Activity of imipenem-relebactam against multi-drug and extensively-drug resistant Burkholderia cepacia complex and Burkholderia gladioli

2021 ◽  
Author(s):  
Scott A. Becka ◽  
Elise T. Zeiser ◽  
John J. LiPuma ◽  
Krisztina M. Papp-Wallace
Keyword(s):  
Burkholderia Cepacia ◽  
Multidrug Resistant ◽  
Burkholderia Cepacia Complex ◽  
Opportunistic Pathogens ◽  
Combination Drug ◽  
Burkholderia Multivorans ◽  
Burkholderia Gladioli ◽  
Stable Adduct ◽  
Treatment Of Infection ◽  
Inhibitor Combination

The Burkholderia cepacia complex (Bcc) and Burkholderia gladioli are opportunistic pathogens that most commonly infect persons with cystic fibrosis or compromised immune systems. Members of the Burkholderia genus are intrinsically multidrug resistant (MDR), possessing both a PenA carbapenemase and an AmpC β-lactamase, which renders treatment of infection due to these species problematic. Here, we tested the β-lactam-β-lactamase inhibitor combination, imipenem-relebactam, against a panel of MDR Bcc and B. gladioli . The addition of relebactam to imipenem dramatically lowered the MICs for Bcc and B . gladioli with only 16% of isolates testing susceptible to imipenem vs. 71.3% being susceptible to the imipenem-relebactam combination. While ceftazidime-avibactam remained the most potent combination drug against this panel of Bcc and B. gladioli , imipenem-relebactam was active against 71.4% of the ceftazidime-avibactam-resistant isolates. Relebactam demonstrated potent inactivation of the Burkholderia multivorans PenA1 with a K i app value of 3.2 μM. Timed mass spectrometry revealed that PenA1 formed a very stable adduct with relebactam, without any detectable desulfation up to 24 hours. Based on our results, imipenem-relebactam may represent an alternative salvage therapy for Bcc and B . gladioli infection, especially in cases where the isolates are resistant to ceftazidime-avibactam.

scholarly journals Distinguishing Species of the Burkholderia cepacia Complex and Burkholderia gladioli by Automated Ribotyping

2000 ◽  
Vol 38 (5) ◽  
pp. 1876-1884 ◽  
Author(s):  
Sylvain Brisse ◽  
Cees M. Verduin ◽  
Dana Milatovic ◽  
Ad Fluit ◽  
Jan Verhoef ◽  
...  
Keyword(s):  
Burkholderia Cepacia ◽  
Burkholderia Cepacia Complex ◽  
Opportunistic Pathogens ◽  
Burkholderia Gladioli ◽  
Microbial Characterization ◽  
Automated Ribotyping ◽  
Level Cluster ◽  
Identification Analysis ◽  
Epidemiological Characterization

Several species belonging to the genus Burkholderia are clinically relevant, opportunistic pathogens that inhabit major environmental reservoirs. Consequently, the availability of means for adequate identification and epidemiological characterization of individual environmental or clinical isolates is mandatory. In the present communication we describe the use of the Riboprinter microbial characterization system (Qualicon, Warwick, United Kingdom) for automated ribotyping of 104 strains of Burkholderia species from diverse sources, including several publicly accessible collections. The main outcome of this analysis was that all strains were typeable and that strains of Burkholderia gladioli and of each species of the B. cepacia complex, includingB. multivorans, B. stabilis, and B. vietnamiensis, were effectively discriminated. Furthermore, different ribotypes were discerned within each species. Ribotyping results were in general agreement with strain classification based on restriction fragment analysis of 16S ribosomal amplicons, but the resolution of ribotyping was much higher. This enabled automated molecular typing below the species level. Cluster analysis of the patterns obtained by ribotyping (riboprints) showed that withinB. gladioli, B. multivorans, and B. cepacia genomovar VI, the different riboprints identified always clustered together. Riboprints of B. cepacia genomovars I and III, B. stabilis, and B. vietnamiensis did not show distinct clustering but rather exhibited the formation of loose assemblages within which several smaller, genomovar-specific clusters were delineated. Therefore, ribotyping proved useful for genomovar identification. Analysis of serial isolates from individual patients demonstrated that infection with a single ribotype had occurred, despite minor genetic differences that were detected by pulsed-field gel electrophoresis of DNA macrorestriction fragments. The automated approach allows very rapid and reliable identification and epidemiological characterization of strains and generates an easily manageable database suited for expansion with information on additional bacterial isolates.

