Emerging Treatment Options for Multidrug-Resistant Bacterial and Fungal Infections

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Antibiotic Therapy in Infectious Diseases".

Deadline for manuscript submissions: closed (15 November 2023) | Viewed by 33148

Special Issue Editors


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Guest Editor
Biomedical and Biotechnological Sciences Department, Section of Microbiology – University of Catania, Catania, Italy
Interests: bacterial genomic; bacterial transcriptomic; antimicrobial resistance; phage therapy

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Guest Editor
Biomedical and Biotechnological Sciences Department, Section of Microbiology – University of Catania, Catania, Italy
Interests: antimicrobial resistance; MRD bacteria; infectious diseases

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Guest Editor
Laboratory of Microbiology and Virology, Ospedale San Raffaele Dibit, Milan, Italy
Interests: Gram-negative bacteria; MDR bacteria; Klebsiella pneumonia; Pseudomonas aeruginosa

Special Issue Information

Dear Colleagues,

Infections by multidrug-resistance (MDR) pathogens are related to increased morbidity, mortality, in-hospital length of stay, and healthcare costs. The emergence of pathogenic microorganisms which cannot be effectively treated with existing drugs has been prioritized by the World Health Organization as one of the top ten global public health threats facing humanity. It has been reported that, without interventions, by the year 2050, 10 million people will die annually as a consequence of MDR infections, unless a global and effective response is achieved to tackle the problem. MDR Gram-negative Enterobacterales, MRSA, and VRE represent cumbersome to treat infections especially in a hospital setting as well as for more vulnerable patients such as those in ICU, where MDR bacteria and fungi could deteriorate the precarious patient clinical conditions. Furthermore, in these delicate settings, emerging MDR Candida spp. strains represent a rising dramatic phenomenon. The growing spread of MDR pathogens needs to be tackled by further research and new approaches in microbiological techniques that will enable the fast identification of resistance patterns; clinical management which assures the best diagnostic pathways avoiding useless antimicrobial therapies and performing the correct source control, and pharmacological options that could target pathogen-specific resistance mechanism avoiding drugs superfluous exposition and adverse events.

This Special Issue aims to collect original articles, literature reviews, and case reports/case series about emerging treatment options against MDR bacteria and fungi, with particular interest in new antibiotics and drug combination.

Dr. Andrea Marino
Dr. Stefano Stracquadanio
Dr. Stefania Stefani
Dr. Floriana Gona
Guest Editors

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Keywords

  • MDR bacteria
  • antibiotic resistance
  • new antimicrobial
  • MDR fungi
  • antifungal therapies
  • alternative strategies

Published Papers (9 papers)

