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1.
Sci Rep ; 12(1): 8763, 2022 May 24.
Article in English | MEDLINE | ID: covidwho-1873545

ABSTRACT

Cefiderocol (CFDC) is a novel chlorocatechol-substituted siderophore antibiotic approved to treat complicated urinary tract infections (cUTI) and hospital-acquired and ventilator-acquired pneumonia (HAP/VAP). Previous work determined that albumin-rich human fluids increase the minimum inhibitory concentration (MICs) of Acinetobacter baumannii against CFDC and reduce the expression of genes related to iron uptake systems. This latter effect may contribute to the need for higher concentrations of CFDC to inhibit growth. The presence of human urine (HU), which contains low albumin concentrations, did not modify MIC values of two carbapenem-resistant A. baumannii. Levels of resistance to CFDC were not modified by HU in strain AMA40 but were reduced in strain AB5075. Expanding the studies to other carbapenem-resistant A. baumannii isolates showed that the presence of HU resulted in unmodified or reduced MIC of CDFC values. The expression of piuA, pirA, bauA, and bfnH determined by qRT-PCR was enhanced in A. baumannii AMA40 and AB5075 by the presence of HU in the culture medium. All four tested genes code for functions related to recognition and transport of ferric-siderophore complexes. The effect of HU on expression of pbp1, pbp3, blaOXA-51-like, blaADC, and blaNDM-1, genes associated with resistance to ß-lactams, as well as genes coding for efflux pumps and porins was variable, showing dependence with the strain analyzed. We conclude that the lack of significant concentrations of albumin and free iron in HU makes this fluid behave differently from others we tested. Unlike other albumin rich fluids, the presence of HU does not impact the antibacterial activity of CFDC when tested against A. baumannii.


Subject(s)
Acinetobacter baumannii , Albumins/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Carbapenems/pharmacology , Cephalosporins , Humans , Iron/pharmacology , Microbial Sensitivity Tests , Siderophores , beta-Lactamases/genetics
2.
Drugs ; 82(5): 533-557, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1827389

ABSTRACT

Sulopenem (formerly known as CP-70,429, and CP-65,207 when a component of a racemic mixture with its R isomer) is an intravenous and oral penem that possesses in vitro activity against fluoroquinolone-resistant, extended spectrum ß-lactamases (ESBL)-producing, multidrug-resistant (MDR) Enterobacterales. Sulopenem is being developed to treat patients with uncomplicated and complicated urinary tract infections (UTIs) as well as intra-abdominal infections. This review will focus mainly on its use in UTIs. The chemical structure of sulopenem shares properties of penicillins, cephalosporins, and carbapenems. Sulopenem is available as an oral prodrug formulation, sulopenem etzadroxil, which is hydrolyzed by intestinal esterases, resulting in active sulopenem. In early studies, the S isomer of CP-65,207, later developed as sulopenem, demonstrated greater absorption, higher drug concentrations in the urine, and increased stability against the renal enzyme dehydropeptidase-1 compared with the R isomer, which set the stage for its further development as a UTI antimicrobial. Sulopenem is active against both Gram-negative and Gram-positive microorganisms. Sulopenem's ß-lactam ring alkylates the serine residues of penicillin-binding protein (PBP), which inhibits peptidoglycan cross-linking. Due to its ionization and low molecular weight, sulopenem passes through outer membrane proteins to reach PBPs of Gram-negative bacteria. While sulopenem activity is unaffected by many ß-lactamases, resistance arises from alterations in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), expression of carbapenemases (e.g., carbapenemase-producing Enterobacterales and in Stenotrophomonas maltophilia), reduction in the expression of outer membrane proteins (e.g., some Klebsiella spp.), and the presence of efflux pumps (e.g., MexAB-OprM in Pseudomonas aeruginosa), or a combination of these mechanisms. In vitro studies have reported that sulopenem demonstrates greater activity than meropenem and ertapenem against Enterococcus faecalis, Listeria monocytogenes, methicillin-susceptible S. aureus (MSSA), and Staphylococcus epidermidis, as well as similar activity to carbapenems against Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. With some exceptions, sulopenem activity against Gram-negative aerobes was less than ertapenem and meropenem but greater than imipenem. Sulopenem activity against Escherichia coli carrying ESBL, CTX-M, or Amp-C enzymes, or demonstrating MDR phenotypes, as well as against ESBL-producing Klebsiella pneumoniae, was nearly identical to ertapenem and meropenem and greater than imipenem. Sulopenem exhibited identical or slightly greater activity than imipenem against many Gram-positive and Gram-negative anaerobes, including Bacteroides fragilis. The pharmacokinetics of intravenous sulopenem appear similar to carbapenems such as imipenem-cilastatin, meropenem, and doripenem. In healthy subjects, reported volumes of distribution (Vd) ranged from 15.8 to 27.6 L, total drug clearances (CLT) of 18.9-24.9 L/h, protein binding of approximately 10%, and elimination half-lives (t½) of 0.88-1.03 h. The estimated renal clearance (CLR) of sulopenem is 8.0-10.6 L/h, with 35.5% ± 6.7% of a 1000 mg dose recovered unchanged in the urine. An ester prodrug, sulopenem etzadroxil, has been developed for oral administration. Initial investigations reported a variable oral bioavailability of 20-34% under fasted conditions, however subsequent work showed that bioavailability is significantly improved by administering sulopenem with food to increase its oral absorption or with probenecid to reduce its renal tubular secretion. Food consumption increases the area under the curve (AUC) of oral sulopenem (500 mg twice daily) by 23.6% when administered alone and 62% when administered with 500 mg of probenecid. Like carbapenems, sulopenem demonstrates bactericidal activity that is associated with the percentage of time that free concentrations exceed the MIC (%f T > MIC). In animal models, bacteriostasis was associated with %f T > MICs ranging from 8.6 to 17%, whereas 2-log10 kill was seen at values ranging from 12 to 28%. No pharmacodynamic targets have been documented for suppression of resistance. Sulopenem concentrations in urine are variable, ranging from 21.8 to 420.0 mg/L (median 84.4 mg/L) in fasted subjects and 28.8 to 609.0 mg/L (median 87.3 mg/L) in those who were fed. Sulopenem has been compared with carbapenems and cephalosporins in guinea pig and murine systemic and lung infection animal models. Studied pathogens included Acinetobacter calcoaceticus, B. fragilis, Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, Proteus vulgaris, and Serratia marcescens. These studies reported that overall, sulopenem was non-inferior to carbapenems but appeared to be superior to cephalosporins. A phase III clinical trial (SURE-1) reported that sulopenem was not non-inferior to ciprofloxacin in women infected with fluoroquinolone-susceptible pathogens, due to a higher rate of asymptomatic bacteriuria in sulopenem-treated patients at the test-of-cure visit. However, the researchers reported superiority of sulopenem etzadroxil/probenecid over ciprofloxacin for the treatment of uncomplicated UTIs in women infected with fluoroquinolone/non-susceptible pathogens, and non-inferiority in all patients with a positive urine culture. A phase III clinical trial (SURE-2) compared intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid with ertapenem in the treatment of complicated UTIs. No difference in overall success was noted at the end of therapy. However, intravenous sulopenem followed by oral sulopenem etzadroxil was not non-inferior to ertapenem followed by oral stepdown therapy in overall success at test-of-cure due to a higher rate of asymptomatic bacteriuria in the sulopenem arm. After a meeting with the US FDA, Iterum stated that they are currently evaluating the optimal design for an additional phase III uncomplicated UTI study to be conducted prior to the potential resubmission of the New Drug Application (NDA). It is unclear at this time whether Iterum intends to apply for EMA or Japanese regulatory approval. The safety and tolerability of sulopenem has been reported in various phase I pharmacokinetic studies and phase III clinical trials. Sulopenem (intravenous and oral) appears to be well tolerated in healthy subjects, with and without the coadministration of probenecid, with few serious drug-related treatment-emergent adverse events (TEAEs) reported to date. Reported TEAEs affecting ≥1% of patients were (from most to least common) diarrhea, nausea, headache, vomiting and dizziness. Discontinuation rates were low and were not different than comparator agents. Sulopenem administered orally and/or intravenously represents a potentially well tolerated and effective option for treating uncomplicated and complicated UTIs, especially in patients with documented or highly suspected antimicrobial pathogens to commonly used agents (e.g. fluoroquinolone-resistant E. coli), and in patients with documented microbiological or clinical failure or patients who demonstrate intolerance/adverse effects to first-line agents. This agent will likely be used orally in the outpatient setting, and intravenously followed by oral stepdown in the hospital setting. Sulopenem also allows for oral stepdown therapy in the hospital setting from intravenous non-sulopenem therapy. More clinical data are required to fully assess the clinical efficacy and safety of sulopenem, especially in patients with complicated UTIs caused by resistant pathogens such as ESBL-producing, Amp-C, MDR E. coli. Antimicrobial stewardship programs will need to create guidelines for when this oral and intravenous penem should be used.


