Editor's Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area.The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

Order results
Result details
Results per page
Select all
Export citation of selected articles as:

Article

Article
Association between Antibiotic Consumption and Resistance in Mink Production
Antibiotics 2022, 11(7), 927; https://doi.org/10.3390/antibiotics11070927 - 09 Jul 2022
Viewed by 540
Abstract
Antibiotic consumption is considered to be a main driver of antibiotic resistant bacteria. Mink breeding follows a distinctive seasonal reproduction cycle, and all of the mink produced in the northern hemisphere are bred, born, and pelted around the same time of year. Some [...] Read more.
Antibiotic consumption is considered to be a main driver of antibiotic resistant bacteria. Mink breeding follows a distinctive seasonal reproduction cycle, and all of the mink produced in the northern hemisphere are bred, born, and pelted around the same time of year. Some of the diseases are age-related, which is reflected in the seasonal variation of antibiotic consumption. The seasonality makes mink a good model for the investigation of the association between antibiotic consumption and resistance. The objectives of this study were (1) to monitor the farm level of antibiotic resistance during one production cycle and (2) to assess the potential associations between antibiotic consumption and resistance. Twenty-four farms were included in this study (Denmark n = 20, Iceland n = 2, and The Netherlands n = 2), following a cohort of animals born in 2018. Staphylococcus delphini and Escherichia coli were isolated from samples of the carcasses and faeces and were collected randomly. The isolates were susceptibility tested and subsequently divided into the sensitive wildtype (WT) and the resistant non-wildtype (NWT) populations. The antibiotic consumption relative to the sampling periods was assessed as having a short-term or a long-term impact, i.e., in two explanatory factors. For both S. delphini and E. coli, a large between-farm variation of NWT profiles was detected. In the final multivariable, generalized linear mixed models, significant associations between NWT isolates and the consumption of specific antibiotics were found: the short-term use of tetracyclines in the growth period was associated with the occurrence of tetracycline NWT E. coli in the growth period (OR: 11.94 [1.78; 89.28]), and the long-term use of macrolide and tetracyclines was associated with the occurrence of erythromycin NWT S. delphini in the weaning period (OR: 18.2 [2.26; 321.36]) and tetracycline NWT S. delphini in the growth period (OR: 8.2 [1.27; 63.31]), respectively. Farms with zero consumption in the study years prior to sampling also had a substantial proportion of NWT isolates, indicating that NWT isolates are persistent and/or widely spread in the environment. Generally, a high occurrence of tetracycline NWTs was observed. NWT isolates with resistance against the most commonly used antibiotics were found on all the farms, stressing the need for routine surveillance and the prudent use of antibiotics. The results offer a preview of the complex relationship between consumption and resistance, demonstrating some significant associations between use and resistance. Moreover, antibiotic-resistant bacteria are present even on farms with no antibiotic consumption over extended periods, and theoretical explanations supported by the data are offered. Full article
Show Figures

Figure 1

Article
Efficacy of Short-Term High Dose Pulsed Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome (PTLDS) and Associated Co-Infections: A Report of Three Cases and Literature Review
Antibiotics 2022, 11(7), 912; https://doi.org/10.3390/antibiotics11070912 - 07 Jul 2022
Viewed by 4183
Abstract
Lyme disease and associated co-infections are increasing worldwide and approximately 20% of individuals develop chronic Lyme disease (CLD)/Post-Treatment Lyme Disease Syndrome (PTLDS) despite early antibiotics. A seven- to eight-week protocol of double dose dapsone combination therapy (DDDCT) for CLD/PTLDS results in symptom remission [...] Read more.
Lyme disease and associated co-infections are increasing worldwide and approximately 20% of individuals develop chronic Lyme disease (CLD)/Post-Treatment Lyme Disease Syndrome (PTLDS) despite early antibiotics. A seven- to eight-week protocol of double dose dapsone combination therapy (DDDCT) for CLD/PTLDS results in symptom remission in approximately 50% of patients for one year or longer, with published culture studies indicating higher doses of dapsone demonstrate efficacy against resistant biofilm forms of Borrelia burgdorferi. The purpose of this study was, therefore, to evaluate higher doses of dapsone in the treatment of resistant CLD/PTLDS and associated co-infections. A total of 25 patients with a history of Lyme and associated co-infections, most of whom had ongoing symptoms despite several courses of DDDCT, took one or more courses of high dose pulsed dapsone combination therapy (200 mg dapsone × 3–4 days and/or 200 mg BID × 4 days), depending on persistent symptoms. The majority of patients noticed sustained improvement in eight major Lyme symptoms, including fatigue, pain, headaches, neuropathy, insomnia, cognition, and sweating, where dapsone dosage, not just the treatment length, positively affected outcomes. High dose pulsed dapsone combination therapy may represent a novel therapeutic approach for the treatment of resistant CLD/PTLDS, and should be confirmed in randomized, controlled clinical trials. Full article
Show Figures

Figure 1

Article
Antibacterial Activity against Clinical Isolates and In Vivo Efficacy of Coralmycins
Antibiotics 2022, 11(7), 902; https://doi.org/10.3390/antibiotics11070902 - 06 Jul 2022
Viewed by 618
Abstract
Coralmycins, such as coralmycin A and DH-coralmycin A, have novel molecular skeletons and have been reported to exhibit potent antibacterial activity against standard Gram-positive bacterial strains. Here, the in vitro antibacterial activity against an extensive clinical isolate collection, time-kill kinetics, pharmacokinetics (PK), and [...] Read more.
Coralmycins, such as coralmycin A and DH-coralmycin A, have novel molecular skeletons and have been reported to exhibit potent antibacterial activity against standard Gram-positive bacterial strains. Here, the in vitro antibacterial activity against an extensive clinical isolate collection, time-kill kinetics, pharmacokinetics (PK), and in vivo efficacy of coralmycins were studied. Coralmycin A showed potent antibacterial activity with an MIC90 of 1 mg/L against 73 clinical methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci isolates, which was 2–8 times higher than the corresponding activities of DH-coralmycin A, vancomycin, daptomycin, and linezolid, and against 73 vancomycin-resistant Enterococcus and Streptococcus pneumoniae isolates, which was 4–16 times higher than the corresponding activities of DH-coralmycin A, daptomycin, and linezolid. Pharmacokinetic analysis after i.v. injection showed that coralmycins have a moderate volume of distribution and moderate-to-high clearance in mice. The coralmycin A and DH-coralmycin A bioavailability values were 61.3% and 11.7%, respectively, after s.c. administration. In a mouse respiratory tract infection model, coralmycin A showed bacteriostatic and bactericidal in vivo efficacies at an s.c. administration of 4 and 100 mg/kg bid, respectively; these efficacies were similar to those of vancomycin at 4 and 20 mg/kg bid, respectively. The present findings indicate that coralmycin A has great potential as a new class of antibiotic for treating infections caused by multidrug-resistant Gram-positive bacteria. Full article
(This article belongs to the Special Issue Discovery and Development of Novel Antibacterial Agents)
Show Figures

