scholarly journals Pharmacokinetic and Pharmacodynamic Evaluation of P-873 versus Klebsiella pneumoniae in a Neutropenic Murine Thigh Infection Model

2013 ◽  
Vol 57 (4) ◽  
pp. 1971-1973 ◽  
Author(s):  
Lucinda M. Lamb ◽  
Jared L. Crandon ◽  
David P. Nicolau
Keyword(s):  
Protein Synthesis ◽  
Klebsiella Pneumoniae ◽  
Infection Model ◽  
Protein Synthesis Inhibitors ◽  
Content Type ◽  
Pharmacokinetic Properties

ABSTRACTP-873 is a novel compound in the RX-04 pyrrolocytosine series of protein synthesis inhibitors currently under development by Rib-X Pharmaceuticals. We evaluated the pharmacodynamic and pharmacokinetic properties of this compound againstKlebsiella pneumoniaeusing a murine neutropenic thigh infection model. P-873 demonstrated potent and rapidin vivoactivity against this organism with enhanced penetration and duration of exposure in thigh tissue.

scholarly journals In Vivo Pharmacodynamic Characterization of a Novel Odilorhabdin Antibiotic, NOSO-502, against Escherichia coli and Klebsiella pneumoniae in a Murine Thigh Infection Model

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Miao Zhao ◽  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
Jamie VanHecker ◽  
David R. Andes
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Subcutaneous Administration ◽  
Dose Fractionation ◽  
Infection Model ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Content Type ◽  
The Mean

ABSTRACT NOSO-502 is a novel odilorhabdin antibiotic with potent activity against Enterobacteriaceae. The goal of these studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitude best correlated with efficacy in the murine thigh infection model. Six Escherichia coli and 6 Klebsiella pneumoniae isolates were utilized. MICs were determined using CLSI methods and ranged from 1 to 4 mg/liter. A neutropenic murine thigh infection model was utilized for all treatment studies. Single-dose plasma pharmacokinetics were determined in mice after subcutaneous administration of 7.81, 31.25, 125, and 500 mg/kg of body weight. Pharmacokinetic studies exhibited peak concentration (Cmax) values of 1.49 to 84.6 mg/liter, area under the concentration-time curve from 0 h to infinity (AUC0–∞) values of 1.94 to 352 mg · h/liter, and beta elimination half-lives of 0.41 to 1.1 h. Dose fractionation studies were performed using total drug doses of 7.81 mg/kg to 2,000 mg/kg fractionated into regimens of every 3 h (q3h), q6h, q12h, or q24h. Nonlinear regression analysis demonstrated that AUC/MIC was the PK/PD parameter that best correlated with efficacy (R2, 0.86). In subsequent studies, we used the neutropenic murine thigh infection model to determine the magnitude of NOSO-502 AUC/MIC needed for the efficacy against a diverse group of Enterobacteriaceae. Mice were treated with 4-fold-increasing doses (range, 3.91 to 1,000 mg/kg) of NOSO-502 every 6 h. The mean 24-h free-drug AUC/MIC (fAUC)/MIC) magnitudes associated with net stasis and 1-log kill endpoint for K. pneumoniae were 4.22 and 17.7, respectively. The mean fAUC/MIC magnitude associated with net stasis endpoint for E. coli was 10.4. NOSO-502 represents a promising novel, first-in-class odilorhabdin antibiotic with in vivo potency against Enterobacteriaceae.

scholarly journals In VitroandIn VivoActivities of OP0595, a New Diazabicyclooctane, against CTX-M-15-Positive Escherichia coli and KPC-Positive Klebsiella pneumoniae

2016 ◽  
Vol 60 (5) ◽  
pp. 3001-3006 ◽  
Author(s):  
Akihiro Morinaka ◽  
Yuko Tsutsumi ◽  
Keiko Yamada ◽  
Yoshihiro Takayama ◽  
Shiro Sakakibara ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Infection Model ◽  
Gram Negative Bacteria ◽  
Content Type ◽  
Effective Combination ◽  
Time Kill ◽  
Lactamase Inhibitor

