Concentration-resistance relationship and PK/PD evaluation of danofloxacin against emergence of resistant Pasteurella multocida in an in vitro dynamic model.

AIMS: This study aimed to assess the pharmacokinetic/pharmacodynamic (PK/PD) targets of danofloxacin to minimize the risk of selecting resistant P. multocida mutants and to identify the mechanisms underlying their resistance in an in vitro dynamic model, attaining the optimum dosing regimen of danofloxacin to improve its clinical efficacy based on the mutant selection window (MSW) hypothesis. METHODS AND RESULTS: Danofloxacin at seven dosing regimens and five days of treatment were simulated to quantify the bactericidal kinetics and enrichment of resistant mutants upon continuous antibiotic exposure. The magnitudes of PK/PD targets associated with different efficacies were determined in the model. The 24 h danofloxacin area under the concentration-time curve to MIC ratios (AUC24h/MIC) associated with bacteriostatic, bactericidal and eradication effects against P. multocida were 34, 52, and 64 h. This translates to average danofloxacin concentrations (Cav) over 24 h being 1.42, 2.17, and 2.67 times the MIC, respectively. An AUC/MIC-dependent antibacterial efficacy and AUC/MPC (mutant prevention concentration)-dependent enrichment of P. multocida mutants in which maximum losses in danofloxacin susceptibility occurred at a simulated AUC24h/MIC ratio of 72 h (i.e. Cav of 3 times the MIC). The overexpression of efflux pumps (acrAB-tolC) and their regulatory genes (marA, soxS, and ramA) was associated with reduced susceptibility in danofloxacin-exposed P. multocida. The AUC24h/MPC ratio of 19 h (i.e. Cav of 0.8 times the MPC) was determined to be the minimum mutant prevention target value for the selection of resistant P. multocida mutants. CONCLUSIONS: The emergence of P. multocida resistance to danofloxacin exhibited a concentration-dependent pattern and was consistent with the MSW hypothesis. The current clinical dosing regimen of danofloxacin (2.5 mg kg-1) may have a risk of treatment failure due to inducible fluoroquinolone resistance.

Pharmacokinetic/pharmacodynamic evaluation of gamithromycin against rabbit pasteurellosis.

BACKGROUND: Gamithromycin is an effective therapy for bovine and swine respiratory diseases but not utilized for rabbits. Given its potent activity against respiratory pathogens, we sought to determine the pharmacokinetic profiles, antimicrobial activity and target pharmacokinetic/pharmacodynamic (PK/PD) exposures associated with therapeutic effect of gamithromycin against Pasteurella multocida in rabbits. RESULTS: Gamithromycin showed favorable PK properties in rabbits, including high subcutaneous bioavailability (86.7 ± 10.7%) and low plasma protein binding (18.5-31.9%). PK analysis identified a mean plasma peak concentration (Cmax) of 1.64 ± 0.86 mg/L and terminal half-life (T1/2) of 31.5 ± 5.74 h after subcutaneous injection. For P. multocida, short post-antibiotic effects (PAE) (1.1-5.3 h) and post-antibiotic sub-inhibitory concentration effects (PA-SME) (6.6-9.1 h) were observed after exposure to gamithromycin at 1 to 4× minimal inhibitory concentration (MIC). Gamithromycin demonstrated concentration-dependent bactericidal activity and the PK/PD index area under the concentration-time curve over 24 h (AUC24h)/MIC correlated well with efficacy (R2 > 0.99). The plasma AUC24h/MIC ratios of gamithromycin associated with the bacteriostatic, bactericidal and bacterial eradication against P. multocida were 15.4, 24.9 and 27.8 h in rabbits, respectively. CONCLUSIONS: Subcutaneous administration of 6 mg/kg gamithromycin reached therapeutic concentrations in rabbit plasma against P. multocida. The PK/PD ratios determined herein in combination with ex vivo activity and favorable rabbit PK indicate that gamithromycin may be used for the treatment of rabbit pasteurellosis.

Phosphorylation of androgen receptor by mTORC1 promotes liver steatosis and tumorigenesis.