Figure 1

Article
Enhanced Antibacterial Activity of Dermaseptin through Its Immobilization on Alginate Nanoparticles—Effects of Menthol and Lactic Acid on Its Potentialization
Antibiotics 2022, 11(6), 787; https://doi.org/10.3390/antibiotics11060787 - 09 Jun 2022
Viewed by 732
Abstract
Dermaseptin B2 (DRS-B2) is an antimicrobial peptide secreted by Phyllomedusa bicolor, which is an Amazonian tree frog. Here, we show that the adsorption of DRS-B2 on alginate nanoparticles (Alg NPs) results in a formulation (Alg NPs + DRS-B2) with a remarkable antibacterial [...] Read more.
Dermaseptin B2 (DRS-B2) is an antimicrobial peptide secreted by Phyllomedusa bicolor, which is an Amazonian tree frog. Here, we show that the adsorption of DRS-B2 on alginate nanoparticles (Alg NPs) results in a formulation (Alg NPs + DRS-B2) with a remarkable antibacterial activity against Escherichia coli ATCC 8739 and E. coli 184 strains, which are sensitive and resistant, respectively, to colistin. The antibacterial activity, obtained with this new formulation, is higher than that obtained with DRS-B2 alone. Of note, the addition of lactic acid or menthol to this new formulation augments its antibacterial activity against the aforementioned Gram-negative bacilli. The safety of DRS-B2, and also that of the new formulation supplemented or not with a small molecule such as lactic acid or menthol has been proven on the human erythrocytes and the eukaryotic cell line types HT29 (human) and IPEC-1 (animal). Similarly, their stability was determined under the conditions mimicking the gastrointestinal tract with different conditions: pH, temperature, and the presence of digestive enzymes. Based on all the obtained data, we assume that these new formulations are promising and could be suggested, after in vivo approval and completing regulation aspects, as alternatives to antibiotics to fight infections caused by Gram-negative bacilli such as E. coli. Full article
Show Figures

Figure 1

Article
The Urinary Resistome of Clinically Healthy Companion Dogs: Potential One Health Implications
Antibiotics 2022, 11(6), 780; https://doi.org/10.3390/antibiotics11060780 - 08 Jun 2022
Viewed by 831
Abstract
An interdisciplinary approach to antimicrobial resistance (AMR) is essential to effectively address what is projected to soon become a public health disaster. Veterinary medicine accounts for a majority of antimicrobial use, and mainly in support of industrial food animal production (IFAP), which has [...] Read more.
An interdisciplinary approach to antimicrobial resistance (AMR) is essential to effectively address what is projected to soon become a public health disaster. Veterinary medicine accounts for a majority of antimicrobial use, and mainly in support of industrial food animal production (IFAP), which has significant exposure implications for human and nonhuman animals. Companion dogs live in close proximity to humans and share environmental exposures, including food sources. This study aimed to elucidate the AMR-gene presence in microorganisms recovered from urine from clinically healthy dogs to highlight public health considerations in the context of a species-spanning framework. Urine was collected through cystocentesis from 50 companion dogs in Southern California, and microbial DNA was analyzed using next-generation sequencing. Thirteen AMR genes in urine from 48% of the dogs {n=24} were detected. The most common AMR genes were aph(3′)Ia, and ermB, which confer resistance to aminoglycosides and MLS (macrolides, lincosamides, streptogramins) antibiotics, respectively. Antibiotic-resistance profiles based on the AMR genes detected, and the intrinsic resistance profiles of bacterial species, were inferred in 24% of the samples {n=12} for 57 species, with most belonging to Streptococcus, Staphylococcus, and Corynebacterium genera. The presence of AMR genes that confer resistance to medically important antibiotics suggests that dogs may serve as reservoirs of clinically relevant resistomes, which is likely rooted in excessive IFAP antimicrobial use. Full article
(This article belongs to the Special Issue Antibiotic Use in Veterinary)
Show Figures

Figure 1

Article
Synergism between the Synthetic Antibacterial and Antibiofilm Peptide (SAAP)-148 and Halicin
Antibiotics 2022, 11(5), 673; https://doi.org/10.3390/antibiotics11050673 - 17 May 2022
Viewed by 1169
Abstract
Recently, using a deep learning approach, the novel antibiotic halicin was discovered. We compared the antibacterial activities of two novel bactericidal antimicrobial agents, i.e., the synthetic antibacterial and antibiofilm peptide (SAAP)-148 with this antibiotic halicin. Results revealed that SAAP-148 was more effective than [...] Read more.
Recently, using a deep learning approach, the novel antibiotic halicin was discovered. We compared the antibacterial activities of two novel bactericidal antimicrobial agents, i.e., the synthetic antibacterial and antibiofilm peptide (SAAP)-148 with this antibiotic halicin. Results revealed that SAAP-148 was more effective than halicin in killing planktonic bacteria of antimicrobial-resistant (AMR) Escherichia coli, Acinetobacter baumannii and Staphylococcus aureus, especially in biologically relevant media, such as plasma and urine, and in 3D human infection models. Surprisingly, SAAP-148 and halicin were equally effective against these bacteria residing in immature and mature biofilms. As their modes of action differ, potential favorable interactions between SAAP-148 and halicin were investigated. For some specific strains of AMR E. coli and S. aureus synergism between these agents was observed, whereas for other strains, additive interactions were noted. These favorable interactions were confirmed for AMR E. coli in a 3D human bladder infection model and AMR S. aureus in a 3D human epidermal infection model. Together, combinations of these two novel antimicrobial agents hold promise as an innovative treatment for infections not effectively treatable with current antibiotics. Full article
Show Figures

Figure 1

Article
Antimicrobial Susceptibility of Enterococcus Isolates from Cattle and Pigs in Portugal: Linezolid Resistance Genes optrA and poxtA
Antibiotics 2022, 11(5), 615; https://doi.org/10.3390/antibiotics11050615 - 03 May 2022
Viewed by 899
Abstract
Enterococci are part of the commensal gut microbiota of mammals, with Enterococcus faecalis and Enterococcus faecium being the most clinically relevant species. This study assesses the prevalence and diversity of enterococcal species in cattle (n = 201) and pig (n = [...] Read more.
Enterococci are part of the commensal gut microbiota of mammals, with Enterococcus faecalis and Enterococcus faecium being the most clinically relevant species. This study assesses the prevalence and diversity of enterococcal species in cattle (n = 201) and pig (n = 249) cecal samples collected in 2017. Antimicrobial susceptibility profiles of E. faecium (n = 48) and E. faecalis (n = 84) were assessed by agar and microdilution methods. Resistance genes were screened through PCR and nine strains were analyzed by Whole Genome Sequencing. A wide range of enterococci species was found colonizing the intestines of pigs and cattle. Overall, the prevalence of resistance to critically important antibiotics was low (except for erythromycin), and no glycopeptide-resistant isolates were identified. Two daptomycin-resistant E. faecalis ST58 and ST93 were found. Linezolid-resistant strains of E. faecalis (n = 3) and E. faecium (n = 1) were detected. Moreover, oxazolidinone resistance determinants optrA (n = 8) and poxtA (n = 2) were found in E. faecalis (ST16, ST58, ST207, ST474, ST1178) and E. faecium (ST22, ST2138). Multiple variants of optrA were found in different genetic contexts, either in the chromosome or plasmids. We highlight the importance of animals as reservoirs of resistance genes to critically important antibiotics. Full article
(This article belongs to the Special Issue Antimicrobial Resistance and Antibiotic Alternatives in Livestock)
Show Figures

