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Strategies for Combatting Multidrug-Resistant and Extensively Drug-Resistant Bacteria: Current Challenges and Future Prospects

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A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "The Global Need for Effective Antibiotics".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 13761

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Prof. Dr. Adriána Liptáková

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Guest Editor

Comenius University Medical School, Bratislava, Slovakia
Interests: antibiotic resistance; bacteriophages; autovaccine; HBV; HCV

Dr. Bożena Futoma-Kołoch

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Guest Editor

Department of Microbiology, University of Wroclaw, Wroclaw, Poland
Interests: cross-resistance; antibiotic resistance; efflux pumps; Salmonella
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Dear Colleagues,

Antimicrobial resistance is currently considered one of the most important threats to global public health by the World Health Organization. Globally, multidrug-resistant (MDR) and extensively drug-resistant (EDR) bacterial pathogens are spreading. Although the acquisition of resistance is a natural process, the misuse of antibiotics, inadequate surveillance, and the poorly controlled regulation of antibiotics in clinical medicine and in the livestock industry potentiate the uprise and worldwide spread of MDR bacteria.

Mortality caused by resistance to antibiotics is a major health problem, causing more than 33,000 deaths in Europe annually. Already alarming, the number of deaths worldwide is predicted to increase to more than 10 million by 2050, although predictions are difficult to make in this field.

We should focus on new strategies, including those that are not only related novel antimicrobial drugs but as well as those related to uncommon drug strategies such as use of bacteriophages, autovaccines, or personalized microbiota and antimicrobial stewardship with updated guidelines.

We hope you find this topic exciting and will join our journey to find new and innovative strategies to decrease the mortality and morbidity of patients suffering from MDR and EDR pathogens.

Dr. Adriána Liptáková
Dr. Bożena Futoma-Kołoch
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

MDR bacteria
EDR bacteria
novel antimicrobial drugs
novel therapeutical approaches against MDR
novel therapeutical approaches against EDR
guidelines
personalized microbiota
bacteriophages
autovaccine therapy
antimicrobial stewardship

Related Special Issue

Strategies for Combatting Multidrug-Resistant and Extensively Drug-Resistant Bacteria, 2nd Edition in Antibiotics

Published Papers (9 papers)

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Research

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23 pages, 5377 KiB

Open AccessArticle

High Diversity but Monodominance of Multidrug-Resistant Bacteria in Immunocompromised Pediatric Patients with Acute Lymphoblastic Leukemia Developing GVHD Are Not Associated with Changes in Gut Mycobiome

by Sara Sardzikova, Kristina Andrijkova, Peter Svec, Gabor Beke, Lubos Klucar, Gabriel Minarik, Viktor Bielik, Alexandra Kolenova and Katarina Soltys

Antibiotics 2023, 12(12), 1667; https://doi.org/10.3390/antibiotics12121667 - 27 Nov 2023

Viewed by 1209

Abstract

Graft-versus-host disease (GvHD) is a severe complication after hematopoietic stem cell transplantation (HSCT). Our study focused on identifying multidrug-resistant (MDR) gut bacteria associated with GvHD-prone guts and association with gut microbiota (GM) diversity, bacteriome, and mycobiome composition in post-HSCT patients. We examined 11 pediatric patients with acute lymphoblastic leukemia (ALL), including six with GvHD, within three time points: seven days pre-HSCT, seven days post-, and 28 days post-HSCT. The gut microbiome and its resistome were investigated using metagenomic sequencing, taxonomically classified with Kraken2, and statistically evaluated for significance using appropriate tests. We observed an increase in the abundance of MDR bacteria, mainly Enterococcus faecium strains carrying msr(C), erm(T), aac(6′)-li, dfrG, and ant(6)-la genes, in GvHD patients one week post-HSCT. Conversely, non-GvHD patients had more MDR beneficial bacteria pre-HSCT, promoting immunosurveillance, with resistance genes increasing one-month post-HSCT. MDR beneficial bacteria included the anti-inflammatory Bacteroides fragilis, Ruminococcus gnavus, and Turicibacter, while most MDR bacteria represented the dominant species of GM. Changes in the gut mycobiome were not associated with MDR bacterial monodominance or GvHD. Significant α-diversity decline (Shannon index) one week and one month post-HSCT in GvHD patients (p < 0.05) was accompanied by increased Pseudomonadota and decreased Bacteroidota post-HSCT. Our findings suggest that MDR commensal gut bacteria may preserve diversity and enhance immunosurveillance, potentially preventing GvHD in pediatric ALL patients undergoing HSCT. This observation has therapeutic implications. Full article