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Research

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14 pages, 547 KiB  
Article
Clinical Efficacy of Sitafloxacin–Colistin–Meropenem and Colistin–Meropenem in Patients with Carbapenem-Resistant and Multidrug-Resistant Acinetobacter baumannii Hospital-Acquired Pneumonia (HAP)/Ventilator-Associated Pneumonia (VAP) in One Super-Tertiary Hospital in Bangkok, Thailand: A Randomized Controlled Trial
by Manasawee Wantanatavatod and Panuwat Wongkulab
Antibiotics 2024, 13(2), 137; https://doi.org/10.3390/antibiotics13020137 - 30 Jan 2024
Viewed by 1129
Abstract
Background: Carbapenem-resistant A. baumannii (CRAB) hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) is now a therapeutic problem worldwide. Method: An open-label, randomized, superiority, single-blind trial was conducted in Rajavithi Hospital, a super-tertiary care facility in Bangkok, Thailand. CRAB HAP/VAP patients were randomly assigned to receive [...] Read more.
Background: Carbapenem-resistant A. baumannii (CRAB) hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) is now a therapeutic problem worldwide. Method: An open-label, randomized, superiority, single-blind trial was conducted in Rajavithi Hospital, a super-tertiary care facility in Bangkok, Thailand. CRAB HAP/VAP patients were randomly assigned to receive either sitafloxacin–colistin–meropenem or colistin–meropenem. Outcomes in the two groups were then assessed with respect to mortality, clinical response, and adverse effects. Result: Between April 2021 and April 2022, 77 patients were treated with combinations of either sitafloxacin plus colistin plus meropenem (n = 40) or colistin plus meropenem (n = 37). There were no significant differences between the two groups with respect to all-cause mortality rates at 7 days and 14 days (respectively, 7.5% vs. 2.7%; p = 0.616, and 10% vs. 10%; p = 1). Patients who received sitafloxacin–colistin–meropenem showed improved clinical response compared with patients who received colistin–meropenem in terms of both intention-to-treat (87.5% vs. 62.2%; p = 0.016) and per-protocol analysis (87.2% vs. 67.7%; p = 0.049). There were no significant differences between the two groups with respect to adverse effects. Conclusions: Adding sitafloxacin as a third agent to meropenem plus colistin could improve clinical outcomes in CRAB HAP/VAP with little or no impact on adverse effects. In short, sitafloxacin–meropenem–colistin could be another therapeutic option for combatting CRAB HAP/VAP. Full article
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17 pages, 2379 KiB  
Article
Evaluation of the Effects of Heteroaryl Ethylene Molecules in Combination with Antibiotics: A Preliminary Study on Control Strains
by Carmelo Bonomo, Paolo Giuseppe Bonacci, Dalida Angela Bivona, Alessia Mirabile, Dafne Bongiorno, Emanuele Nicitra, Andrea Marino, Carmela Bonaccorso, Giuseppe Consiglio, Cosimo Gianluca Fortuna, Stefania Stefani and Nicolò Musso
Antibiotics 2023, 12(8), 1308; https://doi.org/10.3390/antibiotics12081308 - 10 Aug 2023
Cited by 1 | Viewed by 1070
Abstract
The discovery of compounds with antibacterial activity is crucial in the ongoing battle against antibiotic resistance. We developed two QSAR models to design six novel heteroaryl drug candidates and assessed their antibacterial properties against nine ATCC strains, including Enterococcus faecalis, Staphylococcus aureus [...] Read more.
The discovery of compounds with antibacterial activity is crucial in the ongoing battle against antibiotic resistance. We developed two QSAR models to design six novel heteroaryl drug candidates and assessed their antibacterial properties against nine ATCC strains, including Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and also Salmonella enterica and Escherichia coli, many of which belong to the ESKAPE group. We combined PB4, a previously tested compound from published studies, with GC-VI-70, a newly discovered compound, with the best cytotoxicity/MIC profile. By testing sub-MIC concentrations of PB4 with five antibiotics (linezolid, gentamycin, ampicillin, erythromycin, rifampin, and imipenem), we evaluated the combination’s efficacy against the ATCC strains. To assess the compounds’ cytotoxicity, we conducted a 24 h and 48 h 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on colorectal adenocarcinoma (CaCo-2) cells. We tested the antibiotics alone and in combination with PB4. Encouragingly, PB4 reduced the MIC values for GC-VI-70 and for the various clinically used antibiotics. However, it is essential to note that all the compounds studied in this research exhibited cytotoxic activity against cells. These findings highlight the potential of using these compounds in combination with antibiotics to enhance their effectiveness at lower concentrations while minimizing cytotoxic effects. Full article