Subject(s)
Bacteriuria , Methicillin-Resistant Staphylococcus aureus , Prodrugs , Urinary Tract Infections , Adenosine Monophosphate/pharmacology , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Bacteriuria/chemically induced , Bacteriuria/drug therapy , Carbapenems/pharmacology , Cephalosporins/pharmacology , Ciprofloxacin/pharmacology , Ertapenem , Escherichia coli , Female , Fluoroquinolones/pharmacology , Gram-Negative Bacteria , Guinea Pigs , Humans , Imipenem/pharmacology , Lactams , Male , Membrane Proteins/pharmacology , Meropenem/pharmacology , Mice , Probenecid/pharmacology , Prodrugs/pharmacology , Staphylococcus aureus , Urinary Tract Infections/drug therapy , beta-Lactamases/pharmacology
4.
J Med Microbiol ; 71(4)2022 Apr.
Article in English | MEDLINE | ID: covidwho-1788579

ABSTRACT

Introduction. Carbapenem-resistant Acinetobacter baumannii (CRAB) is the primary pathogen causing hospital-acquired infections. The spread of CRAB is mainly driven by the dissemination of resistant clones, and in Latin America, International Clones IC-1 (also known as clonal complex CC1), IC-4 (CC15) and IC-5 (CC79) are the most prevalent.Gap Statement. There are no documented outbreaks of CRAB International Clone 2 (IC-2) reported in Brazil.Aim. To describe a large outbreak of CRAB caused by the uncommon IC-2 in a Brazilian COVID-19 hospital.Methodology. From May 2020 to May 2021, 224 patients infected or colonized with CRAB were identified in a single hospital; 92 % of them were also infected with SARS-CoV-2. From these patients, 137 isolates were recovered and subjected to antimicrobial susceptibility testing, PCR analysis and molecular typing. Whole-genome sequencing and downstream analysis were carried out on a representative isolate (the first available isolate).Results. In 76 % of the patients, a single OXA-23-producing CRAB IC-2 was identified. All the isolates were susceptible to polymyxin B, but highly resistant (>95 %) to aminoglycosides, fluoroquinolones and beta-lactams. Genomic analysis revealed that the representative isolate also carried the 16S rRNA Methylase ArmA, which was detected for the first time in this species in Brazil.Conclusion. We report the rapid spread of an emerging CRAB clone responsible for causing a large outbreak in a hospital in Brazil, a country with predominance of other CRAB clones. Continuous and prospective surveillance is warranted to evaluate the impact of this clone in Brazilian hospital settings.