Figure 1

Article
Impact of COVID-19 on Antimicrobial Consumption and Spread of Multidrug-Resistance in Bacterial Infections
Antibiotics 2022, 11(4), 535; https://doi.org/10.3390/antibiotics11040535 - 18 Apr 2022
Cited by 6 | Viewed by 1192
Abstract
The spread of COVID-19 pandemic may have affected antibiotic consumption patterns and the prevalence of colonized or infected by multidrug-resistant (MDR) bacteria. We investigated the differences in the consumption of antibiotics easily prone to resistance and the prevalence of MDR bacteria during the [...] Read more.
The spread of COVID-19 pandemic may have affected antibiotic consumption patterns and the prevalence of colonized or infected by multidrug-resistant (MDR) bacteria. We investigated the differences in the consumption of antibiotics easily prone to resistance and the prevalence of MDR bacteria during the COVID-19 pandemic (March 2020 to September 2021) compared to in the pre-pandemic period (March 2018 to September 2019). Data on usage of antibiotics and infections caused by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Acinetobacter baumannii (CRAB), and carbapenem-resistant Pseudomonas aeruginosa (CRPA) were obtained from hospitalized patients in four university hospitals. The consumption of penicillin with β-lactamase inhibitors (3.4% in ward, 5.8% in intensive care unit (ICU)), and carbapenems (25.9% in ward, 12.1% in ICU) increased during the pandemic period. The prevalence of MRSA (4.7%), VRE (49.0%), CRE (22.4%), and CRPA (20.1%) isolated in clinical samples from the ward and VRE (26.7%) and CRE (36.4%) isolated in clinical samples from the ICU were significantly increased, respectively. Meanwhile, only the prevalence of CRE (38.7%) isolated in surveillance samples from the ward increased. The COVID-19 pandemic is associated with increased consumption of antibiotics and has influenced the prevalence of infections caused by MDR isolates. Full article
Show Figures

Figure 1

Article
Stapling of Peptides Potentiates the Antibiotic Treatment of Acinetobacter baumannii In Vivo
Antibiotics 2022, 11(2), 273; https://doi.org/10.3390/antibiotics11020273 - 19 Feb 2022
Cited by 1 | Viewed by 1895
Abstract
The rising incidence of multidrug resistance in Gram-negative bacteria underlines the urgency for novel treatment options. One promising new approach is the synergistic combination of antibiotics with antimicrobial peptides. However, the use of such peptides is not straightforward; they are often sensitive to [...] Read more.
The rising incidence of multidrug resistance in Gram-negative bacteria underlines the urgency for novel treatment options. One promising new approach is the synergistic combination of antibiotics with antimicrobial peptides. However, the use of such peptides is not straightforward; they are often sensitive to proteolytic degradation, which greatly limits their clinical potential. One approach to increase stability is to apply a hydrocarbon staple to the antimicrobial peptide, thereby fixing them in an α-helical conformation, which renders them less exposed to proteolytic activity. In this work we applied several different hydrocarbon staples to two previously described peptides shown to act on the outer membrane, L6 and L8, and tested their activity in a zebrafish embryo infection model using a clinical isolate of Acinetobacter baumannii as a pathogen. We show that the introduction of such a hydrocarbon staple to the peptide L8 improves its in vivo potentiating activity on antibiotic treatment, without increasing its in vivo antimicrobial activity, toxicity or hemolytic activity. Full article
Show Figures

Figure 1

Article
Factors Affecting Antibiotic Prescription among Hospital Physicians in a Low-Antimicrobial-Resistance Country: A Qualitative Study
Antibiotics 2022, 11(1), 98; https://doi.org/10.3390/antibiotics11010098 - 13 Jan 2022
Cited by 2 | Viewed by 973
Abstract
Antimicrobial resistance (AMR) is a threat to hospital patients. Antimicrobial stewardship programs (ASPs) can counteract AMR. To optimize ASPs, we need to understand what affects physicians’ antibiotic prescription from several contexts. In this study, we aimed to explore the factors affecting hospital physicians’ [...] Read more.
Antimicrobial resistance (AMR) is a threat to hospital patients. Antimicrobial stewardship programs (ASPs) can counteract AMR. To optimize ASPs, we need to understand what affects physicians’ antibiotic prescription from several contexts. In this study, we aimed to explore the factors affecting hospital physicians’ antibiotic choices in a low-resistance country to identify potential targets for future ASPs. We interviewed 14 physicians involved in antibiotic prescription in a Norwegian hospital. The interviews were audiotaped, transcribed verbatim, and analyzed using thematic analysis. The main factors affecting antibiotic prescription were a high work pressure, insufficient staff resources, and uncertainties regarding clinical decisions. Treatment expectations from patients and next of kin, benevolence towards the patients, suboptimal microbiological testing, and limited time for infectious disease specialists to offer advisory services also affected the antibiotic choices. Future ASP efforts should evaluate the system organization and prioritizations to address and manage potential time-pressure issues. To limit the use of broad-spectrum antibiotics, improving microbiology testing and the routines for consultations with infectious disease specialists seems beneficial. We also identified a need among the prescribing physicians for a debate on ethical antibiotic questions. Full article
(This article belongs to the Special Issue Antimicrobial Prescribing and Stewardship, 2nd Volume)
Show Figures

Figure 1

Article
Antimicrobial Resistance and Environmental Health: A Water Stewardship Framework for Global and National Action
Antibiotics 2022, 11(1), 63; https://doi.org/10.3390/antibiotics11010063 - 05 Jan 2022
Cited by 3 | Viewed by 1127
Abstract
Antimicrobial resistance (AMR) is a global health crisis that affects all life on Earth. In 2015, the World Health Organization developed guidance to combat AMR in accordance with a One Health framework considering human, animal, and environment sectors of planetary health. This study [...] Read more.
Antimicrobial resistance (AMR) is a global health crisis that affects all life on Earth. In 2015, the World Health Organization developed guidance to combat AMR in accordance with a One Health framework considering human, animal, and environment sectors of planetary health. This study reviewed global guidance and 25 National Action Plans to evaluate thematic priorities in One Health AMR approaches using a novel framework that additionally facilitated the identification of water-related stewardship gaps, as water resources are recognized as the primary environmental AMR reservoir and dissemination pathway. This review found that global and national stewardship primarily focuses on mitigating antibiotic use in the human and animal sectors, overlooking environmental drivers, particularly diverse environmental waters. The findings of this study highlight the need to broaden the scope of water-related AMR concerns beyond water, sanitation, and hygiene (WASH) infrastructure for water supply and wastewater treatment, and account for environmental waters in AMR development and dissemination, particularly in low-income countries where half a billion people rely on environmental waters to meet daily needs. Equitably accounting for water environments, supplies, and waste in AMR prevention, mitigation, surveillance, and innovation can significantly enhance the integration of environmental objectives in One Health AMR stewardship. Full article
Show Figures

