Antibiotics

11 pages, 1836 KiB

Open AccessEditor’s ChoiceArticle

Nifedipine Potentiates Susceptibility of Salmonella Typhimurium to Different Classes of Antibiotics

by David Haschka, Manuel Grander, Johannes Eibensteiner, Stefanie Dichtl, Sabine Koppelstätter and Günter Weiss

Antibiotics 2021, 10(10), 1200; https://doi.org/10.3390/antibiotics10101200 - 01 Oct 2021

Cited by 2 | Viewed by 1982

Abstract

The calcium channel blocker nifedipine induces cellular iron export, thereby limiting the availability of the essential nutrient iron for intracellular pathogens, resulting in bacteriostatic activity. To study if nifedipine may exert a synergistic anti-microbial activity when combined with antibiotics, we used the mouse [...] Read more.

The calcium channel blocker nifedipine induces cellular iron export, thereby limiting the availability of the essential nutrient iron for intracellular pathogens, resulting in bacteriostatic activity. To study if nifedipine may exert a synergistic anti-microbial activity when combined with antibiotics, we used the mouse macrophage cell line RAW267.4, infected with the intracellular bacterium Salmonella Typhimurium, and exposed the cells to varying concentrations of nifedipine and/or ampicillin, azithromycin and ceftriaxone. We observed a significant additive effect of nifedipine in combination with various antibiotics, which was not observed when using Salmonella, with defects in iron uptake. Of interest, increasing intracellular iron levels increased the bacterial resistance to treatment with antibiotics or nifedipine or their combination. We further showed that nifedipine increases the expression of the siderophore-binding peptide lipocalin-2 and promotes iron storage within ferritin, where the metal is less accessible for bacteria. Our data provide evidence for an additive effect of nifedipine with conventional antibiotics against Salmonella, which is partly linked to reduced bacterial access to iron. Full article

(This article belongs to the Special Issue Development of Antimicrobial Biomaterials and Natural Alternatives against Biofilms and Implant-Related Infections)

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10 pages, 518 KiB

Open AccessEditor’s ChoiceArticle

Management of Common Infections in German Primary Care: A Cross-Sectional Survey of Knowledge and Confidence among General Practitioners and Outpatient Pediatricians

by Peter Konstantin Kurotschka, Elena Tiedemann, Dominik Wolf, Nicola Thier, Johannes Forster, Johannes G. Liese and Ildiko Gagyor

Antibiotics 2021, 10(9), 1131; https://doi.org/10.3390/antibiotics10091131 - 20 Sep 2021

Cited by 2 | Viewed by 2360

Abstract

Outpatient antibiotic use is closely related to antimicrobial resistance and in Germany, almost 70% of antibiotic prescriptions in human health are issued by primary care physicians (PCPs). The aim of this study was to explore PCPs, namely General Practitioners’ (GPs) and outpatient pediatricians’ [...] Read more.

Outpatient antibiotic use is closely related to antimicrobial resistance and in Germany, almost 70% of antibiotic prescriptions in human health are issued by primary care physicians (PCPs). The aim of this study was to explore PCPs, namely General Practitioners’ (GPs) and outpatient pediatricians’ (PDs) knowledge of guideline recommendations on rational antimicrobial treatment, the determinants of confidence in treatment decisions and the perceived need for training in this topic in a large sample of PCPs from southern Germany. Out of 3753 reachable PCPs, 1311 completed the survey (overall response rate = 34.9%). Knowledge of guideline recommendations and perceived confidence in making treatment decisions were high in both GPs and PDs. The two highest rated influencing factors on prescribing decisions were reported to be guideline recommendations and own clinical experiences, hence patients’ demands and expectations were judged as not influencing treatment decisions. The majority of physicians declared to have attended at least one specific training course on antibiotic use, yet almost all the participating PCPs declared to need more training on this topic. More studies are needed to explore how consultation-related and context-specific factors could influence antibiotic prescriptions in general and pediatric primary care in Germany beyond knowledge. Moreover, efforts should be undertaken to explore the training needs of PCPs in Germany, as this would serve the development of evidence-based educational interventions targeted to the improvement of antibiotic prescribing decisions rather than being focused solely on knowledge of guidelines. Full article

(This article belongs to the Special Issue Antibiotics and Infectious Respiratory Diseases)

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14 pages, 305 KiB

Open AccessEditor’s ChoiceArticle

A Study in a Regional Hospital of a Mid-Sized Spanish City Indicates a Major Increase in Infection/Colonization by Carbapenem-Resistant Bacteria, Coinciding with the COVID-19 Pandemic

by Estefanía Cano-Martín, Inés Portillo-Calderón, Patricia Pérez-Palacios, José María Navarro-Marí, María Amelia Fernández-Sierra and José Gutiérrez-Fernández

Antibiotics 2021, 10(9), 1127; https://doi.org/10.3390/antibiotics10091127 - 18 Sep 2021

Cited by 5 | Viewed by 2946

Abstract

Bacterial resistance to antibiotics has proven difficult to control over the past few decades. The large group of multidrug-resistant bacteria includes carbapenemase-producing bacteria (CPB), for which limited therapeutic options and infection control measures are available. Furthermore, carbapenemases associate with high-risk clones that are [...] Read more.

Bacterial resistance to antibiotics has proven difficult to control over the past few decades. The large group of multidrug-resistant bacteria includes carbapenemase-producing bacteria (CPB), for which limited therapeutic options and infection control measures are available. Furthermore, carbapenemases associate with high-risk clones that are defined by the sequence type (ST) to which each bacterium belongs. The objectives of this cross-sectional and retrospective study were to describe the CPB population isolated in a third-level hospital in Southern Spain between 2015 and 2020 and to establish the relationship between the ST and the epidemiological situation defined by the hospital. CPB were microbiologically studied in all rectal and pharyngeal swabs and clinical samples received between January 2015 and December 2020, characterizing isolates using MicroScan and mass spectrometry. Carbapenemases were detected by PCR and Sanger sequencing, and STs were assigned by multilocus sequence typing (MLST). Isolates were genetically related by pulsed-field gel electrophoresis using Xbal, Spel, or Apal enzymes. The episodes in which each CPB was isolated were recorded and classified as involved or non-involved in an outbreak. There were 320 episodes with CPB during the study period: 18 with K. pneumoniae, 14 with Klebisella oxytoca, 9 with Citrobacter freundii, 11 with Escherichia coli, 46 with Enterobacter cloacae, 70 with Acinetobacter baumannii, and 52 with Pseudomonas aeruginosa. The carbapenemase groups detected were OXA, VIM, KPC, and NDM with various subgroups. Synchronous relationships were notified between episodes of K. pneumoniae and outbreaks for ST15, ST258, ST307, and ST45, but not for the other CPB. There was a major increase in infections with CPB over the years, most notably during 2020, coinciding with the COVID-19 pandemic. This study highlights the usefulness of gene sequencing techniques to control the spread of these microorganisms, especially in healthcare centers. These techniques offer faster results, and a reduction in their cost may make their real-time application more feasible. The combination of epidemiological data with real-time molecular sequencing techniques can provide a major advance in the transmission control of these CPB and in the management of infected patients. Real-time sequencing is essential to increase precision and thereby control outbreaks and target infection prevention measures in a more effective manner. Full article

(This article belongs to the Special Issue Carbapenemase-Producing Enterobacterales)

13 pages, 1194 KiB

Open AccessEditor’s ChoiceArticle

Environmental and Pathogenic Carbapenem Resistant Bacteria Isolated from a Wastewater Treatment Plant Harbour Distinct Antibiotic Resistance Mechanisms

by Micaela Oliveira, Inês Carvalho Leonardo, Mónica Nunes, Ana Filipa Silva and Maria Teresa Barreto Crespo

Antibiotics 2021, 10(9), 1118; https://doi.org/10.3390/antibiotics10091118 - 16 Sep 2021

Cited by 12 | Viewed by 3367

Abstract

Wastewater treatment plants are important reservoirs and sources for the dissemination of antibiotic resistance into the environment. Here, two different groups of carbapenem resistant bacteria—the potentially environmental and the potentially pathogenic—were isolated from both the wastewater influent and discharged effluent of a full-scale [...] Read more.

Wastewater treatment plants are important reservoirs and sources for the dissemination of antibiotic resistance into the environment. Here, two different groups of carbapenem resistant bacteria—the potentially environmental and the potentially pathogenic—were isolated from both the wastewater influent and discharged effluent of a full-scale wastewater treatment plant and characterized by whole genome sequencing and antibiotic susceptibility testing. Among the potentially environmental isolates, there was no detection of any acquired antibiotic resistance genes, which supports the idea that their resistance mechanisms are mainly intrinsic. On the contrary, the potentially pathogenic isolates presented a broad diversity of acquired antibiotic resistance genes towards different antibiotic classes, especially β-lactams, aminoglycosides, and fluoroquinolones. All these bacteria showed multiple β-lactamase-encoding genes, some with carbapenemase activity, such as the bla_KPC-type genes found in the Enterobacteriaceae isolates. The antibiotic susceptibility testing assays performed on these isolates also revealed that all had a multi-resistance phenotype, which indicates that the acquired resistance is their major antibiotic resistance mechanism. In conclusion, the two bacterial groups have distinct resistance mechanisms, which suggest that the antibiotic resistance in the environment can be a more complex problematic than that generally assumed. Full article

(This article belongs to the Special Issue Antibiotic Resistance in Wastewater and Its Treatment)

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14 pages, 996 KiB

Open AccessEditor’s ChoiceReview

Old and New Beta-Lactamase Inhibitors: Molecular Structure, Mechanism of Action, and Clinical Use

by Davide Carcione, Claudia Siracusa, Adela Sulejmani, Valerio Leoni and Jari Intra

Antibiotics 2021, 10(8), 995; https://doi.org/10.3390/antibiotics10080995 - 17 Aug 2021

Cited by 42 | Viewed by 8720

Abstract

The β-lactams have a central place in the antibacterial armamentarium, but the increasing resistance to these drugs, especially among Gram-negative bacteria, is becoming one of the major threats to public health worldwide. Treatment options are limited, and only a small number of novel [...] Read more.

The β-lactams have a central place in the antibacterial armamentarium, but the increasing resistance to these drugs, especially among Gram-negative bacteria, is becoming one of the major threats to public health worldwide. Treatment options are limited, and only a small number of novel antibiotics are in development. However, one of the responses to this threat is the combination of β-lactam antibiotics with β-lactamase inhibitors, which are successfully used in the clinic for overcoming resistance by inhibiting β-lactamases. The existing inhibitors inactivate most of class A and C serine β-lactamases, but several of class D and B (metallo-β-lactamase) are resistant. The present review provides the status and knowledge concerning current β-lactamase inhibitors and an update on research efforts to identify and develop new and more efficient β-lactamase inhibitors. Full article

(This article belongs to the Special Issue Antibiotic Use in Clinical Infection: How to Reinvent Old Molecules and How to Squeeze Out New Ones)

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14 pages, 1144 KiB

Open AccessEditor’s ChoiceReview

MALDI-TOF Mass Spectrometry Technology as a Tool for the Rapid Diagnosis of Antimicrobial Resistance in Bacteria

by Eun-Jeong Yoon and Seok Hoon Jeong

Antibiotics 2021, 10(8), 982; https://doi.org/10.3390/antibiotics10080982 - 14 Aug 2021

Cited by 27 | Viewed by 6215

Abstract

Species identification by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a routine diagnostic process for infectious diseases in current clinical settings. The rapid, low-cost, and simple to conduct methodology is expanding its application in clinical microbiology laboratories to diagnose the [...] Read more.

