scholarly journals Preclinical Assessment of Bacteriophage Therapy against Experimental Acinetobacter baumannii Lung Infection

Viruses ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 33
Author(s):  
Sandra-Maria Wienhold ◽  
Markus C. Brack ◽  
Geraldine Nouailles ◽  
Gopinath Krishnamoorthy ◽  
Imke H. E. Korf ◽  
...  
Keyword(s):  
Single Dose ◽  
Acinetobacter Baumannii ◽  
Human Lung ◽  
Lung Infection ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Lytic Phage ◽  
Bacterial Burden ◽  
Bacteriophage Therapy ◽  
Cellular Recruitment

Respiratory infections caused by multidrug-resistant Acinetobacter baumannii are difficult to treat and associated with high mortality among critically ill hospitalized patients. Bacteriophages (phages) eliminate pathogens with high host specificity and efficacy. However, the lack of appropriate preclinical experimental models hampers the progress of clinical development of phages as therapeutic agents. Therefore, we tested the efficacy of a purified lytic phage, vB_AbaM_Acibel004, against multidrug-resistant A. baumannii clinical isolate RUH 2037 infection in immunocompetent mice and a human lung tissue model. Sham- and A. baumannii-infected mice received a single-dose of phage or buffer via intratracheal aerosolization. Group-specific differences in bacterial burden, immune and clinical responses were compared. Phage-treated mice not only recovered faster from infection-associated hypothermia but also had lower pulmonary bacterial burden, lower lung permeability, and cytokine release. Histopathological examination revealed less inflammation with unaffected inflammatory cellular recruitment. No phage-specific adverse events were noted. Additionally, the bactericidal effect of the purified phage on A. baumannii was confirmed after single-dose treatment in an ex vivo human lung infection model. Taken together, our data suggest that the investigated phage has significant potential to treat multidrug-resistant A. baumannii infections and further support the development of appropriate methods for preclinical evaluation of antibacterial efficacy of phages.

scholarly journals Assessment of the In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) against Carbapenem-Resistant Acinetobacter baumannii in the Neutropenic Murine Lung Infection Model

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Lindsay M. Avery ◽  
Kamilia Abdelraouf ◽  
David P. Nicolau
Keyword(s):  
Acinetobacter Baumannii ◽  
Lung Infection ◽  
Infection Model ◽  
Bacterial Burden ◽  
In Vivo Efficacy ◽  
Content Type ◽  
Murine Lung ◽  
Carbapenem Resistant ◽  
The Mean

ABSTRACT We evaluated the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) against cefepime-resistant Acinetobacter baumannii strains (n = 13) in the neutropenic murine lung infection model. Twelve isolates were meropenem resistant. In control animals and those that received cefepime or zidebactam alone, the mean bacterial growth at 24 h was >2 log10 CFU/lung compared with 0-h controls (6.32 ± 0.33 log10 CFU/lung). WCK 5222 produced a decline in the bacterial burden for all isolates (mean reduction, −3.34 ± 0.85 log10 CFU/lung) and demonstrated remarkable potency.

Humanized Exposures of a β-Lactam-β-Lactamase Inhibitor, Tazobactam, versus Non-β-Lactam-β-Lactamase Inhibitor, Avibactam, with or without Colistin, against Acinetobacter baumannii in Murine Thigh and Lung Infection Models

Pharmacology ◽  
2018 ◽  
Vol 101 (5-6) ◽  
pp. 255-261 ◽  
Author(s):  
Marguerite L. Monogue ◽  
George Sakoulas ◽  
Victor Nizet ◽  
David P. Nicolau
Keyword(s):  
Acinetobacter Baumannii ◽  
Lung Infection ◽  
Multidrug Resistant ◽  
Lung Model ◽  
Infection Model ◽  
Peptide Antibiotics ◽  
Infection Models ◽  
Lactamase Inhibitor

β-lactam-β-lactamase inhibitors (BLIs) have previously demonstrated antimicrobial activity against Acinetobacter baumannii (AB). Colistin retains the highest susceptibility rate against A. baumannii, and has demonstrated synergy with other antimicrobials, including β-lactam-BLIs. Therefore, we assessed the potential individual activity and synergistic combinations in vivo against carbapenem-susceptible (CS) and multidrug-resistant (MDR) A. baumannii isolates in neutropenic thigh and lung infection models. In vitro, colistin and tazobactam MICs were 1 and 16 µg/mL against AB 25–49 (CS) and 1 and 128 µg/mL against AB 5075 (MDR) respectively. In the lung model, tazobactam alone and in combination with colistin achieved a 1-log reduction in CFU, while colistin alone was not active against AB 25–49. No activity was observed against AB 5075. In the thigh model, tazobactam with and without colistin was bacteriostatic against AB 25–49 but did not demonstrate any activity against AB 5075. Avibactam and colistin alone and in combination were not active against either isolate. No synergy was observed; however, we found tazobactam activity against A. baumannii. This activity was not observed for the non-β-lactam-BLI, avibactam. This suggests that binding to penicillin-binding proteins of the β-lactam molecule is required for tazobactam activity against A. baumannii. These data point to an added role of β-lactam-BLIs beyond their primary purpose of β-lactamase inhibition in the treatment of MDR A. baumannii infections by enhancing the activity of peptide antibiotics, a property that is not shared by the novel non-β-lactam-BLIs. Future studies are needed to define tazobactam and colistin activity in an A. baumannii infection model.

