Phage Therapy for a Multidrug-Resistant Acinetobacter baumannii Craniectomy Site Infection

Abstract In the era of antibiotic resistance, alternative treatment options for multidrug-resistant bacterial infections are being explored. We present a case of multidrug-resistant Acinetobacter baumannii infection treated with bacteriophages. Clinical trials are needed to further investigate bacteriophage therapy as an option to treat multidrug-resistant bacterial infections.

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Carbapenemase Genes and Multidrug Resistance of Acinetobacter Baumannii: A Cross Sectional Study of Patients with Pneumonia in Southern Vietnam

Antibiotics ◽

10.3390/antibiotics8030148 ◽

2019 ◽

Vol 8 (3) ◽

pp. 148 ◽

Cited By ~ 5

Author(s):

Cuong Hoang Quoc ◽

Thao Nguyen Thi Phuong ◽

Hai Nguyen Duc ◽

Trung Tran Le ◽

Hang Tran Thi Thu ◽

...

Keyword(s):

Antibiotic Resistance ◽

Acinetobacter Baumannii ◽

Demographic Data ◽

Treatment Options ◽

Bacterial Pathogen ◽

Multidrug Resistant ◽

Cross Sectional Study ◽

Cross Sectional ◽

Carbapenem Resistant ◽

Hospital Acquired

Background: Acinetobacter baumannii (Ab) is an opportunistic bacterial pathogen found in hospital-acquired infections including nosocomial pneumonia, especially multidrug-resistant Ab. This study aims to survey the drug resistance profiles of Ab isolated from patients in Thong Nhat Dong Nai General Hospital and assess the relationship between genotypes and antibiotic resistance; Methods: Ninety-seven Ab strains isolated from 340 lower respiratory tract specimens among pneumonia patients were used to screen the most common local carbapenemase genes. Antimicrobial susceptibility testing results and demographic data were collected and minimum inhibitory concentrations (MIC) of colistin were also determined; Results: Over 80% and 90% of Ab strains were determined as carbapenem-resistant and multidrug-resistant (MDR), respectively. Most of the strains carried carbapenemase genes, including blaOXA-51, blaOXA-23-like, blaOXA-58-like, and blaNDM-1, with proportions of 97 (100%), 76 (78.4%), 10 (10.3%), 6 (6.2%), respectively. Amongst these genes, blaOXA-23-like was the only gene which significantly influenced the resistance (p < 0.0001); and Conclusions: The severity of Ab antibiotic resistance is urgent and specifically related to carbapenemase encoding genes. Therefore, screening of MDR Ab and carbapenemase for better treatment options is necessary.

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Stemming the tide of antibiotic resistance by exploiting bacteriophages

The Biochemist ◽

10.1042/bio20200074 ◽

2020 ◽

Vol 42 (6) ◽

pp. 6-11

Author(s):

Michael J Love ◽

Renwick C J Dobson ◽

Craig Billington

Keyword(s):

Clinical Trials ◽

Antibiotic Resistance ◽

Bacterial Infections ◽

Ad Hoc ◽

Phage Therapy ◽

Antibiotic Use ◽

Alternative Strategies ◽

Life Saving ◽

Regulatory Guidelines ◽

Future Supply

The growing prevalence of antibiotic resistance is a global crisis. It is predicted that by 2050, antibiotic resistance-related deaths will exceed by 10 million per year. Thus, there is an urgent need for alternative strategies that can either replace or supplement antibiotic use. Bacteriophages and their encoded lytic proteins, called endolysins, have both shown promise as antibiotic alternatives. Bacteriophages were first investigated as therapeutics nearly a century ago, but the success of antibiotics led to phage therapy being largely abandoned in Western medicine until recently. While sporadic reports of life-saving successes in the ad hoc use of phage therapy have emerged, properly designed, robust clinical trials and clear regulatory guidelines are required before the true potential of phage therapy can be realized. In addition, despite endolysin research still being in its infancy, the early successes of endolysin-based therapeutics already entering clinical trials are an exciting glimpse into the future. No stone can be left unturned in the discovery and development of novel therapeutics if we are to ensure a future supply of effective treatments for bacterial infections.

