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 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 Bactericidal Activities of Meropenem and Ertapenem against Extended-Spectrum-β-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae in a Neutropenic Mouse Thigh Model

2007 ◽  
Vol 51 (4) ◽  
pp. 1481-1486 ◽  
Author(s):  
C. Andrew DeRyke ◽  
Mary Anne Banevicius ◽  
Hong Wei Fan ◽  
David P. Nicolau
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Infection Model ◽  
Bacterial Reduction ◽  
Efficacy Analysis ◽  
Percent Time ◽  
Extended Spectrum ◽  
Wide Range

ABSTRACT The purpose of this study was to examine the in vivo efficacies of meropenem and ertapenem against extended-spectrum-β-lactamase (ESBL)-producing isolates with a wide range of MICs. Human-simulated dosing regimens in mice were designed to approximate the free drug percent time above the MIC (fT>MIC) observed for humans following meropenem at 1 g every 8 h and ertapenem at 1 g every 24 h. An in vivo neutropenic mouse thigh infection model was used to examine the bactericidal effects against 31 clinical ESBL Escherichia coli and Klebsiella pneumoniae isolates and 2 non-ESBL isolates included for comparison at a standard 105 inoculum. Three isolates were examined at a high 107 inoculum as well. Meropenem displayed greater in vitro potency, with a median MIC (range) (μg/ml) of 0.125 (0.03 to 32), than did ertapenem, with 0.5 (0.012 to 128). Seven of the 31 ESBL isolates were removed from the efficacy analysis due to their inability to establish infection in the mouse model. When MICs were ≤1.5 μg/ml for ertapenem (≤0.5 μg/ml for meropenem), similar reductions in CFU (≈ 2-log kill) were observed for both ertapenem (fT>MIC ≥ 23%) and meropenem (fT>MIC ≥ 75%). Ertapenem showed bacterial regrowth for seven of eight isolates, with MICs of ≥2 μg/ml (fT>MIC ≤ 20%), while meropenem displayed antibacterial potency that varied from a static effect to a 1-log bacterial reduction in these isolates (fT>MIC = 30 to 65%). At a 107 inoculum, both agents eradicated bacteria due to adequate exposures (fT>MIC = 20 to 45%). Due to low MICs, no difference in bacterial kill was noted for the majority of ESBL isolates tested. However, for isolates with raised ertapenem MICs of ≥2 μg/ml, meropenem displayed sustained efficacy due to its greater in vitro potency and higher resultant fT>MIC.

scholarly journals Polymyxin Triple Combinations against Polymyxin-Resistant, Multidrug-Resistant, KPC-Producing Klebsiella pneumoniae

2020 ◽  
Vol 64 (8) ◽  
Author(s):  
Su Mon Aye ◽  
Irene Galani ◽  
Heidi Yu ◽  
Jiping Wang ◽  
Ke Chen ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Triple Therapy ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Bacterial Killing ◽  
Standard Dosage ◽  
Time Kill

ABSTRACT Resistance to polymyxin antibiotics is increasing. Without new antibiotic classes, combination therapy is often required. We systematically investigated bacterial killing with polymyxin-based combinations against multidrug-resistant (including polymyxin-resistant), carbapenemase-producing Klebsiella pneumoniae. Monotherapies and double- and triple-combination therapies were compared to identify the most efficacious treatment using static time-kill studies (24 h, six isolates), an in vitro pharmacokinetic/pharmacodynamic model (IVM; 48 h, two isolates), and the mouse thigh infection model (24 h, six isolates). In static time-kill studies, all monotherapies (polymyxin B, rifampin, amikacin, meropenem, or minocycline) were ineffective. Initial bacterial killing was enhanced with various polymyxin B-containing double combinations; however, substantial regrowth occurred in most cases by 24 h. Most polymyxin B-containing triple combinations provided greater and more sustained killing than double combinations. Standard dosage regimens of polymyxin B (2.5 mg/kg of body weight/day), rifampin (600 mg every 12 h), and amikacin (7.5 mg/kg every 12 h) were simulated in the IVM. Against isolate ATH 16, no viable bacteria were detected across 5 to 25 h with triple therapy, with regrowth to ∼2-log10 CFU/ml occurring at 48 h. Against isolate BD 32, rapid initial killing of ∼3.5-log10 CFU/ml at 5 h was followed by a slow decline to ∼2-log10 CFU/ml at 48 h. In infected mice, polymyxin B monotherapy (60 mg/kg/day) generally was ineffective. With triple therapy (polymyxin B at 60 mg/kg/day, rifampin at 120 mg/kg/day, and amikacin at 300 mg/kg/day), at 24 h there was an ∼1.7-log10 CFU/thigh reduction compared to the starting inoculum for all six isolates. Our results demonstrate that the polymyxin B-rifampin-amikacin combination significantly enhanced in vitro and in vivo bacterial killing, providing important information for the optimization of polymyxin-based combinations in patients.

