Resistance to nitrofurantoin is an indicator of extensive drug-resistant (XDR) Enterobacteriaceae

2021 ◽  
Vol 70 (4) ◽  
Author(s):  
Balaram Khamari ◽  
Prakash Kumar ◽  
Bulagonda Eswarappa Pradeep
Keyword(s):  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Treatment Options ◽  
Strong Association ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Content Type ◽  
Link Type

Introduction. Nitrofurantoin is one of the preferred antibiotics in the treatment of uropathogenic multidrug-resistant (MDR) infections. However, resistance to nitrofurantoin in extensively drug-resistant (XDR) bacteria has severely limited the treatment options. Gap statement. Information related to co-resistance or collateral sensitivity (CS) with reference to nitrofurantoin resistant bacteria is limited. Aim. To study the potential of nitrofurantoin resistance as an indicator of the XDR phenotype in Enterobacteriaceae . Methods. One hundred (45 nitrofurantoin-resistant, 21 intermediately resistant and 34 nitrofurantoin-susceptible) Enterobacteriaceae were analysed in this study. Antibiotic susceptibility testing (AST) against nitrofurantoin and 17 other antimicrobial agents across eight different classes was performed by using the Vitek 2.0 system. The isolates were screened for the prevalence of acquired antimicrobial resistance (AMR) and efflux pump genes by PCR. Results. In total, 51 % of nitrofurantoin-resistant and 28 % of intermediately nitrofurantoin resistant isolates exhibited XDR characteristics, while only 3 % of nitrofurantoin-sensitive isolates were XDR (P=0.0001). Significant co-resistance was observed between nitrofurantoin and other tested antibiotics (β-lactam, cephalosporin, carbapenem, aminoglycoside and tetracycline). Further, the prevalence of AMR and efflux pump genes was higher in the nitrofurantoin-resistant strains compared to the susceptible isolates. A strong association was observed between nitrofurantoin resistance and the presence of bla PER-1, bla NDM-1, bla OXA-48, ant(2) and oqxA-oqxB genes. Tigecycline (84 %) and colistin (95 %) were the only antibiotics to which the majority of the isolates were susceptible. Conclusion. Nitrofurantoin resistance could be an indicator of the XDR phenotype among Enterobacteriaceae , harbouring multiple AMR and efflux pump genes. Tigecycline and colistin are the only antibiotics that could be used in the treatment of such XDR infections. A deeper understanding of the co-resistance mechanisms in XDR pathogens and prescription of AST-based appropriate combination therapy may help mitigate this problem.

scholarly journals Current Perspectives on Treatment of Gram-Positive Infections in India: What Is the Way Forward?

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Atul P. Kulkarni ◽  
Vasant C. Nagvekar ◽  
Balaji Veeraraghavan ◽  
Anup R. Warrier ◽  
Deepak TS ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Antimicrobial Agents ◽  
Treatment Options ◽  
Pharmacokinetic Profile ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Tolerability Profile ◽  
Drug Resistant ◽  
Gram Positive ◽  
Favourable Pharmacokinetic Profile

The emerging antimicrobial resistance leading to gram-positive infections (GPIs) is one of the major public health threats worldwide. GPIs caused by multidrug resistant bacteria can result in increased morbidity and mortality rates along with escalated treatment cost and hospitalisation stay. In India, GPIs, particularly methicillin-resistant Staphylococcus aureus (MRSA) prevalence among invasive S. aureus isolates, have been reported to increase exponentially from 29% in 2009 to 47% in 2014. Apart from MRSA, rising prevalence of vancomycin-resistant enterococci (VRE), which ranges from 1 to 9% in India, has raised concerns. Moreover, the overall mortality rate among patients with multidrug resistant GPIs in India is reported to be 10.8% and in ICU settings, the mortality rate is as high as 16%. Another challenge is the spectrum of adverse effects related to the safety and tolerability profile of the currently available drugs used against GPIs which further makes the management and treatment of these multidrug resistant organisms a complex task. Judicious prescription of antimicrobial agents, implementation of antibiotic stewardship programmes, and antibiotic policies in hospitals are essential to reduce the problem of drug-resistant infections in India. The most important step is development of newer antimicrobial agents with novel mechanisms of action and favourable pharmacokinetic profile. This review provides a synopsis about the current burden, treatment options, and the challenges faced by the clinicians in the management of GPIs such as MRSA, Quinolone-resistant Staphylococcus, VRE, and drug-resistant pneumococcus in India.

