scholarly journals Synergistic Effect of a Pleuromutilin Derivative with Tetracycline against Streptococcus suis In Vitro and in the Neutropenic Thigh Infection Model

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3522
Author(s):  
Fang Chen ◽  
Meng-Chao Wei ◽  
Yi-Dan Luo ◽  
Zhen Jin ◽  
You-Zhi Tang
Keyword(s):  
Antimicrobial Activity ◽  
Synergistic Effect ◽  
Therapeutic Strategy ◽  
Streptococcus Suis ◽  
Infection Model ◽  
Additive Effects ◽  
Bacterial Reduction ◽  
Checkerboard Assay

Tetracycline (TET) has been widely used in the treatment of Streptococcus suis (S. suis) infection. However, it was found that the efficacy of many antibiotics in S. suis decreased significantly, especially tetracycline. In this study, GML-12 (a novel pleuromutilin derivative) was used in combination with TET against 12 S. suis isolates. In the checkerboard assay, the TET/GML-12 combination exhibited synergistic and additive effects against S. suis isolates (n = 12). In vitro time-killing assays and in vivo therapeutic experiments were used to confirm the synergistic effect of the TET/GML-12 combination against S. suis strains screened based on an FICI ≤ 0.5. In time-killing assays, the TET/GML-12 combination showed a synergistic effect or an additive effect against three isolates with a bacterial reduction of over 2.4-log10 CFU/mL compared with the most active monotherapy. Additionally, the TET/GML-12 combination displayed potent antimicrobial activity against four isolates in a mouse thigh infection model. These results suggest that the TET/GML-12 combination may be a potential therapeutic strategy for S. suis infection.

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 Antimicrobial Effects of Ibuprofen Combined with Standard of Care Antimicrobials against Cystic Fibrosis Pathogens

2021 ◽  
Author(s):  
Qingquan Chen ◽  
Marleini Ilanga ◽  
Sabona B Simbassa ◽  
Bhagath Chirra ◽  
Kush N Shah ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Antimicrobial Activity ◽  
Standard Of Care ◽  
Infection Model ◽  
High Dose ◽  
Synergistic Activity ◽  
Drug Resistant ◽  
Anti Inflammatory

Cystic Fibrosis (CF) is a common fatal genetic disease caused by mutations happened to cystic fibrosis transmembrane conductance regulator (CFTR) gene. Lungs of CF patients are often colonized or infected with microorganisms. Drug resistant bacterial infection has been problematic in cystic fibrosis patient. The chronic bacterial infections and concomitant airway inflammation could damage the lung and lead to respiratory failure. Several clinical trials have demonstrated that high-dose ibuprofen reduces the rate of pulmonary function decline in CF patients. This beneficial effect has been attributed to the anti-inflammatory properties of ibuprofen. Previously, we have confirmed that high-dose ibuprofen demonstrated antimicrobial activity against P. aeruginosa in in vitro and in vivo. However, no study has examined the antimicrobial effect of combining ibuprofen with standard-of-care (SoC) antimicrobials. Here, we evaluated possible synergistic activity of combinations of common nonsteroidal anti-inflammatory drugs (NSAIDs), namely, aspirin, naproxen, and ibuprofen, with commonly used antibiotics for CF patients. The drug combinations were screened against different CF clinical isolates. Drugs that demonstrated efficacy in the presence of ibuprofen were further verified synergistic effects between these antimicrobials and NSAIDs. Finally, the survival analysis of an P. aeruginosa murine infection model was used to demonstrate the efficacy of synergistic combination. Our results suggest that combinations of ibuprofen with commonly used antibiotics demonstrate synergistic antimicrobial activity against drug resistant, clinical bacterial strains in in vitro. The efficacy of combination ceftazidime and ibuprofen was demonstrated in in vivo.

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 Postantibiotic and Sub-MIC Effects of Exebacase (Lysin CF-301) Enhance Antimicrobial Activity againstStaphylococcus aureus

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Jun Taek Oh ◽  
Cara Cassino ◽  
Raymond Schuch
Keyword(s):  
Antimicrobial Activity ◽  
Cell Wall ◽  
The United States ◽  
Infection Model ◽  
Postantibiotic Effect ◽  
Content Type ◽  
Wall Ultrastructure ◽  
Bacterial Fitness