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 Assessment of the In Vivo Activity of SPR741 in Combination with Azithromycin against Multidrug-Resistant Enterobacteriaceae Isolates in the Neutropenic Murine Thigh Infection Model

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Sean M. Stainton ◽  
Kamilia Abdelraouf ◽  
Luke Utley ◽  
Michael J. Pucci ◽  
Troy Lister ◽  
...  
Keyword(s):  
Potential Role ◽  
Wide Spectrum ◽  
Structural Similarity ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Bacterial Burden ◽  
Content Type ◽  
Novel Agent

ABSTRACT SPR741 is a novel agent with structural similarity to polymyxins that is capable of potentiating the activities of various classes of antibiotics. Previously published studies indicated that although Enterobacteriaceae isolates had minimal susceptibilities to azithromycin (AZM), the in vitro antimicrobial activity of AZM against Enterobacteriaceae was enhanced when it was combined with SPR741. The current study evaluated the in vivo activity of human-simulated regimens (HSR) of AZM equivalent to clinical doses of 500 mg given intravenously (i.v.) every 24 h (q24h) and SPR741 equivalent to clinical doses of 400 mg q8h i.v. (1-h infusion), alone and in combination, against multidrug-resistant (MDR) Enterobacteriaceae . We studied 30 MDR Enterobacteriaceae isolates expressing a wide spectrum of β-lactamases (ESBL, NDM, VIM, and KPC), including a subset of isolates positive for genes conferring macrolide resistance ( mphA , mphE , ermB , and msr ). In vivo activity was assessed as the change in log 10 CFU per thigh at 24 h compared with 0 h. Treatment with AZM alone was associated with net growth of 2.60 ± 0.83 log 10 CFU/thigh. Among isolates with AZM MICs of ≤16 mg/liter, treatment with AZM-SPR741was associated with an average reduction in bacterial burden of −0.53 ± 0.82 log 10 CFU/thigh, and stasis to 1-log kill was observed in 9/11 isolates (81.8%). Combination therapy with an AZM-SPR741 HSR showed promising in vivo activity against MDR Enterobacteriaceae isolates with AZM MICs of ≤16 mg/liter, including those producing a variety of β-lactamases. These data support a potential role for AZM-SPR741 in the treatment of infections due to MDR Enterobacteriaceae .

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 Therapeutic Effect and Mechanisms of the Novel Monosulfactam 0073

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Ying Sun ◽  
Xueyuan Liao ◽  
Zhigang Huang ◽  
Yaliu Xie ◽  
Yanbin Liu ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Serial Passage ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Infection Model ◽  
The Novel ◽  
Gram Negative ◽  
Content Type

ABSTRACT This study aimed to evaluate the antimicrobial activity of the novel monosulfactam 0073 against multidrug-resistant Gram-negative bacteria in vitro and in vivo and to characterize the mechanisms underlying 0073 activity. The in vitro activities of 0073, aztreonam, and the combination with avibactam were assessed by MIC and time-kill assays. The safety of 0073 was evaluated using 3-(4,5-dimethylthizol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and acute toxicity assays. Murine thigh infection and pneumonia models were employed to define in vivo efficacy. A penicillin-binding protein (PBP) competition assay and confocal microscopy were conducted. The inhibitory action of 0073 against β-lactamases was evaluated by the half-maximal inhibitory concentration (IC50), and resistance development was evaluated via serial passage. The monosulfactam 0073 showed promising antimicrobial activity against Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii isolates producing metallo-β-lactamases (MBLs) and serine β-lactamases. In preliminary experiments, compound 0073 exhibited safety both in vitro and in vivo. In the murine thigh infection model and the pneumonia models in which infection was induced by P. aeruginosa and Klebsiella pneumoniae, 0073 significantly reduced the bacterial burden. Compound 0073 targeted several PBPs and exerted inhibitory effects against some serine β-lactamases. Finally, 0073 showed a reduced propensity for resistance selection compared with that of aztreonam. The novel monosulfactam 0073 exhibited increased activity against β-lactamase-producing Gram-negative organisms compared with the activity of aztreonam and showed good safety profiles both in vitro and in vivo. The underlying mechanisms may be attributed to the affinity of 0073 for several PBPs and its inhibitory activity against some serine β-lactamases. These data indicate that 0073 represents a potential treatment for infections caused by β-lactamase-producing multidrug-resistant bacteria.

