scholarly journals Intrinsic Class D β-Lactamases of Clostridium difficile

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Marta Toth ◽  
Nichole K. Stewart ◽  
Clyde Smith ◽  
Sergei B. Vakulenko
Keyword(s):  
Clostridium Difficile ◽  
Broad Spectrum ◽  
Antimicrobial Agents ◽  
Catalytic Efficiency ◽  
Content Type ◽  
Mechanism Of Resistance ◽  
Class D ◽  
Infection Resistance ◽  
High Level ◽  
Clostridium Cochlearium

ABSTRACT Clostridium difficile is the causative agent of the deadly C. difficile infection. Resistance of the pathogen to β-lactam antibiotics plays a major role in the development of the disease, but the mechanism of resistance is currently unknown. We discovered that C. difficile encodes class D β-lactamases, i.e., CDDs, which are intrinsic to this species. We studied two CDD enzymes, CDD-1 and CDD-2, and showed that they display broad-spectrum, high catalytic efficiency against various β-lactam antibiotics, including penicillins and expanded-spectrum cephalosporins. We demonstrated that the cdd genes are poorly expressed under the control of their own promoters and contribute only partially to the observed resistance to β-lactams. However, when the cdd1 gene was expressed under the control of efficient promoters in the antibiotic-sensitive Clostridium cochlearium strain, it produced high-level resistance to β-lactams. Taken together, the results determined in this work demonstrate the existence in C. difficile of intrinsic class D β-lactamases which constitute a reservoir of highly potent enzymes capable of conferring broad-spectrum, clinically relevant levels of resistance to β-lactam antibiotics. This discovery is a significant contribution to elucidation of the mechanism(s) of resistance of the clinically important pathogen C. difficile to β-lactam antibiotics. IMPORTANCE C. difficile is a spore-forming anaerobic bacterium which causes infection of the large intestine with high mortality rates. The C. difficile infection is difficult to prevent and treat, as the pathogen is resistant to many antimicrobial agents. Prolonged use of β-lactam antibiotics for treatment of various infectious diseases triggers the infection, as these drugs suppress the abundance of protective gut bacteria, allowing the resistant C. difficile bacteria to multiply. While resistance of C. difficile to β-lactam antibiotics plays the major role in the development of the disease, the mechanism of resistance is unknown. The significance of our research is in the discovery in C. difficile of β-lactamases, enzymes that destroy β-lactam antibiotics. These findings ultimately can help to combat deadly C. difficile infections.

scholarly journals Characterizations of Clinical Isolates of Clostridium difficile by Toxin Genotypes and by Susceptibility to 12 Antimicrobial Agents, Including Fidaxomicin (OPT-80) and Rifaximin: a Multicenter Study in Taiwan

2012 ◽  
Vol 56 (7) ◽  
pp. 3943-3949 ◽  
Author(s):  
Chun-Hsing Liao ◽  
Wen-Chien Ko ◽  
Jang-Jih Lu ◽  
Po-Ren Hsueh
Keyword(s):  
Clostridium Difficile ◽  
Care Setting ◽  
Antimicrobial Agents ◽  
Teaching Hospitals ◽  
Binary Toxin ◽  
Content Type ◽  
Vancomycin Mics ◽  
Major Teaching ◽  
Southern Taiwan

