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Multi-Drug Resistant Gram-Negative Infections: Molecular Epidemiology, Microbiological Diagnosis and Antimicrobial...
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Multi-Drug Resistant Gram-Negative Infections: Molecular Epidemiology, Microbiological Diagnosis and Antimicrobial Treatment

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Antibiotics Use and Antimicrobial Stewardship".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 26063

Special Issue Editors

Dr. Simone Ambretti

E-Mail Website
Guest Editor
IRCCS Azienda Ospedaliera, Universitaria di Bologna, Policlinico di S.Orsola, Bologna, Italy
Interests: antimicrobial resistance
Special Issues, Collections and Topics in MDPI journals
Dr. Paolo Gaibani

E-Mail Website
Guest Editor
IRCCS Azienda Ospedaliera, Universitaria di Bologna, Policlinico di S.Orsola, Bologna, Italy
Interests: antimicrobial resistance; genomic analysis; molecular epidemiology
Special Issues, Collections and Topics in MDPI journals
Dr. Tommaso Giani

E-Mail Website
Guest Editor
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
Interests: carbapenemase-producing Klebsiella pneumoniae; ceftazidime-avibactam resistance in KPC-producing microorganisms; ceftolozane-tazobactam-resistant P. aeruginosa
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Infections caused by gram-negative pathogens have become increasingly prevalent in recent years, representing a serious global threat to public health. Antimicrobial resistance is a worldwide problem and multi-drug resistant organisms (MDRo) are a cause for major concern because of their clinical and economic impact, with high morbidity and mortality rates, higher hospital and antibiotic costs, and longer lengths of stay in hospitals and intensive care units. The majority of the burden is related to healthcare-acquired infections caused by gram-negative multi-drug resistant organisms, including extended-spectrum β-lactamase (ESBL-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Acinetobacter baumannii (CRAB), and MDR Pseudomonas aeruginosa.

Since the 2000s, there has been a steady increase in the rates of these pathogens determined by the rapid spread of resistance mechanisms. The management of MDR gram-negative infections requires a multidisciplinary approach, including innovative strategies for diagnosis, infection control and therapy.

Traditional cultural methods have turn-around times that are considered suboptimal, in particular for severe infections in critical patients. For this reason, rapid diagnostic tests able to detect timely gram-negative organisms and their resistance markers represent an important tool of antimicrobial stewardship. Moreover, the knowledge of resistance mechanisms and of the molecular epidemiology of bacterial isolates plays a crucial role in the understanding of how antimicrobial resistance develops and spreads among strains and between patients. The antimicrobial treatment of MDR gram-negative pathogens is often limited to a few agents with in vitro activity. Some new drugs with promising activity against these organisms have recently been developed (ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, cefiderocol), increasing the treatment options for infected patients.

We invite authors to send in their manuscripts in the following areas of interest:

  • novel in vitro diagnostic tools for MDR gram-negative detection and antimicrobial susceptibility testing;
  • molecular epidemiology of gram-negative pathogens and resistance mechanisms;
  • evaluation of antimicrobial treatment regimens for MDR gram-negatives infections;
  • new drugs against MDR gram-negatives: clinical use, in vitro susceptibility testing and emerging resistance.

Dr. Simone Ambretti
Dr. Paolo Gaibani
Dr. Tommaso Giani
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • gram-negative infections
  • multi-drug resistant
  • rapid diagnostic testing
  • molecular epidemiology
  • new drugs
  • antimicrobial treatment

Published Papers (10 papers)

