Omadacycline: a therapeutic review of use in community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections.

Omadacycline is a novel aminomethylcycline antimicrobial, US FDA approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It is not susceptible to common tetracycline resistance mechanisms, and has demonstrated efficacy against a broad spectrum of pathogens including resistant isolates, which are increasing in prevalence and complexity. It is available in both intravenous and oral formats, and can be administered in single, once daily doses or multiple doses, with no dosing adjustments required for sex, age, hepatic or renal impairment. It can be a good option for patients with low treatment adherence, and oral therapy may be used to reduce length of hospitalization for iv. treatment. This article reviews the in vitro and in vivo activity, PK/PD profile, integrated data from clinical trials including clinical efficacy and safety profile, and looks to future application of omadacycline.

Eravacycline for the treatment of complicated intra-abdominal infections.

Introduction: Complicated intra-abdominal infections (cIAIs) are among the most frequent infections, contributing to significant morbidity and healthcare costs. Several medical needs remain unmet, related to the pharmacokinetic capacities of the available drugs and their limited spectrum of activity for targeting multidrug-resistant Gram-negative and Gram-positive bacteria. Eravacycline, a new synthetic fluorocycline, could have useful properties in cIAIs.Areas covered: The antimicrobial activity of eravacycline against the microorganisms most frequently cultured in cIAIs has been confirmed in worldwide panels of clinical isolates, including enterococci, ESBL-producing Enterobacteriaceae, Acinetobacter baumannii and anaerobes. Pharmacokinetic data demonstrate interesting characteristics with good tissue concentrations including biliary tract and digestive tissues. At a conventional dosage of 1 mg/kg q12h, no adjustment is required on the basis of race or gender, or in elderly (≥ 65 years old) patients, patients with renal impairment or patients undergoing hemodialysis. Phase 2 and 3 trials assessing the clinical efficacy and safety of eravacycline demonstrated non-inferiority versus carbapenems and a good safety profile.Expert opinion: Eravacycline may be particularly suitable for the treatment of cIAIs. Results from clinical trials and real-world data are now expected in specific subgroups of patients to confirm the safety profile and efficacy observed in registration trials.

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Bacillus anthracis Infection in BALB/c Mice and Cynomolgus Macaques.

The fluorocycline TP-271 was evaluated in mouse and nonhuman primate (NHP) models of inhalational anthrax. BALB/c mice were exposed by nose-only aerosol to Bacillus anthracis Ames spores at a level of 18 to 88 lethal doses sufficient to kill 50% of exposed individuals (LD50). When 21 days of once-daily dosing was initiated at 24 h postchallenge (the postexposure prophylaxis [PEP] study), the rates of survival for the groups treated with TP-271 at 3, 6, 12, and 18 mg/kg of body weight were 90%, 95%, 95%, and 84%, respectively. When 21 days of dosing was initiated at 48 h postchallenge (the treatment [Tx] study), the rates of survival for the groups treated with TP-271 at 6, 12, and 18 mg/kg TP-271 were 100%, 91%, and 81%, respectively. No deaths of TP-271-treated mice occurred during the 39-day posttreatment observation period. In the NHP model, cynomolgus macaques received an average dose of 197 LD50 of B. anthracis Ames spore equivalents using a head-only inhalation exposure chamber, and once-daily treatment of 1 mg/kg TP-271 lasting for 14 or 21 days was initiated within 3 h of detection of protective antigen (PA) in the blood. No (0/8) animals in the vehicle control-treated group survived, whereas all 8 infected macaques treated for 21 days and 4 of 6 macaques in the 14-day treatment group survived to the end of the study (56 days postchallenge). All survivors developed toxin-neutralizing and anti-PA IgG antibodies, indicating an immunologic response. On the basis of the results obtained with the mouse and NHP models, TP-271 shows promise as a countermeasure for the treatment of inhalational anthrax.

In Vitro and In Vivo Activity of Omadacycline against Two Biothreat Pathogens, Bacillus anthracis and Yersinia pestis.

The in vitro activity and in vivo efficacy of omadacycline (OMC) were evaluated against the causative pathogens of anthrax and plague, Bacillus anthracis and Yersinia pestis, respectively. MICs of OMC were determined by broth microdilution according to CLSI guidelines for 30 isolates each of Y. pestis and B. anthracis The in vivo efficacy of omadacycline was studied at a range of dosages in both a postexposure prophylaxis (PEP) murine model of anthrax and plague as well as in a delayed treatment model of inhalational anthrax. Omadacycline was active in vitro against Y. pestis (MIC90 of 1 µg/ml) and B. anthracis (MIC90 of 0.06 µg/ml). Omadacycline was less active in vitro than ciprofloxacin (CIP) against Y. pestis (CIP MIC90 of 0.03 µg/ml) but was more potent in vitro against B. anthracis (CIP MIC90 of 0.12 µg/ml). In the mouse model of infection, the survival curves for all treatment cohorts differed significantly from the vehicle control (P = 0.004). The median survival for the vehicle-treated controls was 6 days postchallenge, while all antibiotic-treated mice survived the entire study. Omadacycline treatment with 5, 10, or 20 mg/kg of body weight twice daily for 14 days had significant efficacy over the vehicle control in the treatment of aerosolized B. anthracis Additionally, for postexposure prophylaxis treatment of mice infected with Y. pestis, the survival curves for omadacycline (40 mg/kg twice daily), ciprofloxacin, and doxycycline cohorts differed significantly from the vehicle control (P < 0.0001). Omadacycline is potent and demonstrates efficacy against both B. anthracis and Y. pestis The well-characterized oral and intravenous pharmacokinetics, safety, and tolerability warrant further assessment of the potential utility of omadacycline in combating these serious biothreat organisms.