Species identification by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a routine diagnostic process for infectious diseases in current clinical settings. The rapid, low-cost, and simple to conduct methodology is expanding its application in clinical microbiology laboratories to diagnose the antimicrobial resistance (AMR) in microorganisms. Primarily, antimicrobial susceptibility testing is able to be carried out either by comparing the area under curve of MALDI spectra of bacteria grown in media with antimicrobial drugs or by identifying the shift peaks of bacteria grown in media including ¹³C isotope with antimicrobial drugs. Secondly, the antimicrobial resistance is able to be determined through identifying (i) the antimicrobial-resistant clonal groups based on the fingerprints of the clone, (ii) the shift peak of the modified antimicrobial drug, which is inactivated by the resistance determinant, (iii) the shift peak of the modified antimicrobial target, (iv) the peak specific for the antimicrobial determinant, and (v) the biomarkers that are coproduced proteins with AMR determinants. This review aims to present the current usage of the MALDI-TOF MS technique for diagnosing antimicrobial resistance in bacteria, varied approaches for AMR diagnostics using the methodology, and the future applications of the methods for the accurate and rapid identification of AMR in infection-causing bacterial pathogens. Full article

(This article belongs to the Special Issue Rapid Diagnostics of the Antimicrobial Resistance)

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12 pages, 2815 KiB

Open AccessEditor’s ChoiceArticle

A Repeated State of Acidification Enhances the Anticariogenic Biofilm Activity of Glass Ionomer Cement Containing Fluoro-Zinc-Silicate Fillers

by Traithawit Naksagoon, Shoji Takenaka, Ryoko Nagata, Maki Sotozono, Tatsuya Ohsumi, Takako Ida, Naoki Edanami, Takeyasu Maeda and Yuichiro Noiri

Antibiotics 2021, 10(8), 977; https://doi.org/10.3390/antibiotics10080977 - 13 Aug 2021

Cited by 2 | Viewed by 2096

Abstract

This study aimed to evaluate the anticariogenic biofilm activity of a novel zinc-containing glass ionomer cement, Caredyne Restore (CR), using a flow-cell system that reproduces Stephan responses. Streptococcus mutans biofilms were cultured on either CR or hydroxyapatite (HA) discs mounted on a modified [...] Read more.

This study aimed to evaluate the anticariogenic biofilm activity of a novel zinc-containing glass ionomer cement, Caredyne Restore (CR), using a flow-cell system that reproduces Stephan responses. Streptococcus mutans biofilms were cultured on either CR or hydroxyapatite (HA) discs mounted on a modified Robbins device. The media were allowed to flow at a speed of 2 mL/min for 24 h while exposed to an acidic buffer twice for 30 min to mimic dietary uptake. Acid exposure enhanced biofilm inhibition in the CR group, which showed 2.6 log CFU/mm² in viable cells and a 2 log copies/mL reduction in total cells compared to the untreated group after 24 h of incubation, suggesting enhanced anticariogenic activity due to the release of fluoride and zinc ions. However, there was no difference in the number of viable and total cells between the two experimental groups after 24 h of incubation in the absence of an acidic environment. The anticariogenic biofilm activity of CR occurs in acidic oral environments, for example in the transient pH drop following dietary uptake. CR restorations are recommended in patients at high risk of caries due to hyposalivation, difficulty brushing, and frequent sugar intake. Full article

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8 pages, 677 KiB

Open AccessEditor’s ChoicePerspective

Biosynthetic Potential of Streptomyces Rationalizes Genome-Based Bioprospecting

by Balasubramanian Cibichakravarthy and Polapass Arul Jose

Antibiotics 2021, 10(7), 873; https://doi.org/10.3390/antibiotics10070873 - 19 Jul 2021

Cited by 4 | Viewed by 2735

Abstract

Streptomyces are the most prolific source of structurally diverse microbial natural products. Advancing genome-based analysis reveals the previously unseen potential of Streptomyces to produce numerous novel secondary metabolites, which allows us to take natural product discovery to the next phase. However, at present [...] Read more.

Streptomyces are the most prolific source of structurally diverse microbial natural products. Advancing genome-based analysis reveals the previously unseen potential of Streptomyces to produce numerous novel secondary metabolites, which allows us to take natural product discovery to the next phase. However, at present there is a huge disproportion between the rate of genome reports and discovery of new compounds. From this perspective of harnessing the enduring importance of Streptomyces, we discuss the recent genome-directed advancements inspired by hidden biosynthetic wealth that provide hope for future antibiotics. Full article

(This article belongs to the Special Issue Discovery and Biosynthesis of Novel Antibiotic from Streptomyces)

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30 pages, 6960 KiB

Open AccessEditor’s ChoiceArticle

A Fine-Tuned Lipophilicity/Hydrophilicity Ratio Governs Antibacterial Potency and Selectivity of Bifurcated Halogen Bond-Forming NBTIs

by Anja Kolarič, Maja Kokot, Martina Hrast, Matjaž Weiss, Irena Zdovc, Jurij Trontelj, Simon Žakelj, Marko Anderluh and Nikola Minovski

Antibiotics 2021, 10(7), 862; https://doi.org/10.3390/antibiotics10070862 - 15 Jul 2021

Cited by 11 | Viewed by 5015

Abstract

Herein, we report the design of a focused library of novel bacterial topoisomerase inhibitors (NBTIs) based on innovative mainly monocyclic right-hand side fragments active against DNA gyrase and Topo IV. They exhibit a very potent and wide range of antibacterial activity, even against [...] Read more.

Herein, we report the design of a focused library of novel bacterial topoisomerase inhibitors (NBTIs) based on innovative mainly monocyclic right-hand side fragments active against DNA gyrase and Topo IV. They exhibit a very potent and wide range of antibacterial activity, even against some of the most concerning hard-to-treat pathogens for which new antibacterials are urgently needed, as reported by the WHO and CDC. NBTIs enzyme activity and whole cell potency seems to depend on the fine-tuned lipophilicity/hydrophilicity ratio that governs the permeability of those compounds through the bacterial membranes. Lipophilicity of NBTIs is apparently optimal for passing through the membrane of Gram-positive bacteria, but the higher, although not excessive lipophilicity and suitable hydrophilicity seems to determine the passage through Gram-negative bacterial membranes. However, due to the considerable hERG inhibition, which is still at least two orders of magnitude away from MICs, continued optimization is required to realize their full potential. Full article

(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)

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25 pages, 465 KiB

Open AccessEditor’s ChoiceReview

Role of RND Efflux Pumps in Drug Resistance of Cystic Fibrosis Pathogens

by Viola Camilla Scoffone, Gabriele Trespidi, Giulia Barbieri, Samuele Irudal, Elena Perrin and Silvia Buroni

Antibiotics 2021, 10(7), 863; https://doi.org/10.3390/antibiotics10070863 - 15 Jul 2021

Cited by 19 | Viewed by 4014

Abstract

Drug resistance represents a great concern among people with cystic fibrosis (CF), due to the recurrent and prolonged antibiotic therapy they should often undergo. Among Multi Drug Resistance (MDR) determinants, Resistance-Nodulation-cell Division (RND) efflux pumps have been reported as the main contributors, due [...] Read more.

Drug resistance represents a great concern among people with cystic fibrosis (CF), due to the recurrent and prolonged antibiotic therapy they should often undergo. Among Multi Drug Resistance (MDR) determinants, Resistance-Nodulation-cell Division (RND) efflux pumps have been reported as the main contributors, due to their ability to extrude a wide variety of molecules out of the bacterial cell. In this review, we summarize the principal RND efflux pump families described in CF pathogens, focusing on the main Gram-negative bacterial species (Pseudomonas aeruginosa, Burkholderia cenocepacia, Achromobacter xylosoxidans, Stenotrophomonas maltophilia) for which a predominant role of RND pumps has been associated to MDR phenotypes. Full article

(This article belongs to the Special Issue The Structural and Functional Study of Efflux Pumps Belonging to the RND Transporters Family from Gram-Negative Bacteria)

9 pages, 482 KiB

Open AccessEditor’s ChoiceArticle

National Facilitators and Barriers to the Implementation of Incentives for Antibiotic Access and Innovation

by Christine Årdal, Yohann Lacotte, Suzanne Edwards, Marie-Cécile Ploy and on behalf of the European Union Joint Action on Antimicrobial Resistance and Healthcare-Associated Infections (EU-JAMRAI)

Antibiotics 2021, 10(6), 749; https://doi.org/10.3390/antibiotics10060749 - 21 Jun 2021

Cited by 4 | Viewed by 2932

Abstract

Prominent reports have assessed the challenges to antibiotic innovation and recommended implementing “pull” incentives, i.e., mechanisms that give increased and predictable revenues for important, marketed antibiotics. We set out to understand countries’ perceptions of these recommendations, through frank and anonymous dialogue. In 2019 [...] Read more.

Prominent reports have assessed the challenges to antibiotic innovation and recommended implementing “pull” incentives, i.e., mechanisms that give increased and predictable revenues for important, marketed antibiotics. We set out to understand countries’ perceptions of these recommendations, through frank and anonymous dialogue. In 2019 and 2020, we performed in-depth interviews with national policymakers and antibiotic resistance experts in 13 countries (ten European countries and three non-European) for a total of 73 individuals in 27 separate interviews. Interviewees expressed high-level support for antibiotic incentives in 11 of 13 countries. There is recognition that new economic incentives are needed to maintain a reliable supply to essential antibiotics. However, most countries are uncertain which incentives may be appropriate for their country, which antibiotics should be included, how to implement incentives, and how much it will cost. There is a preference for a multinational incentive, so long as it is independent of national pricing, procurement, and reimbursement processes. Nine countries indicated a preference for a model that ensures access to both existing and new antibiotics, with the highest priority for existing antibiotics. Twelve of thirteen countries indicated that shortages of existing antibiotics is a serious problem. Since countries are skeptical about the public health value of many recently approved antibiotics, there is a mismatch regarding revenue expectations between policymakers and antibiotic innovators. This paper presents important considerations for the design and implementation of antibiotic pull mechanisms. We also propose a multinational model that appears to match the needs of both countries and innovators. Full article

(This article belongs to the Section The Global Need for Effective Antibiotics)

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16 pages, 8515 KiB

Open AccessEditor’s ChoiceArticle

Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid

by Emmanuela Adjei-Sowah, Yue Peng, Jason Weeks, Jennifer H. Jonason, Karen L. de Mesy Bentley, Elysia Masters, Yugo Morita, Gowrishankar Muthukrishnan, Philip Cherian, X. Eric Hu, Charles E. McKenna, Frank H. Ebetino, Shuting Sun, Edward M. Schwarz and Chao Xie

Antibiotics 2021, 10(6), 732; https://doi.org/10.3390/antibiotics10060732 - 17 Jun 2021

Cited by 12 | Viewed by 3909

Abstract

The use of local antibiotics to treat bone infections has been questioned due to a lack of clinical efficacy and emerging information about Staphylococcus aureus colonization of the osteocyte-lacuno canalicular network (OLCN). Here we propose bisphosphonate-conjugated antibiotics (BCA) using a “target and release” [...] Read more.

The use of local antibiotics to treat bone infections has been questioned due to a lack of clinical efficacy and emerging information about Staphylococcus aureus colonization of the osteocyte-lacuno canalicular network (OLCN). Here we propose bisphosphonate-conjugated antibiotics (BCA) using a “target and release” approach to deliver antibiotics to bone infection sites. A fluorescent bisphosphonate probe was used to demonstrate bone surface labeling adjacent to bacteria in a S. aureus infected mouse tibiae model. Bisphosphonate and hydroxybisphosphonate conjugates of sitafloxacin and tedizolid (BCA) were synthesized using hydroxyphenyl and aminophenyl carbamate linkers, respectively. The conjugates were adequately stable in serum. Their cytolytic activity versus parent drug on MSSA and MRSA static biofilms grown on hydroxyapatite discs was established by scanning electron microscopy. Sitafloxacin O-phenyl carbamate BCA was effective in eradicating static biofilm: no colony formation units (CFU) were recovered following treatment with 800 mg/L of either the bisphosphonate or α-hydroxybisphosphonate conjugated drug (p < 0.001). In contrast, the less labile tedizolid N-phenyl carbamate linked BCA had limited efficacy against MSSA, and MRSA. CFU were recovered from all tedizolid BCA treatments. These results demonstrate the feasibility of BCA eradication of S. aureus biofilm on OLCN bone surfaces and support in vivo drug development of a sitafloxacin BCA. Full article

(This article belongs to the Special Issue Development of Antimicrobial Biomaterials and Natural Alternatives against Biofilms and Implant-Related Infections)

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12 pages, 560 KiB

Open AccessEditor’s ChoicePerspective

Basics for Improved Use of Phages for Therapy

by Philip Serwer, Elena T. Wright, Jorge De La Chapa and Cara B. Gonzales

Antibiotics 2021, 10(6), 723; https://doi.org/10.3390/antibiotics10060723 - 16 Jun 2021

Cited by 10 | Viewed by 2943

Abstract

Blood-borne therapeutic phages and phage capsids increasingly reach therapeutic targets as they acquire more persistence, i.e., become more resistant to non-targeted removal from blood. Pathogenic bacteria are targets during classical phage therapy. Metastatic tumors are potential future targets, during use of drug delivery [...] Read more.