Subject(s)
Acinetobacter Infections , Acinetobacter baumannii , COVID-19 , Acinetobacter Infections/epidemiology , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/genetics , Brazil/epidemiology , COVID-19/epidemiology , Clone Cells , Humans , Microbial Sensitivity Tests , Multilocus Sequence Typing , Pandemics , Prospective Studies , RNA, Ribosomal, 16S , SARS-CoV-2/genetics , beta-Lactamases/genetics
5.
Front Cell Infect Microbiol ; 12: 823626, 2022.
Article in English | MEDLINE | ID: covidwho-1775645

ABSTRACT

The serious challenge of antimicrobial resistance continues to threaten public health and lingers in the era of the coronavirus disease 2019 (COVID-19), declared pandemic by the World Health Organization. While the pandemic has triggered the importance of infection control practices and preventive measures such as physical distancing, hand hygiene, travel reduction and quarantine, the ongoing alarm of antimicrobial resistance seems to accompany the pandemic too. Antimicrobial resistance has been fostered during COVID-19, possibly due to high rate of empirical antibiotic utilization in COVID-19 patients, increased use of biocides, and the disruption of proper healthcare for other conditions. Specifically, carbapenemase-producing Gram-negative bacteria have shown to cause secondary bacterial infections in patients hospitalized for COVID-19. Clinical and microbiological evidence of such infections is accumulating in different parts of the world. With the resilient nature of carbapenemases, their association with mortality, and the limited treatment options available, concerns regarding this group of antibiotic-hydrolyzing enzymes during the pandemic are expected to upsurge. While the additional burden carbapenemases exert on healthcare is worrisome, it remains hidden or abandoned among the various health consequences of the pandemic. The purpose of this minireview is to shed a light on carbapenemase-associated infections during such unprecedented time of COVID-19. A focused insight shall be made into carbapenemases, their implications for COVID-19 patients, and the features and consequences of co-infection, with a review of available evidence from pertinent literature. The importance of increased surveillance for carbapenemase-producers and optimizing their management in relation to the pandemic, shall be addressed as well.


Subject(s)
COVID-19 , Bacterial Proteins , Humans , Pandemics , beta-Lactamases
7.
J Antimicrob Chemother ; 77(3): 625-632, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1713678

ABSTRACT

OBJECTIVES: Tigecycline is a last-resort antibiotic used to treat lethal infections caused by carbapenem-resistant Enterobacterales; however, plasmid-borne tigecycline resistance tmexCD-toprJ gene clusters can confer tigecycline resistance. The aim of the study was to identify novel subtypes and the spread of tmexCD-toprJ. METHODS: Five non-duplicate isolates of different species, carrying tmexCD-toprJ gene clusters or novel subtypes, were isolated from patients across China between November 2018 and June 2019. WGS was performed using Illumina and Nanopore platforms. A phylogenetic tree was constructed using a dataset of 77 sequences carrying the tmexCD-toprJ gene clusters, 72 of which were downloaded from NCBI with a blastn identity cut-off of 95%. RESULTS: We detected six different transfer units and two novel subtypes (tmexC1D1.2-toprJ1 and tmexC2D2.2-toprJ2) of the tmexCD-toprJ gene clusters. Among the six transfer units, three were mediated by IS26, while the rest were presumably mediated by Tn5393, hypothetical integrases (xerD-hp clusters-umuC-integrases-tnfxB2-tmexC2D2-toprJ2-umuC) and hypothetical units (hp-hp-hp-tnfxB2-tmexC2D2.2-toprJ2-ΔTn5393-Tn6292). Moreover, two tmexCD-toprJ-like gene clusters co-located on the same plasmid with blaNDM in five isolates. Phylogenetic analysis revealed that tmexCD-toprJ gene clusters may have originated in Pseudomonas spp., being mainly distributed in Pseudomonas spp. and Klebsiella spp. (64/77). Most tmexCD-toprJ gene clusters in Enterobacterales were located on plasmids, indicating that the gene clusters have a high inter-species transfer risk after transfer to Enterobacterales. CONCLUSIONS: In summary, to the best of our knowledge, this is the first report of tmexCD-toprJ gene clusters being isolated from Enterobacter cloacae and Klebsiella oxytoca, revealing that these multiple transfer units should be further studied because of their clinical significance.


Subject(s)
Enterobacter cloacae , Klebsiella oxytoca , Carbapenems/pharmacology , Enterobacter cloacae/genetics , Humans , Klebsiella oxytoca/genetics , Microbial Sensitivity Tests , Multigene Family , Phylogeny , beta-Lactamases/genetics
8.
Nature ; 602(7896): 343-348, 2022 02.
Article in English | MEDLINE | ID: covidwho-1671588

