Antibiotic–non-antibiotic combinations for combating extremely drug-resistant Gram-negative ‘superbugs’

2017 ◽  
Vol 61 (1) ◽  
pp. 115-125 ◽  
Author(s):  
Elena K. Schneider ◽  
Felisa Reyes-Ortega ◽  
Tony Velkov ◽  
Jian Li
Keyword(s):  
Therapeutic Strategy ◽  
Polymyxin B ◽  
Drug Resistant ◽  
Combination Strategy ◽  
Gram Negative ◽  
Antibiotic Drugs ◽  
Antibiotic Drug ◽  
The Status ◽  
Potential Benefits ◽  
Synergistic Combinations

The emergence of antimicrobial resistance of Gram-negative pathogens has become a worldwide crisis. The status quo for combating resistance is to employ synergistic combinations of antibiotics. Faced with this fast-approaching post-antibiotic era, it is critical that we devise strategies to prolong and maximize the clinical efficacy of existing antibiotics. Unfortunately, reports of extremely drug-resistant (XDR) Gram-negative pathogens have become more common. Combining antibiotics such as polymyxin B or the broad-spectrum tetracycline and minocycline with various FDA-approved non-antibiotic drugs have emerged as a novel combination strategy against otherwise untreatable XDR pathogens. This review surveys the available literature on the potential benefits of employing antibiotic–non-antibiotic drug combination therapy. The apex of this review highlights the clinical utility of this novel therapeutic strategy for combating infections caused by ‘superbugs’.

scholarly journals Antibiotic Hybrids: the Next Generation of Agents and Adjuvants against Gram-Negative Pathogens?

2018 ◽  
Vol 31 (2) ◽  
Author(s):  
Ronald Domalaon ◽  
Temilolu Idowu ◽  
George G. Zhanel ◽  
Frank Schweizer
Keyword(s):  
Antibacterial Agents ◽  
Therapeutic Strategy ◽  
Antimicrobial Effect ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Intrinsic Resistance ◽  
Gram Negative ◽  
The Past ◽  
Antibiotic Drug

SUMMARYThe global incidence of drug-resistant Gram-negative bacillary infections has been increasing, and there is a dire need to develop novel strategies to overcome this problem. Intrinsic resistance in Gram-negative bacteria, such as their protective outer membrane and constitutively overexpressed efflux pumps, is a major survival weapon that renders them refractory to current antibiotics. Several potential avenues to overcome this problem have been at the heart of antibiotic drug discovery in the past few decades. We review some of these strategies, with emphasis on antibiotic hybrids either as stand-alone antibacterial agents or as adjuvants that potentiate a primary antibiotic in Gram-negative bacteria. Antibiotic hybrid is defined in this review as a synthetic construct of two or more pharmacophores belonging to an established agent known to elicit a desired antimicrobial effect. The concepts, advances, and challenges of antibiotic hybrids are elaborated in this article. Moreover, we discuss several antibiotic hybrids that were or are in clinical evaluation. Mechanistic insights into how tobramycin-based antibiotic hybrids are able to potentiate legacy antibiotics in multidrug-resistant Gram-negative bacilli are also highlighted. Antibiotic hybrids indeed have a promising future as a therapeutic strategy to overcome drug resistance in Gram-negative pathogens and/or expand the usefulness of our current antibiotic arsenal.

scholarly journals Resurgence of Polymyxin B for MDR/XDR Gram-Negative Infections: An Overview of Current Evidence

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Suneel Kumar Garg ◽  
Omender Singh ◽  
Deven Juneja ◽  
Niraj Tyagi ◽  
Amandeep Singh Khurana ◽  
...  
Keyword(s):  
Decision Making ◽  
Literature Review ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Current Evidence ◽  
Drug Resistant ◽  
Gram Negative

Polymyxin B has resurged in recent years as a last resort therapy for Gram-negative multidrug-resistant (MDR) and extremely drug resistant (XDR) infections. Understanding newer evidence on polymyxin B is necessary to guide clinical decision making. Here, we present a literature review of polymyxin B in Gram-negative infections with update on its pharmacology.

scholarly journals Lysophosphatidylcholine Potentiates Antibacterial Activity of Polymyxin B

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Jitender Yadav ◽  
Sana Ismaeel ◽  
Ayub Qadri
Keyword(s):  
Antibacterial Activity ◽  
Polymyxin B ◽  
Resistant Bacteria ◽  
Bacterial Membrane ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Drug Resistant Bacteria

ABSTRACT Polymyxin B, used to treat infections caused by antibiotic-resistant Gram-negative bacteria, produces nephrotoxicity at its current dosage. We show that a combination of nonbactericidal concentration of this drug and lysophosphatidylcholine (LPC) potently inhibits growth of Salmonella and at least two other Gram-negative bacteria in vitro. This combination makes bacterial membrane porous and causes degradation of DnaK, the regulator of protein folding. Polymyxin B-LPC combination may be an effective and safer regimen against drug-resistant bacteria.