Blood-borne therapeutic phages and phage capsids increasingly reach therapeutic targets as they acquire more persistence, i.e., become more resistant to non-targeted removal from blood. Pathogenic bacteria are targets during classical phage therapy. Metastatic tumors are potential future targets, during use of drug delivery vehicles (DDVs) that are phage derived. Phage therapy has, to date, only sometimes been successful. One cause of failure is low phage persistence. A three-step strategy for increasing persistence is to increase (1) the speed of lytic phage isolation, (2) the diversity of phages isolated, and (3) the effectiveness and speed of screening phages for high persistence. The importance of high persistence-screening is illustrated by our finding here of persistence dramatically higher for coliphage T3 than for its relative, coliphage T7, in murine blood. Coliphage T4 is more persistent, long-term than T3. Pseudomonas chlororaphis phage 201phi2-1 has relatively low persistence. These data are obtained with phages co-inoculated and separately assayed. In addition, highly persistent phage T3 undergoes dispersal to several murine organs and displays tumor tropism in epithelial tissue (xenografted human oral squamous cell carcinoma). Dispersal is an asset for phage therapy, but a liability for phage-based DDVs. We propose increased focus on phage persistence—and dispersal—screening. Full article

(This article belongs to the Special Issue Phage Therapy to Control Pathogenic Bacteria)

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17 pages, 5061 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections

by Hang Thi Nguyen, Mahmud T. Morshed, Daniel Vuong, Andrew Crombie, Ernest Lacey, Sanjay Garg, Hongfei Pi, Lucy Woolford, Henrietta Venter, Stephen W. Page, Andrew M. Piggott, Darren J. Trott and Abiodun D. Ogunniyi

Antibiotics 2021, 10(6), 727; https://doi.org/10.3390/antibiotics10060727 - 16 Jun 2021

Cited by 1 | Viewed by 3038

Abstract

Our recent focus on the “lost antibiotic” unguinol and related nidulin-family fungal natural products identified two semisynthetic derivatives, benzguinols A and B, with unexpected in vitro activity against Staphylococcus aureus isolates either susceptible or resistant to methicillin. Here, we show further activity of [...] Read more.

Our recent focus on the “lost antibiotic” unguinol and related nidulin-family fungal natural products identified two semisynthetic derivatives, benzguinols A and B, with unexpected in vitro activity against Staphylococcus aureus isolates either susceptible or resistant to methicillin. Here, we show further activity of the benzguinols against methicillin-resistant isolates of the animal pathogen Staphylococcus pseudintermedius, with minimum inhibitory concentration (MIC) ranging 0.5–1 μg/mL. When combined with sub-inhibitory concentrations of colistin, the benzguinols demonstrated synergy against Gram-negative reference strains of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa (MICs of 1–2 μg/mL in the presence of colistin), whereas the benzguinols alone had no activity. Administration of three intraperitoneal (IP) doses of 20 mg/kg benzguinol A or B to mice did not result in any obvious adverse clinical or pathological evidence of acute toxicity. Importantly, mice that received three 20 mg/kg IP doses of benzguinol A or B at 4 h intervals exhibited significantly reduced bacterial loads and longer survival times than vehicle-only treated mice in a bioluminescent S. aureus murine sepsis challenge model. We conclude that the benzguinols are potential candidates for further development for specific treatment of serious bacterial infections as both stand-alone antibiotics and in combination with existing antibiotic classes. Full article

(This article belongs to the Section Novel Antimicrobial Agents)

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14 pages, 605 KiB

Open AccessEditor’s ChoiceArticle

Impact of an Antimicrobial Stewardship Program on the Incidence of Carbapenem Resistant Gram-Negative Bacilli: An Interrupted Time-Series Analysis

by Teresa López-Viñau, Germán Peñalva, Lucrecia García-Martínez, Juan José Castón, Montserrat Muñoz-Rosa, Ángela Cano, Manuel Recio, José Miguel Cisneros, Elena Pérez-Nadales, José Rumbao Aguirre, Elena García-Martínez, Inmaculada Salcedo, José Ramón del Prado, Carmen de la Fuente, Luis Martínez-Martínez, Irene Gracia-Ahufinger and Julián Torre-Cisneros

Antibiotics 2021, 10(5), 586; https://doi.org/10.3390/antibiotics10050586 - 16 May 2021

Cited by 11 | Viewed by 3748

Abstract

Carbapenem-resistant Gram-negative bacilli (CR-GNB) are a critical public health threat, and carbapenem use contributes to their spread. Antimicrobial stewardship programs (ASPs) have proven successful in reducing antimicrobial use. However, evidence on the impact of carbapenem resistance remains unclear. We evaluated the impact of [...] Read more.

Carbapenem-resistant Gram-negative bacilli (CR-GNB) are a critical public health threat, and carbapenem use contributes to their spread. Antimicrobial stewardship programs (ASPs) have proven successful in reducing antimicrobial use. However, evidence on the impact of carbapenem resistance remains unclear. We evaluated the impact of a multifaceted ASP on carbapenem use and incidence of CR-GNB in a high-endemic hospital. An interrupted time-series analysis was conducted one year before and two years after starting the ASP to assess carbapenem consumption, CR-GNB incidence, death rates of sentinel events, and other variables potentially related to CR-GNB incidence. An intense reduction in carbapenem consumption occurred after starting the intervention and was sustained two years later (relative effect −83.51%; 95% CI −87.23 to −79.79). The incidence density of CR-GNB decreased by −0.915 cases per 1000 occupied bed days (95% CI −1.743 to −0.087). This effect was especially marked in CR-Klebsiella pneumoniae and CR-Escherichia coli, reversing the pre-intervention upward trend and leading to a relative reduction of −91.15% (95% CI −105.53 to −76.76) and −89.93% (95% CI −107.03 to −72.83), respectively, two years after starting the program. Death rates did not change. This ASP contributed to decreasing CR-GNB incidence through a sustained reduction in antibiotic use without increasing mortality rates. Full article

(This article belongs to the Section Antibiotics Use and Antimicrobial Stewardship)

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17 pages, 2587 KiB

Open AccessEditor’s ChoiceArticle

Apt (Adenine Phosphoribosyltransferase) Mutation in Laboratory-Selected Vancomycin-Intermediate Staphylococcus aureus

by Reena Lamichhane-Khadka, Santosh Dulal, Jesus A. Cuaron, Richard Pfeltz, Sushim Kumar Gupta, Brian J. Wilkinson and John E. Gustafson

Antibiotics 2021, 10(5), 583; https://doi.org/10.3390/antibiotics10050583 - 14 May 2021

Cited by 2 | Viewed by 3225

Abstract

Comparative genomic sequencing of laboratory-derived vancomycin-intermediate Staphylococcusaureus (VISA) (MM66-3 and MM66-4) revealed unique mutations in both MM66-3 (in apt and ssaA6), and MM66-4 (in apt and walK), compared to hetero-VISA parent strain MM66. Transcriptional profiling revealed that both MM66 VISA [...] Read more.

Comparative genomic sequencing of laboratory-derived vancomycin-intermediate Staphylococcusaureus (VISA) (MM66-3 and MM66-4) revealed unique mutations in both MM66-3 (in apt and ssaA6), and MM66-4 (in apt and walK), compared to hetero-VISA parent strain MM66. Transcriptional profiling revealed that both MM66 VISA shared 79 upregulated genes and eight downregulated genes. Of these, 30.4% of the upregulated genes were associated with the cell envelope, whereas 75% of the downregulated genes were associated with virulence. In concordance with mutations and transcriptome alterations, both VISA strains demonstrated reduced autolysis, reduced growth in the presence of salt and reduced virulence factor activity. In addition to mutations in genes linked to cell wall metabolism (ssaA6 and walK), the same mutation in apt which encodes adenine phosphoribosyltransferase, was confirmed in both MM66 VISA. Apt plays a role in both adenine metabolism and accumulation and both MM66 VISA grew better than MM66 in the presence of adenine or 2-fluoroadenine indicating a reduction in the accumulation of these growth inhibiting compounds in the VISA strains. MM66 apt mutants isolated via 2-fluoroadenine selection also demonstrated reduced susceptibility to the cell wall lytic dye Congo red and vancomycin. Finding that apt mutations contribute to reduced vancomycin susceptibility once again suggests a role for altered purine metabolism in a VISA mechanism. Full article

(This article belongs to the Section Mechanism and Evolution of Antibiotic Resistance)

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21 pages, 3769 KiB

Open AccessEditor’s ChoiceReview

Clinical Pharmacology of Bacteriophage Therapy: A Focus on Multidrug-Resistant Pseudomonas aeruginosa Infections

by Dana Holger, Razieh Kebriaei, Taylor Morrisette, Katherine Lev, Jose Alexander and Michael Rybak

Antibiotics 2021, 10(5), 556; https://doi.org/10.3390/antibiotics10050556 - 11 May 2021

Cited by 8 | Viewed by 5201

Abstract

Pseudomonas aeruginosa is one of the most common causes of healthcare-associated diseases and is among the top three priority pathogens listed by the World Health Organization (WHO). This Gram-negative pathogen is especially difficult to eradicate because it displays high intrinsic and acquired resistance [...] Read more.

Pseudomonas aeruginosa is one of the most common causes of healthcare-associated diseases and is among the top three priority pathogens listed by the World Health Organization (WHO). This Gram-negative pathogen is especially difficult to eradicate because it displays high intrinsic and acquired resistance to many antibiotics. In addition, growing concerns regarding the scarcity of antibiotics against multidrug-resistant (MDR) and extensively drug-resistant (XDR) P. aeruginosa infections necessitate alternative therapies. Bacteriophages, or phages, are viruses that target and infect bacterial cells, and they represent a promising candidate for combatting MDR infections. The aim of this review was to highlight the clinical pharmacology considerations of phage therapy, such as pharmacokinetics, formulation, and dosing, while addressing several challenges associated with phage therapeutics for MDR P. aeruginosa infections. Further studies assessing phage pharmacokinetics and pharmacodynamics will help to guide interested clinicians and phage researchers towards greater success with phage therapy for MDR P. aeruginosa infections. Full article

(This article belongs to the Section Bacteriophages)

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11 pages, 511 KiB

Open AccessEditor’s ChoiceArticle

Serious Neurological Adverse Events of Ceftriaxone

by Clémence Lacroix, Annie-Pierre Bera-Jonville, François Montastruc, Lionel Velly, Joëlle Micallef and Romain Guilhaumou

Antibiotics 2021, 10(5), 540; https://doi.org/10.3390/antibiotics10050540 - 06 May 2021

Cited by 16 | Viewed by 5645

Abstract

We described ceftriaxone-induced CNS adverse events through the largest case series of Adverse Drug Reactions (ADRs) reports, from 1995 to 2017, using the French Pharmacovigilance Database. In total, 152 cases of serious CNS ADRs were analyzed; 112 patients were hospitalized or had a [...] Read more.

We described ceftriaxone-induced CNS adverse events through the largest case series of Adverse Drug Reactions (ADRs) reports, from 1995 to 2017, using the French Pharmacovigilance Database. In total, 152 cases of serious CNS ADRs were analyzed; 112 patients were hospitalized or had a prolonged hospitalization (73.7%), 12 dead (7.9%) and 16 exhibited life-threatening ADRs (10.5%). The median age was 74.5 years, mainly women (55.3%), with a median creatinine clearance of 35 mL/min. Patients mainly exhibited convulsions, status epilepticus, myoclonia (n = 75, 49.3%), encephalopathy (n = 45, 29.6%), confused state (n = 34, 22.4%) and hallucinations (n = 16, 10.5%). The median time of onset was 4 days, and the median duration was 4.5 days. The mean daily dose was 1.7 g mainly through an intravenous route (n = 106, 69.7%), and three patients received doses above maximal dose of Summary of Product Characteristics. Ceftriaxone plasma concentrations were recorded for 19 patients (12.5%), and 8 were above the toxicity threshold. Electroencephalograms (EEG) performed for 32.9% of the patients (n = 50) were abnormal for 74% (n = 37). We described the world’s biggest case series of ceftriaxone-induced serious CNS ADRs. Explorations (plasma concentrations, EEG) are contributive to confirm the ceftriaxone toxicity-induced. Clinicians may be cautious with the use of ceftriaxone, especially in the older age or renal impairment population. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics of Drugs)

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18 pages, 4410 KiB

Open AccessEditor’s ChoiceArticle

Discovery of Pyrrolidine-2,3-diones as Novel Inhibitors of P. aeruginosa PBP3

by Arancha López-Pérez, Stefan Freischem, Immanuel Grimm, Oliver Weiergräber, Andrew J. Dingley, María Pascual López-Alberca, Herbert Waldmann, Waldemar Vollmer, Kamal Kumar and Cuong Vuong

Antibiotics 2021, 10(5), 529; https://doi.org/10.3390/antibiotics10050529 - 04 May 2021

Cited by 11 | Viewed by 3850

Abstract

The alarming threat of the spread of multidrug resistant bacteria currently leaves clinicians with very limited options to combat infections, especially those from Gram-negative bacteria. Hence, innovative strategies to deliver the next generation of antibacterials are urgently needed. Penicillin binding proteins (PBPs) are [...] Read more.

