Antibiotics

13 pages, 373 KiB

Open AccessArticle

Prevalence of Antimicrobial Resistance Among the WHO’s AWaRe Classified Antibiotics Used to Treat Urinary Tract Infections in Diabetic Women

by Ahmad Hamdan, Mohannad N. AbuHaweeleh, Leena Al-Qassem, Amira Kashkoul, Izzaldin Alremawi, Umna Hussain, Sara Khan, Menatalla M. S. ElBadway, Tawanda Chivese, Habib H. Farooqui and Susu M. Zughaier

Antibiotics 2024, 13(12), 1218; https://doi.org/10.3390/antibiotics13121218 (registering DOI) - 14 Dec 2024

Abstract

Background and Objectives: Diabetes is linked to a higher risk of urinary tract infections (UTIs) in women, often leading to recurrent antibiotic treatments. Frequent antibiotic use for UTIs can contribute to antimicrobial resistance (AMR), a critical public health threat that increases treatment [...] Read more.

Background and Objectives: Diabetes is linked to a higher risk of urinary tract infections (UTIs) in women, often leading to recurrent antibiotic treatments. Frequent antibiotic use for UTIs can contribute to antimicrobial resistance (AMR), a critical public health threat that increases treatment failure. This study investigated the prevalence of AMR and its associated factors among women with UTIs, comparing those with and without diabetes. Results: The study population had a mean age of 52 years (SD = 23) for the women without diabetes and 68 years (SD = 14) for those with diabetes. Resistance was highest for cefazolin and levofloxacin in the Access and Watch antibiotic groups, while ciprofloxacin was the most frequently prescribed antibiotic. AMR prevalence was 35.7% among the women with diabetes and 21.3% among those without. After adjustment, AMR was significantly associated with both uncomplicated diabetes (OR 1.14, 95% CI 1.08–1.21) and complicated diabetes (OR 1.54, 95% CI 1.45–1.64), as well as with higher numbers of prescribed antibiotics (OR 277.39, 95% CI 253.79–303.17). Methods: Using a cross-sectional cohort from the Physionet database, we analyzed data on 116,902 female participants treated for UTIs, including their antibiotic exposure, diabetes status, comorbidities, and hospital admission details. Antimicrobials were classified per the WHO’s AWaRe criteria. The primary outcome was AMR identified in urine cultures, and the association with diabetes status was evaluated using multivariable logistic regression. Conclusions: Our findings highlight the need for focused antimicrobial stewardship in women with diabetes to reduce the AMR rates in this vulnerable group. Full article

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

17 pages, 2840 KiB

Open AccessArticle

Evaluation of Metronidazole Resistance of Vaginal Swab Isolates from South African Women Treated for Bacterial Vaginosis

by Timo Schwebs, Ann-Katrin Kieninger, Lenka Podpera Tisakova, Vera Oberbauer, Rocío Berdaguer, Andile Mtshali, Gugulethu Mzobe, Anne Rompalo, Adrian Mindel, Marothi Letsoalo, Nigel Garrett, Sinaye Ngcapu and Lorenzo Corsini

Antibiotics 2024, 13(12), 1217; https://doi.org/10.3390/antibiotics13121217 (registering DOI) - 14 Dec 2024

Abstract

Background/Objectives: The high recurrence rate of bacterial vaginosis (BV) after antibiotic treatment is at least partially attributed to resistant bacteria. The CAPRISA 083 (CAP083) study investigated the influence of metronidazole (MTZ) treatment on the vaginal microbiome in 56 South African women diagnosed [...] Read more.

Background/Objectives: The high recurrence rate of bacterial vaginosis (BV) after antibiotic treatment is at least partially attributed to resistant bacteria. The CAPRISA 083 (CAP083) study investigated the influence of metronidazole (MTZ) treatment on the vaginal microbiome in 56 South African women diagnosed with BV. To explore the etiology of recurrent BV in this cohort, we retrospectively analyzed vaginal swabs collected in CAP083 before and after MTZ treatment. Methods: We isolated over 1200 bacterial strains, including Gardnerella, Lactobacillus, Prevotella, and Fannyhessa, and determined the minimum inhibitory concentration (MIC) of MTZ and the resistance status according to CLSI and EUCAST guidelines. Results: At baseline, 64% (CLSI) of Gardnerella isolates were resistant to MTZ, rising to 80% after MTZ treatment by the 12-week visit. Lactobacillus species consistently exhibited resistance of 100%, while Fannyhessea vaginae maintained resistance rates of 78–91% across visits. Prevotella strains varied, showing two susceptible isolates at baseline and one resistant isolate at the 6-week visit. Susceptible and resistant Gardnerella isolates were often isolated from the same swab, and 70% (CLSI) of participants had at least one resistant Gardnerella strain already at baseline. Sensitive Gardnerella isolates were not a predictor of an MTZ-mediated reduction in Gardnerella abundance. Conclusions: Our data indicate that the 23% cure rate in CAP083 was associated with a combination of a high share of MTZ-resistant bacteria at baseline, a potentially insufficient MTZ dose regimen, and a constantly high average abundance of Gardnerella. Future research should explore novel therapeutic strategies to enhance treatment efficacy and combat antibiotic resistance. Full article