(This article belongs to the Special Issue Strategies for Combatting Multidrug-Resistant and Extensively Drug-Resistant Bacteria: Current Challenges and Future Prospects)

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9 pages, 691 KiB

Open AccessEditor’s ChoiceArticle

In Vitro Susceptibility of Aztreonam-Vaborbactam, Aztreonam-Relebactam and Aztreonam-Avibactam Associations against Metallo-β-Lactamase-Producing Gram-Negative Bacteria

by Cécile Emeraud, Sandrine Bernabeu and Laurent Dortet

Antibiotics 2023, 12(10), 1493; https://doi.org/10.3390/antibiotics12101493 - 29 Sep 2023

Viewed by 1223

Abstract

Background: Despite the availability of new options (ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam and cefiderocol), it is still very difficult to treat infections caused by metallo-β-lactamase (MBLs)-producers resistant to aztreonam. The in vitro efficacy of aztreonam in association with avibactam, vaborbactam or relebactam was evaluated on a collection of MBL-producing Enterobacterales, MBL-producing P. aeruginosa and highly drug-resistant S. maltophilia. Methods: A total of fifty-two non-duplicate MBL-producing Enterobacterales, five MBL-producing P. aeruginosa and five multidrug-resistant S. maltophila isolates were used in this study. The minimum inhibitory concentrations (MICs) of aztreonam, meropenem-vaborbactam and imipenem-relebactam were determined by Etest^® (bioMérieux, La Balme-les-Grottes) according to EUCAST recommendations. For aztreonam-avibactam, aztreonam-vaborbactam and aztreonam-relebactam associations, the MICs were determined using Etest^® on Mueller-Hinton (MH) agar supplemented with 8 mg/L of avibactam, 8 mg/L of vaborbactam and 4 mg/L of relebactam. The MICs were interpreted according to EUCAST guidelines. Results: The susceptibility rates of aztreonam-avibactam, aztreonam-vaborbactam and aztreonam-relebactam with a standard exposure of aztreonam (1g × 3, IV) were 84.6% (44/52), 55.8% and 34.6% for Enterobacterales and 0% for all combinations for P. aeruginosa and S. maltophila. The susceptibility rates of aztreonam-avibactam, aztreonam-vaborbactam and aztreonam-relebactam with a high exposure of aztreonam (2g × 4, IV) were 92.3%, 78.9% and 57.7% for Enterobacterales, 75%, 60% and 60% for P. aeruginosa and 100%, 100% and 40% for S. maltophila. Conclusions: As previously demonstrated for an aztreonam/ceftazidime-avibactam combination, aztreonam plus imipenem-relebactam and aztreonam plus meropenem-vaborbactam might be useful options, but with potentially lower efficiency, to treat infections caused by aztreonam-non-susceptible MBL-producing Gram-negative strains. Full article

(This article belongs to the Special Issue Strategies for Combatting Multidrug-Resistant and Extensively Drug-Resistant Bacteria: Current Challenges and Future Prospects)

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16 pages, 3223 KiB

Open AccessArticle

Carbapenem-Resistant Klebsiella pneumoniae in COVID-19 Era—Challenges and Solutions

by Jozef Ficik, Michal Andrezál, Hana Drahovská, Miroslav Böhmer, Tomáš Szemes, Adriána Liptáková and Lívia Slobodníková

Antibiotics 2023, 12(8), 1285; https://doi.org/10.3390/antibiotics12081285 - 04 Aug 2023

Cited by 1 | Viewed by 1354

Abstract

The COVID-19 era brought about new medical challenges, which, together with nosocomial bacterial infections, resulted in an enormous burden for the healthcare system. One of the most alarming nosocomial threats was carbapenem-resistant Klebsiella pneumoniae (CRKP). Monitoring CRKP incidence and antimicrobial resistance globally and locally is vitally important. In a retrospective study, the incidence of CRKP in the pre-COVID-19 period (2017–2019) and the COVID-19 pandemic (2020–2022) was investigated in the Central Military Hospital in Ružomberok, Slovak Republic. The relative incidence of CRKP significantly increased during the COVID-19 period—by 4.8 times, from 0.18 to 0.76%. At the same time, 47% of CRKP-positive patients also had COVID-19. Twenty-six KPC and sixty-nine NDM-producing isolates were identified. CRKPs isolated in the year 2022 were submitted to whole genome sequencing, and their susceptibility was tested to cefiderocol, ceftazidime–avibactam, imipenem–relebactam and meropenem–vaborbactam, with excellent results. KPC-producing isolates were also highly susceptible to colistin (92%). The NDM isolates revealed lower susceptibility rates, including only 57% colistin susceptibility. ST-307 prevailed in KPC and ST-11 in NDM isolates. Despite the excellent activity of new antimicrobials, rational antibiotic policy must be thoroughly followed, supported by complementary treatments and strict anti-epidemic precautions. Full article