The alarming threat of the spread of multidrug resistant bacteria currently leaves clinicians with very limited options to combat infections, especially those from Gram-negative bacteria. Hence, innovative strategies to deliver the next generation of antibacterials are urgently needed. Penicillin binding proteins (PBPs) are proven targets inhibited by β-lactam antibiotics. To discover novel, non-β-lactam inhibitors against PBP3 of Pseudomonas aeruginosa, we optimised a fluorescence assay based on a well-known thioester artificial substrate and performed a target screening using a focused protease-targeted library of 2455 compounds, which led to the identification of pyrrolidine-2,3-dione as a potential scaffold to inhibit the PBP3 target. Further chemical optimisation using a one-pot three-component reaction protocol delivered compounds with excellent target inhibition, initial antibacterial activities against P. aeruginosa and no apparent cytotoxicity. Our investigation revealed the key structural features; for instance, 3-hydroxyl group (R²) and a heteroaryl group (R¹) appended to the N-pyrroldine-2,3-dione via methylene linker required for target inhibition. Overall, the discovery of the pyrrolidine-2,3-dione class of inhibitors of PBP3 brings opportunities to target multidrug-resistant bacterial strains and calls for further optimisation to improve antibacterial activity against P. aeruginosa. Full article

(This article belongs to the Special Issue New Potent Antibacterial Agents)

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8 pages, 257 KiB

Open AccessEditor’s ChoicePerspective

Should the Increased Awareness of the One Health Approach Brought by the COVID-19 Pandemic Be Used to Further Tackle the Challenge of Antimicrobial Resistance?

by Mohamed Rhouma, Michelle Tessier, Cécile Aenishaenslin, Pascal Sanders and Hélène Carabin

Antibiotics 2021, 10(4), 464; https://doi.org/10.3390/antibiotics10040464 - 20 Apr 2021

Cited by 12 | Viewed by 3979

Abstract

Several experts have expressed their concerns regarding the potential increase in antimicrobial resistance (AMR) during the COVID-19 pandemic as a consequence of the increase in antimicrobial and biocide use in humans globally. However, the impact of the pandemic on antimicrobial use (AMU) and [...] Read more.

Several experts have expressed their concerns regarding the potential increase in antimicrobial resistance (AMR) during the COVID-19 pandemic as a consequence of the increase in antimicrobial and biocide use in humans globally. However, the impact of the pandemic on antimicrobial use (AMU) and AMR in animals has yet to be discussed and evaluated. Indeed, veterinary practices have been hugely impacted by the pandemic and its restrictive measures around the world. In this perspective, we call for more research to estimate the impact of COVID-19 on AMU and AMR in both humans and animals, as well as on the environment, in coherence with the One Health approach. In addition, we argue that the current pandemic is an opportunity to accelerate the implementation of a One Health approach to tackle the AMR crisis at the global scale. Indeed, the momentum created by the increased general awareness of both the public and decision-makers for the development and maintenance of effective drugs to treat human infections, as well as for the importance of a One Health approach to prevent the emergence of infectious diseases, should be used as a lever to implement global collaborative and sustainable solutions to the complex challenges of AMR. Full article

(This article belongs to the Special Issue Antibiotic Resistance: A One-Health Approach)

25 pages, 909 KiB

Open AccessEditor’s ChoiceReview

Mechanisms of Antibiotic Resistance in Important Gram-Positive and Gram-Negative Pathogens and Novel Antibiotic Solutions

by Loukas Kakoullis, Eleni Papachristodoulou, Paraskevi Chra and George Panos

Antibiotics 2021, 10(4), 415; https://doi.org/10.3390/antibiotics10040415 - 10 Apr 2021

Cited by 84 | Viewed by 25386

Abstract

Multidrug-resistant bacteria have on overwhelming impact on human health, as they cause over 670,000 infections and 33,000 deaths annually in the European Union alone. Of these, the vast majority of infections and deaths are caused by only a handful of species—multi-drug resistant Escherichia [...] Read more.

Multidrug-resistant bacteria have on overwhelming impact on human health, as they cause over 670,000 infections and 33,000 deaths annually in the European Union alone. Of these, the vast majority of infections and deaths are caused by only a handful of species—multi-drug resistant Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus spp., Acinetobacter spp. and Klebsiella pneumoniae. These pathogens employ a multitude of antibiotic resistance mechanisms, such as the production of antibiotic deactivating enzymes, changes in antibiotic targets, or a reduction of intracellular antibiotic concentration, which render them insusceptible to multiple antibiotics. The purpose of this review is to summarize in a clinical manner the resistance mechanisms of each of these 6 pathogens, as well as the mechanisms of recently developed antibiotics designed to overcome them. Through a basic understanding of the mechanisms of antibiotic resistance, the clinician can better comprehend and predict resistance patterns even to antibiotics not reported on the antibiogram and can subsequently select the most appropriate antibiotic for the pathogen in question. Full article

(This article belongs to the Special Issue Clinical Approach to Antibiotic Resistance: The Definitive Issue)

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16 pages, 1781 KiB

Open AccessEditor’s ChoiceArticle

Overview and Evaluation of Existing Guidelines for Rational Antimicrobial Use in Small-Animal Veterinary Practice in Europe

by Fergus Allerton, Cameron Prior, Arzu Funda Bagcigil, Els Broens, Bénédicte Callens, Peter Damborg, Jeroen Dewulf, Maria-Eleni Filippitzi, Luís Pedro Carmo, Jonathan Gómez-Raja, Erez Harpaz, Ana Mateus, Mirja Nolff, Clare J. Phythian, Dorina Timofte, Flavia Zendri and Lisbeth Rem Jessen

Antibiotics 2021, 10(4), 409; https://doi.org/10.3390/antibiotics10040409 - 09 Apr 2021

Cited by 26 | Viewed by 7254

Abstract

Antimicrobial stewardship guidelines (ASGs) represent an important tool to help veterinarians optimize their antimicrobial use with the objective of decreasing antimicrobial resistance. The aim of this study was to map and qualitatively assess the ASGs for antimicrobial use in cats and dogs in [...] Read more.

Antimicrobial stewardship guidelines (ASGs) represent an important tool to help veterinarians optimize their antimicrobial use with the objective of decreasing antimicrobial resistance. The aim of this study was to map and qualitatively assess the ASGs for antimicrobial use in cats and dogs in Europe. Country representatives of the European Network for Optimization of Veterinary Antimicrobial Treatment (ENOVAT) were asked to identify ASGs published in their countries. All collated ASGs updated since January 2010 containing recommendations on antimicrobial therapy for at least three conditions affecting different organ systems in cats and dogs underwent detailed review including AGREE II analysis. Out of forty countries investigated, fifteen ASGs from eleven countries met the inclusion criteria. Several critical principles of antimicrobial use were identified, providing a framework that should assist development of stewardship guidance. The AGREE II analysis highlighted several methodological limitations of the currently available ASGs. This study sheds light on the lack of national ASGs for dogs and cats in multiple European countries and should encourage national bodies to prioritize guideline development in small animals. A greater awareness of the need to use a structured approach to guideline development could improve the quality of ASGs in the future. Full article

(This article belongs to the Special Issue Antimicrobial Stewardship in Veterinary Medicine)

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16 pages, 3642 KiB

Open AccessEditor’s ChoiceArticle

Biosynthesis and Heterologous Expression of Cacaoidin, the First Member of the Lanthidin Family of RiPPs

by Fernando Román-Hurtado, Marina Sánchez-Hidalgo, Jesús Martín, Francisco Javier Ortiz-López and Olga Genilloud

Antibiotics 2021, 10(4), 403; https://doi.org/10.3390/antibiotics10040403 - 08 Apr 2021

Cited by 19 | Viewed by 4370

Abstract

Cacaoidin is produced by the strain Streptomyces cacaoi CA-170360 and represents the first member of the new lanthidin (class V lanthipeptides) RiPP family. In this work, we describe the complete identification, cloning and heterologous expression of the cacaoidin biosynthetic gene cluster, which shows [...] Read more.

Cacaoidin is produced by the strain Streptomyces cacaoi CA-170360 and represents the first member of the new lanthidin (class V lanthipeptides) RiPP family. In this work, we describe the complete identification, cloning and heterologous expression of the cacaoidin biosynthetic gene cluster, which shows unique RiPP genes whose functions were not predicted by any bioinformatic tool. We also describe that the cacaoidin pathway is restricted to strains of the subspecies Streptomyces cacaoi subsp. cacaoi found in public genome databases, where we have also identified the presence of other putative class V lanthipeptide pathways. This is the first report on the heterologous production of a class V lanthipeptide. Full article

(This article belongs to the Special Issue Discovery and Biosynthesis of Novel Antibiotic from Streptomyces)

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14 pages, 1820 KiB

Open AccessEditor’s ChoiceArticle

Novel Soil-Derived Beta-Lactam, Chloramphenicol, Fosfomycin and Trimethoprim Resistance Genes Revealed by Functional Metagenomics

by Inka Marie Willms, Maja Grote, Melissa Kocatürk, Lukas Singhoff, Alina Andrea Kraft, Simon Henning Bolz and Heiko Nacke

Antibiotics 2021, 10(4), 378; https://doi.org/10.3390/antibiotics10040378 - 03 Apr 2021

Cited by 4 | Viewed by 3018

Abstract

Antibiotic resistance genes (ARGs) in soil are considered to represent one of the largest environmental resistomes on our planet. As these genes can potentially be disseminated among microorganisms via horizontal gene transfer (HGT) and in some cases are acquired by clinical pathogens, knowledge [...] Read more.

Antibiotic resistance genes (ARGs) in soil are considered to represent one of the largest environmental resistomes on our planet. As these genes can potentially be disseminated among microorganisms via horizontal gene transfer (HGT) and in some cases are acquired by clinical pathogens, knowledge about their diversity, mobility and encoded resistance spectra gained increasing public attention. This knowledge offers opportunities with respect to improved risk prediction and development of strategies to tackle antibiotic resistance, and might help to direct the design of novel antibiotics, before further resistances reach hospital settings or the animal sector. Here, metagenomic libraries, which comprise genes of cultivated microorganisms, but, importantly, also those carried by the uncultured microbial majority, were screened for novel ARGs from forest and grassland soils. We detected three new beta-lactam, a so far unknown chloramphenicol, a novel fosfomycin, as well as three previously undiscovered trimethoprim resistance genes. These ARGs were derived from phylogenetically diverse soil bacteria and predicted to encode antibiotic inactivation, antibiotic efflux, or alternative variants of target enzymes. Moreover, deduced gene products show a minimum identity of ~21% to reference database entries and confer high-level resistance. This highlights the vast potential of functional metagenomics for the discovery of novel ARGs from soil ecosystems. Full article

(This article belongs to the Special Issue The Distribution of Antibiotic Resistance in Terrestrial Ecosystems)

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12 pages, 1846 KiB

Open AccessEditor’s ChoiceArticle

In Vitro Synergistic Interactions of Isavuconazole and Echinocandins against Candida auris

by Unai Caballero, Sarah Kim, Elena Eraso, Guillermo Quindós, Valvanera Vozmediano, Stephan Schmidt and Nerea Jauregizar

Antibiotics 2021, 10(4), 355; https://doi.org/10.3390/antibiotics10040355 - 28 Mar 2021

Cited by 22 | Viewed by 3352

Abstract

Candida auris is an emergent fungal pathogen that causes severe infectious outbreaks globally. The public health concern when dealing with this pathogen is mainly due to reduced susceptibility to current antifungal drugs. A valuable alternative to overcome this problem is to investigate the [...] Read more.

