scholarly journals 1313. MIC Profiling of Ceftazidime-Avibactam (CAZ/AVI) Against Two Carbapenemase producing Klebsiella pneumoniae Isolates

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S668-S669
Author(s):  
Andrei Zidaru ◽  
Brianna M Eales ◽  
Weiqun Wang ◽  
Paul Merlau ◽  
Todd Lasco ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Susceptibility Testing ◽  
Maximum Effect ◽  
Infection Model ◽  
Beta Lactams ◽  
Emax Model ◽  
Carbapenem Resistant ◽  
Persistent Bacteremia ◽  
Parameter Values

Abstract Background Carbapenemases confer resistance against a broad range of beta-lactams with a prevalence of 40-60% among CRE (carbapenem-resistant Enterobacteriaceae). CAZ-AVI is commonly used to treat infections due to CPE (carbapenemase-producing Enterobacteriaceae), typically guided by susceptibility testing with a single AVI concentration. This methodology does not take into consideration varying AVI concentration observed in vivo, and may not reliably predict positive clinical outcomes. Our objective was to investigate a novel susceptibility testing method to guide CAZ-AVI therapy. Methods Two bloodstream K. pneumoniae isolates (CAZ/AVI susceptible) from an abdominal source were recovered from 2 unrelated patients. Both patients were treated with CAZ/AVI, but had discordant outcomes: KP118 (eradication within 24h) and KP286 (persistent bacteremia for over 30 days). Carbapenemase production in the 2 isolates was confirmed via Carba NP test, and CAZ susceptibility was determined in a clinically relevant range of AVI concentration (0 - 16 mg/L). The concentration-response was characterized by the sigmoid inhibitory maximum effect (Emax) model. The best-fit parameter values were used to predict %T > MICi associated with CAZ/AVI exposures expected in peritoneal fluid after standard dosing (2.5g q8h). These CAZ/AVI exposures were simulated in the hollow-fiber infection model (HFIM), and the bacterial responses were correlated to observed clinical outcomes. Results The AVI-dependent reduction in CAZ MIC was well characterized in both strains (R2 > 0.98). In HFIM, sustained suppression of KP118 (T > MICi = 100%) was observed over 5 days, but not with KP286 (T > MICi < 100%). These observations are consistent with the clinical courses of the patients. Conclusion The discordant patient outcomes could be explained by MIC profiling of CAZ/AVI. This method appears to be more robust than conventional susceptibility testing, and the clinical utility of this approach should be further investigated. Disclosures All Authors: No reported disclosures

scholarly journals Optimizing pharmacokinetics/pharmacodynamics of β-lactam/β-lactamase inhibitor combinations against high inocula of ESBL-producing bacteria

2020 ◽  
Vol 76 (1) ◽  
pp. 179-183 ◽  
Author(s):  
Vincent H Tam ◽  
Henrietta Abodakpi ◽  
Weiqun Wang ◽  
Kimberly R Ledesma ◽  
Paul R Merlau ◽  
...  
Keyword(s):  
Standard Dose ◽  
Recursive Partitioning ◽  
Hollow Fibre ◽  
Infection Model ◽  
Emax Model ◽  
Inoculum Effect ◽  
The Impact ◽  
Lactamase Inhibitor

