In vitro and in vivo analysis of antimicrobial agents alone and in combination against multi-drug resistant Acinetobacter baumannii

Drug-resistant Acinetobacter baumannii (A. baumannii) infections are a critical global problem, with limited treatment choices. This study aims to determine the in vitro activities of colistin–sitafloxacin combinations against multidrug-, carbapenem- and colistin-resistant A. baumannii (MDR-AB, CRAB, CoR-AB, respectively) clinical isolates from tertiary care hospitals. We used the broth microdilution checkerboard and time-kill methods in this study. Synergy was found using both methods. The colistin–sitafloxacin combination showed synergy in MDR-AB, CRAB, and CoR-AB isolates (3.4%, 3.1%, and 20.9%, respectively). No antagonism was found in any type of drug-resistant isolate. The majority of CoR-AB isolates became susceptible to colistin (95.4%). The time-kill method also showed that this combination could suppress regrowth back to the initial inocula of all representative isolates. Our results demonstrated that the colistin–sitafloxacin combination might be an interesting option for the treatment of drug-resistant A. baumannii. However, further in vivo and clinical studies are required.

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Synthesis of 4,4′-(4-Formyl-1H-pyrazole-1,3-diyl)dibenzoic Acid Derivatives as Narrow Spectrum Antibiotics for the Potential Treatment of Acinetobacter Baumannii Infections

Antibiotics ◽

10.3390/antibiotics9100650 ◽

2020 ◽

Vol 9 (10) ◽

pp. 650 ◽

Cited By ~ 1

Author(s):

Evan Delancey ◽

Devin Allison ◽

Hansa Raj KC ◽

David F. Gilmore ◽

Todd Fite ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Inhibitory Concentration ◽

Organ Injury ◽

Resistant Bacteria ◽

Drug Resistant ◽

Antimicrobial Studies ◽

Mammalian Cell Lines ◽

Drug Resistant Bacteria

Acinetobacter baumannii has emerged as one of the most lethal drug-resistant bacteria in recent years. We report the synthesis and antimicrobial studies of 25 new pyrazole-derived hydrazones. Some of these molecules are potent and specific inhibitors of A. baumannii strains with a minimum inhibitory concentration (MIC) value as low as 0.78 µg/mL. These compounds are non-toxic to mammalian cell lines in in vitro studies. Furthermore, one of the potent molecules has been studied for possible in vivo toxicity in the mouse model and found to be non-toxic based on the effect on 14 physiological blood markers of organ injury.

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Combined Use of the Ab105-2фΔCI Lytic Mutant Phage and Different Antibiotics in Clinical Isolates of Multiresistant Acinetobacter Baumannii

10.20944/preprints201910.0025.v1 ◽

2019 ◽

Author(s):

Lucia Blasco ◽

Anton Ambroa ◽

Maria Lopez ◽

Laura Fernandez-Garcia ◽

Ines Bleriot ◽

...

Keyword(s):

Antimicrobial Activity ◽

Acinetobacter Baumannii ◽

Antimicrobial Agents ◽

Galleria Mellonella ◽

Resistant Bacteria ◽

Lytic Phage ◽

Drug Resistant Bacteria ◽

Multiresistant Strains

The global health emergency caused by multi-drug resistant bacteria has led to the search for and development of new antimicrobial agents. Phage therapy is an abandoned antimicrobial therapy that has been resumed in recent years. In this study, we mutated a lysogenic phage from Acinetobacter baumannii into a lytic phage (Ab105-2phiΔCI) showing antimicrobial activity against A.baumannii clinical strains (such as Ab177_GEIH-2000 which showed MICs to meropenem and imipenem of 32 µg/ml and 16 µg/ml, respectively as well as belonging to GEIH-REIPI Spanish Multicenter A. baumannii Study II 2000/2010, Umbrella Genbank Bioproject PRJNA422585). We then enhanced the time kill curves (in vitro) and in Galleria mellonella survival assays (in vivo) antimicrobial activity of the new lytic phage by combining it with carbapenem antibiotics (meropenem and imipenem). We observed in vitro, an antimicrobial synergistic effect (from 4 log to 7 log CFU/ml) with meropenem plus lytic phage in all combinations analysed (0.1, 1 and 10 MOI of Ab105-2phiΔCI mutant as well as 1/4 and 1/8 MIC of meropenem). Moreover, we had a decrease in bacterial growth of 8 log CFU/ml for the combination of imipenem at 1/4 MIC plus lytic phage (Ab105-2phiΔCI mutant) and of 4 log CFU/ml for the combination of imipenem at 1/8 MIC plus lytic phage (Ab105-2phiΔCI mutant) in both MOI 1 and 10. These results were confirmed in in vivo (G. mellonella) obtaining a higher effectiveness in the combination of imipenem and Ab105-2phiΔCI mutant (P<0.05 by Log Rank-Matel Cox test). This approach could help to reduce the emergence of phage resistant bacteria and restore sensitivity to the antibiotics when used to combat multiresistant strains of Acinetobacter baumannii.

