A novel mechanism-based pharmacokinetic–pharmacodynamic (PKPD) model describing ceftazidime/avibactam efficacy against β-lactamase-producing Gram-negative bacteria

2019 ◽  
Author(s):  
Anders N Kristoffersson ◽  
Caterina Bissantz ◽  
Rusudan Okujava ◽  
Andreas Haldimann ◽  
Isabelle Walter ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Dose Finding ◽  
Gram Negative Bacteria ◽  
Data Set ◽  
Gram Negative ◽  
Pkpd Model ◽  
Index Approach ◽  
Antibiotic Effect ◽  
Time Kill

Abstract Background Diazabicyclooctanes (DBOs) are an increasingly important group of non β-lactam β-lactamase inhibitors, employed clinically in combinations such as ceftazidime/avibactam. The dose finding of such combinations is complicated using the traditional pharmacokinetic/pharmacodynamic (PK/PD) index approach, especially if the β-lactamase inhibitor has an antibiotic effect of its own. Objectives To develop a novel mechanism-based pharmacokinetic–pharmacodynamic (PKPD) model for ceftazidime/avibactam against Gram-negative pathogens, with the potential for combination dosage simulation. Methods Four β-lactamase-producing Enterobacteriaceae, covering Ambler classes A, B and D, were exposed to ceftazidime and avibactam, alone and in combination, in static time–kill experiments. A PKPD model was developed and evaluated using internal and external evaluation, and combined with a population PK model and applied in dosage simulations. Results The developed PKPD model included the effects of ceftazidime alone, avibactam alone and an ‘enhancer’ effect of avibactam on ceftazidime in addition to the β-lactamase inhibitory effect of avibactam. The model could describe an extensive external Pseudomonas aeruginosa data set with minor modifications to the enhancer effect, and the utility of the model for clinical dosage simulation was demonstrated by investigating the influence of the addition of avibactam. Conclusions A novel mechanism-based PKPD model for the DBO/β-lactam combination ceftazidime/avibactam was developed that enables future comparison of the effect of avibactam with other DBO/β-lactam inhibitors in simulations, and may be an aid in translating PKPD results from in vitro to animals and humans.

scholarly journals Chemical Composition and in Vitro Antibacterial Activity of the Essential Oil of Minthostachys Mollis (Kunth) Griseb Vaught from the Venezuelan Andes

2009 ◽  
Vol 4 (7) ◽  
pp. 1934578X0900400 ◽  
Author(s):  
Flor D. Mora ◽  
María Araque ◽  
Luis B. Rojas ◽  
Rosslyn Ramírez ◽  
Bladimiro Silva ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Essential Oil ◽  
Chemical Constituents ◽  
Salmonella Typhi ◽  
Inhibitory Effect ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Significant Inhibitory Effect ◽  
In Vitro Antibacterial Activity

Chemical constituents of the essential oil from the leaves of Minthostachys mollis (Kunth) Griseb Vaught var. mollis collected in January 2008 at Tuñame, Trujillo State, Venezuela, were separated and identified by GCMS analysis. The essential oil was obtained by hydrodistillation and thirteen components (98.5% of the sample) were identified by comparison with the Wiley GCMS library data base. The two major components were pulegone (55.2%) and trans-menthone (31.5%). The essential oil showed a significant inhibitory effect against Gram-positive and Gram-negative bacteria, especially Bacillus subtilis and Salmonella typhi (4 μg/mL).

scholarly journals In Vitro Anti-Helicobacter pyloriActivities of New Rifamycin Derivatives, KRM-1648 and KRM-1657

1999 ◽  
Vol 43 (5) ◽  
pp. 1072-1076 ◽  
Author(s):  
Junko K. Akada ◽  
Mutsunori Shirai ◽  
Kenji Fujii ◽  
Kiwamu Okita ◽  
Teruko Nakazawa
Keyword(s):  
Helicobacter Pylori ◽  
Cell Lysis ◽  
Antimicrobial Activities ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Bactericidal Activities ◽  
H Pylori ◽  
Time Kill

ABSTRACT The new rifamycin derivatives KRM-1657 and KRM-1648 were evaluated for their in vitro antimicrobial activities against 44 strains ofHelicobacter pylori. Although the drugs were not very active against other gram-negative bacteria, the MICs at which 90% of isolates are inhibited for these drugs were lower (0.002 and 0.008 μg/ml, respectively) than those of amoxicillin and rifampin forH. pylori. Time-kill studies revealed that the bactericidal activities of these agents were due to cell lysis. The results presented here indicate that these new rifamycin derivatives may be useful for the eradication of H. pylori infections.

