Antibiotics

16 pages, 2619 KiB

Open AccessArticle

Innovative Alignment-Based Method for Antiviral Peptide Prediction

by Daniela de Llano García, Yovani Marrero-Ponce, Guillermin Agüero-Chapin, Francesc J. Ferri, Agostinho Antunes, Felix Martinez-Rios and Hortensia Rodríguez

Antibiotics 2024, 13(8), 768; https://doi.org/10.3390/antibiotics13080768 (registering DOI) - 14 Aug 2024

Abstract

Antiviral peptides (AVPs) represent a promising strategy for addressing the global challenges of viral infections and their growing resistances to traditional drugs. Lab-based AVP discovery methods are resource-intensive, highlighting the need for efficient computational alternatives. In this study, we developed five non-trained but [...] Read more.

Antiviral peptides (AVPs) represent a promising strategy for addressing the global challenges of viral infections and their growing resistances to traditional drugs. Lab-based AVP discovery methods are resource-intensive, highlighting the need for efficient computational alternatives. In this study, we developed five non-trained but supervised multi-query similarity search models (MQSSMs) integrated into the StarPep toolbox. Rigorous testing and validation across diverse AVP datasets confirmed the models’ robustness and reliability. The top-performing model, M13+, demonstrated impressive results, with an accuracy of 0.969 and a Matthew’s correlation coefficient of 0.71. To assess their competitiveness, the top five models were benchmarked against 14 publicly available machine-learning and deep-learning AVP predictors. The MQSSMs outperformed these predictors, highlighting their efficiency in terms of resource demand and public accessibility. Another significant achievement of this study is the creation of the most comprehensive dataset of antiviral sequences to date. In general, these results suggest that MQSSMs are promissory tools to develop good alignment-based models that can be successfully applied in the screening of large datasets for new AVP discovery. Full article

(This article belongs to the Special Issue Computational Approaches in Discovery and Design of Antimicrobial Peptides - 2nd Edition)

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15 pages, 1068 KiB

Open AccessArticle

Multidrug-Resistant Staphylococcus aureus Colonizing Pigs and Farm Workers in Rio de Janeiro State, Brazil: Potential Interspecies Transmission of Livestock-Associated MRSA (LA-MRSA) ST398

by Joana Talim, Ianick Martins, Cassio Messias, Hellen Sabino, Laura Oliveira, Tatiana Pinto, Julia Albuquerque, Aloysio Cerqueira, Ítalo Dolores, Beatriz Moreira, Renato Silveira, Felipe Neves and Renata Rabello

Antibiotics 2024, 13(8), 767; https://doi.org/10.3390/antibiotics13080767 - 14 Aug 2024

Abstract

Multidrug-resistant (MDR) Staphylococcus aureus has been increasingly isolated from pigs and people in close contact with them, especially livestock-associated methicillin-resistant S. aureus (LA-MRSA). In this cross-sectional study, we investigated S. aureus colonization in pigs and farm workers, their resistance profile, and genetic background [...] Read more.

Multidrug-resistant (MDR) Staphylococcus aureus has been increasingly isolated from pigs and people in close contact with them, especially livestock-associated methicillin-resistant S. aureus (LA-MRSA). In this cross-sectional study, we investigated S. aureus colonization in pigs and farm workers, their resistance profile, and genetic background to estimate interspecies transmission potential within farms from Rio de Janeiro state, Brazil, between 2014 and 2019. We collected nasal swabs from 230 pigs and 27 workers from 16 and 10 farms, respectively. Five MDR strains were subjected to whole genome sequencing. Fourteen (6.1%) pigs and seven (25.9%) humans were colonized with S. aureus, mostly (64–71%) MDR strains. Resistance to clindamycin, erythromycin, penicillin, and tetracycline was the most common among the pig and human strains investigated. MDR strains shared several resistance genes [blaZ, dfrG, fexA, lsa(E), and tet(M)]. Pig and human strains recovered from the same farm shared the same genetic background and antimicrobial resistance profile. LA-MRSA ST398-SCCmecV-t011 was isolated from pigs in two farms and from a farm worker in one of them, suggesting interspecies transmission. The association between pig management practices and MDR S. aureus colonization might be investigated in additional studies. Full article

(This article belongs to the Special Issue Use of Antibiotics in Animals and Antimicrobial Resistance)

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15 pages, 793 KiB

Open AccessReview

Practical Application of Aztreonam-Avibactam as a Treatment Strategy for Ambler Class B Metallo-β-Lactamase Producing Enterobacteriaceae

by Darren W. Wong

Antibiotics 2024, 13(8), 766; https://doi.org/10.3390/antibiotics13080766 - 14 Aug 2024

Abstract

Carbapenem-resistant Enterobacteriaceae infections are a considerable challenge for clinicians. In recent years, novel antibiotic options have resulted in a tremendous advance in medical therapy; however, current treatment options are primarily effective for resistance derived from serine-based carbapenemases. The Ambler class B metallo-β-lactamases (MBLs) [...] Read more.

Carbapenem-resistant Enterobacteriaceae infections are a considerable challenge for clinicians. In recent years, novel antibiotic options have resulted in a tremendous advance in medical therapy; however, current treatment options are primarily effective for resistance derived from serine-based carbapenemases. The Ambler class B metallo-β-lactamases (MBLs) remain a critical challenge with decidedly fewer effective options. One intriguing option for these MBL pathogens is the combination of ceftazidime-avibactam with aztreonam. While clinical experience with this regimen is limited, in vitro studies are promising, and limited case reports describe success with this regimen; however, significant challenges preclude widespread adoption of this novel treatment regimen. A systemic literature review was performed to offer recommendations based on current evidence for a practical strategy on how to best integrate the use of aztreonam with avibactam combination therapy. Full article

(This article belongs to the Special Issue Carbapenem Resistant Gram-Negative Pathogens—a Comprehensive Approach to Acinetobacter, Pseudomonas, Enterobacteriaceae, and Stenotrophomonas: A Global Healthcare Threat)

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12 pages, 629 KiB

Open AccessArticle

Exploring the Antimicrobial Resistance Profile of Salmonella typhi and Its Clinical Burden

by Muhammad Asghar, Taj Ali Khan, Marie Nancy Séraphin, Lena F. Schimke, Otavio Cabral-Marques, Ihtisham Ul Haq, Zia-ur-Rehman Farooqi, Susana Campino, Ihsan Ullah and Taane G. Clark

Antibiotics 2024, 13(8), 765; https://doi.org/10.3390/antibiotics13080765 - 14 Aug 2024

Abstract

Background: Typhoid fever caused by Salmonella enterica serovar Typhi (S. typhi) continues to pose a significant risk to public health in developing countries, including Pakistan. This study investigated the epidemiological factors linked to suspected and confirmed S. typhi infections in Peshawar’s hospital [...] Read more.

Background: Typhoid fever caused by Salmonella enterica serovar Typhi (S. typhi) continues to pose a significant risk to public health in developing countries, including Pakistan. This study investigated the epidemiological factors linked to suspected and confirmed S. typhi infections in Peshawar’s hospital population. Methodology: A total of 5735 blood samples of patients with suspected enteric fever were collected from September 2022 to November 2023. S. typhi infection was confirmed using microbiological culture of blood samples, biochemical-based tests, and DNA-sequencing methods. Drug sensitivity testing on cultures was conducted as per the CLSI guidelines. Chi-square tests were used to analyze the clinical and epidemiologic characteristics of 5735 samples stratified by S. typhi infection status, and risk factors were assessed by applying logistic regression models to estimate odds ratios (ORs). Results: The number of confirmed typhoid fever cases in this hospital-based study population was 691 (/5735, 12.0%), more prevalent in males (447/3235 13.8%) and children (0–11 years) (429/2747, 15.6%). Compared to children, the risk of S. typhi infection was lower in adolescence (adjusted OR = 0.52; 95% CI: 0.42–0.66), adulthood (19–59 years; aOR = 0.30; 95% CI: 0.25–0.38), and older adulthood (aOR = 0.08; 95% CI: 0.04–0.18) (p < 0.001). Compared to males, the risk of S. typhi infection was lower in females (aOR = 0.67; 95% CI = 0.56–0.80; p = 0.002). Living in a rural residence (compared to urban) was associated with a higher risk of infection (aOR = 1.38; 95% CI: 1.16–1.63; p = 0.001), while access to a groundwater source (compared to municipal water supply) led to a lower risk (aOR = 0.56; 95% CI: 0.43–0.73; p = 0.002). Vaccination demonstrated a robust protective effect (aOR = 0.069; 95% CI = 0.04–0.11, p = 0.002). For those with typhoid infections, clinical biomarker analysis revealed the presence of leucopenia (65/691, 9.4%), thrombocytopenia (130/691, 18.8%), and elevated alanine aminotransferase (ALT) (402/691, 58.2%) and C-reactive protein (CRP) (690/691, 99.9%) levels. Worryingly, among the positive S. typhi isolates, there was a high prevalence of drug resistance (653/691), including multidrug-resistant (MDR 82/691, 11.9%) and extensively drug-resistant types (XDR, 571/691, 82.6%). Conclusions: This study highlights the importance of age, sex, locality, water source, and vaccination status in shaping the epidemiological landscape of S. typhi in the Peshawar district. It implies that expanding vaccination coverage to the broader population of Khyber Pakhtunkhwa province, particularly in the district of Peshawar, would be beneficial. Full article

(This article belongs to the Special Issue Epidemiology of Clinically Relevant Bacteria and Antimicrobial Resistance)

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18 pages, 2360 KiB

Open AccessArticle

Antimicrobial Properties and Cytotoxicity of LL-37-Derived Synthetic Peptides to Treat Orthopedic Infections

by Vincenzo Pennone, Elisa Angelini, David Sarlah and Arianna B. Lovati

Antibiotics 2024, 13(8), 764; https://doi.org/10.3390/antibiotics13080764 - 14 Aug 2024

Viewed by 87

Abstract

Open fractures and prosthetic joints are prone to bacterial infections, especially those involving biofilms, and are worsened by antibiotic inefficacy and resistance. This highlights the need for targeted treatments against orthopedic infections. LL-37, a human cathelicidin, is known for its antimicrobial properties. This [...] Read more.