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Research

Jump to: Review, Other

17 pages, 321 KiB  
Article
In Vitro Activity of Ceftolozane-Tazobactam against Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa Obtained from Blood Cultures from Sentinel Public Hospitals in South Africa
by Olga Perovic, Ashika Singh-Moodley and Michelle Lowe
Antibiotics 2023, 12(3), 453; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics12030453 - 24 Feb 2023
Cited by 2 | Viewed by 1656
Abstract
Multidrug-resistant (MDR) Gram-negative bacteria are responsible for the majority of healthcare-associated infections and pose a serious threat as they complicate and prolong clinical care. A novel cephalosporin-β-lactamase-inhibitor combination, ceftolozane-tazobactam (C/T) was introduced in 2014, which improved the treatment of MDR pathogens. This study [...] Read more.
Multidrug-resistant (MDR) Gram-negative bacteria are responsible for the majority of healthcare-associated infections and pose a serious threat as they complicate and prolong clinical care. A novel cephalosporin-β-lactamase-inhibitor combination, ceftolozane-tazobactam (C/T) was introduced in 2014, which improved the treatment of MDR pathogens. This study aimed to evaluate the activity of C/T against Escherichia coli (n = 100), Klebsiella pneumoniae (n = 100), and Pseudomonas aeruginosa (n = 100) blood culture isolates in South Africa (SA). Isolates were sequentially selected (2010 to 2020) from the Group for Enteric, Respiratory, and Meningeal Diseases Surveillance (GERMS) programme in SA. Organism identification was performed using the matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI-TOF MS) instrument (Microflex, Bruker Daltonics, Bremen, Germany), and antibiotic susceptibility was performed using the Sensititre instrument (Trek Diagnostic Systems, East Grinstead, UK). C/T resistance was reported in 16 E. coli, 28 K. pneumoniae and 13 P. aeruginosa isolates. Fifty percent of the C/T resistant isolates were subjected to whole-genome sequencing (WGS). According to the whole genome multilocus sequence typing (MLST) analysis, the E. coli isolates (n = 8) belonged to sequence type (ST)10, ST131, ST405, and ST410, the K. pneumoniae isolates (n = 14) belonged to ST1, ST37, ST73, ST101, ST231, ST307, ST336 and ST6065 (novel ST), and the P. aeruginosa isolates (n = 7) belonged to ST111, ST233, ST273, and ST815. The WGS data also showed that all the E. coli isolates harboured aminoglycoside (aph (3′′)-Ib, aph (6)-Id), macrolide (mdfA, mphA), and sulphonamide (sul2) antibiotic resistance genes, all the K. pneumoniae isolates harboured β-lactam (blaCTX-M-15), and sulphonamide (sul2) antibiotic resistance genes, and all the P. aeruginosa isolates harboured aminoglycoside (aph (3′)-IIb), β-lactam (PAO), fosfomycin (fosA), phenicol (catB7), quinolone (crpP), and disinfectant (qacE) antibiotic resistance genes. It is evident that E. coli, K. pneumoniae and P. aeruginosa can adapt pre-existing resistance mechanisms to resist newer β-lactam molecules and inhibitors, since these isolates were not exposed to ceftolozane-tazobactam previously. Full article
(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Infections: Molecular Epidemiology, Microbiological Diagnosis and Antimicrobial Treatment)
15 pages, 693 KiB  
Article
Multicenter Surveillance of Antimicrobial Resistance among Gram-Negative Bacteria Isolated from Bloodstream Infections in Ghana
by Eric S. Donkor, Khitam Muhsen, Sherry A. M. Johnson, Fleischer C. N. Kotey, Nicholas T. K. D. Dayie, Patience B. Tetteh-Quarcoo, Edem M. A. Tette, Mary-Magdalene Osei, Beverly Egyir, Nicholas I. Nii-Trebi, Godfred Owusu-Okyere, Alex Owusu-Ofori, Yonatan Amir, Saritte Perlman, Perdita Hilary Lopes, Adjo Mfodwo, Nicola C. Gordon, Louise Gresham, Mark Smolinski and Dani Cohen
Antibiotics 2023, 12(2), 255; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics12020255 - 27 Jan 2023
Cited by 10 | Viewed by 3045
Abstract
Background: Antimicrobial resistance (AMR) in Gram-negative bacteria-causing bloodstream infections (BSIs), such as Klebsiella pneumoniae and non-typhoidal Salmonella (NTS), is a major public health concern. Nonetheless, AMR surveillance remains scarce in sub-Saharan Africa, where BSI treatment is largely empirical. The aim of the study [...] Read more.