Candida auris is an emergent fungal pathogen that causes severe infectious outbreaks globally. The public health concern when dealing with this pathogen is mainly due to reduced susceptibility to current antifungal drugs. A valuable alternative to overcome this problem is to investigate the efficacy of combination therapy. The aim of this study was to determine the in vitro interactions of isavuconazole with echinocandins against C. auris. Interactions were determined using a checkerboard method, and absorbance data were analyzed with different approaches: the fractional inhibitory concentration index (FICI), Greco universal response surface approach, and Bliss interaction model. All models were in accordance and showed that combinations of isavuconazole with echinocandins resulted in an overall synergistic interaction. A wide range of concentrations within the therapeutic range were selected to perform time-kill curves. These confirmed that isavuconazole–echinocandin combinations were more effective than monotherapy regimens. Synergism and fungistatic activity were achieved with combinations that included isavuconazole in low concentrations (≥0.125 mg/L) and ≥1 mg/L of echinocandin. Time-kill curves revealed that once synergy was achieved, combinations of higher drug concentrations did not improve the antifungal activity. This work launches promising results regarding the combination of isavuconazole with echinocandins for the treatment of C. auris infections. Full article

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28 pages, 2027 KiB

Open AccessEditor’s ChoiceArticle

Antimicrobial Resistance Profile and ExPEC Virulence Potential in Commensal Escherichia coli of Multiple Sources

by Elisa Massella, Federica Giacometti, Paolo Bonilauri, Cameron J. Reid, Steven P. Djordjevic, Giuseppe Merialdi, Cristina Bacci, Laura Fiorentini, Paola Massi, Lia Bardasi, Silva Rubini, Federica Savini, Andrea Serraino and Silvia Piva

Antibiotics 2021, 10(4), 351; https://doi.org/10.3390/antibiotics10040351 - 26 Mar 2021

Cited by 31 | Viewed by 4776

Abstract

We recently described the genetic antimicrobial resistance and virulence profile of a collection of 279 commensal E. coli of food-producing animal (FPA), pet, wildlife and human origin. Phenotypic antimicrobial resistance (AMR) and the role of commensal E. coli as reservoir of extra-intestinal pathogenic [...] Read more.

We recently described the genetic antimicrobial resistance and virulence profile of a collection of 279 commensal E. coli of food-producing animal (FPA), pet, wildlife and human origin. Phenotypic antimicrobial resistance (AMR) and the role of commensal E. coli as reservoir of extra-intestinal pathogenic Escherichia coli (ExPEC) virulence-associated genes (VAGs) or as potential ExPEC pathogens were evaluated. The most common phenotypic resistance was to tetracycline (76/279, 27.24%), sulfamethoxazole/trimethoprim (73/279, 26.16%), streptomycin and sulfisoxazole (71/279, 25.45% both) among the overall collection. Poultry and rabbit were the sources mostly associated to AMR, with a significant resistance rate (p > 0.01) to quinolones, streptomycin, sulphonamides, tetracycline and, only for poultry, to ampicillin and chloramphenicol. Finally, rabbit was the source mostly associated to colistin resistance. Different pandemic (ST69/69*, ST95, ST131) and emerging (ST10/ST10*, ST23, ST58, ST117, ST405, ST648) ExPEC sequence types (STs) were identified among the collection, especially in poultry source. Both ST groups carried high number of ExPEC VAGs (pandemic ExPEC STs, mean = 8.92; emerging ExPEC STs, mean = 6.43) and showed phenotypic resistance to different antimicrobials (pandemic ExPEC STs, mean = 2.23; emerging ExPEC STs, mean = 2.43), suggesting their role as potential ExPEC pathogens. Variable phenotypic resistance and ExPEC VAG distribution was also observed in uncommon ExPEC lineages, suggesting commensal flora as a potential reservoir of virulence (mean = 3.80) and antimicrobial resistance (mean = 1.69) determinants. Full article

(This article belongs to the Special Issue Antimicrobial Resistance: From Farm to Fork)

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12 pages, 1375 KiB

Open AccessEditor’s ChoiceArticle

Novel Seleno- and Thio-Urea Containing Dihydropyrrol-2-One Analogues as Antibacterial Agents

by Shekh Sabir, Tsz Tin Yu, Rajesh Kuppusamy, Basmah Almohaywi, George Iskander, Theerthankar Das, Mark D. P. Willcox, David StClair Black and Naresh Kumar

Antibiotics 2021, 10(3), 321; https://doi.org/10.3390/antibiotics10030321 - 19 Mar 2021

Cited by 12 | Viewed by 3057

Abstract

The quorum sensing (QS) system in multi-drug-resistant bacteria such as P. aeruginosa is primarily responsible for the development of antibiotic resistance and is considered an attractive target for antimicrobial drug discovery. In this study, we synthesised a series of novel selenourea and thiourea-containing [...] Read more.

The quorum sensing (QS) system in multi-drug-resistant bacteria such as P. aeruginosa is primarily responsible for the development of antibiotic resistance and is considered an attractive target for antimicrobial drug discovery. In this study, we synthesised a series of novel selenourea and thiourea-containing dihydropyrrol-2-one (DHP) analogues as LasR antagonists. The selenium DHP derivatives displayed significantly better quorum-sensing inhibition (QSI) activities than the corresponding sulphur analogues. The most potent analogue 3e efficiently inhibited the las QS system by 81% at 125 µM and 53% at 31 µM. Additionally, all the compounds were screened for their minimum inhibitory concentration (MIC) against the Gram-positive bacterium S. aureus, and interestingly, only the selenium analogues showed antibacterial activity, with 3c and 3e being the most potent with a MIC of 15.6 µM. Full article

(This article belongs to the Special Issue Selenium, Metals and Trace Elements in Novel Antimicrobial Compounds)

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13 pages, 3967 KiB

Open AccessEditor’s ChoiceArticle

Transmission of Similar Mcr-1 Carrying Plasmids among Different Escherichia coli Lineages Isolated from Livestock and the Farmer

by Joaquim Viñes, Anna Cuscó, Sebastian Napp, Julio Alvarez, Jose Luis Saez-Llorente, Montserrat Rosàs-Rodoreda, Olga Francino and Lourdes Migura-Garcia

Antibiotics 2021, 10(3), 313; https://doi.org/10.3390/antibiotics10030313 - 17 Mar 2021

Cited by 25 | Viewed by 4499

Abstract

Colistin use has mostly been stopped in human medicine, due to its toxicity. However, nowadays, it still is used as a last-resort antibiotic to treat hospital infections caused by multi-drug resistant Enterobacteriaceae. On the contrary, colistin has been used in veterinary medicine until [...] Read more.

Colistin use has mostly been stopped in human medicine, due to its toxicity. However, nowadays, it still is used as a last-resort antibiotic to treat hospital infections caused by multi-drug resistant Enterobacteriaceae. On the contrary, colistin has been used in veterinary medicine until recently. In this study, 210 fecal samples from pigs (n = 57), calves (n = 152), and the farmer (n = 1) were collected from a farm where E. coli harboring mcr-1–mcr-3 was previously detected. Samples were plated, and mcr-genes presence was confirmed by multiplex-PCR. Hybrid sequencing which determined the presence and location of mcr-1, other antibiotic resistance genes, and virulence factors. Eighteen colistin resistant isolates (13 from calves, four from pigs, and one from the farmer) contained mcr-1 associated with plasmids (IncX4, IncI2, and IncHI2), except for two that yielded mcr-1 in the chromosome. Similar plasmids were distributed in different E. coli lineages. Transmission of mcr-1 to the farmer most likely occurred by horizontal gene transfer from E. coli of calf origin, since plasmids were highly similar (99% coverage, 99.97% identity). Moreover, 33 virulence factors, including stx2 for Shiga toxin E. coli (STEC) were detected, highlighting the role of livestock as a reservoir of pathotypes with zoonotic potential. Full article

(This article belongs to the Special Issue Multidrug-Resistant Bacteria in Animals)

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12 pages, 1163 KiB

Open AccessEditor’s ChoiceArticle

Occurrence and Antimicrobial Resistance of Arcobacter spp. Recovered from Aquatic Environments

by Sonia Sciortino, Pietro Arculeo, Vincenzina Alio, Cinzia Cardamone, Luisa Nicastro, Marco Arculeo, Rosa Alduina and Antonella Costa

Antibiotics 2021, 10(3), 288; https://doi.org/10.3390/antibiotics10030288 - 10 Mar 2021

Cited by 26 | Viewed by 3052

Abstract

Arcobacter spp. are emerging waterborne and foodborne zoonotic pathogens responsible for gastroenteritis in humans. In this work, we evaluated the occurrence and the antimicrobial resistance profile of Arcobacter isolates recovered from different aquatic sources. Besides, we searched for Arcobacter spp. in seaweeds and [...] Read more.

Arcobacter spp. are emerging waterborne and foodborne zoonotic pathogens responsible for gastroenteritis in humans. In this work, we evaluated the occurrence and the antimicrobial resistance profile of Arcobacter isolates recovered from different aquatic sources. Besides, we searched for Arcobacter spp. in seaweeds and the corresponding seawater samples. Bacteriological and molecular methods applied to 100 samples led to the isolation of 28 Arcobacter isolates from 27 samples. The highest prevalence was detected in rivers followed by artificial ponds, streams, well waters, and spring waters. Seaweeds contained a higher percentage of Arcobacter than the corresponding seawater samples. The isolates were identified as Arcobacter butzleri (96.4%) and Arcobacter cryaerophilus (3.6%). All the isolates showed a multi-drug resistance profile, being resistant to at least three different classes of antibiotics. Molecular analysis of genetic determinants responsible for tetracycline resistance in nine randomly chosen isolates revealed the presence of tetO and/or tetW. This work confirms the occurrence and the continuous emergence of antibiotic-resistant Arcobacter strains in environmental samples; also, the presence of quinolone-resistant Arcobacter spp. in aquatic sources used for water supply and irrigation represents a potential risk for human health. Full article

(This article belongs to the Special Issue Antibiotics and Antibiotic Resistance in Aquatic Environments)

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15 pages, 1682 KiB

Open AccessEditor’s ChoiceArticle

Allium Extract Implements Weaned Piglet’s Productive Parameters by Modulating Distal Gut Microbiota

by Miguel Rabelo-Ruiz, Claudia Teso-Pérez, Juan Manuel Peralta-Sánchez, Juan José Ariza, Antonio Manuel Martín-Platero, Óscar Casabuena-Rincón, Patricia Vázquez-Chas, Enrique Guillamón, María Arántzazu Aguinaga-Casañas, Mercedes Maqueda, Eva Valdivia, Alberto Baños and Manuel Martínez-Bueno

Antibiotics 2021, 10(3), 269; https://doi.org/10.3390/antibiotics10030269 - 08 Mar 2021

Cited by 15 | Viewed by 3110

Abstract

Antimicrobial resistance (AMR) has risen as a global threat for human health. One of the leading factors for this emergence has been the massive use of antibiotics growth-promoter (AGPs) in livestock, enhancing the spread of AMR among human pathogenic bacteria. Thus, several alternatives [...] Read more.