Open fractures and prosthetic joints are prone to bacterial infections, especially those involving biofilms, and are worsened by antibiotic inefficacy and resistance. This highlights the need for targeted treatments against orthopedic infections. LL-37, a human cathelicidin, is known for its antimicrobial properties. This study aimed to synthesize and evaluate LL-37-derived antimicrobial peptides (AMPs) for antibacterial efficacy and toxicity. Several truncated LL-37 analogues were created and tested against 18 bacterial strains, both ATCC and orthopedic clinical isolates, using MIC and MBC assays. Synergy with antibiotics and resistance development were also analyzed, alongside cytotoxicity on NIH-3T3 fibroblasts and hemolytic activity assessments. Six AMPs were synthesized, with FK-16 and GF-17 emerging as the most effective. The MIC values ranged from 4.69 to 18.75 µg/mL and 2.34 to 18.75 µg/mL, respectively, against S. epidermidis and S. aureus, with the MBC values matching the MIC values. Cytotoxicity tests showed no toxicity at concentrations below 75 µg/mL for GF-17 and 150 µg/mL for FK-16. Hemolytic activity was below 1% at 18.75 µg/mL for GF-17 and 75 µg/mL for FK-16. These AMPs showed no synergistic effects with antibiotics and no resistance development. FK-16 and GF-17 effectively removed biofilms, particularly against S. epidermidis. Incorporating these AMPs into surgical materials (hydrogels, cements, etc.) could enhance infection control in orthopedic procedures, warranting further in vivo studies. Full article

(This article belongs to the Special Issue Prevention, Diagnostic and Antibiotic Treatment of Periprosthetic Joint and Fracture Related Infection, 2nd Edition)

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Graphical abstract

Graphical abstract
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Effect of selected AMPs at different concentrations on the viability of NIH-3T3 fibroblast compared to cells cultured in CM (NC) and CM supplemented with 0.1% Triton-X100 (PC) assessed by means of the MTT assay. Red dotted lines represent the NC mean value of Abs (0.23). Statistical significance: p < 0.0001 (***). Full article ">Figure 2
Hemolytic activity expressed as a percentage (%). Red dotted line reports the cut off range as ≤1%. Full article ">Figure 3
MIC (A–C) and MBC (D–F) values comparing cLL-37, GF-17 and FK-16. Data were grouped per bacterial genera: Staphylococci (A,D), P. aeruginosa (B,E), E. coli (C,F) and reported as mean ± SEM. Significance, where present, is shown. * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001; **** p ≤ 0.0001. Full article ">Figure 4
Changes in the MIC values of FK-16 and GF-17 on different strains. Full article ">Figure 5
CLSM images of 72-h-old biofilms produced by S. epidermidis ATCC 35984 and GOI1153754-03-14, S. aureus ATCC 49230 and Sau89. In the columns, the untreated biofilm and biofilms after treatments with FK-16, GF-17 and vancomycin are depicted. Scale bars: 100 μm. Red arrows highlight the biofilm disruption by vancomycin, while yellow arrows show the abundance of dead (red) bacteria in the case of FK-16 and GF-17 on S. epidermidis GOI1153754-03-04 biofilms. Full article ">Figure 6
Histograms show the mean ± SD of relative mortality of each treatment in comparison with the controls (untreated). p values are shown where the differences were statistically significant. Full article ">

51 pages, 24336 KiB

Open AccessReview

An Insight into Rational Drug Design: The Development of In-House Azole Compounds with Antimicrobial Activity

by Daniel Ungureanu, Ovidiu Oniga, Cristina Moldovan, Ioana Ionuț, Gabriel Marc, Anca Stana, Raluca Pele, Mihaela Duma and Brîndușa Tiperciuc

Antibiotics 2024, 13(8), 763; https://doi.org/10.3390/antibiotics13080763 - 13 Aug 2024

Viewed by 425

Abstract

Antimicrobial resistance poses a major threat to global health as the number of efficient antimicrobials decreases and the number of resistant pathogens rises. Our research group has been actively involved in the design of novel antimicrobial drugs. The blueprints of these compounds were [...] Read more.

Antimicrobial resistance poses a major threat to global health as the number of efficient antimicrobials decreases and the number of resistant pathogens rises. Our research group has been actively involved in the design of novel antimicrobial drugs. The blueprints of these compounds were azolic heterocycles, particularly thiazole. Starting with oxadiazolines, our research group explored, one by one, the other five-membered heterocycles, developing more or less potent compounds. An overview of this research activity conducted by our research group allowed us to observe an evolution in the methodology used (from inhibition zone diameters to minimal inhibitory concentrations and antibiofilm potential determination) correlated with the design of azole compounds based on results obtained from molecular modeling. The purpose of this review is to present the development of in-house azole compounds with antimicrobial activity, designed over the years by this research group from the departments of Pharmaceutical and Therapeutical Chemistry in Cluj-Napoca. Full article

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

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14 pages, 896 KiB

Open AccessArticle

Rapid Reversal of Carbapenemase-Producing Pseudomonas aeruginosa Epidemiology from bla_VIM- to bla_NDM-harbouring Isolates in a Greek Tertiary Care Hospital

by Efthymia Protonotariou, Georgios Meletis, Nikoletta Vlachodimou, Andigoni Malousi, Areti Tychala, Charikleia Katsanou, Aikaterini Daviti, Paraskevi Mantzana and Lemonia Skoura

Antibiotics 2024, 13(8), 762; https://doi.org/10.3390/antibiotics13080762 - 12 Aug 2024

Viewed by 278

Abstract

Carbapenemase-producing Pseudomonas aeruginosa strains present a specific geographical distribution regarding the type of carbapenemase-encoding genes that they harbor. For more than twenty years, VIM-type enzymes were the only major carbapenemases that were detected among P. aeruginosa isolates in Greece until the emergence of [...] Read more.

Carbapenemase-producing Pseudomonas aeruginosa strains present a specific geographical distribution regarding the type of carbapenemase-encoding genes that they harbor. For more than twenty years, VIM-type enzymes were the only major carbapenemases that were detected among P. aeruginosa isolates in Greece until the emergence of NDM-1-encoding P. aeruginosa in early 2023. In the present study, we present the rapid reversal of the carbapenemase-producing P. aeruginosa epidemiology from bla_VIM- to bla_NDM-harbouring isolates that occurred in our hospital since then. Between January 2023 and February 2024, 139 isolates tested positive for carbapenemase production with the NG-Test CARBA 5 immunochromatographic assay. Eight isolates were processed with the Hybrispot antimicrobial resistance direct flow chip molecular assay, and the first NDM-producing isolate was further analyzed through whole genome sequencing and bioinformatics analysis. Multiple resistance genes were detected by molecular techniques in accordance with the extensively drug-resistant phenotype. The isolate that was subjected to whole-genome sequencing belonged to the P. aeruginosa high-risk clone ST308, and the bla_NDM was located in the chromosome in accordance with previously reported data. During the study period, NDM-producing isolates were increasingly detected, and only five months after their emergence, they overcame VIM producers. Our results indicate the potential of this new clone to spread rapidly and predominate within healthcare institutions, further restricting the already limited treatment options. Full article

(This article belongs to the Special Issue Microbial Resistance to Carbapenems: Epidemiology, Detection and Treatment Options)

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11 pages, 1810 KiB

Open AccessArticle

A Hunt for the Resistance of Haemophilus influnezae to Beta-Lactams

by Mélanie Denizon, Eva Hong, Aude Terrade, Muhamed-Kheir Taha and Ala-Eddine Deghmane

Antibiotics 2024, 13(8), 761; https://doi.org/10.3390/antibiotics13080761 - 12 Aug 2024

Viewed by 286

Abstract

Infections due to Haemophilus influnezae require prompt treatment using beta-lactam antibiotics. We used a collection of 81 isolates obtained between 1940 and 2001 from several countries. Whole genome sequencing showed the high heterogeneity of these isolates but allowed us to track the acquisition [...] Read more.

Infections due to Haemophilus influnezae require prompt treatment using beta-lactam antibiotics. We used a collection of 81 isolates obtained between 1940 and 2001 from several countries. Whole genome sequencing showed the high heterogeneity of these isolates but allowed us to track the acquisition of beta-lactamase, which was first detected in 1980. Modifications of the ftsI gene encoding the penicillin-binding protein 3, PBP3, also involved in resistance to beta-lactams, appeared in 1991. These modifications (G490E, A502V, R517H, and N526K) were associated with resistance to amoxicillin that was not relieved by a beta-lactamase inhibitor (clavulanic acid), but the isolates retained susceptibility to third-generation cephalosporins (3GC). The modeling of the PBP3 structure suggested that these modifications may reduce the accessibility to the PBP3 active site. Other modifications appeared in 1998 and were associated with resistance to 3GC (S357N, M377I, S385T, and L389F). Modeling of the PBP3 structure suggested that they lie near the S379xN motif of the active site of PBP3. Overall resistance to amoxicillin was detected among 25 isolates (30.8%) of this collection. Resistance to sulfonamides was predicted by a genomic approach from the sequences of the folP gene (encoding the dihydropteroate synthase) due to difficulties in interpreting phenotypic anti-microbial testing and found in 13 isolates (16.0%). Our data suggest a slower spread of resistance to sulfonamides, which may be used for the treatment of H. influnezae infections. Genomic analysis may help in the prediction of antibiotic resistance, inform structure–function analysis, and guide the optimal use of antibiotics. Full article

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

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Geographical distribution of H. infuenzae isolates used in this study. The number of isolates is indicated for each country and the period of isolation is indicated between parentheses. The color intensity is proportional to the number of isolates. Full article ">Figure 2
A neighbor network based on the cgMLST allelic profiles of the 81 isolates in this study. Individual isolates are represented by circles and the color of the circle indicates the serotype of the corresponding isolate. The five H. quentini isolates were clustered together (arrow). Full article ">Figure 3
Representation of PBP3 modeled structure. A surface view of the structure in the representation of wild-type PBP3. The three motifs of the active site pocket (S327xxK, S379xN, and K512TG) are shown in red and active S327 is shown in purple). The critical residues for the resistance to amoxicillin (G490 A502, R517, and N526) are shown in green. The critical residues for resistance to amoxicillin (S357, M377, S385, and L389) are shown in blue, particularly M377, which lies very close to the active site pocket. Full article ">Figure 4
Phylogenetic tree of ftsI based on multiple alignments of amino acid sequences deduced by the DNA sequences of the 160 unique PBP3 amino acid sequences. The tree was visualized by SplitsTree4 as described in the Materials Methods section. The four groups of PBP3 were defined according to our previous work [<a href="#B11-antibiotics-13-00761" class="html-bibr">11</a>]. Group 1 (wild-type sequences) and group 2 (no critical mutations) corresponded to amoxicillin-susceptible isolates, group 3 corresponded to mutations (G490E A502V, R517H, and N526K) corresponding to amoxicillin-resistant isolates, and group 4 corresponded to mutations conferring resistance to amoxicillin and 3rd-generation cephalosporins (S357N, M377I, S385T, and L389F). The 21 distinct 207 aa-domains of PBP3 involved in the resistance to beta-lactams of the current study are indicated by arrows in each of the four groups. Full article ">

14 pages, 3474 KiB

Open AccessArticle

A Real-World Data Observational Analysis of the Impact of Liposomal Amphotericin B on Renal Function Using Machine Learning in Critically Ill Patients

by Ignasi Sacanella, Erika Esteve-Pitarch, Jessica Guevara-Chaux, Julen Berrueta, Alejandro García-Martínez, Josep Gómez, Cecilia Casarino, Florencia Alés, Laura Canadell, Ignacio Martín-Loeches, Santiago Grau, Francisco Javier Candel, María Bodí and Alejandro Rodríguez

Antibiotics 2024, 13(8), 760; https://doi.org/10.3390/antibiotics13080760 - 12 Aug 2024

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Abstract

Background: Liposomal amphotericin B (L-AmB) has become the mainstay of treatment for severe invasive fungal infections. However, the potential for renal toxicity must be considered. Aims: To evaluate the incidence of acute kidney injury (AKI) in critically ill patients receiving L-AmB for more [...] Read more.

