Medical Conferences

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2018

2017

A phase 3 randomized, double-blind, multi-centre study to compare the safety and efficacy of oral and IV omadacycline to linezolid for treating adult subjects with ABSSSI (the OASIS study)

Efficacy of Oral and IV Omadacycline vs. Linezolid for Treating Adult Subjects With ABSSSI: Analysis by Infection Type and Pathogen in the OASIS Study

In vitro activity of omadacycline and comparators against Gram-negative bacterial isolates collected from patients in European medical centres (2016):  results from the SENTRY antimicrobial surveillance programme

In vitro extracellular and intracellular activity of omadacycline against Staphylococcus aureus

Efficacy of omadacycline versus linezolid in treating ABSSSI patients from different geographic regions (OASIS trial)

Effects of IV/oral omadacycline versus IV/oral linezolid on lesion size and local signs of ABSSSI in the phase 3 OASIS trial

Safety and Tolerability of IV Omadacycline (OMC) and Tigecycline (TGC) in Healthy Subjects in a Study to Assess Intra-Pulmonary Steady-State Concentrations

In vitro activity of omadacycline and comparators against staphylococci, streptococci and enterococci (including resistant organism subsets) from patients in European medical centres during 2016:  results from the SENTRY antimicrobial surveillance programme

The impact of non-standard test conditions on the in-vitro activity of omadacycline by broth microdilution

The in-vitro activity of omadacycline and comparators against anaerobic bacteria

Economic impact of omadacycline among acute bacterial skin and skin structure infections (ABSSSIs) patients: cost-saving opportunities due to avoidable hospitalizations using an antibiotic with IV-to-oral switch capability

Cost-saving opportunities among hospitalized patients with acute bacterial skin and skin structure infections with omadacycline, a once-daily antibiotic with IV-to-oral transition capability, relative to current standard of inpatient care

Comparison of omadacycline (OMC) and tigecycline (TGC) pharmacodynamics (PD) in the plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) in healthy subjects

 

Characteristics of Hospitalized Patients with ABSSSI Treated with Vancomycin at Greatest Risk for Prolonged Hospital Length of Stay in an Integrated Delivery Network

Patient (Pt) Populations at Greatest Risk for Hospital Readmission or Repeat Emergency Department (ED) Visit within 30 Days of Hospital Discharge among Hospitalized Pts with Acute Bacterial Skin and Skin Structure Infections (ABSSSIs) Treated with Vancomycin

In Vitro Antibacterial Activity of Omadacycline and Comparators Against Key Respiratory, Skin and Skin Structure and Urinary Tract Pathogens Collected from the United States and Europe During the 2016 SENTRY Worldwide Surveillance Program

In Vitro Antibacterial Activity of Omadacycline, a New Aminomethylcycline, Against Gram-Positive and Gram-Negative Bacterial Pathogens Isolated from Patients Attending Canadian Hospitals in 2015: the CANWARD Study

Patient (Pt) Populations at Greatest Risk for Hospital Readmission or Repeat ED Visit within 30 Days of Hospital Discharge among Hospitalized Pts with Community-acquired Bacterial Pneumonia (CABP)

Pharmacokinetics and Safety of Omadacycline in Patients with Uncomplicated Urinary Tract Infections

Pharmacokinetics and Safety of the Aminomethylcycline Antibiotic Omadacycline in Subjects with Impaired Renal Function

Safety and Pharmacokinetic Assessments of the Antibiotic Omadacycline Administered to Healthy Subjects in Oral Multiple Dose Regimens

Effects of Omadacycline vs Moxifloxacin on Gut Microbiota Populations and Clostridium difficile Germination, Proliferation and Toxin Production in an In vitro Model of the Human Gut

A Multi-Site Study Comparing a Commercially Prepared Dried MIC Susceptibility System to the CLSI Broth Microdilution Method for Omadacycline Using Non-Fastidious Gram Positive Organisms

Omadacycline, the First Aminomethylcycline

In Vitro Activity of Omadacycline and Comparator Compounds against Gram-Positive Isolates Collected in the US During 2016 as Part of a Global Surveillance Program

