scholarly journals In VitroSynergistic Effect of Curcumin in Combination with Third Generation Cephalosporins against Bacteria Associated with Infectious Diarrhea

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Nishanth Kumar Sasidharan ◽  
Sreerag Ravikumar Sreekala ◽  
Jubi Jacob ◽  
Bala Nambisan
Keyword(s):  
Synergistic Effect ◽  
New Combination ◽  
Normal Fibroblast ◽  
Infectious Diarrhea ◽  
Combination Drug ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Time Kill ◽  
Third Generation Cephalosporins

Diarrhea is one of the leading causes of morbidity and mortality in humans in developed and developing countries. Furthermore, increased resistance to antibiotics has resulted in serious challenges in the treatment of this infectious disease worldwide. Therefore, there exists a need to develop alternative natural or combination drug therapies. The aim of the present study was to investigate the synergistic effect of curcumin-1 in combination with three antibiotics against five diarrhea causing bacteria. The antibacterial activity of curcumin-1 and antibiotics was assessed by the broth microdilution method, checkerboard dilution test, and time-kill assay. Antimicrobial activity of curcumin-1 was observed against all tested strains. The MICs of curcumin-1 against test bacteria ranged from 125 to 1000 μg/mL. In the checkerboard test, curcumin-1 markedly reduced the MICs of the antibiotics cefaclor, cefodizime, and cefotaxime. Significant synergistic effect was recorded by curcumin-1 in combination with cefotaxime. The toxicity of curcumin-1 with and without antibiotics was tested against foreskin (FS) normal fibroblast and no significant cytotoxicity was observed. From our result it is evident that curcumin-1 enhances the antibiotic potentials against diarrhea causing bacteria inin vitrocondition. This study suggested that curcumin-1 in combination with antibiotics could lead to the development of new combination of antibiotics against diarrhea causing bacteria.

In vitro activity of antimicrobial agents with and without sulbactam, EDTA and sulbactam-EDTA on ESBLs-producing Escherichia coli isolated from healthy Tibetan yaks

2020 ◽  
Author(s):  
Baoguang Liu ◽  
Xiaoling Yuan ◽  
Yiheng Chen ◽  
Xiaoshen Li ◽  
Ming Bai ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Nasal Swab ◽  
Antimicrobial Agents ◽  
Synergistic Effects ◽  
E Coli ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Third Generation Cephalosporins ◽  
Enhance Activity

Abstract Background The spread of ESBLs-producing bacteria has been strikingly rapid in many regions of the world and it causes therapeutic difficulties in everyday practice. The aims of this study were to investigate the prevalence and susceptibilities of ESBLs-producing Escherichia coli isolates from healthy Tibetan yaks in China, to evaluate the activity of drug combinations on ESBLs-producing E. coli isolates. Methods From July 2018 to August 2019, a total of 750 nasal swab samples were tested for the presence of E. coli and ESBLs-producing strains. The MICs of 11 antimicrobial agents alone and combinations with sulbactam, EDTA or sulbactam-EDTA against 240 ESBLs-producing E.coli strains were determined by the broth microdilution method. Results Overall, 59.87% (n = 449) of the samples were positive for E. coli, 240 (53.45%) of 449 E. coli isolates were confirmed to be ESBLs-producing. The addition of sulbactam to the third generation cephalosporins, amikacin and fosfomycin for all isolates resulted in low MICs, increasing the level of susceptibility from 0, 0 and 0% to 50 ~ 87.5, 4.2 and 100% respectively. The addition of EDTA to fluoroquinolones, doxycycline, florfenicol, amikacin and fosfomycin, showed improved activities and resulted in low MICs, increasing the level of susceptibility from 0, 0, 8.3, 0 and 0% to 4.2 ~ 29.2, 33.3, 33.3, 66.7 and 45.8%, respectively. All other antibacterials (except fluoroquinolones, doxycycline and florfenicol), when combined with sulbactam-EDTA, were found to be more active than combinations only with sulbactam or with EDTA against most of isolates, with lower MIC50s and MIC90s. Conclusion In conclusion, ESBLs-producing E. coli isolates were widespread in healthy Tibetan yaks in China. ESBLs-producing E. coli isolates exhibited varying degrees of multidrug resistance. This study these findings suggested that sulbactam can enhance activity of β-lactams and some non-β-lactams of antimicrobial agents and had a synergistic effects with EDTA in improving activities of some families of antimicrobials.