(This article belongs to the Section Antibiotic Therapy in Infectious Diseases)

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17 pages, 863 KiB

Open AccessArticle

Identification of Factors Determining Patterns of Serum C-Reactive Protein Level Reduction in Response to Treatment Initiation in Patients with Drug-Susceptible Pulmonary Tuberculosis

by Agnija Kivrane, Viktorija Ulanova, Solveiga Grinberga, Eduards Sevostjanovs, Anda Viksna, Iveta Ozere, Ineta Bogdanova, Ilze Simanovica, Inga Norvaisa, Leonora Pahirko, Dace Bandere and Renate Ranka

Antibiotics 2024, 13(12), 1216; https://doi.org/10.3390/antibiotics13121216 (registering DOI) - 14 Dec 2024

Abstract

Background: Serum C-reactive protein (CRP) levels vary depending on radiological and bacteriological findings at the time of tuberculosis (TB) diagnosis. However, the utility of this biomarker in monitoring response to anti-TB treatment and identifying patients at risk of treatment failure is not well [...] Read more.

Background: Serum C-reactive protein (CRP) levels vary depending on radiological and bacteriological findings at the time of tuberculosis (TB) diagnosis. However, the utility of this biomarker in monitoring response to anti-TB treatment and identifying patients at risk of treatment failure is not well established. Objectives: This study evaluated the impact of patients’ baseline characteristics and anti-TB drug plasma exposure on the early reduction in serum CRP levels and its relationship with treatment response. Methods: We enrolled 42 patients with drug-susceptible pulmonary TB, who received a standard six-month regimen. The plasma concentrations of four anti-TB drugs were analysed using LC-MS/MS. Clinically relevant data, including serum CRP levels before and 10–12 days after treatment initiation (CRP_10–12d), were obtained from electronic medical records and patient questionnaires. Results: In 10–12 days, the median serum CRP level decreased from 21.9 to 6.4 mg/L. Lower body mass index, positive sputum-smear microscopy results, and lung cavitations at diagnosis were related to higher biomarker levels at both time points; smoking had a more pronounced effect on serum CRP_10–12d levels. Variability in anti-TB drug plasma exposure did not significantly affect the reduction in serum CRP levels. The serum CRP_10–12d levels, or fold change from the baseline, did not predict the time to sputum culture conversion. Conclusions: Disease severity and patient characteristics may influence the pattern of early CRP reduction, while anti-TB drug plasma exposure had no significant effect at this stage. These early changes in serum CRP levels were not a predictor of response to anti-TB therapy. Full article

(This article belongs to the Special Issue Antibiotics and Infectious Respiratory Diseases, 2nd Edition)

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8 pages, 569 KiB

Open AccessArticle

Increased Antibiotic Susceptibility of Gram-Positive Bacteria in Cerebrospinal Fluid Compared to Broth

by Jennifer S. Wirth, Marija Djukic, Katrin Biesner, Utz Reichard, Roland Nau and Jana Seele

Antibiotics 2024, 13(12), 1215; https://doi.org/10.3390/antibiotics13121215 (registering DOI) - 14 Dec 2024

Abstract

Background: In hospital- and community-acquired central nervous system infections, resistant Gram-positive bacteria are an increasing therapeutic challenge. The present approach does not attempt to identify rapidly bactericidal therapies for susceptible pathogens but aims to improve methods to find antibiotic regimens for multi-resistant pathogens [...] Read more.

Background: In hospital- and community-acquired central nervous system infections, resistant Gram-positive bacteria are an increasing therapeutic challenge. The present approach does not attempt to identify rapidly bactericidal therapies for susceptible pathogens but aims to improve methods to find antibiotic regimens for multi-resistant pathogens that are effective in vivo in spite of reduced in vitro susceptibility in culture media. Methods: Antibiotic susceptibility was tested in cerebrospinal fluid (CSF) and Mueller–Hinton broth (Enterococcus faecalis, methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis) or brain–heart infusion (Streptococcus pneumoniae). Results: Minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) were either lower in CSF than in broth or equal in CSF and broth. The difference between MICs in CSF and broth was prominent with gentamicin, levofloxacin, linezolid (staphylococci), and vancomycin (staphylococci and pneumococcus), whereas it was absent with ampicillin (E. faecalis), penicillin G (S. pneumoniae), linezolid (enterococcus and pneumococcus), and vancomycin (enterococcus). In no case was the MIC or MBC higher in CSF than in broth. Conclusions: Several antibiotics possess an antibacterial effect in CSF at lower concentrations than the MICs determined in broth, i.e., MICs in broth underestimate in situ susceptibility in CSF. Full article

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17 pages, 631 KiB

Open AccessArticle

Pooled Antibiotic Susceptibility Testing Performs Within CLSI Standards for Validation When Measured Against Broth Microdilution and Disk Diffusion Antibiotic Susceptibility Testing of Cultured Isolates

by Emery Haley, Frank R. Cockerill, Rick L. Pesano, Richard A. Festa, Natalie Luke, Mohit Mathur, Xiaofei Chen, Jim Havrilla and David Baunoch

Antibiotics 2024, 13(12), 1214; https://doi.org/10.3390/antibiotics13121214 (registering DOI) - 14 Dec 2024

Abstract

Background/Objectives: While new methods for measuring antimicrobial susceptibility have been associated with improved patient outcomes, they should also be validated using standard protocols for error rates and other test metrics. The objective of this study was to validate a novel susceptibility assay [...] Read more.