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10 pages, 252 KiB  
Article
Ceftazidime-Avibactam Treatment for Klebsiella pneumoniae Bacteremia in Preterm Infants in NICU: A Clinical Experience
by Andrea Marino, Sarah Pulvirenti, Edoardo Campanella, Stefano Stracquadanio, Manuela Ceccarelli, Cristina Micali, Lucia Gabriella Tina, Giovanna Di Dio, Stefania Stefani, Bruno Cacopardo and Giuseppe Nunnari
Antibiotics 2023, 12(7), 1169; https://doi.org/10.3390/antibiotics12071169 - 10 Jul 2023
Cited by 3 | Viewed by 1587
Abstract
Ceftazidime/avibactam (CAZ/AVI) is an antibiotic combination approved for the treatment of several infections caused by multi-drug resistant (MDR) Gram-negative bacteria. Neonates admitted to the Neonatal Intensive Care Unit (NICU) are at high risk of developing bacterial infections, and the choice of appropriate antibiotics [...] Read more.
Ceftazidime/avibactam (CAZ/AVI) is an antibiotic combination approved for the treatment of several infections caused by multi-drug resistant (MDR) Gram-negative bacteria. Neonates admitted to the Neonatal Intensive Care Unit (NICU) are at high risk of developing bacterial infections, and the choice of appropriate antibiotics is crucial. However, the use of antibiotics in neonates carries risks such as antibiotic resistance and disruption of gut microbiota. This study aimed to assess the safety and efficacy of CAZ/AVI in preterm infants admitted to the NICU. Retrospective data from preterm infants with Klebsiella pneumoniae bacteremia who received CAZ/AVI were analyzed. Clinical and microbiological responses, adverse events, and outcomes were evaluated. Eight patients were included in the study, all of whom showed clinical improvement and achieved microbiological cure with CAZ/AVI treatment. No adverse drug reactions were reported. Previous antibiotic therapies failed to improve the neonates’ condition, and CAZ/AVI was initiated based on clinical deterioration and epidemiological considerations. The median duration of CAZ/AVI treatment was 14 days, and combination therapy with fosfomycin or amikacin was administered. Previous case reports have also shown positive outcomes with CAZ/AVI in neonates. However, larger trials are needed to further investigate the safety and efficacy of CAZ/AVI in this population. Full article
9 pages, 870 KiB  
Article
Comparison between EUCAST Broth Microdilution and MIC Strip Test in Defining Isavuconazole In Vitro Susceptibility against Candida and Rare Yeast Clinical Isolates
by Maddalena Calvo, Guido Scalia, Concetta Ilenia Palermo, Salvatore Oliveri and Laura Trovato
Antibiotics 2023, 12(2), 251; https://doi.org/10.3390/antibiotics12020251 - 26 Jan 2023
Cited by 2 | Viewed by 1472
Abstract
Isavuconazole is a new broad-spectrum triazole, with significant in vitro activity against yeasts. Isavuconazole in vitro susceptibility can be evaluated through broth microdilution as a reference method. Considering difficulties in equipping such methods in a laboratory routine, a commercial MIC Strip test has [...] Read more.
Isavuconazole is a new broad-spectrum triazole, with significant in vitro activity against yeasts. Isavuconazole in vitro susceptibility can be evaluated through broth microdilution as a reference method. Considering difficulties in equipping such methods in a laboratory routine, a commercial MIC Strip test has been designed. This study aims to implement data about isavuconazole in vitro activity and compare EUCAST broth microdilution and MIC Strip test in defining yeast isavuconazole susceptibility. The study involved 629 isolates from positive blood cultures (January 2017–December 2021). The identified species were C. albicans (283), C. glabrata (53), C. krusei (23), C. tropicalis (68), C. parapsilosis complex (151), C. guilliermondii (12), C. famata (6), S. cerevisiae (12), C. neoformans (5), S. capitata (12), and Rhodotorula species (4). All the isolates were tested with EUCAST microdilution and MIC Strip methods. The total essential agreement between these two methods was 99.3%. As a result, we can consider that both methods are useful in testing isavuconazole susceptibility. Proposed cut-off values (P-ECOFF) were calculated using ECOFFinder software. Further studies could lead to either definitive E-COFF or clinical breakpoints, which represent the most important categorization tool of the laboratory data, allowing a better insertion of an antimicrobial drug in clinical practice. Full article
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Review