Background: Liposomal amphotericin B (L-AmB) has become the mainstay of treatment for severe invasive fungal infections. However, the potential for renal toxicity must be considered. Aims: To evaluate the incidence of acute kidney injury (AKI) in critically ill patients receiving L-AmB for more than 48 h. Methods: Retrospective, observational, single-center study. Clinical, demographic and laboratory variables were obtained automatically from the electronic medical record. AKI incidence was analyzed in the entire population and in patients with a “low” or “high” risk of AKI based on their creatinine levels at the outset of the study. Factors associated with the development of AKI were studied using random forest models. Results: Finally, 67 patients with a median age of 61 (53–71) years, 67% male, a median SOFA of 4 (3–6.5) and a crude mortality of 34.3% were included. No variations in serum creatinine were observed during the observation period, except for a decrease in the high-risk subgroup. A total of 26.8% (total population), 25% (low risk) and 13% (high risk) of patients developed AKI. Norepinephrine, the SOFA score, furosemide (general model), potassium, C-reactive protein and procalcitonin (low-risk subgroup) were the variables identified by the random forest models as important contributing factors to the development of AKI other than L-AmB administration. Conclusions: The development of AKI is multifactorial and the administration of L-AmB appears to be safe in this group of patients. Full article

(This article belongs to the Special Issue Infection Diagnostics and Antimicrobial Therapy for Critical Patient)

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12 pages, 1942 KiB

Open AccessArticle

Global Variation in Escherichia coli mcr-1 Genes and Plasmids from Animal and Human Genomes Following Colistin Usage Restrictions in Livestock

by Biel Garcias, Mayra Alejandra Flores, Mercedes Fernández, William Monteith, Ben Pascoe, Samuel K. Sheppard, Marga Martín, Martí Cortey and Laila Darwich

Antibiotics 2024, 13(8), 759; https://doi.org/10.3390/antibiotics13080759 - 12 Aug 2024

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Abstract

Antimicrobial resistance (AMR) is a significant global health threat, with multidrug-resistant (MDR) bacterial clones becoming a major concern. Polymyxins, especially colistin, have reemerged as last-resort treatments for MDR Gram-negative infections. However, colistin use in livestock has spread mobile colistin resistance (mcr) [...] Read more.

Antimicrobial resistance (AMR) is a significant global health threat, with multidrug-resistant (MDR) bacterial clones becoming a major concern. Polymyxins, especially colistin, have reemerged as last-resort treatments for MDR Gram-negative infections. However, colistin use in livestock has spread mobile colistin resistance (mcr) genes, notably mcr-1, impacting human health. In consequence, its livestock use was banned in 2017, originating a natural experiment to study bacterial adaptation. The aim of this work was to analyse the changes in the mcr-1 genetic background after colistin restriction across the world. This study analyses 3163 Escherichia coli genomes with the mcr-1 gene from human and livestock hosts, mainly from Asia (n = 2621) and Europe (n = 359). Genetic characterisation identifies IncI2 (40.4%), IncX4 (26.7%), and multidrug-resistant IncHI2 (18.8%) as the most common plasmids carrying mcr-1. There were differences in plasmids between continents, with IncX4 (56.6%) being the most common in Europe, while IncI2 (44.8%) was predominant in Asia. Promoter variants related to reduced fitness costs and ISApl1 showed a distinct pattern of association that appears to be associated with adaptation to colistin restriction, which differed between continents. Thus, after the colistin ban, Europe saw a shift to specialised mcr-1 plasmids as IncX4, while ISApl1 decreased in Asia due to changes in the prevalence of the distinct promoter variants. These analyses illustrate the evolution of mcr-1 adaptation following colistin use restrictions and the need for region-specific strategies against AMR following colistin restrictions. Full article

(This article belongs to the Special Issue Antibiotic Resistance, Virulence Profile and Genomic Analysis among Multidrug-Resistant Bacteria Isolated from Humans and Animals)

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Population structure of genomes inferred to contain the mcr-1 gene shows no host specialisation. (A,B) Bar plots showing the ten most common sequence types (ST) (A) and clonal complexes (CC) (B). (C) Minimum spanning tree showing ST distribution between hosts. The ten most common CCs are highlighted with a red circle. Host origin: human (in blue), chicken (in green), swine (in orange) and bovine (in red). Full article ">Figure 2
Association of the distinct plasmid types with promoter variants and inferred ISApl1 carriage. Strongly ISApl1-associated variants (more than 40%) are highlighted in red, while those low associated (less than 5%) are in green. The size of the circle is directly proportional to the number of isolates of each category. Full article ">Figure 3
Global map of frequency of plasmid incompatibility (Inc) groups. Bar plots show the frequency of plasmid Inc groups of the different continents split by the isolate host source. Pie chart diameter is proportional to genome number per country. Colours represent IncHI2 (blue), IncI2 (yellow), IncX4 (purple), and other plasmids (red). Full article ">Figure 4
Distinct adaptation of mcr-1 genomic context following colistin restriction in Asia and Europe. (A,B) promoter variant frequency comparison before and after the colistin ban in Asia and Europe. The size of the circle is proportional to the number of isolates of each category. (C) The percentage of IncI2 Asian isolates from 2010 to 2021 in which ISApl1 is conserved compared to the frequency of variants associated with ISApl1 (red line). (D) The percentage of IncHI2 isolates in Asia in which ISApl1 is conserved from 2012 to 2020 compared to the frequency of variants associated with ISApl1 (red line). The vertical red line marks the colistin restriction. Full article ">

16 pages, 1908 KiB

Open AccessArticle

Synthesis of Second-Generation Analogs of Temporin-SHa Peptide Having Broad-Spectrum Antibacterial and Anticancer Effects

by Arif Iftikhar Khan, Shahzad Nazir, Muhammad Nadeem ul Haque, Rukesh Maharjan, Farooq-Ahmad Khan, Hamza Olleik, Elise Courvoisier-Dezord, Marc Maresca and Farzana Shaheen

Antibiotics 2024, 13(8), 758; https://doi.org/10.3390/antibiotics13080758 - 11 Aug 2024

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Abstract

Antimicrobial peptides (AMPs) are a promising class of therapeutic alternatives with broad-spectrum activity against resistant pathogens. Small AMPs like temporin-SHa (1) and its first-generation analog [G10a]-SHa (2) possess notable efficacy against Gram-positive and Gram-negative bacteria. In an effort to [...] Read more.

Antimicrobial peptides (AMPs) are a promising class of therapeutic alternatives with broad-spectrum activity against resistant pathogens. Small AMPs like temporin-SHa (1) and its first-generation analog [G10a]-SHa (2) possess notable efficacy against Gram-positive and Gram-negative bacteria. In an effort to further improve this antimicrobial activity, second-generation analogs of 1 were synthesised by replacing the natural glycine residue at position-10 of the parent molecule with atypical amino acids, such as D-Phenylalanine, D-Tyrosine and (2-Naphthyl)-D-alanine, to study the effect of hydrophobicity on antimicrobial efficacy. The resultant analogs (3–6) emerged as broad-spectrum antibacterial agents. Notably, the [G10K]-SHa analog (4), having a lysine substitution, demonstrated a 4-fold increase in activity against Gram-negative (Enterobacter cloacae DSM 30054) and Gram-positive (Enterococcus faecalis DSM 2570) bacteria relative to the parent peptide (1). Among all analogs, [G10f]-SHa peptide (3), featuring a D-Phe substitution, showed the most potent anticancer activity against lung cancer (A549), skin cancer (MNT-1), prostate cancer (PC-3), pancreatic cancer (MiaPaCa-2) and breast cancer (MCF-7) cells, achieving an IC₅₀ value in the range of 3.6–6.8 µM; however, it was also found to be cytotoxic against normal cell lines as compared to [G10K]-SHa (4). Peptide 4 also possessed good anticancer activity but was found to be less cytotoxic against normal cell lines as compared to 1 and 3. These findings underscore the potential of second-generation temporin-SHa analogs, especially analog 4, as promising leads to develop new broad-spectrum antibacterial and anticancer agents. Full article

(This article belongs to the Special Issue Discovery and Multifunctionality of Anti-microbial Peptides)

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UPLC profiles of the synthesised peptides; (A) temporin-SHa; (B) [G10a]-SHa; (C) [G10f]-SHa; (D) [G10y]-SHa; (E) [G10n]-SHa and (F) [G10K]-SHa. Full article ">Figure 2
Circular dichroism of temporin SHa, [G10a]-Sha, and newly synthesised second-generation analogs of [G10a]-SHa in 20 mM SDS. Full article ">Figure 3
Antiproliferative effect of SHa derivatives on human cancer cells. The antiproliferative effect of SHa derivatives was measured on dividing cancer cells, as explained in <a href="#sec4-antibiotics-13-00758" class="html-sec">Section 4</a> (Temporin-SHa (1): open black circles, [G10a]-SHa (2): closed red circles, [G10f]-SHa (2): closed green squares, [G10K]-SHa (3): closed black diamonds, [G10n]-SHa (4): inverted open purple triangles, [G10y]-SHa (5): closed blue triangles). Results are expressed as a percentage of cell proliferation, the untreated cells giving 100% proliferation (means ± SD, n = 3). Full article ">Figure 4
Antiproliferative effect of SHa derivatives on human normal/non cancerous cells. The antiproliferative effect of SHa derivatives was measured on dividing normal cells, as explained in <a href="#sec4-antibiotics-13-00758" class="html-sec">Section 4</a> (temporin-SHa (1): open black circles, [G10a]-SHa (2): closed red circles, [G10f]-SHa (2): closed green squares, [G10K]-SHa (3): closed black diamonds, [G10n]-SHa (4): inverted open purple triangles, [G10y]-SHa (5): closed blue triangles). Results are expressed as a percentage of cell proliferation, the untreated cells giving 100% proliferation (means ± SD, n = 3). Full article ">Figure 5
Cytotoxic effect of SHa derivatives on human normal and cancer lung cells. The cytotoxic effect of temporin-SHa (1) derivatives was measured on confluent/non-dividing cells, as explained in <a href="#sec4-antibiotics-13-00758" class="html-sec">Section 4</a>, using human lung cancer (A549 cells) and normal cells (BEAS-2B cells); ([G10a]-SHa (2): closed red circles, [G10f]-SHa (2): closed green squares, [G10K]-SHa (3): closed black diamonds, [G10n]-SHa (4): inverted open purple triangles, [G10y]-SHa (5): closed blue triangles). Results are expressed as a percentage of cell proliferation, the untreated cells giving 100% proliferation (means ± SD, n = 3). Full article ">Scheme 1
Synthesis and structure of temporin-SHa (1), its first-generation [G10a]-SHa peptide (2) and newly synthesised second-generation analogs (3–6). Full article ">

12 pages, 468 KiB

Open AccessArticle

Effect of Adding the Antimicrobial L-Carnitine to Growing Rabbits’ Drinking Water on Growth Efficiency, Hematological, Biochemical, and Carcass Aspects

by Mohamed I. Hassan, Naela Abdel-Monem, Ayman Moawed Khalifah, Saber S. Hassan, Hossam Shahba, Ahmad R. Alhimaidi, In Ho Kim and Hossam M. El-Tahan

Antibiotics 2024, 13(8), 757; https://doi.org/10.3390/antibiotics13080757 - 11 Aug 2024

Viewed by 309

Abstract

The current study was designed to assess the impact of L-carnitine (LC) supplementation in the drinking water of growing Alexandria-line rabbits on performance and physiological parameters. Two hundred eighty-eight 35-day-old rabbits were divided into four groups of twenty-four replicates each (seventy-two rabbits/treatment). The [...] Read more.

The current study was designed to assess the impact of L-carnitine (LC) supplementation in the drinking water of growing Alexandria-line rabbits on performance and physiological parameters. Two hundred eighty-eight 35-day-old rabbits were divided into four groups of twenty-four replicates each (seventy-two rabbits/treatment). The treatment groups were a control group without LC and three groups receiving 0.5, 1, and 1.5 g/L LC in the drinking water intermittently. The results showed that the group receiving 0.5 g LC/L exhibited significant improvements in final body weight, body weight gain, feed conversion ratio, and performance index compared to the other groups. The feed intake remained unaffected except for the 1.5 g LC/L group, which had significantly decreased intake. Hematological parameters improved in all supplemented groups. Compared with those in the control group, the 0.5 g LC/L group showed significant increases in serum total protein and high-density lipoprotein, along with decreased cholesterol and low-density lipoprotein. Compared to other supplemented groups, this group also demonstrated superior carcass traits (carcass, dressing, giblets, and percentage of nonedible parts). In conclusion, intermittent supplementation of LC in the drinking water, particularly at 0.5 g/L twice a week, positively influenced the productivity, hematology, serum lipid profile, and carcass traits of Alexandria-line growing rabbits at 84 days of age. Full article

(This article belongs to the Special Issue Natural Compounds as Antimicrobial Agents, 2nd Edition)

10 pages, 1618 KiB

Open AccessArticle

Loading Dose of Ceftazidime Needs to Be Increased in Critically Ill Patients: A Retrospective Study to Evaluate Recommended Loading Dose with Pharmacokinetic Modelling

by Manon Launay, Edouard Ollier, Benjamin Kably, Félicien Le Louedec, Guillaume Thiery, Julien Lanoiselée and Sophie Perinel-Ragey

Antibiotics 2024, 13(8), 756; https://doi.org/10.3390/antibiotics13080756 - 11 Aug 2024

Viewed by 279

Abstract

To rapidly achieve ceftazidime target concentrations, a 2 g loading dose (LD) is recommended before continuous infusion, but its adequacy in critically ill patients, given their unique pharmacokinetics, needs investigation. This study included patients from six ICUs in Saint-Etienne and Paris, France, who [...] Read more.