scholarly journals In Vitro Activities of a Novel Nanoemulsion against Burkholderia and Other Multidrug-Resistant Cystic Fibrosis-Associated Bacterial Species

2008 ◽  
Vol 53 (1) ◽  
pp. 249-255 ◽  
Author(s):  
John J. LiPuma ◽  
Sivaprakash Rathinavelu ◽  
Bridget K. Foster ◽  
Jordan C. Keoleian ◽  
Paul E. Makidon ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Tract ◽  
Burkholderia Cepacia ◽  
Bacterial Species ◽  
Multidrug Resistant ◽  
Opportunistic Pathogens ◽  
Oil In Water ◽  
Distinct Strain ◽  
Treatment Of Infection

ABSTRACT Respiratory tract infection, most often involving opportunistic bacterial species with broad-spectrum antibiotic resistance, is the primary cause of death in persons with cystic fibrosis (CF). Species within the Burkholderia cepacia complex are especially problematic in this patient population. We investigated a novel surfactant-stabilized oil-in-water nanoemulsion (NB-401) for activity against 150 bacterial isolates recovered primarily from CF respiratory tract specimens. These specimens included 75 Burkholderia isolates and 75 isolates belonging to other CF-relevant species including Pseudomonas, Achromobacter, Pandoraea, Ralstonia, Stenotrophomonas, and Acinetobacter. Nearly one-third of the isolates were multidrug resistant, and 20 (13%) were panresistant based on standard antibiotic testing. All isolates belonging to the same species were genotyped to ensure that each isolate was a distinct strain. The MIC90 of NB-401 was 125 μg/ml. We found no decrease in activity against multidrug-resistant or panresistant strains. MBC testing showed no evidence of tolerance to NB-401. We investigated the activity of NB-401 against a subset of strains grown as a biofilm and against planktonic strains in the presence of CF sputum. Although the activity of NB-401 was decreased under both conditions, the nanoemulsion remained bactericidal for all strains tested. These results support NB-401's potential role as a novel antimicrobial agent for the treatment of infection due to CF-related opportunistic pathogens.

scholarly journals “Switching Partners”: Piperacillin-Avibactam Is a Highly Potent Combination against Multidrug-Resistant Burkholderia cepacia Complex and Burkholderia gladioli Cystic Fibrosis Isolates

2019 ◽  
Vol 57 (8) ◽  
Author(s):  
Elise T. Zeiser ◽  
Scott A. Becka ◽  
Brigid M. Wilson ◽  
Melissa D. Barnes ◽  
John J. LiPuma ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Burkholderia Cepacia ◽  
Multidrug Resistant ◽  
Burkholderia Cepacia Complex ◽  
Content Type ◽  
Burkholderia Gladioli ◽  
Alternative Antibiotic ◽  
And Control

ABSTRACT In persons with cystic fibrosis (CF), airway infection with Burkholderia cepacia complex (Bcc) species or Burkholderia gladioli presents a significant challenge due to inherent resistance to multiple antibiotics. Two chromosomally encoded inducible β-lactamases, a Pen-like class A and AmpC are produced in Bcc and B. gladioli. Previously, ceftazidime-avibactam demonstrated significant potency against Bcc and B. gladioli isolated from the sputum of individuals with CF; however, 10% of the isolates tested resistant to ceftazidime-avibactam. Here, we describe an alternative antibiotic combination to overcome ceftazidime-avibactam resistance. Antimicrobial susceptibility testing was performed on Bcc and B. gladioli clinical and control isolates. Biochemical analysis was conducted on purified PenA1 and AmpC1 β-lactamases from Burkholderia multivorans ATCC 17616. Analytic isoelectric focusing and immunoblotting were conducted on cellular extracts of B. multivorans induced by various β-lactams or β-lactam-β-lactamase inhibitor combinations. Combinations of piperacillin-avibactam, as well as piperacillin-tazobactam plus ceftazidime-avibactam (the clinically available counterpart), were tested against a panel of ceftazidime-avibactam nonsusceptible Bcc and B. gladioli. The piperacillin-avibactam and piperacillin-tazobactam-ceftazidime-avibactam combinations restored susceptibility to 99% of the isolates tested. Avibactam is a potent inhibitor of PenA1 (apparent inhibitory constant [Ki app] = 0.5 μM), while piperacillin was found to inhibit AmpC1 (Ki app = 2.6 μM). Moreover, piperacillin, tazobactam, ceftazidime, and avibactam, as well as combinations thereof, did not induce expression of blapenA1 and blaampC1 in the B. multivorans ATCC 17616 background. When ceftazidime-avibactam is combined with piperacillin-tazobactam, the susceptibility of Bcc and B. gladioli to ceftazidime and piperacillin is restored in vitro. Both the lack of blapenA1 induction and potent inactivation of PenA1 by avibactam likely provide the major contributions toward susceptibility. With in vivo validation, piperacillin-tazobactam-ceftazidime-avibactam may represent salvage therapy for individuals with CF and highly drug-resistant Bcc and B. gladioli infections.

