scholarly journals In vivo efficacy of combination of colistin with fosfomycin or minocycline in a mouse model of multidrug-resistant Acinetobacter baumannii pneumonia

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nam Su Ku ◽  
Su-Hyung Lee ◽  
Young- soun Lim ◽  
Heun Choi ◽  
Jin Young Ahn ◽  
...  
Keyword(s):  
Mouse Model ◽  
Acinetobacter Baumannii ◽  
Synergistic Effects ◽  
Bacterial Load ◽  
Multidrug Resistant ◽  
Therapeutic Options ◽  
Severance Hospital ◽  
Carbapenem Resistant ◽  
Combination Regimens

AbstractUnfortunately, the options for treating multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infections are extremely limited. Recently, fosfomycin and minocycline were newly introduced as a treatment option for MDR A. baumannii infection. Therefore, we investigated the efficacy of the combination of colistin with fosfomycin and minocycline, respectively, as therapeutic options in MDR A. baumannii pneumonia. We examined a carbapenem-resistant A. baumannii isolated from clinical specimens at Severance Hospital, Seoul, Korea. The effect of colistin with fosfomycin, and colistin with minocycline on the bacterial counts in lung tissue was investigated in a mouse model of pneumonia caused by MDR A. baumannii. In vivo, colistin with fosfomycin or minocycline significantly (p < 0.05) reduced the bacterial load in the lungs compared with the controls at 24 and 48 h. In the combination groups, the bacterial loads differed significantly (p < 0.05) from that with the more active antimicrobial alone. Moreover, the combination regimens of colistin with fosfomycin and colistin with minocycline showed bactericidal and synergistic effects compared with the more active antimicrobial alone at 24 and 48 h. This study demonstrated the synergistic effects of combination regimens of colistin with fosfomycin and minocycline, respectively, as therapeutic options in pneumonia caused by MDR A. baumannii.

scholarly journals In Vivo Selection of a Missense Mutation in adeR and Conversion of the Novel blaOXA-164 Gene into blaOXA-58 in Carbapenem-Resistant Acinetobacter baumannii Isolates from a Hospitalized Patient

2010 ◽  
Vol 54 (12) ◽  
pp. 5021-5027 ◽  
Author(s):  
Paul G. Higgins ◽  
Thamarai Schneiders ◽  
Axel Hamprecht ◽  
Harald Seifert
Keyword(s):  
Acinetobacter Baumannii ◽  
Missense Mutation ◽  
Novel Mutation ◽  
Multidrug Resistant ◽  
The Novel ◽  
Reverse Transcription Pcr ◽  
Carbapenem Resistant ◽  
Genes Encoding ◽  
Hospitalized Patient

ABSTRACT The mechanism of stepwise acquired multidrug resistance in Acinetobacter baumannii isolates from a hospitalized patient was investigated. Thirteen consecutive multidrug-resistant isolates were recovered from the same patient over a 2-month period. The Vitek 2 system identified the isolates as meropenem-sensitive Acinetobacter lwoffii; however, molecular identification showed that the isolates were A. baumannii. Etest revealed that the isolates were meropenem resistant. The presence of oxacillinase (OXA)-type enzymes were investigated by sequencing. The clonal relatedness of isolates was assessed by pulsed-field gel electrophoresis (PFGE). Expression of the genes encoding the efflux pumps AdeB and AdeJ was performed by semiquantitative real-time reverse transcription-PCR (qRT-PCR). The adeRS two-component system was sequenced. All isolates had identical PFGE fingerprints, suggesting clonal identity. The first six isolates were positive for the novel bla OXA-164 gene. The following seven isolates, recovered after treatment with a combination of meropenem, amikacin, ciprofloxacin, and co-trimoxazole showed an increase of >7-fold in adeB mRNA transcripts and a missense mutation in bla OXA-164, converting it to bla OXA-58. Sequencing revealed a novel mutation in adeR. These data illustrate how A. baumannii can adapt during antimicrobial therapy, leading to increased antimicrobial resistance.

scholarly journals A Potential Combination Therapy of Berberine Hydrochloride With Antibiotics Against Multidrug-Resistant Acinetobacter baumannii

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaobo Li ◽  
Yanqing Song ◽  
Lina Wang ◽  
Guangbo Kang ◽  
Ping Wang ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Synergistic Effects ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Berberine Hydrochloride ◽  
Transporter Protein ◽  
Antimicrobial Efficiency ◽  
Global Threat