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Bacteriophage therapy: coping with the growing antibiotic resistance problem

Microbiology Australia ◽

10.1071/ma19011 ◽

2019 ◽

Vol 40 (1) ◽

pp. 5 ◽

Cited By ~ 3

Author(s):

Nina Chanishvili ◽

Rustam Aminov

Keyword(s):

Antibiotic Resistance ◽

Infection Control ◽

Phage Therapy ◽

Bacterial Pathogens ◽

Multidrug Resistant ◽

Bacteriophage Therapy ◽

Global Problem ◽

Infection Treatment ◽

Control Options ◽

Accepted Form

The global problem of multidrug-resistant bacterial pathogens requires urgent actions, including the development of therapies supplementary or alternative to antibiotics. One of the infection control options could be phage therapy. This article gives a brief overview of phage therapy potentials as well as the challenges it faces in order to become a widely accepted form of infection treatment.

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Bacteriophage Treatment Rescues Mice Infected with Multidrug-Resistant Klebsiella pneumoniae ST258

mBio ◽

10.1128/mbio.00034-21 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Shayla Hesse ◽

Natalia Malachowa ◽

Adeline R. Porter ◽

Brett Freedman ◽

Scott D. Kobayashi ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Alternative Treatment ◽

Bacterial Infections ◽

Phage Therapy ◽

Treatment Approach ◽

Multidrug Resistant ◽

Sequence Type ◽

Infection Model ◽

Content Type ◽

Treatment Groups

ABSTRACT Severe infections caused by multidrug-resistant Klebsiella pneumoniae sequence type 258 (ST258) highlight the need for new therapeutics with activity against this pathogen. Bacteriophage (phage) therapy is an alternative treatment approach for multidrug-resistant bacterial infections that has shown efficacy in experimental animal models and promise in clinical case reports. In this study, we assessed microbiologic, histopathologic, and survival outcomes following systemic administration of phage in ST258-infected mice. We found that prompt treatment with two phages, either individually or in combination, rescued mice with K. pneumoniae ST258 bacteremia. Among the three treatment groups, mice that received combination phage therapy demonstrated the greatest increase in survival and the lowest frequency of phage resistance among bacteria recovered from mouse blood and tissue. Our findings support the utility of phage therapy as an approach for refractory ST258 infections and underscore the potential of this treatment modality to be enhanced through strategic phage selection. IMPORTANCE Infections caused by multidrug-resistant K. pneumoniae pose a serious threat to at-risk patients and present a therapeutic challenge for clinicians. Bacteriophage (phage) therapy is an alternative treatment approach that has been associated with positive clinical outcomes when administered experimentally to patients with refractory bacterial infections. Inasmuch as these experimental treatments are prepared for individual patients and authorized for compassionate use only, they lack the rigor of a clinical trial and therefore cannot provide proof of efficacy. Here, we demonstrate that administration of viable phage provides effective treatment for multidrug-resistant K. pneumoniae (sequence type 258 [ST258]) bacteremia in a murine infection model. Moreover, we compare outcomes among three distinct phage treatment groups and identify potential correlates of therapeutic phage efficacy. These findings constitute an important first step toward optimizing and assessing phage therapy’s potential for the treatment of severe ST258 infection in humans.

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K2 Capsule Depolymerase Is Highly Stable, Is Refractory to Resistance, and Protects Larvae and Mice from Acinetobacter baumannii Sepsis

Applied and Environmental Microbiology ◽

10.1128/aem.00934-19 ◽

2019 ◽

Vol 85 (17) ◽

Cited By ~ 4

Author(s):

Hugo Oliveira ◽

Ana Mendes ◽

Alexandra G. Fraga ◽

Alice Ferreira ◽

Andreia I. Pimenta ◽

...

Keyword(s):