ABSTRACT

Carbapenems are antibiotics of last resort in the clinic. Owing to their potency and broad-spectrum activity, they are an important part of the antibiotic arsenal. The vital role of carbapenems is exemplified by the approval acquired by Merck from the US Food and Drug Administration (FDA) for the use of an imipenem combination therapy to treat the increased levels of hospital-acquired and ventilator-associated bacterial pneumonia that have occurred during the COVID-19 pandemic1. The C6 hydroxyethyl side chain distinguishes the clinically used carbapenems from the other classes of ß-lactam antibiotics and is responsible for their low susceptibility to inactivation by occluding water from the ß-lactamase active site2. The construction of the C6 hydroxyethyl side chain is mediated by cobalamin- or B12-dependent radical S-adenosylmethionine (SAM) enzymes3. These radical SAM methylases (RSMTs) assemble the alkyl backbone by sequential methylation reactions, and thereby underlie the therapeutic usefulness of clinically used carbapenems. Here we present X-ray crystal structures of TokK, a B12-dependent RSMT that catalyses three-sequential methylations during the biosynthesis of asparenomycin A. These structures, which contain the two metallocofactors of the enzyme and were determined in the presence and absence of a carbapenam substrate, provide a visualization of a B12-dependent RSMT that uses the radical mechanism that is shared by most of these enzymes. The structures provide insight into the stereochemistry of initial C6 methylation and suggest that substrate positioning governs the rate of each methylation event.


Subject(s)
Carbapenems/biosynthesis , Methyltransferases/chemistry , Methyltransferases/metabolism , S-Adenosylmethionine/metabolism , Streptomyces/enzymology , Thienamycins/biosynthesis , Vitamin B 12/metabolism , Binding Sites , Biocatalysis , Coenzymes/metabolism , Crystallography, X-Ray , Kinetics , Methylation , Models, Molecular , Protein Binding , Protein Domains , Streptomyces/metabolism , beta-Lactamase Inhibitors/metabolism , beta-Lactamases/chemistry , beta-Lactamases/metabolism
9.
Eur J Clin Microbiol Infect Dis ; 41(4): 573-580, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1640882

ABSTRACT

PURPOSE: To evaluate the prevalence of multi-carbapenemase-producing Enterobacterales (EB) and the activity of cefiderocol (CFDC), meropenem-vaborbactam (MEV), ceftazidime-avibactam (CZA), and combinations of CZA plus aztreonam (ATM), MEV plus ATM and CFDC plus CZA against them. METHODS: A collection of carbapenemase-producing EB clinical isolates (n = 1242) was investigated by lateral flow immunoassay NG-Test CARBA-5 and molecular testing. Cefiderocol MICs were determined using broth microdilution SensititreTM panel. MICs of CZA and MEV were determined by the gradient diffusion method. Antimicrobial synergy testing was performed using gradient diffusion strip crossing. RESULTS: KPC were the most frequent carbapenemases (83.2%), followed by VIM (9.2 %), OXA-48-like (4.3 %) and NDM enzymes (4.1%). Multi-carbapenemase producers were found in 10 (0.8%) isolates. Three combinations of two different carbapenemases were observed: KPC+VIM (n = 4), NDM+OXA-48-like (n = 4), and VIM+OXA-48-like (n = 2). CFDC showed potent activity against eight out of ten dual-carbapenemases producers, while resistance or reduced susceptibility was shown towards CZA and MEV. CFDC in combination with CZA showed no synergistic effects and only two additive effects on seven (87.5%) of the CFDC-susceptible strains. Conversely, CZA plus ATM and MEV plus ATM combinations were synergistic against all ATM-resistant strains regardless of dual-carbapenemases phenotype. CONCLUSIONS: The occurrence of multi-carbapenemase producers is not uncommon in Northern Italy area. MEV in combination with ATM might be considered as a potential therapeutic option, alternative to CZA plus ATM. CFDC susceptibility testing and synergy evaluation of ATM-based combinations should be performed in the lab routine to evaluate the most in vitro active antimicrobial regimen.


Subject(s)
Aztreonam , COVID-19 , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Azabicyclo Compounds , Aztreonam/pharmacology , Bacterial Proteins/genetics , Boronic Acids , Ceftazidime/pharmacology , Cephalosporins , Drug Combinations , Humans , Meropenem/pharmacology , Microbial Sensitivity Tests , beta-Lactamases/genetics
10.
Microbiol Spectr ; 10(1): e0201521, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1622005

ABSTRACT

Emergency department areas were repurposed as intensive care units (ICUs) for patients with acute respiratory distress syndrome during the initial months of the coronavirus disease 2019 (COVID-19) pandemic. We describe an outbreak of New Delhi metallo-ß-lactamase 1 (NDM-1)-producing Escherichia coli infections in critically ill COVID-19 patients admitted to one of the repurposed units. Seven patients developed infections (6 ventilator-associated pneumonia [VAP] and 1 urinary tract infection [UTI]) due to carbapenem-resistant E. coli, and only two survived. Five of the affected patients and four additional patients had rectal carriage of carbapenem-resistant E. coli. The E. coli strain from the affected patients corresponded to a single sequence type. Rectal screening identified isolates of two other sequence types bearing blaNDM-1. Isolates of all three sequence types harbored an IncFII plasmid. The plasmid was confirmed to carry blaNDM-1 through conjugation. An outbreak of clonal NDM-1-producing E. coli isolates and subsequent dissemination of NDM-1 through mobile elements to other E. coli strains occurred after hospital conversion during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. This emphasizes the need for infection control practices in surge scenarios. IMPORTANCE The SARS-CoV-2 pandemic has resulted in a surge of critically ill patients. Hospitals have had to adapt to the demand by repurposing areas as intensive care units. This has resulted in high workload and disruption of usual hospital workflows. Surge capacity guidelines and pandemic response plans do not contemplate how to limit collateral damage from issues like hospital-acquired infections. It is vital to ensure quality of care in surge scenarios.