Multidrug-resistant (MDR) Acinetobacter baumannii strains can cause severe infections in intensive care units, and are rapidly developing resistance to the last-resort of existing antibiotics, posing a major global threat to health care system. Berberine hydrochloride (BBH), a kind of isoquinoline alkaloids extracted from Berberis and other plants, has been widely used as an antibacterial medicine for its reliable therapeutic efficiency. The in vitro synergistic effects of BBH with antibiotics against MDR A. baumannii were determined. BBH alone had weak antimicrobial activity (e.g., MIC≥256 mg/L) against MDR A. baumannii. However, it dramatically increased the susceptibility of MDR strains against antibiotics with FICI values &lt;0.5, even reversed their resistance to antibiotics (e.g., tigecycline, sulbactam, meropenem and ciprofloxacin). In vivo study has suggested BBH with sulbactam had stronger antimicrobial efficiency than monotherapy in a neutropenic murine thigh infection model. The antibiotic-sensitizing mechanism of action of BBH was evaluated as well. BBH boosted adeB gene expression and bound to the AdeB transporter protein, resulting in low uptake of BBH, which may contribute to less extrusion of antibiotics by the AdeABC pump. Knockout of the adeB gene increased uptake of BBH and diminished the antibiotic sensitization and synergistic effects between antibiotics and BBH in MDR strains. Together, BBH effectively re-sensitizes this MDR pathogen to a range of antibiotics that have become barely effective due to antibiotic resistance, which indicates BBH may be a promising therapeutic adjuvant candidate to combat MDR A. baumannii.

scholarly journals In vitro and in vivo antibacterial activity assays of carvacrol: A candidate for development of innovative treatments against KPC-producing Klebsiella pneumoniae

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246003
Author(s):  
Gleyce Hellen de Almeida de Souza ◽  
Joyce Alencar dos Santos Radai ◽  
Marcia Soares Mattos Vaz ◽  
Kesia Esther da Silva ◽  
Thiago Leite Fraga ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Klebsiella Pneumoniae ◽  
Bacterial Load ◽  
Antimicrobial Effect ◽  
Multidrug Resistant ◽  
Bacterial Cells ◽  
Carbapenem Resistant ◽  
Interesting Candidate

Dissemination of carbapenem-resistant Klebsiella pneumoniae poses a threat to the successful treatment of bacterial diseases and increases the need for new antibacterial agents development. The objective of this study was to determine the antimicrobial activity of carvacrol against multidrug-resistant K. pneumoniae. Carbapenemase production was detected by MALDI-TOF. The PCR and sequencing showed that the blaKPC-2, blaOXA-48, blaNDM-1, blaCTX-M-8 genes were present in carbapenem-resistant K. pneumoniae strains. The polymyxin-resistant K. pneumoniae strain exhibited alterations in mgrB gene. The antimicrobial activity of carvacrol was evaluated in vitro using broth microdilution and time-kill methods. For this, carbapenem-resistant K. pneumoniae and polymyxin-resistant strains, were evaluated. The in vitro results showed that carvacrol had antimicrobial activity against all isolates evaluated. The survival curves showed that carvacrol eradicated all of the bacterial cells within 4 h. The antimicrobial effect of carvacrol in vivo was determined using a mouse model of infection with Klebsiella pneumoniae carbapenemase (KPC). The treatment with carvacrol was associated with increased survival, and significantly reduced bacterial load in peritoneal lavage. In addition, groups treated with carvacrol, had a significant reduction in the total numbers of white cell and significantly increased of platelets when compared to the untreated group. In vivo and in vitro studies showed that carvacrol regimens exhibited significant antimicrobial activity against KPC-producing K. pneumoniae, making it an interesting candidate for development of alternative treatments.

scholarly journals Efficacy of dual carbapenem treatment in a murine sepsis model of infection due to carbapenemase-producing Acinetobacter baumannii

2020 ◽  
Author(s):  
T Cebrero-Cangueiro ◽  
P Nordmann ◽  
M Carretero-Ledesma ◽  
J Pachón ◽  
M E Pachón-Ibáñez
Keyword(s):  
Acinetobacter Baumannii ◽  
Experimental Model ◽  
Bacterial Load ◽  
In Vivo Efficacy ◽  
Female Mice ◽  
Carbapenem Resistant ◽  
Sepsis Model ◽  
Lethal Doses ◽  
Better Than