Figure 1

Article
Characterization and Molecular Determinants for β-Lactam Specificity of the Multidrug Efflux Pump AcrD from Salmonella typhimurium
Antibiotics 2021, 10(12), 1494; https://doi.org/10.3390/antibiotics10121494 - 06 Dec 2021
Cited by 1 | Viewed by 1054
Abstract
Gram-negative Tripartite Resistance Nodulation and cell Division (RND) superfamily efflux pumps confer various functions, including multidrug and bile salt resistance, quorum-sensing, virulence and can influence the rate of mutations on the chromosome. Multidrug RND efflux systems are often characterized by a wide substrate [...] Read more.
Gram-negative Tripartite Resistance Nodulation and cell Division (RND) superfamily efflux pumps confer various functions, including multidrug and bile salt resistance, quorum-sensing, virulence and can influence the rate of mutations on the chromosome. Multidrug RND efflux systems are often characterized by a wide substrate specificity. Similarly to many other RND efflux pump systems, AcrAD-TolC confers resistance toward SDS, novobiocin and deoxycholate. In contrast to the other pumps, however, it in addition confers resistance against aminoglycosides and dianionic β-lactams, such as sulbenicillin, aztreonam and carbenicillin. Here, we could show that AcrD from Salmonella typhimurium confers resistance toward several hitherto unreported AcrD substrates such as temocillin, dicloxacillin, cefazolin and fusidic acid. In order to address the molecular determinants of the S. typhimurium AcrD substrate specificity, we conducted substitution analyses in the putative access and deep binding pockets and in the TM1/TM2 groove region. The variants were tested in E. coli ΔacrBΔacrD against β-lactams oxacillin, carbenicillin, aztreonam and temocillin. Deep binding pocket variants N136A, D276A and Y327A; access pocket variant R625A; and variants with substitutions in the groove region between TM1 and TM2 conferred a sensitive phenotype and might, therefore, be involved in anionic β-lactam export. In contrast, lower susceptibilities were observed for E. coli cells harbouring deep binding pocket variants T139A, D176A, S180A, F609A, T611A and F627A and the TM1/TM2 groove variant I337A. This study provides the first insights of side chains involved in drug binding and transport for AcrD from S. typhimurium. Full article
Show Figures

Figure 1

Article
Lefamulin in Patients with Community-Acquired Bacterial Pneumonia Caused by Atypical Respiratory Pathogens: Pooled Results from Two Phase 3 Trials
Antibiotics 2021, 10(12), 1489; https://doi.org/10.3390/antibiotics10121489 - 04 Dec 2021
Cited by 2 | Viewed by 1212
Abstract
Lefamulin was the first systemic pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia based on two phase 3 trials (Lefamulin Evaluation Against Pneumonia [LEAP]-1 and LEAP-2). This pooled analysis evaluated lefamulin efficacy and safety in adults with [...] Read more.
Lefamulin was the first systemic pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia based on two phase 3 trials (Lefamulin Evaluation Against Pneumonia [LEAP]-1 and LEAP-2). This pooled analysis evaluated lefamulin efficacy and safety in adults with community-acquired bacterial pneumonia caused by atypical pathogens (Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae). In LEAP-1, participants received intravenous lefamulin 150 mg every 12 h for 5–7 days or moxifloxacin 400 mg every 24 h for 7 days, with optional intravenous-to-oral switch. In LEAP-2, participants received oral lefamulin 600 mg every 12 h for 5 days or moxifloxacin 400 mg every 24 h for 7 days. Primary outcomes were early clinical response at 96 ± 24 h after first dose and investigator assessment of clinical response at test of cure (5–10 days after last dose). Atypical pathogens were identified in 25.0% (91/364) of lefamulin-treated patients and 25.2% (87/345) of moxifloxacin-treated patients; most were identified by ≥1 standard diagnostic modality (M. pneumoniae 71.2% [52/73]; L. pneumophila 96.9% [63/65]; C. pneumoniae 79.3% [46/58]); the most common standard diagnostic modality was serology. In terms of disease severity, more than 90% of patients had CURB-65 (confusion of new onset, blood urea nitrogen > 19 mg/dL, respiratory rate ≥ 30 breaths/min, blood pressure <90 mm Hg systolic or ≤60 mm Hg diastolic, and age ≥ 65 years) scores of 0–2; approximately 50% of patients had PORT (Pneumonia Outcomes Research Team) risk class of III, and the remaining patients were more likely to have PORT risk class of II or IV versus V. In patients with atypical pathogens, early clinical response (lefamulin 84.4–96.6%; moxifloxacin 90.3–96.8%) and investigator assessment of clinical response at test of cure (lefamulin 74.1–89.7%; moxifloxacin 74.2–97.1%) were high and similar between arms. Treatment-emergent adverse event rates were similar in the lefamulin (34.1% [31/91]) and moxifloxacin (32.2% [28/87]) groups. Limitations to this analysis include its post hoc nature, the small numbers of patients infected with atypical pathogens, the possibility of PCR-based diagnostic methods to identify non-etiologically relevant pathogens, and the possibility that these findings may not be generalizable to all patients. Lefamulin as short-course empiric monotherapy, including 5-day oral therapy, was well tolerated in adults with community-acquired bacterial pneumonia and demonstrated high clinical response rates against atypical pathogens. Full article
Show Figures

Figure 1

Article
Effect of Ursolic and Oleanolic Acids on Lipid Membranes: Studies on MRSA and Models of Membranes
Antibiotics 2021, 10(11), 1381; https://doi.org/10.3390/antibiotics10111381 - 11 Nov 2021
Cited by 3 | Viewed by 1003
Abstract
Staphylococcus aureus is an opportunistic pathogen and the major causative agent of life-threatening hospital- and community-acquired infections. A combination of antibiotics could be an opportunity to address the widespread emergence of antibiotic-resistant strains, including Methicillin-Resistant S. aureus (MRSA). We here investigated the potential [...] Read more.
Staphylococcus aureus is an opportunistic pathogen and the major causative agent of life-threatening hospital- and community-acquired infections. A combination of antibiotics could be an opportunity to address the widespread emergence of antibiotic-resistant strains, including Methicillin-Resistant S. aureus (MRSA). We here investigated the potential synergy between ampicillin and plant-derived antibiotics (pentacyclic triterpenes, ursolic acid (UA) and oleanolic acid (OA)) towards MRSA (ATCC33591 and COL) and the mechanisms involved. We calculated the Fractional Inhibitory Concentration Index (FICI) and demonstrated synergy. We monitored fluorescence of Bodipy-TR-Cadaverin, propidium iodide and membrane potential-sensitive probe for determining the ability of UA and OA to bind to lipoteichoic acids (LTA), and to induce membrane permeabilization and depolarization, respectively. Both pentacyclic triterpenes were able to bind to LTA and to induce membrane permeabilization and depolarization in a dose-dependent fashion. These effects were not accompanied by significant changes in cellular concentration of pentacyclic triterpenes and/or ampicillin, suggesting an effect mediated through lipid membranes. We therefore focused on membranous effects induced by UA and OA, and we investigated on models of membranes, the role of specific lipids including phosphatidylglycerol and cardiolipin. The effect induced on membrane fluidity, permeability and ability to fuse were studied by determining changes in fluorescence anisotropy of DPH/generalized polarization of Laurdan, calcein release from liposomes, fluorescence dequenching of octadecyl-rhodamine B and liposome-size, respectively. Both UA and OA showed a dose-dependent effect with membrane rigidification, increase of membrane permeabilization and fusion. Except for the effect on membrane fluidity, the effect of UA was consistently higher compared with that obtained with OA, suggesting the role of methyl group position. All together the data demonstrated the potential role of compounds acting on lipid membranes for enhancing the activity of other antibiotics, like ampicillin and inducing synergy. Such combinations offer an opportunity to explore a larger antibiotic chemical space. Full article
(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)
Show Figures

