scholarly journals Distribution and Antimicrobial Activity of Fosfomycin in the Interstitial Fluid of Human Soft Tissues

2000 ◽  
Vol 44 (10) ◽  
pp. 2728-2732 ◽  
Author(s):  
Martin Frossard ◽  
Christian Joukhadar ◽  
Boban M. Erovic ◽  
Peter Dittrich ◽  
Paulus E. Mrass ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissues ◽  
Pharmacokinetic Profile ◽  
Interstitial Space ◽  
Soft Tissue Infections ◽  
Time Curve ◽  
Tract Infections ◽  
High Degree

ABSTRACT Fosfomycin is a broad-spectrum antibiotic which is established as therapy for uncomplicated lower urinary tract infections. In addition, preliminary data indicate that fosfomycin has a potential role in the treatment of soft tissue infections. However, the use of fosfomycin has not been established for this condition, and it is unclear whether the level of fosfomycin penetration into human soft tissues is high enough to eradicate relevant pathogens. To better characterize the antibiotic potential of fosfomycin, we applied a combined in vivo pharmacokinetic-in vitro pharmacodynamic model to human volunteers. For this purpose fosfomycin concentrations in vivo in the fluid of the interstitial space of human soft tissues were measured by microdialysis following intravenous infusion of 4 or 8 g of fosfomycin (n = 6). Subsequently, bacterial isolates with relevance for soft tissue infections were exposed to concentrations according to the in vivo pharmacokinetic profile in the interstitial space fluid obtained by microdialysis. Our experiments indicated a high degree of soft tissue penetration for fosfomycin, with ratios of the area under the concentration-time curve from 0 to 8 h for muscle (AUC0–8muscle )/AUC0–8serum of 0.48 ± 0.08 and 0.53 ± 0.04 and ratios of AUC0–8adipose tissue /AUC0–8serum of 0.74 ± 0.12 and 0.71 ± 0.11 following administration of 4 and 8 g, respectively. In corresponding in vitro simulation experiments with selected isolates of Staphylococcus aureus,Enterobacter cloacae, and Serratia marcescensfor which MICs were 16 μg/ml, organisms were undetectable after a single dosing interval. Fosfomycin exhibits a strong ability to penetrate into the fluid of the interstitial space of soft tissues and reaches levels sufficient to substantially inhibit the growth of relevant bacteria at the target site. We therefore conclude that fosfomycin might qualify as an alternative candidate for the therapy of soft tissue infections.

scholarly journals Pharmacokinetics of Single- and Multiple-Dose Oral Clarithromycin in Soft Tissues Determined by Microdialysis

2007 ◽  
Vol 51 (9) ◽  
pp. 3185-3189 ◽  
Author(s):  
Friederike Traunmüller ◽  
Markus Zeitlinger ◽  
Petra Zeleny ◽  
Markus Müller ◽  
Christian Joukhadar
Keyword(s):  
Skeletal Muscle ◽  
Single Dose ◽  
Steady State ◽  
Soft Tissue ◽  
Soft Tissues ◽  
Interstitial Space ◽  
Soft Tissue Infections ◽  
Time Curve ◽  
Dose Oral ◽  
Subcutaneous Adipose

ABSTRACT The antimicrobial spectrum of clarithromycin renders this antibiotic a frequently used option in the treatment of skin and soft-tissue infections. In most cases, these infections are caused by extracellularly proliferating microorganisms. Thus, clarithromycin concentrations achieved in the interstitial space are considered particularly important for clinical efficacy. In the present study, clarithromycin concentrations in plasma and interstitial-space fluid of subcutaneous adipose tissue and skeletal muscle of six healthy male volunteers were assessed by means of the microdialysis technique after oral single-dose administration of 250 mg and multiple doses of 500 mg of clarithromycin twice a day (b.i.d.). The ratios of the area under the concentration-time curve of free clarithromycin from 0 to 24 h calculated for a single dose of 250 mg (fAUC0-24) in interstitial-space fluid to the fAUC0-24 in plasma were 0.29 ± 0.17 and 0.42 ± 0.18 for subcutis and skeletal muscle, respectively. For 500 mg of clarithromycin at the steady state (3 to 5 days of intake twice daily), the fAUC0-24(b.i.d.) ratios at the steady state were 0.39 ± 0.04 and 0.41 ± 0.19 for subcutis and skeletal muscle, respectively. The half-life was around 2 h after a single dose but increased to approximately 4 h in plasma and tissues after repetitive clarithromycin administration. Based on subsequently performed pharmacokinetic-pharmacodynamic calculations, a dosing regimen of 500 mg b.i.d. may be ineffective in the treatment of soft-tissue infections caused by pathogens with a drug MIC higher than 0.125 mg/liter.