To rapidly achieve ceftazidime target concentrations, a 2 g loading dose (LD) is recommended before continuous infusion, but its adequacy in critically ill patients, given their unique pharmacokinetics, needs investigation. This study included patients from six ICUs in Saint-Etienne and Paris, France, who received continuous ceftazidime infusion with plasma concentration measurements. Using MONOLIX and R, a pharmacokinetic (PK) model was developed, and the literature on ICU patient PK models was reviewed. Simulations calculated the LD needed to reach a 60 mg/L target concentration and assessed ceftazidime exposure for various regimens. Among 86 patients with 223 samples, ceftazidime PK was best described by a one-compartment model with glomerular filtration rate explaining clearance variability. Typical clearance and volume of distribution were 4.45 L/h and 88 L, respectively. The literature median volume of distribution was 37.2 L. Simulations indicated that an LD higher than 2 g was needed to achieve 60 mg/L in 80% of patients, with a median LD of 4.9 g. Our model showed a 4 g LD followed by 6 g/day infusion reached effective concentrations within 1 h, while a 2 g LD caused an 18 h delay in achieving target steady state. Full article

(This article belongs to the Special Issue Pharmacokinetic and Antibiotic Dosing for Intensive Care Unit Patients)

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12 pages, 1643 KiB

Open AccessArticle

Association between Extended Meropenem Regimen and Achievement of Aggressive PK/PD in Patients Receiving Continuous Renal Replacement Therapy for Septic AKI

by Shinya Chihara, Tomoyuki Ishigo, Satoshi Kazuma, Kana Matsumoto, Kunihiko Morita and Yoshiki Masuda

Antibiotics 2024, 13(8), 755; https://doi.org/10.3390/antibiotics13080755 - 11 Aug 2024

Viewed by 332

Abstract

Aggressive pharmacokinetic (PK)/pharmacodynamic (PD) targets have shown better microbiological eradication rates and a lower propensity to develop resistant strains than conservative targets. We investigated whether meropenem blood levels, including aggressive PK/PD, were acceptable in terms of efficacy and safety using a meropenem regimen [...] Read more.

Aggressive pharmacokinetic (PK)/pharmacodynamic (PD) targets have shown better microbiological eradication rates and a lower propensity to develop resistant strains than conservative targets. We investigated whether meropenem blood levels, including aggressive PK/PD, were acceptable in terms of efficacy and safety using a meropenem regimen of 1 g infusion every 8 h over 3 h in patients undergoing continuous renal replacement therapy (CRRT) for septic acute kidney injury (AKI). Aggressive PK/PD targets were defined as the percentage of time that the free concentration (%fT) > 4 × minimal inhibitory concentration (MIC), the toxicity threshold was defined as a trough concentration >45 mg/L, and the percentage of achievement at each MIC was evaluated. The 100% fT > 4 × MIC for a pathogen with an MIC of 0.5 mg/L was 89%, and that for a pathogen with an MIC of 2 mg/L was 56%. The mean steady-state trough concentration of meropenem was 11.9 ± 9.0 mg/L and the maximum steady-state trough concentration was 29.2 mg/L. Simulations using Bayesian estimation showed the probability of achieving 100% fT > 4 × MIC for up to an MIC of 2 mg/L for the administered administration via continuous infusion at 3 g/24 h. We found that an aggressive PK/PD could be achieved up to an MIC of 0.5 mg/L with a meropenem regimen of 1 g infused every 8 h over 3 h for patients receiving CRRT for septic AKI. In addition, the risk of reaching the toxicity range with this regimen is low. In addition, if the MIC was 1–2 mg/L, the simulation results indicated that aggressive PK/PD can be achieved by continuous infusion at 3 g/24 h without increasing the daily dose. Full article

(This article belongs to the Special Issue Clinical Pharmacokinetics, Pharmacodynamics, and/or TDM of Antimicrobial Agents)

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Correlation between eGFR and meropenem clearance. □: QF of 2000 mL/h (n = 5), ×: QF of 1000 mL/h (n = 4). (a) Plot correlation between eGFR (mL/min) and total clearance of MEPM (L/h), (b) Plot correlation between eGFR (mL/min) and MEPM clearance of CVVH (L/h). Abbreviations: MEPM, meropenem; QF, quantity of filtration flow rate; eGFR, estimated glomerular filtration rate; CVVH, continuous venovenous filtration. Full article ">Figure 2
(a) Predictions obtained by Bayesian estimation versus observations of all measured meropenem plasma concentrations. Black line: line of identity. (b) The difference between the predictions obtained by Bayesian estimation and the observations of all measured meropenem plasma concentrations. Dotted lines indicate mean and ± 2 SD. Abbreviations: RMSE, root mean squared error; MAPE, mean absolute percentage error; SD, standard deviation. Full article ">Figure 3
Percentage of patients achieving target PK/PD in each MIC. Abbreviations: MEPM, meropenem; MIC, minimal inhibitory concentration; PK, pharmacokinetic; PD, pharmacodynamic. Full article ">Figure 4
Percentage of cases achieving target PK/PD at each MIC when simulations using Bayesian estimation with 3 g infused over 24 h. Abbreviations: MEPM, meropenem; MIC, minimal inhibitory concentration; PK, pharmacokinetic; PD, pharmacodynamic. Full article ">Figure 5
PTA versus MIC profiles for various simulated MEPM dosing regimens based on the PK/PD targets of 100% fT > 4 × MIC. Dashed horizontal lines represent a PTA of 90%. Abbreviations: MEPM, meropenem; PTA, probability of target attainment; MIC, minimal inhibitory concentration; PK, pharmacokinetics; PD, pharmacodynamics. Full article ">

10 pages, 1900 KiB

Open AccessArticle

Evaluation of Gentamicin Release of PMMA Cements Using Different Methods: HPLC, Elution and Inhibition Zone Testing

by Clemens Kittinger, Johannes Stadler and Klaus Dieter Kühn

Antibiotics 2024, 13(8), 754; https://doi.org/10.3390/antibiotics13080754 - 11 Aug 2024

Viewed by 353

Abstract

(1) Background: There is an ongoing discussion on the elution efficacy of antibiotic-impregnated cements. Our experiments were intended to clarify if there are differences in the antibiotic elution of HPLC compared with inhibition zone testing using eluates or PMMA discs. (2) Materials and [...] Read more.

(1) Background: There is an ongoing discussion on the elution efficacy of antibiotic-impregnated cements. Our experiments were intended to clarify if there are differences in the antibiotic elution of HPLC compared with inhibition zone testing using eluates or PMMA discs. (2) Materials and Methods: Two cement brands with different concentrations of the active ingredient were tested in antimicrobial Kirby–Bauer (disc diffusion) assays. Cement platelets were directly applied on the agar plates and their zone of inhibition was measured. In parallel, the platelets were incubated in phosphate buffered saline (PBS) and at distinct points of time transferred into new buffer. At these time points, 50 µL of the bone cement eluates was used for zone of inhibition testing. Standard gentamicin sulfate solutions served as a control in the same test setup. To verify the microbiological investigations, the antibiotic content of the eluates was also measured via high-performance liquid chromatography (HPLC). (3) Results: The experiments with cement eluates showed better differentiable results than the direct application of the cement discs. The results were also comparable to investigations with HPLC and gentamicin sulfate standard solutions. (4) Conclusions: The results of elution rates are influenced by the test system and the period of observation chosen. The microbial test systems reflect the results of HPLC to the same degree and give evidence of the efficacy of the antibiotics. The HPLC tests on eluates were more suitable in representing differences in release characteristics. Full article

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

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17 pages, 1208 KiB

Open AccessArticle

Evolution of the Antibiotic Resistance Levels, Multi-Resistance Patterns, and Presence of Antibiotic Resistance Genes in E. coli Isolates from the Feces of Breeding Hens during the Rearing Period

by Alejandro Fenollar-Penadés, Pablo Catalá-Gregori, Vicente Tallá-Ferrer, María Ángeles Castillo, Miguel García-Ferrús and Ana Jiménez-Belenguer

Antibiotics 2024, 13(8), 753; https://doi.org/10.3390/antibiotics13080753 - 10 Aug 2024

Viewed by 310

Abstract

The food chain acts as an entry point for antibiotic resistance to reach humans and environment. Because of the importance of the poultry sector, we investigated the prevalence and evolution of antibiotic resistance in Escherichia coli isolates from a series of 14,500 breeding [...] Read more.

The food chain acts as an entry point for antibiotic resistance to reach humans and environment. Because of the importance of the poultry sector, we investigated the prevalence and evolution of antibiotic resistance in Escherichia coli isolates from a series of 14,500 breeding hens and their farm environment during the rearing period. Samples included meconium from one-day-old breeders and fecal samples and boot swabs from the breeding sheds of pullets and adult hens. All E. coli isolates from one-day-old chicks, 77% from feces and 61% from boot swabs, were resistant to at least one antibiotic. Cefotaxime and multi-drug resistance in fecal isolates decreased during the rearing period from 41.2% and 80.8% in one-day-old chicks to 3.8% and 33.8% in adults. All genes studied were detected in E. coli from feces and boot swabs, the most common being bla_TEM (75%), bla_SHV (72%), and qnrB (67%). bla_CMY-2 was detected in 100% of one-day-old breeders. The combination of at least one cephalosporin and one quinolone resistance gene was detected in 68.7% of fecal and boot swab isolates. Our results highlight the need to monitor the prevalence of antibiotic resistance on farms and to take appropriate measures to reduce the risk to public and environmental health. Full article

(This article belongs to the Special Issue Bacteria Isolated from Animals: Virulence, Characterization and Antimicrobial Resistance, 2nd Edition)

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11 pages, 2304 KiB

Open AccessArticle

Trends in Upper Gastrointestinal Bleeding in Children: The Impact of Helicobacter pylori Infection and Non-Steroidal Anti-Inflammatory Drug Use

by Felicia Galos, Mara Ioana Ionescu, Mihai Daniel Luca Mirea, Anca Andreea Boboc, Andreea Ioan and Catalin Boboc

Antibiotics 2024, 13(8), 752; https://doi.org/10.3390/antibiotics13080752 - 10 Aug 2024

Viewed by 309

Abstract

Upper gastrointestinal bleeding (UGIB) is a significant concern in children, contributing to 6–20% of cases in pediatric intensive care units. This study evaluates the roles of Helicobacter pylori (H. pylori) infection and non-steroidal anti-inflammatory drug (NSAID) usage in the etiology of [...] Read more.