In vivo Pharmacodynamic Evaluation of Omadacycline (PTK 0796) against Staphylococcus aureus (SA) in the Murine Thigh Infection Model

Efficacy and Safety of Omadacycline in Chronic Kidney Disease (CKD) Patients With Acute Bacterial Skin and Skin Structure Infections (ABSSSI): A Subgroup Analysis From the OASIS Trial

Efficacy and Safety of Omadacycline in Patients With Acute Bacterial Skin and Skin Structure Infections (ABSSSI) and High Body Mass Index or Diabetes: A Subgroup Analysis From the OASIS Trial

Pharmacometric Comparison of Omadacycline and Tigecycline Epithelial Lining Fluid (ELF) Penetration

Analysis of the Microbiological data from the Omadacycline (OMC) Phase 3 Community-Acquired Bacterial Pneumonia (CABP) trial: The OPTIC study

A Phase 3 Randomized, Double-Blind, Multi-Center Study to Compare the Safety and Efficacy of IV to Oral Omadacycline to Moxifloxacin for the Treatment of Adult Subjects with CABP (The OPTIC Study)

Efficacy and Safety of Omadacycline in Intravenous Drug Using (IVDU) and Hepatitis C-Positive (HCV+) Patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI): A Subgroup Analysis from the OASIS Trial

Cardiac Safety of Omadacycline in the IV/oral Phase 3 Acute Bacterial Skin and Skin Structure Infection (ABSSSI) and in the IV/oral Phase 3 Community-acquired Bacterial Pneumonia (CABP) Studies 

2016

2010

Efficacy of PTK796 in a Rat MRSA Infected Endocarditis (IE) Model

Background: PTK796 is the first semi-synthetic aminomethylcycline in clinical development. It is active in vitro and in vivo against resistant pathogens, particularly MRSA and VRE. The efficacy of PTK796, tigecycline (TGC) and daptomycin (DAP) were tested using a rat infective endocarditis (IE) model with a MRSA 32 strain.

Methods: IE was induced following transcarotid-transaortic valve indwelling catheterization after i.v. infection with 5 x 105 CFU/rat MRSA 32 strain. At 6 hours and the next 4 days post-infection, animals were randomized to receive: i) saline s.c. qd; ii) PTK796 s.c. bid; iii) TGC s.c. bid; or i.v.) DAP s.c. qd. At 18 h after the last treatment, hearts and spleens were removed and quantitatively cultured. The ends of catheters from the left ventricle were qualitatively cultured.

Results: All dosing regimens significantly decreased bacterial counts in all target tissues (P <0.05). ED50 (the dose at which 50% of the animals showed a 3-log reduction in bacterial load relative to the colony counts in salinetreated controls) of PTK796 (bid), TGC (bid), and DAP (qd) were 2.89, 0.97, and below 2.5 mg/kg, respectively.

Conclusions: PTK796 showed efficacy against MRSA 32 strain-induced IE in rats.

  • The rat infective endocarditis (IE) model provides a good system for evaluating antibiotics used for serious infections
  • PTK796 showed good efficacy against a strain of MRSA (susceptible to all the antibiotics tested) in the IE model, reducing bacterial counts in the heart by over 5 log10 CFU/g at a dose of 5 mg/kg
  • PTK796 was less efficacious than tigecycline in the model, especially in the ratio of total heart sterilization (2/6 for PTK796 at 5 mg/kg vs. 5/6 for the same dose of tigecycline)
  • The efficacy of daptomycin in the model was less than the lowest dose tested; therefore a direct comparison with PTK796 cannot be made
  • The efficacy of PTK796 in this MRSA-induced rat IE model indicates the potential utility of PTK796 in Gram-positive infections

 

 

Studies on the Mechanism of Resistance to PTK796 in Pseudomonas aeruginosa and Klebsiella pneumonia

Background: PTK796 is a novel aminomethylcycline compound that is active against Gram-positive and Gram-negative bacteria. Certain Gram-negatives (e.g., P. aeruginosa) are intrinsically less susceptible to PTK796, whereas in others (e.g., K. pneumoniae), reduced susceptiblity can be mutationally acquired. This study was conducted to provide initial insight into the mechanisms of resistance to PTK796 in P. aeruginosa and K. pneumoniae.

