scholarly journals Combination Therapy of Phage vB_KpnM_P-KP2 and Gentamicin Combats Acute Pneumonia Caused by K47 Serotype Klebsiella pneumoniae

2021 ◽  
Vol 12 ◽  
Author(s):  
Zijing Wang ◽  
Ruopeng Cai ◽  
Gang Wang ◽  
Zhimin Guo ◽  
Xiao Liu ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Therapeutic Effect ◽  
Combined Treatment ◽  
Animal Experiments ◽  
Opportunistic Pathogen ◽  
Drug Resistant ◽  
Carbapenem Resistant ◽  
Acute Pneumonia

Klebsiella pneumoniae (K. pneumoniae) is an important nosocomial and community acquired opportunistic pathogen which causes various infections. The emergence of multi-drug resistant (MDR) K. pneumoniae and carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) has brought more severe challenge to the treatment of K. pneumoniae infection. In this study, a novel bacteriophage that specifically infects K. pneumoniae was isolated and named as vB_KpnM_P-KP2 (abbreviated as P-KP2). The biological characteristics of P-KP2 and the bioinformatics of its genome were analyzed, and then the therapeutic effect of P-KP2 was tested by animal experiments. P-KP2 presents high lysis efficiency in vitro. The genome of P-KP2 shows homology with nine phages which belong to “KP15 virus” family and its genome comprises 172,138 bp and 264 ORFs. Besides, P-KP2 was comparable to gentamicin in the treatment of lethal pneumonia caused by K. pneumoniae W-KP2 (K47 serotype). Furthermore, the combined treatment of P-KP2 and gentamicin completely rescued the infected mice. Therefore, this study not only introduces a new member to the phage therapeutic library, but also serves as a reference for other phage-antibiotic combinations to combat MDR pathogens.

scholarly journals Review of therapeutic options for infections with carbapenem-resistant Klebsiella pneumoniae

2020 ◽  
Vol 10 (3) ◽  
pp. 115-124
Author(s):  
Rasmus G. Bandick ◽  
Soraya Mousavi ◽  
Stefan Bereswill ◽  
Markus M. Heimesaat
Keyword(s):  
Clinical Trials ◽  
Klebsiella Pneumoniae ◽  
Control Treatment ◽  
Drug Resistant ◽  
Treatment Regimens ◽  
Combined Application ◽  
Carbapenem Resistant ◽  
Antibiotic Compounds ◽  
Life Threatening

AbstractInfections with multi-drug resistant (MDR) bacteria including carbapenem-resistant Klebsiella pneumoniae are emerging worldwide but are difficult to treat with the currently available antibiotic compounds and therefore constitute serious threats to human health. This prompted us to perform a literature survey applying the MEDLINE database and Cochrane Register of Controlled Trials including clinical trials comparing different treatment regimens for infections caused by carbapenem-resistant K. pneumoniae. Our survey revealed that a combined application of antibiotic compounds such as meropenem plus vaborbactam, meropenem plus colistin and carbapenem plus carbapenem, resulted in significantly increased clinical cure and decreased mortality rates as compared to respective control treatment. However, further research on novel antibiotic compounds, but also on antibiotic-independent molecules providing synergistic or at least resistance-modifying properties needs to be undertaken in vitro as well as in large clinical trials to provide future options in the combat of emerging life-threatening infections caused by MDR bacteria.

scholarly journals Combination Regimens for Treatment of Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections

2016 ◽  
Vol 60 (6) ◽  
pp. 3601-3607 ◽  
Author(s):  
A. Gomez-Simmonds ◽  
B. Nelson ◽  
D. P. Eiras ◽  
A. Loo ◽  
S. G. Jenkins ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Active Agent ◽  
Bloodstream Infections ◽  
Individual Treatment ◽  
Beta Lactam ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Extended Spectrum

Previous studies reported decreased mortality in patients with carbapenemase-producingKlebsiella pneumoniaebloodstream infections (BSIs) treated with combination therapy but included carbapenem-susceptible and -intermediate isolates, as per revised CLSI breakpoints. Here, we assessed outcomes in patients with BSIs caused by phenotypically carbapenem-resistantK. pneumoniae(CRKP) according to the number ofin vitroactive agents received and whether an extended-spectrum beta-lactam (BL) antibiotic, including meropenem, or an extended-spectrum cephalosporin was administered. We retrospectively reviewed CRKP BSIs at two New York City hospitals from 2006 to 2013, where all isolates had meropenem or imipenem MICs of ≥4 μg/ml. Univariate and multivariable models were created to identify factors associated with mortality. Of 141 CRKP BSI episodes, 23% were treated with a single active agent (SAA), 26% were treated with an SAA plus BL, 28% were treated with multiple active agents (MAA), and 23% were treated with MAA plus BL. Ninety percent of isolates had meropenem MICs of ≥16 μg/ml. Thirty-day mortality was 33% overall and did not significantly differ across the four treatment groups in a multivariable model (P= 0.4); mortality was significantly associated with a Pitt bacteremia score of ≥4 (odds ratio [OR], 7.7; 95% confidence interval [CI], 3.2 to 18.1;P= 0.1), and immunosuppression was protective (OR, 0.4; 95% CI, 0.2 to 1.0;P= 0.04). Individual treatment characteristics were also not significantly associated with outcome, including use of SAAs versus MAA (26% versus 38%,P= 0.1) or BL versus no BL (26% versus 39%,P= 0.1). In summary, in patients with CRKP BSIs caused by isolates with high carbapenem MICs, the role of combination therapy remains unclear, highlighting the need for prospective studies to identify optimal treatment regimens.