Figure 1

Article
Correlation between Previous Antibiotic Exposure and COVID-19 Severity. A Population-Based Cohort Study
Antibiotics 2021, 10(11), 1364; https://doi.org/10.3390/antibiotics10111364 - 08 Nov 2021
Cited by 6 | Viewed by 1363
Abstract
We examined the correlation between previous antibiotic exposure and COVID-19 severity using a population-based observational matched cohort study with patient level data obtained for more than 5.8 million people registered in SIDIAP in Catalonia, Spain. We included all patients newly diagnosed with COVID-19 [...] Read more.
We examined the correlation between previous antibiotic exposure and COVID-19 severity using a population-based observational matched cohort study with patient level data obtained for more than 5.8 million people registered in SIDIAP in Catalonia, Spain. We included all patients newly diagnosed with COVID-19 from March to June 2020 and identified all their antibiotic prescriptions in the previous two years. We used a composite severity endpoint, including pneumonia, hospital admission and death due to COVID-19. We examined the influence of high antibiotic exposure (>4 regimens), exposure to highest priority critically important antimicrobials (HPCIA) and recent exposure. Potential confounders were adjusted by logistic regression. A total of 280,679 patients were diagnosed with COVID-19, 146,656 of whom were exposed to at least one antibiotic course (52.3%) during the preceding two years. A total of 25,222 presented severe COVID-19 infection (9%), and the risk of severity was highest among those exposed to antibiotics (OR 1.12; 95% CI: 1.04–1.21). Among all individuals exposed to antibiotics, high, recent and exposure to HPCIAs were correlated with increased COVID severity (OR 1.19; 95% CI: 1.14–1.26; 1.41; 95% CI: 1.36–1.46; and 1.35; 95% CI: 1.30–1.40, respectively). Our findings confirm a significant correlation between previous antibiotic exposure and increased severity of COVID-19 disease. Full article
(This article belongs to the Special Issue Antibiotics Use in Primary Care during COVID-19)
Show Figures

Figure 1

Article
Natural Bred ε2-Phages Have an Improved Host Range and Virulence against Uropathogenic Escherichia coli over Their Ancestor Phages
Antibiotics 2021, 10(11), 1337; https://doi.org/10.3390/antibiotics10111337 - 01 Nov 2021
Cited by 2 | Viewed by 1219
Abstract
Alternative treatments for Escherichia coli infections are urgently needed, and phage therapy is a promising option where antibiotics fail, especially for urinary tract infections (UTI). We used wastewater-isolated phages to test their lytic activity against a panel of 47 E. coli strains reflecting [...] Read more.
Alternative treatments for Escherichia coli infections are urgently needed, and phage therapy is a promising option where antibiotics fail, especially for urinary tract infections (UTI). We used wastewater-isolated phages to test their lytic activity against a panel of 47 E. coli strains reflecting the diversity of strains found in UTI, including sequence type 131, 73 and 69. The plaquing host range (PHR) was between 13 and 63%. In contrast, the kinetic host range (KHR), describing the percentage of strains for which growth in suspension was suppressed for 24 h, was between 0% and 19%, substantially lower than the PHR. To improve the phage host range and their efficacy, we bred the phages by mixing and propagating cocktails on a subset of E. coli strains. The bred phages, which we termed evolution-squared ε2-phages, of a mixture of Myoviridae have KHRs up to 23% broader compared to their ancestors. Furthermore, using constant phage concentrations, Myoviridae ε2-phages suppressed the growth of higher bacterial inocula than their ancestors did. Thus, the ε2-phages were more virulent compared to their ancestors. Analysis of the genetic sequences of the ε2-phages with the broadest host range reveals that they are mosaic intercrossings of 2–3 ancestor phages. The recombination sites are distributed over the whole length of the genome. All ε2-phages are devoid of genes conferring lysogeny, antibiotic resistance, or virulence. Overall, this study shows that ε2-phages are remarkably more suitable than the wild-type phages for phage therapy. Full article
(This article belongs to the Special Issue Benefits of Bacteriophages to Combat Antibiotic-Resistant Bacteria)
Show Figures

Figure 1

Article
Nifedipine Potentiates Susceptibility of Salmonella Typhimurium to Different Classes of Antibiotics
Antibiotics 2021, 10(10), 1200; https://doi.org/10.3390/antibiotics10101200 - 01 Oct 2021
Cited by 1 | Viewed by 864
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
Show Figures

Figure 1

Article
Management of Common Infections in German Primary Care: A Cross-Sectional Survey of Knowledge and Confidence among General Practitioners and Outpatient Pediatricians
Antibiotics 2021, 10(9), 1131; https://doi.org/10.3390/antibiotics10091131 - 20 Sep 2021
Cited by 1 | Viewed by 980
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)
Show Figures

Figure 1

Article
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
Antibiotics 2021, 10(9), 1127; https://doi.org/10.3390/antibiotics10091127 - 18 Sep 2021
Cited by 2 | Viewed by 1359
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)
Article
Environmental and Pathogenic Carbapenem Resistant Bacteria Isolated from a Wastewater Treatment Plant Harbour Distinct Antibiotic Resistance Mechanisms
Antibiotics 2021, 10(9), 1118; https://doi.org/10.3390/antibiotics10091118 - 16 Sep 2021
Cited by 4 | Viewed by 1501
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 blaKPC-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)
Show Figures

Graphical abstract

Article
A Repeated State of Acidification Enhances the Anticariogenic Biofilm Activity of Glass Ionomer Cement Containing Fluoro-Zinc-Silicate Fillers
Antibiotics 2021, 10(8), 977; https://doi.org/10.3390/antibiotics10080977 - 13 Aug 2021
Viewed by 832
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
Show Figures

Figure 1

Article
A Fine-Tuned Lipophilicity/Hydrophilicity Ratio Governs Antibacterial Potency and Selectivity of Bifurcated Halogen Bond-Forming NBTIs
Antibiotics 2021, 10(7), 862; https://doi.org/10.3390/antibiotics10070862 - 15 Jul 2021
Cited by 4 | Viewed by 1408
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)
Show Figures

Figure 1

Article
National Facilitators and Barriers to the Implementation of Incentives for Antibiotic Access and Innovation
Antibiotics 2021, 10(6), 749; https://doi.org/10.3390/antibiotics10060749 - 21 Jun 2021
Cited by 1 | Viewed by 1370
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)
Show Figures

Figure 1

Article
Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid
Antibiotics 2021, 10(6), 732; https://doi.org/10.3390/antibiotics10060732 - 17 Jun 2021
Cited by 4 | Viewed by 1518
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
Show Figures

Figure 1

Article
Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections
Antibiotics 2021, 10(6), 727; https://doi.org/10.3390/antibiotics10060727 - 16 Jun 2021
Viewed by 1486
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)
Show Figures

Figure 1

Article
Impact of an Antimicrobial Stewardship Program on the Incidence of Carbapenem Resistant Gram-Negative Bacilli: An Interrupted Time-Series Analysis
Antibiotics 2021, 10(5), 586; https://doi.org/10.3390/antibiotics10050586 - 16 May 2021
Cited by 3 | Viewed by 1776
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)
Show Figures

Figure 1

Article
Apt (Adenine Phosphoribosyltransferase) Mutation in Laboratory-Selected Vancomycin-Intermediate Staphylococcus aureus
Antibiotics 2021, 10(5), 583; https://doi.org/10.3390/antibiotics10050583 - 14 May 2021
Viewed by 1638
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)
Show Figures

Figure 1

Article
Serious Neurological Adverse Events of Ceftriaxone
Antibiotics 2021, 10(5), 540; https://doi.org/10.3390/antibiotics10050540 - 06 May 2021
Cited by 7 | Viewed by 2068
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)
Show Figures