Methods: MICs were determined by broth microdilution using fresh media. Mutants were selected and spontaneous mutation frequency was measured on PTK796-containing plates. Gene expression was analyzed by Taqman RT-PCR.

Results: The MIC profile of P. aeruginosa efflux defective mutants revealed that deletion of the RND-type efflux pump mexXY reduced the MICs of PTK796 from 64 to 4 mg/mL. Inactivation of mxB had no effect; however, inactivation of mexB in the mexXY background caused an additional 4-fold increase in susceptibility. Less susceptible mutants (MIC 64-128 mg/mL) emerged at a frequency of 2.7x10^-8 when the mexXY-deletion mutant was plated on 32 mg/mL of PTK796. The MICs of chloramphenicol and ciprofloxacin were elevated and squence alterations were detected in nfxB gene (MexCD-OprJ repressor) in these mutants. In a less-susceptible strain of K. pneumoniae (MIC 16 mg/mL), the transcriptional activator ramA and the RND-type efflux pump acrAB were constitutively overexpressed as compared with a susceptible strain (MIC 1 mg/mL, typical for K. pneumoniae).

Conclusions: The results of this study suggested that: 1) similar to tigecycline, the inducible MexXY efflux pump is the major pump contributing to intrinsic decreased susceptibility in P. aeruginosa. with a smaller potential contribution from MexAB-OprM. In the absence of MexXY, MexCD-OprJ expressors emerge, indicating PTK796 is a substrate for this pump; 2) efflux is likely to be a primary determinant of acquired reduced susceptibility in K. pneumoniae, as indicated by overexpression of known tigecycline resistance determinants such as ramA and acrAB.

  • Similar to tigecycline, the inducible MexXY efflux pump appears to be the major pump contributing to intrinsic decreased susceptibility to PTK796 in P. aeruginosa, with a smaller potential contribution from MexAB-OprM
  • In the absence of MexXY, MexCD-OprJ expressors emerge, indicating that PTK796 is a substrate for this pump
  • Efflux is likely to be a primary determinant of acquired reduced susceptibility in K. pneumoniae as indicated by overexpression of known tigecycline resistance determinants such as ramA and acrAB. Gene knockouts are required to confirm the role of RamA and AcrAB in the decreased susceptibility to PTK796 in K. pneumoniae

 

 

In Vitro Evaluation of PTK 0796 Activity Tested against Staphylococcus aureus, Including Hospital- and Community-Associated MRSA Strains from the USA and Europe

Background: PTK796 (PTK) is a novel aminomethylcycline currently under clinical development. PTK activity was evaluated against methicillin-susceptible (MSSA) and -resistant S. aureus (MRSA), including multidrug-resistant strains from documented hospital-acquired (HA) infections and community-associated (CA) infection isolates.

Methods: 325 S. aureus were collected from bloodstream, skin and skin structure, CA and HA pneumonia in USA (35 sites) and European (EU, 31) laboratories. The CLSI broth microdilution method (M07-A8) was utilized (9 comparators) applying fresh Mueller-Hinton media when testing PTK and tigecycline. Cefoxitin disks were used to confirm MRSA. CAMRSA genotypes (USA300 [120] and USA400 [5]) were identified by PFGE and SCCmec typing, and PVL genes.

Results: PTK MIC values for all strains were g/ml. PTK (MIC50/90, 0.25/0.5 g/ml), tigecycline (MIC50/90, 0.12/0.25 g/ml; 100% susceptible) and daptomycin (MIC50/90, 0.25/0.5 g/ml; 100% susceptible) exhibited similar activity against SA, while doxycycline (MIC50/90, 0.12/2 g/ml; 92.6% susceptible) showed elevated MIC values. Overall, the tetracycline derivatives were more active than vancomycin (MIC50/90, 1/1 g/ml; 99.7% susceptible) and linezolid (MIC50/90, 2/2 g/ml; 100% susceptible). PTK inhibited 100.0 and 90.9% of EU and USA HA-MRSA at g/ml, respectively. All EU CA-MRSA were inhibited by PTK of 0.5 g/ml, except for one strain; while USA300/400 MRSA strains were very susceptible to PTK (MIC50/90, 0.12/0.25 g/ml). Conclusions

