From Klebsiella pneumoniae Colonization to Dissemination: An Overview of Studies Implementing Murine Models

Klebsiella pneumoniae is a Gram-negative pathogen responsible for community-acquired and nosocomial infections. The strains of this species belong to the opportunistic group, which is comprised of the multidrug-resistant strains, or the hypervirulent group, depending on their accessory genome, which determines bacterial pathogenicity and the host immune response. The aim of this survey is to present an overview of the murine models mimicking K. pneumoniae infectious processes (i.e., gastrointestinal colonization, urinary, pulmonary, and systemic infections), and the bacterial functions deployed to colonize and disseminate into the host. These in vivo approaches are pivotal to develop new therapeutics to limit K. pneumoniae infections via a modulation of the immune responses and/or microbiota.

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In Vivo Efficacy of Novel Monobactam LYS228 in Murine Models of Carbapenemase-Producing Klebsiella pneumoniae Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02214-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 5

Author(s):

W. J. Weiss ◽

M. E. Pulse ◽

P. Nguyen ◽

E. J. Growcott

Keyword(s):

Klebsiella Pneumoniae ◽

Clinical Development ◽

Murine Models ◽

Bacterial Burden ◽

In Vivo Efficacy ◽

Content Type ◽

Carbapenem Resistant ◽

Infection Models ◽

Resistant Strains

ABSTRACT LYS228 has potent antibacterial activity against carbapenem-resistant strains of Enterobacteriaceae. LYS228 was efficacious in neutropenic thigh models established with Klebsiella pneumoniae producing KPC-2 or NDM-1; pretreatment with uranyl nitrate considerably shifted calculated static doses of LYS228. In murine ascending pyelonephritis, LYS228 reduced bacterial burden in kidney, urine, and bladder. The successful treatment of murine infection models established with carbapenem-resistant K. pneumoniae further supports the clinical development of LYS228.

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In Vivo Efficacy of Simulated Human Dosing Regimens of Prolonged-Infusion Doripenem against Carbapenemase- Producing Klebsiella pneumoniae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00026-10 ◽

2010 ◽

Vol 54 (10) ◽

pp. 4112-4115 ◽

Cited By ~ 42

Author(s):

Catharine C. Bulik ◽

David P. Nicolau

Keyword(s):

Klebsiella Pneumoniae ◽

White Blood Cells ◽

Multidrug Resistant ◽

Gram Negative ◽

Wide Range ◽

Dosing Regimens ◽

Gram Negative Organisms ◽

Immunocompromised Mice

ABSTRACT Carbapenemase-producing Klebsiella pneumoniae (KPC) bacteria are rapidly becoming one of the most detrimental drug-resistant Gram-negative pathogens. Doripenem is the newest FDA-approved carbapenem that has the greatest in vitro potency against a wide range of Gram-negative organisms, including multidrug-resistant organisms. Previous work in an animal model has shown efficacy against Pseudomonas aeruginosa with MICs above the current breakpoints of susceptibility. The purpose of this study is to evaluate the efficacy of 1-g and 2-g dose prolonged infusions of doripenem against KPC isolates in both an immunocompetent and neutropenic murine thigh model. Seven clinical KPC isolates (broth microdilution [BMD] MIC range, 4 to 32 μg/ml; Etest MIC range, 3 to >32 μg/ml) were used. After infection, groups of mice were administered doripenem doses previously shown to simulate the exposures observed in humans after the administration of 1 or 2 g every 8 h as a 4-h infusion. In immunocompromised mice, 1- and 2-g doses of doripenem achieved bacteriostasis against isolates with MICs up to and including 8 μg/ml and 16 μg/ml, respectively. In immunocompetent animals, statistically significant reductions in the number of CFU were observed with overall decreases of approximately 1 log (P < 0.05). While carbapenemase-producing Klebsiella pneumoniae continues to decrease our meager supply of active agents, the ability of doripenem to produce CFU reductions in the presence of white blood cells (WBCs) using humanized exposures suggests the potential utility of this agent in combination against this increasingly problematic pathogen.