Background: Antimicrobial resistance (AMR) in Gram-negative bacteria-causing bloodstream infections (BSIs), such as Klebsiella pneumoniae and non-typhoidal Salmonella (NTS), is a major public health concern. Nonetheless, AMR surveillance remains scarce in sub-Saharan Africa, where BSI treatment is largely empirical. The aim of the study was to determine the distribution and AMR patterns of BSI-causing NTS, K. pneumoniae, and other Gram-negative bacteria in Ghana. Methods: A cross-sectional study was conducted between April and December 2021 at eleven sentinel health facilities across Ghana as part of a pilot study on the feasibility and implementation of the human sector AMR surveillance harmonized protocol in sub-Saharan Africa. Gram-negative bacteria recovered from blood specimens of febrile patients were identified using MALDI-TOF and evaluated for antimicrobial resistance using the BD Phoenix M50 analyzer and Kirby-Bauer disc diffusion. The Department of Medical Microbiology at the University of Ghana served as the reference laboratory. Results: Out of 334 Gram-negative blood isolates, there were 18 (5.4%) NTS, 85 (25.5%) K. pneumoniae, 88 (26.4%) Escherichia coli, 40 (12.0%) Acinetobacter baumannii, 25 (7.5%) Pseudomonas aeruginosa, and 77 (23.1%) other Gram-negative bacteria. As a composite, the isolates displayed high resistance to the antibiotics tested—amoxicillin (89.3%), tetracycline (76.1%), trimethoprim-sulfamethoxazole (71.5%), and chloramphenicol (59.7%). Resistance to third-generation cephalosporins [ceftriaxone (73.7%), cefotaxime (77.8%), and ceftazidime (56.3%)] and fluoroquinolones [ciprofloxacin (55.3%)] was also high; 88% of the isolates were multidrug resistant, and the rate of extended-spectrum beta-lactamase (ESBL) production was 44.6%. Antibiotic resistance in K. pneumoniae followed the pattern of all Gram-negative isolates. Antibiotic resistance was lower in NTS blood isolates, ranging between 16.7–38.9% resistance to the tested antibiotics. Resistance rates of 38.9%, 22.2%, and 27.8% were found for cefotaxime, ceftriaxone, and ceftazidime, respectively, and 27.8% and 23.8% for ciprofloxacin and azithromycin, respectively, which are used in the treatment of invasive NTS. The prevalence of multidrug resistance in NTS isolates was 38.9%. Conclusions: Multicenter AMR surveillance of Gram-negative blood isolates from febrile patients was well-received in Ghana, and the implementation of a harmonized protocol was feasible. High resistance and multidrug resistance to first- or second-choice antibiotics, including penicillins, third-generation cephalosporins, and fluoroquinolones, were found, implying that these antibiotics might have limited effectiveness in BSI treatment in the country. Continuation of AMR surveillance in Gram-negative blood isolates is essential for a better understanding of the extent of AMR in these pathogens and to guide clinical practice and policymaking. Full article
(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Infections: Molecular Epidemiology, Microbiological Diagnosis and Antimicrobial Treatment)
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10 pages, 272 KiB  
Article
Pharmacokinetic/Pharmacodynamic Analysis of Continuous-Infusion Fosfomycin in Combination with Extended-Infusion Cefiderocol or Continuous-Infusion Ceftazidime-Avibactam in a Case Series of Difficult-to-Treat Resistant Pseudomonas aeruginosa Bloodstream Infections and/or Hospital-Acquired Pneumonia
by Milo Gatti, Maddalena Giannella, Matteo Rinaldi, Paolo Gaibani, Pierluigi Viale and Federico Pea
Antibiotics 2022, 11(12), 1739; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11121739 - 02 Dec 2022
Cited by 16 | Viewed by 1976
Abstract
Objectives: To perform a pharmacokinetic/pharmacodynamic (PK/PD) analysis of continuous-infusion (CI) fosfomycin combined with extended-infusion (EI) cefiderocol or CI ceftazidime-avibactam in a case series of severe difficult-to-treat Pseudomonas aeruginosa (DTR-PA) infections. Methods: A single-center retrospective study of patients who were treated with CI fosfomycin [...] Read more.
Objectives: To perform a pharmacokinetic/pharmacodynamic (PK/PD) analysis of continuous-infusion (CI) fosfomycin combined with extended-infusion (EI) cefiderocol or CI ceftazidime-avibactam in a case series of severe difficult-to-treat Pseudomonas aeruginosa (DTR-PA) infections. Methods: A single-center retrospective study of patients who were treated with CI fosfomycin plus EI cefiderocol or CI ceftazidime-avibactam for severe DTR-PA infections and who underwent therapeutic drug monitoring (TDM), from 1 September 2021 to 30 June 2022 was performed. Concentrations were measured at steady-state (Css) for CI fosfomycin and ceftazidime-avibactam and at trough (Cmin) for EI cefiderocol. Joint PK/PD targets of combination therapy were analyzed (thresholds: area-under-the curve to minimum inhibitory concentration (AUC/MIC) ratio > 40.8 for fosfomycin; ceftazidime Css/MIC ratio ≥ 4 coupled with avibactam Css > 4 mg/L for ceftazidime-avibactam; Cmin/MIC ratio ≥ 4 for cefiderocol). Joint PK/PD targets of the combination therapy were analyzed and defined