Upper gastrointestinal bleeding (UGIB) is a significant concern in children, contributing to 6–20% of cases in pediatric intensive care units. This study evaluates the roles of Helicobacter pylori (H. pylori) infection and non-steroidal anti-inflammatory drug (NSAID) usage in the etiology of UGIB in children, with a particular focus on trends observed during the COVID-19 pandemic. We conducted a retrospective analysis of 103 pediatric patients who underwent esophagogastroduodenoscopy (EGD) for UGIB between January 2015 and December 2023. Of these, 88 patients were included in the final analysis, where the source of bleeding was successfully identified. Hematemesis was the most common presentation, and the source of bleeding was identified in 85.43% of cases. The prevalence of H. pylori infection remained stable across the pre-pandemic (39.7%) and post-pandemic (36.7%) periods. However, NSAID usage increased nearly threefold during the pandemic, with 36.7% of post-pandemic UGIB cases associated with NSAID use, compared to 12.1% pre-pandemic. These findings underscore the significant roles of H. pylori and NSAID use in pediatric UGIB, with a notable increase in NSAID-related cases during the pandemic. Full article

(This article belongs to the Special Issue Helicobacter pylori Infection - New Data and Approaches on Diagnosis, Pathogenesis, Antibiotic Resistance and Advances in Therapy)

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12 pages, 1929 KiB

Open AccessArticle

Targeting N-Acetylglucosaminidase in Staphylococcus aureus with Iminosugar Inhibitors

by Janja Sluga, Tihomir Tomašič, Marko Anderluh, Martina Hrast Rambaher, Gregor Bajc, Alen Sevšek, Nathaniel I. Martin, Roland J. Pieters, Marjana Novič and Katja Venko

Antibiotics 2024, 13(8), 751; https://doi.org/10.3390/antibiotics13080751 - 10 Aug 2024

Viewed by 444

Abstract

Bacteria are capable of remarkable adaptations to their environment, including undesirable bacterial resistance to antibacterial agents. One of the most serious cases is an infection caused by multidrug-resistant Staphylococcus aureus, which has unfortunately also spread outside hospitals. Therefore, the development of new [...] Read more.

Bacteria are capable of remarkable adaptations to their environment, including undesirable bacterial resistance to antibacterial agents. One of the most serious cases is an infection caused by multidrug-resistant Staphylococcus aureus, which has unfortunately also spread outside hospitals. Therefore, the development of new effective antibacterial agents is extremely important to solve the increasing problem of bacterial resistance. The bacteriolytic enzyme autolysin E (AtlE) is a promising new drug target as it plays a key role in the degradation of peptidoglycan in the bacterial cell wall. Consequently, disruption of function can have an immense impact on bacterial growth and survival. An in silico and in vitro evaluation of iminosugar derivatives as potent inhibitors of S. aureus (AtlE) was performed. Three promising hit compounds (1, 3 and 8) were identified as AtlE binders in the micromolar range as measured by surface plasmon resonance. The most potent compound among the SPR response curve hits was 1, with a K_D of 19 μM. The K_D value for compound 8 was 88 μM, while compound 3 had a K_D value of 410 μM. Full article

(This article belongs to the Special Issue Recent Advances in Antimicrobial Drug Discovery, 2nd Edition)

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(a) 3D binding model of the NAG-NAM central unit on the AtlE surface (PDB ID: 4PI7); (b) 2D modeled interactions of the NAG-NAM central unit with AtlE (red residue represents the hydrogen bond acceptor, green residue represents the hydrogen bond donor). Full article ">Figure 2
(a) 3D binding model of compounds 1, 3 and 8 on the AtlE surface (PDB ID: 4PI7); (b) 2D modeled interactions of compounds 1, 3 and 8 with AtlE (red residues represent the hydrogen bond acceptors, green residues represent the hydrogen bond donor, and yellow residues represent the hydrophobic interactions). Full article ">Figure 3
Representative SPR sensorgram (response curves) for compound 1-deoxynojirimycin at two different concentrations. Full article ">Figure 4
(a) Representative SPR sensorgrams (response curves) and (b) representative saturation curves with evaluated KD for compounds 1, 3 and 8 at different concentrations. SPR analysis of compound 1, 3 and 8 interactions with the immobilized AtlE. Compounds were injected across immobilized AtlE in serial dilutions for 60 s at a rate of 30 mL/min, and the dissociation was followed for 50 s. Sensorgrams are shown along with the apparent equilibrium dissociation constant (KD) determined from the response curves as a function of the compound concentration injected across AtlE. KD values are the mean ± standard deviation of three titrations. The data were fitted to the steady-state affinity binding model. Full article ">

14 pages, 2122 KiB

Open AccessArticle

Regulation of Antibiotic Resistance Genes on Agricultural Land Is Dependent on Both Choice of Organic Amendment and Prevalence of Predatory Bacteria

by Anna Karin Rosberg, Maria João Silva, Cecilie Skøtt Feidenhans’l, Eddie Cytryn, Edouard Jurkevitch and Rolf Lood

Antibiotics 2024, 13(8), 750; https://doi.org/10.3390/antibiotics13080750 - 10 Aug 2024

Viewed by 607

Abstract

Antibiotic resistance genes (ARGs) are widespread in the environment, and soils, specifically, are hotspots for microorganisms with inherent antibiotic resistance. Manure and sludge used as fertilizers in agricultural production have been shown to contain vast amounts of ARGs, and due to continued applications, [...] Read more.

Antibiotic resistance genes (ARGs) are widespread in the environment, and soils, specifically, are hotspots for microorganisms with inherent antibiotic resistance. Manure and sludge used as fertilizers in agricultural production have been shown to contain vast amounts of ARGs, and due to continued applications, ARGs accumulate in agricultural soils. Some soils, however, harbor a resilience capacity that could depend on specific soil properties, as well as the presence of predatory bacteria that are able to hydrolyse living bacteria, including bacteria of clinical importance. The objectives of this study were to (i) investigate if the antibiotic resistance profile of the soil microbiota could be differently affected by the addition of cow manure, chicken manure, and sludge, and (ii) investigate if the amendments had an effect on the presence of predatory bacteria. The three organic amendments were mixed separately with a field soil, divided into pots, and incubated in a greenhouse for 28 days. Droplet digital PCR (ddPCR) was used to quantify three ARGs, two predatory bacteria, and total number of bacteria. In this study, we demonstrated that the choice of organic amendment significantly affected the antibiotic resistance profile of soil, and promoted the growth of predatory bacteria, while the total number of bacteria was unaffected. Full article

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Schematic overview of the study design. Soil from organic production was added to the pots and complemented with different types of organic amendments: chicken manure, cow manure, and sludge. All pots were watered, covered with black plastic, and incubated in a greenhouse for 28 days. Samples were taken at four time points with four biological replicates. This image was created with <a href="http://BioRender.com" target="_blank">BioRender.com</a> accessed on 4 July 2024. Full article ">Figure 2
Prevalence of antibiotic resistance genes in soil exposed to different organic manure. DNA was extracted from soil exposed to different manure (cow, chicken, or sludge) for a time span of 0, 1, 7, or 28 days. Gene copies of (A) tetA, (B) tetM, and (C) vanA were determined through ddPCR and reported as copies per gram soil. Samples from day 0 represent the additive only (e.g., manure). Each mark (i.e., black dot, red square, and green or blue triangle) represents a true biological sample for which three technical replicates were conducted. For each sample, four biological replicates were taken (i.e., four marks per time point), and is displayed as the four different time points for each amendment on the x-axis, and number of gene copies on the y-axis. * p < 0.05, ** p < 0.01, *** p < 0.001. Full article ">Figure 3
Prevalence of predatory bacteria in soil exposed to different organic manure. DNA was extracted from soil exposed to different manure (cow, chicken, or sludge) for a time span of 0, 1, 7, or 28 days. Gene copies of (A) 16S rRNA of the total bacterial population, (B) 16S rRNA gene copies of Bdellovibrio, and (C) 16S rRNA gene copies of Bacteriovorax were determined through ddPCR and reported as copies per gram soil. Samples from day 0 represent the additive only (e.g., manure). Each mark (i.e., black dot, red square, green or blue triangle) represents a true biological sample for which three technical replicates were conducted. For each sample, four biological replicates were taken (i.e., four marks per time point), and are displayed as the four different time points for each amendment on the x-axis, and number of gene copies on the y-axis. * p < 0.05, ** p < 0.01, *** p < 0.001. Full article ">Figure 4
Prevalence of antibiotic resistance genes in relation to 16S. Gene copy number per gram soil (log10) of antibiotic resistance genes and 16S from all soil samples were collected at 0, 1, 7, and 28 days, and relative values are shown for (A) tetA, (B) tetA, and (C) vanA. Each mark (i.e., black dot, red square, and green or blue triangle) represent a true biological sample for which three technical replicates were conducted. For each sample, four biological replicates were taken (i.e., four marks per time point), and are displayed as the four different time points for each amendment on the x-axis, and number of gene copies on the y-axis. * p < 0.05, ** p < 0.01. Full article ">Figure 5
Correlations between the prevalence of antibiotic resistance genes and the 16S rDNA gene of predatory bacteria. Absolute quantities (gene copy number per gram soil) of predatory bacteria and antibiotic resistance genes from all soil samples were analyzed for correlative values between (A) tetA and Bdellovibrio, (B) tetA and Bacteriovorax, (C) tetM and Bdellovibrio, (D) tetM and Bacteriovorax, (E) vanA and Bdellovibrio, and (F) vanA and Bacteriovorax. Full article ">

10 pages, 843 KiB

Open AccessArticle

Gene emrC Associated with Resistance to Quaternary Ammonium Compounds Is Common among Listeria monocytogenes from Meat Products and Meat Processing Plants in Poland

by Iwona Kawacka and Agnieszka Olejnik-Schmidt

Antibiotics 2024, 13(8), 749; https://doi.org/10.3390/antibiotics13080749 - 9 Aug 2024

Viewed by 397

Abstract

(1) Background: L. monocytogenes is a food pathogen of great importance, characterized by a high mortality rate. Quaternary ammonium compounds (QACs), such as benzalkonium chloride (BC), are often used as disinfectants in food processing facilities. The effectiveness of disinfection procedures is crucial to [...] Read more.

(1) Background: L. monocytogenes is a food pathogen of great importance, characterized by a high mortality rate. Quaternary ammonium compounds (QACs), such as benzalkonium chloride (BC), are often used as disinfectants in food processing facilities. The effectiveness of disinfection procedures is crucial to food safety. (2) Methods: A collection of 153 isolates of L. monocytogenes from meat processing industry was analyzed for their sensitivity to BC using the agar diffusion method. Genes of interest were detected with PCR. (3) Results: Genes emrC, bcrABC, and qacH were found in 64 (41.8%), 6 (3.9%), and 1 isolate (0.7%), respectively, and 79 isolates (51.6%) were classified as having reduced sensitivity to BC. A strong correlation between carrying QACs resistance-related genes and phenotype was found (p-value < 0.0001). Among 51 isolates originating from bacon (collected over 13 months), 48 had the emrC gene, which could explain their persistent presence in a processing facility. Isolates with the ilsA gene (from LIPI-3) were significantly (p-value 0.006) less likely to carry QACs resistance-related genes. (4) Conclusions: Reduced sensitivity to QACs is common among L. monocytogenes from the meat processing industry. Persistent presence of these bacteria in a processing facility is presumably caused by emrC-induced QACs resistance. Full article

(This article belongs to the Special Issue Microbial Resistance Surveillance and Management in Food Systems)

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15 pages, 7966 KiB

Open AccessArticle

Anticandidal Properties of Launaea sarmentosa among the Salt Marsh Plants Collected from Palk Bay and the Gulf of Mannar Coast, Southeastern India

by Smriti Das, Karuppannagounder Rajan Priyanka, Kolandhasamy Prabhu, Ramachandran Vinayagam, Rajendran Rajaram and Sang Gu Kang

Antibiotics 2024, 13(8), 748; https://doi.org/10.3390/antibiotics13080748 - 9 Aug 2024

Viewed by 424

Abstract

Tidal wetlands, commonly known as salt marshes, are highly productive ecosystems in temperate regions worldwide. These environments constitute a unique flora composed primarily of salt-tolerant herbs, grasses, and shrubs. This study investigated the therapeutic properties of ten salt marsh plants collected mainly from [...] Read more.