Antibiotic Resistance ◽

Acinetobacter Baumannii ◽

Bacterial Infections ◽

Multidrug Resistant ◽

Host Immune System ◽

Dependent Manner ◽

Bacterial Cells ◽

Capsular Type ◽

Nosocomial Pathogen ◽

Content Type

ABSTRACT Acinetobacter baumannii is emerging as a major nosocomial pathogen in intensive care units. The bacterial capsules are considered major virulence factors, and the particular A. baumannii capsular type K2 has been associated with high antibiotic resistance. In this study, we identified a K2 capsule-specific depolymerase in a bacteriophage tail spike C terminus, a fragment that was heterologously expressed, and its antivirulence properties were assessed by in vivo experiments. The K2 depolymerase is active under a broad range of environmental conditions and is highly thermostable, with a melting point (Tm) at 67°C. In the caterpillar larva model, the K2 depolymerase protects larvae from bacterial infections, using either pretreatments or with single-enzyme injection after bacterial challenge, in a dose-dependent manner. In a mouse sepsis model, a single K2 depolymerase intraperitoneal injection of 50 μg is able to protect 60% of mice from an otherwise deadly infection, with a significant reduction in the proinflammatory cytokine profile. We showed that the enzyme makes bacterial cells fully susceptible to the host complement system killing effect. Moreover, the K2 depolymerase is highly refractory to resistance development, which makes these bacteriophage-derived capsular depolymerases useful antivirulence agents against multidrug-resistant A. baumannii infections. IMPORTANCE Acinetobacter baumannii is an important nosocomial pathogen resistant to many, and sometimes all, antibiotics. The A. baumannii K2 capsular type has been associated with elevated antibiotic resistance. The capsular depolymerase characterized here fits the new trend of alternative antibacterial agents needed against multidrug-resistant pathogens. They are highly specific, stable, and refractory to resistance, as they do not kill bacteria per se; instead, they remove bacterial surface polysaccharides, which diminish the bacterial virulence and expose them to the host immune system.

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Critically ill patient with multidrug-resistant Acinetobacter baumannii respiratory infection successfully treated with intravenous and nebulized bacteriophage therapy

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00824-21 ◽

2021 ◽

Author(s):

Sohail Rao ◽

Monica Betancourt-Garcia ◽

Yetunde O. Kare-Opaneye ◽

Brett E. Swiercezewski ◽

Jason W. Bennett ◽

...

Keyword(s):

Mechanical Ventilation ◽

Acinetobacter Baumannii ◽

Critically Ill ◽

Respiratory Infection ◽

Bacterial Infections ◽

Multidrug Resistant ◽

Critically Ill Patient ◽

Drug Resistant ◽

Bacteriophage Therapy ◽

Chronic Comorbidities

Hospitalized patients are at risk of developing serious multi-drug resistant bacterial infections. This risk is heightened in patients who are on mechanical ventilation, are immunocompromised, and/or have chronic comorbidities. We report the case of a 52-year-old critically ill patient with a multidrug resistant Acinetobacter baumannii (MDR-A) respiratory infection who was successfully treated with antibiotics and intravenous and nebulized bacteriophage therapy.

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Virulence Potential and Treatment Options of Multidrug-Resistant (MDR) Acinetobacter baumannii

Microorganisms ◽

10.3390/microorganisms9102104 ◽

2021 ◽

Vol 9 (10) ◽

pp. 2104

Author(s):

Sunil Kumar ◽

Razique Anwer ◽

Arezki Azzi

Keyword(s):

Acinetobacter Baumannii ◽

Virulence Factors ◽

Bacterial Infections ◽

Antimicrobial Agents ◽

Treatment Options ◽

Outer Membrane Proteins ◽

Multidrug Resistant ◽

High Rate ◽

World Health ◽

Tract Infections

Acinetobacter baumannii is an opportunistic pathogen which is undoubtedly known for a high rate of morbidity and mortality in hospital-acquired infections. A. baumannii causes life-threatening infections, including; ventilator-associated pneumonia (VAP), meningitis, bacteremia, and wound and urinary tract infections (UTI). In 2017, the World Health Organization listed A. baumannii as a priority-1 pathogen. The prevalence of A. baumannii infections and outbreaks emphasizes the direct need for the use of effective therapeutic agents for treating such infections. Available antimicrobials, such as; carbapenems, tigecycline, and colistins have insufficient effectiveness due to the appearance of multidrug-resistant strains, accentuating the need for alternative and novel therapeutic remedies. To understand and overcome this menace, the knowledge of recent discoveries on the virulence factors of A. baumannii is needed. Herein, we summarized the role of various virulence factors, including; outer membrane proteins, efflux pumps, biofilm, penicillin-binding proteins, and siderophores/iron acquisition systems. We reviewed the recent scientific literature on different A. baumannii virulence factors and the effective antimicrobial agents for the treatment and management of bacterial infections.

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An Overview on the Application of Bacteriophage Therapy in Combating Antibiotics Resistance: A Review

UMYU Journal of Microbiology Research (UJMR) ◽

10.47430/ujmr.2161.015 ◽

2021 ◽

Vol 6 (1) ◽

pp. 113-119

Author(s):

A. F. Aishat ◽

◽

S. B. Manga ◽

I. O. Obaroh ◽

R. J. Bioku ◽

...