Subject(s)
Cross Infection/microbiology , Escherichia coli Infections/microbiology , Escherichia coli/enzymology , Escherichia coli/isolation & purification , beta-Lactamases/metabolism , Adult , Aged , COVID-19/epidemiology , COVID-19/virology , Conjugation, Genetic , Cross Infection/epidemiology , Disease Outbreaks , Escherichia coli/classification , Escherichia coli/genetics , Escherichia coli Infections/epidemiology , Escherichia coli Infections/mortality , Female , Humans , Intensive Care Units/statistics & numerical data , Male , Mexico/epidemiology , Middle Aged , Plasmids/genetics , SARS-CoV-2/physiology , Tertiary Care Centers/statistics & numerical data , beta-Lactamases/genetics
11.
Braz J Microbiol ; 53(1): 205-212, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1611548

ABSTRACT

The prevalence and risk factors for gut carriage of antimicrobial-resistant Escherichia coli among individuals living in the community in Rio de Janeiro, Brazil, are unknown. The aim of this study was to determine the prevalence of colonization with antimicrobial-resistant E. coli, including isolates producing ESBL and harboring plasmid-mediated quinolone resistant (PMQR) genes in this community. We performed a cross-sectional study and analyzed fecal specimens of individuals attending outpatient clinics in the city from January 2015 to July 2019. We investigated susceptibility to antimicrobial agents by disc diffusion tests and used PCR to determine ESBL types, PMQR, and the virulence genes that characterize an isolate as extraintestinal pathogenic E. coli (ExPEC). Among the 623 subjects, 212 (34%) carried an isolate resistant to at least one of the tested antimicrobial agents, with the highest frequencies of resistance to ampicillin (26%), trimethoprim-sulfamethoxazole (19%), cefazolin (14%), and ciprofloxacin (CIP, 9%). In addition, 13% (81) of subjects carried a multidrug-resistant-E. coli (MDR-E), including 47 (8% of all isolates) ESBL-producing E. coli (ESBL-E), mainly of CTX-M-8 (15, 32%) and CTX-M-15 (9, 20%) types. PMQR genes were present in 7% (42) of all isolates, including 60% (32) of the 53 resistant to CIP. Previous use of antimicrobial agents, particularly fluoroquinolones, was a risk factor for colonization with MDR-E (25%, 20/81 vs 13%, 70/542, p = 0.01), ESBL-E (28%, 13/47, vs 13%, 77/576, p = 0.01), and resistance to CIP (26%, 14/53, vs 12%, 70/570, p = 0.01). The most pathogenic phylogroups B2, C, and D were 37% of the MDR-E, 30% of the ESBL-E, 38% of the CIP-resistant, and 31% of PMQR gene carrying E. coli isolates. We show that carriage of MDR-E (mostly ESBL-E) reached high levels in the community in Rio de Janeiro, increased by the selection of antimicrobial agents. Much of the resistant E. coli isolates are potential pathogenic strains. The widespread use of antimicrobial agents during the COVID-19 pandemic in Brazil may have worsened this picture.


Subject(s)
COVID-19 , Escherichia coli Infections , Anti-Bacterial Agents/pharmacology , Brazil/epidemiology , Cross-Sectional Studies , Drug Resistance, Multiple, Bacterial , Escherichia coli , Escherichia coli Infections/epidemiology , Escherichia coli Infections/microbiology , Humans , Microbial Sensitivity Tests , Pandemics , SARS-CoV-2 , beta-Lactamases/genetics
12.
Rev Esp Quimioter ; 35(1): 80-83, 2022 Feb.
Article in Spanish | MEDLINE | ID: covidwho-1609053

ABSTRACT

OBJECTIVE: We carry out an analysis of the bacteremia diagnosed in the Emergency Department during 2020, coinciding with the period of the pandemic. METHODS: We performed a retrospective analysis from March 4, 2020 to December 31, 2020. RESULTS: The number of patients who went to the Emergency Department during the study period and the number of extracted blood cultures decreased by 46.79% and 35.7% compared to the same period in 2019 (p <0.05). 320 bacteremia occurred while 507 occurred in 2019, assuming a decrease of 36.8% (p <0.05). The positivity rate of blood cultures was 7.09% in 2020 and 7.23% in 2019 and the contamination rate was 7.07 % in 2020 and 5.67% in 2019. The most frequently isolated microorganism was Escherichia coli, followed by Staphylococcus aureus and Klebsiella pneumoniae. A 6.62% of the isolated E. coli were carriers of extended-spectrum beta-lactamases (ESBL). The percentage of methicillin-resistant S. aureus was 12.9 % and that of K. pneumoniae ESBL was 11.54%. CONCLUSIONS: During the SARS-CoV-2 pandemic there has been a decrease in the number of bacteremia diagnoses, it is possible that attention was focused especially on COVID, forgetting other diseases, such as bacteremia.