Antimicrobial resistance (AMR) has risen as a global threat for human health. One of the leading factors for this emergence has been the massive use of antibiotics growth-promoter (AGPs) in livestock, enhancing the spread of AMR among human pathogenic bacteria. Thus, several alternatives such as probiotics, prebiotics, or phytobiotics have been proposed for using in animal feeding to maintain or improve productive levels while diminishing the negative effects of AGPs. Reducing the use of antibiotics is a key aspect in the pig rearing for production reasons, as well as for the production of high-quality pork, acceptable to consumers. Here we analyze the potential use of Allium extract as an alternative. In this study, weaned piglets were fed with Allium extract supplementation and compared with control and antibiotic (colistin and zinc oxide) treated piglets. The effects of Allium extract were tested by analyzing the gut microbiome and measuring different productive parameters. Alpha diversity indices decreased significantly in Allium extract group in caecum and colon. Regarding beta diversity, significant differences between treatments appeared only in caecum and colon. Allium extract and antibiotic piglets showed better values of body weight (BW), average daily weight gain (ADG), and feed conversion ratio (FCR) than control group. These results indicate that productive parameters can be implemented by modifying the gut microbiota through phytobiotics such as Allium extract, which will drive to drop the use of antibiotics in piglet diet. Full article

(This article belongs to the Special Issue Alternatives to Clinical Antimicrobials for Animal Production)

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10 pages, 900 KiB

Open AccessEditor’s ChoiceArticle

Increase in Tuberculosis Diagnostic Delay during First Wave of the COVID-19 Pandemic: Data from an Italian Infectious Disease Referral Hospital

by Francesco Di Gennaro, Gina Gualano, Laura Timelli, Pietro Vittozzi, Virginia Di Bari, Raffaella Libertone, Carlotta Cerva, Luigi Pinnarelli, Carla Nisii, Stefania Ianniello, Silvia Mosti, Nazario Bevilacqua, Fabio Iacomi, Annalisa Mondi, Simone Topino, Delia Goletti, Francesco Vaia, Giuseppe Ippolito, Enrico Girardi and Fabrizio Palmieri

Antibiotics 2021, 10(3), 272; https://doi.org/10.3390/antibiotics10030272 - 08 Mar 2021

Cited by 61 | Viewed by 4648

Abstract

Background: The WHO advised that the impact of COVID-19 pandemic on TB services was estimated to be dramatic due to the disruption of TB services. Methods: A retrospective data collection and evaluation was conducted to include all the patients hospitalized for TB at [...] Read more.

Background: The WHO advised that the impact of COVID-19 pandemic on TB services was estimated to be dramatic due to the disruption of TB services. Methods: A retrospective data collection and evaluation was conducted to include all the patients hospitalized for TB at INMI from 9 March to 31 August 2020 (lockdown period and three months thereafter). For the purpose of the study, data from patients hospitalized in the same period of 2019 were also collected. Results: In the period of March–August 2019, 201 patients were hospitalized with a diagnosis of TB, while in the same period of 2020, only 115 patients, with a case reduction of 43%. Patients with weight loss, acute respiratory failure, concurrent extrapulmonary TB, and higher Timika radiographic scores were significantly more frequently hospitalized during 2020 vs. 2019. The median patient delay was 75 days (IQR: 40–100) in 2020 compared to 30 days (IQR: 10–60) in 2019 (p < 0.01). Diagnostic delays in 2020 remain significant in the multiple logistic model (AOR = 6.93, 95%CI: 3.9–12.3). Conclusions: Our experience suggests that COVID-19 pandemic had an impact on TB patient care in terms of higher diagnostic delay, reduction in hospitalization, and a greater severity of clinical presentations. Full article

(This article belongs to the Special Issue Antimicrobial Resistance of Mycobacterium Tuberculosis: Old and New Drugs)

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14 pages, 801 KiB

Open AccessEditor’s ChoiceArticle

Antibiotic Resistant Bloodstream Infections in Pediatric Patients Receiving Chemotherapy or Hematopoietic Stem Cell Transplant: Factors Associated with Development of Resistance, Intensive Care Admission and Mortality

by Elio Castagnola, Francesca Bagnasco, Alessio Mesini, Philipp K. A. Agyeman, Roland A. Ammann, Fabianne Carlesse, Maria Elena Santolaya de Pablo, Andreas H. Groll, Gabrielle M. Haeusler, Thomas Lehrnbecher, Arne Simon, Maria Rosaria D’Amico, Austin Duong, Evgeny A. Idelevich, Marie Luckowitsch, Mariaclaudia Meli, Giuseppe Menna, Sasha Palmert, Giovanna Russo, Marco Sarno, Galina Solopova, Annalisa Tondo, Yona Traubici and Lillian Sung Show full author list Hide full author list

Antibiotics 2021, 10(3), 266; https://doi.org/10.3390/antibiotics10030266 - 05 Mar 2021

Cited by 24 | Viewed by 3026

Abstract

Bloodstream infections (BSI) are a severe complication of antineoplastic chemotherapy or hematopoietic stem cell transplantation (HSCT), especially in the presence of antibiotic resistance (AR). A multinational, multicenter retrospective study in patients aged ≤ 18 years, treated with chemotherapy or HSCT from 2015 to [...] Read more.

Bloodstream infections (BSI) are a severe complication of antineoplastic chemotherapy or hematopoietic stem cell transplantation (HSCT), especially in the presence of antibiotic resistance (AR). A multinational, multicenter retrospective study in patients aged ≤ 18 years, treated with chemotherapy or HSCT from 2015 to 2017 was implemented to analyze AR among non-common skin commensals BSI. Risk factors associated with AR, intensive care unit (ICU) admission and mortality were analyzed by multilevel mixed effects or standard logistic regressions. A total of 1291 BSIs with 1379 strains were reported in 1031 patients. Among Gram-negatives more than 20% were resistant to ceftazidime, cefepime, piperacillin-tazobactam and ciprofloxacin while 9% was resistant to meropenem. Methicillin-resistance was observed in 17% of S. aureus and vancomycin resistance in 40% of E. faecium. Previous exposure to antibiotics, especially to carbapenems, was significantly associated with resistant Gram-negative BSI while previous colonization with methicillin-resistant S. aureus was associated with BSI due to this pathogen. Hematological malignancies, neutropenia and Gram-negatives resistant to >3 antibiotics were significantly associated with higher risk of ICU admission. Underlying disease in relapse/progression, previous exposure to antibiotics, and need of ICU admission were significantly associated with mortality. Center-level variation showed a greater impact on AR, while patient-level variation had more effect on ICU admission and mortality. Previous exposure to antibiotics or colonization by resistant pathogens can be the cause of AR BSI. Resistant Gram-negatives are significantly associated with ICU admission and mortality, with a significant role for the treating center too. The significant evidence of center-level variations on AR, ICU admission and mortality, stress the need for careful local antibiotic stewardship and infection control programs. Full article

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34 pages, 6192 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Fiber–Hydrogel Composites for Wound Healing and Drug Delivery Systems

by Marta O. Teixeira, Joana C. Antunes and Helena P. Felgueiras

Antibiotics 2021, 10(3), 248; https://doi.org/10.3390/antibiotics10030248 - 02 Mar 2021

Cited by 33 | Viewed by 6215

Abstract

In the last decades, much research has been done to fasten wound healing and target-direct drug delivery. Hydrogel-based scaffolds have been a recurrent solution in both cases, with some reaching already the market, even though their mechanical stability remains a challenge. To overcome [...] Read more.

In the last decades, much research has been done to fasten wound healing and target-direct drug delivery. Hydrogel-based scaffolds have been a recurrent solution in both cases, with some reaching already the market, even though their mechanical stability remains a challenge. To overcome this limitation, reinforcement of hydrogels with fibers has been explored. The structural resemblance of fiber–hydrogel composites to natural tissues has been a driving force for the optimization and exploration of these systems in biomedicine. Indeed, the combination of hydrogel-forming techniques and fiber spinning approaches has been crucial in the development of scaffolding systems with improved mechanical strength and medicinal properties. In this review, a comprehensive overview of the recently developed fiber–hydrogel composite strategies for wound healing and drug delivery is provided. The methodologies employed in fiber and hydrogel formation are also highlighted, together with the most compatible polymer combinations, as well as drug incorporation approaches creating stimuli-sensitive and triggered drug release towards an enhanced host response. Full article

(This article belongs to the Special Issue New Biomolecules and Drug Delivery Systems as Alternatives to Conventional Antibiotics)

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30 pages, 1054 KiB

Open AccessEditor’s ChoiceReview

Rapid Methods for Antimicrobial Resistance Diagnostics

by Georgia D. Kaprou, Ieva Bergšpica, Elena A. Alexa, Avelino Alvarez-Ordóñez and Miguel Prieto

Antibiotics 2021, 10(2), 209; https://doi.org/10.3390/antibiotics10020209 - 20 Feb 2021

Cited by 54 | Viewed by 15326

Abstract

Antimicrobial resistance (AMR) is one of the most challenging threats in public health; thus, there is a growing demand for methods and technologies that enable rapid antimicrobial susceptibility testing (AST). The conventional methods and technologies addressing AMR diagnostics and AST employed in clinical [...] Read more.

Antimicrobial resistance (AMR) is one of the most challenging threats in public health; thus, there is a growing demand for methods and technologies that enable rapid antimicrobial susceptibility testing (AST). The conventional methods and technologies addressing AMR diagnostics and AST employed in clinical microbiology are tedious, with high turnaround times (TAT), and are usually expensive. As a result, empirical antimicrobial therapies are prescribed leading to AMR spread, which in turn causes higher mortality rates and increased healthcare costs. This review describes the developments in current cutting-edge methods and technologies, organized by key enabling research domains, towards fighting the looming AMR menace by employing recent advances in AMR diagnostic tools. First, we summarize the conventional methods addressing AMR detection, surveillance, and AST. Thereafter, we examine more recent non-conventional methods and the advancements in each field, including whole genome sequencing (WGS), matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) spectrometry, Fourier transform infrared (FTIR) spectroscopy, and microfluidics technology. Following, we provide examples of commercially available diagnostic platforms for AST. Finally, perspectives on the implementation of emerging concepts towards developing paradigm-changing technologies and methodologies for AMR diagnostics are discussed. Full article

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10 pages, 609 KiB

Open AccessEditor’s ChoiceArticle

Impact of the COVID-19 Pandemic on Antibiotic Prescribing for Common Infections in The Netherlands: A Primary Care-Based Observational Cohort Study

by Alma C. van de Pol, Josi A. Boeijen, Roderick P. Venekamp, Tamara Platteel, Roger A. M. J. Damoiseaux, Marlous F. Kortekaas and Alike W. van der Velden

Antibiotics 2021, 10(2), 196; https://doi.org/10.3390/antibiotics10020196 - 18 Feb 2021

Cited by 47 | Viewed by 4480

Abstract

In 2020, the COVID-19 pandemic brought dramatic changes in the delivery of primary health care across the world, presumably changing the number of consultations for infectious diseases and antibiotic use. We aimed to assess the impact of the pandemic on infections and antibiotic [...] Read more.

In 2020, the COVID-19 pandemic brought dramatic changes in the delivery of primary health care across the world, presumably changing the number of consultations for infectious diseases and antibiotic use. We aimed to assess the impact of the pandemic on infections and antibiotic prescribing in Dutch primary care. All patients included in the routine health care database of the Julius General Practitioners’ Network were followed from March through May 2019 (n = 389,708) and March through May 2020 (n = 405,688). We extracted data on consultations for respiratory/ear, urinary tract, gastrointestinal and skin infections using the International Classification of Primary Care (ICPC) codes. These consultations were combined in disease episodes and linked to antibiotic prescriptions. The numbers of infectious disease episodes (total and those treated with antibiotics), complications, and antibiotic prescription rates (i.e., proportion of episodes treated with antibiotics) were calculated and compared between the study periods in 2019 and 2020. Fewer episodes were observed during the pandemic months than in the same months in 2019 for both the four infectious disease entities and complications such as pneumonia, mastoiditis and pyelonephritis. The largest decline was seen for gastrointestinal infections (relative risk (RR), 0.54; confidence interval (CI), 0.51 to 0.58) and skin infections (RR, 0.71; CI, 0.67 to 0.75). The number of episodes treated with antibiotics declined as well, with the largest decrease seen for respiratory/ear infections (RR, 0.54; CI, 0.52 to 0.58). The antibiotic prescription rate for respiratory/ear infections declined from 21% to 13% (difference −8.0% (CI, −8.8 to −7.2)), yet the prescription rates for other infectious disease entities remained similar or increased slightly. The decreases in primary care infectious disease episodes and antibiotic use were most pronounced in weeks 15–19, mid-COVID-19 wave, after an initial peak in respiratory/ear infection presentation in week 11, the first week of lock-down. In conclusion, our findings indicate that the COVID-19 pandemic has had profound effects on the presentation of infectious disease episodes and antibiotic use in primary care in the Netherlands. Consequently, the number of infectious disease episodes treated with antibiotics decreased. We found no evidence of an increase in complications. Full article

(This article belongs to the Section Antibiotics Use and Antimicrobial Stewardship)

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21 pages, 1459 KiB

Open AccessEditor’s ChoiceReview

Bacteriophage-Derived Depolymerases against Bacterial Biofilm

by Gracja Topka-Bielecka, Aleksandra Dydecka, Agnieszka Necel, Sylwia Bloch, Bożena Nejman-Faleńczyk, Grzegorz Węgrzyn and Alicja Węgrzyn

Antibiotics 2021, 10(2), 175; https://doi.org/10.3390/antibiotics10020175 - 10 Feb 2021

Cited by 44 | Viewed by 7011

Abstract

In addition to specific antibiotic resistance, the formation of bacterial biofilm causes another level of complications in attempts to eradicate pathogenic or harmful bacteria, including difficult penetration of drugs through biofilm structures to bacterial cells, impairment of immunological response of the host, and [...] Read more.

