosing and maintenance dosing regimens were recommended to be adjusted according to patient's renal function and serum ALB concentration. In addition, it is necessary to perform follow-up therapeutic drug monitoring of teicoplanin at least once every week.

Tf2O-Mediated P(O)-N Bond Formation of Either P(O)-OH or P(O)-H Reagents with Multitype Amines.

We have developed a Tf2O-mediated approach for the direct amination of either P(O)-OH or P(O)-H reagents with a variety of aliphatic or aromatic amines. Without the requirement of precious metals and toxic reagents, this protocol provides an alternative route to various phosphinamides and phosphoramides. The reaction proceeds under simple and mild conditions and can be effectively scaled up with similar efficiency.

Intraventricular colistin sulphate as a last resort therapy in a patient with multidrug-resistant Acinetobacter baumannii induced post-neurosurgical ventriculitis.

Limited therapeutic options exist for multidrug-resistant/extensively drug-resistant Acinetobacter baumannii (MDR/XDR-Ab) meningitis/ventriculitis. A combination of intravenous and intraventricular (IVT)/intrathecal (IT) polymyxins achieves good therapeutic outcomes for cases of healthcare-associated MDR/XDR-Ab meningitis/ventriculitis. Colistin is commercially available as colistin sulphate and its sulphomethylated derivative. However, the effect and safety of colistin sulphate in the treatment of MDR/XDR-Ab meningitis/ventriculitis has not been reported. We report on a 66-year-old male patient who developed post-neurosurgical ventriculitis caused by MDR-Ab. IVT concomitant intravenous colistin sulphate was used as a last-resort antimicrobial therapy, the patient's ventriculitis was dramatically improved, and the concentrations of CSF colistin were higher than the MIC breakpoint throughout the treatment. Meanwhile, no nephrotoxicity or neurotoxicity was observed during the treatment.

Trough polymyxin B plasma concentration is an independent risk factor for its nephrotoxicity.

AIMS: Data regarding clinical pharmacokinetic/toxicodynamic (PK/TD) of polymyxin B is short of direct quantitative data. This study aims to investigate the risk factors of polymyxin B associated acute kidney injury (AKI) and to assess the relationship between polymyxin B plasma levels and its nephrotoxicity. METHODS: A retrospective study was performed in adult patients treated with polymyxin B. Risk factors associated with AKI and plasma trough concentrations of polymyxin B were identified via medical record review. A multivariate logistic regression model was established and the risk of polymyxin B-associated AKI were predicted by a receiver operating characteristic curve, with maximal Youden index used to identify safety thresholds among the study population. RESULTS: Fifty-four adult patients were included in the study. AKI was detected in 14 patients during polymyxin B treatment (25.9%, 14 out of 54). Cmin (odds ratio [OR] 2.071; 95% confidence interval [CI] 1.235-3.472) and baseline serum creatinine (OR 1.024; 95% CI 1.005-1.043) were significant independent risk factors for developing AKI. The area under the ROC curve of the combined predictor was larger based on the above factors. When the Youden index was at maximum, the optimal cut-off point was 6.678 of the ROC curve. When Cmin ≥ 3.13 mg/L, the probability of AKI was more than 50%. CONCLUSION: In this study, when the calculated combined predictor value was >6.678, there was an increased risk of AKI. Maintaining a polymyxin B Cmin level below 3.13 mg/L may be helpful in reducing the incidence of polymyxin B associated nephrotoxicity.

DMSO-Catalyzed Double P-O Bond or Double P-S Bond Formations of Phosphinic Acids.

A DMSO-catalyzed double P-O bond or double P-S bond formation of phosphinic acid with an O- or S-containing nucleophile has been developed. Under metal-free and mild conditions, this simple procedure provides a compatible and rapid access to a variety of phosphonates and dithiophosphates. The DFT calculation of stabilization energy (SE) and the mechanism studies demonstrated that the "just right" Lewis base property and the relatively "soft" interaction strength with the phosphenium-dication ensure the unique catalytic activity of DMSO in this transformation.

Effects of repeated allopurinol administration on rat cytochrome P450 activity.

Allopurinol is a popular and widely-prescribed anti-hyperuricemic agent that has been implicated in drug interactions with substrates of several cytochrome P450 (CYP) enzymes. The effect of repeated allopurinol administration (20 mg/kg, once daily for 14 days) on metabolic activity of CYP was assessed in rats. This was a randomized, double-blind, two-way crossover study with a 4-week washout period between phases. The substrates used in this study were phenacetin (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19) and dextromethorphan (CYP2D6). Validated HPLC-MS/MS was used to quantify all compounds. Our study showed that allopurinol administration inhibited CYP1A2 activity, causing a significant increase in AUC (0-infinity) (P < 0.01) and t1/2 (P < 0.05) of phenacetin, and a distinct decline in CL (P < 0.01). However, there were no significant differences of another three probe drugs in plasma concentrations and the corresponding pharmacokinetic parameters between the allopurinol-treated and normal saline-treated rats. The findings in this study suggested that allopurinol could inhibit CYP1A2 but did not influence CYP2C9, CYP2C19 and CYP2D6 enzymes.