Evaluation of the in vitro interaction of fosfomycin and meropenem against metallo-β-lactamase–producing Pseudomonas aeruginosa using Etest and time-kill assay

2020 ◽  
pp. jim-2020-001573
Author(s):  
Sanjida Jahan ◽  
Heather Davis ◽  
Deborah S Ashcraft ◽  
George A Pankey
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inhibitory Concentration ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Time Kill ◽  
In Vitro Interaction ◽  
Antimicrobial Combinations

Pseudomonas aeruginosa is a nosocomial pathogen containing various resistance mechanisms. Among them, metallo-β-lactamase (MBL)–producing Pseudomonas are difficult to treat. Fosfomycin is an older antibiotic that has recently seen increased usage due to its activity against a broad spectrum of multidrug-resistant organisms. Our aim was to evaluate the combination of fosfomycin and meropenem against 20 MBL-producing P. aeruginosa (100% meropenem-resistant and 20% fosfomycin-resistant) using both an Etest minimal inhibitory concentration (MIC): MIC method and time-kill assay. MICs for fosfomycin and meropenem were determined by Etest and by broth microdilution method for the latter. The combination demonstrated synergy by Etest in 3/20 (15%) isolates and 5/20 (25%) isolates by time-kill assay. Results from the Etest method and time-kill assay were in agreement for 14/20 (70%) of isolates. No antagonism was found. Comparing both methods, Etest MIC: MIC method may be useful to rapidly evaluate other antimicrobial combinations.

scholarly journals In vitro efficacy of vancomycin combined with fosfomycin against Vancomycin-Resistant Enterococci strains

2019 ◽  
Vol 36 (2) ◽  
Author(s):  
Gulseren Aktas
Keyword(s):  
Inhibitory Concentration ◽  
Distinct Advantage ◽  
Creative Commons ◽  
Microdilution Method ◽  
Vancomycin Resistant Enterococci ◽  
Broth Microdilution Method ◽  
Vancomycin Resistant ◽  
Time Kill ◽  
Open Access Article

Objective: Enterococci have been isolated frequently worldwide and have difficulties in the treatment. Combination antibiotherapies have a distinct advantage over monotherapies in terms of their synergistic effect. In the study, it was aimed to investigate in vitro activity of vancomycin combined with fosfomycin against VRE strains. Methods: A total of 30 VRE strains were included in the study. Bacterial identifications of the strains were undertaken using conventional routine methods. The resistance to agents tested was investigated by using the broth microdilution method. Glucose-6-phosphate (25 mcg/mL) for fosfomycin were used in all experiments. The activity of antibiotics in combination was assessed using a broth microcheckerboard. The fractional inhibitory concentration index (FICI) was interpreted as follows: synergism, FICI ≤0.5. Additionally, two strains in 30 VRE were studied to determine the time-kill curves to verify the synergistic results. For each strain, antibiotics were studied alone and in combination at the minimum inhibitory concentration (1xMIC) values. Results: Susceptibility rate to fosfomycin was found at 26.6 % (8/30). The MIC50, MIC90 and MIC interval values of antimicrobials were 512, 512, and 512 - 1024 mcg/mL for vancomycin, and 128, 160, and 64 - 224 mcg/mL for fosfomycin, respectively. The rate of synergism was found as 100 % by both checkerboard and time-kill methods. Conclusion: The result shows that the combination of vancomycin with fosfomycin could be an alternative in the treatment of infections caused by VRE. doi: https://doi.org/10.12669/pjms.36.2.1347 How to cite this:Aktas G. In vitro efficacy of vancomycin combined with fosfomycin against Vancomycin-Resistant Enterococci strains. Pak J Med Sci. 2020;36(2):281-285. doi: https://doi.org/10.12669/pjms.36.2.1347 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

scholarly journals Combination of Epicatechin 3-Gallate from Euphorbia hirta and Cefepime Promotes Potential Synergistic Eradication Action against Resistant Clinical Isolate of Pseudomonas aeruginosa