scholarly journals Elucidating the Pharmacokinetics/Pharmacodynamics of Aerosolized Colistin against Multidrug-Resistant Acinetobacter baumannii and Klebsiella pneumoniae in a Mouse Lung Infection Model

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Yu-Wei Lin ◽  
Qi Tony Zhou ◽  
Mei-Ling Han ◽  
Ke Chen ◽  
Nikolas J. Onufrak ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Acinetobacter Baumannii ◽  
Lung Infection ◽  
Multidrug Resistant ◽  
Dose Fractionation ◽  
Mouse Lung ◽  
Infection Model ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Content Type

ABSTRACT The pharmacokinetics/pharmacodynamics (PK/PD) of aerosolized colistin was investigated against Acinetobacter baumannii and Klebsiella pneumoniae over 24 h in a neutropenic mouse lung infection model. Dose fractionation studies were performed over 2.64 to 23.8 mg/kg/day, and the data were fitted to a sigmoid inhibitory model. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC) in the epithelial lining fluid was the most predictive PK/PD index for aerosolized colistin against both pathogens. Our study provides important pharmacological information for optimizing aerosolized colistin.

scholarly journals Characterization and Sequencing of a Novel Phage Abp95 Against Multi-genotypes of Carbapenem-resistant Acinetobacter Baumannii

2021 ◽  
Author(s):  
Li Huang ◽  
Siyi Huang ◽  
Lingli Jiang ◽  
Jingjie Tan ◽  
Xueping Yan ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Host Range ◽  
Phage Therapy ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Lytic Phage ◽  
Carbapenem Resistant ◽  
Wide Host Range ◽  
A Genome ◽  
Tract Infections

Abstract Acinetobacter baumannii has become a challenging conditional pathogen. A. baumannii can lead to different infections, such as wound or urinary tract infections and pneumonia. As an alternative strategy for antibiotic-resistant A. baumannii infections, phage therapy had been used and approved by several governments. Previously we had reported two potential phage therapy candidates named Abp1 and Abp9. In this study, a wide host range lytic phage Abp95 were isolated and sequenced. The biological characteristics of Abp95 are also stuied. Abp95 belongs to the myoviridae family, containing a G+C content of 38.07% with a genome of 43,176 bp. Abp95 genome encodes 77 hypothetical genes, without any known virulence genes. With a diabetic wound infection model, Abp95 could accelerate wound healing though clearing local infections of multidrug-resistant A. baumannii. In conclusion, wide host range lytic phage Abp95 shows the potential as phage therapy candidate against multi-genotypes of Carbapenem-Resistant Acinetobacter baumannii.

scholarly journals Successful Treatment of Staphylococcus aureus Prosthetic Joint Infection with Bacteriophage Therapy

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1182
Author(s):  
Claudia Ramirez-Sanchez ◽  
Francis Gonzales ◽  
Maureen Buckley ◽  
Biswajit Biswas ◽  
Matthew Henry ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Prosthetic Joint Infection ◽  
Joint Infection ◽  
Multidrug Resistant ◽  
Successful Outcome ◽  
Prolonged Treatment ◽  
Lytic Phage ◽  
Bacteriophage Therapy ◽  
Prosthetic Joint ◽  
Knee Joint Infection

Successful joint replacement is a life-enhancing procedure with significant growth in the past decade. Prosthetic joint infection occurs rarely; it is a biofilm-based infection that is poorly responsive to antibiotic alone. Recent interest in bacteriophage therapy has made it possible to treat some biofilm-based infections, as well as those caused by multidrug-resistant pathogens, successfully when conventional antibiotic therapy has failed. Here, we describe the case of a 61-year-old woman who was successfully treated after a second cycle of bacteriophage therapy administered at the time of a two-stage exchange procedure for a persistent methicillin-sensitive Staphylococcus aureus (MSSA) prosthetic knee-joint infection. We highlight the safety and efficacy of both intravenous and intra-articular infusions of bacteriophage therapy, a successful outcome with a single lytic phage, and the development of serum neutralization with prolonged treatment.

scholarly journals Proof-of-Principle Study in a Murine Lung Infection Model of Antipseudomonal Activity of Phage PEV20 in a Dry-Powder Formulation