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Isolation and characterization of Siphoviridae phage infecting extensively drug-resistant Acinetobacter baumannii and evaluation of therapeutic efficacy in vitro and in vivo

Journal of Medical Microbiology ◽

10.1099/jmm.0.001002 ◽

2019 ◽

Vol 68 (7) ◽

pp. 1096-1108 ◽

Cited By ~ 3

Author(s):

Phitchayapak Wintachai ◽

Ampapan Naknaen ◽

Rattanaruji Pomwised ◽

Supayang Piyawan Voravuthikunchai ◽

Duncan R. Smith

Keyword(s):

Acinetobacter Baumannii ◽

Therapeutic Efficacy ◽

Drug Resistant ◽

Isolation And Characterization ◽

Extensively Drug Resistant

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Using the Chinese herb Scutellaria barbata against extensively drug-resistant Acinetobacter baumannii infections: in vitro and in vivo studies

BMC Complementary and Alternative Medicine ◽

10.1186/s12906-018-2151-7 ◽

2018 ◽

Vol 18 (1) ◽

Cited By ~ 10

Author(s):

Chin-Chuan Tsai ◽

Chi-Shiuan Lin ◽

Chun-Ru Hsu ◽

Chiu-Ming Chang ◽

I-Wei Chang ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Chinese Herb ◽

In Vivo Studies ◽

Drug Resistant ◽

Scutellaria Barbata ◽

Extensively Drug Resistant

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Colistin Dependence in Extensively Drug-Resistant Acinetobacter baumannii Strain Is Associated with ISAjo2 and ISAba13 Insertions and Multiple Cellular Responses

International Journal of Molecular Sciences ◽

10.3390/ijms22020576 ◽

2021 ◽

Vol 22 (2) ◽

pp. 576

Author(s):

Sherley Chamoun ◽

Jenny Welander ◽

Mihaela-Maria Martis-Thiele ◽

Maria Ntzouni ◽

Carina Claesson ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Lipid A ◽

Antimicrobial Agents ◽

Bacterial Pathogen ◽

Lipid Profiling ◽

Membrane Asymmetry ◽

Resistance Nodulation Division ◽

Lipid A Biosynthesis

The nosocomial opportunistic Gram-negative bacterial pathogen Acinetobacter baumannii is resistant to multiple antimicrobial agents and an emerging global health problem. The polymyxin antibiotic colistin, targeting the negatively charged lipid A component of the lipopolysaccharide on the bacterial cell surface, is often considered as the last-resort treatment, but resistance to colistin is unfortunately increasing worldwide. Notably, colistin-susceptible A. baumannii can also develop a colistin dependence after exposure to this drug in vitro. Colistin dependence might represent a stepping stone to resistance also in vivo. However, the mechanisms are far from clear. To address this issue, we combined proteogenomics, high-resolution microscopy, and lipid profiling to characterize and compare A. baumannii colistin-susceptible clinical isolate (Ab-S) of to its colistin-dependent subpopulation (Ab-D) obtained after subsequent passages in moderate colistin concentrations. Incidentally, in the colistin-dependent subpopulation the lpxA gene was disrupted by insertion of ISAjo2, the lipid A biosynthesis terminated, and Ab-D cells displayed a lipooligosaccharide (LOS)-deficient phenotype. Moreover, both mlaD and pldA genes were perturbed by insertions of ISAjo2 and ISAba13, and LOS-deficient bacteria displayed a capsule with decreased thickness as well as other surface imperfections. The major changes in relative protein abundance levels were detected in type 6 secretion system (T6SS) components, the resistance-nodulation-division (RND)-type efflux pumps, and in proteins involved in maintenance of outer membrane asymmetry. These findings suggest that colistin dependence in A. baumannii involves an ensemble of mechanisms seen in resistance development and accompanied by complex cellular events related to insertional sequences (ISs)-triggered LOS-deficiency. To our knowledge, this is the first study demonstrating the involvement of ISAjo2 and ISAba13 IS elements in the modulation of the lipid A biosynthesis and associated development of dependence on colistin.