(This article belongs to the Special Issue Strategies for Combatting Multidrug-Resistant and Extensively Drug-Resistant Bacteria: Current Challenges and Future Prospects)

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14 pages, 664 KiB

Open AccessArticle

High Emergence of Multidrug-Resistant Sequence Type 131 Subclade C2 among Extended-Spectrum β-Lactamase (ESBL)-Producing Escherichia coli Isolated from the University Hospital Bratislava, Slovakia

by Ján Koreň, Michal Andrezál, Elham Ozaee, Hana Drahovská, Martin Wawruch, Adriána Liptáková and Tibor Maliar

Antibiotics 2023, 12(7), 1209; https://doi.org/10.3390/antibiotics12071209 - 20 Jul 2023

Viewed by 1009

Abstract

The expansion of sequence type 131 (ST131) extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (E. coli) represents major worldwide challenges. E. coli strains originating from healthcare facilities (labeled No. 1 and No. 2) of the University Hospital Bratislava (UHB) were analyzed for ST131 emergence, including its (sub)lineages and clonal relatedness. Antimicrobial resistance was determined in most strains. Of a total of 354 E. coli strains, 263 (74.3%) belonged to ST131; of these, 177 (67.3%) were from No. 1. Generally, among 260 ST131 E. coli, clades A/B were confirmed in 20 (7.7%), while clade C was noted in 240 (92.3%) strains; within them, subclades were detected as follows: C0 (17; 7.1%), C1 (3; 1.2%), and C2 (220; 91.7%). Among fifteen randomly selected E. coli strains that were investigated for ST and clonal relatedness, seven STs were identified: eight (53.3%) ST131, two (13.3%) ST73, and one each (6.7%) of ST10, ST12, ST14, ST1193, and ST1196. From No. 1, two ST131 in the first internal clinic and one ST131 from No. 2 in the aftercare department were highly clonally related, suggesting possible epidemiological association. Antimicrobial resistance was as follows: ciprofloxacin 93.8%, ceftazidime 78.4%, meropenem 0%, fosfomycin 2.9% and nitrofurantoin 1.4%. Prevention of ESBL-producing E. coli dissemination, especially for ST131 clade C2, is inevitably necessary for reducing drug resistance and decreasing healthcare-associated infections. Full article

(This article belongs to the Special Issue Strategies for Combatting Multidrug-Resistant and Extensively Drug-Resistant Bacteria: Current Challenges and Future Prospects)

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14 pages, 2145 KiB

Open AccessEditor’s ChoiceArticle

Moving toward Extensively Drug-Resistant: Four-Year Antimicrobial Resistance Trends of Acinetobacter baumannii from the Largest Department of Internal Medicine in Slovakia

by Yashar Jalali, Adriána Liptáková, Monika Jalali and Juraj Payer

Antibiotics 2023, 12(7), 1200; https://doi.org/10.3390/antibiotics12071200 - 18 Jul 2023

Cited by 2 | Viewed by 1131

Abstract

A. baumannii imposes a great burden on medical systems worldwide. Surveillance of trends of antibiotic resistance provides a great deal of information needed for antimicrobial stewardship programmes nationwide. Clinical data from long-term, continuous surveillance on trends of antibiotic resistance of A. baumannii in Slovakia is missing. One hundred and forty-nine samples of A. baumannii were isolated over a period of four years. A panel of 19 antibiotics from seven antibiotic categories were tested for the bacterium’s susceptibility. Resistance results were evaluated, and the significance of patterns was estimated using simple linear regression analysis. All isolates were more than 85% resistant to at least 13 out of the 19 tested antibiotics. A significant rise in resistance was recorded for aminoglycosides and imipenem from 2019 to 2022. Colistin and ampicillin-sulbactam have been the only antibiotics maintaining more than 80% efficacy on the bacterium to date. A significant rise in extensively drug-resistant (XDR) strains among carbapenem-resistant (CR) isolates has been recorded. Multidrug-resistance (MDR) among all A. baumannii isolates and XDR among CR strains of the bacterium have risen significantly in the last four years. Full article