BACKGROUND AND AIMS: Androgen receptor (AR) has been reported to play an important role in the development and progression of man's prostate cancer. Hepatocellular carcinoma (HCC) is also male-dominant, but the role of AR in HCC remains poorly understood. Mechanistic target of rapamycin complex 1 (mTORC1) also has been reported to be highly activated in HCC. In this study, we aimed to explore the role of AR phosphorylation and its relationship with mTORC1 in hepatocarcinogenesis. APPROACH AND RESULTS: In vitro experiment, we observed that mTORC1 interacts with hepatic AR and phosphorylates it at S96 in response to nutrient and mitogenic stimuli in HCC cells. S96 phosphorylation promotes the stability, nuclear localization, and transcriptional activity of AR, which enhances de novo lipogenesis and proliferation in hepatocytes and induces liver steatosis and hepatocarcinogenesis in mice independently and cooperatively with androgen. Furthermore, high ARS96 phosphorylation is observed in human liver steatotic and HCC tissues and is associated with overall survival and disease-free survival, which has been proven as an independent survival predictor for patients with HCC. CONCLUSIONS: AR S96 phosphorylation by mTORC1 drives liver steatosis and HCC development and progression independently and cooperatively with androgen, which not only explains why HCC is man-biased but also provides a target molecule for prevention and treatment of HCC and a potential survival predictor in patients with HCC.

Design, Synthesis, and Bioactivity of Eighteen Novel 2H-1,4-Benzoxazin-3(4H)-one Containing a Propanolamine Moiety.

To develop a novel skeleton for broad-spectrum pesticides with high-efficiency against tea tree diseases, a series of aniline 2H-1,4-benzoxazin-3(4H)-one derivatives containing a propanolamine structure was synthesized and confirmed by 1 H-NMR, 13 C-NMR, 19 F-NMR, HRMS, and single-crystal diffraction analysis. Bioactivities were evaluated against tobacco mosaic virus (TMV, the model virus), three kinds of bacteria, and five typical plant fungi. Bioassay results showed that compound 2i (EC50 =395.05 µg/mL) had the best curative activity against TMV, 3d (EC50 =45.70 µg/mL) had the best inhibitory activity against Pseudomonas syringae pv. Actinidiae, and 3a (EC50 =13.53 µg/mL) had the best inhibitory activity against Pestalotiopsis trachicarpicola. Scanning electron microscope morphological observation of P. trachicarpicola treated with 0, 100, and 200 µg/mL 3a revealed dried, flattened and folded outer walls of the hyphae at higher concentrations, leading to inhibition of fungal growth. The broad-spectrum bioactivities (against viruses, bacteria and fungi) of this series of target compounds indicate that these 2H-1,4-benzoxazin-3(4H)-one derivatives containing a propanolamine moiety are potential skeletons for developing pesticides with wide-ranging activities against various tea tree diseases.

A 10-Year Prevalence Survey and Clinical Features Analysis of Pressure Injury in a Tertiary Hospital in China, 2009-2018.

OBJECTIVE: To describe the 10-year prevalence of pressure injury (PI) in a tertiary hospital in China and determine the clinical characteristics of inpatients with PI. METHODS: The authors performed a retrospective analysis of PI cases extracted from the electronic health record of a tertiary hospital. The trend of PI prevalence over 10 years was described by estimating the average percent change (EAPC). Comorbidities were described with the Charlson Comorbidity Index (CCI). The clinical characteristics of PI were described using the number of cases and composition ratio. RESULTS: The overall prevalence of PI was 0.59% (5,838/986,404). From 2009 to 2018, the rate increased from 0.19% to 1.00% (EAPC = 22.46%). When stage I PIs were excluded, the prevalence of PI ranged from 0.15% to 0.79% (EAPC = 21.90%). The prevalence of hospital-acquired PI was 0.13%. Prevalence increased with age (Ptrend < .001) and was significantly higher in men than women (P < .001). Patients with PI were more widely distributed in the ICU (20.58%), vasculocardiology department (11.73%), gastroenterology department (10.18%), and OR (8.29%). Of patients with PI, 71.3% had a CCI score 4 or higher. CONCLUSIONS: The PI prevalence in the study facility increased rapidly over the study period. Pressure injuries among patients in the gastroenterology department and in the community deserve more attention. The CCI may be a good indicator for PI risk assessment.