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25 pages, 1245 KiB  
Review
Resistance in Pseudomonas aeruginosa: A Narrative Review of Antibiogram Interpretation and Emerging Treatments
by Federico Giovagnorio, Andrea De Vito, Giordano Madeddu, Saverio Giuseppe Parisi and Nicholas Geremia
Antibiotics 2023, 12(11), 1621; https://doi.org/10.3390/antibiotics12111621 - 12 Nov 2023
Cited by 3 | Viewed by 4322
Abstract
Pseudomonas aeruginosa is a ubiquitous Gram-negative bacterium renowned for its resilience and adaptability across diverse environments, including clinical settings, where it emerges as a formidable pathogen. Notorious for causing nosocomial infections, P. aeruginosa presents a significant challenge due to its intrinsic and acquired [...] Read more.
Pseudomonas aeruginosa is a ubiquitous Gram-negative bacterium renowned for its resilience and adaptability across diverse environments, including clinical settings, where it emerges as a formidable pathogen. Notorious for causing nosocomial infections, P. aeruginosa presents a significant challenge due to its intrinsic and acquired resistance mechanisms. This comprehensive review aims to delve into the intricate resistance mechanisms employed by P. aeruginosa and to discern how these mechanisms can be inferred by analyzing sensitivity patterns displayed in antibiograms, emphasizing the complexities encountered in clinical management. Traditional monotherapies are increasingly overshadowed by the emergence of multidrug-resistant strains, necessitating a paradigm shift towards innovative combination therapies and the exploration of novel antibiotics. The review accentuates the critical role of accurate antibiogram interpretation in guiding judicious antibiotic use, optimizing therapeutic outcomes, and mitigating the propagation of antibiotic resistance. Misinterpretations, it cautions, can inadvertently foster resistance, jeopardizing patient health and amplifying global antibiotic resistance challenges. This paper advocates for enhanced clinician proficiency in interpreting antibiograms, facilitating informed and strategic antibiotic deployment, thereby improving patient prognosis and contributing to global antibiotic stewardship efforts. Full article
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24 pages, 2303 KiB  
Review
Potential Strategies to Control the Risk of Antifungal Resistance in Humans: A Comprehensive Review
by Ali A. Rabaan, Tarek Sulaiman, Shamsah H. Al-Ahmed, Zainab A. Buhaliqah, Ali A. Buhaliqah, Buthina AlYuosof, Mubarak Alfaresi, Mona A. Al Fares, Sara Alwarthan, Mohammed S. Alkathlan, Reem S. Almaghrabi, Abdulmonem A. Abuzaid, Jaffar A. Altowaileb, Maha Al Ibrahim, Eman M. AlSalman, Fatimah Alsalman, Mohammad Alghounaim, Ahmed S. Bueid, Awad Al-Omari and Ranjan K. Mohapatra
Antibiotics 2023, 12(3), 608; https://doi.org/10.3390/antibiotics12030608 - 18 Mar 2023
Cited by 7 | Viewed by 4665
Abstract
Fungal infections are becoming one of the main causes of morbidity and mortality in people with weakened immune systems. Mycoses are becoming more common, despite greater knowledge and better treatment methods, due to the regular emergence of resistance to the antifungal medications used [...] Read more.
Fungal infections are becoming one of the main causes of morbidity and mortality in people with weakened immune systems. Mycoses are becoming more common, despite greater knowledge and better treatment methods, due to the regular emergence of resistance to the antifungal medications used in clinical settings. Antifungal therapy is the mainstay of patient management for acute and chronic mycoses. However, the limited availability of antifungal drug classes limits the range of available treatments. Additionally, several drawbacks to treating mycoses include unfavourable side effects, a limited activity spectrum, a paucity of targets, and fungal resistance, all of which continue to be significant issues in developing antifungal drugs. The emergence of antifungal drug resistance has eliminated accessible drug classes as treatment choices, which significantly compromises the clinical management of fungal illnesses. In some situations, the emergence of strains resistant to many antifungal medications is a major concern. Although new medications have been developed to address this issue, antifungal drug resistance has grown more pronounced, particularly in patients who need long-term care or are undergoing antifungal prophylaxis. Moreover, the mechanisms that cause resistance must be well understood, including modifications in drug target affinities and abundances, along with biofilms and efflux pumps that diminish intracellular drug levels, to find novel antifungal drugs and drug targets. In this review, different classes of antifungal agents, and their resistance mechanisms, have been discussed. The latter part of the review focuses on the strategies by which we can overcome this serious issue of antifungal resistance in humans. Full article
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19 pages, 1252 KiB  
Review
Evidence-Based Treatment of Pseudomonas aeruginosa Infections: A Critical Reappraisal
by Arta Karruli, Christian Catalini, Chiara D’Amore, Francesco Foglia, Fabio Mari, Arjan Harxhi, Massimiliano Galdiero and Emanuele Durante-Mangoni
Antibiotics 2023, 12(2), 399; https://doi.org/10.3390/antibiotics12020399 - 16 Feb 2023
Cited by 13 | Viewed by 13507
Abstract
Multidrug-resistant (MDR)/extensively drug-resistant (XDR) Pseudomonas aeruginosa is emerging as a major threat related to adverse patient outcomes. The goal of this review is to describe evidence-based empiric and targeted treatment regimens that can be exploited when dealing with suspected or confirmed infections due [...] Read more.
Multidrug-resistant (MDR)/extensively drug-resistant (XDR) Pseudomonas aeruginosa is emerging as a major threat related to adverse patient outcomes. The goal of this review is to describe evidence-based empiric and targeted treatment regimens that can be exploited when dealing with suspected or confirmed infections due to MDR/XDR P. aeruginosa. P. aeruginosa has inherent resistance to many drug classes, the capacity to form biofilms, and most importantly, the ability to quickly acquire resistance to ongoing treatments. Based on the presence of risk factors for MDR/XDR infections and local epidemiology, where large proportions of strains are resistant to classic beta-lactams, the recommended empirical treatment for suspected P. aeruginosa infections is based on ceftolozane-tazobactam or ceftazidime-avibactam. Where local epidemiology indicates low rates of MDR/XDR and there are no risk factors, a third or fourth generation cephalosporin can be used in the context of a “carbapenem-sparing” strategy. Whenever feasible, antibiotic de-escalation is recommended after antimicrobial susceptibility tests suggest that it is appropriate, and de-escalation is based on different resistance mechanisms. Cefiderocol and imipenem-cilastatin-relebactam withstand most resistance mechanisms and may remain active in cases with resistance to other new antibiotics. Confronting the growing threat of MDR/XDR P. aeruginosa, treatment choices should be wise, sparing newer antibiotics when dealing with a suspected/confirmed susceptible P. aeruginosa strain and choosing the right option for MDR/XDR P. aeruginosa based on specific types and resistance mechanisms. Full article
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Other