  • Overall, PTK796 was very active against all S. aureus isolates tested in this investigation (MIC50/90) regardless of isolate origin (geographic or hospital/ community) or resistance phenotype to other antimicrobial agents.
  • Among MRSA isolates combined, strains from Europe had slightly higher PTK796 MIC50/90 values (two-fold) compared to isolates from the USA. These results appear to be associated with the decreased susceptibility to doxycycline documented among MRSA isolates from Europe.
  • The in vitro activity established in this study coupled with pharmacokinetic/pharmacodynamic and target attainment results would suggest that PTK796 is a promising antimicrobial agent for the treatment of serious MDR S. aureus infections.

 

 

Antimicrobial Activity of PTK 0796 Tested against Gram-Positive Organisms Causing Bloodstream Infections in 2009

Background: PTK796 (PTK; 7-dimethylamino, 9-(2,2- dimethyl-propyl)-aminomethylcycline) is a novel antibacterial agent of the tetracycline family, which is under clinical development (IV and oral formulations). We evaluated the activity of PTK against Gram-positive (GP) cocci collected from bloodstream infections (BSI) in hospitals worldwide during 2009.

Methods: 3670 strains from 62 medical centers (USA, Europe and Latin America) were collected and tested for susceptibility (S) against PTK, tigecycline (TIG) and 14 other comparators by CLSI broth microdilution methods. The collection includes S. aureus (SA; 1,697; 37.2% MRSA), coagulase-negative staphylococci (CoNS; 640), E. faecalis (EF; 564; 3.0% vancomycin [VAN] resistance [R]), E. faecium (EFM; 368; 48.4% VAN-R), S. pneumoniae (SPN; 211); β-haemolytic streptococci (βHS; 170), viridans group streptococci (VGS; 9) and others (11).

Results: PTK was very active against oxacillin-S (MSSA) and MRSA with a MIC90 of 0.5 µg/ml for both groups (see Table). PTK activity against SA was eight- and four-fold greater than linezolid and VAN, respectively, and similar to daptomycin and TIG. CoNS exhibited slightly higher PTK MIC values (MIC50/90, 0.25/2 µg/ml) compared to SA, with a bimodal distribution. EF (MIC90, 0.5 µg/ml) and EFM (MIC90, 0.25 µg/ml) were very S to PTK and R to VAN did not adversely affect PTK activity against enterococci. SPN, βHS and VGS exhibited very low PTK MIC values (MIC90, 0.12 µg/ml for all groups)

Conclusions: PTK demonstrated potent activity against a large collection of recent (2009) GP isolates from BSI. Its activity was similar to that of TIG and was not affected by R to other antimicrobial classes

  • PTK796 demonstrated potent activity against a large collection of recent (2009) Gram-positive isolates from bacteremias, including MRSA and VRE.
  • PTK796 activity was similar (within one doubling dilution) to that of tigecycline and was not affected by resistance to other antimicrobial classes.
  • These data suggest a potentially important clinical role for PTK796 in the treatment of BSI caused by Gram-positive organisms, include multidrugresistant strains.

 

 

Pharmacokinetics of Intravenous and Oral PTK796, A New Aminomethylcycline Antibiotic

Background: PTK796 is a novel semi-synthetic compound related to the tetracyclines and specifically derived from minocycline. It has activity against MRSA and pathogens expressing tetracycline resistance. PTK796 is being developed for clinical use with both intravenous (IV) and oral (PO) administration. The current proposed therapeutic dose is 100 mg IV or 300 mg PO administered once daily.

Methods: The pharmacokinetics of PTK796 were evaluated in the following studies:

  • Study 1: Single ascending dose of IV PTK796 in healthy males, 25-600 mg (n=5-6 in each dose group, total n=41)
  • Study 2: Crossover study, single dose of IV (100 mg) and oral (300 mg) PTK796 in 16 healthy males or females
  • Study 3: Single dose of IV PTK796 in 6 healthy males and 6 females, 100 mg. Plasma PTK796 concentrations were quantified by a validated LC-MS/MS method with a lower limit of quantitation of 20.0 ng/mL.