Tidal wetlands, commonly known as salt marshes, are highly productive ecosystems in temperate regions worldwide. These environments constitute a unique flora composed primarily of salt-tolerant herbs, grasses, and shrubs. This study investigated the therapeutic properties of ten salt marsh plants collected mainly from Palk Bay and Mannar Gulf against Candida disease. This study examined the changes in natural plant products associated with their anti-Candida growth activity during two distinct seasonal changes—monsoon and summer. The potential of the salt marshes to inhibit the growth of five different Candida strains was assessed using four solvents. In phytochemical analysis, the extracts obtained from a Launaea sarmentosa exhibited the highest results compared to the other plant extracts. Fourier transform infrared spectroscopy revealed 12 peaks with alkane, aldehyde, amine, aromatic ester, phenol, secondary alcohol, and 1,2,3,4-tetrasubstituted. Gas-chromatography–mass spectrometry detected 30 compounds. Cyclotetracosane, lupeol, β-amyrin, and 12-oleanen-3-yl acetate showed the highest peak range. In particular, plant samples collected during the monsoon season were more effective in preventing Canda growth than the summer plant samples. In the monsoon season, the salt marsh plant extracted with ethyl acetate showed a high anti-Candida growth activity, while in the summer, the acetone extract exhibited a higher anti-Candida growth activity than the other solvents. The hexane extract of L. sarmentosa showed the highest inhibition zone against all Candidal strains. Furthermore, compounds, such as β-amyrin, lupeol, and oxirane, from the hexane extract of L. sarmentosa play a vital role in anti-Candida activity. This paper reports the potential of tidal marsh plant extracts for developing new antifungal agents for Candida infections. Full article

(This article belongs to the Special Issue Innovations in Antibacterial Agents: Combating Resistance, Improving Efficacy and Exploring New Mechanisms)

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Anticandial properties of salt marsh plants exhibited as the zone of inhibition against Candidal strains during the monsoon season ((a)—Acetone; (b)—Ethyl Acetate; (c)—Methonal and (d)—Hexane). Full article ">Figure 2
Anticandidal properties of salt marsh plants exhibiting zone of inhibition against Candidal strains during the summer season ((a)—Acetone; (b)—Ethyl acetate; (c)—Methanol; and (d)—Hexane). Full article ">Figure 3
Anticandidal activity of saltmarsh plant Launaea sarmentosa extract exhibits the highest inhibition (CA—Candida albicans; CR—Candida kefyr; CKr—Candida krusei; CT—Candida tropicalis; CP—Candida parapsilosis). Full article ">Figure 4
FT−IR spectrum showing the peaks obtained from the hexane extract of salt marsh Launaea sarmentosa. Full article ">Figure 5
GC-MS showing the peaks obtained from the hexane extract of saltmarsh Launaea sarmentosa. Full article ">Figure 6
Sampling sites of salt marsh plants collected from Palk Bay and the Gulf of Mannar. Full article ">Figure 7
Salt marsh plants collected from Palk Bay and the Gulf of Mannar ((A) Ipomoea pes-caprae, (B) Suaeda maritima, (C) Sesuvium portulacastrum, (D) Heliotropium curassavicum, (E) Launaea sarmentosa, (F) Bulbostylis barbata, (G) Salicornia brachiata, (H) Spinifex littoreus, (I) Fimbristylis spathacea, and (J) Artiplex halimus). Full article ">

11 pages, 876 KiB

Open AccessSystematic Review

The Effect of Antibiotics on the Eradication of Multidrug-Resistant Organisms in Intestinal Carriers—A Systematic Review with Meta-Analysis

by Maja Johanne Søndergaard Knudsen, Ingrid Maria Cecilia Rubin and Andreas Munk Petersen

Antibiotics 2024, 13(8), 747; https://doi.org/10.3390/antibiotics13080747 - 9 Aug 2024

Viewed by 326

Abstract

Objectives: The aim of this systematic review was to investigate the effect of antibiotics on the eradication of multidrug-resistant organisms (MRO) in intestinal carriers. We defined multidrug-resistant organisms as vancomycin-resistant Enterococcus faecium (VREfm), and multidrug-resistant Gram-negative Enterobacterales. Methods: We searched the EMBASE, Cochrane [...] Read more.

Objectives: The aim of this systematic review was to investigate the effect of antibiotics on the eradication of multidrug-resistant organisms (MRO) in intestinal carriers. We defined multidrug-resistant organisms as vancomycin-resistant Enterococcus faecium (VREfm), and multidrug-resistant Gram-negative Enterobacterales. Methods: We searched the EMBASE, Cochrane Central, and PubMed databases from inception to medio November 2023. We included randomised and controlled clinical trials (RCTs), that investigated the effect of antibiotics on the eradication of multidrug-resistant organisms in intestinal carriers. Finally, we performed a meta-analysis. Results: We included five RTCs in the systematic review. In four studies an effect of antibiotics on the eradication of MRO was shown at the end of intervention, but it was not sustained at follow-up. In the fifth study, the effect at the end of intervention was not reported, and there was no observed effect of the intervention at follow-up. We included four studies in the meta-analysis, and it suggests an effect of antibiotics on the eradication of MRO in intestinal carriers at the end of follow-up with a p-value of 0.04 (95% confidence interval 1.02–1.95). None of the studies reported a significant increase in resistance to the study drug. Gastrointestinal disorders were the most frequent non-severe adverse event. Conclusions: The effect of antibiotics on the eradication of multidrug-resistant organisms in intestinal carriers was not statistically significant in any of the five included studies; however, we found a significant effect in the pooled meta-analysis. As the confidence interval is large, we cannot determine the clinical importance of this finding, and it should be further investigated. Full article

(This article belongs to the Special Issue Pathogenic and Antibiotic-Resistant Bacteria in Gut Microbiota)

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26 pages, 3224 KiB

Open AccessReview

Plant-Derived Antimicrobials and Their Crucial Role in Combating Antimicrobial Resistance

by Paola Angelini

Antibiotics 2024, 13(8), 746; https://doi.org/10.3390/antibiotics13080746 - 9 Aug 2024

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Abstract

Antibiotic resistance emerged shortly after the discovery of the first antibiotic and has remained a critical public health issue ever since. Managing antibiotic resistance in clinical settings continues to be challenging, particularly with the rise of superbugs, or bacteria resistant to multiple antibiotics, [...] Read more.

Antibiotic resistance emerged shortly after the discovery of the first antibiotic and has remained a critical public health issue ever since. Managing antibiotic resistance in clinical settings continues to be challenging, particularly with the rise of superbugs, or bacteria resistant to multiple antibiotics, known as multidrug-resistant (MDR) bacteria. This rapid development of resistance has compelled researchers to continuously seek new antimicrobial agents to curb resistance, despite a shrinking pipeline of new drugs. Recently, the focus of antimicrobial discovery has shifted to plants, fungi, lichens, endophytes, and various marine sources, such as seaweeds, corals, and other microorganisms, due to their promising properties. For this review, an extensive search was conducted across multiple scientific databases, including PubMed, Elsevier, ResearchGate, Scopus, and Google Scholar, encompassing publications from 1929 to 2024. This review provides a concise overview of the mechanisms employed by bacteria to develop antibiotic resistance, followed by an in-depth exploration of plant secondary metabolites as a potential solution to MDR pathogens. In recent years, the interest in plant-based medicines has surged, driven by their advantageous properties. However, additional research is essential to fully understand the mechanisms of action and verify the safety of antimicrobial phytochemicals. Future prospects for enhancing the use of plant secondary metabolites in combating antibiotic-resistant pathogens will also be discussed. Full article

(This article belongs to the Special Issue Antimicrobial Activity of Plant-Derived Products and Synthetic Derivatives, 2nd Edition)

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11 pages, 1696 KiB

Open AccessArticle

Nosocomial Bacteria Inhibition with Polymyxin B: In Silico Gene Mining and In Vitro Analysis

by Jayendra Chunduru, Nicholas LaRoe, Jeremy Garza, Abdul N. Hamood and Paul W. Paré

Antibiotics 2024, 13(8), 745; https://doi.org/10.3390/antibiotics13080745 - 8 Aug 2024

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Abstract

Multidrug-resistant bacteria present a significant public health challenge; such pathogens exhibit reduced susceptibility to conventional antibiotics, limiting current treatment options. Cationic non-ribosomal peptides (CNRPs) such as brevicidine and polymyxins have emerged as promising candidates to block Gram-negative bacteria. To investigate the capability of [...] Read more.

Multidrug-resistant bacteria present a significant public health challenge; such pathogens exhibit reduced susceptibility to conventional antibiotics, limiting current treatment options. Cationic non-ribosomal peptides (CNRPs) such as brevicidine and polymyxins have emerged as promising candidates to block Gram-negative bacteria. To investigate the capability of bacteria to biosynthesize CNRPs, and specifically polymyxins, over 11,000 bacterial genomes were mined in silico. Paenibacillus polymyxa was identified as having a robust biosynthetic capacity, based on multiple polymyxin gene clusters. P. polymyxa biosynthetic competence was confirmed by metabolite characterization via HPLC purification and MALDI TOF/TOF analysis. When grown in a selected medium, the metabolite yield was 4 mg/L with a 20-fold specific activity increase. Polymyxin B (PMB) was assayed with select nosocomial pathogens, including Pseudomonas aeruginosa, Klebsiella pneumonia, and Acinetobacter baumaii, which exhibited minimum inhibitory concentrations of 4, 1, and 1 µg/mL, respectively. Full article

(This article belongs to the Section Antimicrobial Peptides)