Background/Objectives: While new methods for measuring antimicrobial susceptibility have been associated with improved patient outcomes, they should also be validated using standard protocols for error rates and other test metrics. The objective of this study was to validate a novel susceptibility assay for complicated and recurrent urinary tract infections (UTIs): pooled antibiotic susceptibility testing (P-AST). This assay was compared to broth microdilution (BMD) and disk diffusion (DD), following Clinical and Laboratory Standards Institute (CLSI) guidelines for assessment of error rates and agreement. Methods: This study analyzed consecutive fresh clinical urine specimens submitted for UTI diagnostic testing. Upon receipt, the urine samples were subjected in parallel to standard urine culture and multiplex polymerase chain reaction (M-PCR) for microbial identification and quantification. Specimens with the same monomicrobial non-fastidious bacteria detected by both M-PCR and standard urine culture (SUC) underwent standard antibiotic susceptibility testing (AST) and P-AST antibiotic susceptibility testing. Analysis was also undertaken to assess the presence of heteroresistance for specimens with P-AST-resistant and BMD/DD consensus-susceptible results. Results: The performance measures without correction for heteroresistance showed essential agreement (EA%) of ≥90%, very major errors (VMEs) of <1.5%, and major errors (MEs) of <3.0% for P-AST, all meeting the threshold guidelines established by CLSI for AST. The categorical agreement (CA%) also met acceptable criteria (>88%), as the majority of the errors were minor (mEs) with essential agreement. The very major and major error rates for P-AST decreased to <1.0% when heteroresistance was accounted for. Conclusions: The P-AST assay methodology is validated within acceptable parameters when compared to broth microdilution and disk diffusion using CLSI criteria. Full article

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

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23 pages, 4609 KiB

Open AccessArticle

Synthesis of Temporin-SHa Retro Analogs with Lysine Addition/Substitution and Antibiotic Conjugation to Enhance Antibacterial, Antifungal, and Anticancer Activities

by Shahzad Nazir, Arif Iftikhar Khan, Rukesh Maharjan, Sadiq Noor Khan, Muhammad Adnan Akram, Marc Maresca, Farooq-Ahmad Khan and Farzana Shaheen

Antibiotics 2024, 13(12), 1213; https://doi.org/10.3390/antibiotics13121213 - 13 Dec 2024

Abstract

In the face of rising the threat of resistant pathogens, antimicrobial peptides (AMPs) offer a viable alternative to the current challenge due to their broad-spectrum activity. This study focuses on enhancing the efficacy of temporin-SHa derived NST-2 peptide (1), which is [...] Read more.

In the face of rising the threat of resistant pathogens, antimicrobial peptides (AMPs) offer a viable alternative to the current challenge due to their broad-spectrum activity. This study focuses on enhancing the efficacy of temporin-SHa derived NST-2 peptide (1), which is known for its antimicrobial and anticancer activities. We synthesized new analogs of 1 using three strategies, i.e., retro analog preparation, lysine addition/substitution, and levofloxacin conjugation. Analogs were tested in terms of their antibacterial, antifungal, and anticancer activities. Analog 2, corresponding to retro analog of NST-2, was found to be more active but also more hemolytic, reducing its selectivity index and therapeutic potential. The addition of lysine (in analog 3) and lysine substitution (in analog 7) reduced the hemolytic effect resulting in safer peptides. Conjugation with levofloxacin on the lysine side chain (in analogs 4 and 5) decreased the hemolytic effect but unfortunately also the antimicrobial and anticancer activities of the analogs. Oppositely, conjugation with levofloxacin at the N-terminus of the peptide via the β-alanine linker (in analogs 6 and 8) increased their antimicrobial and anticancer activity but also their hemolytic effect, resulting in less safe/selective analogs. In conclusion, lysine addition/substitution and levofloxacin conjugation, at least at the N-terminal position through the β-alanine linker, were found to enhance the therapeutic potential of retro analogs of NST-2 whereas other modifications decreased the activity or increased the toxicity of the peptides. Full article

(This article belongs to the Section Antimicrobial Peptides)

45 pages, 16580 KiB

Open AccessReview

Bisindole Compounds—Synthesis and Medicinal Properties

by Maria Marinescu

Antibiotics 2024, 13(12), 1212; https://doi.org/10.3390/antibiotics13121212 - 13 Dec 2024

Abstract

The indole nucleus stands out as a pharmacophore, among other aromatic heterocyclic compounds with remarkable therapeutic properties, such as benzimidazole, pyridine, quinoline, benzothiazole, and others. Moreover, a series of recent studies refer to strategies for the synthesis of bisindole derivatives, with various medicinal [...] Read more.