Tf2O/DMSO-mediated dual activation of aryl phosphinate to access various aryl phosphonates.

A metal-free method for the dual activation of aryl phosphinate has been developed; the P-H and P-O bonds are sequentially activated by the Tf2O/DMSO system. Without the requirement of metals and unstable P-reagents, this one-pot procedure provides a convenient and practical access to a variety of aryl phosphonates. A mechanism involving twice generation of electrophilic P-species and two SN-processes is proposed on the basis of the control experiments.

Modification of Vancomycin Dosing in Cardiac Surgery With Cardiopulmonary Bypass.

This study aims to assess the risk factors for insufficient vancomycin concentrations for its prophylactic use in adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and to modify the dosing regimen to achieve appropriate plasma concentrations. A total of 27 patients with vancomycin dosing of 1 to 1.5 g based on a weight cutoff of 67 kg were included, of which only 13 (48.15%) had vancomycin plasma concentration >15 mg/L at surgical closure. Risk factors of vancomycin concentration <15 mg/L at surgical-site closure were confirmed by multivariate logistic regression analysis, which showed that CPB duration was an independent predictor. Patients with CPB duration >4 hours had significantly lower vancomycin concentrations and lower proportion in achieving target vancomycin concentration at the end of CPB and surgical closure. For patients with CPB >4 hours, the modified dosing regimen that a second dose of 0.5 to 0.75 g added at 4 hours since the onset of CPB improved the target achievement of vancomycin concentration at surgical closure. Taken together, CPB duration >4 hours was the risk factor for insufficient vancomycin concentration at surgical closure, while our modified dosing could improve the vancomycin concentrations for its prophylactic use in patients undergoing cardiac surgery with CPB.

Using 16S rDNA Sequencing Technology to Preliminarily Analyze Intestinal Flora in Children with Mycoplasma pneumoniae Pneumonia.

Objective: We investigated changes in the intestinal flora of children with Mycoplasma pneumoniae pneumonia (MPP). Methods: Between September 2019 and November 2019, stool samples from 14 children with MPP from The Fourth Hospital of Baotou city, Inner Mongolia Autonomous Region, were collected and divided into general treatment (AF) and probiotic (AFY) groups, according to the treatment of "combined Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus cereus tablets live". High-throughput 16S rDNA sequencing was used to identify intestinal flora. Results: Intestinal flora abundance and diversity in children with MPP were decreased. Both Shannon and Simpson indices were lower in the AF group when compared with healthy controls ( P < 0.05). When compared with healthy controls, the proportion of Enterorhabdus was lower in the AF group, while the proportion of Lachnoclostridium was higher ( P < 0.05). The proportion of Bifidobacteria and Akkermansia was lower in the AFY group but Enterococcus, Lachnoclostridium, Roseburia, and Erysipelatoclostridium proportions were higher. The proportion of Escherichia coli- Shigella in the AFY group after treatment was decreased ( P < 0.05). Conclusions: The intestinal flora of children with MPP is disturbed, manifested as decreased abundance and diversity, and decreased Bifidobacteria. Our probiotic mixture partly improved intestinal flora disorders.

Efficacy and Pharmacodynamic Target Attainment for Ceftazidime-Avibactam Off-Label Dose Regimens in Patients with Continuous or Intermittent Venovenous Hemodialysis: Two Case Reports.

Limited data are available for ceftazidime-avibactam (CZA) dosing in patients receiving renal replacement therapy, especially the data on the dosing in patients receiving intermittent hemodialysis (IHD). In this report, we firstly described a case in which CZA was administered as 2.5 g after each time of IHD, and a dose of 1.25 g was added on the 48th-hour for the 72-h interdialytic interval. Plasma concentrations of CZA measured at different time indicated that > 50% of administered ceftazidime and avibactam were removed during the 4-h hemodialysis. In addition, we described another case on continuous venovenous hemodialysis (CVVHD), in which CZA was administered as 2.5 g q12h in 2-h infusions. The dose regimen for these two cases could achieve trough concentration of ceftazidime higher than fourfold of the MIC and trough concentration of avibactam higher than the threshold of 1 µg/mL during the treatment, and exert efficient antimicrobial effect.

Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients.