Abstract Objectives Reduced in vitro β-lactam activity against a dense bacterial population is well recognized. It is commonly attributed to the presence of β-lactamase(s) and it is unknown whether the inoculum effect could be diminished by a β-lactamase inhibitor. We evaluated different β-lactam/β-lactamase inhibitor combinations in suppressing a high inoculum of ESBL-producing bacteria. Methods Three clinical isolates expressing representative ESBLs (CTX-M-15 and SHV-12) were examined. The impact of escalating β-lactamase inhibitor (tazobactam or avibactam) concentrations on β-lactam (piperacillin or ceftazidime) MIC reduction was characterized by an inhibitory sigmoid Emax model. The effect of various dosing regimens of β-lactam/β-lactamase inhibitor combinations was predicted using %T>MICi and selected exposures were experimentally validated in a hollow-fibre infection model over 120 h. The threshold exposure to suppress bacterial regrowth was identified using recursive partitioning. Results A concentration-dependent reduction in β-lactam MIC was observed (r2 ≥0.93). Regrowth could be suppressed in all six experiments using %T>MICi ≥73.6%, but only one out of six experiments below the threshold (P = 0.015). The exposures to suppress regrowth might be attained using the clinical dose of avibactam, but a much higher dose than the standard dose would be needed for tazobactam. Conclusions A dense population of ESBL-producing bacteria could be suppressed by an optimized dosing regimen of selected β-lactam/β-lactamase inhibitor combinations. The reversibility of enzyme inhibition could play an important role in diminishing the inoculum effect. In vivo investigations to validate these findings are warranted.

scholarly journals In Vitro and In Vivo Activity of AS101 against Carbapenem-Resistant Acinetobacter baumannii

2021 ◽  
Vol 14 (8) ◽  
pp. 823
Author(s):  
Tsung-Ying Yang ◽  
Sung-Pin Tseng ◽  
Heather Nokulunga Dlamini ◽  
Po-Liang Lu ◽  
Lin Lin ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Antibacterial Activities ◽  
Treated Group ◽  
Infection Model ◽  
High Dose ◽  
Mouse Infection Model ◽  
Carbapenem Resistant ◽  
Time Kill

The increasing trend of carbapenem-resistant Acinetobacter baumannii (CRAB) worldwide has become a concern, limiting therapeutic alternatives and increasing morbidity and mortality rates. The immunomodulation agent ammonium trichloro (dioxoethylene-O,O′-) tellurate (AS101) was repurposed as an antimicrobial agent against CRAB. Between 2016 and 2018, 27 CRAB clinical isolates were collected in Taiwan. The in vitro antibacterial activities of AS101 were evaluated using broth microdilution, time-kill assay, reactive oxygen species (ROS) detection and electron microscopy. In vivo effectiveness was assessed using a sepsis mouse infection model. The MIC range of AS101 for 27 CRAB isolates was from 0.5 to 32 µg/mL, which is below its 50% cytotoxicity (approximately 150 µg/mL). Bactericidal activity was confirmed using a time-kill assay. The antibacterial mechanism of AS101 was the accumulation of the ROS and the disruption of the cell membrane, which, in turn, results in cell death. The carbapenemase-producing A. baumannii mouse sepsis model showed that AS101 was a better therapeutic effect than colistin. The mice survival rate after 120 h was 33% (4/12) in the colistin-treated group and 58% (7/12) in the high-dose AS101 (3.33 mg/kg/day) group. Furthermore, high-dose AS101 significantly decreased bacterial population in the liver, kidney and spleen (all p < 0.001). These findings support the concept that AS101 is an ideal candidate for further testing in future studies.

scholarly journals Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

2013 ◽  
Vol 58 (2) ◽  
pp. 1005-1018 ◽  
Author(s):  
M. Agudelo ◽  
C. A. Rodriguez ◽  
C. A. Pelaez ◽  
O. Vesga
Keyword(s):  
Guinea Pig ◽  
Susceptibility Testing ◽  
Degradation Products ◽  
Active Pharmaceutical Ingredient ◽  
Infection Model ◽  
Content Type ◽  
Infection Models ◽  
Generic Products