ABSTRACTCF-301 (exebacase) is a recombinantly produced bacteriophage-derived lysin (cell wall hydrolase) and is the first agent of this class to enter clinical development in the United States for treating bacteremia including endocarditis due toStaphylococcus aureus. Whereas rapid bactericidal activity is the hallmarkin vitroandin vivoresponse to CF-301 at exposures higher than the MIC, prolonged antimicrobial activity, mediated by cell wall damage, is predicted at concentrations less than the MIC. In the current study, a series ofin vitropharmacodynamic parameters, including the postantibiotic effect (PAE), postantibiotic sub-MIC effect (PA-SME), and sub-MIC effect (SME), were studied to determine how short-duration and sub-MIC CF-301 exposures affect the growth of surviving staphylococci and extend its antimicrobial activity. Mean PAE, PA-SME, and SME values up to 4.8, 9.3, and 9.8 h, respectively, were observed against 14 staphylococcal strains tested in human serum; growth delays were extended by 6 h in the presence of daptomycin. Exposures to CF-301 at sub-MIC levels as low as 0.001× to 0.01× MIC (∼1 to 10 ng/ml) resulted in aberrant cell wall ultrastructure, increased membrane permeability, dissipation of membrane potential, and inhibition of virulence phenotypes, including agglutination and biofilm formation. A mouse thigh infection model designed to study the PAE was used to confirm our findings and demonstratein vivogrowth delays of ≥19.3 h. Our findings suggest that at CF-301 concentrations less than the MIC during therapeutic use, sustained reductions in bacterial fitness and virulence may substantially enhance efficacy.

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 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 and in vivo Pharmacodynamics of Colistin and Aztreonam Alone and in Combination against Multidrug-Resistant Pseudomonas aeruginosa

Chemotherapy ◽  
2016 ◽  
Vol 62 (2) ◽  
pp. 105-110 ◽  
Author(s):  
Yuka Yamagishi ◽  
Mao Hagihara ◽  
Hideo Kato ◽  
Jun Hirai ◽  
Naoya Nishiyama ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Activity ◽  
Antimicrobial Resistance ◽  
Multidrug Resistant ◽  
In Vivo Study ◽  
Infection Model ◽  
High Dose ◽  
Combination Therapies

Background: Reports of Pseudomonas aeruginosa with high antimicrobial resistance have steadily emerged, threatening the utility of a mainstay in antipseudomonal therapy. This study evaluated the antimicrobial activities of various combination therapies against P. aeruginosa with high antimicrobial resistance, including multidrug-resistant P. aeruginosa (MDRP) using an in vitro and in vivo study. Methods: We evaluated 24 combination therapies, including colistin, aztreonam, meropenem, ceftazidime, ciprofloxacin, amikacin, rifampicin, arbekacin and piperacillin against 15 MDRP isolates detected at Aichi Medical University Hospital with the break-point checkerboard method. Based on the results of the in vitro study, we evaluated antimicrobial activity against highly antimicrobial-resistant P. aeruginosa with an in vivo murine thigh infection model. Results: The combination regimens including colistin and aztreonam showed higher antimicrobial activity against the 15 MDRP isolates. In the in vivo study, the high-dose colistin monotherapy (16 mg/kg every 12 h) achieved greater log10 CFU changes than the normal-dose colistin regimen (8 mg/kg every 12 h) against 5 P. aeruginosa isolates, including 2 MDRP isolates (p < 0.05). Aztreonam monotherapy (400 mg every 8 h) yielded bacterial densities similar to untreated control mice for the MDRP isolate evaluated. The combination therapy with a higher dose of colistin had superior antimicrobial activity against 5 P. aeruginosa with colistin (MIC 0.5 μg/ml) and aztreonam (MIC ≥128 μg/ml) than colistin monotherapy. Conclusion: The data suggest that the combination treatment of colistin and aztreonam could be the most useful for treating highly resistant P. aeruginosa with a higher susceptibility to colistin, including MDRP infections.

scholarly journals Growth and pathogenesis of Enteropathogenic E.coli as affected by bacteriocin produced and purified from Lactobacillus isolates with or without Quercus infectoria

2012 ◽  
Vol 36 (0E) ◽  
pp. 1-7
Author(s):  
Hassan A. Abdul-Ratha
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Activity ◽  
Antibacterial Activity ◽  
Synergistic Effect ◽  
Herbal Drugs ◽  
Bacteriocin Activity ◽  
Recovery Yield ◽  
Quercus Infectoria

The antimicrobial activity of Lactobacilli has been widely exploited for prevention offood –borne pathogens e.g.: Escherichia coli being the major cause of diarrhea especially inchildren, because of bacteriocin activity and the importance of herbal drugs, hence this studywas designed to evaluate the synergistic effect of plant extract and bacteriocin produced byLactobacillus on the growth and pathogenesis of Enteropathogenic Ecoli.1. The Plantaricin production was induced by adding the mutagenic agent Mitomycin C.2. Purification of Plantaricin was made by heating crude plantaricin at 80ºC for 10min andthen purified by two steps method including extraction with n-butanol followed by gelfiltration chromatography on Sepharose 6B column. The results showed that the specificactivity was 1600 AU/mg protein with 8 purification folds and 12% recovery yield.3. The antibacterial activity of Quercus infectoria with concentration 300 mg/ml wasshowed highly antibacterial activity in vitro and in vivo.4. The result showed synergistic effect of Plantaricin with Quercus infectoria extract afterexperimental infection that induced by orally dosing with Escherichia coli in vivo. A result ofhistopathological study was recorded recovery of tissue.

scholarly journals XDR-Klebsiella pneumoniae isolates harboring blaOXA-48: In vitro and in vivo evaluation using a murine thigh-infection model