(This article belongs to the Special Issue Strategies for Combatting Multidrug-Resistant and Extensively Drug-Resistant Bacteria: Current Challenges and Future Prospects)

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9 pages, 582 KiB

Open AccessArticle

Screening for Metallo-Beta-Lactamases Using Non-Carbapenem Agents: Effective Detection of MBL-Producing Enterobacterales and Differentiation of Carbapenem-Resistant Enterobacterales

by Kentarou Takei, Hajime Kanamori, Asami Nakayama, Mikiko Chiba, Yumiko Takei, Issei Seike, Chiho Kitamura, Hiroaki Baba, Kengo Oshima and Koichi Tokuda

Antibiotics 2023, 12(7), 1146; https://doi.org/10.3390/antibiotics12071146 - 03 Jul 2023

Cited by 1 | Viewed by 1367

Abstract

Metallo-beta-lactamases (MBLs) are enzymes that break down carbapenem antibiotics, leading to carbapenem-resistant organisms. Carbapenemase-resistant Enterobacterales (CRE) is one of them. Outbreaks of CRE infection can occur in healthcare facilities and lead to increased deaths, illness, and medical costs. This study was conducted to detect MBLs using non-carbapenem agents and exclude MBLs among CRE isolates. A total of 3776 non-duplicate sequential Enterobacterales isolates from a single facility were screened between January 2019 and December 2022 using non-carbapenem agents, ceftazidime and cefoperazone/sulbactam. Positive 153 isolates (4.0%) were further tested using carbapenemase-confirmation tests and verified through polymerase chain reaction (PCR) testing. Fifteen imipenemase (IMP)-type MBL-producing Enterobacterales (0.4%) including one susceptible to carbapenems were identified. Moreover, 160 isolates (4.2%) meeting the criteria for CRE were directly subjected to PCR testing. All fourteen CRE isolates with MBLs identified through PCR testing were found to be the same strains screened using ceftazidime and cefoperazone/sulbactam. Screening using ceftazidime and cefoperazone/sulbactam can effectively detect MBL-producing Enterobacterales strains. This screening method showed comparable results to screening with meropenem, potentially serving as a supplementary approach and contributing to differentiating between MBL- and non-MBL-producing CRE strains. Our findings support these screening methods, particularly in regions where IMP-type MBLs are prevalent. Full article

(This article belongs to the Special Issue Strategies for Combatting Multidrug-Resistant and Extensively Drug-Resistant Bacteria: Current Challenges and Future Prospects)

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15 pages, 3585 KiB

Open AccessArticle

Antimicrobial Potential of Metabolites in Fungal Strains Isolated from a Polluted Stream: Annulohypoxylon stygium WL1B5 Produces Metabolites against Extended-Spectrum Beta-Lactamase-Positive Escherichia coli

by Walter Oliva Pinto Filho Segundo, Roberta Silva de Oliveira, Rildo Mendes Lima, Paulo Alexandre Lima Santiago, Luciana Aires de Oliveira, Ana Cláudia Alves Cortez, Emerson Silva Lima, Érica Simplício de Souza, Hagen Frickmann and João Vicente Braga de Souza

Antibiotics 2023, 12(1), 27; https://doi.org/10.3390/antibiotics12010027 - 24 Dec 2022

Cited by 2 | Viewed by 2025

Abstract

The emergence of multidrug resistance in bacterial pathogens is a growing public health concern requiring solutions including the discovery of new antimicrobial drugs. Fungi have been used for decades as a source of antimicrobials. Ongoing screenings for newly characterized fungal strains producing antimicrobials include environments that are difficult to access like the deep sea, glaciers, wastewaters and environments polluted due to human activity. In the present study, fungal microorganisms were isolated from water samples taken from a polluted stream in the city of Manaus, AM, Brazil, and screened for antimicrobial effects against Escherichia coli. Using extracts from five isolates (Annulohypoxylon stygium WL1B5, Colletotrichum fructicola WL3B9, Clonostachys rosea WL5B18, Clonostachys rosea WL8B28 and Trichoderma harzianum WL9B49), antimicrobial activity against the reference strains Escherichia coli ATCC 25922 as well as E. coli NCTC 13353, an extended-spectrum beta-lactamase-positive strain, was observed. Inhibition zones ranged from 1 to 35.9 mm and a minimum inhibitory concentration of 400 µg/mL could be demonstrated. Assessments of the metabolites of Annulohypoxylon stygium WL1B5 allowed us to identify nodulisporone and daidzein, which have already been associated with antimicrobial activity. The findings confirm the feasibility of isolating fungal strains from polluted sites producing metabolites that can serve as potential future alternatives for the treatment of multidrug-resistant bacteria. Full article