ABSTRACTA total of 403 nonduplicate isolates ofClostridium difficilewere collected at three major teaching hospitals representing northern, central, and southern Taiwan from January 2005 to December 2010. Of these 403 isolates, 170 (42.2%) were presumed to be nontoxigenic due to the absence of genes for toxins A or B or binary toxin. The remaining 233 (57.8%) isolates carried toxin A and B genes, and 39 (16.7%) of these also had binary toxin genes. The MIC90of all isolates for fidaxomicin and rifaximin was 0.5 μg/ml (range, ≤0.015 to 0.5 μg/ml) and >128 μg/ml (range, ≤0.015 to >128 μg/ml), respectively. All isolates were susceptible to metronidazole (MIC90of 0.5 μg/ml; range, ≤0.03 to 4 μg/ml). Two isolates had reduced susceptibility to vancomycin (MICs, 4 μg/ml). Only 13.6% of isolates were susceptible to clindamycin (MIC of ≤2 μg/ml). Nonsusceptibility to moxifloxacin (n= 81, 20.1%) was accompanied by single or multiple mutations ingyrAandgyrBgenes in all but eight moxifloxacin-nonsusceptible isolates. Two previously unreportedgyrBmutations might independently confer resistance (MIC, 16 μg/ml), Ser416 to Ala and Glu466 to Lys. Moxifloxacin-resistant isolates were cross-resistant to ciprofloxacin and levofloxacin, but some moxifloxacin-nonsusceptible isolates remained susceptible to gemifloxacin or nemonoxacin at 0.5 μg/ml. This study found the diversity of toxigenic and nontoxigenic strains ofC. difficilein the health care setting in Taiwan. All isolates tested were susceptible to metronidazole and vancomycin. Fidaxomicin exhibited potentin vitroactivity against all isolates tested, while the more than 10% of Taiwanese isolates with rifaximin MICs of ≥128 μg/ml raises concerns.

scholarly journals High-Level Carbapenem Resistance in OXA-232-Producing Raoultella ornithinolytica Triggered by Ertapenem Therapy

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Alina Iovleva ◽  
Roberta T. Mettus ◽  
Christi L. McElheny ◽  
Marissa P. Griffith ◽  
Mustapha M. Mustapha ◽  
...  
Keyword(s):  
Rapid Development ◽  
Carbapenem Resistance ◽  
Resistant Isolate ◽  
Clinical Microbiology Laboratory ◽  
Loss Of Function ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D ◽  
Fold Reduction ◽  
High Level

ABSTRACT OXA-232 is an OXA-48-group class D β-lactamase that hydrolyzes expanded-spectrum cephalosporins and carbapenems at low levels. Clinical strains producing OXA-232 are sometimes susceptible to carbapenems, making it difficult to identify them in the clinical microbiology laboratory. We describe the development of carbapenem resistance in sequential clinical isolates of Raoultella ornithinolytica carrying blaOXA-232 in a hospitalized patient, where the ertapenem MIC increased from 0.5 μg/ml to 512 μg/ml and the meropenem MIC increased from 0.125 μg/ml to 32 μg/ml during the course of ertapenem therapy. Whole-genome sequencing (WGS) analysis identified loss-of-function mutations in ompC and ompF in carbapenem-resistant isolates that were not present in the initial carbapenem-susceptible isolate. Complementation of a carbapenem-resistant isolate with an intact ompF gene resulted in 16- to 32-fold reductions in carbapenem MICs, whereas complementation with intact ompC resulted in a 2-fold reduction in carbapenem MICs. Additionally, blaOXA-232 expression increased 2.9-fold in a carbapenem-resistant isolate. Rapid development of high-level carbapenem resistance in initially carbapenem-susceptible OXA-232-producing R. ornithinolytica under selective pressure from carbapenem therapy highlights the diagnostic challenges in detecting Enterobacteriaceae strains producing this inefficient carbapenemase.

scholarly journals Characterization of clinical Clostridium difficile isolates by PCR ribotyping and detection of toxin genes in Austria, 2006–2007

2008 ◽  
Vol 57 (6) ◽  
pp. 702-708 ◽  
Author(s):  
A. Indra ◽  
D. Schmid ◽  
S. Huhulescu ◽  
M. Hell ◽  
R. Gattringer ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Pseudomembranous Colitis ◽  
Antimicrobial Agents ◽  
Toxic Megacolon ◽  
Health Care Facilities ◽  
Reference Laboratory ◽  
Specimen Collection ◽  
Pcr Ribotyping ◽  
High Level

