scholarly journals Evaluating a tylosin dosage regimen for treatment of Staphylococcus delphini infection in mink (Neovison vison): a pharmacokinetic-pharmacodynamic approach

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Amir Atabak Ronaghinia ◽  
Julie Melsted Birch ◽  
Henrik Lauritz Frandsen ◽  
Pierre-Louis Toutain ◽  
Peter Damborg ◽  
...  
Keyword(s):  
Dosage Regimen ◽  
Animal Experiments ◽  
Bactericidal Effect ◽  
Mechanistic Modeling ◽  
Oral Dosage ◽  
Serum Samples ◽  
Time Curve ◽  
Mixed Effect ◽  
Free Concentration

AbstractStaphylococcus delphini is one of the most common pathogens isolated from mink infections, especially dermatitis. Tylosin (TYL) is used frequently against these infections, although no evidence-based treatment regimen exists. This study aimed to explore the dosage of TYL for infections caused by S. delphini in mink. Two animal experiments with a total of 12 minks were conducted to study the serum pharmacokinetic (PK) characteristics of TYL in mink after 10 mg/kg IV and oral dosing, respectively. The concentration of TYL in serum samples collected before and eight times during 24 h after TYL administration was quantitated with liquid chromatography quadrupole time-of-flight mass spectrometry, and the TYL disposition was analyzed using non-linear mixed effect analysis. The pharmacodynamics (PD) of TYL against S. delphini were studied using semi-mechanistic modeling of in vitro time-kill experiments. PKPD modeling and simulation were done to establish the PKPD index and dosage regimen. The disposition of TYL was described by a two-compartmental model. The area under the free concentration–time curve of TYL over the minimum inhibitory concentration of S. delphini (fAUC/MIC) was determined as PKPD index with breakpoints of 48.9 and 98.7 h for bacteriostatic and bactericidal effect, respectively. The calculated daily oral dose of TYL was 2378 mg/kg, which is 238-fold higher than the currently used TYL oral dosage regimen in mink (10 mg/kg). Accordingly, sufficient TYL concentrations are impossible to achieve in mink plasma, and use of this drug for extra-intestinal infections in this animal species must be discouraged.

scholarly journals Apotransferrin in Combination with Ciprofloxacin Slows Bacterial Replication, Prevents Resistance Amplification, and Increases Antimicrobial Regimen Effect

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Paul G. Ambrose ◽  
Brian D. VanScoy ◽  
Brian M. Luna ◽  
Jun Yan ◽  
Amber Ulhaq ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Bactericidal Effect ◽  
Bacterial Density ◽  
Infection Model ◽  
Time Curve ◽  
Content Type ◽  
Wide Range ◽  
Bacterial Replication ◽  
The Impact

ABSTRACT There has been renewed interest in combining traditional small-molecule antimicrobial agents with nontraditional therapies to potentiate antimicrobial effects. Apotransferrin, which decreases iron availability to microbes, is one such approach. We conducted a 48-h one-compartment in vitro infection model to explore the impact of apotransferrin on the bactericidal activity of ciprofloxacin. The challenge panel included four Klebsiella pneumoniae isolates with ciprofloxacin MIC values ranging from 0.08 to 32 mg/liter. Each challenge isolate was subjected to an ineffective ciprofloxacin monotherapy exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC/MIC ratio] ranging from 0.19 to 96.6) with and without apotransferrin. As expected, the no-treatment and apotransferrin control arms showed unaltered prototypical logarithmic bacterial growth. We identified relationships between exposure and change in bacterial density for ciprofloxacin alone (R2 = 0.64) and ciprofloxacin in combination with apotransferrin (R2 = 0.84). Addition of apotransferrin to ciprofloxacin enabled a remarkable reduction in bacterial density across a wide range of ciprofloxacin exposures. For instance, at a ciprofloxacin AUC/MIC ratio of 20, ciprofloxacin monotherapy resulted in nearly 2 log10 CFU increase in bacterial density, while the combination of apotransferrin and ciprofloxacin resulted in 2 log10 CFU reduction in bacterial density. Furthermore, addition of apotransferrin significantly reduced the emergence of ciprofloxacin-resistant subpopulations compared to monotherapy. These data demonstrate that decreasing the rate of bacterial replication with apotransferrin in combination with antimicrobial therapy represents an opportunity to increase the magnitude of the bactericidal effect and to suppress the growth rate of drug-resistant subpopulations.