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Shanmugapriya Perumal ◽  
Roziahanim Mahmud ◽  
Nornisah Mohamed
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Bacterial Infections ◽  
Membrane Damage ◽  
Scanning Electron Micrographs ◽  
Euphorbia Hirta ◽  
Cell Membrane Damage ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Time Kill

Pseudomonas aeruginosa is naturally resistant to many classes of antipseudomonal antibiotics due to the species ability to easily acquire resistance. Plant-based antibacterial agent in combination with the existing antibiotic proposes an alternative treatment regimen for the eradication of resistant bacterial infections. The antibacterial effects of the isolated epicatechin 3-gallate compound from Euphorbia hirta in combination with cefepime were investigated in vitro against resistant P. aeruginosa. The fractional inhibitory concentration index of the combination was determined using checkerboard broth microdilution method. Epicatechin 3-gallate combined with cefepime had produced synergistic effect against P. aeruginosa (with average FIC index of 0.24). The MIC of epicatechin 3-gallate was effectively reduced to MIC/4, MIC/8, MIC/16, and MIC/32 in the presence of cefepime. Time-kill study of epicatechin 3-gallate combined with cefepime exhibited remarkable bactericidal activity where the eradication of P. aeruginosa occurred within 4 h of treatment. Scanning electron micrographs revealed apparent cell membrane damage and leakage of cytoplasmic contents from P. aeruginosa cells which eventually led to the cell lysis after the combination treatment of epicatechin 3-gallate and cefepime. The potential of epicatechin 3-gallate to act synergistically with cefepime against clinically resistant P. aeruginosa strain possibly will maximize the successful outcomes when choosing empirical antibiotic treatment in hospitals or health care institutions.

scholarly journals In Vitro Activity of Omadacycline, a New Tetracycline Analog, and Comparators against Clostridioides difficile

2020 ◽  
Vol 64 (8) ◽  
Author(s):  
Khurshida Begum ◽  
Eugénie Bassères ◽  
Julie Miranda ◽  
Chris Lancaster ◽  
Anne J. Gonzales-Luna ◽  
...  
Keyword(s):  
Large Scale ◽  
Anaerobic Bacteria ◽  
Oral Antibiotic ◽  
Content Type ◽  
Microdilution Method ◽  
Clostridioides Difficile ◽  
Broth Microdilution Method ◽  
Time Kill ◽  
Further Development

ABSTRACT Omadacycline is a potent aminomethylcycline with in vitro activity against Gram-positive, Gram-negative, and anaerobic bacteria. Preliminary data demonstrated that omadacycline has in vitro activity against Clostridioides difficile; however, large-scale in vitro studies have not been done. The purpose of this study was to assess the in vitro susceptibility of omadacycline and comparators on a large biobank of clinical C. difficile isolates. In vitro C. difficile susceptibility to omadacycline and comparators (fidaxomicin, metronidazole, and vancomycin) was assessed using the broth microdilution method. Minimum bactericidal concentrations (MBCs) and time-kill assays were assessed for pharmacodynamics analysis, and whole-genome sequencing was performed in a subset of isolates to assess distribution of MICs and resistance determinants. Two hundred fifty clinical C. difficile isolates collected between 2015 and 2018 were tested for in vitro susceptibility of omadacycline and comparators. Ribotypes included F001 (n = 5), F002 (n = 56), F014-020 (n = 66), F017 (n = 8), F027 (n = 53), F106 (n = 45), and F255 (n = 17). Omadacycline demonstrated potent in vitro activity with an MIC range of 0.016 to 0.13 μg/ml, an MIC50 of 0.031 μg/ml, and an MIC90 of 0.031 μg/ml. No difference was observed for omadacycline MIC50 and MIC90 values stratified by ribotype, disease severity, or vancomycin susceptibility. Bactericidal activity was confirmed in time-kill studies. No difference was observed in MIC based on C. difficile phylogeny. Further development of omadacycline as an intravenous and oral antibiotic directed toward C. difficile infection is warranted.