In order to assess the lethality of Clostridium difficile-associated disease (CDAD) and the PCR ribotypes prevalent in Austria, the Austrian Agency for Health and Food Safety requested isolates of C. difficile from patients in a structured but arbitrary sampling scheme. In the allocated period from February 2006 to January 2007, local hospital laboratories within each of the nine provinces were asked to submit C. difficile isolates from at least ten cases of CDAD. Confirmation of species identification, toxin detection, susceptibility testing against four antimicrobial agents and typing using a PCR ribotyping method were performed at the reference laboratory. In total, 149 isolates of putative C. difficile were submitted, from which 142 were included for study. Antimicrobial susceptibility patterns revealed resistance to clindamycin in 57 % and high-level resistance to moxifloxacin in 38 % of isolates tested. CDAD manifested as diarrhoea (including eight cases of bloody diarrhoea) in 126 cases (88.7 %), as pseudomembranous colitis in 15 cases (10.6 %) and as toxic megacolon in one case. Twelve of the 142 patients died within 30 days of specimen collection (8.45 % lethality). A lethal outcome occurred in 2/15 cases (13.3 %) when pseudomembranous colitis was present and in 10/126 cases (7.9 %) in the absence of pseudomembranous colitis or toxic megacolon. Among the 142 isolates from 25 health-care facilities, 41 PCR ribotype patterns were found. The most frequent ribotypes were AI-5 (including six lethal cases out of 26 patients), 014 (two out of 24) and 053 (one out of 24). The typing patterns demonstrated the occurrence of clusters in hospitals.

scholarly journals In VitroAntibacterial Activity of the Ceftazidime-Avibactam Combination against Enterobacteriaceae, Including Strains with Well-Characterized β-Lactamases

2015 ◽  
Vol 59 (4) ◽  
pp. 1931-1934 ◽  
Author(s):  
Premavathy Levasseur ◽  
Anne-Marie Girard ◽  
Christine Miossec ◽  
John Pace ◽  
Ken Coleman
Keyword(s):  
Antibacterial Activity ◽  
Antimicrobial Agents ◽  
The Novel ◽  
Content Type ◽  
Class A ◽  
Fixed Weight ◽  
Class D ◽  
Resistant Strains ◽  
Esbl Producers

ABSTRACTThe novel β-lactamase inhibitor avibactam is a potent inhibitor of class A, class C, and some class D enzymes. Thein vitroantibacterial activity of the ceftazidime-avibactam combination was determined for a collection ofEnterobacteriaceaeclinical isolates; this collection was enriched for resistant strains, including strains with characterized serine β-lactamases. The inhibitor was added either at fixed weight ratios to ceftazidime or at fixed concentrations, with the latter type of combination consistently resulting in greater potentiation of antibacterial activity. In the presence of 4 μg/ml of avibactam, the ceftazidime MIC50and MIC90(0.25 and 2 μg/ml, respectively) were both below the CLSI breakpoint for ceftazidime. Further comparisons with reference antimicrobial agents were performed using this fixed inhibitor concentration. Against most ceftazidime-susceptible and -nonsusceptible isolates, the addition of avibactam resulted in a significant increase in ceftazidime activity, with MICs generally reduced 256-fold for extended-spectrum β-lactamase (ESBL) producers, 8- to 32-fold for CTX-M producers, and >128-fold for KPC producers. Overall, MICs of a ceftazidime-avibactam combination were significantly lower than those of the comparators piperacillin-tazobactam, cefotaxime, ceftriaxone, and cefepime and similar or superior to those of imipenem.

scholarly journals Broad-Spectrum Antimicrobial and Antibiofilm Activity of a Natural Clay Mineral from British Columbia, Canada

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Shekooh Behroozian ◽  
Sarah L. Svensson ◽  
Loretta Y. Li ◽  
Julian E. Davies
Keyword(s):  
Antibacterial Activity ◽  
Clay Mineral ◽  
Broad Spectrum ◽  
Chelating Agents ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Low Ph ◽  
Natural Clay ◽  
Content Type ◽  
History Of