scholarly journals Genomic evolution and local epidemiology of Klebsiella pneumoniae from a major hospital in Beijing, China, over a 15 year period: dissemination of known and novel high-risk clones

2021 ◽  
Author(s):  
Mattia Palmieri ◽  
Kelly L. Wyres ◽  
Caroline Mirande ◽  
Zhao Qiang ◽  
Ye Liyan ◽  
...  
Keyword(s):  
High Risk ◽  
Klebsiella Pneumoniae ◽  
Type Species ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Virulence Plasmid ◽  
Content Type ◽  
Origin And Evolution ◽  
Link Type ◽  
Beijing China

Klebsiella pneumoniae is a frequent cause of nosocomial and severe community-acquired infections. Multidrug-resistant (MDR) and hypervirulent (hv) strains represent major threats, and tracking their emergence, evolution and the emerging convergence of MDR and hv traits is of major importance. We employed whole-genome sequencing (WGS) to study the evolution and epidemiology of a large longitudinal collection of clinical K. pneumoniae isolates from the H301 hospital in Beijing, China. Overall, the population was highly diverse, although some clones were predominant. Strains belonging to clonal group (CG) 258 were dominant, and represented the majority of carbapenemase-producers. While CG258 strains showed high diversity, one clone, ST11-KL47, represented the majority of isolates, and was highly associated with the KPC-2 carbapenemase and several virulence factors, including a virulence plasmid. The second dominant clone was CG23, which is the major hv clone globally. While it is usually susceptible to multiple antibiotics, we found some isolates harbouring MDR plasmids encoding for ESBLs and carbapenemases. We also reported the local emergence of a recently described high-risk clone, ST383. Conversely to strains belonging to CG258, which are usually associated to KPC-2, ST383 strains seem to readily acquire carbapenemases of different types. Moreover, we found several ST383 strains carrying the hypervirulence plasmid. Overall, we detected about 5 % of simultaneous carriage of AMR genes (ESBLs or carbapenemases) and hypervirulence genes. Tracking the emergence and evolution of such strains, causing severe infections with limited treatment options, is fundamental in order to understand their origin and evolution and to limit their spread. This article contains data hosted by Microreact.

scholarly journals Functional Characterization of AbaQ, a Novel Efflux Pump Mediating Quinolone Resistance inAcinetobacter baumannii

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
María Pérez-Varela ◽  
Jordi Corral ◽  
Jesús Aranda ◽  
Jordi Barbé
Keyword(s):  
Acinetobacter Baumannii ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Functional Characterization ◽  
Multidrug Resistant ◽  
Quinolone Resistance ◽  
Nosocomial Pathogen ◽  
Content Type ◽  
Mfs Transporter

ABSTRACTAcinetobacter baumanniihas emerged as an important multidrug-resistant nosocomial pathogen. In previous work, we identified a putative MFS transporter, AU097_RS17040, involved in the pathogenicity ofA. baumannii(M. Pérez-Varela, J. Corral, J. A. Vallejo, S. Rumbo-Feal, G. Bou, J. Aranda, and J. Barbé, Infect Immun 85:e00327-17, 2017,https://doi.org/10.1128/IAI.00327-17). In this study, we analyzed the susceptibility to diverse antimicrobial agents ofA. baumanniicells defective in this transporter, referred to as AbaQ. Our results showed that AbaQ is mainly involved in the extrusion of quinolone-type drugs inA. baumannii.

scholarly journals A Tailspike with Exopolysaccharide Depolymerase Activity from a New Providencia stuartii Phage Makes Multidrug-Resistant Bacteria Susceptible to Serum-Mediated Killing

2020 ◽  
Vol 86 (13) ◽  
Author(s):  
Hugo Oliveira ◽  
Graça Pinto ◽  
Bruna Mendes ◽  
Oscar Dias ◽  
Hanne Hendrix ◽  
...  
Keyword(s):  
Immune System ◽  
Prolonged Exposure ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Specific Substrate ◽  
Drug Resistant ◽  
Nosocomial Pathogen ◽  
Content Type ◽  
Serum Killing ◽  
Providencia Stuartii