scholarly journals Elimination of Extracellular Adenosine Triphosphate for the Rapid Prediction of Quantitative Plate Counts in 24 h Time-Kill Studies against Carbapenem-Resistant Gram-Negative Bacteria

2020 ◽  
Vol 8 (10) ◽  
pp. 1489
Author(s):  
Yiying Cai ◽  
Jonathan J. Ng ◽  
Hui Leck ◽  
Jocelyn Q. Teo ◽  
Jia-Xuan Goh ◽  
...  
Keyword(s):  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Infection Models ◽  
Rapid Prediction ◽  
Atp Bioluminescence ◽  
Plate Counts ◽  
Time Kill

Traditional in vitro time-kill studies (TKSs) require viable plating, which is tedious and time-consuming. We used ATP bioluminescence, with the removal of extracellular ATP (EC-ATP), as a surrogate for viable plating in TKSs against carbapenem-resistant Gram-negative bacteria (CR-GNB). Twenty-four-hour TKSs were conducted using eight clinical CR-GNB (two Escherichia coli, two Klebsiella spp., two Acinetobacter baumannii, two Pseudomonas aeruginosa) with multiple single and two-antibiotic combinations. ATP bioluminescence and viable counts were determined at each timepoint (0, 2, 4, 8, 24 h), with and without apyrase treatment. Correlation between ATP bioluminescence and viable counts was determined for apyrase-treated and non-apyrase-treated samples. Receiver operator characteristic curves were plotted to determine the optimal luminescence threshold to discriminate between inhibitory/non-inhibitory and bactericidal/non-bactericidal combinations, compared to viable counts. After treatment of bacteria with 2 U/mL apyrase for 15 min at 37 °C, correlation to viable counts was significantly higher compared to untreated samples (p < 0.01). Predictive accuracies of ATP bioluminescence were also significantly higher for apyrase-treated samples in distinguishing inhibitory (p < 0.01) and bactericidal (p = 0.03) combinations against CR-GNB compared to untreated samples, when all species were collectively analyzed. We found that ATP bioluminescence can potentially replace viable plating in TKS. Our assay also has applications in in vitro and in vivo infection models.

scholarly journals In Vitro Activities of ME1036 (CP5609), a Novel Parenteral Carbapenem, against Methicillin-Resistant Staphylococci

2004 ◽  
Vol 48 (8) ◽  
pp. 2831-2837 ◽  
Author(s):  
Mizuyo Kurazono ◽  
Takashi Ida ◽  
Keiko Yamada ◽  
Yoko Hirai ◽  
Takahisa Maruyama ◽  
...  
Keyword(s):  
Multiple Drug ◽  
Gram Negative Bacteria ◽  
Coagulase Negative Staphylococci ◽  
Gram Positive ◽  
Gram Negative ◽  
Methicillin Resistant ◽  
Gram Positive Bacteria ◽  
Multiple Drug Resistant ◽  
Time Kill

ABSTRACT ME1036, formerly CP5609, is a novel parenteral carbapenem with a 7-acylated imidazo[5,1-b]thiazole-2-yl group directly attached to the carbapenem moiety of the C-2 position. The present study evaluated the in vitro activities of ME1036 against clinical isolates of gram-positive and gram-negative bacteria. ME1036 displayed broad activity against aerobic gram-positive and gram-negative bacteria. Unlike other marketed β-lactam antibiotics, ME1036 maintained excellent activity against multiple-drug-resistant gram-positive bacteria, such as methicillin-resistant staphylococci and penicillin-resistant Streptococcus pneumoniae (PRSP). The MICs of this compound at which 90% of isolates were inhibited were 2 μg/ml for methicillin-resistant Staphylococcus aureus (MRSA), 2 μg/ml for methicillin-resistant coagulase-negative staphylococci, and 0.031 μg/ml for PRSP. In time-kill studies with six strains of MRSA, ME1036 at four times the MIC caused a time-dependent decrease in the numbers of viable MRSA cells. The activity of ME1036 against MRSA is related to its high affinity for penicillin-binding protein 2a, for which the 50% inhibitory concentration of ME1036 was approximately 300-fold lower than that of imipenem. In conclusion, ME1036 demonstrated a broad antibacterial spectrum and high levels of activity in vitro against staphylococci, including β-lactam-resistant strains.

scholarly journals DAYA HAMBAT JUS APEL MANALAGI (MALUS SYLVESTRIS) TERHADAP PERTUMBUHAN BAKTERI PORPHYROMONAS GINGIVALIS SECARA IN-VITRO