scholarly journals Bactericidal Effect and Pharmacodynamics of Cethromycin (ABT-773) in a Murine Pneumococcal Pneumonia Model

2002 ◽  
Vol 46 (10) ◽  
pp. 3185-3192 ◽  
Author(s):  
Myo-Kyoung Kim ◽  
Wen Zhou ◽  
Pamela R. Tessier ◽  
Dawei Xuan ◽  
Min Ye ◽  
...  
Keyword(s):  
Goodness Of Fit ◽  
Drug Exposure ◽  
Bactericidal Effect ◽  
Free Drug ◽  
Bacterial Density ◽  
Maximum Effect ◽  
Time Curve ◽  
Initiation Of Therapy

ABSTRACT Cethromycin (ABT-773), a new ketolide, possesses potent in vitro activity against Streptococcus pneumoniae. The objective of this study was to investigate the in vivo bactericidal activity of cethromycin against macrolide-susceptible and -resistant S. pneumoniae in a murine pneumonia model and to describe the pharmacodynamic (PD) profile of cethromycin. Eight (two macrolide susceptible, six macrolide resistant) clinical isolates of S. pneumoniae were investigated. Cyclophosphamide administration rendered ICR mice transiently neutropenic prior to intratracheal inoculation with 0.05 ml of an S. pneumoniae suspension containing 107 to 108 CFU/ml. Oral cethromycin was initiated 12 to 14 h postinoculation over a dosage range of 0.1 to 800 mg/kg of body weight/day. Lungs from seven to eight mice per treatment and control groups were collected at 0 and 24 h posttherapy to assess bacterial density. The cumulative mortality (n = 12 to 13) was assessed at 120 h (end of therapy) and at 192 h (3 days posttherapy). Recovery of pneumococci from the lungs of infected animals prior to the initiation of therapy ranged from 4.6 to 7.2 log10 CFU. Growth in untreated control animals over a 24-h study period increased 0.3 to 2.7 log10 CFU. Cethromycin demonstrated a substantial bactericidal effect, regardless of macrolide susceptibility. Correlation between changes in bacterial density (24 h) and survival over both 120 and 192 h were statistically significant. All three PD parameters demonstrated a significant correlation with changes in log10 CFU/lung (Spearman's correlation coefficient, P < 0.001); however, the goodness of fit as assessed with the maximum effect (E max) model revealed that the maximum concentration of free drug in serum (C max free)/MIC and the area under the free drug concentration-time curve (AUCfree)/MIC best explained the relationship between drug exposure and reductions in viable bacterial counts. These data reveal that an approximate cethromycin AUCfree/MIC of 50 or C max free/MIC of 1 results in bacteriostatic effects, while higher values (twofold) maximize survival.

scholarly journals Increased Concentrations of Antibody-Bound Circulatory Cell-Free DNA in Rheumatoid Arthritis

2007 ◽  
Vol 53 (9) ◽  
pp. 1609-1614 ◽  
Author(s):  
Xiao-Yan Zhong ◽  
Ines von Mühlenen ◽  
Ying Li ◽  
Anjeung Kang ◽  
Anurag Kumar Gupta ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Animal Experiments ◽  
Basic Research ◽  
Healthy Controls ◽  
Serum Samples ◽  
Cell Free Dna ◽  
Free Dna ◽  
New Evidence