scholarly journals Quinolones for the Treatment ofNeisseria GonorrhoeaeandChlamydia Trachomatis

1993 ◽  
Vol 1 (2) ◽  
pp. 108-113 ◽  
Author(s):  
Sebastian Faro
Keyword(s):  
Urinary Tract ◽  
Soft Tissue ◽  
Chlamydia Trachomatis ◽  
Urinary Tract Infections ◽  
Single Agent ◽  
Moderate Activity ◽  
Sexually Transmitted ◽  
Tract Infections

The most commonly sexually transmitted bacteria areNeisseria gonorrhoeaeandChlamydia trachomatis.The quinolones ofloxacin and ciprofloxacin have been shown to have activity against both of these bacteria in vitro and in vivo. Ofloxacin is particularly well suited for the treatment ofN. gonorrhoeaeandC. trachomatiscervical infection, which can be considered the earliest manifestation of pelvic inflammatory disease (PID). Not only can ofloxacin be effectively used as a single agent, it is also useful in treating urinary tract infections caused by Enterobacteriaceae. Although it has moderate activity against anaerobes in general, ofloxacin does have activity against the anaerobes commonly isolated from female patients with soft tissue pelvic infections. Thus, ofloxacin has the potential for being utilized to treat early salpingitis.

The Need to Develop New Antimicrobial Molecules, as Revealed by in vitro Assessment of Drug Resistance in Staphylococcal Skin Infections Treated with Autologous Bacterial Vaccine

2020 ◽  
Vol 71 (8) ◽  
pp. 292-303
Author(s):  
Madalina Preda ◽  
Alina-Alexandra Serbanescu ◽  
Mara Madalina Mihai ◽  
Gabriela-Loredana Popa ◽  
Loredana Cornelia Sabina Manolescu ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Antimicrobial Resistance ◽  
Soft Tissues ◽  
The Body ◽  
Laboratory Research ◽  
Soft Tissue Infections ◽  
Resistance Profile ◽  
Bacterial Vaccine ◽  
Staphylococcus Spp

Staphylococcus spp. is a facultative pathogen, which can be found in the commensal microbiota of humans, most often in moist skinfolds and mucous membranes. This microorganism has the ability to cause various infections, in almost every organ of the body, with an increased frequency in the skin and soft tissues, being involved in pathologies like acne, folliculitis, furunculosis, hidradenitis suppurativa, cellulitis, abscesses, but also in secondary infections in diseases with an altered cutaneous barrier. The prolonged evolution of these diseases and severe outcome can be influenced by various factors, most importantly being the antimicrobial resistance. We have evaluated the antimicrobial susceptibility profiles, according to the Comite de l` Antibiogramme de la Societe Francaise de Microbiologie recommendations, for strains of Staphylococcus spp. isolated from acne or different types of skin and soft tissue infections in patients recommended to receive autologous bacterial vaccine. Most frequent identified species was Staphylococcus epidermidis, followed by Staphylococcus aureus. The antimicrobial resistance was higher for antibiotics usually used in the treatment of skin and soft tissue infections, with interesting differences of the resistance profile for the strains isolated from patients before receiving autologous bacterial vaccine compared with the ones from individuals already treated. Another important finding was represented by the differences in the resistance profile according to the age group of the patients. The results of this study underline the importance of antimicrobial resistance surveillance in finding new molecules and alternative therapies, the necessity of a personalized approach in medical acts and of a continuous connection between clinic and laboratory research.