as optimal when both were achieved, quasi-optimal if only one of the two was achieved, and suboptimal if none of the two was achieved). The relationship between joint PK/PD target attainment and microbiological response was assessed. Results: Six patients (three pneumonia, two BSI + pneumonia, and one BSI) were included. The joint PK/PD targets were optimal in four cases and quasi-optimal in the other two. Microbiological eradication (ME) occurred in 4/4 of patients with optimal joint PK/PD targets and in one of the two patients with quasi-optimal joint PK/PD targets. Conclusions: Attaining optimal joint PK/PD targets with a combo-therapy of CI fosfomycin plus EI cefiderocol or CI ceftazidime-avibactam could represent an effective strategy for granting favorable microbiological outcomes in patients with DTR-PA pneumonia and/or BSI. Full article
(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Infections: Molecular Epidemiology, Microbiological Diagnosis and Antimicrobial Treatment)
10 pages, 600 KiB  
Article
Synergistic Effect of Clinically Available Beta-Lactamase Inhibitors Combined with Cefiderocol against Carbapenemase-Producing Gram-Negative Organisms
by Gabriele Bianco, Paolo Gaibani, Sara Comini, Matteo Boattini, Giuliana Banche, Cristina Costa, Rossana Cavallo and Patrice Nordmann
Antibiotics 2022, 11(12), 1681; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11121681 - 22 Nov 2022
Cited by 3 | Viewed by 1574
Abstract
The role of β-lactamases in reduced susceptibility or resistance to cefiderocol has been supported by recent reports. The purpose of this study was to investigate the in vitro impact of clinically available β-lactamase inhibitors on cefiderocol activity against characterized carbapenemase-producing Gram-negative isolates. A [...] Read more.
The role of β-lactamases in reduced susceptibility or resistance to cefiderocol has been supported by recent reports. The purpose of this study was to investigate the in vitro impact of clinically available β-lactamase inhibitors on cefiderocol activity against characterized carbapenemase-producing Gram-negative isolates. A collection of 39 well-characterized Gram-negative isolates obtained from various clinical sources and countries were included. Cefiderocol antimicrobial susceptibility was evaluated via reference broth microdilution. The chequerboard microdilution method and time–kill assays were used to determine the synergy of tazobactam, avibactam, vaborbactam and relebactam in combination with cefiderocol. MICs of cefiderocol presented a 4- to 256-fold reduction against Klebsiella pneumoniae carbapenemase (KPC)-producing Gram-negative isolates (predominantly K. pneumoniae) when avibactam, vaborbactam and relebactam were combined individually. Notably, the KPC-inhibitors led to a 4- to 32-fold reduction in cefiderocol MICs in the four cefiderocol-resistant KPC-producing K. pneumoniae isolates, showing restoration of cefiderocol susceptibility (MIC ≤ 2 mg/L) in ten out of twelve cases. Tazobactam led to a 4- to 64-fold decrease in cefiderocol MICs only in K. pneumoniae strains harbouring blaKPC-41, blaKPC-31, blaKPC-53 and blaKPC-66. The synergistic effect of all serine-β-lactamase inhibitors on cefiderocol activity was also shown in OXA-48-like-producing Enterobacterales strains. Conversely, a combination of β-lactamases inhibitors with cefiderocol was not synergistic with all OXA-23-like-producing strains and most metallo-β-lactamases producers. In conclusion, the addition of clinically available serine β-lactamase inhibitors to cefiderocol might represent an important development in the formulation to increase its spectrum and therapeutic efficacy, and to limit in vivo resistance emergence. Full article
(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Infections: Molecular Epidemiology, Microbiological Diagnosis and Antimicrobial Treatment)
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8 pages, 502 KiB  
Article
Epidemiology and In Vitro Activity of Ceftazidime/Avibactam, Meropenem/Vaborbactam and Imipenem/Relebactam against KPC-Producing K. pneumoniae Collected from Bacteremic Patients, 2018 to 2020
by Federica Bovo, Donatella Lombardo, Tiziana Lazzarotto, Simone Ambretti and Paolo Gaibani
Antibiotics 2022, 11(11), 1621; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11111621 - 14 Nov 2022
Cited by 6 | Viewed by 1361
Abstract
The management of KPC-producing K. pneumoniae (KPC-Kp) in bloodstream infections (BSIs) represent a serious clinical challenge. In this study, the aim is to assess the incidence of resistance to novel β-lactams-β-lactamase inhibitor combinations (βL-βLICs), such as ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MER-VAB) and imipenem-relebactam (IMI-REL), [...] Read more.