Figure 1

Article
Discovery of Pyrrolidine-2,3-diones as Novel Inhibitors of P. aeruginosa PBP3
Antibiotics 2021, 10(5), 529; https://doi.org/10.3390/antibiotics10050529 - 04 May 2021
Cited by 4 | Viewed by 1808
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)
Show Figures

Figure 1

Article
Overview and Evaluation of Existing Guidelines for Rational Antimicrobial Use in Small-Animal Veterinary Practice in Europe
Antibiotics 2021, 10(4), 409; https://doi.org/10.3390/antibiotics10040409 - 09 Apr 2021
Cited by 3 | Viewed by 2062
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)
Show Figures

Figure 1

Article
Biosynthesis and Heterologous Expression of Cacaoidin, the First Member of the Lanthidin Family of RiPPs
Antibiotics 2021, 10(4), 403; https://doi.org/10.3390/antibiotics10040403 - 08 Apr 2021
Cited by 6 | Viewed by 1928
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)
Show Figures

Figure 1

Article
Novel Soil-Derived Beta-Lactam, Chloramphenicol, Fosfomycin and Trimethoprim Resistance Genes Revealed by Functional Metagenomics
Antibiotics 2021, 10(4), 378; https://doi.org/10.3390/antibiotics10040378 - 03 Apr 2021
Cited by 1 | Viewed by 1325
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)
Show Figures

Figure 1

Article
Novel Seleno- and Thio-Urea Containing Dihydropyrrol-2-One Analogues as Antibacterial Agents
Antibiotics 2021, 10(3), 321; https://doi.org/10.3390/antibiotics10030321 - 19 Mar 2021
Cited by 7 | Viewed by 1579
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)
Show Figures

Figure 1

Article
Transmission of Similar Mcr-1 Carrying Plasmids among Different Escherichia coli Lineages Isolated from Livestock and the Farmer
Antibiotics 2021, 10(3), 313; https://doi.org/10.3390/antibiotics10030313 - 17 Mar 2021
Cited by 7 | Viewed by 2151
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)
Show Figures

Figure 1

Article
Allium Extract Implements Weaned Piglet’s Productive Parameters by Modulating Distal Gut Microbiota
Antibiotics 2021, 10(3), 269; https://doi.org/10.3390/antibiotics10030269 - 08 Mar 2021
Cited by 9 | Viewed by 1566
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)
Show Figures

Figure 1

Article
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
Antibiotics 2021, 10(3), 266; https://doi.org/10.3390/antibiotics10030266 - 05 Mar 2021
Cited by 6 | Viewed by 1503
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
Show Figures

Figure 1

Article
Burkholderia Bacteria Produce Multiple Potentially Novel Molecules that Inhibit Carbapenem-Resistant Gram-Negative Bacterial Pathogens
Antibiotics 2021, 10(2), 147; https://doi.org/10.3390/antibiotics10020147 - 02 Feb 2021
Cited by 6 | Viewed by 1338
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)
Show Figures

Figure 1

Article
The Prevalence and Clinical Significance of Anaerobic Bacteria in Major Liver Resection
Antibiotics 2021, 10(2), 139; https://doi.org/10.3390/antibiotics10020139 - 31 Jan 2021
Cited by 1 | Viewed by 851
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
Show Figures

Graphical abstract

Article
Key Parameters on the Antibacterial Activity of Silver Camphor Complexes
Antibiotics 2021, 10(2), 135; https://doi.org/10.3390/antibiotics10020135 - 30 Jan 2021
Cited by 4 | Viewed by 1274
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
Show Figures

Graphical abstract

Review

Review
Insights in the Development and Uses of Alternatives to Antibiotic Growth Promoters in Poultry and Swine Production
Antibiotics 2022, 11(6), 766; https://doi.org/10.3390/antibiotics11060766 - 02 Jun 2022
Viewed by 10911
Abstract
The overuse and misuse of antibiotics has contributed to the rise and spread of multidrug-resistant bacteria. To address this global public health threat, many countries have restricted the use of antibiotics as growth promoters and promoted the development of alternatives to antibiotics in [...] Read more.
The overuse and misuse of antibiotics has contributed to the rise and spread of multidrug-resistant bacteria. To address this global public health threat, many countries have restricted the use of antibiotics as growth promoters and promoted the development of alternatives to antibiotics in human and veterinary medicine and animal farming. In food-animal production, acidifiers, bacteriophages, enzymes, phytochemicals, probiotics, prebiotics, and antimicrobial peptides have shown hallmarks as alternatives to antibiotics. This review reports the current state of these alternatives as growth-promoting factors for poultry and swine production and describes their mode of action. Recent findings on their usefulness and the factors that presently hinder their broader use in animal food production are identified by SWOT (strength, weakness, opportunity, and threat) analysis. The potential for resistance development as well as co- and cross-resistance with currently used antibiotics is also discussed. Using predetermined keywords, we searched specialized databases including Scopus, Web of Science, and Google Scholar. Antibiotic resistance cannot be stopped, but its spreading can certainly be hindered or delayed with the development of more alternatives with innovative modes of action and a wise and careful use of antimicrobials in a One Health approach. Full article
(This article belongs to the Special Issue Antimicrobial Resistance and Antibiotic Alternatives in Livestock)
Show Figures

Graphical abstract

Review
Use of Novel Antibiograms to Determine the Need for Earlier Susceptibility Testing and Administration for New β-Lactam/β-Lactamase Inhibitors in the United States
Antibiotics 2022, 11(5), 660; https://doi.org/10.3390/antibiotics11050660 - 14 May 2022
Viewed by 2385
Abstract
Antimicrobial resistance is a global public health threat, and gram-negative bacteria, such as Enterobacterales and Pseudomonas aeruginosa, are particularly problematic with difficult-to-treat resistance phenotypes. To reduce morbidity and mortality, a reduction in the time to effective antimicrobial therapy (TTET) is needed, especially among [...] Read more.
Antimicrobial resistance is a global public health threat, and gram-negative bacteria, such as Enterobacterales and Pseudomonas aeruginosa, are particularly problematic with difficult-to-treat resistance phenotypes. To reduce morbidity and mortality, a reduction in the time to effective antimicrobial therapy (TTET) is needed, especially among critically ill patients. The antibiogram is an effective clinical tool that can provide accurate antimicrobial susceptibility information and facilitate early antimicrobial optimization, decrease TTET, and improve outcomes such as mortality, hospital length of stay, and costs. Guidance is lacking on how to validate the susceptibility to new antibacterial agents. Commonly used traditional and combination antibiograms may not adequately assist clinicians in making treatment decisions. Challenges with the current susceptibility testing of new β-lactam/β-lactamase inhibitor combinations persist, impacting the appropriate antibacterial choice and patient outcomes. Novel antibiograms such as syndromic antibiograms that incorporate resistant gram-negative phenotypes and/or minimum inhibitory concentration distributions may assist in determining the need for earlier susceptibility testing or help define an earlier optimal use of the new β-lactam/β-lactamase inhibitors. The purpose of this review is to emphasize novel antibiogram approaches that are capable of improving the time to susceptibility testing and administration for new β-lactam/β-lactamase inhibitors so that they are earlier in a patient’s treatment course. Full article
(This article belongs to the Special Issue Antimicrobial Use, Resistance and Stewardship)
Show Figures