scholarly journals In Vitro Activity of Dalbavancin against Refractory Multidrug-Resistant (MDR) Staphylococcus aureus Isolates

Antibiotics ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 865
Author(s):  
Dafne Bongiorno ◽  
Lorenzo Mattia Lazzaro ◽  
Stefania Stefani ◽  
Floriana Campanile
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Reference Strain ◽  
Multidrug Resistant ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
High Prevalence ◽  
Time Kill ◽  
Reference Strains

The high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infections, always treated with vancomycin and daptomycin, has led to the emergence of vancomycin-intermediate (VISA), heteroresistant vancomycin-intermediate (hVISA) and daptomycin non-susceptible (DNS) S. aureus. Even if glycopeptides and daptomycin remain the keystone for treatment of resistant S. aureus, the need for alternative therapies that target MRSA has now become imperative. The in vitro antibacterial and bactericidal activity of dalbavancin was evaluated against clinically relevant S. aureus showing raised antibiotic resistance levels, from methicillin-susceptible to Multidrug-Resistant (MDR) MRSA, including hVISA, DNS and rifampicin-resistant (RIF-R) strains. A total of 124 S. aureus strains were tested for dalbavancin susceptibility, by the broth microdilution method. Two VISA and 2 hVISA reference strains, as well as a vancomycin-resistant (VRSA) reference strain and a methicillin-susceptible Staphylococcus aureus (MSSA) reference strain, were included as controls. Time–kill curves were assayed to assess bactericidal activity. Dalbavancin demonstrated excellent in vitro antibacterial and bactericidal activity against all S. aureus resistance classes, including hVISA and DNS isolates. The RIF-R strains showed the highest percentage of isolates with non-susceptibility, reflecting the correlation between rpoB mutations and VISA/hVISA emergence. Our observations suggest that dalbavancin can be considered as an effective alternative for the management of severe MRSA infections also sustained by refractory phenotypes.

scholarly journals In vitro synergism of simvastatin and fluconazole against Candida species

2012 ◽  
Vol 54 (4) ◽  
pp. 197-199 ◽  
Author(s):  
Everardo Albuquerque Menezes ◽  
Antônio Alexandre de Vasconcelos Júnior ◽  
Carlla Lorena Façanha Silva ◽  
Fábio Ximenes Plutarco ◽  
Maria da Conceição dos Santos Oliveira Cunha ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Susceptibility Testing ◽  
Inhibitory Concentration ◽  
Fungal Infections ◽  
Candida Spp ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Antifungal Action ◽  
Systemic Infections

Systemic fungal infections are responsible for high mortality rates. Several species of fungi may be involved, but Candida spp. is the most prevalent. Simvastatin is used to lower cholesterol and also exhibits antifungal action. The aim of this study was to evaluate the synergistic action of simvastatin with fluconazole against strains of Candida spp. Susceptibility testing was performed according to protocol M27-A3, by broth microdilution method and the synergistic effect of simvastatin and fluconazole was calculated based on FICI (Fractional Inhibitory Concentration Index). Eleven strains were evaluated, and simvastatin showed a synergistic effect with fluconazole against 10 (91%) of the Candida spp. strains tested. Simvastatin may be a valuable drug in the treatment of systemic infections caused by Candida spp.

scholarly journals 1279. In Vitro Activity of Nacubactam (OP0595) Alone and in Combination with β-Lactams against β-Lactamase-Producing Enterobacterales Isolated in Japan