The management of KPC-producing K. pneumoniae (KPC-Kp) in bloodstream infections (BSIs) represent a serious clinical challenge. In this study, the aim is to assess the incidence of resistance to novel β-lactams-β-lactamase inhibitor combinations (βL-βLICs), such as ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MER-VAB) and imipenem-relebactam (IMI-REL), in KPC-Kp strains collected during a three-year period from patients with bacteremia. KPC-Kp strains resistant to βL-βLICs were selected for whole-genome sequencing. A total of 133 K. pneumoniae strains were isolated, and KPC-Kp strains were the most represented (87.2%). In 2018, resistance to CAZ-AVI and MER-VAB was 6.5% and 14.5%, respectively. In 2019, KPC-Kp resistance to CAZ-AVI and MER-VAB remained at low levels, with values of 12.9% and 3.2%, respectively. During 2020, CAZ-AVI resistance was detected in 2/23 of KPC-Kp strains (8.7%). IMI-REL was the most active βL-βLIC, inhibiting >98% of the isolates, while CAZ-AVI and MER-VAB inhibited 87–93% and 85–97% of the KPC producers, respectively. Correlations between genotypic traits and resistance to βL-βLICs showed that KPC-Kp strains resistant to CAZ-AVI harbored a mutation within the blaKPC-3 gene, while all KPC-Kp strains resistant to CAZ-AVI, MER-VAB and/or IMI-REL carried the blaKPC-3 gene. Moreover, genetic analysis of porin genes showed that 14/16 of KPC-Kp resistant isolates possessed a truncated OmpK35 and glycine (G) and aspartic acid (D) insertions at positions 134–135 within OmpK36, whereas 2/16 displayed truncated OmpK35 and OmpK36 porins. Novel βL-βLICs are promising agents against KPC-Kp infections; however, the emergence of resistance to these agents highlights the need for continuous surveillance and application of enhanced antimicrobial stewardship. Full article
(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Infections: Molecular Epidemiology, Microbiological Diagnosis and Antimicrobial Treatment)
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11 pages, 2876 KiB  
Article
Evaluation of Three Carbapenemase-Phenotypic Detection Methods and Emergence of Diverse VIM and GES Variants among Pseudomonas aeruginosa Isolates in Tunisia
by Sana Ferjani, Elaa Maamar, Asma Ferjani, Lamia Kanzari and Ilhem Boutiba Ben Boubaker
Antibiotics 2022, 11(7), 858; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11070858 - 27 Jun 2022
Cited by 7 | Viewed by 1692
Abstract
Background: Since 2012, few reports on the molecular epidemiology of Pseudomonas aeruginosa were reported in Tunisia. Objectives: This study aimed to evaluate carbapenem-resistance determinants and molecular epidemiology and to compare the carbapenemase-phenotypic detection methods of multidrug-resistant P. aeruginosa isolates. Methods: During a period [...] Read more.
Background: Since 2012, few reports on the molecular epidemiology of Pseudomonas aeruginosa were reported in Tunisia. Objectives: This study aimed to evaluate carbapenem-resistance determinants and molecular epidemiology and to compare the carbapenemase-phenotypic detection methods of multidrug-resistant P. aeruginosa isolates. Methods: During a period of four years (2014 to 2017), all imipenem-ceftazidime-resistant P. aeruginosa isolates were retrospectively selected at the microbial laboratory of Charles Nicolle hospital of Tunis. These isolates were examined by the modified Hodge test, modified carbapenem inactivation method (mCIM), and another mCIM, called CIMTris, and their performance was evaluated using PCR analysis as the gold standard. Results: A total of 35 isolates were recovered among patients hospitalized in different units. All strains were colistin-susceptible.All carbapenem-resistant isolates showed a high-level resistance to carbapenems. CIMTris and mCIM showed 96.15% and 46.15% sensitivity and 44.44% and 100% specificity, respectively, for detecting carbapenemase production.Conclusions: CIMTris is a promising approach for detecting carbapenemase activity in P. aeruginosa and merits further testing. Moreover, this study described the first detection of GES-5- and GES-9-producing P. aeruginosa in Tunisia as well as the co-occurrence of the blaGES-5 and blaVIM-11 carbapenemase genes in one isolate. These findings are of great concern because the rapid dissemination of MDR strains represents a major therapeutic and epidemiological threat. Full article
(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Infections: Molecular Epidemiology, Microbiological Diagnosis and Antimicrobial Treatment)
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16 pages, 2127 KiB  
Article
Effects of Verapamil and Two Bisbenzylisoquinolines, Curine and Guattegaumerine Extracted from Isolona hexaloba, on the Inhibition of ABC Transporters from Pseudomonas aeruginosa