ABSTRACTGram-negative bacteria are evolving to produce β-lactamases of increasing diversity that challenge antimicrobial chemotherapy. OP0595 is a new diazabicyclooctane serine β-lactamase inhibitor which acts also as an antibiotic and as a β-lactamase-independent β-lactam “enhancer” againstEnterobacteriaceae. Here we determined the optimal concentration of OP0595 in combination with piperacillin, cefepime, and meropenem, in addition to the antibacterial activity of OP0595 alone and in combination with cefepime, inin vitrotime-kill studies and anin vivoinfection model against five strains of CTX-M-15-positiveEscherichia coliand five strains of KPC-positiveKlebsiella pneumoniae. An OP0595 concentration of 4 μg/ml was found to be sufficient for an effective combination with all three β-lactam agents. In bothin vitrotime-kill studies and anin vivomodel of infection, cefepime-OP0595 showed stronger efficacy than cefepime alone against all β-lactamase-positive strains tested, whereas OP0595 alone showed weaker or no efficacy. Taken together, these data indicate that combinational use of OP0595 and a β-lactam agent is important to exert the antimicrobial functions of OP0595.

scholarly journals In VivoPharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model

2016 ◽  
Vol 60 (8) ◽  
pp. 4764-4769 ◽  
Author(s):  
Alexander J. Lepak ◽  
David R. Andes
Keyword(s):  
Staphylococcus Aureus ◽  
Single Dose ◽  
Streptococcus Pneumoniae ◽  
Klebsiella Pneumoniae ◽  
Dose Response ◽  
Lung Infection ◽  
Infection Model ◽  
Content Type ◽  
Murine Lung

ABSTRACTDelafloxacin is a broad-spectrum anionic fluoroquinolone under development for the treatment of bacterial pneumonia. The goal of the study was to determine the pharmacokinetic/pharmacodynamic (PK/PD) targets in the murine lung infection model forStaphylococcus aureus,Streptococcus pneumoniae, andKlebsiella pneumoniae. Four isolates of each species were utilized forin vivostudies: forS. aureus, one methicillin-susceptible and three methicillin-resistant isolates;S. pneumoniae, two penicillin-susceptible and two penicillin-resistant isolates;K. pneumoniae, one wild-type and three extended-spectrum beta-lactamase-producing isolates. MICs were determined using CLSI methods. A neutropenic murine lung infection model was utilized for all treatment studies, and drug dosing was by the subcutaneous route. Single-dose plasma pharmacokinetics was determined in the mouse model after administration of 2.5, 10, 40, and 160 mg/kg. Forin vivostudies, 4-fold-increasing doses of delafloxacin (range, 0.03 to 160 mg/kg) were administered every 6 h (q6h) to infected mice. Treatment outcome was measured by determining organism burden in the lung (CFU counts) at the end of each experiment (24 h). The Hill equation for maximum effect (Emax) was used to model the dose-response data. The magnitude of the PK/PD index, the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC), associated with net stasis and 1-log kill endpoints was determined in the lung model for all isolates. MICs ranged from 0.004 to 1 mg/liter. Single-dose PK parameter ranges include the following: for maximum concentration of drug in serum (Cmax), 2 to 70.7 mg/liter; AUC from 0 h to infinity (AUC0–∞), 2.8 to 152 mg · h/liter; half-life (t1/2), 0.7 to 1 h. At the start of therapy mice had 6.3 ± 0.09 log10CFU/lung. In control mice the organism burden increased 2.1 ± 0.44 log10CFU/lung over the study period. There was a relatively steep dose-response relationship observed with escalating doses of delafloxacin. Maximal organism reductions ranged from 2 log10to more than 4 log10. The median free-drug AUC/MIC magnitude associated with net stasis for each species group was 1.45, 0.56, and 40.3 forS. aureus,S. pneumoniae, andK. pneumoniae, respectively. AUC/MIC targets for the 1-log kill endpoint were 2- to 5-fold higher. Delafloxacin demonstratedin vitroandin vivopotency against a diverse group of pathogens, including those with phenotypic drug resistance to other classes. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints for delafloxacin for the treatment of lower respiratory tract infections involving these pathogens.

scholarly journals In Vitro-In Vivo Discordance with Humanized Piperacillin-Tazobactam Exposures against Piperacillin-Tazobactam-Resistant/Pan-β-Lactam-Susceptible Klebsiella pneumoniae Strains