ABSTRACTSeveral studies with animal models have demonstrated that bioequivalence of generic products of antibiotics like vancomycin, as currently defined, do not guarantee therapeutic equivalence. However, the amounts and characteristics of impurities and degradation products in these formulations do not violate the requirements of the U.S. Pharmacopeia (USP). Here, we provide experimental data with three generic products of meropenem that help in understanding how these apparently insignificant chemical differences affect thein vivoefficacy. Meropenem generics were compared with the innovatorin vitroby microbiological assay, susceptibility testing, and liquid chromatography/mass spectrometry (LC/MS) analysis andin vivowith the neutropenic guinea pig soleus infection model (Pseudomonas aeruginosa) and the neutropenic mouse thigh (P. aeruginosa), brain (P. aeruginosa), and lung (Klebisella pneumoniae) infection models, adding the dihydropeptidase I (DHP-I) inhibitor cilastatin in different proportions to the carbapenem. We found that the concentration and potency of the active pharmaceutical ingredient,in vitrosusceptibility testing, and mouse pharmacokinetics were identical for all products; however, two generics differed significantly from the innovator in the guinea pig and mouse models, while the third generic was therapeutically equivalent under all conditions. Trisodium adducts in a bioequivalent generic made it more susceptible to DHP-I hydrolysis and less stable at room temperature, explaining its therapeutic nonequivalence. We conclude that the therapeutic nonequivalence of generic products of meropenem is due to greater susceptibility to DHP-I hydrolysis. These failing generics are compliant with USP requirements and would remain undetectable under current regulations.

scholarly journals Assessment of the In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) against Carbapenem-Resistant Acinetobacter baumannii in the Neutropenic Murine Lung Infection Model

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Lindsay M. Avery ◽  
Kamilia Abdelraouf ◽  
David P. Nicolau
Keyword(s):  
Acinetobacter Baumannii ◽  
Lung Infection ◽  
Infection Model ◽  
Bacterial Burden ◽  
In Vivo Efficacy ◽  
Content Type ◽  
Murine Lung ◽  
Carbapenem Resistant ◽  
The Mean

ABSTRACT We evaluated the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) against cefepime-resistant Acinetobacter baumannii strains (n = 13) in the neutropenic murine lung infection model. Twelve isolates were meropenem resistant. In control animals and those that received cefepime or zidebactam alone, the mean bacterial growth at 24 h was >2 log10 CFU/lung compared with 0-h controls (6.32 ± 0.33 log10 CFU/lung). WCK 5222 produced a decline in the bacterial burden for all isolates (mean reduction, −3.34 ± 0.85 log10 CFU/lung) and demonstrated remarkable potency.

scholarly journals In VivoPharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Streptococcus suis Serotype 2 at Varied Initial Inoculum Sizes

2015 ◽  
Vol 60 (2) ◽  
pp. 1114-1120 ◽  
Author(s):  
Chunna Guo ◽  
Xiaoping Liao ◽  
Mingru Wang ◽  
Feng Wang ◽  
Chaoqun Yan ◽  
...  
Keyword(s):  
Severe Disease ◽  
Streptococcus Suis ◽  
Dose Fractionation ◽  
Fourth Generation ◽  
Maximum Effect ◽  
Infection Model ◽  
Human Beings ◽  
Content Type

ABSTRACTStreptococcus suisserotype 2 is an emerging zoonotic pathogen and causes severe disease in both pigs and human beings. Cefquinome (CEQ), a fourth-generation cephalosporin, exhibits broad-spectrum activity against Gram-positive bacteria such asS. suis. This study evaluated thein vitroandin vivoantimicrobial activities of CEQ against four strains ofS. suisserotype 2 in a murine neutropenic thigh infection model. We investigated the effect of varied inoculum sizes (106to 108CFU/thigh) on the pharmacokinetic (PK)/pharmacodynamic (PD) indices and magnitudes of a particular PK/PD index or dose required for efficacy. Dose fractionation studies included total CEQ doses ranging from 0.625 to 640 mg/kg/24 h. Data were analyzed via a maximum effect (Emax) model using nonlinear regression. The PK/PD studies demonstrated that the percentage of time that serum drug levels were above the MIC of free drug (%ƒT>MIC) in a 24-h dosing interval was the primary index driving the efficacy of both inoculum sizes (R2= 91% andR2= 63%). CEQ doses of 2.5 and 40 mg/kg body weight produced prolonged postantibiotic effects (PAEs) of 2.45 to 8.55 h. Inoculum sizes had a significant influence on CEQ efficacy. Compared to the CEQ exposure and dosages in tests using standard inocula, a 4-fold dose (P= 0.006) and a 2-fold exposure time (P= 0.01) were required for a 1-log kill using large inocula of 108CFU/thigh.