by Christian Hulen, Pierre-Jean Racine, Marc Feuilloley, Abdelhakim Elomri and Nour-Eddine Lomri
Antibiotics 2022, 11(5), 700; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11050700 - 21 May 2022
Cited by 4 | Viewed by 2021
Abstract
The biological effects of alkaloids, curine, guattegaumerine, and verapamil, on Pseudomonas aeruginosa were investigated. These molecules did not inhibit P. aeruginosa growth but increased the sensitivity of this bacterium to carbenicillin, novobiocin, and erythromycin. The results of another study indicate that curine and [...] Read more.
The biological effects of alkaloids, curine, guattegaumerine, and verapamil, on Pseudomonas aeruginosa were investigated. These molecules did not inhibit P. aeruginosa growth but increased the sensitivity of this bacterium to carbenicillin, novobiocin, and erythromycin. The results of another study indicate that curine and guattegaumerine were competitors of verapamil and acted as inhibitors of eukaryotic ABCB1 efflux pump. A BLAST-P carried out between a bacterial MDR transporter LmrA from Lactococcus lactis, a human MDR1/P-glycoprotein (ABCB1), and ABC proteins of P.aeruginosa highlighted five potential candidates that have this bacterium. A study on the sensitivity to carbenicillin in the presence of verapamil allowed us to identify the product of gene PA1113 as the ABC transporter involved in the influx of carbenicillin. Similarly, novobiocin transport performed in the presence of verapamil and a docking analysis highlighted protein MsbA (Lipid A flippase, gene PA4997) as a potential candidate in novobiocin efflux. MsbA has previously been identified as a multidrug transporter in E. coli, and as P. aeruginosa MsbA presented 76% identity with E. coli MsbA, it is possible that novobiocin efflux involves this ABC transporter, accounting for about 30% of the bacterium resistance to this antibiotic. Full article
(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Infections: Molecular Epidemiology, Microbiological Diagnosis and Antimicrobial Treatment)
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13 pages, 558 KiB  
Article
The Spread of NDM-1 and NDM-7-Producing Klebsiella pneumoniae Is Driven by Multiclonal Expansion of High-Risk Clones in Healthcare Institutions in the State of Pará, Brazilian Amazon Region
by Yan Corrêa Rodrigues, Amália Raiana Fonseca Lobato, Ana Judith Pires Garcia Quaresma, Lívia Maria Guimarães Dutra Guerra and Danielle Murici Brasiliense
Antibiotics 2021, 10(12), 1527; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10121527 - 14 Dec 2021
Cited by 9 | Viewed by 2952
Abstract
Carbapenem resistance among Klebsiella pneumoniae isolates is often related to carbapenemase genes, located in genetic transmissible elements, particularly the blaKPC gene, which variants are spread in several countries. Recently, reports of K. pneumoniae isolates harboring the blaNDM gene have increased dramatically [...] Read more.
Carbapenem resistance among Klebsiella pneumoniae isolates is often related to carbapenemase genes, located in genetic transmissible elements, particularly the blaKPC gene, which variants are spread in several countries. Recently, reports of K. pneumoniae isolates harboring the blaNDM gene have increased dramatically along with the dissemination of epidemic high-risk clones (HRCs). In the present study, we report the multiclonal spread of New Delhi metallo-beta-lactamase (NDM)-producing K. pneumoniae in different healthcare institutions in the state of Pará, Northern Brazil. A total of 23 NDM-producing isolates were tested regarding antimicrobial susceptibility testing features, screening of carbapenemase genes, and genotyping by multilocus sequencing typing (MLST). All K. pneumoniae isolates were determined as multidrug-resistant (MDR), being mainly resistant to carbapenems, cephalosporins, and fluoroquinolones. The blaNDM-7 (60.9%—14/23) and blaNDM-1 (34.8%—8/23) variants were detected. MLST genotyping revealed the predomination of HRCs, including ST11/CC258, ST340/CC258, ST15/CC15, ST392/CC147, among others. To conclude, the present study reveals the contribution of HRCs and non-HRCs in the spread of NDM-1 and NDM-7-producing K. pneumoniae isolates in Northern (Amazon region) Brazil, along with the first detection of NDM-7 variant in Latin America and Brazil, highlighting the need for surveillance and control of strains that may negatively impact healthcare and antimicrobial resistance. Full article
(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Infections: Molecular Epidemiology, Microbiological Diagnosis and Antimicrobial Treatment)
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Review

