<i>In Vitro</i>
            Activity of KBP-7072, a Novel Third-Generation Tetracycline, against 531 Recent Geographically Diverse and Molecularly Characterized Acinetobacter baumannii Species Complex Isolates

Huband, Michael D; Mendes, Rodrigo E.; Pfaller, Michael A.; Lindley, Jill; Strand, Gregory J.; Benn, Vincent; Zhang, Jay; Li, Li; Zhang, Min; Tan, Xiaojuan; Liu, Qingmei; Flamm, Robert K.

doi:10.1128/aac.02375-19

Cited by 18 publications

(14 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[19][20][21] on values <1 mcg/mL across a range of pathogens, including typical and atypical pathogens associated with CABP. [22][23][24] In a murine mouse model of pneumonia, peak KBP-7072 concentrations ranged from 0.12 to 25.2 mcg/mL. 17 Thus, the doses used in this study were severalfold greater than previously reported to produce static and cidal effects.…”

Section: Discussionmentioning

confidence: 99%

Nonclinical Pharmacokinetics, Protein Binding, and Elimination of KBP-7072, an Aminomethylcycline Antibiotic, in Animal Models

Tan

Zhang

Liu

et al. 2020

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

KBP-7072 is a semisynthetic aminomethylcycline with broad-spectrum activity against Gram-positive and Gram-negative pathogens, including multidrug-resistant bacterial strains. The pharmacokinetics (PK) of KBP-7072 after oral and intravenous (i.v.) administrations of single and multiple doses were investigated in animal models, including during fed and fasted states, and the protein binding and excretion characteristics were also evaluated. In Sprague-Dawley (SD) rats, beagle dogs, and CD-1 mice, KBP-7072 demonstrated a linear PK profile after the administration of single oral and i.v. and multiple oral doses. The oral bioavailability ranged from 12% to 32%. The mean time to maximum concentration (Tmax) ranged from 0.5 to 4 h, and the mean half-life ranged from approximately 6 to 11 h. The administration of oral doses in the fed state resulted in marked reductions in the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) compared with dosing in fasted animals. The mean bound fractions of KBP-7072 were 77.5%, 69.8%, 64.5%, 69.3%, and 69.2% in mouse, rat, dog, monkey, and human plasma, respectively. Following a single 22.5-mg/kg oral dose of KBP-7072 in SD rats, the cumulative excretion in feces was 64% and that in urine was 2.5% of the administered dose. The PK results in animal models are consistent with single- and multiple-ascending-dose studies in healthy volunteers and confirm the suitability of KBP-7072 for once-daily oral and i.v. administration in clinical studies.

show abstract

Section: Discussionmentioning

confidence: 99%

Nonclinical Pharmacokinetics, Protein Binding, and Elimination of KBP-7072, an Aminomethylcycline Antibiotic, in Animal Models

Tan

Zhang

Liu

et al. 2020

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…The mean f AUC/MIC ratio required for achieving a bacteriostatic effect of KBP-7072 was 4.39 and for achieving 1-log 10 kill and 2-log 10 kill was 8.34 and 13.46, respectively. Previous in vitro studies with KBP-7072 demonstrated MIC 90 values <1 μg/mL across a range of Gram-negative and Gram-positive pathogens, including multidrug resistant and typical and atypical pathogens associated with CABP (Huband et al, 2020). 15…”

Section: Discussionmentioning

confidence: 97%

In VivoEfficacy and PK/PD Modeling of KBP-7072, An Aminomethylcycline Antibiotic, in Neutropenic Pneumonia and Thigh Infection Models

