Determination of Atypical Nonlinear Plasma–Protein-Binding Behavior of Tigecycline Using an In Vitro Microdialysis Technique

Mukker, Jatinder Kaur; Singh, Ravi Shankar Prasad; Derendorf, Hartmut

doi:10.1002/jps.23872

Cited by 27 publications

(14 citation statements)

References 25 publications

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“…Since the values reported for ELF and AC are assumed to represent unbound drug concentrations, total plasma concentrations are often corrected for protein binding and unbound plasma concentration are used to understand drug distribution and penetration. The mean plasma protein binding of omadacycline has been reported to be 20%, whereas the protein binding of tigecycline can range from 71% to 89% since tigecycline protein binding is concentration dependent (e.g., the unbound fraction is increased with an increase in the total concentration) ( 31 , 39 ). For omadacycline, the respective ELF and AC penetration ratios based on unbound plasma concentrations would be 1.84 and 32.2, whereas those based on total plasma concentrations would be 1.47 and 25.8.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Omadacycline and Tigecycline Pharmacokinetics in the Plasma, Epithelial Lining Fluid, and Alveolar Cells of Healthy Adult Subjects

Gotfried

Horn

Garrity-Ryan

et al. 2017

Antimicrob Agents Chemother

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The steady-state concentrations of omadacycline and tigecycline in the plasma, epithelial lining fluid (ELF), and alveolar cells (AC) of 58 healthy adult subjects were obtained. Subjects were administered either omadacycline at 100 mg intravenously (i.v.) every 12 h for two doses followed by 100 mg i.v. every 24 h for three doses or tigecycline at an initial dose of 100 mg i.v. followed by 50 mg i.v. every 12 h for six doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject following the start of the fifth dose of omadacycline at 0.5, 1, 2, 4, 8, 12, or 24 h and after the start of the seventh dose of tigecycline at 2, 4, 6, or 12 h. The value of the area under the concentration-time curve (AUC) from time zero to 24 h postdosing (AUC0–24) (based on mean concentrations) in ELF and the ratio of the ELF to total plasma omadacycline concentration based on AUC0–24 values were 17.23 mg · h/liter and 1.47, respectively. The AUC0–24 value in AC was 302.46 mg · h/liter, and the ratio of the AC to total plasma omadacycline concentration was 25.8. In comparison, the values of the AUC from time zero to 12 h postdosing (AUC0–12) based on the mean concentrations of tigecycline in ELF and AC were 3.16 and 38.50 mg · h/liter, respectively. The ratio of the ELF and AC to total plasma concentrations of tigecycline based on AUC0–12 values were 1.71 and 20.8, respectively. The pharmacokinetic advantages of higher and sustained concentrations of omadacycline compared to those of tigecycline in plasma, ELF, and AC suggest that omadacycline is a promising antibacterial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens.

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Section: Discussionmentioning

confidence: 99%

Comparison of Omadacycline and Tigecycline Pharmacokinetics in the Plasma, Epithelial Lining Fluid, and Alveolar Cells of Healthy Adult Subjects

Gotfried

Horn

Garrity-Ryan

et al. 2017

Antimicrob Agents Chemother

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“…Tetracyclines are known to chelate metal ions but our group has recently investigated the interaction of metal ions with the extent of plasma protein binding of tigecycline (TIG) which exhibits atypical nonlinear plasma protein binding (i.e. decrease in free fraction as total concentrations increase followed by an increase in free fraction at highest concentrations) [1], a phenomenon also observed with other tetracyclines [2,3]. Thinking of what potential interaction TIG may have in vitro with chelators, a pharmacokinetic interaction may occur due to the competition of chelators for metal ions, allowing for more unchelated drug, which may lead to enhanced activity.…”