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Complete Genome Sequence of Klebsiella pneumoniae Myophage Magnus

Microbiology Resource Announcements ◽

10.1128/mra.01049-19 ◽

2019 ◽

Vol 8 (39) ◽

Author(s):

Laura E. Acevedo Ugarriza ◽

Jordyn Michalik-Provasek ◽

Heather Newkirk ◽

Mei Liu ◽

Jason J. Gill ◽

...

Keyword(s):

Public Health ◽

Klebsiella Pneumoniae ◽

Genome Sequence ◽

Complete Genome Sequence ◽

Complete Genome ◽

Multidrug Resistant ◽

Public Health Issue ◽

Gram Negative ◽

Content Type ◽

Resistant Strains

Bacteriophage Magnus infects Klebsiella pneumoniae, a Gram-negative pathogen whose multidrug-resistant strains are a public health issue. Here, we describe the annotation of the 157,741-bp Magnus genome and its similarity to other myophages.

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Distribution of Extended-Spectrum β-Lactamase (ESBL)-Encoding Genes among Multidrug-Resistant Gram-Negative Pathogens Collected from Three Different Countries

Antibiotics ◽

10.3390/antibiotics10030247 ◽

2021 ◽

Vol 10 (3) ◽

pp. 247

Author(s):

Khaled S. M. Azab ◽

Mohamed Ali Abdel-Rahman ◽

Hussien H. El-Sheikh ◽

Ehab Azab ◽

Adil A. Gobouri ◽

...

Keyword(s):

Escherichia Coli ◽

Pseudomonas Aeruginosa ◽

Saudi Arabia ◽

Klebsiella Pneumoniae ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Gram Negative ◽

Extended Spectrum ◽

Resistant Strains ◽

Encoding Genes

The incidence of Extended-spectrum β-lactamase (ESBL)-encoding genes (blaCTX-M and blaTEM) among Gram-negative multidrug-resistant pathogens collected from three different countries was investigated. Two hundred and ninety-two clinical isolates were collected from Egypt (n = 90), Saudi Arabia (n = 162), and Sudan (n = 40). Based on the antimicrobial sensitivity against 20 antimicrobial agents from 11 antibiotic classes, the most resistant strains were selected and identified using the Vitek2 system and 16S rRNA gene sequence analysis. A total of 85.6% of the isolates were found to be resistant to more than three antibiotic classes. The ratios of the multidrug-resistant strains for Egypt, Saudi Arabia, and Sudan were 74.4%, 90.1%, and 97.5%, respectively. Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa showed inconstant resistance levels to the different classes of antibiotics. Escherichia coli and Klebsiella pneumoniae had the highest levels of resistance against macrolides followed by penicillins and cephalosporin, while Pseudomonas aeruginosa was most resistant to penicillins followed by classes that varied among different countries. The isolates were positive for the presence of the blaCTX-M and blaTEM genes. The blaCTX-M gene was the predominant gene in all isolates (100%), while blaTEM was detected in 66.7% of the selected isolates. This work highlights the detection of multidrug-resistant bacteria and resistant genes among different countries. We suggest that the medical authorities urgently implement antimicrobial surveillance plans and infection control policies for early detection and effective prevention of the rapid spread of these pathogens.

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Antimicrobial Peptides and their Multiple Effects at Sub-Inhibitory Concentrations

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200427090912 ◽

2020 ◽

Vol 20 (14) ◽

pp. 1264-1273 ◽

Cited By ~ 1

Author(s):

Bruno Casciaro ◽

Floriana Cappiello ◽

Walter Verrusio ◽

Mauro Cacciafesta ◽

Maria Luisa Mangoni

Keyword(s):

Antimicrobial Peptides ◽

Inhibitory Concentration ◽

Multidrug Resistant ◽

Mechanisms Of Action ◽

New Drugs ◽

Lead Compounds ◽

Bacterial Pathogenicity ◽

Growth Inhibitory ◽

Resistant Strains ◽

Conventional Antibiotics

The frequent occurrence of multidrug-resistant strains to conventional antimicrobials has led to a clear decline in antibiotic therapies. Therefore, new molecules with different mechanisms of action are extremely necessary. Due to their unique properties, antimicrobial peptides (AMPs) represent a valid alternative to conventional antibiotics and many of them have been characterized for their activity and cytotoxicity. However, the effects that these peptides cause at concentrations below the minimum growth inhibitory concentration (MIC) have yet to be fully analyzed along with the underlying molecular mechanism. In this mini-review, the ability of AMPs to synergize with different antibiotic classes or different natural compounds is examined. Furthermore, data on microbial resistance induction are reported to highlight the importance of antibiotic resistance in the fight against infections. Finally, the effects that sub-MIC levels of AMPs can have on the bacterial pathogenicity are summarized while showing how signaling pathways can be valid therapeutic targets for the treatment of infectious diseases. All these aspects support the high potential of AMPs as lead compounds for the development of new drugs with antibacterial and immunomodulatory activities.