In Vivo Pharmacodynamic Evaluation of Omadacycline (PTK 0796) against Streptococcus pneumoniae in the Murine Pneumonia Model.

Omadacycline is a novel aminomethylcycline antibiotic in clinical development for community-acquired bacterial pneumonia (CABP). We used a neutropenic murine pneumonia infection model to characterize the in vivo pharmacodynamic activity of omadacycline against Streptococcus pneumoniae Four strains with various phenotypic resistances to other antimicrobials, including tetracyclines, were utilized. Drug concentration measurements were performed in the plasma and epithelial lining fluid (ELF) after administration of 0.5, 2, 8, and 32 mg/kg. Pharmacokinetic parameters were calculated using a noncompartmental model and were linear over the dose range. Penetration into ELF ranged from 72 to 102%. Omadacycline demonstrated net cidal activity in relation to the initial burden against all four strains. The pharmacokinetic/pharmacodynamic index AUC/MIC correlated well with efficacy (R2 = 0.74). The plasma 24-h static dose AUC/MIC values were 16 to 20 (24-h ELF AUC/MIC of 14 to 18). A 1-log10 kill was achieved at 24-h plasma AUC/MIC values of 6.1 to 180 (24-h ELF AUC/MIC values 6.0 to 200). A 2-log10 kill was achieved at 24-h plasma AUC/MIC values of 19 to 56 (24-h ELF AUC/MIC of 17 to 47). The targets identified in this study in combination with in vitro potency and favorable human pharmacokinetics make omadacycline an attractive candidate for further development and study in patients with CABP.

Omadacycline: development of a novel aminomethylcycline antibiotic for treating drug-resistant bacterial infections.

Omadacycline is a first-in-class aminomethylcycline antibiotic that circumvents common tetracycline resistance mechanisms. In vitro omadacycline has potent activity against Gram-positive aerobic bacteria including methicillin-resistant Staphylococcus aureus, penicillin-resistant and multidrug-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus spp. It is also active against common Gram-negative aerobes, some anaerobes and atypical bacteria including Legionella spp. and Chlamydia spp. Ongoing Phase III clinical trials with omadacycline are investigating once daily doses of 100 mg intravenously followed by once-daily doses of 300 mg orally for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This paper provides an overview of the microbiology, nonclinical evaluations, clinical pharmacology and initial clinical experience with omadacycline.

Eravacycline Pharmacokinetics and Challenges in Defining Humanized Exposure In Vivo.

We assessed the pharmacokinetic profile of eravacycline, a novel antibiotic of the tetracycline class, and determined the dose in an immunocompetent murine thigh infection model that would provide free-drug exposure similar to that observed in humans after the administration of 1 mg/kg intravenously (i.v.) every 12 h (q12h). Eravacycline demonstrated a nonlinear protein-binding profile. The 2.5-mg/kg i.v. q12h dose in mice resulted in an area under the concentration-time curve for the free, unbound fraction of the drug of 1.64 mg · h/liter, which closely resembles the human exposure level.

Short-term toxicity assessments of an antibiotic metabolite in Wistar rats and its metabonomics analysis by ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.

4-Epi-oxytetracycline (4-EOTC), one of main oxytetracycline (OTC) metabolites, can be commonly detected in food and environment. The toxicity and effects of OTC on animals have been well characterized; however, its metabolites have never been studied systemically. This study aims to investigate 15-day oral dose toxicity and urine metabonomics changes of 4-EOTC after repeated administration in Wistar rats at daily doses of 0.5, 5.0 and 50.0mg/kg bw (bodyweight). Hematology and clinical chemistry parameters, including white blood cell count, red blood cell count, total protein, globulin and albumin/globulin, were obviously altered in rats of 5.0 and 50.0mg/kg bw. Histopathology changes of kidney and liver tissues were also observed in high-dose groups. Urinary metabolites from all groups were analyzed using ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Seventeen metabolites contributing to the clusters were identified as potential biomarkers from multivariate analysis, including aminoadipic acid, 6-phosphogluconate, sebacic acid, pipecolic acid, etc. The significant changes of these biomarkers demonstrated metabonomic variations in treated rats, especially lysine and purine metabolism. For the first time in this paper, we combined the results of toxicity and metabonomics induced by 4-EOTC for the serious reconsideration of the safety and potential risks of antibiotics and its degradation metabolites.

Guidelines for the use of acitretin in psoriasis. Psoriasis Group of the Spanish Academy of Dermatology and Venereology.