The indole nucleus stands out as a pharmacophore, among other aromatic heterocyclic compounds with remarkable therapeutic properties, such as benzimidazole, pyridine, quinoline, benzothiazole, and others. Moreover, a series of recent studies refer to strategies for the synthesis of bisindole derivatives, with various medicinal properties, such as antimicrobial, antiviral, anticancer, anti-Alzheimer, anti-inflammatory, antioxidant, antidiabetic, etc. Also, a series of natural bisindole compounds are mentioned in the literature for their various biological properties and as a starting point in the synthesis of other related bisindoles. Drawing from these data, we have proposed in this review to provide an overview of the synthesis techniques and medicinal qualities of the bisindolic compounds that have been mentioned in recent literature from 2010 to 2024 as well as their numerous uses in the chemistry of materials, nanomaterials, dyes, polymers, and corrosion inhibitors. Full article

(This article belongs to the Section Novel Antimicrobial Agents)

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Graphical abstract

15 pages, 3605 KiB

Open AccessArticle

Restoring Multidrug-Resistant Escherichia coli Sensitivity to Ampicillin in Combination with (−)-Epigallocatechin Gallate

by Anong Kiddee, Atchariya Yosboonruang, Achiraya Siriphap, Grissana Pook-In, Chittakun Suwancharoen, Acharaporn Duangjai, Ratsada Praphasawat, Masami Suganuma and Anchalee Rawangkan

Antibiotics 2024, 13(12), 1211; https://doi.org/10.3390/antibiotics13121211 - 13 Dec 2024

Abstract

Multidrug-resistant (MDR) bacteria, especially Escherichia coli, are a major contributor to healthcare-associated infections globally, posing significant treatment challenges. This study explores the efficacy of (−)-epigallocatechin gallate (EGCG), a natural constituent of green tea, in combination with ampicillin (AMP) to restore the effectiveness [...] Read more.

Multidrug-resistant (MDR) bacteria, especially Escherichia coli, are a major contributor to healthcare-associated infections globally, posing significant treatment challenges. This study explores the efficacy of (−)-epigallocatechin gallate (EGCG), a natural constituent of green tea, in combination with ampicillin (AMP) to restore the effectiveness of AMP against 40 isolated MDR E. coli strains. Antimicrobial activity assays were conducted to determine the minimum inhibitory concentrations (MIC) of EGCG using the standard microdilution technique. Checkerboard assays were employed to assess the potential synergistic effects of EGCG combined with AMP. The pharmacodynamic effects of the combination were evaluated through time-kill assays. Outer membrane disruption was analyzed by measuring DNA and protein leakage and with assessments using N-phenyl-1-naphthylamine (NPN) and rhodamine 123 (Rh123) fluorescence dyes. Biofilm eradication studies involved biofilm formation assays and preformed biofilm biomass and viability assays. Scanning electron microscopy (SEM) was used to examine changes in cellular morphology. The results indicated that EGCG demonstrated activity against all isolates, with MICs ranging from 0.5 to 2 mg/mL, while AMP exhibited MIC values between 1.25 and 50 mg/mL. Importantly, the EGCG-AMP combination showed enhanced efficacy compared to either treatment alone, as indicated by a fractional inhibitory concentration index between 0.009 and 0.018. The most pronounced synergy was observed in 13 drug-resistant strains, where the MIC for EGCG dropped to 8 µg/mL (from 1 mg/mL alone) and that for AMP to 50 µg/mL (from 50 mg/mL alone), achieving a 125-fold and 1000-fold reduction, respectively. Time-kill assays revealed that the bactericidal effect of the EGCG-AMP combination occurred within 2 h. The mechanism of EGCG action includes the disruption of membrane permeability and biofilm eradication in a dose-dependent manner. SEM confirmed that the combination treatment consistently outperformed the individual treatments. This study underscores the potential of restoring AMP efficacy in combination with EGCG as a promising strategy for treating MDR E. coli infections. Full article

(This article belongs to the Special Issue Antimicrobial Activity of Different Plant Extracts, Plant-Derived Compounds and Synthetic Derivatives of Natural Compounds on Pathogenic Microorganisms, 2nd Edition)

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10 pages, 1461 KiB

Open AccessArticle

Prevalence of Vancomycin-Variable Enterococci from the Bloodstream in the Korea Global Antibiotic Resistance Surveillance System, 2017–2022

by Sung Young Lee, Ji-Hyun Nam, Jung Wook Kim, Soo Hyun Kim and Jung Sik Yoo

Antibiotics 2024, 13(12), 1210; https://doi.org/10.3390/antibiotics13121210 (registering DOI) - 12 Dec 2024

Abstract

Vancomycin-variable enterococci (VVE), though genetically containing van genes, are phenotypically sensitive to vancomycin. If VVE is undetected or does not grow on the vancomycin-resistant enterococci (VRE) selection medium, or both, it can acquire resistance upon exposure to vancomycin. This characteristic is clinically important [...] Read more.