Background: Linezolid is associated with myelosuppression, which may cause failure in optimally treating bacterial infections. The study aimed to define the pharmacokinetic/toxicodynamic (PK/TD) threshold for critically ill patients and to identify a dosing strategy for critically ill patients with renal insufficiency. Methods: The population pharmacokinetic (PK) model was developed using the NONMEM program. Logistic regression modeling was conducted to determine the toxicodynamic (TD) threshold of linezolid-induced myelosuppression. The dosing regimen was optimized based on the Monte Carlo simulation of the final model. Results: PK analysis included 127 linezolid concentrations from 83 critically ill patients at a range of 0.25-21.61 mg/L. Creatinine clearance (CrCL) was identified as the only covariate of linezolid clearance that significantly explained interindividual variability. Thirty-four (40.97%) of the 83 patients developed linezolid-associated myelosuppression. Logistic regression analysis showed that the trough concentration (Cmin) was a significant predictor of myelosuppression in critically patients, and the threshold for Cmin in predicting myelosuppression with 50% probability was 7.8 mg/L. The Kaplan-Meier plot revealed that the overall median time from the initiation of therapy to the development of myelosuppression was 12 days. Monte Carlo simulation indicated an empirical dose reduction to 600 mg every 24 h was optimal to balance the safety and efficacy in critically ill patients with CrCL of 30-60 ml/min, 450 mg every 24 h was the alternative for patients with CrCL <30 ml/min, and 600 mg every 12 h was recommended for patients with CrCL ≥60 ml/min. Conclusion: Renal function plays a significant role in linezolid PKs for critically ill patients. A dose of 600 mg every 24 h was recommended for patients with CrCL <60 ml/min to minimize linezolid-induced myelosuppression.

Systematic profiling of SARS-CoV-2-specific IgG responses elicited by an inactivated virus vaccine identifies peptides and proteins for predicting vaccination efficacy.

One of the best ways to control COVID-19 is vaccination. Among the various SARS-CoV-2 vaccines, inactivated virus vaccines have been widely applied in China and many other countries. To understand the underlying protective mechanism of these vaccines, it is necessary to systematically analyze the humoral responses that are triggered. By utilizing a SARS-CoV-2 microarray with 21 proteins and 197 peptides that fully cover the spike protein, antibody response profiles of 59 serum samples collected from 32 volunteers immunized with the inactivated virus vaccine BBIBP-CorV were generated. For this set of samples, the microarray results correlated with the neutralization titers of the authentic virus, and two peptides (S1-5 and S2-22) were identified as potential biomarkers for assessing the effectiveness of vaccination. Moreover, by comparing immunized volunteers to convalescent and hospitalized COVID-19 patients, the N protein, NSP7, and S2-78 were identified as potential biomarkers for differentiating COVID-19 patients from individuals vaccinated with the inactivated SARS-CoV-2 vaccine. The comprehensive profile of humoral responses against the inactivated SARS-CoV-2 vaccine will facilitate a deeper understanding of the vaccine and provide potential biomarkers for inactivated virus vaccine-related applications.

Mycoplasma pneumoniae Macrolide Resistance and MLVA Typing in Children in Beijing, China, in 2016: Is It Relevant?

OBJECTIVE: The aim of this study is to investigate the macrolide resistance rate and molecular type with multiple-locus variable-number tandem-repeat analysis (MLVA) of Mycoplasma pneumoniae of Beijing in 2016 in pediatric patients. METHODS: Real-time quantitative polymerase chain reaction (PCR) was used to identify M. pneumoniae, and MLVA was performed. The domain V of the 23S rRNA was sequenced to detect macrolide-resistant point mutations. We also investigated the activities of antibiotics against M. pneumoniae isolates in vitro. RESULTS: The PCR detection rate of M. pneumoniae in children in Beijing was 40%, and the macrolide resistance rate was 66%. The A2063G mutation in the 23S rRNA V region is the dominant mutation (137/146, 93.84%), whereas the A2064G mutation is rare (9/146, 6.16%). Seventy-three samples were typed successfully by MLVA typing, including 86.3% (63/73) were MLVA type 4-5-7-2, and 13.7% (10/73) were MLVA type 3-5-6-2. No other types were found. No strains were resistant to levofloxacin or tetracycline. CONCLUSION: In 2016, a specific decrease in the macrolide resistance rate occurred in Beijing. The detection rate and macrolide resistance rate of outpatients are lower than those of inpatients. The A2063G mutants M. pneumoniae have high levels of resistance to erythromycin and azithromycin. The primary MLVA type is 4-5-7-2, followed by 3-5-6-2. No other MLVA types were detected. No strains resistant to tetracycline or levofloxacin were found in vitro.

Epidemiology and mechanism of drug resistance of Mycoplasma pneumoniae in Beijing, China: A multicenter study.