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Silver Nanoparticles and Their Antibacterial Applications

International Journal of Molecular Sciences ◽

10.3390/ijms22137202 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7202

Author(s):

Tamara Bruna ◽

Francisca Maldonado-Bravo ◽

Paul Jara ◽

Nelson Caro

Keyword(s):

Silver Nanoparticles ◽

Antibacterial Agents ◽

Multidrug Resistant ◽

Secondary Effects ◽

Cytotoxic Effects ◽

Factors Affecting ◽

Gram Positive Bacteria ◽

Resistant Strains

Silver nanoparticles (AgNPs) have been imposed as an excellent antimicrobial agent being able to combat bacteria in vitro and in vivo causing infections. The antibacterial capacity of AgNPs covers Gram-negative and Gram-positive bacteria, including multidrug resistant strains. AgNPs exhibit multiple and simultaneous mechanisms of action and in combination with antibacterial agents as organic compounds or antibiotics it has shown synergistic effect against pathogens bacteria such as Escherichia coli and Staphylococcus aureus. The characteristics of silver nanoparticles make them suitable for their application in medical and healthcare products where they may treat infections or prevent them efficiently. With the urgent need for new efficient antibacterial agents, this review aims to establish factors affecting antibacterial and cytotoxic effects of silver nanoparticles, as well as to expose the advantages of using AgNPs as new antibacterial agents in combination with antibiotic, which will reduce the dosage needed and prevent secondary effects associated to both.

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Arginine Is a Critical Substrate for the Pathogenesis of Pseudomonas aeruginosa in Burn Wound Infections

mBio ◽

10.1128/mbio.02160-16 ◽

2017 ◽

Vol 8 (2) ◽

Cited By ~ 16

Author(s):

Jake Everett ◽

Keith Turner ◽

Qiuxian Cai ◽

Vernita Gordon ◽

Marvin Whiteley ◽

...

Keyword(s):

Antimicrobial Agents ◽

Hospital Setting ◽

Multidrug Resistant ◽

Burn Patients ◽

Burn Wound ◽

Burn Wounds ◽

Resistant Strains ◽

High Doses ◽

Ubiquitous Presence

ABSTRACT Environmental conditions affect bacterial behavior and can greatly influence the course of an infection. However, the environmental cues that elicit bacterial responses in specific infection sites are relatively unknown. Pseudomonas aeruginosa is ubiquitous in nature and typically innocuous. However, it is also one of the most prevalent causes of fatal sepsis in burn wound patients. The aim of this study was to determine the impact of environmental factors, specifically the availability of arginine, on the pathogenesis of P. aeruginosa in burn wound infections. Comparison of burned versus noninjured tissue revealed that l-arginine (l-Arg) was significantly depleted in burn wounds as a consequence of elevated arginase produced by myeloid-derived suppressor cells. We also observed that l-Arg was a potent chemoattractant for P. aeruginosa, and while low concentrations of l-Arg increased P. aeruginosa’s swimming motility, high concentrations resulted in diminished swimming. Based on these observations, we tested whether the administration of exogenous l-Arg into the burn wound could attenuate the virulence of P. aeruginosa in thermally injured mice. Administration of l-Arg resulted in decreased P. aeruginosa spread and sepsis and increased animal survival. Taken together, these data demonstrate that the availability of environmental arginine greatly influences the virulence of P. aeruginosa in vivo and may represent a promising phenotype-modulating tool for future therapeutic avenues. IMPORTANCE Despite our growing understanding of the pathophysiology of burn wounds and the evolution of techniques and practices to manage infections, sepsis remains a significant medical concern for burn patients. P. aeruginosa continues to be a leader among all causes of bacteremic infections due to its tendency to cause complications in immunocompromised patients and its ubiquitous presence in the hospital setting. With the unforgiving emergence of multidrug-resistant strains, it is critical that alternative strategies to control or prevent septic infections in burn patients be developed in parallel with novel antimicrobial agents. In this study, we observed that administration of l-Arg significantly reduced bacterial spread and sepsis in burned mice infected with P. aeruginosa. Given the safety of l-Arg in high doses and its potential wound-healing benefits, this conditionally essential amino acid may represent a useful tool to modulate bacterial behavior in vivo and prevent sepsis in burn patients. IMPORTANCE Despite our growing understanding of the pathophysiology of burn wounds and the evolution of techniques and practices to manage infections, sepsis remains a significant medical concern for burn patients. P. aeruginosa continues to be a leader among all causes of bacteremic infections due to its tendency to cause complications in immunocompromised patients and its ubiquitous presence in the hospital setting. With the unforgiving emergence of multidrug-resistant strains, it is critical that alternative strategies to control or prevent septic infections in burn patients be developed in parallel with novel antimicrobial agents. In this study, we observed that administration of l-Arg significantly reduced bacterial spread and sepsis in burned mice infected with P. aeruginosa. Given the safety of l-Arg in high doses and its potential wound-healing benefits, this conditionally essential amino acid may represent a useful tool to modulate bacterial behavior in vivo and prevent sepsis in burn patients.