Abstract Background: Increased concentrations of cell-free DNA have been found in several disorders and have been interpreted as evidence of increased rates of cell death or turnover. Evidence from in vitro and animal experiments suggests that DNA may play a role in the pathogenesis of rheumatoid arthritis (RA). Methods: We measured cell-free DNA in plasma and serum from patients with RA and healthy controls by use of quantitative PCR for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) DNA. We used protein G Sepharose™ bead adsorption of plasma and elution to isolate antibody-bound DNA. Results: In paired plasma and serum samples of 16 healthy controls the median GAPDH copies were 4500 genome equivalents (GE)/mL plasma (range 319–21 000) and in 26 RA patients 17 000 GE/mL plasma (2100–2 375 000, P = 0.0001). In the serum from normal controls the median GAPDH copies were 35 000 GE/mL (1700–239 000) and from RA patients 222 000 GE/mL (21 000–2 375 000, P = 0.004). A median of 81% of the cell-free DNA in RA was associated with antibody compared with 9% in healthy controls (P = 0.001). The concentrations of DNA did not vary with the type of therapy patients received. Conclusions: These results provide new evidence for a role of cell-free DNA-antibody complexes in the etiology of RA, suggest new avenues for basic research, and may prove to be relevant to diagnosis and assessment of therapy.

scholarly journals BACTERICIDAL EFFECT OF HUMAN SERUM ON BORRELIA MIYAMOTOI, CAUSATIVE AGENT OF IXODES TICK-BORNE BORRELIOSIS (ITBB-BM)

2018 ◽  
pp. 58-67 ◽  
Author(s):  
A. E. Platonov ◽  
J. .. Koetsveld ◽  
O. A. Stukolova ◽  
A. S. Dolgova ◽  
N. M. Kolyasnikova ◽  
...  
Keyword(s):  
Human Serum ◽  
Protein Microarray ◽  
Bactericidal Effect ◽  
Dark Field ◽  
Immune Serum ◽  
Heat Inactivation ◽  
Borrelia Miyamotoi ◽  
Serum Samples ◽  
Variable Major Proteins

Aim. Our aim was to study the bactericidal effect of human serum on Borrelia miyamotoi in vitro. Materials and methods. B. miyamotoi spirochetes (strains HT31 and LB-2001) were incubated in non-immune serum of healthy donors (SHD) and in heat inactivated complement-depleted SHD, as well as in serum samples of the patients recovered from ITBB-BM. The viability, that is motility, of borrelia after incubation was investigated by dark-field microscopy. The levels ofserum antibody to B.miyamofoi-specificproteins (GlpQ enzyme and four variable major proteins Vlpl5/16, Vlpl8, Vspl, and Vlp5) were measured by specially designed plane protein microarray. Results. Borrelia fully retain their viability in non-immune SHD, but their motility is partially or completely suppressed by the addition of serum from ITBB-BM convalescents or rabbit antibodies to Д. miyamotoi. The immobilizing effect of the immune serum is substantially inhibited by its heat-inactivation, which indicates that immobilizing effect is mediated by the complement system. Conclusion. Antibody-dependent complement-mediated bactericidal action ofhuman blood serum is probably not the only and 100% effective mechanism for human defense against B. miyamotoi infection, but requires support from cellular immunity.

scholarly journals Comparative Efficacies of Human Simulated Exposures of Tedizolid and Linezolid against Staphylococcus aureus in the Murine Thigh Infection Model

2012 ◽  
Vol 56 (8) ◽  
pp. 4403-4407 ◽  
Author(s):  
R. A. Keel ◽  
P. R. Tessier ◽  
J. L. Crandon ◽  
D. P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Density ◽  
Infection Model ◽  
Immunocompetent Mouse ◽  
Time Curve ◽  
Free Concentration ◽  
Content Type ◽  
The Mean