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Rachel Yoon Kyung Chang ◽  
Ke Chen ◽  
Jiping Wang ◽  
Martin Wallin ◽  
Warwick Britton ◽  
...  
Keyword(s):  
Lung Infection ◽  
Treated Group ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Dry Powder ◽  
Intratracheal Administration ◽  
Promising Alternative ◽  
Content Type ◽  
Powder Formulation

ABSTRACT Bacteriophage therapy is a promising alternative treatment to antibiotics, as it has been documented to be efficacious against multidrug-resistant bacteria with minimal side effects. Several groups have demonstrated the efficacy of phage suspension in vivo to treat lung infections using intranasal delivery; however, phage dry-powder administration to the lungs has not yet been explored. Powder formulations provide potential advantages over a liquid formulation, including easy storage, transport, and administration. The purpose of this study was to assess the bactericidal activities of phage dry-powder formulations against multidrug-resistant (MDR) strain Pseudomonas aeruginosa FADDI-PA001 in a mouse lung infection model. Phage PEV20 spray dried with lactose and leucine produced an inhalable powder at a concentration of 2 × 107 PFU/mg. P. aeruginosa lung infection was established by intratracheal administration of the bacterial suspension to neutropenic mice. At 2 h after the bacterial challenge, the infected mice were treated with 2 mg of the phage powder using a dry-powder insufflator. At 24 h after the phage treatment, the bacterial load in the lungs was decreased by 5.3 log10 (P < 0.0005) in the phage-treated group compared with that in the nontreated group. Additionally, the phage concentration in the lungs was increased by 1 log10 at 24 h in the treated group. These results demonstrate the feasibility of a pulmonary delivery of phage PEV20 dry-powder formulation for the treatment of lung infection caused by antibiotic-resistant P. aeruginosa.

scholarly journals Efficacy of Apramycin against Multidrug-Resistant Acinetobacter baumannii in the Murine Neutropenic Thigh Model

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Anthony D. Kang ◽  
Kenneth P. Smith ◽  
Anders H. Berg ◽  
Katherine A. Truelson ◽  
George M. Eliopoulos ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Maximum Concentration ◽  
Area Under The Curve ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Gram Negative ◽  
Content Type ◽  
Model Treatment

ABSTRACT Apramycin, an aminocyclitol aminoglycoside, was rapidly bactericidal against Acinetobacter baumannii . In a neutropenic murine thigh infection model, treatment-associated A. baumannii CFU reductions of >4 log 10 per thigh were observed for all exposures for which area under the curve (AUC)/MIC ratio was >50 and maximum concentration of drug in serum ( C max )/MIC was ≈10 or higher. Based on these findings, we suggest that apramycin deserves further preclinical exploration as a repurposed therapeutic for multidrug-resistant Gram-negative pathogens, including A. baumannii .

scholarly journals Assessment of the In Vivo Activity of SPR741 in Combination with Azithromycin against Multidrug-Resistant Enterobacteriaceae Isolates in the Neutropenic Murine Thigh Infection Model

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Sean M. Stainton ◽  
Kamilia Abdelraouf ◽  
Luke Utley ◽  
Michael J. Pucci ◽  
Troy Lister ◽  
...  
Keyword(s):  
Potential Role ◽  
Wide Spectrum ◽  
Structural Similarity ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Bacterial Burden ◽  
Content Type ◽  
Novel Agent

ABSTRACT SPR741 is a novel agent with structural similarity to polymyxins that is capable of potentiating the activities of various classes of antibiotics. Previously published studies indicated that although Enterobacteriaceae isolates had minimal susceptibilities to azithromycin (AZM), the in vitro antimicrobial activity of AZM against Enterobacteriaceae was enhanced when it was combined with SPR741. The current study evaluated the in vivo activity of human-simulated regimens (HSR) of AZM equivalent to clinical doses of 500 mg given intravenously (i.v.) every 24 h (q24h) and SPR741 equivalent to clinical doses of 400 mg q8h i.v. (1-h infusion), alone and in combination, against multidrug-resistant (MDR) Enterobacteriaceae . We studied 30 MDR Enterobacteriaceae isolates expressing a wide spectrum of β-lactamases (ESBL, NDM, VIM, and KPC), including a subset of isolates positive for genes conferring macrolide resistance ( mphA , mphE , ermB , and msr ). In vivo activity was assessed as the change in log 10 CFU per thigh at 24 h compared with 0 h. Treatment with AZM alone was associated with net growth of 2.60 ± 0.83 log 10 CFU/thigh. Among isolates with AZM MICs of ≤16 mg/liter, treatment with AZM-SPR741was associated with an average reduction in bacterial burden of −0.53 ± 0.82 log 10 CFU/thigh, and stasis to 1-log kill was observed in 9/11 isolates (81.8%). Combination therapy with an AZM-SPR741 HSR showed promising in vivo activity against MDR Enterobacteriaceae isolates with AZM MICs of ≤16 mg/liter, including those producing a variety of β-lactamases. These data support a potential role for AZM-SPR741 in the treatment of infections due to MDR Enterobacteriaceae .

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