ABSTRACT Worldwide increases in antibiotic resistance and the dearth of new antibiotics have created a global crisis in the treatment of infectious diseases. These concerns highlight the pressing need for novel antimicrobial agents. Natural clay minerals have a long history of therapeutic and biomedical applications and have lately received specific attention for their potent antimicrobial properties. In particular, Kisameet clay (KC) has strong antibacterial activity against a variety of multidrug-resistant (MDR) bacterial pathogens in vitro. Here, we have extended the known spectrum of activity of KC by demonstrating its efficacy against two major fungal pathogens, Candida albicans and Cryptococcus neoformans. In addition, KC also exhibits potent activity against the opportunistic bacterial pathogen Mycobacterium marinum, a model organism for M. ulcerans infection. Moreover, aqueous KC leachates (KC-L) exhibited broad-spectrum antibacterial activity, eradicated Gram-negative and Gram-positive biofilms, and prevented their formation. The mechanism(s) underlying KC antibacterial activity appears to be complex. Adjusting KC-L to neutral pH rendered it inactive, indicating a contribution of pH, although low pH alone was insufficient for its antibacterial activity. Treatment of KC minerals with cation-chelating agents such as EDTA, 2,2′-bipyridyl, and deferoxamine reduced the antibacterial activity, while supplementation of KC-L with these chelating agents eliminated the inhibitory activity. Together, the data suggest a positive role for divalent and trivalent cations, including iron and aluminum, in bacterial inhibition by KC. Collectively, these studies demonstrate the range of KC bioactivity and provide a better understanding of the mechanism underlying its antibacterial effects. IMPORTANCE The escalating emergence of multidrug-resistant (MDR) bacteria, together with the paucity of novel antimicrobial agents in antibiotic development, is recognized as a worldwide public health crisis. Kisameet clay (KC), found in British Columbia (BC), Canada, is a clay mineral with a long history of therapeutic applications among people of the First Nations. We previously reported the antibacterial activity of KC against a group of MDR clinical pathogens. Here, we demonstrate its activity against two major human-pathogenic fungal species, as well as against bacterial biofilms, which underlie many recalcitrant bacterial infections. In these studies, we also identified several geochemical characteristics of KC, such as metal ions and low pH, which are involved in its antibacterial activity. These findings provide a better understanding of the components of KC antibacterial activity and a basis for developing defined preparations of this clay mineral for therapeutic applications.

Cranial zygomycosis caused by Saksenaea vasiformis

1977 ◽  
Vol 46 (1) ◽  
pp. 97-103 ◽  
Author(s):  
David F. Dean ◽  
Libero Ajello ◽  
Richard S. Irwin ◽  
William K. Woelk ◽  
Gregory J. Skarulis
Keyword(s):  
Fungal Infection ◽  
Surgical Therapy ◽  
Broad Spectrum ◽  
Early Identification ◽  
Antimicrobial Agents ◽  
Severe Head Trauma ◽  
Content Type ◽  
Disease Agent ◽  
First Time ◽  
Fine Print

✓ A previously healthy youth who had sustained severe head trauma and had received steroids and broad-spectrum antimicrobial agents developed a cranial zygomycotic infection with Saksenaea vasiformis. This is the first time this zygomycete has been implicated as a disease agent. Early identification of the fungal infection and subsequent vigorous medical and surgical therapy led to recovery.

scholarly journals Fluoroquinolone and Macrolide Exposure Predict Clostridium difficile Infection with the Highly Fluoroquinolone- and Macrolide-Resistant Epidemic C. difficile Strain BI/NAP1/027

2015 ◽  
Vol 60 (1) ◽  
pp. 418-423 ◽  
Author(s):  
Jeffrey T. Wieczorkiewicz ◽  
Bert K. Lopansri ◽  
Adam Cheknis ◽  
James R. Osmolski ◽  
David W. Hecht ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Restriction Endonuclease Analysis ◽  
First Episode ◽  
Retrospective Case ◽  
Content Type ◽  
High Level ◽  
Control Study ◽  
Level Resistance ◽  
Endonuclease Analysis ◽  
Multiple Antibiotics