Keyword(s):

Bacterial Infections ◽

Phage Therapy ◽

Multidrug Resistant ◽

Antibiotics Resistance ◽

Therapeutic Approaches ◽

Bacteriophage Therapy ◽

Advantages And Disadvantages ◽

Naturally Occurring ◽

Bacterial Viruses ◽

Novel Therapeutic

The practice of phage therapy, which uses bacterial viruses (phages) to treat bacterial infections, has been around for almost a century. The universal decline in the effectiveness of antibiotics has generated renewed interest in revisiting this practice. Conventionally, phage therapy relies on the use of naturally-occurring phages to infect and lyse bacteria at the site of infection. Biotechnological advances have further expanded the repertoire of potential phage therapeutics to include novel strategies using bioengineered phages and purified phage lytic proteins. Current research on the use of phages and their lytic proteins, specifically against multidrug resistant bacterial infections, suggests phage therapy has the potential to be used as either an alternative or a supplement to antibiotic treatments. Antibacterial therapies, whether phage- or antibioticbased, have relative advantages and disadvantages accordingly. Many considerations must be taken into account when designing novel therapeutic approaches for preventing and treating bacterial infections. Although much is still unknown about the interactions between phage, bacteria, and human host, the time to take phage therapy seriously seems to be rapidly approaching Keywords: Antibiotic resistance; Antimicrobial; Bacteriophage; Biofilms; Multidrug resistance; Phage; Phage safety; Therapy.

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Radiation-Inactivated Acinetobacter baumannii Vaccine Candidates

Vaccines ◽

10.3390/vaccines9020096 ◽

2021 ◽

Vol 9 (2) ◽

pp. 96

Author(s):

Stephen J. Dollery ◽

Daniel V. Zurawski ◽

Elena K. Gaidamakova ◽

Vera Y. Matrosova ◽

John K. Tobin ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Treatment Options ◽

Bacterial Pathogen ◽

Multidrug Resistant ◽

Bacterial Cells ◽

Wound Infections ◽

Protein Profiles ◽

Vaccine Candidates ◽

Rich Media ◽

Life Threatening

Acinetobacter baumannii is a bacterial pathogen that is often multidrug-resistant (MDR) and causes a range of life-threatening illnesses, including pneumonia, septicemia, and wound infections. Some antibiotic treatments can reduce mortality if dosed early enough before an infection progresses, but there are few other treatment options when it comes to MDR-infection. Although several prophylactic strategies have been assessed, no vaccine candidates have advanced to clinical trials or have been approved. Herein, we rapidly produced protective whole-cell immunogens from planktonic and biofilm-like cultures of A. baumannii, strain AB5075 grown using a variety of methods. After selecting a panel of five cultures based on distinct protein profiles, replicative activity was extinguished by exposure to 10 kGy gamma radiation in the presence of a Deinococcus antioxidant complex composed of manganous (Mn2+) ions, a decapeptide, and orthophosphate. Mn2+ antioxidants prevent hydroxylation and carbonylation of irradiated proteins, but do not protect nucleic acids, yielding replication-deficient immunogenic A. baumannii vaccine candidates. Mice were immunized and boosted twice with 1.0 × 107 irradiated bacterial cells and then challenged intranasally with AB5075 using two mouse models. Planktonic cultures grown for 16 h in rich media and biofilm cultures grown in static cultures underneath minimal (M9) media stimulated immunity that led to 80–100% protection.

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Phage-Encoded Endolysins

Antibiotics ◽

10.3390/antibiotics10020124 ◽

2021 ◽

Vol 10 (2) ◽

pp. 124

Author(s):

Fatma Abdelrahman ◽

Maheswaran Easwaran ◽

Oluwasegun I. Daramola ◽

Samar Ragab ◽

Stephanie Lynch ◽

...

Keyword(s):

Clinical Trials ◽

Cell Wall ◽

Antibiotic Resistance ◽

Bacterial Infections ◽

Therapeutic Strategies ◽

Therapeutic Application ◽

Significant Evidence ◽

Crucial Information

Due to the global emergence of antibiotic resistance, there has been an increase in research surrounding endolysins as an alternative therapeutic. Endolysins are phage-encoded enzymes, utilized by mature phage virions to hydrolyze the cell wall from within. There is significant evidence that proves the ability of endolysins to degrade the peptidoglycan externally without the assistance of phage. Thus, their incorporation in therapeutic strategies has opened new options for therapeutic application against bacterial infections in the human and veterinary sectors, as well as within the agricultural and biotechnology sectors. While endolysins show promising results within the laboratory, it is important to document their resistance, safety, and immunogenicity for in-vivo application. This review aims to provide new insights into the synergy between endolysins and antibiotics, as well as the formulation of endolysins. Thus, it provides crucial information for clinical trials involving endolysins.

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