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Graphical abstract

Graphical abstract
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(A). Estimated non-ribosomal peptide length (average) in select genera (purple) and average cationic residues per peptide (blue): Paenibacillus n = 602 (range of peptide length = 1–30), Brevibacillus n = 249 (range of peptide length = 1–33), Streptomyces n = 2592 (range of peptide length = 1–56), Bacillus n = 4840 (range of peptide length = 1–26), Pseudomonas n = 1758 (range of peptide length = 1–48), and Burkholderia n = 1915 (range of peptide length = 1–28). (B). Fraction of bacteria that contain essential predicted residues for PPPB. legend for circle graph (C). Total number of organisms with the biological potential of producing polymyxin (* commercially available). Range of peptide length (n) (P. lentus DSM 25539 (1–15), P. sp. IHB B 3084, P. polymyxa CR1 (2–14), P. polymyxa ZF129 (3–13) P. polymyxa J (3–14), P. polymyxa Sb3-1 (4–12), P. polymyxa SQR-21, ATCC 15970, HY96-2 (4–13), P. polymyxa E681, YC0136, P. peoriae HS311 (4–14), P. sp. lzh-N1 (4–16), and P. sp. M-152 (4–18). Full article ">Figure 1 Cont.
(A). Estimated non-ribosomal peptide length (average) in select genera (purple) and average cationic residues per peptide (blue): Paenibacillus n = 602 (range of peptide length = 1–30), Brevibacillus n = 249 (range of peptide length = 1–33), Streptomyces n = 2592 (range of peptide length = 1–56), Bacillus n = 4840 (range of peptide length = 1–26), Pseudomonas n = 1758 (range of peptide length = 1–48), and Burkholderia n = 1915 (range of peptide length = 1–28). (B). Fraction of bacteria that contain essential predicted residues for PPPB. legend for circle graph (C). Total number of organisms with the biological potential of producing polymyxin (* commercially available). Range of peptide length (n) (P. lentus DSM 25539 (1–15), P. sp. IHB B 3084, P. polymyxa CR1 (2–14), P. polymyxa ZF129 (3–13) P. polymyxa J (3–14), P. polymyxa Sb3-1 (4–12), P. polymyxa SQR-21, ATCC 15970, HY96-2 (4–13), P. polymyxa E681, YC0136, P. peoriae HS311 (4–14), P. sp. lzh-N1 (4–16), and P. sp. M-152 (4–18). Full article ">Figure 2
Media effect on P. polymyxa growth [ATCC-recommended media (M178, blue), tryptic soy broth (TSB, red), tryptic soy broth with starch (20 g/L) (TSB S20, green), tryptic soy broth with starch (40 g/L) (TSB S40, purple), Luria–Bertani broth (LB, orange), and yeast extract peptone dextrose (YPD, dark green)] (three trials in triplicate and error bars are SDs). Full article ">Figure 3
Fragmented MS/MS peaks using TOF of 1203.3698 Da peak; y-axis on right shows absolute intensity. Full article ">Figure 4
PMB inhibits the growth of several bacterial pathogens. The MBIC of PMB to each strain was determined as described in the Materials and Methods section. (A) The effect of PMB on three P. aeruginosa multidrug-resistant strains (MRSN 17849, MRSN 18560, and MRSN 2108. (B) The effect of PMB on the K. pneumoniae strain KP-UTI-2 and the A. baumannii strain AB-10. Bars indicate the means of three independent experiments. *, p < 0.05; ****, p < 0.0001; ns, not significant. Statistical significance (****) was determined using a two-way ANOVA with Tukey’s multiple comparison test. The growth of P. aeruginosa strains MRSN-17849 and MRSN-2108 was inhibited by 4 mg/mL (no CFU was recovered). Similarly, the K. pneumoniae strain KP-UTI-2 and the A. baumannii strain AB-10 were inhibited by 2 mg/mL. In the graphs, we included 4–5 CFUs for each point to conduct the statistical analysis. Full article ">

21 pages, 3340 KiB

Open AccessArticle

Development of Xanthoangelol-Derived Compounds with Membrane-Disrupting Effects against Gram-Positive Bacteria

by Siyu Yang, Fangquan Liu, Yue Leng, Meiyue Zhang, Lei Zhang, Xuekun Wang and Yinhu Wang

Antibiotics 2024, 13(8), 744; https://doi.org/10.3390/antibiotics13080744 - 7 Aug 2024

Viewed by 425

Abstract

Infections caused by multidrug-resistant pathogens have emerged as a serious threat to public health. To develop new antibacterial agents to combat such drug-resistant bacteria, a class of novel amphiphilic xanthoangelol-derived compounds were designed and synthesized by mimicking the structure and function of antimicrobial [...] Read more.

Infections caused by multidrug-resistant pathogens have emerged as a serious threat to public health. To develop new antibacterial agents to combat such drug-resistant bacteria, a class of novel amphiphilic xanthoangelol-derived compounds were designed and synthesized by mimicking the structure and function of antimicrobial peptides (AMPs). Among them, compound 9h displayed excellent antimicrobial activity against the Gram-positive strains tested (MICs = 0.5–2 μg/mL), comparable to vancomycin, and with low hemolytic toxicity and good membrane selectivity. Additionally, compound 9h demonstrated rapid bactericidal effects, low resistance frequency, low cytotoxicity, and good plasma stability. Mechanistic studies further revealed that compound 9h had good membrane-targeting ability and was able to destroy the integrity of bacterial cell membranes, causing an increase in intracellular ROS and the leakage of DNA and proteins, thus accelerating bacterial death. These results make 9h a promising antimicrobial candidate to combat bacterial infection. Full article

(This article belongs to the Topic Antimicrobial Agents and Nanomaterials)

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15 pages, 15950 KiB

Open AccessArticle

In Vitro Inhibitory Effect of Silver Diamine Fluoride Combined with Potassium Iodide against Mixed-Species Biofilm Formation on Human Root Dentin

by Jutharat Manuschai, Maki Sotozono, Shoji Takenaka, Niraya Kornsombut, Ryouhei Takahashi, Rui Saito, Ryoko Nagata, Takako Ida and Yuichiro Noiri

Antibiotics 2024, 13(8), 743; https://doi.org/10.3390/antibiotics13080743 - 7 Aug 2024

Viewed by 316

Abstract

Applying a saturated potassium iodide (KI) solution immediately after silver diamine fluoride (SDF) application may affect the inhibitory effects of SDF on biofilm formation. This study compared the efficacy of 38% SDF with and without KI on preventing mixed-species biofilm formation on human [...] Read more.

Applying a saturated potassium iodide (KI) solution immediately after silver diamine fluoride (SDF) application may affect the inhibitory effects of SDF on biofilm formation. This study compared the efficacy of 38% SDF with and without KI on preventing mixed-species biofilm formation on human root dentin surfaces and assessed ion incorporation into root dentin. The biofilms, composed of Streptococcus mutans, Lactobacillus rhamnosus, and Actinomyces naeslundii, were grown on specimen surfaces treated with either SDF or SDF + KI. After 24 h, the biofilms were evaluated using scanning electron microscopy, live/dead staining, adenosine triphosphate (ATP) assays, colony-forming unit (CFU) counts, and quantitative polymerase chain reaction. A Mann–Whitney U test was used to compare the results between the groups. Ion incorporation was assessed using an electron probe microanalyzer. The relative ATP content in the SDF + KI group was significantly higher than that in the SDF group (p < 0.05). However, biofilm morphology and the logarithmic reduction in CFUs and bacterial DNA were comparable across the groups. The SDF + KI treatment resulted in less silver and fluoride ion incorporation than that yielded by SDF alone. The inhibitory effects of SDF and SDF + KI on mixed-species biofilm formation were almost equivalent, although KI application affected the ion incorporation. Full article

(This article belongs to the Special Issue Antimicrobial Agents in Oral Diseases: Prophylaxis and Therapy between New and Old Molecules, 2nd Edition)

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Representative scanning electron microscopy (SEM) images of cariogenic biofilms formed on root dentin surfaces in the SDF (c,d), SDF + KI (g,h), and corresponding control groups (a,b,e,f) after 24 h of incubation. White arrows indicate the biofilm clusters. SDF: silver diamine fluoride; KI: potassium iodide; scale bars = 100 µm. Full article ">Figure 2
Confocal laser scanning microscopy (CLSM) analysis of mixed-species biofilms consisting of S. mutans, L. rhamnosus, and A. naeslundii formed on root dentin surfaces. (a–p) Representative three-dimensional reconstructed images corresponding to live/dead staining; scale bars = 20 µm (top view) and 30 µm (3D view). The green signal is due to the SYTO9 dye which indicates live cells, while the red signal is due to propidium iodide which marks the dead cells. (q) Ratio of dead to live cells. SDF: silver diamine fluoride; KI: potassium iodide. Full article ">Figure 3
Relative ATP content of biofilm on root dentin surfaces. Data from the control of each test group were used as the standard for calculating the relative content in comparison with the other groups. ATP: adenosine triphosphate; SDF: silver diamine fluoride; KI: potassium iodide. Full article ">Figure 4
Log reduction in viable cell number (CFU/mL) of S. mutans, L. rhamnosus, and A. naeslundii in the SDF and SDF + KI groups (n = 5). Medians, quartiles, and extreme values are given. SDF: silver diamine fluoride; KI: potassium iodide. Full article ">Figure 5
Log reduction in DNA concentration (copies/mL) of S. mutans, L. rhamnosus, A. naeslundii, and 16S rDNA in the SDF and SDF + KI groups (n = 5). Medians, quartiles, and extreme values are given. SDF: silver diamine fluoride; KI: potassium iodide. Full article ">Figure 6
Silver and fluoride distribution profiles in the longitudinal section of root dentin specimens after incubation for 24 h in the control (a–d), SDF (b–e), and SDF + KI (c–f) groups. Arrowheads indicate the disc surface. SDF: silver diamine fluoride; KI: potassium iodide. Full article ">Figure 7
Experimental flow chart. MRD: modified Robbins device; SDF: silver diamine fluoride; KI: potassium iodide; Sm: S. mutans; Lr: L. rhamnosus; An: A. naeslundii; BHI: brain–heart infusion; SEM: scanning electron microscopy; CLSM: confocal laser scanning microscopy; ATP: adenosine triphosphate; qPCR: quantitative polymerase chain reaction; EPMA: electron probe microanalyzer. Full article ">

11 pages, 1656 KiB

Open AccessArticle

Immunomodulatory Effects and Protection in Sepsis by the Antibiotic Moxifloxacin

by Tiago R. Velho, Helena Raquel, Nuno Figueiredo, Ana Neves-Costa, Dora Pedroso, Isa Santos, Katharina Willmann and Luís F. Moita

Antibiotics 2024, 13(8), 742; https://doi.org/10.3390/antibiotics13080742 - 7 Aug 2024

Viewed by 358

Abstract

Sepsis is a leading cause of death in Intensive Care Units. Despite its prevalence, sepsis remains insufficiently understood, with no substantial qualitative improvements in its treatment in the past decades. Immunomodulatory agents may hold promise, given the significance of TNF-α and IL-1β as [...] Read more.

Sepsis is a leading cause of death in Intensive Care Units. Despite its prevalence, sepsis remains insufficiently understood, with no substantial qualitative improvements in its treatment in the past decades. Immunomodulatory agents may hold promise, given the significance of TNF-α and IL-1β as sepsis mediators. This study examines the immunomodulatory effects of moxifloxacin, a fluoroquinolone utilized in clinical practice. THP1 cells were treated in vitro with either PBS or moxifloxacin and subsequently challenged with lipopolysaccharide (LPS) or E. coli. C57BL/6 mice received intraperitoneal injections of LPS or underwent cecal ligation and puncture (CLP), followed by treatment with PBS, moxifloxacin, meropenem or epirubicin. Atm^−/− mice underwent CLP and were treated with either PBS or moxifloxacin. Cytokine and organ lesion markers were quantified via ELISA, colony-forming units were assessed from mouse blood samples, and DNA damage was evaluated using a comet assay. Moxifloxacin inhibits the secretion of TNF-α and IL-1β in THP1 cells stimulated with LPS or E. coli. Intraperitoneal administration of moxifloxacin significantly increased the survival rate of mice with severe sepsis by 80% (p < 0.001), significantly reducing the plasma levels of cytokines and organ lesion markers. Notably, moxifloxacin exhibited no DNA damage in the comet assay, and Atm^−/− mice were similarly protected following CLP, boasting an overall survival rate of 60% compared to their PBS-treated counterparts (p = 0.003). Moxifloxacin is an immunomodulatory agent, reducing TNF-α and IL-1β levels in immune cells stimulated with LPS and E. coli. Furthermore, moxifloxacin is also protective in an animal model of sepsis, leading to a significant reduction in cytokines and organ lesion markers. These effects appear unrelated to its antimicrobial activity or induction of DNA damage. Full article