Mycoplasma pneumoniae (M. pneumoniae) is one of the most common causes of community-acquired respiratory tract infections (RTIs). We aimed to investigate the prevalence of M. pneumoniae infection, antibiotic resistance and genetic diversity of M. pneumoniae isolates across multiple centers in Beijing, China. P1 protein was detected by Nested PCR to analyze the occurrence of M. pneumoniae in pediatric patients with RTI. M. pneumoniae isolates were cultured and analyzed by Nested-PCR to determine their genotypes. Broth microdilution method was used to determine the minimum inhibitory concentration (MIC) of antibiotics. Out of 822 children with RTI admitted to 11 hospitals in Beijing, 341 (41.48%) were positive for M. pneumoniae by Nested PCR and 236 (69.21%) samples had mutations in 23S rRNA domain V. The highest proportion of M. pneumoniae positive samples was observed in school-age children (118/190; 62.11%) and in pediatric patients with pneumonia (220/389; 56.56%). Out of 341 M. pneumoniae positive samples, 99 (12.04%) isolates were successfully cultured and the MIC values were determined for 65 M. pneumoniae strains. Out of these, 57 (87.69%) strains were resistant to macrolides, and all 65 strains were sensitive to tetracyclines or quinolones. M. pneumoniae P1 type I and P1 type II strains were found in 57/65 (87.69%) and 8/65 (12.31%) of cultured isolates, respectively. Overall, we demonstrated a high prevalence of M. pneumoniae infection and high macrolide resistance of M. pneumoniae strains in Beijing. School-age children were more susceptible to M. pneumoniae, particularly the children with pneumonia. Thus, establishment of a systematic surveillance program to fully understand the epidemiology of M. pneumoniae is critical for the standardized use of antibiotics in China.

Inhibitory effects of resistin-13-peptide on the proliferation, adhesion, and invasion of MDA-MB-231 in human breast carcinoma cells.

To investigate the potential effects of resistin-13-peptide on the growth, adhesion, and invasion in human breast carcinoma cells, MDA-MB-231. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay and colony-forming assay were used to assess the proliferation effects of resistin-13-peptide. The adhesive ability was investigated by cell adhesion assay, and the invasive potential was assessed using a transwell model. Activities of matrix metalloproteinase (MMP)-2 and MMP-9 were measured by zymography analysis and western blotting. Tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 were determined by western blotting. In this study, we performed in vivo experiments and determined the effect of resistin-13-peptide on tumor growth and other organs, especially ovaries in a xenograft model using the cell line studied. Resistin-13-peptide inhibited MDA-MB-231 cell growth and colony formation in a dose- and time-dependent manner. Meanwhile, the invasive and adhesive abilities of MDA-MB-231 cells were yet cut down by resistin-13-peptide in a dose-dependent manner. Resistin-13-peptide decreased the gelatinolytic activities of both MMP-2 and MMP-9 and enhanced the protein expression of TIMP-1 and TIMP-2, which were secreted from the MDA-MB-231 cells. The animal experiments found that the growth of tumors was repressed by resistin-13-peptide, which affected other organs in the same time. Especially, ovaries did not have pathological changes yet. Treatment with resistin-13-peptide is effective in suppressing tumor proliferation, adhesion, and invasion. The possible mechanism is downregulation of MMPs and upregulation of TIMPs.

[Factors related to Glycophorin A mutation frequency of workers exposed to benzene.].

OBJECTIVE: To analyze related factors which affect GPA mutation frequency of workers exposed to benzene, with the Glycophorin A (GPA) mutation assay and explore the possibility of GPA mutation frequency as an index of predicting the risk of benzene poisoning. METHODS: The erythrocytes were bound with fluorescent-labeled monoclonal antibody after isolated and fixed from the peripheral blood, and then the GPA mutation assay was performed using the flow cytometry (FCM). The related factors of GPA mutation frequency were analyzed by statistical methods. RESULTS: The GPA mutation frequency of chronic benzene poisonings was significantly higher than that of their controls (P < 0.05). Significant direct correlation was found between age, length of service, accumulative exposure score and the GPA mutation frequency of workers exposed to benzene (P < 0.01). However, there was significantly inverse correlation between the 3AB index and the GPA mutation frequency (GPAN0: r(s) = -0.589, P < 0.01, GPANN: r(s) = -0.615, P < 0.01). In the multiple factor regression analysis on GPA mutation frequency, benzene exposure and individual susceptibility both entered model of multiple factors analysis, the coefficient of determination of benzene-exposed workers was 0.819. CONCLUSION: Exposure to benzene and individual susceptibility are the most important factors that affect GPA mutation frequency. GPA mutation frequency increases with the benzene exposure and individual susceptibility.

[Professor LUO Cai-gui's experience of using acupoint "Baliao" for treatment of low back pain].

Professor LUO Cai-gui's experience of acupuncture at acupoint "Baliao" with twisting manipulation for treatment of low back pain is introduced. This method has significant efficacy on improving low back pain and numbness of lower extremities, which is characterized with short-time manipulation, quick de-qi and long effective time. The acupuncture methods, manipulations, precautions, etc. are elaborated in details. A typical case is added.