Vancomycin-variable enterococci (VVE), though genetically containing van genes, are phenotypically sensitive to vancomycin. If VVE is undetected or does not grow on the vancomycin-resistant enterococci (VRE) selection medium, or both, it can acquire resistance upon exposure to vancomycin. This characteristic is clinically important for the treatment and prevention of VRE. This study aims to analyze the prevalence and characteristics of VVE in Korea through the Global Antibiotic Resistance Surveillance System (Kor-GLASS) and emphasize the importance of VVE. A total of 3342 enterococcal bloodstream isolates were collected through the Kor-GLASS between 2017 and 2022. Antibiotic susceptibility testing, van gene detection, and multilocus sequence typing were conducted with all the isolates. The trends in the domestic prevalence of VVE were analyzed and compared with global prevalence data. Among the isolates, 197 (5.9%), including 124 Enterococcus faecium and 73 E. faecalis, were identified as VVE. While the VRE incidence has declined in Korea since 2020, the VVE incidence is significantly rising. In Korea, only the vanA gene has been detected in both VRE and VVE, and no other van gene variants have been identified. Most of these isolates belong to CC17 (91.3%), with ST17, ST817, and ST80 as the predominant types. We have shown that continuous surveillance is essential in Korea due to the persistently high prevalence of VRE and the potential evolution of VVE into VRE. Consequently, it is critical to evaluate Enterococcus species isolated from domestic clinical settings for their phenotypic vancomycin resistance and the molecular detection of van genes, irrespective of the strain. Full article

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21 pages, 413 KiB

Open AccessReview

Perspectives on the Use of Echinocandins in the Neonatal Intensive Care Unit

by Niki Dermitzaki, Foteini Balomenou, Dimitra Gialamprinou, Vasileios Giapros, Dimitrios Rallis and Maria Baltogianni

Antibiotics 2024, 13(12), 1209; https://doi.org/10.3390/antibiotics13121209 (registering DOI) - 12 Dec 2024

Abstract

The neonatal intensive care unit (NICU) population, especially low birth weight and critically ill neonates, is at risk of invasive Candida infections, which are associated with high mortality rates and unfavorable long-term outcomes. The timely initiation of an appropriate antifungal treatment has been [...] Read more.

The neonatal intensive care unit (NICU) population, especially low birth weight and critically ill neonates, is at risk of invasive Candida infections, which are associated with high mortality rates and unfavorable long-term outcomes. The timely initiation of an appropriate antifungal treatment has been demonstrated to enhance the prognosis. Factors that should be considered in the choice of an antifungal agent include the causative Candida strain, the presence and location of deep tissue infection, any previous use of antifungal prophylaxis, and the presence of implanted devices. Amphotericin B and fluconazole, the first-line drugs for neonatal candidiasis, are not always suitable due to several limitations in terms of efficacy and adverse effects. Therefore, alternative antifungals have been studied and used in neonates when conventional antifungals are ineffective or contraindicated. This narrative review aims to provide an overview of the current literature regarding the use of echinocandins in the neonatal population. The three echinocandins, micafungin, caspofungin, and anidulafungin, share characteristics that make them useful for the treatment of neonatal candidiasis, including activity against a wide range of Candida strains and Candida biofilms and a favorable safety profile. Full article

(This article belongs to the Special Issue New Insights into Prevention, Diagnosis, and Treatment of Neonatal Sepsis and Short- and Long-Term Outcomes)

15 pages, 1746 KiB

Open AccessArticle

Dairy Cattle and the Iconic Autochthonous Cattle in Northern Portugal Are Reservoirs of Multidrug-Resistant Escherichia coli

by Sandra Quinteira, Rui Dantas, Luís Pinho, Carla Campos, Ana R. Freitas, Nuno V. Brito and Carla Miranda

Antibiotics 2024, 13(12), 1208; https://doi.org/10.3390/antibiotics13121208 - 11 Dec 2024

Abstract

Background/Objectives: Animals destined for human consumption play a key role in potentially transmitting bacteria carrying antibiotic resistance genes. However, there is limited knowledge about the carriage of antibiotic-resistant bacteria in native breeds. We aimed to characterize the phenotypic profiles and antibiotic resistance genes [...] Read more.