Subject(s)
Bacteremia , COVID-19 , Escherichia coli Infections , Klebsiella Infections , Methicillin-Resistant Staphylococcus aureus , Anti-Bacterial Agents/therapeutic use , Bacteremia/diagnosis , Bacteremia/drug therapy , Bacteremia/epidemiology , Escherichia coli , Escherichia coli Infections/drug therapy , Humans , Klebsiella Infections/drug therapy , Klebsiella pneumoniae , Retrospective Studies , SARS-CoV-2 , Tertiary Care Centers , beta-Lactamases
13.
Eur J Clin Microbiol Infect Dis ; 41(3): 495-500, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1603573

ABSTRACT

The objective was to study ceftazidime-avibactam resistant and susceptible Klebsiella pneumoniae isolated from a patient admitted to the Policlinico Umberto I of Rome for SARS-CoV2. Data on the evolution of patient's conditions, antimicrobial therapies, and microbiological data were collected. Whole-genome sequencing performed by Illumina and Nanopore sequencing methods were used to type the strains. During the hospitalization, a SARS-CoV2-infected patient was colonized by a KPC-producing K. pneumoniae strain and empirically treated with ceftazidime-avibactam (CZA) when presenting spiking fever symptoms. Successively, ST2502 CZA-resistant strain producing the KPC-31 variant gave a pulmonary infection to the patient. The infection was treated with high doses of meropenem. The KPC-31-producing strain disappeared but the patient remained colonized by a KPC-3-producing K. pneumoniae strain. An interplay between highly conserved KPC-31- and KPC-3-producing ST2502 strains occurred in the SARS-CoV2 patient during the hospitalization, selected by CZA and carbapenem treatments, respectively.


Subject(s)
Anti-Bacterial Agents , COVID-19 , Klebsiella Infections , Meropenem , Anti-Bacterial Agents/therapeutic use , Bacterial Proteins/genetics , COVID-19/complications , Ceftazidime/therapeutic use , Drug Combinations , Humans , Klebsiella Infections/drug therapy , Klebsiella pneumoniae/genetics , Meropenem/therapeutic use , Microbial Sensitivity Tests , beta-Lactamases/genetics
14.
J Hosp Infect ; 120: 48-56, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1549920

ABSTRACT

BACKGROUND: An outbreak of VIM carbapenemase-expressing Enterobacter cloacae complex occurred between March and October 2020 in an intensive care unit (ICU) of a tertiary care and teaching hospital in France. At the same time, the hospital was facing the COVID-19 first wave. AIM: To describe the management of an outbreak caused by a VIM-producing Enterobacter cloacae complex strain during the COVID-19 pandemic in an ICU and to show the importance of an integrated approach. METHODS: A multi-focal investigation was conducted including descriptive and molecular epidemiology, environmental screening, and assessment of infection prevention and control measures. FINDINGS: A total of 14 cases were identified in this outbreak with a high attributable mortality rate (85.7%). The outbreak management was coordinated by a crisis cell, and involved the implementation of multi-disciplinary actions such as: enhanced hygiene measures, microbiological and molecular analysis of patients and environmental E. cloacae complex strains, and simulation-based teaching. All 23 E. cloacae complex strains isolated from patients and environment samples belonged to multi-locus sequence type ST78 and carried bla-VIM4 gene. Using Fourier transform infrared spectroscopy, all but two isolates were also found to belong to a single cluster. Although the source of this outbreak could not be pinpointed, the spread of the strain was controlled thanks to this multi-focal approach and multi-disciplinary implementation. CONCLUSION: This investigation highlighted the usefulness of Fourier transform infra-red spectroscopy in the rapid typing of outbreak strains as well as the importance of an integrated approach to successfully fight against multidrug-resistant micro-organism dissemination and healthcare-associated infections.


Subject(s)
COVID-19 , Cross Infection , Enterobacteriaceae Infections , Anti-Bacterial Agents , Bacterial Proteins , Cross Infection/epidemiology , Cross Infection/prevention & control , Disease Outbreaks , Enterobacter cloacae/genetics , Enterobacteriaceae Infections/epidemiology , Hospitals , Humans , Intensive Care Units , Microbial Sensitivity Tests , Pandemics , SARS-CoV-2 , beta-Lactamases/genetics
15.
Genome Med ; 13(1): 182, 2021 11 17.
Article in English | MEDLINE | ID: covidwho-1523323

ABSTRACT

BACKGROUND: Clinical metagenomics (CMg) has the potential to be translated from a research tool into routine service to improve antimicrobial treatment and infection control decisions. The SARS-CoV-2 pandemic provides added impetus to realise these benefits, given the increased risk of secondary infection and nosocomial transmission of multi-drug-resistant (MDR) pathogens linked with the expansion of critical care capacity. METHODS: CMg using nanopore sequencing was evaluated in a proof-of-concept study on 43 respiratory samples from 34 intubated patients across seven intensive care units (ICUs) over a 9-week period during the first COVID-19 pandemic wave. RESULTS: An 8-h CMg workflow was 92% sensitive (95% CI, 75-99%) and 82% specific (95% CI, 57-96%) for bacterial identification based on culture-positive and culture-negative samples, respectively. CMg sequencing reported the presence or absence of ß-lactam-resistant genes carried by Enterobacterales that would modify the initial guideline-recommended antibiotics in every case. CMg was also 100% concordant with quantitative PCR for detecting Aspergillus fumigatus from 4 positive and 39 negative samples. Molecular typing using 24-h sequencing data identified an MDR-K. pneumoniae ST307 outbreak involving 4 patients and an MDR-C. striatum outbreak involving 14 patients across three ICUs. CONCLUSION: CMg testing provides accurate pathogen detection and antibiotic resistance prediction in a same-day laboratory workflow, with assembled genomes available the next day for genomic surveillance. The provision of this technology in a service setting could fundamentally change the multi-disciplinary team approach to managing ICU infections. The potential to improve the initial targeted treatment and rapidly detect unsuspected outbreaks of MDR-pathogens justifies further expedited clinical assessment of CMg.