Cleaning the palate and tongue without nausea: a mixed methods study exploring the appropriate depth and direction of oral care.

BACKGROUND: It is advisable to clean the palate and tongue thoroughly during oral care to protect against nosocomial infections. However, improper cleaning may cause nausea. To date, no robust data are available regarding how to implement this procedure properly. Furthermore, traditional cotton balls, forceps and normal saline are still used in clinical in China. This mixed methods study aimed to explore the appropriate depth and direction of cleaning methods for palates and tongues without causing nausea and the factors influencing cleaning depth and discomfort in traditional oral care. METHODS: Our study recruited students (n = 276) from a medical university. The first phase was a quantitative study, in which forceps were slowly inserted into their throats until the gag reflex was triggered, and then, the insertion depth was measured. After that, participants were randomly divided into two groups. In group A, palates and tongues were cleaned coronally and then sagittally, with the converse order used for group B. The extent of nausea was measured. Additionally, the qualitative data were types of discomfort other than nausea reported by the participants. RESULTS: The tolerable depths (without causing nausea) for cleaning the palate and tongue were 6.75 ± 1.07 cm and 6.92 ± 1.11 cm, respectively. Participants of male sex and with high BMI (overweight/obese) were associated with greater tolerable cleaning depth. The extent of nausea caused by cleaning both the palate and the tongue sagittally was higher than that elicited by coronal cleaning (p = 0.025 and p = 0.003, respectively). Other discomforts included itching, saltiness and coldness. CONCLUSION: It is appropriate to increase the cleaning depth of the palate and tongue for adult males and overweight/obese individuals. Moreover, coronal cleaning causes lower levels of nausea, and traditional oral care appliances should be improved.

In Vivo Pharmacodynamic Target Assessment of Antofloxacin against Streptococcus pneumoniae and Staphylococcus aureus in a Neutropenic Murine Pneumonia Model.

We determined in vivo efficacy and target PK/PD exposures of antofloxacin against Streptococcus pneumoniae and Staphylococcus aureus in the murine pneumonia model. The mean plasma free drug area under the concentration-time curve/MIC (fAUC/MIC) targets associated with stasis and 1-log10 and 2-log10 kill effects were 8.93, 19.2, and 48.1, respectively, for S. pneumoniae, whereas they were 30.5, 55.4, and 115.8, respectively, for S. aureus The fAUC/MIC targets in murine lung epithelial lining fluids (ELF) for the same endpoints were nearly 2-fold higher than those in plasma.

Activity of Tigecycline or Colistin in Combination with Zidovudine against Escherichia coli Harboring tet(X) and mcr-1.

Alternative therapeutic options are urgently needed against multidrug-resistant Escherichia coli infections, especially in situations of preexisting tigecycline and colistin resistance. Here, we investigated synergistic activity of the antiretroviral drug zidovudine in combination with tigecycline or colistin against E. coli harboring tet(X) and mcr-1 in vitro and in a murine thigh infection model. Zidovudine and tigecycline/colistin combinations achieved synergistic killing and significantly decreased bacterial burdens by >2.5-log10 CFU/g in thigh tissues compared to each monotherapy.

The false smut pathogen Ustilaginoidea virens requires rice stamens for false smut ball formation.

Rice false smut has emerged as a serious grain disease in rice production worldwide. The disease is characterized by the transformation of individual rice florets into false smut balls, which is caused by the fungal pathogen Ustilaginoidea virens. To date, little is known about the host factors required for false smut ball formation by U. virens. In this study, we identified histological determinants for the formation of false smut balls by inoculating U. virens into rice floral mutants defective with respect to individual floral parts. The results showed that U. virens could form mature false smut balls in rice floral mutants with defective pistils, but failed to develop false smut balls in the superwoman mutant lacking stamens, identifying that U. virens requires rice stamens to complete its infection cycle. Comparative transcriptome analysis indicated a list of candidate host genes that may facilitate nutrient acquisition by U. virens from the rice stamens, such as SWEET11, SWEET14 and SUT5, and genes involved in the biosynthesis of trehalose and raffinose family sugars. These data pinpoint rice stamens as the key target organ of U. virens infection and provide a valuable starting point for dissecting the molecular mechanism of false smut ball formation.