scholarly journals Cathelicidin LL-37 in Severe Streptococcus pyogenes Soft Tissue Infections in Humans

2008 ◽  
Vol 76 (8) ◽  
pp. 3399-3404 ◽  
Author(s):  
Linda Johansson ◽  
Pontus Thulin ◽  
Parham Sendi ◽  
Erika Hertzén ◽  
Adam Linder ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Confocal Microscopy ◽  
Bacterial Resistance ◽  
Resistance Mechanism ◽  
Soft Tissue Infections ◽  
Bacterial Surface ◽  
Life Threatening ◽  
Severe Soft Tissue

ABSTRACT Severe soft tissue infections, such as necrotizing fasciitis and severe cellulitis, caused by group A streptococci (GAS) are rapidly progressing life-threatening infections characterized by massive bacterial loads in the tissue even late after the onset of infection. Antimicrobial peptides are important components of the innate host defense, and cathelicidins have been shown to protect against murine necrotic skin infections caused by GAS. However, it has been demonstrated that the streptococcal cysteine protease SpeB proteolytically inactivates the human cathelicidin LL-37 in vitro. Here we have investigated the expression of LL-37 and its interaction with GAS and SpeB during acute severe soft tissue infections by analyses of patient tissue biopsy specimens. The results showed large amounts of LL-37, both the proform (hCAP18) and the mature peptide, in the tissue. Confocal microscopy identified neutrophils as the main source of the peptide. A distinct colocalization between the bacteria and LL-37 could be noted, and bacterial loads showed positive correlation to the LL-37 levels. Areas with high LL-37 levels coincided with areas with large amounts of SpeB. Confocal microscopy confirmed strong colocalization of GAS, SpeB, and LL-37 at the bacterial surface. Taken together, the findings of this study provide in vivo support of the hypothesis that SpeB-mediated inactivation of LL-37 at the streptococcal surface represents a bacterial resistance mechanism at the infected tissue site in patients with severe GAS tissue infections.

scholarly journals A Pharmacokinetic Evaluation of a Pectin-Based Oral Multiparticulate Matrix Carrier of Carbamazepine

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Seth Kwabena Amponsah ◽  
Simon Yeboah ◽  
Kennedy Kwami Edem Kukuia ◽  
Benoit Banga N’guessan ◽  
Ofosua Adi-Dako
Keyword(s):  
Citric Acid ◽  
Elimination Rate ◽  
Pharmacokinetic Profile ◽  
Maximum Plasma ◽  
Acid Solutions ◽  
Time Curve ◽  
In Vivo Models ◽  
Cocoa Pod Husks

Background. Carbamazepine is a drug used in the treatment of neurological disorders such as epilepsy. However, due to its erratic absorption, oral bioavailability is often poor. There is, therefore, the need to develop alternative formulations for carbamazepine with better pharmacokinetic characteristics. Aim. The aim of this study was to formulate an oral modified-release multiparticulate matrix of carbamazepine from cocoa pod husk (CPH) pectin and evaluate the pharmacokinetic profile of this formulation using in vitro and in vivo models. Methods. CPH pectin was extracted from cocoa pod husks with hot aqueous and citric acid solutions. Oral multiparticulate carbamazepine matrices were formulated from CPH pectin cross-linked with calcium. The formulation was evaluated for carbamazepine content and release profile in vitro. For in vivo pharmacokinetic profile estimation, rats were put into 4 groups of 5 animals each to receive carbamazepine multiparticulate matrix formulations A and B, carbamazepine powder, and Tegretol CR®. Animals in each group received 200 mg/kg of each drug via the oral route. Maximum plasma concentration C max , area under the concentration-time curve (AUC), elimination rate constant K e , and terminal half-life t 1 / 2 of the formulations were estimated by noncompartmental analysis. Results. The pectin extraction from fresh cocoa pod husks using hot aqueous and citric acid solutions gave pectin yields of 9.63% and 11.54%, respectively. The drug content of carbamazepine in CPH pectin formulations A and B was 95% and 96%, respectively. There was controlled and sustained release of carbamazepine for both formulations A and B in vitro. AUC0⟶36 (176.20 ± 7.97 µg.h/mL), C max (8.45 ± 0.71 μg/mL), T max (12 ± 1.28 h), and t 1 / 2 (13.75 ± 3.28 h) of formulation A showed a moderately enhanced and comparable pharmacokinetic profile to Tegretol CR® (AUC0⟶36: 155 ± 7.15 µg.h/mL, C max : 8.24 ± 0.45 μg/mL, T max : 8.0 ± 2.23 h, and t 1 / 2 : 13.51 ± 2.87 h). Conclusion. Findings from the study suggest that formulations of CPH pectin had the potential to control and maintain therapeutic concentrations of carbamazepine in circulation over a period of time in the rat model.