Background/Objectives: Animals destined for human consumption play a key role in potentially transmitting bacteria carrying antibiotic resistance genes. However, there is limited knowledge about the carriage of antibiotic-resistant bacteria in native breeds. We aimed to characterize the phenotypic profiles and antibiotic resistance genes in Escherichia coli isolated from bovines, including three native Portuguese bovine breeds. Methods: Forty-nine E. coli isolates were selected from 640 fecal samples pooled by age group (eight adult or eight calf samples) from each farm, representing both dairy cattle raised in intensive systems and meat cattle raised in extensive systems in Northern Portugal. The presumptive E. coli colonies plated onto MacConkey agar were confirmed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). The antibiotic resistance profiles were screened by antimicrobial susceptibility testing (EUCAST/CLSI guidelines), and the antibiotic resistance genes by PCR. Results: Most isolates showed resistance to ampicillin (69%), tetracycline (57%), gentamicin (55%), and trimethoprim + sulfamethoxazole (53%), with no resistance to imipenem. Resistance to at least one antibiotic was found in 92% of isolates, while 59% exhibited multidrug resistance. Most calf isolates, including those from native breeds, showed a multidrug-resistant phenotype. Among the adults, this was only observed in Holstein-Friesian and Barrosã cattle. None of the Holstein-Friesian isolates were susceptible to all the tested antibiotics. ESBL-producing E. coli was identified in 39% of isolates, including those from Holstein-Friesian calves and adults, Cachena calves and Minhota adults. The sul2 gene was detected in 69% of isolates, followed by bla_CTX-M (45%), aac(3′)-IV (41%), and aac(6′)-Ib-cr (31%), with a higher prevalence in adults. Conclusions: This pioneering study highlights the concerning presence of multidrug-resistant E. coli in native Portuguese cattle breeds. Full article

(This article belongs to the Special Issue Rise of Antibiotic Resistance: Mechanisms Involved and Solutions to Tackle It)

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11 pages, 2016 KiB

Open AccessArticle

Fusion Partner Facilitates Expression of Cell-Penetrating Peptide L2 in Pichia pastoris

by Xuan Li, Na Yang, Yuxin Fang, Ruoyu Mao, Ya Hao, Da Teng, Na Dong, Anshan Shan and Jianhua Wang

Antibiotics 2024, 13(12), 1207; https://doi.org/10.3390/antibiotics13121207 - 11 Dec 2024

Abstract

Background: L2 is formed by combining the pheromone of Streptococcus agalactiae (S. agalactiae) and a cell-penetrating peptide (CPP) with cell-penetrating selectivity. L2 has more significant penetration and better specificity for killing S. agalactiae. However, the production of AMPs by chemical [...] Read more.

Background: L2 is formed by combining the pheromone of Streptococcus agalactiae (S. agalactiae) and a cell-penetrating peptide (CPP) with cell-penetrating selectivity. L2 has more significant penetration and better specificity for killing S. agalactiae. However, the production of AMPs by chemical synthesis is always a challenge because of the production cost. Methods: This study was devoted to the heterologous expression of the cell-penetrating peptide L2 in Pichia pastoris using SUMO and a short acidic fusion tag as fusion partners, and the high-density expression of SUMO-L2 was achieved in a 5 L fermenter. Results: The results showed that SUMO-L2 expression in the 5 L fermenter reached 629 mg/L. The antibacterial activity of recombinant L2 was examined; the minimum inhibitory concentration (MICs) and minimum bactericidal concentration (MBCs) of purified L2 were 4–8 μg/mL and 8–16 μg/mL against S. agalactiae after 84 h of lysis with 50% formic acid. Conclusions: The findings suggest that SUMO is a suitable fusion tag to express cell-penetrating peptide L2. Full article

(This article belongs to the Special Issue Bioactive Peptides and Their Antibiotic Activity)

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11 pages, 408 KiB

Open AccessArticle

Pseudomonas aeruginosa Isolation from Urine Culture in Hospitalised Patients: Incidence of Complicated Urinary Tract Infections and Asymptomatic Bacteriurias and Impact on Treatment of the EUCAST 2020 Update

by Carlo Pallotto, Paolo Milani, Caterina Catalpi, Donatella Pietrella, Giuseppe Curcio, Filippo Allegrucci, Anna Gidari, Elisabetta Svizzeretto, Giovanni Genga, Andrea Tommasi, Antonella Mencacci and Daniela Francisci

Antibiotics 2024, 13(12), 1206; https://doi.org/10.3390/antibiotics13121206 - 11 Dec 2024

Abstract

Background. Urinary tract infections (UTIs) and asymptomatic bacteriurias (ABU) represent a large field of interest for antimicrobial stewardship programmes especially after 2020 EUCAST update in antimicrobial susceptibility testing interpretation and the possible related increase in carbapenems’ prescription rate. The aim of this study [...] Read more.