ABSTRACT Providencia stuartii is emerging as a significant drug-resistant nosocomial pathogen, which encourages the search for alternative therapies. Here, we have isolated Providencia stuartii phage Stuart, a novel podovirus infecting multidrug-resistant hospital isolates of this bacterium. Phage Stuart is a proposed member of a new Autographivirinae subfamily genus, with a 41,218-bp genome, direct 345-bp repeats at virion DNA ends, and limited sequence similarity of proteins to proteins in databases. Twelve out of the 52 predicted Stuart proteins are virion components. We found one to be a tailspike with depolymerase activity. The tailspike could form a highly thermostable oligomeric β-structure migrating close to the expected trimer in a nondenaturing gel. It appeared to be essential for the infection of three out of four P. stuartii hosts infected by phage Stuart. Moreover, it degraded the exopolysaccharide of relevant phage Stuart hosts, making the bacteria susceptible to serum killing. Prolonged exposure of a sensitive host to the tailspike did not cause the emergence of bacteria resistant to the phage or to serum killing, opposite to the prolonged exposure to the phage. This indicates that phage tail-associated depolymerases are attractive antivirulence agents that could complement the immune system in the fight with P. stuartii. IMPORTANCE The pace at which multidrug-resistant strains emerge has been alarming. P. stuartii is an infrequent but relevant drug-resistant nosocomial pathogen causing local to systemic life-threatening infections. We propose an alternative approach to fight this bacterium based on the properties of phage tailspikes with depolymerase activity that degrade the surface bacterial polymers, making the bacteria susceptible to the immune system. Unlike antibiotics, phage tailspikes have narrow and specific substrate spectra, and by acting as antivirulent but not bactericidal agents they do not cause the selection of resistant bacteria.

scholarly journals Membrane Perturbation Action Mode and Structure-Activity Relationships of Protonectin, a Novel Antimicrobial Peptide from the Venom of the Neotropical Social Wasp Agelaia pallipes pallipes

2013 ◽  
Vol 57 (10) ◽  
pp. 4632-4639 ◽  
Author(s):  
Kairong Wang ◽  
Wen Dang ◽  
Jiexi Yan ◽  
Ru Chen ◽  
Xin Liu ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Antimicrobial Agents ◽  
Social Wasp ◽  
Multidrug Resistant ◽  
Structural Features ◽  
Helical Conformation ◽  
Resistant Bacteria ◽  
Content Type ◽  
Natural Analog ◽  
Action Mode

ABSTRACTWith the extensive use of antibiotics, multidrug-resistant bacteria emerge frequently. New antimicrobial agents with novel modes of action are urgently needed. It is now widely accepted that antimicrobial peptides (AMPs) could be promising alternatives to conventional antibiotics. In this study, we aimed to study the antimicrobial activity and mechanism of action of protonectin, a cationic peptide from the venom of the neotropical social waspAgelaia pallipes pallipes. We demonstrated that protonectin exhibits potent antimicrobial activity against a spectrum of bacteria, including multidrug-resistant strains. To further understand this mechanism, the structural features of protonectin and its analogs were studied by circular dichroism (CD). The CD spectra demonstrated that protonectin and its natural analog polybia-CP formed a typical α-helical conformation in the membrane-mimicking environment, while its proline-substituted analog had much lower or even no α-helix conformation. Molecular dynamics simulations indicated that the α-helical conformation in the membrane is required for the exhibition of antibacterial activity. In conclusion, protonectin exhibits potent antimicrobial activity by disruption of the integrity of the bacterial membrane, and its α-helical confirmation in the membrane is essential for this action.

scholarly journals IS5Element Integration, a Novel Mechanism for RapidIn VivoEmergence of Tigecycline Nonsusceptibility in Klebsiella pneumoniae