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
S. M. Stainton ◽  
M. L. Monogue ◽  
D. P. Nicolau
Keyword(s):  
Klebsiella Pneumoniae ◽  
Lung Infection ◽  
Infection Model ◽  
Clinical Implications ◽  
Content Type ◽  
Murine Lung ◽  
Resistance Profile ◽  
Phenotypic Profile

ABSTRACT Recent findings have identified Klebsiella pneumoniae strains that are pan-β-lactam susceptible (PBL-S) but piperacillin-tazobactam resistant (TZP-R) in vitro. We assessed the efficacy of a humanized exposure of piperacillin-tazobactam (TZP) against 12 TZP-R/PBL-S K. pneumoniae isolates in an immunocompromised murine lung infection model. Discordance between the in vitro resistance profile and the in vivo efficacy of human-simulated TZP exposures against this phenotypic profile was observed. Additional studies are required to define the clinical implications of these TZP-R/PBL-S strains.

scholarly journals In Vitro Discordance with In Vivo Activity: Humanized Exposures of Ceftazidime-Avibactam, Aztreonam, and Tigecycline Alone and in Combination against New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae in a Murine Lung Infection Model

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
M. L. Monogue ◽  
L. M. Abbo ◽  
R. Rosa ◽  
J. F. Camargo ◽  
O. Martinez ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Lung Infection ◽  
Multidrug Resistant ◽  
Infection Model ◽  
New Delhi ◽  
Beta Lactamase ◽  
Bacterial Reduction ◽  
Content Type

ABSTRACT The management of infections with New Delhi metallo-beta-lactamase-1 (NDM)-producing bacteria remains clinically challenging given the multidrug resistant (MDR) phenotype associated with these bacteria. Despite resistance in vitro, ceftazidime-avibactam previously demonstrated in vivo activity against NDM-positive Enterobacteriaceae. Herein, we observed in vitro synergy with ceftazidime-avibactam and aztreonam against an MDR Klebsiella pneumoniae harboring NDM. In vivo, humanized doses of ceftazidime-avibactam monotherapy resulted in >2 log10 CFU bacterial reduction; therefore, no in vivo synergy was observed.

scholarly journals Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase

2016 ◽  
Vol 60 (10) ◽  
pp. 6271-6280 ◽  
Author(s):  
Andrés Palencia ◽  
Xianfeng Li ◽  
Wei Bu ◽  
Wai Choi ◽  
Charles Z. Ding ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Mycobacterium Tuberculosis ◽  
Cell Activity ◽  
Trna Synthetase ◽  
Protein Synthesis Inhibitor ◽  
Drug Resistant ◽  
Protein Synthesis Inhibitors ◽  
Synthesis Inhibitor ◽  
Content Type

ABSTRACTThe recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains ofMycobacterium tuberculosishighlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective againstM. tuberculosisin TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), toM. tuberculosisLeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity againstM. tuberculosis. Importantly, their good oral bioavailability translates intoin vivoefficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.

scholarly journals In Vivo Pharmacodynamic Target Determination for Delafloxacin against Klebsiella pneumoniae and Pseudomonas aeruginosa in the Neutropenic Murine Pneumonia Model

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Miao Zhao ◽  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
David R. Andes
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
Area Under The Curve ◽  
Lung Infection ◽  
Free Drug ◽  
Infection Model ◽  
Phase 3 ◽  
Content Type ◽  
Target Determination

ABSTRACT Delafloxacin is a broad-spectrum anionic fluoroquinolone that has completed a phase 3 study for community-acquired bacterial pneumonia. We investigated the pharmacodynamic target for delafloxacin against 12 Klebsiella pneumoniae and 5 Pseudomonas aeruginosa strains in the neutropenic murine lung infection model. The median 24-h free-drug area under the curve (fAUC)/MIC values associated with net stasis and 1-log kill were 28.6 and 64.1 for K. pneumoniae, respectively. The 24-h fAUC/MIC values associated with net stasis and 1-log kill for P. aeruginosa were 5.66 and 14.3, respectively.

scholarly journals Double-Carbapenem Therapy for Carbapenemase-Producing Klebsiella pneumoniae

2011 ◽  
Vol 55 (6) ◽  
pp. 3002-3004 ◽  
Author(s):  
Catharine C. Bulik ◽  
David P. Nicolau
Keyword(s):  
Klebsiella Pneumoniae ◽  
Treatment Options ◽  
Infection Model ◽  
Content Type ◽  
Enhanced Activity