scholarly journals Combination of Colistin and Azidothymidine Demonstrates Synergistic Activity against Colistin-Resistant, Carbapenem-Resistant Klebsiella pneumoniae

2020 ◽  
Vol 8 (12) ◽  
pp. 1964
Author(s):  
Ya-Ting Chang ◽  
Tsung-Ying Yang ◽  
Po-Liang Lu ◽  
Shang-Yi Lin ◽  
Liang-Chun Wang ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Therapeutic Option ◽  
Rapid Evolution ◽  
Toxicity Testing ◽  
World Health ◽  
Synergistic Activity ◽  
Carbapenem Resistant

Carbapenem-resistant Enterobacteriaceae (CRE) is listed as an urgent threat by the World Health Organization because of the limited therapeutic options, rapid evolution of resistance mechanisms, and worldwide dissemination. Colistin is a common backbone agent among the “last-resort” antibiotics for CRE; however, its emerging resistance among CRE has taken the present dilemma to the next level. Azidothymidine (AZT), a thymidine analog used to treat human immunodeficiency virus/acquired immunodeficiency syndrome, has been known to possess antibacterial effects against Enterobacteriaceae. In this study, we investigated the combined effects of AZT and colistin in 40 clinical isolates of colistin-resistant, carbapenem-resistant K. pneumoniae (CCRKP). Eleven of the 40 isolates harbored Klebsiella pneumoniae carbapenemase. The in vitro checkerboard method and in vivo nematode killing assay both revealed synergistic activity between the two agents, with fractional inhibitory concentration indexes of ≤0.5 in every strain. Additionally, a significantly lower hazard ratio was observed for the nematodes treated with combination therapy (0.288; p < 0.0001) compared with either AZT or colistin treatment. Toxicity testing indicated potentially low toxicity of the combination therapy. Thus, the AZT–colistin combination could be a potentially favorable therapeutic option for treating CCRKP.

scholarly journals Repurposing the anti-viral drug zidovudine (AZT) in combination with meropenem as an effective treatment for infections with multi-drug resistant, carbapenemase-producing strains of Klebsiella pneumoniae

2020 ◽  
Vol 78 (9) ◽  
Author(s):  
Alexandra E DeSarno ◽  
Benjamin J Parcell ◽  
Peter J Coote
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Galleria Mellonella ◽  
Larval Mortality ◽  
Therapeutic Benefit ◽  
Drug Resistant ◽  
Bacterial Proliferation ◽  
Global Threat ◽  
Time Kill

Abstract Multi-drug resistant (MDR) Klebsiella pneumoniae represent a global threat to healthcare due to lack of effective treatments and high mortality rates. The aim of this research was to explore the potential of administering zidovudine (AZT) in combination with an existing antibiotic to treat resistant K. pneumoniae infections. Two MDR K. pneumoniae strains were employed, producing either the NDM-1 or KPC-3 carbapenemase. Efficacy of combinations of AZT with meropenem were compared with monotherapies against infections in Galleria mellonella larvae by measuring larval mortality and bacterial burden. The effect of the same combinations in vitro was determined via checkerboard and time-kill assays. In vitro, both K. pneumoniae strains were resistant to meropenem but were susceptible to AZT. In G. mellonella, treatment with either AZT or meropenem alone offered minimal therapeutic benefit against infections with either strain. In contrast, combination therapy of AZT with meropenem presented significantly enhanced efficacy compared to monotherapies. This was correlated with prevention of bacterial proliferation within the larvae but not elimination. Checkerboard assays showed that the interaction between AZT and meropenem was not synergistic but indifferent. In summary, combination therapy of AZT with meropenem represents a potential treatment for carbapenemase-producing MDR K. pneumoniae and merits further investigation.

scholarly journals Biosynthesis of Zinc Oxide Nanoparticles from Acacia nilotica (L.) Extract to Overcome Carbapenem-Resistant Klebsiella Pneumoniae