scholarly journals 1115. Evaluation of Gepotidacin (GSK2140944) Pharmacokinetics and Food Effect in Japanese Subjects

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S650-S651
Author(s):  
Mohammad Hossain ◽  
Courtney Tiffany ◽  
Aline Barth ◽  
Aparna Raychaudhuri ◽  
Etienne F Dumont
Keyword(s):  
Tolerability Profile ◽  
Time Curve ◽  
Fed State ◽  
Fasted State ◽  
Drug Concentrations ◽  
Tract Infections ◽  
Oral Doses ◽  
Japanese Subjects

Abstract Background Gepotidacin, a novel, first-in-class triazaacenaphthylene antibiotic, inhibits bacterial replication and has in vitro and in vivo activity against key pathogens, including drug-resistant strains, associated with a range of infections. Gepotidacin is currently in Phase 3 clinical studies for the treatment of uncomplicated urinary tract infections and gonorrhea. This study (NCT02853435) was designed to assess gepotidacin pharmacokinetics (PK) in Japanese subjects (fasted and fed). Methods A tablet formulation of 750 mg gepotidacin free base was used in the study, which was conducted in two parts: Part 1, gepotidacin PK was assessed following 1500 and 3000 mg single oral doses in the fasted state; and Part 2, gepotidacin PK was assessed following 1500, 2250, and 3000 mg single oral doses in the fed state. Serial blood and urine samples were collected in both study parts. Results Part 1: The area under the plasma drug concentration-time curve from time 0 to infinity (AUC[0–∞]) and maximum observed concentration (Cmax) were slightly higher in Japanese subjects than in Caucasian subjects at the same dose levels and with the same formulation. Following gepotidacin dosing in the fasted state, the 1500 mg dose was tolerated, while the 3000 mg dose was poorly tolerated with mild or moderate gastro-intestinal adverse effects (GI AEs) reported by most subjects shortly after being dosed. Part 2: PK was linear with doses in the range of 1500–3000 mg. Administration of gepotidacin 3000 mg tablets in the fed state slightly reduced Cmax and slightly increased AUC at the 3000 mg dose level. The 1500 and 2250 mg doses were tolerated while the 3000 mg dose was better tolerated compared to the fasted state with fewer and short-lived GI AEs, mostly mild in intensity. After oral administration of 1500–3000 mg, high urine drug concentrations were achieved, remaining above the minimum inhibitory concentration of 4 μg/mL for up to 24 hours. Conclusion The PK of gepotidacin following administration of a single oral dose to Japanese subjects was linear from 1500–3000 mg and food decreased Cmax without impact on exposure (AUC). Administration of gepotidacin with food resulted in an improved GI tolerability profile at the higher dose tested in Japanese subjects. Disclosures Mohammad Hossain, PhD, GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and past/current shareholder in GlaxoSmithKline plc.) Courtney Tiffany, BSc, GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and past/current shareholder in GlaxoSmithKline plc.) Aline Barth, MSC;PHD, GlaxoSmithKline plc. (Employee, Shareholder, Employee of and shareholder in GlaxoSmithKline plc.) Aparna Raychaudhuri, Ph.D., GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and past/current shareholder in GlaxoSmithKline plc.) Etienne F. Dumont, MD, GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and shareholder in GlaxoSmithKline plc.)