scholarly journals Pharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Staphylococcus aureus Infection

2014 ◽  
Vol 58 (6) ◽  
pp. 3008-3012 ◽  
Author(s):  
Jing Wang ◽  
Qi Shan ◽  
Huanzhong Ding ◽  
Chaoping Liang ◽  
Zhenling Zeng
Keyword(s):  
Staphylococcus Aureus ◽  
Body Weight ◽  
Maximum Effect ◽  
Infection Model ◽  
Content Type ◽  
Chromatography Tandem Mass Spectrometry ◽  
Attractive Option ◽  
Liquid Chromatography Tandem Mass ◽  
Dosing Strategy

ABSTRACTCefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity againstStaphylococcus aureus. The objective of our study was to examine thein vivoactivity of cefquinome againstS. aureusstrains by using a neutropenic mouse thigh infection model. Cefquinome kinetics and protein binding in infected neutropenic mice were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS).In vivopostantibiotic effects (PAEs) were determined after a dose of 100 mg/kg of body weight in mice infected withS. aureusstrain ATCC 29213. The animals were treated by subcutaneous injection of cefquinome at doses of 2.5 to 320 mg/kg of body weight per day divided into 1, 2, 3, 6, or 12 doses over 24 h. Cefquinome exhibited time-dependent killing and producedin vivoPAEs at 2.9 h. The percentage of time that serum concentrations were above the MIC (%T>MIC) was the pharmacokinetic-pharmacodynamic (PK-PD) index that best described the efficacy of cefquinome. Subsequently, we employed a similar dosing strategy by using increasing total cefquinome doses that increased 4-fold and were administered every 4 h to treat animals infected with six additionalS. aureusisolates. A sigmoid maximum effect (Emax) model was used to estimate the magnitudes of the ratios of the %Tthat the free-drug serum concentration exceeded the MIC (%T>fMIC) associated with net bacterial stasis, a 0.5-log10CFU reduction from baseline, and a 1-log10CFU reduction from baseline; the respective values were 30.28 to 36.84%, 34.38 to 46.70%, and 43.50 to 54.01%. The clear PAEs and potent bactericidal activity make cefquinome an attractive option for the treatment of infections caused byS. aureus.

scholarly journals 1299. In Vitro-In Vivo Discordance with β-lactams against Metallo-β-lactamase-Producing Enterobacterales: Implications for Susceptibility Testing

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S664-S664
Author(s):  
Kamilia Abdelraouf ◽  
Sergio Reyes ◽  
David P Nicolau
Keyword(s):  
Susceptibility Testing ◽  
Infection Model ◽  
Research Support ◽  
In Vitro Susceptibility ◽  
Fold Reduction ◽  
Testing Medium ◽  
Zinc Concentrations ◽  
In Vitro Susceptibility Testing