Phototherapy, classic systemic treatments (methotrexate, acitretin, and ciclosporin), and biologic agents (etanercept, infliximab, adalimumab, and ustekinumab) constitute a broad therapeutic arsenal that increases the likelihood of achieving control of severe and extensive disease in patients with psoriasis. Acitretin continues to be a very valuable tool in both monotherapy, in which it is combined with other systemic treatments (classic or biologic), and in sequential therapy. Thanks to its lack of a direct immunosuppressive effect and its ability to achieve a long-term response, acitretin has an important role in the treatment of psoriasis, although this has not always been acknowledged in relevant treatment guidelines. We present consensus guidelines for the use of acitretin in psoriasis drawn up by the Psoriasis Group of the Spanish Academy of Dermatology and Venereology. These guidelines provide a detailed account of acitretin, including pharmacological properties, indications and contraindications, adverse effects, and factors that should be taken into account to enhance the safe use of this drug. They also propose treatment strategies for use in routine clinical practice. The overall aim of these guidelines is to define the criteria for the use and management of acetretin in psoriasis.

Administration of doxycycline hydrochloride via drinking water to turkeys under laboratory and field conditions.

A series of experiments were carried out in order to determine doxycycline hydrochloride (DoxHCl) plasma levels in 6-wk-old turkeys medicated via drinking water containing DoxHCl at a concentration of 250 mg/L under laboratory and field conditions. Maximal plasma concentration (Cmax) values of 5.7 (+/-1.0) microgram/mL and 4.9 (+/-1.4) micrograms/mL obtained after DoxHCl administration during 2 and 7 d, respectively, were not significantly different. A significant difference was found between the area under the plasma concentration-time profile, calculated between 0 and 168 h (AUC(0-168)), Cmax, and the minimal plasma concentration (Cmin) values obtained after medication with a DoxHCl solution at a concentration of 250 mg/L (431.9 +/- 96.6 micrograms.h/mL, 4.9 +/- 1.4 micrograms/mL and 0.7 +/- 0.3 microgram/mL) and after medication with a DoxHCl solution at a concentration of 750 mg/L (1,176.5 +/- 201.8 micrograms.h/mL, 12.5 +/- 2.7 micrograms/mL and 2.9 +/- 0.4 micrograms/mL), respectively. The increase in body weight was also significantly higher for turkeys medicated with a DoxHCl solution at a concentration of 750 mg/L (83.7 g/d) than for the lower concentration (35.6 g/d). The DoxHCl solution uptake significantly decreased with the increase of DoxHCl concentration. A Cmax value of 1.7 +/- 0.6 micrograms/mL and a Cmin value of 0.5 +/- 0.1 microgram/mL were observed during the field experiment. Water consumption under laboratory conditions was followed for tap water (70 +/- 50 mL/kg.d) and for a DoxHCl solution at a concentration of 250 mg/L supplemented with 1 g anhydrous citric acid/L (119 +/- 6 mL/kg.d) and revealed to be not significantly different. The variability was significantly higher for tap water than for the DoxHCl solution. The stability of the DoxHCl solution containing 1 g citric acid/L over 24 h was 99% expressed as the percentage of the initial concentration.

Slow-acting, disease-modifying osteoarthritis agents.

There is evidence to suggest that tetracyclines have benefit beyond their antimicrobial activity. The ability to inhibit metalloproteinase activity may provide a disease-modifying effect in OA, and available data suggest that further investigation is warranted. Controlled, double-blind, prospective clinical studies have not been completed. The canine cruciate ligament transection model studies are frequently cited as the most convincing in vivo evidence of a benefit of oral tetracycline therapy for the treatment of OA. Until more evidence becomes available, the use of tetracyclines as therapeutic agents for OA should be considered investigational.

Detection of tetracyclines and efflux pump inhibitors.

Screening assays for the detection of tetracyclines and inhibitors of tetracycline efflux pumps are described. The tetracycline assay is based on the observation that the tetA(B) gene encoding the efflux pump of transposon Tn10 is induced by tetracycline. The Escherichia coli strain designed to detect tetracyclines contains a single copy of a tetA(B)-lacZ transcriptional fusion integrated into the chromosome and the tetR gene encoding the tetracycline repressor on a plasmid. The assay specifically detects tetracyclines of distinct structures, but not other classes of drugs. A strain capable of detecting inhibitors of the TetA(B) efflux pump contained the tetA(B)-lacZ fusion and, in addition, a tetA(B) structural gene lacking its transcriptional regulatory signals which mediated resistance to only 5 micrograms of tetracycline per ml. This strain was more refractory to induction by tetracycline because of the action of the pump. Inhibitors were detected in two ways: (i) beta-galactosidase induction in the presence of 5 ng of tetracycline per ml, a subinducing concentration, and (ii) growth inhibition in the presence of 5 micrograms of tetracycline per ml. A strain designed to detect inhibitors of the Tet(K) efflux pump from Staphylococcus aureus was constructed by substituting the tet(K) structural gene for the tetA(B) gene. Nocardamine and other siderophores were found to interfere with the action of tetracycline efflux pumps.