Abstract Objectives To evaluate the in vivo efficacy of a dual carbapenem combination containing imipenem plus meropenem against carbapenem-resistant Acinetobacter baumannii producing carbapenemases OXA-23 or OXA-58. Methods An experimental model of peritonitis using C57BL/6J female mice was developed and the minimum lethal doses were calculated for infections due to OXA-23 or OXA-58 producers of A. baumannii clinical isolates. The efficacies of the carbapenems in monotherapy and in combination were tested. Results Meropenem was better than imipenem in mice infected with either of the carbapenem-resistant A. baumannii (CRAb) strains. The combination of meropenem plus imipenem significantly improved the clearance of CRAbs from spleen compared with non-treated groups. The carbapenem-containing combination was better than imipenem for treating mice infected with both carbapenemase producers. In blood, the carbapenem combination significantly decreased the bacterial load of the OXA-23 producers compared with imipenem or meropenem used in monotherapy. Conclusions These results suggest that dual carbapenem combination could be an option for the treatment of infections due to carbapenemase-producing A. baumannii such as OXA-23 and OXA-58 producers.

scholarly journals Antimicrobial and Anti-Biofilm Peptide Octominin for Controlling Multidrug-Resistant Acinetobacter baumannii

2021 ◽  
Vol 22 (10) ◽  
pp. 5353
Author(s):  
E. H. T. Thulshan Jayathilaka ◽  
Dinusha C. Rajapaksha ◽  
Chamilani Nikapitiya ◽  
Mahanama De Zoysa ◽  
Ilson Whang
Keyword(s):  
Acinetobacter Baumannii ◽  
Biofilm Formation ◽  
Mammalian Cells ◽  
Multiple Drug Resistance ◽  
Bacterial Load ◽  
Multidrug Resistant ◽  
Multiple Drug ◽  
Ros Generation ◽  
Percentage Survival

Acinetobacter baumannii is a serious nosocomial pathogen with multiple drug resistance (MDR), the control of which has become challenging due to the currently used antibiotics. Our main objective in this study is to determine the antibacterial and antibiofilm activities of the antimicrobial peptide, Octominin, against MDR A. baumannii and derive its possible modes of actions. Octominin showed significant bactericidal effects at a low minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of 5 and 10 µg/mL, respectively. Time-kill kinetic analysis and bacterial viability tests revealed that Octominin showed a concentration-dependent antibacterial activity. Field-emission scanning electron microscopy (FE-SEM) analysis revealed that Octominin treatment altered the morphology and membrane structure of A. baumannii. Propidium iodide (PI) and reactive oxygen species (ROS) generation assays showed that Octominin increased the membrane permeability and ROS generation in A. baumannii, thereby causing bacterial cell death. Further, a lipopolysaccharides (LPS) binding assay showed an Octominin concentration-dependent LPS neutralization ability. Biofilm formation inhibition and eradication assays further revealed that Octominin inhibited biofilm formation and showed a high biofilm eradication activity against A. baumannii. Furthermore, up to a concentration of 100 µg/mL, Octominin caused no hemolysis and cell viability changes in mammalian cells. An in vivo study in zebrafish showed that the Octominin-treated group had a significantly higher relative percentage survival (54.1%) than the untreated group (16.6%). Additionally, a reduced bacterial load and fewer alterations in histological analysis confirmed the successful control of A. baumannii by Octominin in vivo. Collectively, these data suggest that Octominin exhibits significant antibacterial and antibiofilm activities against the multidrug-resistant A. baumannii, and this AMP can be developed further as a potent AMP for the control of antibiotic resistance.

scholarly journals 1273. Efficacy of Cefiderocol against carbapenem-resistant A. baumannii and P. aeruginosa in ventilator-associated pneumonia mouse model

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S653-S653
Author(s):  
Kenji Ota ◽  
Norihito Kaku ◽  
Naoki Uno ◽  
Kei Sakamoto ◽  
Kosuke Kosai ◽  
...  
Keyword(s):  
Mouse Model ◽  
Bacterial Load ◽  
Bactericidal Effect ◽  
Resistant Bacteria ◽  
Bacterial Suspension ◽  
Ventilator Associated Pneumonia ◽  
Gram Negative ◽  
Treatment Regimens ◽  
Carbapenem Resistant