Abstract Background Using murine models of thigh and lung infection, we previously reported the potent in vivo activity of carbapenem human-simulated regimens against metallo-β-lactamase-producing Enterobacterales despite the observed resistance in vitro (JAC 2020 Apr 1;75(4):997-1005, AAC 2014;58(3):1671-7). In the current study, we examined the in vivo activity of cefepime human-simulated regimen against metallo-β-lactamase-producing Enterobacterales in a murine thigh infection model. Methods A population of clinical (n=21) and isogenic engineered (n=5) metallo-β-lactamase-producing Enterobacterales isolates expressing VIM, IMP or NDM but not co-expressing ESBLs or serine carbapenemases were utilized. KPC-producing strains (n=3) were included as positive controls. MICs of cefepime, piperacillin-tazobactam and meropenem were determined using broth microdilution in conventional cation-adjusted Muller Hinton and EDTA-supplemented broth at EDTA concentration of 300 mg/L (zinc-limited). The in vivo efficacy of a cefepime human-simulated regimen (2 g q8h as 2 h infusion) was determined in the neutropenic murine thigh infection model against the test isolates. Efficacy was measured as the change in log10cfu/thigh at 24 h compared with 0 h controls. Results Metallo-β-lactamase-producing Enterobacterales were found to be cefepime, piperacillin-tazobactam and meropenem non-susceptible in conventional broth. Supplementation with EDTA resulted in multi-fold reduction in the MICs and restoration of susceptibility. In accordance with the MICs generated in the zinc-limited broth, the administration of cefepime human-simulated regimen was associated with substantial bacterial reductions among mice infected with the clinical as well as the isogenic engineered metallo-β-lactamase-producing isolates. As anticipated with serine-based resistance, absence of MIC reduction in zinc-limited broth and lack of in vivo activity against KPC-producers were observed. Conclusion For metallo-β-lactamase-producing Enterobacterales, in vitro susceptibility testing to β-lactams with conventional media such as cation-adjusted Muller Hinton broth, a zinc-rich testing medium, is flawed since it does not recapitulate the host environment in which zinc concentrations are low. Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

scholarly journals Pharmacodynamics of Isavuconazole in an Aspergillus fumigatus Mouse Infection Model

2015 ◽  
Vol 59 (5) ◽  
pp. 2855-2866 ◽  
Author(s):  
Seyedmojtaba Seyedmousavi ◽  
Roger J. M. Brüggemann ◽  
Jacques F. Meis ◽  
Willem J. G. Melchers ◽  
Paul E. Verweij ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Drug Exposure ◽  
Quantitative Relationship ◽  
Maximum Effect ◽  
Infection Model ◽  
Wild Type ◽  
Content Type ◽  
Type Isolate ◽  
Mouse Infection Model

ABSTRACTAzole resistance is an emerging problem inAspergillus fumigatuswhich translates into treatment failure. Alternative treatments with new azoles may improve therapeutic outcome in invasive aspergillosis (IA) even for strains with decreased susceptibility to current azoles. Thein vivoefficacy of 0.25, 1, 4, 16, 64, 128, 256, and 512 mg/kg of body weight/day prodrug isavuconazonium sulfate (BAL8557) (isavuconazole [ISA]-equivalent doses of 0.12, 0.48, 1.92, 7.68, 30.7, 61.4, 122.9, and 245.8 mg/kg/day, respectively) administered by oral gavage was assessed in an immunocompetent murine model of IA against four clinicalA. fumigatusisolates: a wild-type isolate (ISA MICEUCAST, 0.5 mg/liter) and three azole-resistant isolates harboring substitutions in thecyp51Agene: G54W (ISA MICEUCAST, 0.5 mg/liter), M220I (ISA MICEUCAST, 4 mg/liter), and TR34/L98H (ISA MICEUCAST, 8 mg/liter). The maximum effect (100% survival) was reached at a prodrug isavuconazonium sulfate dose of 64 mg/kg for the wild-type isolate, 128 mg/kg for the G54W mutant, and 256 mg/kg two times per day (q12) for the M220I mutant. A maximum response was not achieved with the TR34/L98H isolates with the highest dose of prodrug isavuconazonium sulfate (256 mg/kg q12). For a survival rate of 50%, the effective AUC0–24/MICEUCASTratio for ISA total drug was 24.73 (95% confidence interval, 22.50 to 27.18). The efficacy of isavuconazole depended on both the drug exposure and the isavuconazole MIC of the isolates. The quantitative relationship between exposure and effect (AUC0–24/MIC) can be used to optimize the treatment of human infections byA. fumigatus, including strains with decreased susceptibility.