Section: Introductionmentioning

confidence: 99%

Enhanced in vitro activity of tigecycline in the presence of chelating agents

Deitchman

Singh

Rand

et al. 2018

International Journal of Antimicrobial Agents

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The lack of availability of novel antibiotic agents and the rise of resistance to existing therapies has led clinicians to utilise combination therapy to adequately treat bacterial infections. Here we examined how chelators may impact the in vitro activity of tigecycline (TIG) against Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae. Minimum inhibitory concentrations (MICs) were determined by broth dilution with and without various combinations of chelators (EDTA and other tetracyclines) and metal ions (i.e. calcium, magnesium). Trimethoprim (TMP) was used as a non-chelating control. Addition of metal ions led to increases in MICs, whilst addition of EDTA led to decreases in MICs. The chelating effects of EDTA were reversed by addition of magnesium and most profoundly calcium. Similar effects of EDTA and calcium were observed for tetracycline (TET) and TMP. When other tetracyclines (TET, oxytetracycline (OXY) and chlortetracycline (CHL)) were used as chelators at concentrations below their MICs, TIG MICs decreased for P. aeruginosa but not for E. coli. Some decreases in TIG MICs were observed for K. pneumoniae when TET and CHL were added. A dose-dependent decrease in TIG MIC was observed for TET and was reversed by the addition of calcium. The presence of effects of EDTA and calcium on TMP MICs indicates that mechanisms outside of TIG chelation likely play a role in enhanced activity. Full characterisation of an unexpected interaction such as TIG-TET with different microorganisms could provide valuable insights into the underlying mechanisms and design of physiologically viable chelators as candidates for future combinations regimens.

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“…Its availability as an intravenous or oral formulation, a long serum half-life, and once-daily administration are also benefits of this nextgeneration tetracycline (7). Of note, it is the only tetracycline with low fractional binding to serum proteins (20%); in contrast, other tetracyclines are characterized by high protein binding and a low percentage of free drug in serum (11). This is important when comparing MIC values, as in vitro tests are done in the absence of serum.…”

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confidence: 99%

Antimicrobial Activity of Omadacycline Tested against Clinical Bacterial Isolates from Hospitals in Mainland China, Hong Kong, and Taiwan: Results from the SENTRY Antimicrobial Surveillance Program (2013 to 2016)

Carvalhaes

Huband

Reinhart³

et al. 2019

Antimicrob Agents Chemother

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Omadacycline is a derivative of minocycline and the first agent of the aminomethylcycline class. A total of 3,282 organisms (1 per patient) were consecutively collected from patients hospitalized in China (including Hong Kong) and Taiwan. Susceptibility testing was performed by broth microdilution methods in a central laboratory (JMI Laboratories). The collection included Gram-positive and Gram-negative organisms from patients with pneumonia, bloodstream, skin, community-acquired respiratory, and other infections. Omadacycline was very potent againstStaphylococcus aureus(n= 689; MIC50/90, 0.12/0.25 mg/liter), including methicillin-resistantStaphylococcus aureus(MRSA;n= 299; MIC50/90, 0.12/0.5 mg/liter), and had similar activity across geographic regions. Omadacycline was very active againstStreptococcus pneumoniae(highest MIC, 0.25 mg/liter), β-hemolytic streptococci (highest MIC, 1 mg/liter), viridans group streptococci (highest MIC, 0.25 mg/liter), andEnterococcusspp. (highest MIC, 0.5 mg/liter) from all geographic regions. Overall, 53.8% ofS. pneumoniaeisolates were penicillin resistant (penicillin MIC, ≥2 mg/liter) and 10.7% of enterococci (21.2% amongE. faeciumisolates) were vancomycin resistant. Omadacycline was active againstHaemophilus influenzae(MIC50/90, 0.5/1 mg/liter) regardless of β-lactamase production and was active againstMoraxella catarrhalis(MIC50/90, ≤0.12/0.25 mg/liter). AgainstEnterobacteriaceae, omadacycline was most active againstEscherichia coli(MIC50/90, 1/2 mg/liter),Klebsiella oxytoca(MIC50/90, 1/4 mg/liter), andEnterobacter cloacae(MIC50/90, 2/4 mg/liter). Omadacycline had potentin vitroactivity against Gram-positive and Gram-negative pathogens isolated from China and Taiwan and retained activity against problem pathogens, such as MRSA, vancomycin-resistant enterococci (VRE), penicillin-resistantS. pneumoniae(PRSPN), and extended-spectrum β-lactamase-producingE. coli. The observed MIC profile in Chinese isolates was very similar to that seen in the U.S. and European surveillance studies.

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Determination of Atypical Nonlinear Plasma–Protein-Binding Behavior of Tigecycline Using an In Vitro Microdialysis Technique

Cited by 27 publications

References 25 publications

Comparison of Omadacycline and Tigecycline Pharmacokinetics in the Plasma, Epithelial Lining Fluid, and Alveolar Cells of Healthy Adult Subjects

Comparison of Omadacycline and Tigecycline Pharmacokinetics in the Plasma, Epithelial Lining Fluid, and Alveolar Cells of Healthy Adult Subjects

Enhanced in vitro activity of tigecycline in the presence of chelating agents

Antimicrobial Activity of Omadacycline Tested against Clinical Bacterial Isolates from Hospitals in Mainland China, Hong Kong, and Taiwan: Results from the SENTRY Antimicrobial Surveillance Program (2013 to 2016)

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