2019 ◽  
Vol 244 (18) ◽  
pp. 1658-1664
Author(s):  
Noha A Kamel ◽  
Wafaa N El-Tayeb ◽  
Mona R El-Ansary ◽  
Mohamed T Mansour ◽  
Khaled M Aboshanab
Keyword(s):  
Klebsiella Pneumoniae ◽  
Synergistic Effect ◽  
Cancer Patients ◽  
Bacterial Count ◽  
Infection Model ◽  
Drug Resistant ◽  
Extensively Drug Resistant ◽  
Pediatric Cancer Patients

Blood stream infection with extensively drug-resistant-carbapenamase producing Klebsiella (K.) pneumoniae usually represents a major threat with medical challenges among hospitalized cancer patients with poor functional status and underlying diseases. Accordingly, the aim of the study was to evaluate the efficacy of different antibiotics either alone or in combinations against extensively drug-resistant-OXA-48 producing K. pneumoniae clinical isolates that were previously recovered from febrile neutropenic pediatric cancer patients. The antimicrobial activity of amikacin, gentamicin, colistin, ertapenem, imipenem, meropenem and tigecycline was assessed by broth microdilution method. The results revealed that all the tested OXA-48 producing K. pneumoniae isolates exhibited extensively drug-resistant phenotype and all of them were susceptible to tigecycline. Checkerboard method was used to determine the fraction inhibitory concentration index, to further classify the effect of antibiotic combination as synergistic, additive, indifferent, or antagonistic effect. The results revealed that in vitro dual carbapenem combination of ertapenem with meropenem had shown synergistic effect against all of the tested isolates. Additionally, synergistic effect of meropenem with colistin was detected among three of four isolates tested. Herein we investigated the in vivo activity of colistin, meropenem alone and in combination in a rat thigh infection model. The results showed that addition of meropenem to colistin was not effective at reduction of bacterial count as compared to colistin alone at 24 h post treatment. Accordingly, we can conclude that in vitro antibiotic combinations of dual carbapenems (ertapenem plus meropenem) and meropenem plus colistin showed synergism in 100% and 75% of the tested isolates, respectively. Colistin alone had significantly reduced bacterial count while its combination with meropenem was not superior to monotherapy in murine thigh infection model. Impact statement The present study aimed to evaluate the effectiveness of various antibiotics both in vitro and in vivo using murine animal model either alone or in combination against various strains of extensively drug-resistant (XDR) Klebsiella pneumoniae, life-threatening pathogens of relevant medical importance isolated from febrile neutropenic pediatric cancer patients. This work also emphasizes how to select the appropriate antibiotics options and help the physicians to choice the appropriate antibiotic for the treatment of such superbugs (extensively drug-resistant (XDR) Klebsiella pneumoniae). The results showed that in vitro dual carbapenem combination of ertapenem with meropenem had shown synergistic effect against all of the tested XDR isolates. Antibiotic combinations of dual carbapenems and meropenem plus colistin showed synergism in 100% and 75% of the testes isolates, respectively. Results of the in vivo evaluation, colistin alone had significantly reduced bacterial count while its combination with meropenem was not superior to monotherapy.

scholarly journals Combined With Mefloquine, Resurrect Colistin Active in Colistin-Resistant Pseudomonas aeruginosa in vitro and in vivo

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaodong Zhang ◽  
Yining Zhao ◽  
Luozhu Feng ◽  
Mengxin Xu ◽  
Yiru Ge ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Synergistic Effect ◽  
Biofilm Formation ◽  
Galleria Mellonella ◽  
Synergistic Effects ◽  
Alternative Therapy ◽  
Multidrug Resistant ◽  
Infection Model

Colistin is a polymyxin antibiotic that is widely used for the treatment of multidrug resistant (MDR) Pseudomonas aeruginosa infections, as the last resort. Over the past few years, unreasonable use of antibiotics has resulted in an increase in MDR strains, including colistin-resistant P. aeruginosa. The present study aimed to explore the synergistic effects of mefloquine in combination with colistin for the treatment of colistin-resistant P. aeruginosa in vivo and in vitro. The synergistic effect of the combination of mefloquine and colistin was investigated in vitro using checkerboard method, time-killing assay, biofilm formation inhibition test, and biofilm eradication test. The study also explored the synergistic effects of this combination of drugs in vivo, using a Galleria mellonella infection model. The results for checkerboard method and time killing curve indicated that mefloquine in combination with colistin showed a good antibacterial activity. Furthermore, the combination of these two drugs inhibited biofilm formation and eradicated pre-formed mature biofilms. This synergistic effect was visualized using scanning electron microscopy (SEM), wherein the results showed that the combination of mefloquine and colistin reduced biofilm formation significantly. Further, the application of this combination of drugs to in vivo infection model significantly increased the survival rate of G. mellonella larvae. Altogether, the combination of mefloquine and colistin showed a good synergistic effect in vitro and in vivo, and highlighted its potential to be used as an alternative therapy for the treatment of colistin-resistant P. aeruginosa infection.

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