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Carbapenem-Resistant Klebsiella pneumoniae Clinical Isolates: In Vivo Virulence Assessment in Galleria mellonella and Potential Therapeutics by Polycationic Oligoethyleneimine

Antibiotics ◽

10.3390/antibiotics10010056 ◽

2021 ◽

Vol 10 (1) ◽

pp. 56

Author(s):

Dalila Mil-Homens ◽

Maria Martins ◽

José Barbosa ◽

Gabriel Serafim ◽

Maria J. Sarmento ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Galleria Mellonella ◽

Multidrug Resistant ◽

In Vitro Models ◽

Clinical Isolates ◽

In Vivo Model ◽

Virulence Potential ◽

Hospital Acquired

Klebsiella pneumoniae, one of the most common pathogens found in hospital-acquired infections, is often resistant to multiple antibiotics. In fact, multidrug-resistant (MDR) K. pneumoniae producing KPC or OXA-48-like carbapenemases are recognized as a serious global health threat. In this sense, we evaluated the virulence of K. pneumoniae KPC(+) or OXA-48(+) aiming at potential antimicrobial therapeutics. K. pneumoniae carbapenemase (KPC) and the expanded-spectrum oxacillinase OXA-48 isolates were obtained from patients treated in medical care units in Lisbon, Portugal. The virulence potential of the K. pneumonia clinical isolates was tested using the Galleria mellonella model. For that, G. mellonella larvae were inoculated using patients KPC(+) and OXA-48(+) isolates. Using this in vivo model, the KPC(+) K. pneumoniae isolates showed to be, on average, more virulent than OXA-48(+). Virulence was found attenuated when a low bacterial inoculum (one magnitude lower) was tested. In addition, we also report the use of a synthetic polycationic oligomer (L-OEI-h) as a potential antimicrobial agent to fight infectious diseases caused by MDR bacteria. L-OEI-h has a broad-spectrum antibacterial activity and exerts a significantly bactericidal activity within the first 5-30 min treatment, causing lysis of the cytoplasmic membrane. Importantly, the polycationic oligomer showed low toxicity against in vitro models and no visible cytotoxicity (measured by survival and health index) was noted on the in vivo model (G. mellonella), thus L-OEI-h is foreseen as a promising polymer therapeutic for the treatment of MDR K. pneumoniae infections.

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Multidrug-Resistant Gram-Negative Bacilli: A Retrospective Study of Trends in a Tertiary Healthcare Unit

Medicina ◽

10.3390/medicina54060092 ◽

2018 ◽

Vol 54 (6) ◽

pp. 92 ◽

Cited By ~ 6

Author(s):

Delia Muntean ◽

Florin-George Horhat ◽

Luminița Bădițoiu ◽

Victor Dumitrașcu ◽

Iulia-Cristina Bagiu ◽

...