(This article belongs to the Special Issue Strategies for Combatting Multidrug-Resistant and Extensively Drug-Resistant Bacteria: Current Challenges and Future Prospects)

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Review

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12 pages, 1360 KiB

Open AccessReview

Laboratory Surveillance, Quality Management, and Its Role in Addressing Antimicrobial Resistance in Africa: A Narrative Review

by Khalid Musa, Ijeoma Okoliegbe, Tassabeeh Abdalaziz, Ahmed Taha Aboushady, John Stelling and Ian M. Gould

Antibiotics 2023, 12(8), 1313; https://doi.org/10.3390/antibiotics12081313 - 14 Aug 2023

Cited by 1 | Viewed by 1454

Abstract

AMR is a major public health concern that calls for extensive work and a multidisciplinary team approach. The high prevalence of infectious diseases in African nations leads to widespread antibiotic usage and eventual antimicrobial resistance, which has significant negative effects on people’s health, the economy, and society. Additionally, inadequate or nonexistent antimicrobial drug regulations, inappropriate prescription practices, and restrictions on public health prevention initiatives such as immunization, water and sanitation, and sexual health may all contribute to the emergence of AMR. Despite the need for laboratory quality assurance, many African laboratories confront substantial difficulties in implementing efficient quality assurance programs. AMR surveillance in Africa is hampered by a lack of laboratory capacity, insufficient data collection and analysis, and poor stakeholder collaboration. Several initiatives and programs, including the World Health Organization’s Global Antimicrobial Resistance and Use Surveillance System (GLASS), the Africa Centres for Disease Control and Prevention (Africa CDC) Antimicrobial Resistance Surveillance Network (AMRSNET), and the Fleming Fund, a UK government initiative aimed at tackling AMR in low- and middle-income countries, have been established to strengthen AMR surveillance in Africa and globally. Full article

(This article belongs to the Special Issue Strategies for Combatting Multidrug-Resistant and Extensively Drug-Resistant Bacteria: Current Challenges and Future Prospects)

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Other

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11 pages, 835 KiB

Open AccessSystematic Review

Predicting Extended-Spectrum Beta-Lactamase and Carbapenem Resistance in Enterobacteriaceae Bacteremia: A Diagnostic Model Systematic Review and Meta-Analysis

by Tristan T. Timbrook and McKenna J. Fowler

Antibiotics 2023, 12(9), 1452; https://doi.org/10.3390/antibiotics12091452 - 17 Sep 2023

Cited by 1 | Viewed by 1953

Abstract

Enterobacteriaceae bacteremia, particularly when associated with antimicrobial resistance, can result in increased mortality, emphasizing the need for timely effective therapy. Clinical risk prediction models are promising tools, stratifying patients based on their risk of resistance due to ESBL and carbapenemase-producing Enterobacteriaceae in bloodstream infections (BSIs) and, thereby, improving therapeutic decisions. This systematic review and meta-analysis synthesized the literature on the performance of these models. Searches of PubMed and EMBASE led to the identification of 10 relevant studies with 6106 unique patient encounters. Nine studies concerned ESBL prediction, and one focused on the prediction of carbapenemases. For the two ESBL model derivation studies, the discrimination performance showed sensitivities of 53–85% and specificities of 93–95%. Among the four ESBL model derivation and validation studies, the sensitivities were 43–88%, and the specificities were 77–99%. The sensitivity and specificity for the subsequent external validation studies were 7–37% and 88–96%, respectively. For the three external validation studies, only two models were evaluated across multiple studies, with a pooled AUROC of 65–71%, with one study omitting the sensitivity/specificity. Only two studies measured clinical utility through hypothetical therapy assessments. Given the limited evidence on their interventional application, it would be beneficial to further assess these or future models, to better understand their clinical utility and ensure their safe and impactful implementation. Full article

(This article belongs to the Special Issue Strategies for Combatting Multidrug-Resistant and Extensively Drug-Resistant Bacteria: Current Challenges and Future Prospects)

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