In addition to specific antibiotic resistance, the formation of bacterial biofilm causes another level of complications in attempts to eradicate pathogenic or harmful bacteria, including difficult penetration of drugs through biofilm structures to bacterial cells, impairment of immunological response of the host, and accumulation of various bioactive compounds (enzymes and others) affecting host physiology and changing local pH values, which further influence various biological functions. In this review article, we provide an overview on the formation of bacterial biofilm and its properties, and then we focus on the possible use of phage-derived depolymerases to combat bacterial cells included in this complex structure. On the basis of the literature review, we conclude that, although these bacteriophage-encoded enzymes may be effective in destroying specific compounds involved in the formation of biofilm, they are rarely sufficient to eradicate all bacterial cells. Nevertheless, a combined therapy, employing depolymerases together with antibiotics and/or other antibacterial agents or factors, may provide an effective approach to treat infections caused by bacteria able to form biofilms. Full article

(This article belongs to the Special Issue Bacteriolysins and Other Phage-Based Strategies to Combat Bacterial Infections)

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9 pages, 1533 KiB

Open AccessEditor’s ChoicePerspective

Controversy about the Role of Rifampin in Biofilm Infections: Is It Justified?

by Nora Renz, Andrej Trampuz and Werner Zimmerli

Antibiotics 2021, 10(2), 165; https://doi.org/10.3390/antibiotics10020165 - 05 Feb 2021

Cited by 21 | Viewed by 4514

Abstract

Rifampin is a potent antibiotic against staphylococcal implant-associated infections. In the absence of implants, current data suggest against the use of rifampin combinations. In the past decades, abundant preclinical and clinical evidence has accumulated supporting its role in biofilm-related infections.In the present article, [...] Read more.

Rifampin is a potent antibiotic against staphylococcal implant-associated infections. In the absence of implants, current data suggest against the use of rifampin combinations. In the past decades, abundant preclinical and clinical evidence has accumulated supporting its role in biofilm-related infections.In the present article, experimental data from animal models of foreign-body infections and clinical trials are reviewed. The risk for emergence of rifampin resistance and multiple drug interactions are emphasized. A recent randomized controlled trial (RCT) showing no beneficial effect of rifampin in patients with acute staphylococcal periprosthetic joint infection treated with prosthesis retention is critically reviewed and data interpreted. Given the existing strong evidence demonstrating the benefit of rifampin, the conduction of an adequately powered RCT with appropriate definitions and interventions would probably not comply with ethical standards. Full article

(This article belongs to the Special Issue Prosthetic Joint Infection: The Challenges of Prevention, Diagnosis and Treatment and Opportunities for Future Research)

12 pages, 3357 KiB

Open AccessEditor’s ChoiceBrief Report

First Report of an Extensively Drug-Resistant ST23 Klebsiella pneumoniae of Capsular Serotype K1 Co-Producing CTX-M-15, OXA-48 and ArmA in Spain

by Marta Hernández, Luis López-Urrutia, David Abad, Mónica De Frutos Serna, Alain A. Ocampo-Sosa and José María Eiros

Antibiotics 2021, 10(2), 157; https://doi.org/10.3390/antibiotics10020157 - 04 Feb 2021

Cited by 17 | Viewed by 3208

Abstract

An extensively drug-resistant (XDR) Klebsiella pneumoniae isolate MS3802 from a tracheostomy exudate was whole-genome sequenced using MiSeq and Oxford Nanopore MinION platforms in order to identify the antimicrobial resistance and virulence determinates and their genomic context. Isolate MS3802 belonged to the clone ST23 [...] Read more.

An extensively drug-resistant (XDR) Klebsiella pneumoniae isolate MS3802 from a tracheostomy exudate was whole-genome sequenced using MiSeq and Oxford Nanopore MinION platforms in order to identify the antimicrobial resistance and virulence determinates and their genomic context. Isolate MS3802 belonged to the clone ST23 and presented a capsular serotype K1, associated with hypervirulent K. pneumoniae (hvKp) isolates. The isolate harboured a chromosomally encoded bla_CTX-M-15 gene and contained a large IncHI1B hybrid virulence/resistance plasmid carrying another copy of the bla_CTX-M-15 and the virulence factors iucABCD-iutA, iroBCDN, rmpA and rmpA2. The carbapenemase gene bla_OXA-48 was found in a Tn1999-like transposon and the 16S rRNA methylase armA gen located in the vicinity of other antibiotic-resistant genes on an IncM2 plasmid. This study represents, to the best of our knowledge, the first description of a bla_CTX-M-15-, bla_OXA-48- and armA-harbouring K. pneumoniae of ST23 and capsular serotype K1 in Spain. Our report emphasizes the importance of implementing new surveillance strategies to monitor the risk of emergence and spread of such XDR and hypervirulent K. pneumoniae isolates. Full article

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15 pages, 335 KiB

Open AccessEditor’s ChoiceReview

Antimicrobial Prophylaxis and Modifications of the Gut Microbiota in Children with Cancer

by Gianluca Bossù, Riccardo Di Sario, Alberto Argentiero and Susanna Esposito

Antibiotics 2021, 10(2), 152; https://doi.org/10.3390/antibiotics10020152 - 03 Feb 2021

Cited by 5 | Viewed by 3008

Abstract

In children with cancer, chemotherapy can produce cytotoxic effects, resulting in immunosuppression and an augmented risk of febrile neutropenia and bloodstream infections. This has led to widespread use of antibiotic prophylaxis which, combined with intensive chemotherapy treatment, could have a long-term effect on [...] Read more.

In children with cancer, chemotherapy can produce cytotoxic effects, resulting in immunosuppression and an augmented risk of febrile neutropenia and bloodstream infections. This has led to widespread use of antibiotic prophylaxis which, combined with intensive chemotherapy treatment, could have a long-term effect on the gastrointestinal microbiome. In this review, we aimed to analyze the current literature about the widespread use of antibiotic prophylaxis in children experiencing infectious complications induced by chemotherapy and its effects on the gut microbiome. Our review of the literature shows that antimicrobial prophylaxis in children with cancer is still a trending topic and, at the moment, there are not enough data to define universal guidelines. Children with cancer experience long and painful medical treatments and side effects, which are associated with great economic and social burdens, important psychological consequences, and dysbiosis induced by antibiotics and also by chemotherapy. Considering the importance of a healthy gut microbiota, studies are needed to understand the impact of dysbiosis in response to therapy in these children and to define how to modulate the microbiome to favor a positive therapeutic outcome. Full article

(This article belongs to the Special Issue The Effects of Antibiotics and Various Other Drugs on Microbiota: Roles in Health and Disease)

19 pages, 579 KiB

Open AccessEditor’s ChoiceArticle

Burkholderia Bacteria Produce Multiple Potentially Novel Molecules that Inhibit Carbapenem-Resistant Gram-Negative Bacterial Pathogens

by Eliza Depoorter, Evelien De Canck, Tom Coenye and Peter Vandamme

Antibiotics 2021, 10(2), 147; https://doi.org/10.3390/antibiotics10020147 - 02 Feb 2021

Cited by 14 | Viewed by 3382

Abstract

Antimicrobial resistance in Gram-negative pathogens represents a global threat to human health. This study determines the antimicrobial potential of a taxonomically and geographically diverse collection of 263 Burkholderia (sensu lato) isolates and applies natural product dereplication strategies to identify potentially novel molecules. Antimicrobial [...] Read more.

Antimicrobial resistance in Gram-negative pathogens represents a global threat to human health. This study determines the antimicrobial potential of a taxonomically and geographically diverse collection of 263 Burkholderia (sensu lato) isolates and applies natural product dereplication strategies to identify potentially novel molecules. Antimicrobial activity is almost exclusively present in Burkholderia sensu stricto bacteria and rarely observed in the novel genera Paraburkholderia, Caballeronia, Robbsia, Trinickia, and Mycetohabitans. Fourteen isolates show a unique spectrum of antimicrobial activity and inhibited carbapenem-resistant Gram-negative bacterial pathogens. Dereplication of the molecules present in crude spent agar extracts identifies 42 specialized metabolites, 19 of which represented potentially novel molecules. The known identified Burkholderia metabolites include toxoflavin, reumycin, pyrrolnitrin, enacyloxin, bactobolin, cepacidin, ditropolonyl sulfide, and antibiotics BN-227-F and SF 2420B, as well as the siderophores ornibactin, pyochelin, and cepabactin. Following semipreparative fractionation and activity testing, a total of five potentially novel molecules are detected in active fractions. Given the molecular formula and UV spectrum, two of those putative novel molecules are likely related to bactobolins, and another is likely related to enacyloxins. The results from this study confirm and extend the observation that Burkholderia bacteria present exciting opportunities for the discovery of potentially novel bioactive molecules. Full article

(This article belongs to the Section Novel Antimicrobial Agents)

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12 pages, 897 KiB

Open AccessEditor’s ChoiceArticle

The Prevalence and Clinical Significance of Anaerobic Bacteria in Major Liver Resection

by Jens Strohäker, Sophia Bareiß, Silvio Nadalin, Alfred Königsrainer, Ruth Ladurner and Anke Meier

Antibiotics 2021, 10(2), 139; https://doi.org/10.3390/antibiotics10020139 - 31 Jan 2021

Cited by 4 | Viewed by 2254

Abstract

(1) Background: Anaerobic infections in hepatobiliary surgery have rarely been addressed. Whereas infectious complications during the perioperative phase of liver resections are common, there are very limited data on the prevalence and clinical role of anaerobes in this context. Given the risk of [...] Read more.

(1) Background: Anaerobic infections in hepatobiliary surgery have rarely been addressed. Whereas infectious complications during the perioperative phase of liver resections are common, there are very limited data on the prevalence and clinical role of anaerobes in this context. Given the risk of contaminated bile in liver resections, the goal of our study was to investigate the prevalence and outcome of anaerobic infections in major hepatectomies. (2) Methods: We retrospectively analyzed the charts of 245 consecutive major hepatectomies that were performed at the department of General, Visceral, and Transplantation Surgery of the University Hospital of Tuebingen between July 2017 and August 2020. All microbiological cultures were screened for the prevalence of anaerobic bacteria and the patients’ clinical characteristics and outcomes were evaluated. (3) Results: Of the 245 patients, 13 patients suffered from anaerobic infections. Seven had positive cultures from the biliary tract during the primary procedure, while six had positive culture results from samples obtained during the management of complications. Risk factors for anaerobic infections were preoperative biliary stenting (p = 0.002) and bile leaks (p = 0.009). All of these infections had to be treated by intervention and adjunct antibiotic treatment with broad spectrum antibiotics. (4) Conclusions: Anaerobic infections are rare in liver resections. Certain risk factors trigger the antibiotic coverage of anaerobes. Full article

(This article belongs to the Special Issue Antimicrobial Susceptibility and Clinical Findings of Anaerobic Bacteria)

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14 pages, 4652 KiB

Open AccessEditor’s ChoiceArticle

Key Parameters on the Antibacterial Activity of Silver Camphor Complexes

by Joana P. Costa, Sílvia A. Sousa, Adelino M. Galvão, J. Miguel Mata, Jorge H. Leitão and M. Fernanda N. N. Carvalho

Antibiotics 2021, 10(2), 135; https://doi.org/10.3390/antibiotics10020135 - 30 Jan 2021

Cited by 7 | Viewed by 2777

Abstract

Nine new complexes with camphor imine or camphor sulfonimine ligands were synthesized and analytically and spectroscopically characterized, aiming to identify the key parameters that drive the antibacterial activity of the complexes with metal cores and imine substituents with distinct electronic and steric characteristics. [...] Read more.