ABSTRACTAntibiotics have been shown to influence the risk of infection with specificClostridium difficilestrains as well as the risk ofC. difficileinfection (CDI). We performed a retrospective case-control study of patients infected with the epidemic BI/NAP1/027 strain in a U.S. hospital following recognition of increased CDI severity and culture of stools positive byC. difficiletoxin immunoassay. Between 2005 and 2007, 72% (103/143) of patients with first-episode CDIs were infected with the BI strain by restriction endonuclease analysis (REA) typing. Most patients received multiple antibiotics within 6 weeks of CDI onset (median of 3 antibiotic classes). By multivariate analysis, fluoroquinolone and macrolide exposure was more frequent among BI cases than among non-BI-infected controls (odds ratio [OR] for fluoroquinolones, 3.2; 95% confidence interval [CI], 1.3 to 7.5; (P< 0.001; OR for macrolides, 5.2; 95% CI, 1.1 to 24.0;P= 0.04)). In contrast, clindamycin use was less frequent among the BI cases than among the controls (OR, 0.1; 95% CI, 0.03 to 0.4;P= 0.001). High-level resistance to moxifloxacin and azithromycin was more frequent among BI strains (moxifloxacin, 49/102 [48%] BI versus 0/40 non-BI,P= 0.0001; azithromycin, 100/102 [98%] BI versus 22/40 [55%] non-BI,P= 0.0001). High-level resistance to clindamycin was more frequent among non-BI strains (22/40 [55%] non-BI versus 7/102 [7%] BI,P= 0.0001). Fluoroquinolone use, macrolide use, andC. difficileresistance to these antibiotic classes were associated with infection by the epidemic BI strain ofC. difficilein a U.S. hospital during a time when CDI rates were increasing nationally due to the highly fluoroquinolone-resistant BI/NAP1/027 strain.

scholarly journals Susceptibility of Clostridium difficile Isolates of Varying Antimicrobial Resistance Phenotypes to SMT19969 and 11 Comparators

2015 ◽  
Vol 60 (1) ◽  
pp. 689-692 ◽  
Author(s):  
Jane Freeman ◽  
Jonathan Vernon ◽  
Richard Vickers ◽  
Mark H. Wilcox
Keyword(s):  
Clostridium Difficile ◽  
Antimicrobial Resistance ◽  
Geometric Mean ◽  
Multiple Resistance ◽  
Content Type ◽  
High Level

ABSTRACTWe determined thein vitroactivity of SMT19969 and 11 comparators, including metronidazole, vancomycin, and fidaxomicin, against 107C. difficileisolates of different antimicrobial resistance phenotypes. Fidaxomicin and SMT19969 were the most active. The fidaxomicin and SMT19969 geometric mean MICs were highest in ribotypes known to show multiple resistance. Coresistance to linezolid and moxifloxacin was evident in ribotypes 001, 017, 027, and 356. The high-level ceftriaxone resistance in ribotypes 356 and 018 was location linked.

scholarly journals Complete Genome Sequence of Peptacetobacter (Clostridium) hiranonis Strain DGF055142, Isolated from Dog Feces from Flagstaff, Arizona, USA, 2019

2021 ◽  
Vol 10 (9) ◽  
Author(s):  
Nathan E. Stone ◽  
Amalee E. Nunnally ◽  
Chandler C. Roe ◽  
Heidie M. Hornstra ◽  
David M. Wagner ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Genome Sequence ◽  
Complete Genome Sequence ◽  
Complete Genome ◽  
Illumina Miseq ◽  
Single Chromosome ◽  
Content Type ◽  
Long Reads ◽  
Oxford Nanopore ◽  
Infection Resistance

ABSTRACT A single-chromosome closed genome of Peptacetobacter (Clostridium) hiranonis strain DGF055142 was generated using Illumina MiSeq short reads paired with Oxford Nanopore MinION long reads. This isolate was obtained from a canine in Flagstaff, Arizona, in 2019. Peptacetobacter (C.) hiranonis was hypothesized to contribute to canine Clostridium difficile infection resistance.

scholarly journals Novel Tet(L) Efflux Pump Variants Conferring Resistance to Tigecycline and Eravacycline in Staphylococcus Spp.

2021 ◽  
Author(s):  
Nannan Wang ◽  
Dexi Li ◽  
Stefan Schwarz ◽  
Shangshang Qin ◽  
Hong Yao ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Broad Spectrum ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Clinical Treatment ◽  
Content Type ◽  
Staphylococcus Spp

Tigecycline and eravacycline are both important last-resort broad spectrum antimicrobial agents. The presence of novel Tet(L) efflux pump variants conferring the resistance to tigecycline and eravacycline in Staphylococcus spp. and its potential transmission to S. aureus will compromise the efficacy of tigecycline and eravacycline treatment for S. aureus associated infection in vivo and may lead to clinical treatment failure.

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