2014 ◽  
Vol 58 (10) ◽  
pp. 6151-6156 ◽  
Author(s):  
Lindsey E. Nielsen ◽  
Erik C. Snesrud ◽  
Fatma Onmus-Leone ◽  
Yoon I. Kwak ◽  
Ricardo Avilés ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Insertion Element ◽  
Content Type ◽  
Reverse Transcription Quantitative Pcr ◽  
Antimicrobial Susceptibility Tests ◽  
Susceptibility Tests

ABSTRACTTigecycline nonsusceptibility is concerning because tigecycline is increasingly relied upon to treat carbapenem- or colistin-resistant organisms. InEnterobacteriaceae, tigecycline nonsusceptibility is mediated by the AcrAB-TolC efflux pump, among others, and pump activity is often a downstream effect of mutations in their transcriptional regulators, cognate repressor genes, or noncoding regions, as demonstrated inEnterobacteriaceaeandAcinetobacterisolates. Here, we report the emergence of tigecycline nonsusceptibility in a longitudinal series of multidrug-resistant (MDR) and extensively drug-resistant (XDR)Klebsiella pneumoniaeisolates collected during tigecycline therapy and the elucidation of its resistance mechanisms. Clinical isolates were recovered prior to and during tigecycline therapy of a 2.5-month-old Honduran neonate. Antimicrobial susceptibility tests to tigecycline determined that the MIC increased from 1 to 4 μg/ml prior to the completion of tigecycline therapy. Unlike other studies, we did not find increased expression oframA,ramR,oqxA,acrB,marA, orrarAgenes by reverse transcription-quantitative PCR (qRT-PCR). Whole-genome sequencing revealed an IS5insertion element in nonsusceptible isolates 85 bp upstream of a putative efflux pump operon, here namedkpgABC, previously unknown to be involved in resistance. Introduction of thekpgABCgenes in a non-kpgABCbackground increased the MIC of tigecycline 4-fold and is independent of a functional AcrAB-TolC pump. This is the first report to propose a function forkpgABCand identify an insertion element whose presence correlated with thein vivodevelopment of tigecycline nonsusceptibility inK. pneumoniae.

scholarly journals Rational Design of Engineered Cationic Antimicrobial Peptides Consisting Exclusively of Arginine and Tryptophan, and Their Activity against Multidrug-Resistant Pathogens

2013 ◽  
Vol 57 (6) ◽  
pp. 2511-2521 ◽  
Author(s):  
Berthony Deslouches ◽  
Jonathan D. Steckbeck ◽  
Jodi K. Craigo ◽  
Yohei Doi ◽  
Timothy A. Mietzner ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Rational Design ◽  
Antimicrobial Agents ◽  
Divalent Cations ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Broth Culture ◽  
Cationic Antimicrobial Peptides ◽  
Content Type ◽  
Amphipathic Helices

ABSTRACTThe emergence of multidrug-resistant (MDR) pathogens underscores the need for new antimicrobial agents to overcome the resistance mechanisms of these organisms. Cationic antimicrobial peptides (CAPs) provide a potential source of new antimicrobial therapeutics. We previously characterized a lytic base unit (LBU) series of engineered CAPs (eCAPs) of 12 to 48 residues demonstrating maximum antibacterial selectivity at 24 residues. Further, Trp substitution in LBU sequences increased activity against bothP. aeruginosaandS. aureusunder challenging conditions (e.g., saline, divalent cations, and serum). Based on these findings, we hypothesized that the optimal length and, therefore, the cost for maximum eCAP activity under physiologically relevant conditions could be significantly reduced using only Arg and Trp arranged to form idealized amphipathic helices. Hence, we developed a novel peptide series, composed only of Arg and Trp, in a sequence predicted and verified by circular dichroism to fold into optimized amphipathic helices. The most effective antimicrobial activity was achieved at 12 residues in length (WR12) against a panel of both Gram-negative and Gram-positive clinical isolates, including extensively drug-resistant strains, in saline and broth culture and at various pH values. The results demonstrate that the rational design of CAPs can lead to a significant reduction in the length and the number of amino acids used in peptide design to achieve optimal potency and selectivity against specific pathogens.

scholarly journals In vivo emergence of resistance to cefiderocol in an XDR Pseudomonas aeruginosa and an MDR Citrobacter koseri after prolonged therapy: a case report.