Subject(s)
COVID-19/pathology , Cross Infection/transmission , Metagenomics , Anti-Bacterial Agents/therapeutic use , COVID-19/virology , Coinfection/drug therapy , Coinfection/microbiology , Corynebacterium/genetics , Corynebacterium/isolation & purification , Cross Infection/microbiology , DNA, Bacterial/chemistry , DNA, Bacterial/metabolism , Drug Resistance, Multiple, Bacterial/genetics , Female , Humans , Intensive Care Units , Klebsiella pneumoniae/genetics , Klebsiella pneumoniae/isolation & purification , Male , Middle Aged , Polymorphism, Single Nucleotide , SARS-CoV-2/isolation & purification , Sequence Analysis, DNA , beta-Lactamases/genetics
16.
Microbiol Spectr ; 9(3): e0112221, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1511426

ABSTRACT

Whole-genome sequencing was used to characterize carbapenemase-producing Enterobacterales (CPE) strains recovered from rectal screening swab samples obtained from children at a tertiary-care pediatric hospital in Qatar during a 3-year period. A total of 72 CPE isolates recovered from 61 fecal carriers were characterized. Escherichia coli (47 isolates [65.3%]) and Klebsiella pneumoniae (22 isolates [30.6%]) were the most common species identified. High levels of genetic diversity were observed for both species. These 72 isolates produced 78 carbapenemases, characterized as either NDM-type (41 enzymes [52.6%]) or OXA-48-type (37 enzymes [47.4%]). NDM-5 (24 enzymes [30.8%]), NDM-1 (15 enzymes [19.2%]), and OXA-181 (15 enzymes [19.2%]) were the most common variants detected within each type. Twenty-three NDM producers exhibited difficult-to-treat resistance, compared with only 2 of the OXA-48 producers. Multiple comorbidities were identified in 88.5% of the patients, whereas recent travel history to countries in which CPE are endemic was documented for 57.4% of the patients. All 9 blaOXA-48-type-gene-containing E. coli sequence type 38 (ST38) strains were isolated from patients without international travel history. The mean quarterly incidence of fecal carriage decreased more than 6-fold after the implementation of coronavirus disease 2019 (COVID-19)-related international travel restrictions in Qatar in mid-March 2020. Our data suggest that NDM-type and OXA-48-type carbapenemases expressed by a large diversity of E. coli and K. pneumoniae genotypes are largely dominant in the pediatric population of Qatar. Although our data indicate successful local expansion of E. coli ST38 strains harboring blaOXA-244 genes, at least within health care settings, blaOXA-48-type and blaNDM-type genes appear to have been mainly introduced sporadically by asymptomatic carriers who visited or received health care in some nearby countries in which the genes are endemic. IMPORTANCE To the best of our knowledge, this is the first study addressing the molecular characteristics of CPE in a pediatric population in Qatar using whole-genome sequencing. Since several countries in the Arabian Peninsula share relatively similar demographic patterns and international links, it is plausible that the molecular characteristics of CPE in children, at least in the middle and eastern parts of the region, are similar to those observed in our study.


Subject(s)
Bacterial Proteins/chemistry , Enterobacteriaceae/enzymology , Feces/chemistry , beta-Lactamases/chemistry , Adolescent , Anti-Bacterial Agents , Bacterial Proteins/genetics , Bacterial Proteins/isolation & purification , COVID-19 , Child , Enterobacteriaceae/genetics , Enterobacteriaceae/isolation & purification , Escherichia coli/enzymology , Escherichia coli/genetics , Genotype , Humans , Klebsiella pneumoniae/enzymology , Klebsiella pneumoniae/genetics , Microbial Sensitivity Tests , Mutation , Qatar , Retrospective Studies , SARS-CoV-2 , Whole Genome Sequencing , beta-Lactamases/genetics , beta-Lactamases/isolation & purification
17.
J Glob Antimicrob Resist ; 27: 267-272, 2021 12.
Article in English | MEDLINE | ID: covidwho-1492262

ABSTRACT

OBJECTIVES: Patients hospitalised abroad can become colonised with multidrug-resistant bacteria and import them to their home countries. In this study, we characterised an OXA-484 carbapenemase-producing Escherichia coli strain from a Swiss patient infected by SARS-CoV-2 and repatriated from India. METHODS: At admission to Switzerland (April 2021), the patient undertook a nasopharyngeal swab to search for SARS-CoV-2 and a rectal swab to detect multidrug-resistant bacteria. Both SARS-CoV-2 and E. coli isolates were whole-genome sequenced and analysed for phylogenetic relatedness. RESULTS: The patient was infected with the SARS-CoV-2 B.1.617.2 lineage (VOC Delta), a lineage that began to be reported across Switzerland at that time. He was also colonised with a sequence type 410 (ST410) E. coli strain (L3452210II) producing OXA-484, a single amino acid variant of OXA-181. The blaOXA-484 gene was carried by a 51.5 kb IncX3 plasmid identical to those described in blaOXA-181-harbouring ST410 E. coli strains. Core genome analysis showed that L3452210II was identical (ΔSNV ≤23) to two ST410 OXA-484 producers recently reported in Qatar and Germany, but differed from other ST410 OXA-181 producers reported worldwide. CONCLUSION: The patient was infected by an emerging SARS-CoV-2 variant and also imported an E. coli producing OXA-484, an OXA-48-like carbapenemase not yet reported in Switzerland. The genetic background of L3452210II indicated that blaOXA-484 shared the same plasmid as blaOXA-181, but its bacterial host differed from most of the pandemic OXA-181-producing ST410 strains reported previously. This case description underlines that the COVID-19 crisis can contribute to the worldwide spread of emerging carbapenemase producers.