scholarly journals Benzydamine Reverses TMexCD-TOprJ-Mediated High-Level Tigecycline Resistance in Gram-Negative Bacteria

2021 ◽  
Vol 14 (9) ◽  
pp. 907
Author(s):  
Ziwen Tong ◽  
Tianqi Xu ◽  
Tian Deng ◽  
Jingru Shi ◽  
Zhiqiang Wang ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Galleria Mellonella ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Intracellular Accumulation ◽  
Gram Negative ◽  
Resistance Nodulation Division ◽  
High Level

Recently, a novel efflux pump gene cluster called tmexCD1-toprJ1 and its variants have been identified, which undermine the antibacterial activity of tigecycline, one of the last remaining options effective against multidrug-resistant (MDR) Gram-negative bacteria. Herein, we report the potent synergistic effect of the non-steroidal anti-inflammatory drug benzydamine in combination with tigecycline at sub-inhibitory concentrations against various temxCD-toprJ-positive Gram-negative pathogens. The combination of benzydamine and tigecycline killed all drug-resistant pathogens during 24 h of incubation. In addition, the evolution of tigecycline resistance was significantly suppressed in the presence of benzydamine. Studies on the mechanisms of synergism showed that benzydamine disrupted the bacterial proton motive force and the functionality of this kind of novel plasmid-encoded resistance-nodulation-division efflux pump, thereby promoting the intracellular accumulation of tigecycline. Most importantly, the combination therapy of benzydamine and tigecycline effectively improved the survival of Galleria mellonella larvae compared to tigecycline monotherapy. Our findings provide a promising drug combination therapeutic strategy for combating superbugs carrying the tmexCD-toprJ gene.

scholarly journals The Susceptibility of MDR-K. Pneumoniae to Polymyxin B Plus its Nebulised Form Versus Polymyxin B Alone in Critically Ill South Asian Patients

2021 ◽  
Vol 7 (1) ◽  
pp. 28-36
Author(s):  
Md. Jahidul Hasan ◽  
Raihan Rabbani ◽  
Ahmad Mursel Anam ◽  
Ario Santini ◽  
Shihan Mahmud Redwanul Huq
Keyword(s):  
Intensive Care ◽  
Critically Ill ◽  
South Asian ◽  
Polymyxin B ◽  
Ventilator Associated Pneumonia ◽  
Drug Resistant ◽  
Gram Negative ◽  
Asian Patients ◽  
Group 2 ◽  
Group 1

Abstract Introduction Critically ill patients in intensive care units are at high risk of dying not only from the severity of their illness but also from secondary causes such as hospital-acquired infections. USA national medical record-data show that approximately 10% of patients on mechanical ventilation in an intensive care unit developed ventilator-associated pneumonia. Polymyxin B has been used intravenously in the treatment of multi-drug resistant gram-negative infections, either as a monotherapy or with other potentially effective antibiotics, and the recent international guidelines have emphasised the use of nebulised polymyxin B together with intravenous polymyxin B to gain the optimum clinical outcome in ventilator-associated pneumonia cases caused by multi-drug resistant gram-negative infections. Methods One hundred and seventy-eight patients with ventilator-associated pneumonia due to multi-drug resistant K. pneumoniae were identified during the study period. Following the inclusion and exclusion criteria, 121 patients were enrolled in the study and randomly allocated to two study groups. Group 1 patients were treated with intravenous Polymyxin B plus nebulised polymyxin B (n=64) and Group 2 patients with intravenous Polymyxin B alone (n=57). The study aimed to compare the use of Polymyxin B plus its nebulised form to polymyxin B alone, in the treatment of MDR-K. pneumoniae associated ventilator-associated pneumonia in critically ill patients. Results In Group 1, a complete clearance of K. pneumoniae was found in fifty-nine patients (92.1%; n=64) compared to forty patients (70.1%, n=57) in the Group 2 (P<0.003). The average time till extubation was significantly higher in Group 2 compared to Group 1 (P<0.05). The total length-of-stay in the ICU was significantly higher in Group 2 compared to Group 1. (P<0.05). These results support the view that the Polymyxin B dual-route regime may be considered as an appropriate antibiotic therapy, in critically ill South Asian patients with ventilator-associated pneumonia.

scholarly journals Effectiveness and safety of polymyxin B for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria in Thailand

2018 ◽  
Vol Volume 11 ◽  
pp. 1219-1224 ◽  
Author(s):  
Thundon Ngamprasertchai ◽  
Adhiratha Boonyasiri ◽  
Lantharita Charoenpong ◽  
Sireethorn Nimitvilai ◽  
Narisorn Lorchirachoonkul ◽  
...  
Keyword(s):  
Polymyxin B ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Gram Negative ◽  
Extensively Drug Resistant
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