Tan¹,

Zhang²,

Liu³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

17KBP-7072 is a novel aminomethylcycline with broad-spectrum activity against Gram-positive 18 and Gram-negative multidrug resistant bacterial isolates and strains. Antibacterial activity and the 19 PK/PD relationship were assessed using in vivo infection models. Six to 8-week-old female CD-20 1 mice were randomized to oral KBP-7072, minocycline and vehicle in a Klebsiella pneumoniae 21 murine model, and KBP-7072, linezolid and vehicle for a Streptococcus pneumoniae murine 22 model. Each animal was inoculated with K. pneumoniae or S. pneumoniae placed on the tip of 23 the nares. KBP-7072 and antibiotics were started 3 hours post inoculation and continued for 3 24 days for K. pneumoniae, and were started 18 hours post inoculation and continued for 3 days for 25 S. pneumoniae. Animals were euthanized at 0 (control group), 24, 48 or 72 hours post final dose. 26In vivo efficacy and PK/PD parameters were determined in Staphylococcus aureus isolate 27 (6424MRSA-363), K. pneumoniae isolate (6680kpn-522), and E. coli isolate (6691eco-558) 28 murine thigh infection models. In vivo efficacy and PK/PD parameters (fAUC/MIC, fC max /MIC 29 and %T>MIC free ) were calculated. Respiratory infection occurred in all inoculated mice. KBP-30 7072 produced a significant (p<0.05 to <0.001) dose-dependent decrease in colony forming units 31 (CFUs) at all doses and a dose-dependent increase in survival rate (p<0.001 vs. vehicle). The 32 median survival in all KBP-7072-treated groups was significantly greater vs. comparators 33 (p<0.001). These results demonstrate potent in vivo efficacy for KBP-7072 and determined that 34 the AUC/MIC parameter was optimal for assessing bacteriostatic and bactericidal effects of 35 KBP-7072. 36 37 38 39

show abstract

“…Aminoglycosides in combination with other antibiotics are usually prescribed for treating meningitis or bacteremia and have shown promising activity against A. baumannii in in vivo and in vitro studies [ 119 , 137 ]. Tetracycline is also preferred to treat A. baumannii infections in several experimental and clinical studies [ 138 ].…”

Section: Antimicrobial Therapymentioning

confidence: 99%

Virulence Potential and Treatment Options of Multidrug-Resistant (MDR) Acinetobacter baumannii

2021

View full text Add to dashboard Cite

Acinetobacter baumannii is an opportunistic pathogen which is undoubtedly known for a high rate of morbidity and mortality in hospital-acquired infections. A. baumannii causes life-threatening infections, including; ventilator-associated pneumonia (VAP), meningitis, bacteremia, and wound and urinary tract infections (UTI). In 2017, the World Health Organization listed A. baumannii as a priority-1 pathogen. The prevalence of A. baumannii infections and outbreaks emphasizes the direct need for the use of effective therapeutic agents for treating such infections. Available antimicrobials, such as; carbapenems, tigecycline, and colistins have insufficient effectiveness due to the appearance of multidrug-resistant strains, accentuating the need for alternative and novel therapeutic remedies. To understand and overcome this menace, the knowledge of recent discoveries on the virulence factors of A. baumannii is needed. Herein, we summarized the role of various virulence factors, including; outer membrane proteins, efflux pumps, biofilm, penicillin-binding proteins, and siderophores/iron acquisition systems. We reviewed the recent scientific literature on different A. baumannii virulence factors and the effective antimicrobial agents for the treatment and management of bacterial infections.

show abstract

In Vitro Activity of KBP-7072, a Novel Third-Generation Tetracycline, against 531 Recent Geographically Diverse and Molecularly Characterized Acinetobacter baumannii Species Complex Isolates

Cited by 18 publications

References 16 publications

Nonclinical Pharmacokinetics, Protein Binding, and Elimination of KBP-7072, an Aminomethylcycline Antibiotic, in Animal Models

Nonclinical Pharmacokinetics, Protein Binding, and Elimination of KBP-7072, an Aminomethylcycline Antibiotic, in Animal Models

In VivoEfficacy and PK/PD Modeling of KBP-7072, An Aminomethylcycline Antibiotic, in Neutropenic Pneumonia and Thigh Infection Models

Virulence Potential and Treatment Options of Multidrug-Resistant (MDR) Acinetobacter baumannii

Contact Info

Product

Resources

About