Figure 1

Review
The Use of Bacteriophages in Biotechnology and Recent Insights into Proteomics
Antibiotics 2022, 11(5), 653; https://doi.org/10.3390/antibiotics11050653 - 13 May 2022
Viewed by 1109
Abstract
Phages have certain features, such as their ability to form protein–protein interactions, that make them good candidates for use in a variety of beneficial applications, such as in human or animal health, industry, food science, food safety, and agriculture. It is essential to [...] Read more.
Phages have certain features, such as their ability to form protein–protein interactions, that make them good candidates for use in a variety of beneficial applications, such as in human or animal health, industry, food science, food safety, and agriculture. It is essential to identify and characterize the proteins produced by particular phages in order to use these viruses in a variety of functional processes, such as bacterial detection, as vehicles for drug delivery, in vaccine development, and to combat multidrug resistant bacterial infections. Furthermore, phages can also play a major role in the design of a variety of cheap and stable sensors as well as in diagnostic assays that can either specifically identify specific compounds or detect bacteria. This article reviews recently developed phage-based techniques, such as the use of recombinant tempered phages, phage display and phage amplification-based detection. It also encompasses the application of phages as capture elements, biosensors and bioreceptors, with a special emphasis on novel bacteriophage-based mass spectrometry (MS) applications. Full article
(This article belongs to the Special Issue Frontiers in Phage Therapy)
Show Figures

Figure 1

Review
Companion Animals—An Overlooked and Misdiagnosed Reservoir of Carbapenem Resistance
Antibiotics 2022, 11(4), 533; https://doi.org/10.3390/antibiotics11040533 - 17 Apr 2022
Cited by 4 | Viewed by 1221
Abstract
The dissemination of antimicrobial-resistance is a major global threat affecting both human and animal health. Carbapenems are human use β-lactams of last resort; thus. the dissemination of carbapenemase-producing (CP) bacteria creates severe limitations for the treatment of multidrug-resistant bacteria in hospitalized patients. Even [...] Read more.
The dissemination of antimicrobial-resistance is a major global threat affecting both human and animal health. Carbapenems are human use β-lactams of last resort; thus. the dissemination of carbapenemase-producing (CP) bacteria creates severe limitations for the treatment of multidrug-resistant bacteria in hospitalized patients. Even though carbapenems are not routinely used in veterinary medicine, reports of infection or colonization by carbapenemase-producing Enterobacterales in companion animals are being reported. NDM-5 and OXA-48-like carbapenemases are among the most frequently reported in companion animals. Like in humans, Escherichia coli and Klebsiella pneumoniae are the most represented CP Enterobacterales found in companion animals, alongside with Acinetobacter baumannii. Considering that the detection of carbapenemase-producing Enterobacterales presents several difficulties, misdiagnosis of CP bacteria in companion animals may lead to important animal and public-health consequences. It is of the upmost importance to ensure an adequate monitoring and detection of CP bacteria in veterinary microbiology in order to safeguard animal health and minimise its dissemination to humans and the environment. This review encompasses an overview of the carbapenemase detection methods currently available, aiming to guide veterinary microbiologists on the best practices to improve its detection for clinical or research purposes. Full article
(This article belongs to the Special Issue Antibiotic Resistance and Antimicrobial Use in Companion Animals)
Show Figures

Figure 1

Review
Diagnosis of Bloodstream Infections: An Evolution of Technologies towards Accurate and Rapid Identification and Antibiotic Susceptibility Testing
Antibiotics 2022, 11(4), 511; https://doi.org/10.3390/antibiotics11040511 - 12 Apr 2022
Cited by 1 | Viewed by 1400
Abstract
Bloodstream infections (BSI) are a leading cause of death worldwide. The lack of timely and reliable diagnostic practices is an ongoing issue for managing BSI. The current gold standard blood culture practice for pathogen identification and antibiotic susceptibility testing is time-consuming. Delayed diagnosis [...] Read more.
Bloodstream infections (BSI) are a leading cause of death worldwide. The lack of timely and reliable diagnostic practices is an ongoing issue for managing BSI. The current gold standard blood culture practice for pathogen identification and antibiotic susceptibility testing is time-consuming. Delayed diagnosis warrants the use of empirical antibiotics, which could lead to poor patient outcomes, and risks the development of antibiotic resistance. Hence, novel techniques that could offer accurate and timely diagnosis and susceptibility testing are urgently needed. This review focuses on BSI and highlights both the progress and shortcomings of its current diagnosis. We surveyed clinical workflows that employ recently approved technologies and showed that, while offering improved sensitivity and selectivity, these techniques are still unable to deliver a timely result. We then discuss a number of emerging technologies that have the potential to shorten the overall turnaround time of BSI diagnosis through direct testing from whole blood—while maintaining, if not improving—the current assay’s sensitivity and pathogen coverage. We concluded by providing our assessment of potential future directions for accelerating BSI pathogen identification and the antibiotic susceptibility test. While engineering solutions have enabled faster assay turnaround, further progress is still needed to supplant blood culture practice and guide appropriate antibiotic administration for BSI patients. Full article
(This article belongs to the Special Issue Rapid Diagnostics of the Antimicrobial Resistance)
Show Figures

Figure 1

Review
Understanding microRNAs in the Context of Infection to Find New Treatments against Human Bacterial Pathogens
Antibiotics 2022, 11(3), 356; https://doi.org/10.3390/antibiotics11030356 - 08 Mar 2022
Viewed by 1229
Abstract
The development of RNA-based anti-infectives has gained interest with the successful application of mRNA-based vaccines. Small RNAs are molecules of RNA of <200 nucleotides in length that may control the expression of specific genes. Small RNAs include small interference RNAs (siRNAs), Piwi-interacting RNAs [...] Read more.
The development of RNA-based anti-infectives has gained interest with the successful application of mRNA-based vaccines. Small RNAs are molecules of RNA of <200 nucleotides in length that may control the expression of specific genes. Small RNAs include small interference RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), or microRNAs (miRNAs). Notably, the role of miRNAs on the post-transcriptional regulation of gene expression has been studied in detail in the context of cancer and many other genetic diseases. However, it is also becoming apparent that some human miRNAs possess important antimicrobial roles by silencing host genes essential for the progress of bacterial or viral infections. Therefore, their potential use as novel antimicrobial therapies has gained interest during the last decade. The challenges of the transport and delivery of miRNAs to target cells are important, but recent research with exosomes is overcoming the limitations in RNA-cellular uptake, avoiding their degradation. Therefore, in this review, we have summarised the latest developments in the exosomal delivery of miRNA-based therapies, which may soon be another complementary treatment to pathogen-targeted antibiotics that could help solve the problem caused by multidrug-resistant bacteria. Full article
(This article belongs to the Special Issue Alternative Approaches to Treating Antimicrobial Resistant Infections)
Show Figures

Figure 1

Review
Review and Comparison of Antimicrobial Resistance Gene Databases
Antibiotics 2022, 11(3), 339; https://doi.org/10.3390/antibiotics11030339 - 04 Mar 2022
Cited by 3 | Viewed by 1550
Abstract
As the prevalence of antimicrobial resistance genes is increasing in microbes, we are facing the return of the pre-antibiotic era. Consecutively, the number of studies concerning antibiotic resistance and its spread in the environment is rapidly growing. Next generation sequencing technologies are widespread [...] Read more.
As the prevalence of antimicrobial resistance genes is increasing in microbes, we are facing the return of the pre-antibiotic era. Consecutively, the number of studies concerning antibiotic resistance and its spread in the environment is rapidly growing. Next generation sequencing technologies are widespread used in many areas of biological research and antibiotic resistance is no exception. For the rapid annotation of whole genome sequencing and metagenomic results considering antibiotic resistance, several tools and data resources were developed. These databases, however, can differ fundamentally in the number and type of genes and resistance determinants they comprise. Furthermore, the annotation structure and metadata stored in these resources can also contribute to their differences. Several previous reviews were published on the tools and databases of resistance gene annotation; however, to our knowledge, no previous review focused solely and in depth on the differences in the databases. In this review, we compare the most well-known and widely used antibiotic resistance gene databases based on their structure and content. We believe that this knowledge is fundamental for selecting the most appropriate database for a research question and for the development of new tools and resources of resistance gene annotation. Full article
(This article belongs to the Special Issue Genetic Background of Antimicrobial Resistance)
Show Figures