scholarly journals Diagnostically and Experimentally Useful Panel of Strains from the Burkholderia cepacia Complex

2000 ◽  
Vol 38 (2) ◽  
pp. 910-913 ◽  
Author(s):  
Eshwar Mahenthiralingam ◽  
Tom Coenye ◽  
Jacqueline W. Chung ◽  
David P. Speert ◽  
John R. W. Govan ◽  
...  
Keyword(s):  
New Species ◽  
Burkholderia Cepacia ◽  
Burkholderia Cepacia Complex ◽  
Opportunistic Pathogens ◽  
Epidemiological Analysis ◽  
Burkholderia Multivorans ◽  
Burkholderia Vietnamiensis ◽  
Important Group ◽  
Two New Species

Two new species, Burkholderia multivorans andBurkholderia vietnamiensis, and three genomovars (genomovars I, III, and IV) currently constitute the Burkholderia cepacia complex. A panel of 30 well-characterized strains representative of each genomovar and new species was assembled to assist with identification, epidemiological analysis, and virulence studies on this important group of opportunistic pathogens.

scholarly journals Evaluation of the electron transfer flavoprotein as an antibacterial target in Burkholderia cenocepacia

2017 ◽  
Vol 63 (10) ◽  
pp. 857-863 ◽  
Author(s):  
Maria S. Stietz ◽  
Christina Lopez ◽  
Osasumwen Osifo ◽  
Marcelo E. Tolmasky ◽  
Silvia T. Cardona
Keyword(s):  
Electron Transfer ◽  
Burkholderia Cepacia ◽  
Multidrug Resistant ◽  
Burkholderia Cenocepacia ◽  
Burkholderia Cepacia Complex ◽  
Infection Model ◽  
Electron Transfer Flavoprotein ◽  
C Elegans

There are hundreds of essential genes in multidrug-resistant bacterial genomes, but only a few of their products are exploited as antibacterial targets. An example is the electron transfer flavoprotein (ETF), which is required for growth and viability in Burkholderia cenocepacia. Here, we evaluated ETF as an antibiotic target for Burkholderia cepacia complex (Bcc). Depletion of the bacterial ETF during infection of Caenorhabditis elegans significantly extended survival of the nematodes, proving that ETF is essential for survival of B. cenocepacia in this host model. In spite of the arrest in respiration in ETF mutants, the inhibition of etf expression did not increase the formation of persister cells, when treated with high doses of ciprofloxacin or meropenem. To test if etf translation could be inhibited by RNA interference, antisense oligonucleotides that target the etfBA operon were synthesized. One antisense oligonucleotide was effective in inhibiting etfB translation in vitro but not in vivo, highlighting the challenge of reduced membrane permeability for the design of drugs against B. cenocepacia. This work contributes to the validation of ETF of B. cenocepacia as a target for antibacterial therapy and demonstrates the utility of a C. elegans liquid killing assay to validate gene essentiality in an in vivo infection model.

scholarly journals Conservation of resistance nodulation cell division efflux pump mediated antibiotic resistance in Burkholderia cepacia complex and Burkholderia pseudomallei complex species

2021 ◽  
Author(s):  
Nawarat Somprasong ◽  
Jinhee Yi ◽  
Carina M. Hall ◽  
Jessica R. Webb ◽  
Jason W. Sahl ◽  
...  
Keyword(s):  
Cell Division ◽  
Burkholderia Cepacia ◽  
Burkholderia Pseudomallei ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Burkholderia Cepacia Complex ◽  
Complex Species ◽  
Functional Studies ◽  
Rnd Efflux Pump

Burkholderia cepacia complex (Bcc) and Burkholderia pseudomallei complex (Bpc) species include pathogens that are typically multidrug resistant. Dominant intrinsic and acquired multidrug resistance mechanisms are efflux mediated by pumps of the resistance nodulation cell division (RND) family. From comparative bioinformatic and, in many instances, functional studies we infer that RND pump-based resistance mechanisms are conserved in Burkholderia . We propose to use these findings as a foundation for adoption of a uniform RND efflux pump nomenclature.