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20 pages, 386 KiB  
Review
Resistance to Ceftazidime/Avibactam, Meropenem/Vaborbactam and Imipenem/Relebactam in Gram-Negative MDR Bacilli: Molecular Mechanisms and Susceptibility Testing
by Paolo Gaibani, Tommaso Giani, Federica Bovo, Donatella Lombardo, Stefano Amadesi, Tiziana Lazzarotto, Marco Coppi, Gian Maria Rossolini and Simone Ambretti
Antibiotics 2022, 11(5), 628; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11050628 - 06 May 2022
Cited by 47 | Viewed by 5685
Abstract
Multidrug resistance (MDR) represents a serious global threat due to the rapid global spread and limited antimicrobial options for treatment of difficult-to-treat (DTR) infections sustained by MDR pathogens. Recently, novel β-lactams/β-lactamase inhibitor combinations (βL-βLICs) have been developed for the treatment of DTR infections [...] Read more.
Multidrug resistance (MDR) represents a serious global threat due to the rapid global spread and limited antimicrobial options for treatment of difficult-to-treat (DTR) infections sustained by MDR pathogens. Recently, novel β-lactams/β-lactamase inhibitor combinations (βL-βLICs) have been developed for the treatment of DTR infections due to MDR Gram-negative pathogens. Although novel βL-βLICs exhibited promising in vitro and in vivo activities against MDR pathogens, emerging resistances to these novel molecules have recently been reported. Resistance to novel βL-βLICs is due to several mechanisms including porin deficiencies, increasing carbapenemase expression and/or enzyme mutations. In this review, we summarized the main mechanisms related to the resistance to ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam in MDR Gram-negative micro-organisms. We focused on antimicrobial activities and resistance traits with particular regard to molecular mechanisms related to resistance to novel βL-βLICs. Lastly, we described and discussed the main detection methods for antimicrobial susceptibility testing of such molecules. With increasing reports of resistance to novel βL-βLICs, continuous attention should be maintained on the monitoring of the phenotypic traits of MDR pathogens, into the characterization of related mechanisms, and on the emergence of cross-resistance to these novel antimicrobials. Full article
(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Infections: Molecular Epidemiology, Microbiological Diagnosis and Antimicrobial Treatment)