Background. Urinary tract infections (UTIs) and asymptomatic bacteriurias (ABU) represent a large field of interest for antimicrobial stewardship programmes especially after 2020 EUCAST update in antimicrobial susceptibility testing interpretation and the possible related increase in carbapenems’ prescription rate. The aim of this study was to evaluate the impact of the 2020 EUCAST update on antibiotic prescription in UTI due to Pseudomonas aeruginosa organism and their characteristics. Methods. A retrospective observational study. We enrolled all the patients with P. aeruginosa isolation from urine, admitted to our hospital from 2018 to 2021. We compared demographic, clinical, and microbiological characteristics and treatment between cases before 2020 EUCAST update (period A, 2018–2019) and after it (period B, 2020–2021). Results. A total of 643 cases was analysed, 278 in period A and 365 in period B; 65% were ABU. Carbapenems’ prescription rate significantly increased in period B when considering ABU alone (21.4% vs. 41%, p = 0.016) and all the treated cases (treated ABU and UTI; 27.8% vs. 41.4%, p = 0.013); anti-Pseudomonas cephalosporins prescription significantly decreased in period B when considering ABU alone (15.7% vs. 3.6%, p = 0.021), UTI alone (20.7% vs. 5.9%, p = 0.009) and all the treated cases (18.5% vs. 5.9%, p = 0.001). Conclusions. The 2020 EUCAST update could have contributed to an increase in carbapenem prescriptions. UTI and ABU represent a large field of interest for stewardship interventions both from a diagnostic and therapeutic point of view. Full article

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

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9 pages, 1074 KiB

Open AccessArticle

A 15-Year Observational Cohort of Acute Empyema at a Single-Center in Japan

by Nobuhiro Asai, Wataru Ohashi, Yuichi Shibata, Daisuke Sakanashi, Hideo Kato, Mao Hagihara, Hiroyuki Suematsu and Hiroshige Mikamo

Antibiotics 2024, 13(12), 1205; https://doi.org/10.3390/antibiotics13121205 - 11 Dec 2024

Abstract

Introduction: Despite the advancements in diagnostic methods and antibiotic treatment, empyema is a critical respiratory infection, showing a high mortality rate of 10–25%. Patients and Methods: To evaluate the bacterial etiology and prognostic factors of acute empyema, we conducted this long-term retrospective cohort [...] Read more.

Introduction: Despite the advancements in diagnostic methods and antibiotic treatment, empyema is a critical respiratory infection, showing a high mortality rate of 10–25%. Patients and Methods: To evaluate the bacterial etiology and prognostic factors of acute empyema, we conducted this long-term retrospective cohort study at our institute between 2008 and 2022. Results: A total of 80 patients were enrolled in this cohort. The median age was 72 years (range 19 to 93 years), and 61 (76%) were male. The most common underlying disease was malignancy, seen in 28 (35%). The mean Charlson comorbidity index (CCI) was 2.7 (±2.4). The 30-day and in-hospital mortality were 9 (11%) and 15 (19%), respectively. Univariate analysis revealed that healthcare-associated infection, inappropriate treatment, high CCI score, performance status (PS) of 2–4, and isolation of potentially drug-resistant (PDR) pathogens were poor prognostic factors. Finally, multivariate analysis showed that high CCI score (p = 0.009) and isolation of PDR pathogens (p = 0.011) were independent poor prognostic factors for in-hospital death in acute empyema. Conclusions: We found that higher CCI scores and isolation of PDR pathogens were independent poor prognostic factors for in-hospital mortality among empyema patients. Full article

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12 pages, 1398 KiB

Open AccessArticle

Antimicrobial Use in the Animal Sector in Japan from 2011 to 2022

by Yuta Hosoi, Mari Matsuda, Michiko Kawanishi, Saki Harada, Mio Kumakawa, Hideto Sekiguchi, Tetsuo Asai and Tatsuro Sekiya

Antibiotics 2024, 13(12), 1204; https://doi.org/10.3390/antibiotics13121204 - 10 Dec 2024

Abstract

Background/Objectives: Evaluating antimicrobial use (AMU) is essential in the investigation and implementation of antimicrobial resistance (AMR) prevention measures. Here, we examined AMU using an index (mg/kg biomass) that considers the antimicrobial sales volume and livestock biomass in Japan from 2011 to 2022. Methods: [...] Read more.

Background/Objectives: Evaluating antimicrobial use (AMU) is essential in the investigation and implementation of antimicrobial resistance (AMR) prevention measures. Here, we examined AMU using an index (mg/kg biomass) that considers the antimicrobial sales volume and livestock biomass in Japan from 2011 to 2022. Methods: Antimicrobial sales volumes were obtained from JVARM data, and biomass data were obtained from reliable statistics. Beef cattle, dairy cattle, pigs, broiler chickens, layer chickens, fish raised in freshwater, and fish raised in seawater were targeted in this study. Results: Tetracycline accounted for 39%, macrolides for 18%, penicillins for 12%, and sulfonamides for 11% of the sales in 2022. The peak antimicrobial sales volume was 847 tons in 2017, and then declined to 766 tons by 2022 with fluctuations in the interim. From the perspective of mg/kg biomass, AMU tended to increase in beef cattle, dairy cattle, and fish raised in seawater, while pigs, broilers, layers, and fish raised in freshwater showed a decreasing trend. In broilers, the decreasing trend that could not be confirmed by sales amount alone was detected using the newly established index. Conclusions: By calculating the mg/kg biomass, it became possible to create an interpretation that is different from that of the simple sales quantity data. We believe that this indicator is stable, transparent, and easily understandable for national monitoring. Full article