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S655-S655
Author(s):  
Yu Nagira ◽  
Keiko Yamada ◽  
Hayato Okade ◽  
Nami Senju ◽  
Yuko Tsutsumi ◽  
...  
Keyword(s):  
Enzyme Stability ◽  
Antimicrobial Effect ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Microdilution Method ◽  
Class D ◽  
Broth Microdilution Method ◽  
Time Kill ◽  
Lactamase Inhibitor

Abstract Background Nacubactam (NAC) is a novel serine β-lactamase inhibitor in clinical development, and inhibits Ambler class A, class C, and some class D β-lactamases. In addition, it has penicillin-binding protein (PBP) 2-dependent antibacterial activity and an ‘enhancer’ effect when combined with β-lactams bound to PBP3. This study assessed the in vitro activity of NAC alone and in combination with β-lactams against IMP-type metallo-β-lactamase-producing and ESBL-producing Enterobacterales isolated in Japan. Methods The MICs for the clinical isolates in Japan were determined and time kill studies were performed. IMP and ESBL genes were detected by PCR. The MICs were determined by broth microdilution method following CLSI methodology. β-lactams and NAC were tested as a ratio of 1:1. Time kill profiles were also studied according to CLSI methodology. Results The MIC50/MIC90s of NAC alone against 112 IMP-producing Enterobacterales and 154 ESBL-producing Enterobacterales were 2/ >32 and 2/8 mg/L, respectively. Regarding the MICs of cefepime (FEP)/NAC and aztreonam (ATM)/NAC against IMP-producing isolates, the MIC90s were 2 and 1 mg/L and the MIC ranges were 0.06 - 32 and 0.06 - 4 mg/L, respectively. The MIC90s of FEP/NAC and ATM/NAC against ESBL-producing isolates were 0.5 and 1 mg/L. These MIC90s of β-lactam/NAC against IMP-producing and ESBL-producing isolates were significantly lower than those of β-lactam alone (>128 mg/L). The highest MIC of ATM/NAC against IMP-producing isolates was lower than that of FEP/NAC. In addition, bactericidal activities of β-lactam/NAC were observed at the lower concentration of β-lactam compared to that of β-lactam alone. Conclusion NAC in combination with β-lactams showed excellent in vitro activities against not only ESBL-producing Enterobacterales but also IMP-producing Enterobacterales isolated in Japan. ATM/NAC tended to show higher antimicrobial effect against IMP-producing isolates by the enzyme stability of ATM. These results support the complex activities of NAC which works as a β-lactamase inhibitor, an antibacterial agent and also an enhancer when combined with β-lactams. Furthermore, these will be useful for selecting a partner β-lactam for NAC. Disclosures Yu Nagira, MS, Meiji Seika Pharma Co., Ltd. (Employee) Keiko Yamada, BS, Meiji Seika Pharma Co., Ltd. (Employee) Hayato Okade, Ph.D, Meiji Seika Pharma Co., Ltd. (Employee) Nami Senju, BS, Meiji Seika Pharma Co., Ltd. (Employee) Yuko Tsutsumi, MS, Meiji Seika Pharma Co., Ltd. (Employee) Yuji Tabata, Ph.D, Meiji Seika Pharma Co., Ltd. (Employee)

scholarly journals In VitroActivity of Ceftaroline-Avibactam against Gram-Negative and Gram-Positive Pathogens Isolated from Patients in Canadian Hospitals from 2010 to 2012: Results from the CANWARD Surveillance Study

2013 ◽  
Vol 57 (11) ◽  
pp. 5600-5611 ◽  
Author(s):  
James A. Karlowsky ◽  
Heather J. Adam ◽  
Melanie R. Baxter ◽  
Philippe R. S. Lagacé-Wiens ◽  
Andrew J. Walkty ◽  
...  
Keyword(s):  
Klebsiella Oxytoca ◽  
Enterobacter Aerogenes ◽  
Enterobacter Cloacae ◽  
Morganella Morganii ◽  
Content Type ◽  
E Coli ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Third Generation Cephalosporins