scholarly journals The Novel β-Lactam Enhancer Zidebactam Augments theIn VivoPharmacodynamic Activity of Cefepime in a Neutropenic Mouse LungAcinetobacter baumanniiInfection Model

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
S. S. Bhagwat ◽  
H. Periasamy ◽  
S. S. Takalkar ◽  
S. R. Palwe ◽  
H. N. Khande ◽  
...  
Keyword(s):  
Bactericidal Effect ◽  
Multidrug Resistant ◽  
Mouse Lung ◽  
Infection Model ◽  
Bactericidal Action ◽  
Content Type ◽  
Time Kill ◽  
The Impact

ABSTRACTWCK 5222 is a combination of cefepime and the high-affinity PBP2-binding β-lactam enhancer zidebactam. The cefepime-zidebactam combination is active against multidrug-resistant Gram-negative bacteria, including carbapenemase-expressingAcinetobacter baumannii. The mechanism of action of the combination involves concurrent multiple penicillin binding protein inhibition, leading to the enhanced bactericidal action of cefepime. The aim of the present study was to assess the impact of the zidebactam-mediated enhancedin vitrobactericidal action in modulating the percentage of the time that the free drug concentration remains above the MIC (percentfT>MIC) for cefepime required for thein vivokilling ofA. baumannii. Cefepime and cefepime-zidebactam MICs were comparable and ranged from 2 to 16 mg/liter for theA. baumanniistrains (n = 5) employed in the study. Time-kill studies revealed the improved killing of these strains by the cefepime-zidebactam combination compared to that by the constituents alone. Employing a neutropenic mouse lung infection model, exposure-response analyses for all theA. baumanniistrains showed that the cefepimefT>MIC required for 1-log10kill was 38.9%. In the presence of a noneffective dose of zidebactam, the cefepimefT>MIC requirement dropped significantly to 15.5%, but it still rendered a 1-log10kill effect. Thus, zidebactam mediated the improvement in cefepime’s bactericidal effect observed in time-kill studies, manifestedin vivothrough the lowering of cefepime’s pharmacodynamic requirement. This is a first-ever study demonstrating a β-lactam enhancer role of zidebactam that helps augment thein vivoactivity of cefepime by reducing the magnitude of its pharmacodynamically relevant exposures againstA. baumannii.

scholarly journals Efficacy of Humanized Exposures of Cefiderocol (S-649266) against a Diverse Population of Gram-Negative Bacteria in a Murine Thigh Infection Model

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Marguerite L. Monogue ◽  
Masakatsu Tsuji ◽  
Yoshinori Yamano ◽  
Roger Echols ◽  
David P. Nicolau
Keyword(s):  
Antibacterial Activity ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Gram Negative Bacteria ◽  
Diverse Population ◽  
Gram Negative ◽  
Content Type ◽  
Log Reduction

ABSTRACT Cefiderocol (S-649266) is a novel siderophore cephalosporin with potent in vitro activity against clinically encountered multidrug-resistant (MDR) Gram-negative isolates; however, its spectrum of antibacterial activity against these difficult-to-treat isolates remains to be fully explored in vivo. Here, we evaluated the efficacy of cefiderocol humanized exposures in a neutropenic murine thigh model to support a suitable MIC breakpoint. Furthermore, we compared cefiderocol's efficacy with humanized exposures of meropenem and cefepime against a subset of these phenotypically diverse isolates. Ninety-five Gram-negative isolates were studied. Efficacy was determined as the change in log10 CFU at 24 h compared with 0-h controls. Bacterial stasis or ≥1 log reduction in 67 isolates with MICs of ≤4 μg/ml was noted in 77, 88, and 85% of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa, respectively. For isolates with MICs of ≥8 μg/ml, bacterial stasis or ≥1 log10 reduction was observed in only 2 of 28 (8 Enterobacteriaceae, 19 A. baumannii, and 1 P. aeruginosa) strains. Against highly resistant meropenem and cefepime organisms, cefiderocol maintained its in vivo efficacy. Overall, humanized exposures of cefiderocol produced similar reductions in bacterial density for organisms with MICs of ≤4 μg/ml, whereas isolates with MICs of ≥8 μg/ml generally displayed bacterial growth in the presence of the compound. Data derived in the current study will assist with the delineation of MIC susceptibility breakpoints for cefiderocol against these important nosocomial Gram-negative pathogens; however, additional clinical data are required to substantiate these observations.

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