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Moxifloxacin inhibits the secretion of IL-1β and TNF-α. THP-1 cells were incubated with Escherichia coli (A,B) or lipopolysaccharide (LPS) (C,D), with moxifloxacin at concentrations of 5, 10 and 20 μM. IL-1β and TNF-α were reduced with both the stimuli. ns: non-significant; *: p < 0.05; **: p < 0.01. Full article ">Figure 2
Moxifloxacin protection against sepsis. (A) Survival of C57BL/6 WT mice subjected to CLP treated with carrier (PBS), epirubicin (0.6 μg/g body weight) or moxifloxacin (20 μg/g body weight), at time of procedure and 24 h later. (B) Survival of C57BL/6 WT with LPS treated with PBS or moxifloxacin (20 μg/g body weight). (C) Survival of ATM-KO mice subjected to CLP treated with carrier (PBS) or moxifloxacin (20 μg/g body weight) at time of procedure and 24 h later. ns: non-significant; *: p < 0.05; **: p < 0.01; ***: p < 0.001; ****: p < 0.0001. Full article ">Figure 3
Moxifloxacin has anti-inflammatory and protective effects in vivo. Moxifloxacin reduces inflammation and tissue lesions associated with CLP, as assessed by the reduced plasma levels of TNFα (A), IL1β (B), IL6 (C), and LDH (E), ALT (F) and urea (G) in C57BL/6 WT animals 24 h after CLP followed by treatment with PBS (C + P), epirubicin (C + E), moxifloxacin (C + MX) or meropenem (C + MP). Lactate levels were not changed between all groups (H). Polymicrobial load (CFU) in blood (D) of C57BL/6 WT animals 24 h after CLP followed by treatment with PBS (C + P), moxifloxacin (C + MX) or meropenem (C + MP). ns: non-significant; *: p < 0.05; **: p < 0.01; ***: p < 0.001. Full article ">Figure 4
DNA damage in THP-1 cells treated with moxifloxacin and etoposide. Comet assay performed on THP-1 cells verified that DNA damage is similar in all groups incubated with PBS (A), E. coli (B), and with moxifloxacin (4 h), at 5 (C), 10 (D) and 20 (E) μM following stimulation with E. coli. On the other hand, treatment with etoposide (F) resulted in increased average of DNA in tail, representing high DNA damage. Full article ">

13 pages, 2488 KiB

Open AccessArticle

Virulence and Antimicrobial Resistance Characterization of Glaesserella parasuis Isolates Recovered from Spanish Swine Farms

by Alba González-Fernández, Oscar Mencía-Ares, María José García-Iglesias, Máximo Petrocchi-Rilo, Rubén Miguélez-Pérez, César Bernardo Gutiérrez-Martín and Sonia Martínez-Martínez

Antibiotics 2024, 13(8), 741; https://doi.org/10.3390/antibiotics13080741 - 6 Aug 2024

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Abstract

Glaesserella (Haemophilus) parasuis, the causative agent of Glässer’s disease, is present in most pig farms as an early colonizer of the upper respiratory tract. It exhibits remarkable variability in virulence and antimicrobial resistance (AMR), with virulent strains capable of inducing [...] Read more.

Glaesserella (Haemophilus) parasuis, the causative agent of Glässer’s disease, is present in most pig farms as an early colonizer of the upper respiratory tract. It exhibits remarkable variability in virulence and antimicrobial resistance (AMR), with virulent strains capable of inducing respiratory or systemic disease. This study aimed to characterize the virulence and the AMR profiles in 65 G. parasuis isolates recovered from Spanish swine farms. Virulence was assessed using multiplex leader sequence (LS)-PCR targeting vtaA genes, with all isolates identified as clinical (presumed virulent). Pathotyping based on ten pangenome genes revealed the virulent HPS_22970 as the most frequent (83.1%). Diverse pathotype profiles were observed, with 29 unique gene combinations and two isolates carrying only potentially non-virulent pangenome genes. AMR phenotyping showed widespread resistance, with 63.3% classified as multidrug resistant, and high resistance to clindamycin (98.3%) and tylosin (93.3%). A very strong association was found between certain pathotype genes and AMR phenotypes, notably between the virulent HPS_22970 and tetracycline resistance (p < 0.001; Φ = 0.58). This study reveals the wide diversity and complexity of G. parasuis pathogenicity and AMR phenotype, emphasizing the need for the targeted characterization of clinical isolates to ensure appropriate antimicrobial treatments and the implementation of prophylactic measures against virulent strains. Full article

(This article belongs to the Special Issue Antimicrobial Resistance and Virulence in Veterinary Pathogens)

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Pathotype characterization of 65 G. parasuis isolates from Spanish swine farms: (a) pathotype clustering based on the presence of ten pangenome genes, using the unweighted pair group method with arithmetic mean (UPGMA) as the hierarchical clustering method; (b) frequency (%) of each pathotype gene; and (c) principal component analysis (PCA) of the ten evaluated pangenome genes, showing grouping based on pathologic process and TbpB cluster of each G. parasuis isolate. Full article ">Figure 2
Antimicrobial resistance (AMR) characterization at the class level of 60 G. parasuis isolates from Spanish swine farms: (a) AMR phenotype clustering based on antimicrobial classes, using the unweighted pair group method with arithmetic mean (UPGMA) as the hierarchical clustering method, and (b) principal component analysis (PCA) of the AMR patterns, showing grouping based on the TbpB cluster of each G. parasuis isolate. Full article ">Figure 3
Network associations between pathotype genes and antimicrobial resistance (AMR) at the class level in 60 G. parasuis isolates from Spanish swine farms. Node size is determined by the percentage occurrence of the pathotype gene or AMR class. Edge size is proportional to the magnitude of the association based on the Φ coefficient. The network was constructed using significant associations (p < 0.05). Full article ">

10 pages, 572 KiB

Open AccessArticle

Epidemiology and Impact of Anti-Pneumococcal Vaccination and COVID-19 on Resistance of Streptococcus pneumoniae Causing Invasive Disease in Piedmont, Italy

by Alessandro Bondi, Emanuele Koumantakis, Antonio Curtoni, Anna Maria Barbui, Marco Peradotto, Daniela Lombardi, Roberto Casale, Silvia Alizzi, Elisa Zanotto, Lorena Charrier, Rossana Cavallo and Cristina Costa

Antibiotics 2024, 13(8), 740; https://doi.org/10.3390/antibiotics13080740 - 6 Aug 2024

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Abstract

Background: The international surveillance of antimicrobial resistance (AMR) reports S. pneumoniae as one of leading causes of death associated with AMR. Against invasive disease, several vaccinations are available and a reduction in AMR in S. pneumoniae has been observed. Here, we evaluated the [...] Read more.

Background: The international surveillance of antimicrobial resistance (AMR) reports S. pneumoniae as one of leading causes of death associated with AMR. Against invasive disease, several vaccinations are available and a reduction in AMR in S. pneumoniae has been observed. Here, we evaluated the impact of anti-pneumococcal vaccination policy and the SARS-CoV2 outbreak on AMR in S. pneumoniae causing invasive disease. Methods: We collected all strains of S. pneumoniae causing invasive disease from 2008 in the Piedmont region (Italy). Each strain was typed in order to identify the serogroup and data about AMR were collected. The population under surveillance was classified as infants, children, adults, and the old population. Results: We collected n = 2076 S. pneumoniae strains, with 21.9% and 40.3% being resistant to penicillin G and erythromycin, respectively. We reported an increased risk of infection with penicillin-resistant S. pneumoniae among all populations and evaluated whether the infection was caused by a serotype included in the vaccine formulation. A similar increase was observed after the SARS-CoV2 outbreak. Conclusions: In the Piedmont region, subsequently to the introduction of anti-pneumococcal vaccination, a significant increase in the risk of penicillin G-resistant invasive pneumococcal disease among infants and old population was reported. No significant impact was found for the SARS-CoV2 outbreak. Full article

(This article belongs to the Special Issue Clinical Guidelines and Real Practice of Antimicrobial Pharmacotherapy)

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12 pages, 5776 KiB

Open AccessArticle

Cemented Calcar-Guided Short-Stem Prostheses in Geriatric Patients: Short-Term Results from a Prospective Observational Study

by Bertram Regenbrecht, Ahmed Yaseen, Gideon Wagener and Michael Wild

Antibiotics 2024, 13(8), 739; https://doi.org/10.3390/antibiotics13080739 - 6 Aug 2024

Viewed by 331

Abstract

Both cementless and cemented stems have exhibited favorable long-term outcomes in total hip arthroplasty. Nonetheless, in elderly patients, cemented hips offer an advantage due to their reduced risk of periprosthetic fractures. This study aimed to assess the initial outcomes of 28 patients who [...] Read more.

Both cementless and cemented stems have exhibited favorable long-term outcomes in total hip arthroplasty. Nonetheless, in elderly patients, cemented hips offer an advantage due to their reduced risk of periprosthetic fractures. This study aimed to assess the initial outcomes of 28 patients who underwent unilateral cemented total hip arthroplasty utilizing a calcar-guided A2 stem (ARTIQO GmbH, Lüdinghausen, Germany). Various types of antibiotic-loaded bone cement were employed. During follow-up, we recorded demographic data and comorbidities and employed standardized clinical assessment tools, including the Harris Hip Score. Radiographic assessments included preoperative, postoperative, and follow-up imaging to evaluate subsidence, osteolysis, and bone resorption. The results indicated that among the 28 patients, 5 withdrew consent and 2 patients passed away from unrelated causes. Additionally, one prosthesis was explanted due to the undersizing of the cement stopper, which resulted in an inadequate cement mantle. As a result, 20 patients underwent a 1-year follow-up, revealing noteworthy enhancements in clinical scores, with no instances of radiolucent lines or osteolysis. No infections were detected. In summary, our short-term experience with this particular cemented short-stem design yielded promising results, exhibiting excellent functional outcomes, no aseptic loosening attributable to the stem, and no infections. Further clinical studies and registry data are essential to corroborate these findings. Full article

(This article belongs to the Special Issue Local Antibiotics: Antibiotic Loaded Bone Cement and Drug Containing Medical Devices in Orthopaedic Surgery)

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The cemented A2 stem (courtesy of ARTIQO). Full article ">Figure 2
Case #1: Female patient, 81 years old, with osteoporotic bone, coxa vara, and a Dorr C femur. (a) Preoperative planning for a cemented A2 stem combined with a cementless ANA.NOVA Alpha Cup. The image shows good reconstruction of the leg length and offset. (b,c) Postoperative anteroposterior (b) and axial (c) radiographic imaging 1 week postoperatively. Correct position of the stem and complete cement mantle. Full article ">Figure 2 Cont.
Case #1: Female patient, 81 years old, with osteoporotic bone, coxa vara, and a Dorr C femur. (a) Preoperative planning for a cemented A2 stem combined with a cementless ANA.NOVA Alpha Cup. The image shows good reconstruction of the leg length and offset. (b,c) Postoperative anteroposterior (b) and axial (c) radiographic imaging 1 week postoperatively. Correct position of the stem and complete cement mantle. Full article ">Figure 3
(a) Case #2: Osteoarthritis, female, 85 years old, bilateral sequential implantation of an A2 stem, Dorr B-C femora. (b) Left side: slight distalization of the cement stopper. (c) Right side: no positional change of the cement stopper during the operation. Full article ">Figure 3 Cont.
(a) Case #2: Osteoarthritis, female, 85 years old, bilateral sequential implantation of an A2 stem, Dorr B-C femora. (b) Left side: slight distalization of the cement stopper. (c) Right side: no positional change of the cement stopper during the operation. Full article ">Figure 4
(a) Case #3: Osteoarthritis, female, 81 years old, preoperative planning. (b) Correct implant position 1 week postoperatively. Homogeneous cement mantle. Full article ">Figure 4 Cont.
(a) Case #3: Osteoarthritis, female, 81 years old, preoperative planning. (b) Correct implant position 1 week postoperatively. Homogeneous cement mantle. Full article ">

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Antibiotics, Volume 13, Issue 8 (August 2024) – 88 articles

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