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Rapid acquisition and modulation of colistin-resistance by an extensively drug-resistant Acinetobacter baumannii: case report and review of current literature

Microbiologia Medica ◽

10.4081/mm.2016.5869 ◽

2016 ◽

Vol 31 (3) ◽

Author(s):

Jari Intra ◽

Roberta M. Sala ◽

Eduardo Beck ◽

Paolo Brambilla

Keyword(s):

Acinetobacter Baumannii ◽

Current Literature ◽

Antimicrobial Agents ◽

Present Report ◽

Drug Resistant ◽

Colistin Resistance ◽

Rapid Acquisition ◽

Extensively Drug Resistant ◽

Clinical Resistance

Acinetobacter baumannii has emerged as a major cause of healthcare-associated infections. It commonly expresses clinical resistance to multiple antimicrobial agents, and hence, it is considered the paradigm of an extensively drug-resistant (XDR) bacterium. XDR A. baumannii is a rapidly emerging pathogen, especially in the intensive care unit (ICU), causing nosocomial infections including sepsis, ventilatorassociated pneumonia, meningitis, peritonitis, urinary tract infection, and central venous catheter-related infection. In the present report, we described an in vivo evolution of A. baumannii strain from a colistinsusceptibility to a colistin-resistance state. A 65-year-old male, who suffered a duodenal ulcer, two days after hospitalization and during the stay in ICU, contracted a pneumonia and peritoneal infection by a carbapenem-resistant A. baumannii strain. After a combination treatment with colistin, vancomycin plus imipenem, and within seven days, the pathogen rapidly evolved in seven days to a pandrug-resistant phenotype. As the antimicrobial treatment was stopped, the A. baumannii isolate changed another time its profile to colistin, becoming newly susceptible, showing a very high level of adaptability to external conditions. We also have reviewed here the current literature on this worryingly public health threat.

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Comparative genomics of Acinetobacter baumannii and therapeutic bacteriophages from a patient undergoing phage therapy

10.1101/2021.12.14.472731 ◽

2021 ◽

Author(s):

Mei Liu ◽

Adriana C Hernandez-Morales ◽

James Clark ◽

Tram T. Le ◽

Biswajit Biswas ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Phage Therapy ◽

The United States ◽

Modern Human ◽

Sequence Type ◽

Drug Resistant ◽

Capsule Locus ◽

Phage Treatment

In 2016, a 68-year-old patient with a disseminated multi-drug resistant Acinetobacter baumannii infection was treated using lytic bacteriophages in one of the first modern human clinical uses of phage therapy in the United States. Due to the emergency nature of the treatment there was little time to thoroughly characterize the phages used in this intervention or the pathogen itself. Here we report the genomes of the nine phages used for treatment and three strains of A. baumannii isolated prior to and during treatment. The eight phages used in the initial treatment were found to be a group of closely related T4-like myophages; the ninth phage, AbTP3Φ1, was found to be an unrelated Fri1-like podophage. Analysis of 19 A. baumannii isolates collected before and during phage treatment showed that resistance to the T4-like phages appeared as early as two days following the start of treatment. Three A. baumannii strains (TP1, TP2 and TP3) collected before and during treatment were sequenced to closure, and all contained a 3.9 Mb chromosome of sequence type 570 with a KL116 capsule locus and identical 8.7 kb plasmids. Phage-insensitive mutants of A. baumannii strain TP1 were generated in vitro and the majority of identified mutations were located in the bacterial capsule locus. The presence of the same mutation in both the in vitro mutants and in phage-insensitive isolates TP2 and TP3, which evolved in vivo during phage treatment, indicate that in vitro investigations can produce results that are relevant and predictive for the in vivo environment.

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SPR741, an Antibiotic Adjuvant, Potentiates the In Vitro and In Vivo Activity of Rifampin against Clinically Relevant Extensively Drug-Resistant Acinetobacter baumannii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01239-17 ◽

2017 ◽

Vol 61 (12) ◽

Cited By ~ 24

Author(s):

Daniel V. Zurawski ◽

Alexandria A. Reinhart ◽

Yonas A. Alamneh ◽

Michael J. Pucci ◽

Yuanzheng Si ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Ventilator Associated Pneumonia ◽

Drug Resistant ◽

Proof Of Concept ◽

Bacterial Burden ◽

Content Type ◽

Extensively Drug Resistant ◽

Animal Survival

ABSTRACT Acinetobacter baumannii is responsible for 10% of all nosocomial infections and has >50% mortality rates when causing ventilator-associated pneumonia. In this proof-of-concept study, we evaluated SPR741, an antibiotic adjuvant that permeabilizes the Gram-negative membrane, in combination with rifampin against AB5075, an extensively drug-resistant (XDR) A. baumannii strain. In standard in vitro assays and in a murine pulmonary model, we found that this drug combination can significantly reduce bacterial burden and promote animal survival despite an aggressive infection.

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