Epidemiological and PK/PD cutoff values determination and PK/PD-based dose assessment of gamithromycin against Haemophilus parasuis in piglets.

BACKGROUND: Gamithromycin is a macrolide approved for the treatment of bovine and swine respiratory diseases. Our study aims to establish the clinical breakpoint and optimum dose regimen for gamithromycin against Haemophilus parasuis in piglets. RESULTS: Gamithromycin was well absorbed and fully bioavailable (87.2-101%) after intramuscular and subcutaneous administrations. The MICs of gamithromycin for 192 clinical H. parasuis isolates ranged from 0.008 to 128 mg/L and the epidemiological cutoff (ECOFF) was calculated as 1.0 mg/L. A large potentiation effect of serum on in vitro susceptibility of gamithromycin was observed for H. parasuis, with broth/serum ratios of 8.93 for MICs and 4.46 for MBCs, respectively. The postantibiotic effects were 1.5 h (1 × MIC) and 2.4 h (4 × MIC), and the postantibiotic sub-MIC effects ranged from 2.7 to 4.3 h. Gamithromycin had rapid and concentration-dependent killing against H. parasuis, and the AUC24h/MIC ratio correlated well with ex vivo efficacy (R2 = 0.97). The AUC24h/MIC targets in serum associated with bacteriostatic, bactericidal and eradication activities were 15.8, 30.3 and 41.2, respectively. The PK/PD-based population dose prediction indicated a probability of target attainment (PTA) for the current marketed dose (6 mg/kg) of 88.9% against H. parasuis. The calculated gamithromycin dose for a PTA ≥ 90% was 6.55 mg/kg. Based on Monte Carlo simulations, the PK/PD cutoff (COPD) was determined to be 0.25 mg/L. CONCLUSION: The determined cutoffs and PK/PD-based dose prediction will be of great importance in gamithromycin resistance surveillance and serve as an important step in the establishment of optimum dose regimen and clinical breakpoints.

Role of Purine Biosynthesis in Persistent Methicillin-Resistant Staphylococcus aureus Infection.

Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (PB) represents an important subset of S. aureus endovascular infections. In this study, we investigated potential genetic mechanisms underlying the persistent outcomes. Compared with resolving bacteremia (RB) isolates (defined as isolates associated with negative results of blood cultures 2-4 days after initiation of therapy), PB strains (defined as isolates associated with positive results of blood cultures ≥7 days after initiation of therapy) had significantly earlier onset activation of key virulence regulons and structural genes (eg, sigB, sarA, sae, and cap5), higher expression of purine biosynthesis genes (eg, purF), and faster growth rates, with earlier entrance into stationary phase. Importantly, an isogenic strain set featuring a wild-type MRSA isolate, a purF mutant strain, and a purF-complemented strain and use of strategic purine biosynthesis inhibitors implicated a causal relationship between purine biosynthesis and the in vivo persistent outcomes. These observations suggest that purine biosynthesis plays a key role in the outcome of PB and may represent a new target for enhanced efficacy in treating life-threatening MRSA infections.

In Vivo Bioluminescent Monitoring of Therapeutic Efficacy and Pharmacodynamic Target Assessment of Antofloxacin against Escherichia coli in a Neutropenic Murine Thigh Infection Model.

Antimicrobial resistance among uropathogens has increased the rates of infection-related morbidity and mortality. Antofloxacin is a novel fluoroquinolone with broad-spectrum antibacterial activity against urinary Gram-negative bacilli, such as Escherichia coli This study monitored the in vivo efficacy of antofloxacin using bioluminescent imaging and determined pharmacokinetic (PK)/pharmacodynamic (PD) targets against E. coli isolates in a neutropenic murine thigh infection model. The PK properties were determined after subcutaneous administration of antofloxacin at 2.5, 10, 40, and 160 mg/kg of body weight. Following thigh infection, the mice were treated with 2-fold-increasing doses of antofloxacin from 2.5 to 80 mg/kg administered every 12 h. Efficacy was assessed by quantitative determination of the bacterial burdens in thigh homogenates and was compared with the bioluminescent density. Antofloxacin demonstrated both static and killing endpoints in relation to the initial burden against all study strains. The PK/PD index area under the concentration-time curve (AUC)/MIC correlated well with efficacy (R2 = 0.92), and the dose-response relationship was relatively steep, as observed with escalating doses of antofloxacin. The mean free drug AUC/MIC targets necessary to produce net bacterial stasis and 1-log10 and 2-log10 kill for each isolate were 38.7, 66.1, and 147.0 h, respectively. In vivo bioluminescent imaging showed a rapid decrease in the bioluminescent density at free drug AUC/MIC exposures that exceeded the stasis targets. The integration of these PD targets combined with the results of PK studies with humans will be useful in setting optimal dosing regimens for the treatment of urinary tract infections due to E. coli.