scholarly journals Target Site Concentrations of Ciprofloxacin after Single Intravenous and Oral Doses

2002 ◽  
Vol 46 (12) ◽  
pp. 3724-3730 ◽  
Author(s):  
Martin Brunner ◽  
Heino Staβ ◽  
Jan-Georg Möller ◽  
Claudia Schrolnberger ◽  
Boban Erovic ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Interstitial Fluid ◽  
Soft Tissues ◽  
Interstitial Space ◽  
Target Site ◽  
Crossover Fashion ◽  
Bacterial Strains ◽  
Concentration Time

ABSTRACT To characterize the potential of ciprofloxacin penetration into human soft tissues following intravenous (i.v.) and oral (p.o.) administration, we measured the free ciprofloxacin concentrations in interstitial space fluid of skeletal muscle and subcutaneous adipose tissue by microdialysis. In addition, ciprofloxacin concentrations were measured in cantharis-induced skin blisters, saliva, and capillary plasma and were compared to the total concentrations in venous plasma. Furthermore, a pharmacodynamic in vitro model was used to simulate in vivo pharmacokinetics in bacterial culture. Eight healthy volunteers received ciprofloxacin in an open randomized crossover fashion either as a single i.v. infusion of 400 mg over 60 min or as a single p.o. dose of 500 mg. For both tissues the mean areas under the concentration-time curves (AUCs) for interstitial space fluid (AUCinterstitial fluids) were significantly lower than the corresponding AUCplasmas, with AUCinterstitial fluid/AUCplasma ratios ranging from 0.38 to 0.68. For skeletal muscle, the AUCinterstitial fluid was significantly higher after administration of 400 mg i.v. than after administration of 500 mg p.o., with a ratio of the AUC after p.o. administration/AUC after i.v. administration of 0.64. The ratio of the concentration in skeletal muscle/concentration in plasma increased over the entire observation period, implying that ciprofloxacin concentrations were not at steady state. The ratio of the concentration in skin blister fluid/concentration in plasma reached values above 4, indicating a preferential penetration of ciprofloxacin into inflamed lesions. The concentrations in saliva and capillary blood were similar to the corresponding total levels in plasma. In vitro both in vivo ciprofloxacin concentration-time profiles were equally effective against select bacterial strains. In conclusion, single-dose administration of two bioequivalent dosage forms of ciprofloxacin might lead to differences in target site pharmacokinetics. These differences, however, are not related to a difference in target site pharmacodynamics.

A Multiscale Model for the Indentation of Type-I Collagen Soft Tissue Equivalents

2010 ◽  
Author(s):  
Mohammad F. Hadi ◽  
Fabien J. Delalondre ◽  
Cameron W. Smith ◽  
Lijuan Zhang ◽  
Mark S. Shephard ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Type I Collagen ◽  
Soft Tissues ◽  
Analytical Techniques ◽  
Multiscale Model ◽  
Hertzian Contact ◽  
Analytical Models ◽  
Type I

Indentation has become a popular research technique for the mechanical characterization of collagen-based soft tissues. The popularity of the method stems from its requirement of a modestly sized sample, from its ability to be applied in vitro as well as in vivo, and from the ready availability of instrumentation and analytical techniques borrowed from a long tradition of its application to non-biological materials. Many analytical models for the indentation of collagen-based soft tissues rely on a Hertzian contact model. Such a model emphasizes the contributions of an idealized material in compression over the contributions of the material in tension. However, this approach largely neglects the role of the collagen microstructure in soft tissue that has the capacity to carry far greater mechanical loads in tension rather than in compression.

scholarly journals Use of Carbapenems against Clinical, Nontyphoid Salmonella Isolates: Results fromIn VitroandIn VivoAnimal Studies