Subject(s)
COVID-19 , Escherichia coli Infections , Escherichia coli Proteins , Anti-Bacterial Agents , Bacterial Proteins , Escherichia coli/genetics , Escherichia coli Proteins/genetics , Humans , Male , Microbial Sensitivity Tests , Phylogeny , SARS-CoV-2 , beta-Lactamases
18.
Antimicrob Resist Infect Control ; 10(1): 151, 2021 10 21.
Article in English | MEDLINE | ID: covidwho-1484323

ABSTRACT

Concomitant prevention of SARS-CoV-2 and extensively drug-resistant bacteria transmission is a difficult challenge in intensive care units dedicated to COVID-19 patients. We report a nosocomial cluster of four patients carrying NDM-1 plasmid-encoded carbapenemase-producing Enterobacter cloacae. Two main factors may have contributed to cross-transmission: misuse of gloves and absence of change of personal protective equipment, in the context of COVID-19-associated shortage. This work highlights the importance of maintaining infection control measures to prevent CPE cross-transmission despite the difficult context and that this type of outbreak can potentially involve several species of Enterobacterales.


Subject(s)
Carbapenem-Resistant Enterobacteriaceae/isolation & purification , Coinfection/epidemiology , Cross Infection/epidemiology , Enterobacter cloacae/isolation & purification , Enterobacteriaceae Infections/epidemiology , Infection Control/methods , Bacterial Proteins , COVID-19 , Carbapenem-Resistant Enterobacteriaceae/genetics , Disease Outbreaks , Enterobacter cloacae/genetics , Enterobacteriaceae Infections/microbiology , Enterobacteriaceae Infections/transmission , Humans , Intensive Care Units , Personal Protective Equipment , SARS-CoV-2 , beta-Lactamases
19.
United European Gastroenterol J ; 9(9): 1027-1038, 2021 11.
Article in English | MEDLINE | ID: covidwho-1460274

ABSTRACT

BACKGROUND: With increasing number of clinical trials relating to fecal microbiota transplantation (FMT), it is crucial to identify and recruit long-term, healthy, and regular fecal donors. OBJECTIVE: We aimed to report the outcomes of screening and recruitment of fecal donors for FMT. METHODS: Potential donors were recruited via advertisement through internal mass emails at a university. They were required to undergo a pre-screening telephone interview, a detailed questionnaire, followed by blood and stool investigations. RESULTS: From January 2017 to December 2020, 119 potential donors were assessed with 75 failed pre-screening. Reasons for failure included: inability to come back for regular and long-term donation (n = 19), high body mass index (n = 17), underlying chronic illness or on long-term medications (n = 11), being healthcare professionals (n = 10), use of antibiotics within 3 months (n = 5) and others (n = 13). Forty-four donors completed questionnaires and 11 did not fulfill the clinical criteria. Of the remaining 33 potential donors who had stool and blood tests, 21 failed stool investigations (19 extended-spectrum beta-lactamase [ESBL] organisms, one Clostridioides difficile, one C. difficile plus Methicillin Resistant Staphylococcus aureus), one failed blood tests (high serum alkaline phosphatase level), one required long-term medication and nine withdrew consent and/or lost to follow-up. In total, only one out of 119 (0.8%) potential donors was successfully recruited as a regular donor. CONCLUSION: There was a high failure rate in donor screening for FMT. Main reasons for screening failure included high prevalence of positive ESBL organisms in stool and failed commitment to regular stool donation.


Subject(s)
Donor Selection , Fecal Microbiota Transplantation , Adolescent , Adult , COVID-19 , Feces/microbiology , Female , Hong Kong , Humans , Male , Middle Aged , Pandemics , Prevalence , Young Adult , beta-Lactamases
20.
J Antimicrob Chemother ; 76(10): 2538-2545, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1447597

ABSTRACT

OBJECTIVES: To assess the spread of New Delhi metallo-ß-lactamase-1 (NDM-1)-producing Klebsiella pneumoniae ST147 organisms in Poland since an introduction from Tunisia in March 2015, including their phylogenetic position in the global population of the high-risk clone. METHODS: Out of 8925 unique NDM-positive K. pneumoniae isolates identified in Poland from April 2015 till December 2019, 126 isolates, including the Tunisian imports, were related by PFGE and blaNDM gene-carrying Tn125 transposon derivatives. Forty-seven representative isolates were sequenced by Illumina MiSeq. The phylogeny, resistome, virulome and plasmid replicons were analysed and compared with the international ST147 strains. Plasmids of six isolates were studied by the MinION sequencing. RESULTS: A high homogeneity of the 47 isolates was observed, with minor variations in their resistomes and plasmid replicon profiles. However, the detailed SNP comparison discerned a strict outbreak cluster of 40 isolates. All of the organisms were grouped within the ST147 phylogenetic international lineage, and four NDM-1 producers from Tunisia, Egypt and France were the closest relatives of the Polish isolates. Yersiniabactin genes (YbST280 type) were located within the ICEKpn12-like element in most of the outbreak isolates, characterized by O2v1 and KL64 antigen loci. The blaNDM-1 genes were located in double-replicon IncFIIK2+IncFIBK plasmids. CONCLUSIONS: The continuous spread of K. pneumoniae ST147 NDM-1 in Poland since 2015, largely in the Warsaw area, is demonstrated by this genomic analysis. The isolates showed a high degree of homogeneity, and close relatedness to organisms spreading in the Mediterranean region.


Subject(s)
Klebsiella Infections , Klebsiella pneumoniae , Anti-Bacterial Agents , Humans , Klebsiella Infections/epidemiology , Klebsiella pneumoniae/genetics , Microbial Sensitivity Tests , Phylogeny , Plasmids/genetics , Poland/epidemiology , beta-Lactamases/genetics
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