Increased activity of linezolid in combination with rifampicin in a murine pneumonia model due to MRSA.

Objectives: The chloramphenicol/florfenicol resistance gene cfr, which mediates cross-resistance to linezolid and other classes of antimicrobial agents, represents a global therapeutic challenge due to its dissemination among MDR nosocomial pathogens, including MRSA. This study aimed to compare the efficacy of the linezolid/rifampicin combination in a murine pneumonia model caused by cfr-positive and cfr-negative clinical MRSA strains. Methods: Synergistic activity between linezolid and rifampicin was evaluated by chequerboard and time-kill assays. Pharmacokinetic profiles in plasma and epithelial lining fluid (ELF) as well as the therapeutic efficacy of linezolid alone and in combination with rifampicin were investigated in a murine pneumonia model. The Emax Hill equation was used to model the dose-response relationship. Results: Increased susceptibility of the study MRSA strains to linezolid was observed with the rifampicin combination (MIC decreased 2- to 16-fold versus linezolid alone). The combination had synergistic activity (fractional inhibitory concentration index ≤0.5) against all cfr-positive MRSA isolates. Linezolid demonstrated excellent pulmonary penetration with an ELF/fplasma AUC ratio of 2.68 ±âŸ0.17. The addition of rifampicin significantly improved the efficacy of linezolid in the pneumonia model due to cfr-positive and cfr-negative MRSA strains. The fAUC/MIC targets of linezolid associated with stasis, 1 log10 kill and 2 log10 kill were 15.9, 38.8 and 175 in plasma, and 43.5, 108 and 415 in ELF, respectively. Importantly, the linezolid fAUC/MIC targets in both plasma and ELF were 2.4-6.7 times lower in combined linezolid/rifampicin therapy versus linezolid monotherapy (P < 0.005). Conclusions: Combination of linezolid with rifampicin significantly improved the efficacy of linezolid in the murine pneumonia model caused by MRSA strains in the presence and absence of the cfr gene.

Analysis of 246 sentinel lymph node biopsies of patients with clinical primary breast cancer by application of carbon nanoparticle suspension.

AIM: This study aims to explore the accuracy, specificity and laws of axillary lymph node metastasis predicted by sentinel lymph node biopsy (SLNB) by comparing axillary lymph node status via SLNB and axillary lymph node dissection (ALND) with nanocarbon as the tracer. METHODS: Forty six patients were retrospectively analyzed. These patients underwent SLNB with nanocarbon as the tracer from March 2013 to April 2014. RESULTS: Two hundred and forty six patients of sentinel lymph node (SLN) were successfully detected. Among these patients, 8 patients had 1 SLN (3.25%), 33 patients had 2 SLN (13.41%), 46 patients had 3 SLN (18.70%), 51 patients had 4 SLN (20.73%), 40 patients had 5 SLN (16.26%), 24 patients had 6 SLN (9.76%) and 24 patients had 7 or more SLN (9.76%). The SLNB success rate of nanocarbon staining in the 246 cases was 99.59%, accuracy rate was 97.06% and sensitivity was 93.22%. Furthermore, false negatives were found in four patients, and the false-negative rate was 6.78%. The number of lymph node metastasis in the SLNB and ALND of early-stage breast cancer was analyzed. When the number of SLN dissection was 1, 2, 3, 4, 5, 6 or 7, the coincidence rate of lymph node metastasis for SLNB and ALND was 80.00, 84.36, 78.57, 88.89, 90.48, 80.00, 73.68 and 78.36, respectively. CONCLUSION: Sentinel lymph node biopsy performed using the nanocarbon staining method is simple, easy and reliable, and it can be used to predict the axillary status of breast cancer in the early stage.