2012 ◽  
Vol 56 (6) ◽  
pp. 2916-2922 ◽  
Author(s):  
Hung-Jen Tang ◽  
Chi-Chung Chen ◽  
Chun-Cheng Zhang ◽  
Kuo Chen Cheng ◽  
Shyh-Ren Chiang ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Survival Rates ◽  
Pharmacokinetic Profile ◽  
Multidrug Resistant ◽  
Time Curve ◽  
Content Type ◽  
Percent Time ◽  
Clinical Investigations

ABSTRACTThe emergence of multidrug-resistantSalmonellaisolates has created the need for new therapeutic agents. We evaluated the intracellular activity of four carbapenem compounds against clinical nontyphoidSalmonella(NTS) isolatesin vitroandex vivo. Subsequently, the efficacy of carbapenem treatment against selectedSalmonellaisolatesin vivowas assessed using a murine peritonitis model. The MIC50and MIC90for doripenem, ertapenem, imipenem, and meropenem against 126 NTS isolates were found to be 0.062 and 0.062, 0.015 and 0.015, 0.5 and 1, and 0.031 and 0.031 μg/ml, respectively. The intracellular killing effect of ertapenem was sustained for 24 h and was superior to that of imipenem, meropenem, and doripenem; its effect was comparable to that of ceftriaxone. Ertapenem demonstrated an excellent pharmacokinetic profile with a percent time above the MIC of 75.5% and an area under the concentration-time curve/MIC ratio of 20,733. When peritoneal exudate cells were examined directlyex vivofrom mice withSalmonella-induced peritonitis, cells from mice treated with ertapenem and ceftriaxone had intracellular and extracellular bacterial counts reduced 102- to 104-fold and exhibited killing effects similar to each other. The survival rates of mice inoculated with 1 × 105and 106CFU of a ceftriaxone-susceptibleSalmonellaisolate that were subsequently treated with ertapenem or ceftriaxone were 100% and 90%, respectively. When mice were inoculated with 5 × 104and 105CFU of a ceftriaxone-resistant and ciprofloxacin-resistantSalmonellaisolate, mice treated with ertapenem had a higher survival rate than mice treated with ceftriaxone (70% versus 0% and 50% versus 0%, respectively;P< 0.001). Our results suggest that ertapenem is at least as effective as ceftriaxone in treating murineSalmonellainfections and show that further clinical investigations on the potential use of ertapenem in treatment of humanSalmonellainfections are warranted.

scholarly journals In Vitro and In Vivo Antibacterial Activities of L-084, a Novel Oral Carbapenem, against Causative Organisms of Respiratory Tract Infections

2001 ◽  
Vol 45 (1) ◽  
pp. 203-207 ◽  
Author(s):  
Shuichi Miyazaki ◽  
Takayuki Hosoyama ◽  
Nobuhiko Furuya ◽  
Yoshikazu Ishii ◽  
Tetsuya Matsumoto ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Respiratory Tract Infections ◽  
Antibacterial Activities ◽  
Time Curve ◽  
Infection Models ◽  
Underlying Mechanisms ◽  
Tract Infections ◽  
Better Than

ABSTRACT L-084 (a prodrug of LJC 11,036 [L-036]) is a new oral carbapenem. Here we compared the in vitro and in vivo antibacterial activities of L-036 with those of imipenem, faropenem, ceditoren-pivoxil, cefdinir, amoxicillin, and levofloxacin. The MICs at which 90% of the isolates were inhibited of L-036 against methicillin-susceptible staphylococci,Streptococcus pneumoniae including penicillin-resistant organisms, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae including ampicillin-resistant organisms, Legionella pneumophila, andMoraxella catarrhalis were equal to or less than 1 μg/ml. In pharmacokinetics studies of L-084 in lungs of mice, the maximum concentration in serum, half-life, and area under the concentration-time curve of this drug were 9.09 μg/g of tissue, 6.18 h, and 31.0 μg · h/ml, respectively. In murine respiratory infection models of penicillin-susceptible and -resistantS. pneumoniae and H. influenzae, the efficacies of L-084 were better than those of reference drugs. Our results indicate that the in vitro high potency and good distribution in the lungs might be the underlying mechanisms of its efficacy in the murine model of pneumonia.

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