Abstract Background Cefiderocol (CFDC) is a novel cephalosporin with siderophore structure, characterized by transportation through siderophore receptor on outer membrane of Gram-negative bacteria and structural stability against beta-lactamase. The antimicrobial activity against multidrug resistant bacteria is demonstrated in vitro and in vivo. In this study, we aimed to elucidate the in vivo efficacy of CFDC using ventilator-associated pneumonia (VAP) mouse model. Methods The minimum inhibitory concentration (MIC) of CFDC and meropenem (MEPM) against the test Acinetobacter baumannii (Ab) and Pseudomonas aeruginosa (Pa) isolates were measured by broth microdilution assay. Iron depleted medium was used for CFDC. For VAP mouse models, neutropenia was induced by cyclophosphamide intraperitoneal administration, followed by intubation of sterile tube in the trachea and inoculation of bacterial suspension. PK analysis were performed in infected mice, in order to determine treatment regimens to achieve targeted time above MIC (TAM) of free concentrations in plasma. Treatment was initiated 3 hours post infection and continued up to 120 h for survival analysis. To investigate the bactericidal effect, the mice were sacrificed to count bacterial load in the lung at 48 h and 24 h for VAP-Ab and Pa, respectively. Results MICs(mg/L) of CFDC and MEPM against Ab were 0.5 and 128, and Pa were 0.008 and 16, respectively. The treatment regimens to achieve target MIC were shown in Table 1. In order to assess dose dependency of CFDC, required doses to achieve TAM of 70%, 90%, and 100% were calculated. These doses used in the studies were achievable in human for CFDC, but not for MEPM due to high MICs of the test strains. In treatment study for VAP-Ab, bactericidal effect was achieved at TAM &gt; 70% in CFDC groups, as well as TAM 30% in MEPM group. In VAP-Pa, bactericidal effect was observed at TAM &gt; 90% in CFDC groups, as well as TAM 30% in MEPM group. Table 1.Treatment regimen and free TAM against VAP-Ab and Pa Figure 1. Bacterial load in the lungs of VAP-Ab and Pa Conclusion The efficacy of CFDC against VAP-Ab and Pa were demonstrated in this study. Although 90% free TAM was required for bactericidal effect, CFDC was shown to be effective against carbapenem-resistant Gram-negative pathogens at the recommended clinical dosing regimen. Disclosures Katsunori Yanagihara, MD, PhD, Shionogi & Co.,Ltd. (Grant/Research Support)

Pegylated LyeTx I-b peptide is effective against carbapenem-resistant Acinetobacter baumannii in an in vivo model of pneumonia and shows reduced toxicity

2021 ◽  
Vol 609 ◽  
pp. 121156
Author(s):  
Júlio César Moreira Brito ◽  
William Gustavo Lima ◽  
Jarbas Magalhães Resende ◽  
Débora Cristina Sampaio de Assis ◽  
Daiane Boff ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
In Vivo Model ◽  
Carbapenem Resistant ◽  
Reduced Toxicity

scholarly journals 694. In vitro Antibacterial Activity of Sulbactam–Durlobactam (ETX2514SUL) Against 121 Recent Acinetobacter baumannii Isolated from Patients in India

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S314-S314
Author(s):  
Alita Miller ◽  
Sarah McLeod ◽  
Tarun Mathur ◽  
Ian Morrissey
Keyword(s):  
Antibacterial Activity ◽  
Acinetobacter Baumannii ◽  
Package Insert ◽  
Multidrug Resistant ◽  
Antibiotic Resistant ◽  
Carbapenem Resistant ◽  
In Vitro Antibacterial Activity ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

Abstract Background The incidence of infections caused by multidrug-resistant Acinetobacter baumannii is increasing at an alarming rate in Southeast Asia and other parts of the world. Sulbactam (SUL) has intrinsic antibacterial activity against A. baumannii; however, the prevalence of β-lactamases in this species has limited its therapeutic use. Durlobactam (ETX2514, DUR) is a novel β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C and D β-lactamases. DUR restores SUL in vitro activity against multidrug-resistant A. baumannii. Against >3,600 globally diverse, clinical isolates from 2012–2017, addition of 4 mg/L DUR reduced the SUL MIC90 from >32 to 2 mg/L. SUL-DUR is currently in Phase 3 clinical development for the treatment of infections caused by carbapenem-resistant Acinetobacter spp.The goal of this study was to determine the activity of SUL-DUR and comparator antibiotics (amikacin (AMK), ampicillin-sulbactam (AMP-SUL), cefoperazone-sulbactam (CFP-SUL) and meropenem (MEM)) against A. baumannii isolated from hospitalized patients in India. Methods A total of 121 clinical A. baumannii isolates from multiple hospital settings and infection sources were collected between 2016–2019 from six geographically diverse hospitals in India. Species identification was performed by MALDI-TOF. Susceptibility of these isolates to SUL-DUR (10µg/10µg) and comparator antibiotics was determined by disk diffusion using CLSI methodology and interpretive criteria, except for CFP-SUL, for which resistance was defined using breakpoints from the CFP-SUL package insert. Results As shown in Table 1, resistance of this collection of isolates to marketed agents was extremely high. In contrast, based on preliminary breakpoint criteria, only 11.5% of isolates were resistant to SUL-DUR. Conclusion The in vitro antibacterial activity of SUL-DUR was significantly more potent than comparator agents against multidrug-resistant A. baumannii isolates collected from diverse sites in India. These data support the continued development of SUL-DUR for the treatment of antibiotic-resistant infections caused by A. baumannii. Disclosures All authors: No reported disclosures.

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