In Vivo Pharmacokinetic and Pharmacodynamic Profiles of Antofloxacin against Klebsiella pneumoniae in a Neutropenic Murine Lung Infection Model.

Antofloxacin is a novel broad-spectrum fluoroquinolone under development for the treatment of infections caused by a diverse group of bacterial species. We explored the pharmacodynamic (PD) profile and targets of antofloxacin against seven Klebsiella pneumoniae isolates by using a neutropenic murine lung infection model. Plasma and bronchopulmonary pharmacokinetic (PK) studies were conducted at single subcutaneous doses of 2.5, 10, 40, and 160 mg/kg of body weight. Mice were infected intratracheally with K. pneumoniae and treated using 2-fold-increasing total doses of antofloxacin ranging from 2.5 to 160 mg/kg/24 h administered in 1, 2, 3, or 4 doses. The Emax Hill equation was used to model the dose-response data. Antofloxacin could penetrate the lung epithelial lining fluid (ELF) with pharmacokinetics similar to those in plasma with linear elimination half-lives over the dose range. All study strains showed a 3-log10 or greater reduction in bacterial burden and prolonged postantibiotic effects (PAEs) ranging from 3.2 to 5.3 h. Dose fractionation response curves were steep, and the free-drug area under the concentration-time curve over 24 h (AUC0-24)/MIC ratio was the PD index most closely linked to efficacy (R2 = 0.96). The mean free-drug AUC0-24/MIC ratios required to achieve net bacterial stasis, a 1-log10 kill, and a 2-log10 kill for each isolate were 52.6, 89.9, and 164.9, respectively. When integrated with human PK data, these PD targets could provide a framework for further optimization of dosing regimens. This could make antofloxacin an attractive option for the treatment of respiratory tract infections involving K. pneumoniae.

Increased activity of colistin in combination with amikacin against Escherichia coli co-producing NDM-5 and MCR-1.

Objectives: Colistin and carbapenem are two lines of last-resort antibiotics against lethal infections caused by MDR Gram-negative pathogens. The emergence of carbapenemase-positive Escherichia coli with colistin resistance poses a serious threat to public health worldwide. Here we report, for the first time (to the best of our knowledge), a novel combination therapy used for the treatment of E. coli co-producing MCR-1 and NDM-5. Methods: The MICs of colistin were determined alone and with 1-4 mg/L amikacin. A 7-by-4 time-kill array of colistin (0, 0.5, 1, 2, 4, 8 and 16 mg/L) and amikacin (0, 1, 2 and 4 mg/L) over 48 h was designed to characterize the in vitro activity of these agents alone and in combination against each E. coli isolate at an inoculum of 10 6 and 10 8 cfu/mL. The sigmoid E max model was utilized for better delineation of the concentration-effect relationship of each combination. In vivo effectiveness was investigated using a mouse model (combination therapy with intraperitoneal colistin plus amikacin compared with monotherapy). Results: For colistin-resistant isolates, the addition of amikacin demonstrated augmented susceptibility, reducing colistin MICs below the current susceptibility breakpoint. A concentration-dependent decrease in the EC 50 values of colistin was observed for all study isolates in the presence of increasing amikacin concentrations. Further in vivo treatment experiments demonstrated that this combination could achieve 1.5-2.8 log 10 killing after 24 h of therapy, while monotherapy was unable to achieve such a killing effect. Conclusions: The combination of colistin and amikacin may be a promising therapeutic option for the treatment of lethal infections caused by NDM-5-bearing MCR-1-positive superbugs.

Pharmacokinetic and pharmacodynamic modeling of sarafloxacin against avian pathogenic Escherichia coli in Muscovy ducks.