ABSTRACTThe limited treatment options available for carbapenemase-producingKlebsiella pneumoniae(KPC) have made it a formidable pathogen. Previously we have shown the enhanced activity of pharmacodynamically optimized doripenem against KPC. Capitalizing on KPC's increased affinity for ertapenem, we evaluated the efficacy of a combination of ertapenem and doripenem in both anin vitrochemostat and anin vivomurine thigh infection model. Overall, the combination of doripenem plus ertapenem demonstrated enhanced efficacy over either agent alone.

scholarly journals A Novel Ketolide, RBx 14255, with Activity against Multidrug-Resistant Streptococcus pneumoniae

2014 ◽  
Vol 58 (8) ◽  
pp. 4283-4289 ◽  
Author(s):  
V. Samuel Raj ◽  
Tarani Kanta Barman ◽  
Vandana Kalia ◽  
Kedar Purnapatre ◽  
Smita Dube ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Pulmonary Infection ◽  
Systemic Infection ◽  
Multidrug Resistant ◽  
Infection Model ◽  
The Novel ◽  
Content Type ◽  
Pharmacokinetic Properties

ABSTRACTWe present here the novel ketolide RBx 14255, a semisynthetic macrolide derivative obtained by the derivatization of clarithromycin, for itsin vitroandin vivoactivities against sensitive and macrolide-resistantStreptococcus pneumoniae. RBx 14255 showed excellentin vitroactivity against macrolide-resistantS. pneumoniae, including an in-house-generated telithromycin-resistant strain (S. pneumoniae3390 NDDR). RBx 14255 also showed potent protein synthesis inhibition against telithromycin-resistantS. pneumoniae3390 NDDR. The binding affinity of RBx 14255 toward ribosomes was found to be more than that for other tested drugs. Thein vivoefficacy of RBx 14255 was determined in murine pulmonary infection induced by intranasal inoculation ofS. pneumoniaeATCC 6303 and systemic infection withS. pneumoniae3390 NDDR strains. The 50% effective dose (ED50) of RBx 14255 againstS. pneumoniaeATCC 6303 in a murine pulmonary infection model was 3.12 mg/kg of body weight. In addition, RBx 14255 resulted in 100% survival of mice with systemic infection caused by macrolide-resistantS. pneumoniae3390 NDDR at 100 mg/kg four times daily (QID) and at 50 mg/kg QID. RBx 14255 showed favorable pharmacokinetic properties that were comparable to those of telithromycin.

Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo

2019 ◽  
Vol 74 (11) ◽  
pp. 3211-3216 ◽  
Author(s):  
Stephan Göttig ◽  
Denia Frank ◽  
Eleonora Mungo ◽  
Anika Nolte ◽  
Michael Hogardt ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Selection Pressure ◽  
Galleria Mellonella ◽  
Phenotypic Characterization ◽  
Infection Model ◽  
Development Of Resistance ◽  
Time Kill

Abstract Objectives The β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is active against KPC-producing Enterobacterales. Herein, we present molecular and phenotypic characterization of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae that emerged in vivo and in vitro. Methods Sequence analysis of blaKPC-3 was performed from clinical and in vitro-generated ceftazidime/avibactam-resistant K. pneumoniae isolates. Time–kill kinetics and the Galleria mellonella infection model were applied to evaluate the activity of ceftazidime/avibactam and imipenem alone and in combination. Results The ceftazidime/avibactam-resistant clinical K. pneumoniae isolate revealed the amino acid change D179Y in KPC-3. Sixteen novel mutational changes in KPC-3 among in vitro-selected ceftazidime/avibactam-resistant isolates were described. Time–kill kinetics showed the emergence of a resistant subpopulation under selection pressure with either imipenem or ceftazidime/avibactam. However, combined selection pressure with imipenem plus ceftazidime/avibactam prevented the development of resistance and resulted in bactericidal activity. Concordantly, the G. mellonella infection model revealed that monotherapy with ceftazidime/avibactam is prone to select for resistance in vivo and that combination therapy with imipenem results in significantly better survival. Conclusions Ceftazidime/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time–kill kinetics as well as an in vivo infection model we postulate a combination therapy of ceftazidime/avibactam and imipenem as a strategy to prevent the development of ceftazidime/avibactam resistance in KPC-producing Enterobacterales in vivo.

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