Nine new complexes with camphor imine or camphor sulfonimine ligands were synthesized and analytically and spectroscopically characterized, aiming to identify the key parameters that drive the antibacterial activity of the complexes with metal cores and imine substituents with distinct electronic and steric characteristics. The antimicrobial activity of all complexes was evaluated by determining their minimum inhibitory concentrations (MIC) against the Gram-negative Escherichia coli ATCC25922, Pseudomonas aeruginosa 477, and Burkholderia contaminans IST408, and the Gram-positive Staphylococcus aureus Newman. Camphor imine complexes based on the hydroxyl silver center ({Ag(OH)}) typically perform better than those based on the nitrate silver center ({Ag(NO₃)}), while ligands prone to establish hydrogen bonding facilitate interactions with the bacterial cell surface structures. A different trend is observed for the silver camphor sulfonimine complexes that are almost non-sensitive to the nature of the metal cores {Ag(OH)} or {Ag(NO₃)} and display low sensitivity to the Y substituent. The antibacterial activities of the Ag(I) camphor sulfonimine complexes are higher than those of the camphor imine analogues. All the complexes display higher activity towards Gram-negative strains than towards the Gram-positive strain. Full article

(This article belongs to the Special Issue The Quest for Novel Antimicrobials: From Chemical Synthesis and Discovery to Mechanisms of Action and Resistance)

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28 pages, 2744 KiB

Open AccessEditor’s ChoiceReview

Staphylococcal Biofilms: Challenges and Novel Therapeutic Perspectives

by Christian Kranjec, Danae Morales Angeles, Marita Torrissen Mårli, Lucía Fernández, Pilar García, Morten Kjos and Dzung B. Diep

Antibiotics 2021, 10(2), 131; https://doi.org/10.3390/antibiotics10020131 - 29 Jan 2021

Cited by 67 | Viewed by 6197

Abstract

Staphylococci, like Staphylococcus aureus and S. epidermidis, are common colonizers of the human microbiota. While being harmless in many cases, many virulence factors result in them being opportunistic pathogens and one of the major causes of hospital-acquired infections worldwide. One of these [...] Read more.

Staphylococci, like Staphylococcus aureus and S. epidermidis, are common colonizers of the human microbiota. While being harmless in many cases, many virulence factors result in them being opportunistic pathogens and one of the major causes of hospital-acquired infections worldwide. One of these virulence factors is the ability to form biofilms—three-dimensional communities of microorganisms embedded in an extracellular polymeric matrix (EPS). The EPS is composed of polysaccharides, proteins and extracellular DNA, and is finely regulated in response to environmental conditions. This structured environment protects the embedded bacteria from the human immune system and decreases their susceptibility to antimicrobials, making infections caused by staphylococci particularly difficult to treat. With the rise of antibiotic-resistant staphylococci, together with difficulty in removing biofilms, there is a great need for new treatment strategies. The purpose of this review is to provide an overview of our current knowledge of the stages of biofilm development and what difficulties may arise when trying to eradicate staphylococcal biofilms. Furthermore, we look into promising targets and therapeutic methods, including bacteriocins and phage-derived antibiofilm approaches. Full article

(This article belongs to the Special Issue Natural Antimicrobials and Alternatives to Antimicrobials)

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24 pages, 2786 KiB

Open AccessEditor’s ChoiceReview

How to Evaluate Non-Growing Cells—Current Strategies for Determining Antimicrobial Resistance of VBNC Bacteria

by Susanne Fleischmann, Christian Robben, Thomas Alter, Peter Rossmanith and Patrick Mester

Antibiotics 2021, 10(2), 115; https://doi.org/10.3390/antibiotics10020115 - 26 Jan 2021

Cited by 36 | Viewed by 6642

Abstract

Thanks to the achievements in sanitation, hygiene practices, and antibiotics, we have considerably improved in our ongoing battle against pathogenic bacteria. However, with our increasing knowledge about the complex bacterial lifestyles and cycles and their plethora of defense mechanisms, it is clear that [...] Read more.

Thanks to the achievements in sanitation, hygiene practices, and antibiotics, we have considerably improved in our ongoing battle against pathogenic bacteria. However, with our increasing knowledge about the complex bacterial lifestyles and cycles and their plethora of defense mechanisms, it is clear that the fight is far from over. One of these resistance mechanisms that has received increasing attention is the ability to enter a dormancy state termed viable but non-culturable (VBNC). Bacteria that enter the VBNC state, either through unfavorable environmental conditions or through potentially lethal stress, lose their ability to grow on standard enrichment media, but show a drastically increased tolerance against antimicrobials including antibiotics. The inability to utilize traditional culture-based methods represents a considerable experimental hurdle to investigate their increased antimicrobial resistance and impedes the development and evaluation of effective treatments or interventions against bacteria in the VBNC state. Although experimental approaches were developed to detect and quantify VBNCs, only a few have been utilized for antimicrobial resistance screening and this review aims to provide an overview of possible methodological approaches. Full article

(This article belongs to the Special Issue Antimicrobial Resistance of Dormant Bacterial Cells)

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32 pages, 1148 KiB

Open AccessEditor’s ChoiceReview

Elicitation of Stress-Induced Phenolic Metabolites for Antimicrobial Applications against Foodborne Human Bacterial Pathogens

by Ashish Christopher, Dipayan Sarkar and Kalidas Shetty

Antibiotics 2021, 10(2), 109; https://doi.org/10.3390/antibiotics10020109 - 23 Jan 2021

Cited by 7 | Viewed by 3347

Abstract

Foodborne bacterial pathogens in consumed foods are major food safety concerns worldwide, leading to serious illness and even death. An exciting strategy is to use novel phenolic compounds against bacterial pathogens based on recruiting the inducible metabolic responses of plant endogenous protective defense [...] Read more.

Foodborne bacterial pathogens in consumed foods are major food safety concerns worldwide, leading to serious illness and even death. An exciting strategy is to use novel phenolic compounds against bacterial pathogens based on recruiting the inducible metabolic responses of plant endogenous protective defense against biotic and abiotic stresses. Such stress-inducible phenolic metabolites have high potential to reduce bacterial contamination, and particularly improve safety of plant foods. The stimulation of plant protective response by inducing biosynthesis of stress-inducible phenolics with antimicrobial properties is among the safe and effective strategies that can be targeted for plant food safety and human gut health benefits. Metabolically driven elicitation with physical, chemical, and microbial elicitors has shown significant improvement in the biosynthesis of phenolic metabolites with antimicrobial properties in food and medicinal plants. Using the above rationale, this review focuses on current advances and relevance of metabolically driven elicitation strategies to enhance antimicrobial phenolics in plant food models for bacterial-linked food safety applications. Additionally, the specific objective of this review is to explore the potential role of redox-linked pentose phosphate pathway (PPP) regulation for enhancing biosynthesis of stress-inducible antibacterial phenolics in elicited plants, which are relevant for wider food safety and human health benefits. Full article

(This article belongs to the Special Issue Development of Novel Anti-microbials to Reduce Bacterial Contamination of Food)

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13 pages, 1386 KiB

Open AccessEditor’s ChoiceArticle

Enhanced Antimicrobial and Antibiofilm Effect of New Colistin-Loaded Human Albumin Nanoparticles

by Sara Scutera, Monica Argenziano, Rosaria Sparti, Federica Bessone, Gabriele Bianco, Chiara Bastiancich, Carlotta Castagnoli, Maurizio Stella, Tiziana Musso and Roberta Cavalli

Antibiotics 2021, 10(1), 57; https://doi.org/10.3390/antibiotics10010057 - 08 Jan 2021

Cited by 30 | Viewed by 3023

Abstract

Multidrug-resistant (MDR) Gram-negative bacteria (GNB), such as Acinetobacter and Klebsiella, are responsible for severe hospital-acquired infections. Colistin, despite its toxicity and low tissue penetration, is considered the last resort antibiotic against these microorganisms. Of concern, the use of Colistin has recently been [...] Read more.

Multidrug-resistant (MDR) Gram-negative bacteria (GNB), such as Acinetobacter and Klebsiella, are responsible for severe hospital-acquired infections. Colistin, despite its toxicity and low tissue penetration, is considered the last resort antibiotic against these microorganisms. Of concern, the use of Colistin has recently been compromised by the emergence of Colistin resistance. Herein, we developed a new formulation consisting of multifunctional chitosan-coated human albumin nanoparticles for the delivery of Colistin (Col/haNPs). Col/haNPs were in vitro characterized for encapsulation efficiency, drug release, stability and cytotoxicity and were evaluated for antibacterial activity against MDR GNB (Acinetobacter baumannii and Klebsiella pneumoniae). Col/haNPs showed sizes lower than 200 nm, high encapsulation efficiency (98.65%) and prolonged in vitro release of Colistin. The safety of the nanoformulation was demonstrated by a negligible cytotoxicity on human fibroblasts and hemolytic activity. Col/haNPs evidenced a high antibacterial effect with a significant decrease in MIC values compared to free Colistin, in particular against Col-resistant strains with a pronounced decline of bacterial growth over time. Moreover, Col/haNPs exhibited an inhibitory effect on biofilm formation that was 4 and 60 fold higher compared to free Colistin, respectively for Colistin susceptible and resistant A. baumannii. Our findings suggest that Col/haNPs could represent a promising Colistin nanocarrier with high antimicrobial activity on MDR GNB. Full article

(This article belongs to the Special Issue Development of Effective Antibacterial Treatment: Lessons from the Past and Novel Approaches)

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15 pages, 4947 KiB

Open AccessEditor’s ChoiceArticle

pH-Responsive “Smart” Hydrogel for Controlled Delivery of Silver Nanoparticles to Infected Wounds

by Hanif Haidari, Zlatko Kopecki, Adam T. Sutton, Sanjay Garg, Allison J. Cowin and Krasimir Vasilev

Antibiotics 2021, 10(1), 49; https://doi.org/10.3390/antibiotics10010049 - 05 Jan 2021

Cited by 64 | Viewed by 5406

Abstract

Persistent wound infections have been a therapeutic challenge for a long time. Current treatment approaches are mostly based on the delivery of antibiotics, but these are not effective for all infections. Here, we report the development of a sensitive pH-responsive hydrogel that can [...] Read more.

Persistent wound infections have been a therapeutic challenge for a long time. Current treatment approaches are mostly based on the delivery of antibiotics, but these are not effective for all infections. Here, we report the development of a sensitive pH-responsive hydrogel that can provide controlled, pH-triggered release of silver nanoparticles (AgNPs). This delivery system was designed to sense the environmental pH and trigger the release of AgNPs when the pH changes from acidic to alkaline, as occurs due to the presence of pathogenic bacteria in the wound. Our results show that the prepared hydrogel restricts the release of AgNPs at acidic pH (pH = 4) but substantially amplifies it at alkaline pH (pH = 7.4 and pH = 10). This indicates the potential use of the hydrogel for the on-demand release of Ag+ depending on the environmental pH. In vitro antibacterial studies demonstrated effective elimination of both Gram-negative and positive bacteria. Additionally, the effective antibacterial dose of Ag+ showed no toxicity towards mammalian skin cells. Collectively, this pH-responsive hydrogel presents potential as a promising new material for the treatment of infected wounds. Full article

(This article belongs to the Special Issue Specialized Coatings Interacting with Human Pathogens)

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22 pages, 3924 KiB

Open AccessEditor’s ChoiceReview

Riboswitches as Drug Targets for Antibiotics

by Vipul Panchal and Ruth Brenk

Antibiotics 2021, 10(1), 45; https://doi.org/10.3390/antibiotics10010045 - 05 Jan 2021

Cited by 53 | Viewed by 7683

Abstract

Riboswitches reside in the untranslated region of RNA and regulate genes involved in the biosynthesis of essential metabolites through binding of small molecules. Since their discovery at the beginning of this century, riboswitches have been regarded as potential antibacterial targets. Using fragment screening, [...] Read more.

Riboswitches reside in the untranslated region of RNA and regulate genes involved in the biosynthesis of essential metabolites through binding of small molecules. Since their discovery at the beginning of this century, riboswitches have been regarded as potential antibacterial targets. Using fragment screening, high-throughput screening and rational ligand design guided by X-ray crystallography, lead compounds against various riboswitches have been identified. Here, we review the current status and suitability of the thiamine pyrophosphate (TPP), flavin mononucleotide (FMN), glmS, guanine, and other riboswitches as antibacterial targets and discuss them in a biological context. Further, we highlight challenges in riboswitch drug discovery and emphasis the need to develop riboswitch specific high-throughput screening methods. Full article

(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)

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