BACKGROUND: This study focused on utilizing pharmacokinetics/pharmacodynamics (PK/PD) modeling to optimize therapeutic dosage regimens of sarafloxacin against avian pathogenic Escherichia. coli O78 strain in Muscovy ducks. The ex vivo PK/PD study of sarafloxacin was conducted in Muscovy ducks after intravenous (i.v.) and oral (p.o.) administrations at a single dose of 10 mg/kg bodyweight (BW). The serum samples were analyzed by reverse phase high-performance liquid chromatography (RP-HPLC) using a fluorescence detection method. Sarafloxacin PK data were analyzed by a non-compartmental method using Winnonlin software. RESULTS: Calculations of the area under the concentration-time curves (AUC0-24h) were 8.57 ± 0.59 and 8.37 ± 0.29 µg · h/ml following i.v. and p.o. administration, respectively. Elimination half-lives (t 1/2ß) were 6.11 ± 0.99 h and 8.21 ± 0.64 h for i.v. injection and p.o. administration, respectively. The mean in vitro plasma protein binding of sarafloxacin was 39.3%. Integration using the sigmoid E max model, the mean values of AUC0-24h/MIC needed for bacteriostatic, bactericidal and bacterial eradication action were 25.4, 40.6, and 94.4 h, respectively. CONCLUSIONS: Sarafloxacin administered at a 10 mg/kg dose may be insufficient for treatment of E. coli O78 infections with an MIC equally to or over 0.125 µg/ml. Furthermore, higher doses of sarafloxacin are required to minimize antimicrobial resistance considering the MPC theory.

Effects of introducing theanine or glutamic acid core to tralopyril on systemicity and insecticidal activity.

Tralopyril was the active agent of a pro-insecticide chlorfenapyr. To simultaneously solve the problems of the phytotoxicity and non-systemic insecticidal activity of tralopyril, four new tralopyril conjugates containing theanine or glutamic acid moieties were designed and synthesized. Their phytotoxicity to tea shoot, phloem systemicity, and insecticidal activity were evaluated. Phytotoxic symptoms were not observed after the tea shoots were exposed to the four conjugates at concentrations of 2mM. The phloem mobility test on Ricinus communis L. seedlings confirmed that all four conjugates were mobile in the sieve tubes. Results of insecticidal activity against the third-instar larvae of Plutella xylostella showed that only conjugate 20 exhibited activity with an LC50 value of 0.5882±0.0504mM. After root application to tea seedlings, conjugate 20 showed obviously systemic insecticidal activity against Dendrothrips minowai Priesner, while chlorfenapyr showed no attribute of that. A new conjugate as potential phloem mobile pro-insecticide candidate was provided and so a novel strategy of pro-insecticide for improved phloem systemicity was proposed.

Establishment of valnemulin susceptibility breakpoint against Clostridium perfringens in rabbits.

Susceptibility breakpoints provide fundamental information for rational administration of antibiotics. The present investigation reports the first valnemulin susceptibility breakpoint (MIC<0.25 µg/mL) against Clostridium perfringens infections in rabbits based on the wild-type cutoff (COWT) and the pharmacokinetics/pharmacodynamic (PK/PD) cutoff (COPD). The established susceptibility breakpoint of valnemulin might be useful in resistance surveillance of pleuromutilins and development of clinical breakpoints.

Influence of Pyranose and Spacer Arm Structures on Phloem Mobility and Insecticidal Activity of New Tralopyril Derivatives.

Six new conjugates were designed and synthesized by introducing glucose, methyl glucuronate or glucuronic acid moieties on tralopyril. Phytotoxicity and phloem mobility results demonstrated that the introduction of glucose, methyl glucuronate or glucuronic acid moieties can simultaneously solve the tough phytotoxicity problem and phloem mobility transformation of tralopyril. Conjugates 12 and 18 containing the glucuronic acid moiety exhibited higher phloem mobility than conjugates 9, 11, 15 and 17. Conjugates 15, 17 and 18 with methoxymethyl groups on the tralopyril pyrrole nitrogen atom showed activity against Plutella xylostella, while conjugates 9, 11 and 12 with a methene group on the pyrrole N showed no activity. Cabbage roots were incubated in a buffered solution containing conjugates 15, 17 and 18 at 4 mM for 72 h. Only 18 showed systemic insecticidal activity with 100% mortalityagainst P. xylostella, while 15 and 17 showed lower activity andchlorfenapyr showed no activity. The glucuronic acid promoiety imparted more phloem mobility to tralopyril than glucose and methyl glucuronate. The methoxymethyl group bond on the tralopyril skeleton was the key factor in determining the insecticidal activity of the conjugates. A promising systemic proinsecticide containing glucuronic acid and tralopyril moieties was proposed.