ABSTRACTTedizolid (formally torezolid) is an expanded-spectrum oxazolidinone with enhancedin vitropotency against Gram-positive pathogens, including methicillin-susceptibleStaphylococcus aureus(MSSA) and methicillin-resistantS. aureus(MRSA). The efficacies of human simulated exposures of tedizolid and linezolid againstS. aureusin an immunocompetent mouse thigh model over 3 days were compared. Four strains of MRSA and one of MSSA with tedizolid and linezolid MICs ranging from 0.25 to 0.5 and from 2 to 4 μg/ml, respectively, were utilized. Tedizolid or linezolid was administered in a regimen simulating a human steady-state 24-h area under the free concentration-time curve of 200 mg every 24 h (Q24) or 600 mg Q12, respectively. Thighs were harvested after 4, 8, 12, 24, 36, 48, and 72 h, and efficacy was determined by the change in bacterial density. The mean bacterial density in control mice increased over the 3-day period. After 24 h of treatment, a reduction in bacterial density of ≥1 log CFU was observed for both the tedizolid and linezolid treatments. Antibacterial activity was enhanced for both agents with a reduction of ≥2.6 log CFU after 72 h of treatment. Any statistically significant differences (P≤ 0.05) in efficacy between the agents were transient and did not persist throughout the 72-h treatment period. The tedizolid and linezolid regimens demonstrated similarin vivoefficacies against theS. aureusisolates tested. Both agents were bacteriostatic at 24 h and bactericidal on the third day of treatment. These data support the clinical utility of tedizolid for skin and skin structure infections caused byS. aureus, as well as the bactericidal activity of the oxazolidinones after 3 days of treatment.

scholarly journals Changes in MIC Alter Responses of Pseudomonas aeruginosa to Tobramycin Exposure

1998 ◽  
Vol 42 (6) ◽  
pp. 1365-1369 ◽  
Author(s):  
L. L. Ioannides-Demos ◽  
L. Liolios ◽  
P. Wood ◽  
W. J. Spicer ◽  
A. J. McLean
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Isolate ◽  
Sublethal Effects ◽  
Bactericidal Effect ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Minor Variation ◽  
Wide Range ◽  
Trough Concentrations

ABSTRACT The pharmacokinetic parameters determining antibiotic efficacy are peak concentrations (C max), minimum (trough) concentrations (C min), and area under the concentration-time curve (AUC). There is general agreement about the importance of C max and AUC for aminoglycosides, but this is not so for maintenance of C min. With in vitro exposures modelling in vivo administration,Pseudomonas aeruginosa reference strain ATCC 27853 (MIC, 1 mg/liter) and a higher-MIC (relatively resistant) clinical isolate (MIC, 4 mg/liter) were used to explore bacteriostatic and bactericidal outcomes. With P. aeruginosa ATCC 27853, kill followed a complete bolus profile with a 30-min postdistribution peak (C peak30) of 10 mg/liter. The clinical isolate required a C peak30 bolus profile of 20 mg/liter for kill, and there was no difference between the efficacies of the bolus and infusion exposures. Bolus profiles that were truncated at 8.5 h and producing sublethal effects were then combined with a wide range of C mins. With aC peak30 profile of 8 mg/liter, P. aeruginosa ATCC 27853 showed a graded bacteriostatic response until a C min of ≥0.8 mg/liter, when complete kill resulted. In contrast, bactericidal effects on the clinical isolate required a C peak30 profile of 18 mg/liter with a C min of ≥1.0 mg/liter. Therefore, C min also contributes to the bactericidal effect of tobramycin, with requirements showing minor variation with change in MIC. Dosing principles for relatively resistant (higher-MIC) organisms are suggested from the data. Relatively higher aminoglycoside doses via infusion regimens are likely to be needed to generate higher peak concentrations and higher AUC values necessary for bactericidal effect in resistant organisms. Maintenance of trough concentrations on the order of 1.0 mg/liter during the interdose interval will tend to guard against the possibility of inadequate peak and AUC exposures for kill.

scholarly journals Pharmacodynamics of Telavancin Studied in anIn VitroPharmacokinetic Model of Infection

2010 ◽  
Vol 55 (2) ◽  
pp. 867-873 ◽  
Author(s):  
Alasdair P. MacGowan ◽  
Alan R. Noel ◽  
Sharon Tomaselli ◽  
Heather C. Elliott ◽  
Karen E. Bowker
Keyword(s):  
Population Analysis ◽  
Clinical Effectiveness ◽  
Bactericidal Effect ◽  
Viable Count ◽  
Time Curve ◽  
Dose Ranging ◽  
Mrsa Strains ◽  
Kill Curve ◽  
Emergence Of Resistance