Keyword(s):

Retrospective Study ◽

Metabolic Diseases ◽

Treatment Options ◽

Acquired Resistance ◽

Multidrug Resistant ◽

Trend Test ◽

Gram Negative ◽

Increasing Trend ◽

Tertiary Healthcare ◽

Resistant Strains

Background and objective: Bacterial multidrug resistance is particularly common in Gram-negative bacilli (GNB), with important clinical consequences regarding their spread and treatment options. The aim of this study was to investigate the trend of multidrug-resistant GNB (MDR-GNB) in high-risk hospital departments, between 2000–2015, in intervals of five years, with the intention of improving antibiotic therapy policies and optimising preventive and control practices. Materials and methods: This is an observational, retrospective study performed in three departments of the most important tertiary healthcare unit in the southwestern part of Romania: the Intensive Care Unit (ICU), the General Surgery Department (GSD), and the Nutrition and Metabolic Diseases Department (NMDD). MDR was defined as acquired resistance to at least one agent in three or more antimicrobial categories. Trends over time were determined by the Cochran–Armitage trend test and linear regression. Results: During the study period, a total of 2531 strains of MDR-GNB were isolated in 1999 patients: 9.20% in 2000, 18.61% in 2005, 37.02% in 2010, and 35.17% in 2015. The most significant increasing trend was recorded in the ICU (gradient = 7.63, R² = 0.842, p < 0.001). The most common MDR-GNB in the ICU was isolated from bronchoalveolar aspiration samples. Concerning the proportion of different species, most of the changes were recorded in the ICU, where a statistically significant increasing trend was observed for Proteus mirabilis (gradient = 2.62, R2 = 0.558, p < 0.001) and Acinetobacter baumannii (gradient = 2.25, R2 = 0.491, p < 0.001). Analysis of the incidence of the main resistance phenotypes proportion identified a statistically significant increase in carbapenem resistance in the ICU (Gradient = 8.27, R² = 0.866, p < 0.001), and an increased proportion of aminoglycoside-resistant strains in all three departments, but more importantly in the ICU and GSD. Conclusion: A statistically significant increasing trend was observed in all three departments; the most significant one was recorded in the ICU, where after 2010, carbapenem-resistant strains were isolated.

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In Vitro Properties of BAL30072, a Novel Siderophore Sulfactam with Activity against Multiresistant Gram-Negative Bacilli

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01525-09 ◽

2010 ◽

Vol 54 (6) ◽

pp. 2291-2302 ◽

Cited By ~ 152

Author(s):

Malcolm G. P. Page ◽

Clothilde Dantier ◽

Eric Desarbre

Keyword(s):

Multidrug Resistant ◽

Unusual Property ◽

Gram Negative ◽

Penicillin Binding Proteins ◽

High Affinity ◽

Class A ◽

Carbapenem Resistant ◽

Lactam Antibiotic ◽

Resistant Strains

ABSTRACT BAL30072 is a new monocyclic β-lactam antibiotic belonging to the sulfactams. Its spectrum of activity against significant Gram-negative pathogens with β-lactam-resistant phenotypes was evaluated and was compared with the activities of reference drugs, including aztreonam, ceftazidime, cefepime, meropenem, imipenem, and piperacillin-tazobactam. BAL30072 showed potent activity against multidrug-resistant (MDR) Pseudomonas aeruginosa and Acinetobacter sp. isolates, including many carbapenem-resistant strains. The MIC90s were 4 μg/ml for MDR Acinetobacter spp. and 8 μg/ml for MDR P. aeruginosa, whereas the MIC90 of meropenem for the same sets of isolates was >32 μg/ml. BAL30072 was bactericidal against both Acinetobacter spp. and P. aeruginosa, even against strains that produced metallo-β-lactamases that conferred resistance to all other β-lactams tested, including aztreonam. It was also active against many species of MDR isolates of the Enterobacteriaceae family, including isolates that had a class A carbapenemase or a metallo-β-lactamase. Unlike other monocyclic β-lactams, BAL30072 was found to trigger the spheroplasting and lysis of Escherichia coli rather than the formation of extensive filaments. The basis for this unusual property is its inhibition of the bifunctional penicillin-binding proteins PBP 1a and PBP 1b, in addition to its high affinity for PBP 3, which is the target of monobactams, such as aztreonam.

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