2018 ◽  
Vol 6 (2) ◽  
pp. 87-92
Author(s):  
Enda Markus Aginta Sembiring ◽  
Yufri Aldi ◽  
Susi Susi
Keyword(s):  
Alveolar Bone ◽  
Inhibitory Effect ◽  
Innate Immune ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Malus Sylvestris ◽  
Experimental Laboratory ◽  
Herbal Plants ◽  
One Way Anova

Background: Periodontitis are one of teeth and mouth disease with prevalence is 50% of adult. Periodontitis is an inflammatory condition that cause damage to connective tissue and alveolar bone. Porphyromonas ginggivalis is one of anaerob gram-negative bacteria that cause periodontitis, these bacteria can withstand host’s defenses mechanism by utilizing a virulence factor panel that cause derived innate immune and inflamatory responses. Apple Manalagi or known as apple Malang is one of the herbal plants in Indonesia. Some studies represented inhibitory effect for bacteria from its substance. Objective:  The objective of this study were to determine inhibitory effect of apple manalagi (Malus sylvestris) for Porphyromonas ginggivalis. Method: Experimental laboratory. In this study Apple Manalagi will be Juiced, Juice Apple Manalagi will divide by 4 concentrate 25%, 50%, 75% and 100%. This study use diluusion method, juice apple Manalagi will aplicated to 5 samples agar MHA for 5 times. The inhibitory effect will calculated with sliding calipers, and then data will process with one way anova. Result: The result didn’t show any inhibision zone in MHA to Porphyromonas ginggivalis so data analysis cann’t be done. Conclusion: Apple Manalagi doesn’t have inhibitory effect for Porphyromonas ginggivalis.

scholarly journals A Hydrogel-Based in Vitro Assay for the Fast Prediction of Antibiotic Accumulation in Gram-Negative Bacteria

2020 ◽  
Author(s):  
Robert Richter ◽  
Mohamed Ashraf M. Kamal ◽  
Mariel A. García-Rivera ◽  
Jerome Kaspar ◽  
Maximilian Junk ◽  
...  
Keyword(s):  
Potato Starch ◽  
Freeze Fracture ◽  
Structural Features ◽  
Projection Area ◽  
Gram Negative Bacteria ◽  
Data Set ◽  
Vitro Assay ◽  
Gram Negative ◽  
Fast Prediction

The pipeline of antibiotics has been for decades on an alarmingly low level. Considering the steadily emerging antibiotic resistance, novel tools are needed for early and easy identification of effective anti-infective compounds. In Gram-negative bacteria, the uptake of anti-infectives is especially limited. We here present a surprisingly simple in vitro model of the Gram-negative bacterial envelope, based on 20% (w/v) potato starch gel, printed on polycarbonate 96-well filter membranes. Rapid permeability measurements across this polysaccharide hydrogel allowed to correctly predict either high or low accumulation for all 16 tested anti-infectives in living E. coli. Freeze-fracture TEM supports that the macromolecular network structure of the starch hydrogel may represent a useful surrogate of the Gram-negative bacterial envelope. Machine learning by random forest analysis of in vitro data revealed minimum projection area, molecular mass, and rigidity as the most critical physicochemical parameters for hydrogel permeability, in agreement with reported structural features needed for uptake into Gram-negative bacteria. Correlating our data set of 27 antibiotics from different structural classes to reported MIC values of seven clinically relevant pathogens allowed to distinguish active from non-active compounds based on their low in vitro permeability and in particular to identify poorly permeable antimicrobial candidates before testing them on living bacteria.<br>

scholarly journals Comparison of methods for detection of in vitro synergy in multidrug-resistant Gram-negative bacteria

2019 ◽  
Author(s):  
Juliana Januario Gaudereto ◽  
Lauro Vieira Perdigão Neto ◽  
Gleice Cristina Leite ◽  
Evelyn Sanchez ◽  
Roberta Ruedas Martins ◽  
...  
Keyword(s):  
Gold Standard ◽  
Clinical Microbiology ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Comparison Of Methods ◽  
Large Collection ◽  
Gold Standard Method ◽  
Gram Negative ◽  
Time Kill