ABSTRACTThe antibacterial effects of telavancin, vancomycin, and teicoplanin against sixStaphylococcus aureusstrains (1 methicillin-susceptibleS. aureus[MSSA] strain, 4 methicillin-resistantS. aureus[MRSA] strains, and 1 vancomycin-intermediateS. aureus[VISA] strain) and threeEnterococcussp. strains (1Enterococcus faecalisstrain, 1Enterococcus faeciumstrain, and 1 vancomycin-resistantE. faecium[VREF] strain) were compared using anin vitropharmacokinetic model of infection. Analyzing the data from all five vancomycin-susceptibleS. aureus(VSSA) strains or all 4 MRSA strains showed that telavancin was superior in its antibacterial effect as measured by the area under the bacterial kill curve at 24 h (AUBKC24) and 48 h (AUBKC48) in comparison to vancomycin or teicoplanin (P< 0.05). Telavancin was also superior to vancomycin and teicoplanin in terms of its greater early killing effect (P< 0.05). Against the threeEnterococcusspp. tested, telavancin was superior to vancomycin in terms of its AUBKC24, AUBKC48, and greater early bactericidal effect (P< 0.05). Dose-ranging studies were performed to provide free-drug area under the concentration-time curve over 24 h in the steady state divided by the MIC (fAUC/MIC) exposures from 0 to 1,617 (7 to 14 exposures per strain) for 5 VSSA, 4 VISA, and the 3Enterococcusstrains. The fAUC/MIC values for a 24-h bacteriostatic effect and a 1-log-unit drop in the viable count were 43.1 ± 38.4 and 50.0 ± 39.0 for VSSA, 3.2 ± 1.3 and 4.3 ± 1.3 for VISA, and 15.1 ± 8.8 and 40.1 ± 29.4 for theEnterococcusspp., respectively. The reason for the paradoxically low fAUC/MIC values for VISA strains is unknown. There was emergence of resistance to telavancin in the dose-ranging studies, as indicated by subpopulations able to grow on plates containing 2× MIC telavancin concentrations compared to the preexposure population analysis profiles. Changes in population analysis profiles were less likely with enterococci than withS. aureus, and the greatest risk of changed profiles occurred for both species at fAUC/MIC ratios of 1 to 10. Maintaining a fAUC/MIC ratio of >50 reduced the risk of subpopulations able to grow on antibiotic-containing media emerging. These data help explain the clinical effectiveness of telavancin against MRSA and indicate that telavancin may have clinically useful activity againstEnterococcusspp., and perhaps also VISA, at human doses of 10 mg/kg of body weight/day. In addition, they support a clinical breakpoint of sensitive at ≤1 mg/liter for bothS. aureusandEnterococcusspp.

Correlation between in vitro and in vivo Data of Radiolabeled Peptide for Tumor Targeting

2019 ◽  
Vol 19 (12) ◽  
pp. 950-960
Author(s):  
Soghra Farzipour ◽  
Seyed Jalal Hosseinimehr
Keyword(s):  
Tumor Targeting ◽  
Single Photon ◽  
Specific Binding ◽  
Specific Interaction ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
Mixed Effect ◽  
Radiolabeled Peptides

Tumor-targeting peptides have been generally developed for the overexpression of tumor specific receptors in cancer cells. The use of specific radiolabeled peptide allows tumor visualization by single photon emission computed tomography (SPECT) and positron emission tomography (PET) tools. The high affinity and specific binding of radiolabeled peptide are focusing on tumoral receptors. The character of the peptide itself, in particular, its complex molecular structure and behaviors influence on its specific interaction with receptors which are overexpressed in tumor. This review summarizes various strategies which are applied for the expansion of radiolabeled peptides for tumor targeting based on in vitro and in vivo specific tumor data and then their data were compared to find any correlation between these experiments. With a careful look at previous studies, it can be found that in vitro unblock-block ratio was unable to correlate the tumor to muscle ratio and the success of radiolabeled peptide for in vivo tumor targeting. The introduction of modifiers’ approaches, nature of peptides, and type of chelators and co-ligands have mixed effect on the in vitro and in vivo specificity of radiolabeled peptides.