2020 ◽  
Author(s):  
Carolina Grande Perez ◽  
Evelyne Maillart ◽  
Véronique Yvette Miendje Deyi ◽  
Te Din Daniel Huang ◽  
Prochore Kamgang ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Class A ◽  
Stewardship Program ◽  
Class D ◽  
Emergence Of Resistance

Abstract The non-fermenters, e.g. Pseudomonas aeruginosa, and the extended spectrum β-lactamases or carbapenemases producing enterobacteriaceae represent a serious threat for patients admitted in Intensive Care Units (ICUs). News antibiotics have been developed to treat multidrug resistant bacteria. However, treatment emerging resistance has been shown for many of these newest antibiotics. Cefiderocol, a siderophore-antibiotic, has been developed to overcome most of the resistance mechanisms and shows great efficacy against most multi-drug resistant and extensively drug resistant Gram-negative bacteria, including the non-fermenters. We report the case of a patient abundantly treated with antibiotics. He received 158 days of antibiotherapy on 230 hospitalization days, including a six-week course of cefiderocol, in 14 different treatment lines. The patient developed a Pseudomonas aeruginosa (MIC: 8 µg/ml, GES type ESBL) and a Citrobacter koseri (MIC: 16 µg/ml, CTX-M group 9 type class A β-lactamase and a class D OXA-1 oxacillinase) resistant to cefiderocol. This antibiotic should be used with caution to preserve its efficacy, within a strict antimicrobial stewardship program.

scholarly journals Efflux Pump Mediated Antimicrobial Resistance by Staphylococci in Health-Related Environments: Challenges and the Quest for Inhibition

Antibiotics ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1502
Author(s):  
Abolfazl Dashtbani-Roozbehani ◽  
Melissa H. Brown
Keyword(s):  
Antimicrobial Resistance ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Current Knowledge ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Multidrug Efflux Pump ◽  
New Antibiotics ◽  
Efflux Pump Inhibitors

The increasing emergence of antimicrobial resistance in staphylococcal bacteria is a major health threat worldwide due to significant morbidity and mortality resulting from their associated hospital- or community-acquired infections. Dramatic decrease in the discovery of new antibiotics from the pharmaceutical industry coupled with increased use of sanitisers and disinfectants due to the ongoing COVID-19 pandemic can further aggravate the problem of antimicrobial resistance. Staphylococci utilise multiple mechanisms to circumvent the effects of antimicrobials. One of these resistance mechanisms is the export of antimicrobial agents through the activity of membrane-embedded multidrug efflux pump proteins. The use of efflux pump inhibitors in combination with currently approved antimicrobials is a promising strategy to potentiate their clinical efficacy against resistant strains of staphylococci, and simultaneously reduce the selection of resistant mutants. This review presents an overview of the current knowledge of staphylococcal efflux pumps, discusses their clinical impact, and summarises compounds found in the last decade from plant and synthetic origin that have the potential to be used as adjuvants to antibiotic therapy against multidrug resistant staphylococci. Critically, future high-resolution structures of staphylococcal efflux pumps could aid in design and development of safer, more target-specific and highly potent efflux pump inhibitors to progress into clinical use.

scholarly journals Targeting the bacterial SOS response for new antimicrobial agents: drug targets, molecular mechanisms and inhibitors

2021 ◽  
Author(s):  
Thomas Lanyon-Hogg
Keyword(s):  
Drug Targets ◽  
Molecular Mechanisms ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Structure And Function ◽  
Drug Resistant ◽  
Target Validation ◽  
Sos Pathway ◽  
And Function

Antimicrobial resistance is a pressing threat to global health, with multidrug-resistant pathogens becoming increasingly prevalent. The bacterial SOS pathway functions in response to DNA damage that occurs during infection, initiating several pro-survival and resistance mechanisms, such as DNA repair and hypermutation. This makes SOS pathway components potential targets that may combat drug-resistant pathogens and decrease resistance emergence. This review discusses the mechanism of the SOS pathway; the structure and function of potential targets AddAB, RecBCD, RecA and LexA; and efforts to develop selective small-molecule inhibitors of these proteins. These inhibitors may serve as valuable tools for target validation and provide the foundations for desperately needed novel antibacterial therapeutics.

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