Abstract The use of combined antibiotic therapy has became an option for infections caused by multidrug-resistant (MDR) bacteria. Time-kill (TK) assay is the gold standard method for evaluation of in vitro synergy; however, it is a time consuming and expensive method. The purpose of this study was to evaluate in vitro synergy using ETEST and disk diffusion methods that can be used routinely in clinical microbiology laboratories. Sixty-two MDR Gram-negative clinical isolates (28 Pseudomonas aeruginosa, 20 Acinetobacter baumannii and 14 Serratia marcescens) were submitted to TK, disk approximation (DA) and MIC:MIC ratio synergy methods. Overall, the agreement between the DA and TK assays for P. aeruginosa and S. marcescens isolates ranged from 57 to 93%. MIC:MIC ratio concordance with TK ranged from 57 to 71%. The best agreement with the TK assay was observed using DA method for A. baumannii isolates for the combination of fosfomycin with meropenem (80%; k= 0,60; P= 0,003). The concordance was also higher for combinations with colistin for colistin-resistant A. baumannii isolates by DA and MIC:MIC ratio methods. The DA and MIC:MIC ratio methods are easier to perform and may be a more viable tool for clinical microbiology laboratories. Moreover, more studies with large collection of strains are needed to evaluate these assays.

scholarly journals In Vitro Antibacterial Activities of AF 3013, the Active Metabolite of Prulifloxacin, against Nosocomial and Community Italian Isolates

2001 ◽  
Vol 45 (12) ◽  
pp. 3616-3622 ◽  
Author(s):  
Maria Pia Montanari ◽  
Marina Mingoia ◽  
Pietro Emanuele Varaldo
Keyword(s):  
Bactericidal Activity ◽  
Active Metabolite ◽  
Antibacterial Activities ◽  
Minimal Bactericidal Concentration ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Bactericidal Activities ◽  
Time Kill

ABSTRACT AF 3013, the active metabolite of prulifloxacin, was tested to determine its inhibitory and bactericidal activities against 396 nosocomial and 258 community Italian isolates. Compared with that of ciprofloxacin, its activity (assessed in MIC and minimal bactericidal concentration tests) was generally similar or greater against gram-positive bacteria and greater against gram-negative bacteria. In time-kill assays using selected isolates, its bactericidal activity was comparable to that of ciprofloxacin.

scholarly journals In Vitro and In Vivo Activities of Novel 2-(Thiazol-2-ylthio)-1β-Methylcarbapenems with Potent Activities against Multiresistant Gram-Positive Bacteria

2003 ◽  
Vol 47 (8) ◽  
pp. 2471-2480 ◽  
Author(s):  
Yutaka Ueda ◽  
Makoto Sunagawa
Keyword(s):  
Bactericidal Activity ◽  
Bacterial Infections ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Log Reduction ◽  
Highly Active ◽  
Time Kill

ABSTRACT SM-197436, SM-232721, and SM-232724 are new 1β-methylcarbapenems with a unique 4-substituted thiazol-2-ylthio moiety at the C-2 side chain. In agar dilution susceptibility testing these novel carbapenems were active against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) with a MIC90 of ≤4 μg/ml. Furthermore, SM-232724 showed strong bactericidal activity against MRSA, in contrast to linezolid, which was bacteriostatic up to four times the MIC. SM-232724 showed good therapeutic efficacy comparable to those of vancomycin and linezolid against systemic infections of MRSA in cyclophosphamide-treated mice. The MICs of SM-197436, SM-232721, and SM-232724 for streptococci, including penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae strains, ranged from ≤0.063 to 0.5 μg/ml. These drugs were the most active β-lactams tested against Enterococcus faecium, and the MIC90 s for ampicillin-resistant E. faecium ranged between 8 and 16 μg/ml, which were slightly higher than the value for linezolid. However, time-kill assays revealed the superior bactericidal activity of SM-232724 compared to those of quinupristin-dalfopristin and linezolid against an E. faecium strain with a 4-log reduction in CFU at four times the MIC after 24 h of exposure to antibiotics. In addition, SM-232724 significantly reduced the numbers of bacteria in a murine abscess model with the E. faecium strain: its efficacy was superior to that of linezolid, although the MICs (2 μg/ml) of these two agents are the same. Among gram-negative bacteria, these three carbapenems were highly active against Haemophilus influenzae (including ampicillin-resistant strains), Moraxella catarrhalis, and Bacteroides fragilis, and showed antibacterial activity equivalent to that of imipenem for Escherichia coli, Klebsiella pneumoniae, and Proteus spp. Thus, these new carbapenems are promising candidates for agents to treat nosocomial bacterial infections by gram-positive and gram-negative bacteria, especially multiresistant gram-positive cocci, including MRSA and vancomycin-resistant enterococci.

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