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10 pages, 290 KiB  
Case Report
Intravenous Fosfomycin: A Potential Good Partner for Cefiderocol. Clinical Experience and Considerations
by Andrea Marino, Stefano Stracquadanio, Edoardo Campanella, Antonio Munafò, Maria Gussio, Manuela Ceccarelli, Renato Bernardini, Giuseppe Nunnari and Bruno Cacopardo
Antibiotics 2023, 12(1), 49; https://doi.org/10.3390/antibiotics12010049 - 28 Dec 2022
Cited by 12 | Viewed by 1687
Abstract
Multidrug resistant Gram-negative bacteremia represents a therapeutic challenge clinicians have to deal with. This concern becomes more difficult when causing germs are represented by carbapenem resistant Acinetobacter baumannii or difficult-to-treat Pseudomonas aeruginosa. Few antibiotics are available against these cumbersome bacteria, although literature [...] Read more.
Multidrug resistant Gram-negative bacteremia represents a therapeutic challenge clinicians have to deal with. This concern becomes more difficult when causing germs are represented by carbapenem resistant Acinetobacter baumannii or difficult-to-treat Pseudomonas aeruginosa. Few antibiotics are available against these cumbersome bacteria, although literature data are not conclusive, especially for Acinetobacter. Cefiderocol could represent a valid antibiotic choice, being a molecule with an innovative mechanism of action capable of overcoming common resistance pathways, whereas intravenous fosfomycin may be an appropriate partner either enhancing cefiderocol activity or avoiding resistance development. Here we report two patients with MDR Gram negative bacteremia who were successfully treated with a cefiderocol/fosfomycin combination. Full article
13 pages, 2440 KiB  
Systematic Review
Efficacy of Tuberculosis Treatment in Patients with Drug-Resistant Tuberculosis with the Use of Bedaquiline: The Experience of the Russian Federation
by Anna Starshinova, Irina Dovgalyk, Ekaterina Belyaeva, Anzhela Glushkova, Nikolay Osipov and Dmitry Kudlay
Antibiotics 2022, 11(11), 1622; https://doi.org/10.3390/antibiotics11111622 - 14 Nov 2022
Cited by 3 | Viewed by 2086
Abstract
In the conditions of the continued growth of multiple- and extensive drug-resistant tuberculosis, use of the new highly effective anti-tuberculosis drugs in this patient category is of great relevance. The aim of the study was determination the efficacy of treatment in patients with [...] Read more.
In the conditions of the continued growth of multiple- and extensive drug-resistant tuberculosis, use of the new highly effective anti-tuberculosis drugs in this patient category is of great relevance. The aim of the study was determination the efficacy of treatment in patients with multidrug- and extensive drug-resistant tuberculosis using bedaquiline based on studies published in the Russian Federation. Materials and methods: The authors analyzed data published in studies from 2014 to 2022; 41 publications were included in total and 17 articles corresponded to the study design. The results of treatment of 1404 tuberculosis patients with MDR/XDR TB were described. Bedaquiline was used according to the standard scheme with a description of the treatment results after 24–26 weeks. Treatment efficacy was estimated according to accepted criteria. Results of the study: The analysis showed that the treatment efficacy on conversion was achieved in 79.5% of cases (95% Cl 76.5–82.3), and recovery was observed in 82.0% of cases (95% Cl 78.6–85.1). Departure from the therapy was observed in rare cases (9.8%; 95% Cl 7.9–12.2). Deaths were recorded in 6.5% of cases (95% Cl 4.9–8.3), which were associated with the severe disease and concomitant pathology in 74.3%. The development of adverse events was noted in half of the patients (55.7%); however, bedaquiline cancellation occurred in a few cases (7.0%; 95% Cl 3.0–13.0). From analyzing data in patients with MDR and XDR TB, the efficacy of treatment was 89.9% (95% Cl 85.9–93.2) and 71.9% (95% Cl 66.2–77.1), respectively. Conclusion: Use of bedaquiline in treatment makes it possible to achieve recovery of patients with MDR/XDR TB in 82.0% of cases with patients dropping out of treatment in 9.8%. At the same time, in patients with MDR TB, recovery was achieved in 89.9% of cases, while in patients with XDR TB, 71.9% of cases recovered. Full article
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