ABSTRACTThein vitroactivities of ceftaroline-avibactam, ceftaroline, and comparative agents were determined for a collection of bacterial pathogens frequently isolated from patients seeking care at 15 Canadian hospitals from January 2010 to December 2012. In total, 9,758 isolates were tested by using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method (document M07-A9, 2012), with MICs interpreted by using CLSI breakpoints (document M100-S23, 2013). Ceftaroline-avibactam demonstrated potent activity (MIC90, ≤0.5 μg/ml) againstEscherichia coli,Klebsiella pneumoniae,Klebsiella oxytoca,Proteus mirabilis,Enterobacter cloacae,Enterobacter aerogenes,Serratia marcescens,Morganella morganii,Citrobacter freundii, andHaemophilus influenzae; >99% of isolates ofE. coli,K. pneumoniae,K. oxytoca,P. mirabilis,M. morganii,C. freundii, andH. influenzaewere susceptible to ceftaroline-avibactam according to CLSI MIC interpretative criteria for ceftaroline. Ceftaroline was less active than ceftaroline-avibactam against all species ofEnterobacteriaceaetested, with rates of susceptibility ranging from 93.9% (P. mirabilis) to 54.0% (S. marcescens). All isolates of methicillin-susceptibleStaphylococcus aureus(MIC90, 0.25 μg/ml) and 99.6% of methicillin-resistantS. aureusisolates (MIC90, 1 μg/ml) were susceptible to ceftaroline; the addition of avibactam to ceftaroline did not alter its activity against staphylococci or streptococci. All isolates ofStreptococcus pneumoniae(MIC90, 0.03 μg/ml),Streptococcus pyogenes(MIC90, ≤0.03 μg/ml), andStreptococcus agalactiae(MIC90, 0.015 μg/ml) tested were susceptible to ceftaroline. We conclude that combining avibactam with ceftaroline expanded its spectrum of activity to include most isolates ofEnterobacteriaceaeresistant to third-generation cephalosporins, including extended-spectrum β-lactamase (ESBL)- and AmpC-producingE. coliand ESBL-producingK. pneumoniae, while maintaining potent activity against staphylococci and streptococci.

scholarly journals Evaluation of Antimicrobial, Antioxidant, and Cytotoxic Activity of Phenolic Preparations of Diverse Composition, Obtained from Elaeagnus rhamnoides (L.) A. Nelson Leaf and Twig Extracts

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2835
Author(s):  
Anna Stochmal ◽  
Bartosz Skalski ◽  
Rostyslav Pietukhov ◽  
Beata Sadowska ◽  
Joanna Rywaniak ◽  
...  
Keyword(s):  
Chemical Composition ◽  
Plasma Lipids ◽  
Biological Properties ◽  
Sea Buckthorn ◽  
Phenolic Antioxidants ◽  
Microdilution Method ◽  
Solid Media ◽  
Broth Microdilution Method ◽  
Markers Of Oxidative Stress

Although the major components of various organs of sea buckthorn have been identified (particularly phenolic compounds), biological properties of many of these phytochemicals still remain poorly characterized. In this study, we focused on the chemical composition and biological activity of preparations that were obtained from sea buckthorn twigs and leaves. The objective was to investigate cytotoxicity of these preparations against human fibroblast line HFF-1, using MTT reduction assay, their anti- or pro-oxidant activities against the effects of a biological oxidant -H2O2/Fe—on human plasma lipids and proteins in vitro (using TBARS and carbonyl groups as the markers of oxidative stress). Antimicrobial activity of the tested preparations against Gram-positive (Staphylococcus aureus, S. epidermidis, Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa), as well as against fungi (Candida albicans, C. glabrata) by the EUCAST-approved broth microdilution method, followed by growth on solid media, were also assessed. Our analysis showed significant differences in chemical composition and biological properties of the tested preparations (A–F). All tested preparations from sea buckthorn twigs (D–F) and one preparation from sea buckthorn leaves (preparation C) may be a new source of phenolic antioxidants for pharmacological and cosmetic applications.

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