scholarly journals Restoring carbapenem efficacy: a novel carbapenem companion targeting metallo-β-lactamases in carbapenem-resistant Enterobacterales

2020 ◽  
Author(s):  
Nicola Ooi ◽  
Victoria E Lee ◽  
Nathan Chalam-Judge ◽  
Rebecca Newman ◽  
Andrew J Wilkinson ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Coli Strain ◽  
Infection Model ◽  
Enzyme Assays ◽  
In Vivo Efficacy ◽  
Carbapenem Resistant ◽  
Life Threatening ◽  
Effective Use ◽  
Time Kill

Abstract Background The dissemination of MBLs compromises effective use of many β-lactams in the treatment of patients with life-threatening bacterial infections. Predicted global increases in the prevalence of MBL-producing carbapenem-resistant Enterobacterales (CRE) are being realized, yielding infections that are untreatable with existing therapies including newly approved β-lactam/β-lactamase inhibitor combinations. Developing MBL inhibitors (MBLIs) now is essential to address the growing threat that MBL-producing CRE pose to patients. Methods A novel MBLI series was assessed by susceptibility testing and time–kill assays. Target activity and selectivity was evaluated using bacterial NDM, VIM and IMP enzyme assays and human matrix metallopeptidase enzyme assays, respectively, and cytotoxicity was assessed in HepG2 cells. In vivo efficacy of meropenem/MBLI combinations was evaluated in a mouse thigh infection model using an NDM-1-producing Escherichia coli strain. Results Combination of MBLIs with carbapenems reduced MICs for NDM/IMP/VIM-producing Enterobacterales by up to 128-fold compared with the carbapenems alone. Supplementation of meropenem with the promising compound 272 reduced the MIC90 from 128 to 0.25 mg/L in a panel of MBL-producing CRE clinical isolates (n = 115). Compound 272 restored the bactericidal activity of meropenem and was non-cytotoxic, potentiating the antimicrobial action of meropenem through specific inhibition of NDM, IMP and VIM. In vivo efficacy was achieved in a mouse thigh infection model with meropenem/272 dosed subcutaneously. Conclusions We have developed a series of rationally designed MBLIs that restore activity of carbapenems against NDM/IMP/VIM-producing Enterobacterales. This series warrants further development towards a novel combination therapy that combats antibiotic-resistant organisms, which pose a critical threat to human health.

scholarly journals The antimicrobial peptide ZY4 combats multidrug-resistantPseudomonas aeruginosaandAcinetobacter baumanniiinfection

2019 ◽  
Vol 116 (52) ◽  
pp. 26516-26522 ◽  
Author(s):  
James Mwangi ◽  
Yizhu Yin ◽  
Gan Wang ◽  
Min Yang ◽  
Ya Li ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Cyclic Peptide ◽  
Disulfide Bridge ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Biofilm Inhibition ◽  
Carbapenem Resistant ◽  
Target Organs ◽  
Induce Resistance

The emergence of carbapenem-resistantAcinetobacter baumanniiandPseudomonas aeruginosaraises fears of untreatable infections and poses the greatest health threats. Antimicrobial peptides (AMPs) are regarded as the most ideal solution to this menace. In this study, a set of peptides was designed based on our previously reported peptide cathelicidin-BF-15, and the lead peptide ZY4, a cyclic peptide stabilized by a disulfide bridge with high stability in vivo (the half-life is 1.8 h), showed excellent activity againstP. aeruginosaandA. baumannii, including standard and clinical multidrug-resistant (MDR) strains. ZY4 killed bacteria by permeabilizing the bacterial membrane and showed low propensity to induce resistance, exhibited biofilm inhibition and eradication activities, and also killed persister cells. Notably, administration of ZY4 decreased susceptibility to lung infection byP. aeruginosaand suppressed dissemination ofP. aeruginosaandA. baumanniito target organs in a mouse septicemia infection model. These findings identify ZY4 as an ideal candidate against MDR bacterial infections.

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