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28 pages, 3806 KiB  
Systematic Review
Prevalence of Multidrug-Resistant and Extended-Spectrum Beta-Lactamase-Producing Shigella Species in Asia: A Systematic Review and Meta-Analysis
by Mohd Zulkifli Salleh, Nik Mohd Noor Nik Zuraina, Khalid Hajissa, Mohamad Ikram Ilias, Kirnpal Kaur Banga Singh and Zakuan Zainy Deris
Antibiotics 2022, 11(11), 1653; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11111653 - 18 Nov 2022
Cited by 9 | Viewed by 2904
Abstract
Shigellosis remains one of the leading causes of morbidity and mortality worldwide and is the second leading cause of diarrheal mortality among all age groups. However, the global emergence of antimicrobial-resistant Shigella strains, limiting the choice of effective drugs for shigellosis, has become [...] Read more.
Shigellosis remains one of the leading causes of morbidity and mortality worldwide and is the second leading cause of diarrheal mortality among all age groups. However, the global emergence of antimicrobial-resistant Shigella strains, limiting the choice of effective drugs for shigellosis, has become the major challenge in the treatment of Shigella infections. The aim of this systematic review and meta-analysis was to provide an updated picture of the prevalence of antimicrobial-resistant Shigella species in Asia. A comprehensive and systematic search was performed on three electronic databases (PubMed, ScienceDirect and Scopus), in which 63 eligible studies published between 2010 and 2022 were identified. From our meta-analysis of proportions using a random-effects model, the overall prevalence of Shigella spp. in Asian patients was estimated to be 8.0% (95% CI: 5.5–10.5). The pooled prevalence rates of multidrug-resistant (MDR) and extended-spectrum beta-lactamase (ESBL)-producing Shigella strains were 68.7% (95% CI: 59.9–77.5) and 23.9% (95% CI: 12.9–34.8), respectively. Concerning recommended antimicrobial drugs for Shigella, the prevalence of resistance was highest for ciprofloxacin (29.8%) and azithromycin (29.2%), followed by ceftriaxone (23.8%), in spite of their importance as first- and second-line treatments for shigellosis. In contrast, resistance to carbapenems, such as ertapenem (0.0%), imipenem (0.1%) and meropenem (0.0%), was almost non-existent among the 49 tested antibiotics. The significantly high prevalence estimation suggests that the multidrug-resistant Shigella is a pressing threat to public health worthy of careful and justified interventions. Effective antibiotic treatment strategies, which may lead to better outcomes for the control and treatment of shigellosis in Asia, are essential. Full article
(This article belongs to the Special Issue Multi-Drug Resistant Gram-Negative Infections: Molecular Epidemiology, Microbiological Diagnosis and Antimicrobial Treatment)
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