Results: Intravenous administration of PTK796 exhibited threecompartment pharmacokinetics, with a rapid initial distribution phase and a large volume of distribution of 300-430 L. The terminal half life of PTK796 was about 18 h and clearance was 11.4 L/h. PTK796 exhibited dose-proportional increases in AUC over the dose range 25-600 mg following IV administration. After oral administration, PTK796 was rapidly absorbed with a median Tmax of 1.8 h (range 1.0 to 3.0 h). The median AUC0-24h after 300 mg PTK796 PO was 5.66 μg*h/mL compared to 5.71 μg*h/mL after 100 mg IV. Based on the median AUC calculation, the oral bioavailability of PTK796 was 33%. In Study 3, the AUC0-24h in females was 7.18±1.03 μg*h/mL and 5.61±0.19 μg*h/mL in males. PTK796 was well tolerated after single IV or PO doses.

Conclusions: PTK796 has dose-proportional pharmacokinetics after intravenous administration. The 100 mg IV and 300 mg PO doses produce comparable exposures. The long half life supports once-daily dosing.

  • PTK796 showed dose-proportional pharmacokinetics after intravenous administration. The 100 mg IV and 300 mg PO doses produced comparable total exposures.
  • The terminal elimination half life supports once-daily dosing.
  • PTK796 administered intravenously and orally was well tolerated

 

 

Identification and Susceptibility of Pathogens Isolated from Patients with Complicated Skin and Skin Structure Infections (cSSSI): Results of a PTK0796 (PTK) Phase 2 Clinical Trial

Background: Paratek conducted a randomized, investigator-blinded Phase 2 clinical trial in adults with cSSSI comparing PTK (100mg IV/200mg oral, QD) with linezolid (LZD) (600mg IV/600 mg oral, Q12h). LZD was supplemented with aztreonam when gram negative infection was suspected. A total of 234 patients were enrolled.

Methods: Patient enrollment isolates were identified and tested at a central laboratory. MICs were determined by broth microdilution using dried panels. Analysis was based on the Clinically Evaluable (CE) population with a pathogen isolated at enrollment (ME).

Results: The predominant pathogen isolated was S. aureus (SA). 67 patients in the PTK arm were clinical successes with 80 isolates of SA (56.3% MRSA) and 59 isolates from 45 clinical successes (67.8% MRSA) in the LZD arm. MIC90s for MRSA and MSSA from each treatment arm were 0.25 µg/ml (PTK) and 2.0 µg/ml (LZD). Other pathogens in the PTK clinical success group included β-hemolytic strep (4 pts, mixed cultures), Gram negative bacteria (5 pts, 4 mixed), E. faecalis (2pts, one mixed), S. hemolyticus (1pt, mixed), and S. constellatus (1pt, only pathogen). In the LZD clinical success group other pathogens included Gram negatives (4 pts , 3 mixed), E. faecium (1pt, mixed), and S. constellatus (2 pts, only pathogen). There were only two clinical failures in the PTK arm, both MSSA (PTK MIC = 0.25 and 0.5 µg/ml, mixed cultures) and three in the LZD arm, 2 MRSA (LZD MIC = 2µg/ml, 1 mixed) and one MSSA (LZD MIC = 2µg/ml, only pathogen).

Conclusions: PTK exhibited excellent efficacy in the Phase 2 trial compared to LZD (CE Success 98% vs 93.2% respectively and ME Success 97.4% vs 93.7%, respectively). S. aureus was the predominant pathogen at enrollment (93.3% from PTK and 87.3% from LZD) the majority of which were MRSA. Susceptibility to PTK and LZD did not differ between MRSA and MSSA and did not differ between treatment arms.

The Phase 2 evaluation of PTK796 in comparison to linezolid indicated that PTK was safe and well tolerated and appeared to be efficacious compared to linezolid. The most common pathogen isolated was S. aureus, the majority of which were MRSA. PTK796 was active against S. aureus, with an MIC90 of 0.25µg/ml. Only two clinical failures occurred in the PTK796 treated group. In neither case was the infection caused by an organism with elevated PTK796 MIC. There were three failures in the linezolid treated group and none of these isolates had elevated MICs to linezolid to account for the lack of success.