Microneedle-Assisted Percutaneous Transport of Magnesium Sulfate

2020 ◽  
Vol 17 (2) ◽  
pp. 140-147
Author(s):  
Karna B. Ghimirey ◽  
Kevin Ita
Keyword(s):  
Confocal Microscopy ◽  
Stratum Corneum ◽  
Magnesium Sulfate ◽  
Inductively Coupled Plasma ◽  
Optical Emission ◽  
Magnesium Concentration ◽  
Porcine Skin ◽  
Time Curve ◽  
Student’S T

Objective: In vitro diffusion experiments were performed to assess the permeation of magnesium sulfate across pig skin. Method: The mean thickness of the dermatomed porcine skin was 648 ± 12 µm. Magnesium concentration was measured using inductively coupled plasma-optical emission spectroscopy. Transdermal flux of magnesium sulfate across MN-treated and untreated porcine skin was obtained from the slope of the steady-state linear portion of cumulative amount versus time curve. Results: Statistical analysis of the results was done with Student’s t-test. The transdermal flux of magnesium sulfate across microneedle-treated porcine skin was 134.19 ± 2.4 µg/cm2/h and transdermal flux across untreated porcine skin was 4.64 ± 0.05 µg/cm2/h. Confocal microscopy was used to visualize the microchannels created by a solid microneedle roller (500 µm). Conclusion: From our confocal microscopy studies, it was evident that the 500 μm long microneedles disrupted the stratum corneum and created microchannels measuring 191 ± 37 µm. The increase in transdermal flux across the microneedle-treated skin was statistically significant compared to that of controls, i.e., without the application of microneedles. With the application of microneedles, the transdermal flux of magnesium permeated over 12 h was approximately 33-fold higher in comparison to passive diffusion across an intact stratum corneum.

Effects of Probiotics in the Management of Infected Chronic Wounds: From Cell Culture to Human Studies

2020 ◽  
Vol 15 (3) ◽  
pp. 193-206
Author(s):  
Brognara Lorenzo ◽  
Salmaso Luca ◽  
Mazzotti Antonio ◽  
Di M. Alberto ◽  
Faldini Cesare ◽  
...  
Keyword(s):  
Chronic Wounds ◽  
Animal Experiments ◽  
Multidrug Resistant ◽  
Preliminary Evidence ◽  
Human Studies ◽  
In Vivo Studies ◽  
Resistant Bacteria ◽  
Keywords Probiotics

Background: Chronic wounds are commonly associated with polymicrobial biofilm infections. In the last years, the extensive use of antibiotics has generated several antibiotic-resistant variants. To overcome this issue, alternative natural treatments have been proposed, including the use of microorganisms like probiotics. The aim of this manuscript was to review current literature concerning the application of probiotics for the treatment of infected chronic wounds. Methods: Relevant articles were searched in the Medline database using PubMed and Scholar, using the keywords “probiotics” and “wound” and “injuries”, “probiotics” and “wound” and “ulcer”, “biofilm” and “probiotics” and “wound”, “biofilm” and “ulcer” and “probiotics”, “biofilm” and “ulcer” and “probiotics”, “probiotics” and “wound”. Results: The research initially included 253 articles. After removal of duplicate studies, and selection according to specific inclusion and exclusion criteria, 19 research articles were included and reviewed, accounting for 12 in vitro, 8 in vivo studies and 2 human studies (three articles dealing with animal experiments included also in vitro testing). Most of the published studies about the effects of probiotics for the treatment of infected chronic wounds reported a partial inhibition of microbial growth, biofilm formation and quorum sensing. Discussion: The application of probiotics represents an intriguing option in the treatment of infected chronic wounds with multidrug-resistant bacteria; however, current results are difficult to compare due to the heterogeneity in methodology, laboratory techniques, and applied clinical protocols. Lactobacillus plantarum currently represents the most studied strain, showing a positive application in burns compared to guideline treatments, and an additional mean in chronic wound infections. Conclusions: Although preliminary evidence supports the use of specific strains of probiotics in certain clinical settings such as infected chronic wounds, large, long-term clinical trials are still lacking, and further research is needed.

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