Figure 1

Review
Beyond Soil-Dwelling Actinobacteria: Fantastic Antibiotics and Where to Find Them
Antibiotics 2022, 11(2), 195; https://doi.org/10.3390/antibiotics11020195 - 02 Feb 2022
Cited by 2 | Viewed by 1699
Abstract
Bacterial secondary metabolites represent an invaluable source of bioactive molecules for the pharmaceutical and agrochemical industries. Although screening campaigns for the discovery of new compounds have traditionally been strongly biased towards the study of soil-dwelling Actinobacteria, the current antibiotic resistance and discovery crisis [...] Read more.
Bacterial secondary metabolites represent an invaluable source of bioactive molecules for the pharmaceutical and agrochemical industries. Although screening campaigns for the discovery of new compounds have traditionally been strongly biased towards the study of soil-dwelling Actinobacteria, the current antibiotic resistance and discovery crisis has brought a considerable amount of attention to the study of previously neglected bacterial sources of secondary metabolites. The development and application of new screening, sequencing, genetic manipulation, cultivation and bioinformatic techniques have revealed several other groups of bacteria as producers of striking chemical novelty. Biosynthetic machineries evolved from independent taxonomic origins and under completely different ecological requirements and selective pressures are responsible for these structural innovations. In this review, we summarize the most important discoveries related to secondary metabolites from alternative bacterial sources, trying to provide the reader with a broad perspective on how technical novelties have facilitated the access to the bacterial metabolic dark matter. Full article
Show Figures

Figure 1

Review
Air Ambulance: Antimicrobial Power of Bacterial Volatiles
Antibiotics 2022, 11(1), 109; https://doi.org/10.3390/antibiotics11010109 - 14 Jan 2022
Cited by 4 | Viewed by 956
Abstract
We are currently facing an antimicrobial resistance crisis, which means that a lot of bacterial pathogens have developed resistance to common antibiotics. Hence, novel and innovative solutions are urgently needed to combat resistant human pathogens. A new source of antimicrobial compounds could be [...] Read more.
We are currently facing an antimicrobial resistance crisis, which means that a lot of bacterial pathogens have developed resistance to common antibiotics. Hence, novel and innovative solutions are urgently needed to combat resistant human pathogens. A new source of antimicrobial compounds could be bacterial volatiles. Volatiles are ubiquitous produced, chemically divers and playing essential roles in intra- and interspecies interactions like communication and antimicrobial defense. In the last years, an increasing number of studies showed bioactivities of bacterial volatiles, including antibacterial, antifungal and anti-oomycete activities, indicating bacterial volatiles as an exciting source for novel antimicrobial compounds. In this review we introduce the chemical diversity of bacterial volatiles, their antimicrobial activities and methods for testing this activity. Concluding, we discuss the possibility of using antimicrobial volatiles to antagonize the antimicrobial resistance crisis. Full article
(This article belongs to the Special Issue The Ecological Role of Antibiotic Production in Bacteria)
Show Figures

Figure 1

Review
Biofilms in Surgical Site Infections: Recent Advances and Novel Prevention and Eradication Strategies
Antibiotics 2022, 11(1), 69; https://doi.org/10.3390/antibiotics11010069 - 07 Jan 2022
Cited by 4 | Viewed by 1273
Abstract
Surgical site infections (SSIs) are common postoperative occurrences due to contamination of the surgical wound or implanted medical devices with community or hospital-acquired microorganisms, as well as other endogenous opportunistic microbes. Despite numerous rules and guidelines applied to prevent these infections, SSI rates [...] Read more.
Surgical site infections (SSIs) are common postoperative occurrences due to contamination of the surgical wound or implanted medical devices with community or hospital-acquired microorganisms, as well as other endogenous opportunistic microbes. Despite numerous rules and guidelines applied to prevent these infections, SSI rates are considerably high, constituting a threat to the healthcare system in terms of morbidity, prolonged hospitalization, and death. Approximately 80% of human SSIs, including chronic wound infections, are related to biofilm-forming bacteria. Biofilm-associated SSIs are extremely difficult to treat with conventional antibiotics due to several tolerance mechanisms provided by the multidrug-resistant bacteria, usually arranged as polymicrobial communities. In this review, novel strategies to control, i.e., prevent and eradicate, biofilms in SSIs are presented and discussed, focusing mainly on two attractive approaches: the use of nanotechnology-based composites and natural plant-based products. An overview of new therapeutic agents and strategic approaches to control epidemic multidrug-resistant pathogenic microorganisms, particularly when biofilms are present, is provided alongside other combinatorial approaches as attempts to obtain synergistic effects with conventional antibiotics and restore their efficacy to treat biofilm-mediated SSIs. Some detection and real-time monitoring systems to improve biofilm control strategies and diagnosis of human infections are also discussed. Full article
Show Figures

Graphical abstract

Review
Efflux Pump Mediated Antimicrobial Resistance by Staphylococci in Health-Related Environments: Challenges and the Quest for Inhibition
Antibiotics 2021, 10(12), 1502; https://doi.org/10.3390/antibiotics10121502 - 07 Dec 2021
Cited by 7 | Viewed by 1494
Abstract
The increasing emergence of antimicrobial resistance in staphylococcal bacteria is a major health threat worldwide due to significant morbidity and mortality resulting from their associated hospital- or community-acquired infections. Dramatic decrease in the discovery of new antibiotics from the pharmaceutical industry coupled with [...] Read more.
The increasing emergence of antimicrobial resistance in staphylococcal bacteria is a major health threat worldwide due to significant morbidity and mortality resulting from their associated hospital- or community-acquired infections. Dramatic decrease in the discovery of new antibiotics from the pharmaceutical industry coupled with increased use of sanitisers and disinfectants due to the ongoing COVID-19 pandemic can further aggravate the problem of antimicrobial resistance. Staphylococci utilise multiple mechanisms to circumvent the effects of antimicrobials. One of these resistance mechanisms is the export of antimicrobial agents through the activity of membrane-embedded multidrug efflux pump proteins. The use of efflux pump inhibitors in combination with currently approved antimicrobials is a promising strategy to potentiate their clinical efficacy against resistant strains of staphylococci, and simultaneously reduce the selection of resistant mutants. This review presents an overview of the current knowledge of staphylococcal efflux pumps, discusses their clinical impact, and summarises compounds found in the last decade from plant and synthetic origin that have the potential to be used as adjuvants to antibiotic therapy against multidrug resistant staphylococci. Critically, future high-resolution structures of staphylococcal efflux pumps could aid in design and development of safer, more target-specific and highly potent efflux pump inhibitors to progress into clinical use. Full article
Show Figures

Figure 1

Back to TopTop