scholarly journals Lysogeny and bacteriophage host range within the Burkholderia cepacia complex

2003 ◽  
Vol 52 (6) ◽  
pp. 483-490 ◽  
Author(s):  
Ross Langley ◽  
Dervla T. Kenna ◽  
Peter Vandamme ◽  
Rebecca Ure ◽  
John R. W. Govan
Keyword(s):  
Host Range ◽  
Burkholderia Cepacia ◽  
Potential Role ◽  
River Sediments ◽  
Burkholderia Cepacia Complex ◽  
Potential Contribution ◽  
Closely Related Species ◽  
Burkholderia Gladioli ◽  
Life Threatening ◽  
Species Specific

The Burkholderia cepacia complex comprises a group of nine closely related species that have emerged as life-threatening pulmonary pathogens in immunocompromised patients, particularly individuals with cystic fibrosis or chronic granulomatous disease. Attempts to explain the genomic plasticity, adaptability and virulence of the complex have paid little attention to bacteriophages, particularly the potential contribution of lysogenic conversion and transduction. In this study, lysogeny was observed in 10 of 20 representative strains of the B. cepacia complex. Three temperate phages and five lytic phages isolated from soils, river sediments or the plant rhizosphere were chosen for further study. Six phages exhibited T-even morphology and two were lambda-like. The host range of individual phages, when tested against 66 strains of the B. cepacia complex and a representative panel of other pseudomonads, was not species-specific within the B. cepacia complex and, in some phages, included Burkholderia gladioli and Pseudomonas aeruginosa. These new data indicate a potential role for phages of the B. cepacia complex in the evolution of these soil bacteria as pathogens of plants, humans and animals, and as novel therapeutic agents.

scholarly journals An investigation of Burkholderia cepacia complex methylomes via SMRT sequencing and mutant analysis

2021 ◽  
Author(s):  
Olga Mannweiler ◽  
Marta Pinto-Carbó ◽  
Martina Lardi ◽  
Kirsty Agnoli ◽  
Leo Eberl
Keyword(s):  
Dna Methylation ◽  
Burkholderia Cepacia ◽  
Membrane Vesicle ◽  
Restriction Enzymes ◽  
Burkholderia Cenocepacia ◽  
Burkholderia Cepacia Complex ◽  
Phenotypic Traits ◽  
Opportunistic Pathogens ◽  
Smrt Sequencing ◽  
Foreign Dna

Bacterial genomes can be methylated at particular motifs by methyltransferases (M). This DNA modification allows restriction endonucleases (R) to discriminate between self and foreign DNA. While the accepted primary function of such restriction modification (RM) systems is to degrade incoming foreign DNA, other roles of RM systems and lone R or M components have been found in genome protection, stability and the regulation of various phenotypes. The Burkholderia cepacia complex (Bcc) is a group of closely related opportunistic pathogens with biotechnological potential. Here, we constructed and analysed mutants lacking various RM components in the clinical Bcc isolate Burkholderia cenocepacia H111 and used SMRT sequencing of single mutants to assign the B. cenocepacia H111 Ms to their cognate motifs. DNA methylation is shown to affect biofilm formation, cell shape, motility, siderophore production and membrane vesicle production. Moreover, DNA methylation had a large effect on the maintenance of the Bcc virulence megaplasmid pC3. Our data also suggest that the gp51 M-encoding gene, which is essential in H111 and is located within a prophage, is required for maintaining the bacteriophage in a lysogenic state, thereby ensuring a constant, low level of phage production within the bacterial population. Importance While genome sequence determines an organism’s proteins, methylation of the nucleotides themselves can confer additional properties. In bacteria, Ms modify specific nucleotide motifs to allow discrimination of ‘self’ from ‘non-self’ DNA, e.g. from bacteriophages. Restriction enzymes detect ‘non-self’ methylation patterns and cut foreign DNA. Furthermore, methylation of promoter regions can influence gene expression and hence affect various phenotypes. In this study, we determined the methylated motifs of four strains from the Burkholderia cepacia complex of opportunistic pathogens. We deleted all genes encoding the restriction and modification components in one of these strains, Burkholderia cenocepacia H111. It is shown that DNA methylation affects various phenotypic traits, the most noteworthy being lysogenicity of a bacteriophage and maintenance of a virulence megaplasmid.

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