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1919
Author(s):  
Elsayim Rasha ◽  
AlOthman Monerah ◽  
Alkhulaifi Manal ◽  
Ali Rehab ◽  
Doud Mohammed ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Zinc Oxide ◽  
Klebsiella Pneumoniae ◽  
Zinc Oxide Nanoparticles ◽  
Acacia Nilotica ◽  
Oxide Nanoparticles ◽  
Zno Nps ◽  
X Ray ◽  
Carbapenem Resistant

Recently, concerns have been raised globally about antimicrobial resistance, the prevalence of which has increased significantly. Carbapenem-resistant Klebsiella pneumoniae (KPC) is considered one of the most common resistant bacteria, which has spread to ICUs in Saudi Arabia. This study was established to investigate the antibacterial activity of biosynthesized zinc oxide nanoparticles (ZnO-NPs) against KPC in vitro and in vivo. In this study, we used the aqueous extract of Acacia nilotica (L.) fruits to mediate the synthesis of ZnO-NPs. The nanoparticles produced were characterized by UV-vis spectroscopy, zetasizer and zeta potential analyses, X-ray diffraction (XRD) spectroscopy, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and transmission electron microscopy (TEM). The antimicrobial activity of ZnO-NPs against KPC was determined via the well diffusion method, and determining minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), the results showed low MIC and MBC when compared with the MIC and MBC of Imipenem and Meropenem antibiotics. The results of in vitro analysis were supported by the results upon applying ZnO-NP ointment to promote wound closure of rats, which showed better wound healing than the results with imipenem ointment. The biosynthesized ZnO-NPs showed good potential for use against bacteria due to their small size, applicability, and low toxicity to human cells.

Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo

2019 ◽  
Vol 74 (11) ◽  
pp. 3211-3216 ◽  
Author(s):  
Stephan Göttig ◽  
Denia Frank ◽  
Eleonora Mungo ◽  
Anika Nolte ◽  
Michael Hogardt ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Selection Pressure ◽  
Galleria Mellonella ◽  
Phenotypic Characterization ◽  
Infection Model ◽  
Development Of Resistance ◽  
Time Kill

Abstract Objectives The β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is active against KPC-producing Enterobacterales. Herein, we present molecular and phenotypic characterization of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae that emerged in vivo and in vitro. Methods Sequence analysis of blaKPC-3 was performed from clinical and in vitro-generated ceftazidime/avibactam-resistant K. pneumoniae isolates. Time–kill kinetics and the Galleria mellonella infection model were applied to evaluate the activity of ceftazidime/avibactam and imipenem alone and in combination. Results The ceftazidime/avibactam-resistant clinical K. pneumoniae isolate revealed the amino acid change D179Y in KPC-3. Sixteen novel mutational changes in KPC-3 among in vitro-selected ceftazidime/avibactam-resistant isolates were described. Time–kill kinetics showed the emergence of a resistant subpopulation under selection pressure with either imipenem or ceftazidime/avibactam. However, combined selection pressure with imipenem plus ceftazidime/avibactam prevented the development of resistance and resulted in bactericidal activity. Concordantly, the G. mellonella infection model revealed that monotherapy with ceftazidime/avibactam is prone to select for resistance in vivo and that combination therapy with imipenem results in significantly better survival. Conclusions Ceftazidime/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time–kill kinetics as well as an in vivo infection model we postulate a combination therapy of ceftazidime/avibactam and imipenem as a strategy to prevent the development of ceftazidime/avibactam resistance in KPC-producing Enterobacterales in vivo.

scholarly journals Doripenem MICs andompK36Porin Genotypes of Sequence Type 258, KPC-Producing Klebsiella pneumoniae May Predict Responses to Carbapenem-Colistin Combination Therapy among Patients with Bacteremia

2014 ◽  
Vol 59 (3) ◽  
pp. 1797-1801 ◽  
Author(s):  
Ryan K. Shields ◽  
M. Hong Nguyen ◽  
Brian A. Potoski ◽  
Ellen G. Press ◽  
Liang Chen ◽  
...  
Keyword(s):  
Amino Acids ◽  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Sequence Type ◽  
Content Type

ABSTRACTTreatment failures of a carbapenem-colistin regimen among patients with bacteremia due to sequence type 258 (ST258), KPC-2-producingKlebsiella pneumoniaewere significantly more likely if both agents were inactivein vitro, as defined by a colistin MIC of >2 μg/ml and the presence of either a majorompK36porin mutation (guanine and alanine insertions at amino acids 134 and 135 [ins aa 134–135 GD], IS5promoter insertion [P= 0.007]) or a doripenem MIC of >8 μg/ml (P= 0.01). MajorompK36mutations among KPC-K. pneumoniaestrains are important determinants of carbapenem-colistin responsesin vitroandin vivo.

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