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20 pages, 1048 KiB

Open AccessReview

Artificial Intelligence and Machine Learning Applications to Pharmacokinetic Modeling and Dose Prediction of Antibiotics: A Scoping Review

by Iria Varela-Rey, Enrique Bandín-Vilar, Francisco José Toja-Camba, Antonio Cañizo-Outeiriño, Francisco Cajade-Pascual, Marcos Ortega-Hortas, Víctor Mangas-Sanjuan, Miguel González-Barcia, Irene Zarra-Ferro, Cristina Mondelo-García and Anxo Fernández-Ferreiro

Antibiotics 2024, 13(12), 1203; https://doi.org/10.3390/antibiotics13121203 - 10 Dec 2024

Abstract

Background and Objectives: The use of artificial intelligence (AI) and, in particular, machine learning (ML) techniques is growing rapidly in the healthcare field. Their application in pharmacokinetics is of potential interest due to the need to relate enormous amounts of data and to [...] Read more.

Background and Objectives: The use of artificial intelligence (AI) and, in particular, machine learning (ML) techniques is growing rapidly in the healthcare field. Their application in pharmacokinetics is of potential interest due to the need to relate enormous amounts of data and to the more efficient development of new predictive dose models. The development of pharmacokinetic models based on these techniques simplifies the process, reduces time, and allows more factors to be considered than with classical methods, and is therefore of special interest in the pharmacokinetic monitoring of antibiotics. This review aims to describe the studies that use AI, mainly oriented to ML techniques, for dose prediction and analyze their results in comparison with the results obtained by classical methods. Furthermore, in the review, the techniques employed and the metrics to evaluate the precision are described to improve the compression of the results. Methods: A systematic search was carried out in the EMBASE, OVID, and PubMed databases and the results obtained were analyzed in detail. Results: Of the 13 articles selected, 10 were published in the last three years. Vancomycin was monitored in seven and none of the studies were performed on new antibiotics. The most used techniques were XGBoost and neural networks. Comparisons were conducted in most cases against population pharmacokinetic models. Conclusions: AI techniques offer promising results. However, the diversity in terms of the statistical metrics used and the low power of some of the articles make the overall assessment difficult. For now, AI-based ML techniques should be used in addition to classical population pharmacokinetic models in clinical practice. Full article

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

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24 pages, 3297 KiB

Open AccessArticle

7-O-Carboxylic Acid-Substituted 3-O-Alkyl Difluoroquercetin; An Aztreonam-Potentiating Agent Against Carbapenemase-Producing Pseudomonas aeruginosa Through Simultaneous Inhibition of Metallo-β-Lactamase and Efflux Pump

by Seongyeon Lee, Taegum Lee, Mi Kyoung Kim, Joong Hoon Ahn, Seri Jeong, Ki-Ho Park and Youhoon Chong

Antibiotics 2024, 13(12), 1202; https://doi.org/10.3390/antibiotics13121202 - 10 Dec 2024

Abstract

Background/Objectives: Previously, we reported that 3-O-alkyl difluoroquercetins (di-F-Q) potentiates the antimicrobial activity of aztreonam (ATM) against metallo-β-lactamase (MBL)-producing P. aeruginosa through simultaneous inhibition of MBLs and efflux pumps. However, the ATM-potentiating activity of the 3-O-alkyl di-F-Q was observed only [...] Read more.

Background/Objectives: Previously, we reported that 3-O-alkyl difluoroquercetins (di-F-Q) potentiates the antimicrobial activity of aztreonam (ATM) against metallo-β-lactamase (MBL)-producing P. aeruginosa through simultaneous inhibition of MBLs and efflux pumps. However, the ATM-potentiating activity of the 3-O-alkyl di-F-Q was observed only at high and potentially toxic concentrations (32 mg/L). Methods: As both MBLs and efflux pumps reside in the periplasm of Gram-negative bacteria, their inhibitors should accumulate in the periplasmic space. However, the outer membrane porins, the major entry pathway in Gram-negative bacteria, allow the passive diffusion of hydrophilic polar molecules across the outer membrane. Thus, we reasoned that the introduction of a polar substituent at 7-OH position of 3-O-alkyl di-F-Q would enhance its periplasmic concentration to result in potentiation of ATM at lower concentrations. Results: The title compound 5 exhibited inhibitory activity against NDM-1 as well as the efflux pump of P. aeruginosa, which resulted in synergistical potentiation of ATM. A combination of ATM (8 mg/L) and 5 (8 mg/L) inhibited 80% of the ATM-resistant CPPA, while ATM alone did not show any inhibition. In addition, only 4 mg/L of 5 was needed to reduce the MIC₉₀ of ATM four-fold in ATM-resistant CPPA (n = 15). The time–kill data further supported the effectiveness of the combined treatment of ATM with 5, and the combination of ATM (1xMIC) with 8 mg/L of 5 showed bactericidal effects in every bacterial strain tested (PA-002, bla_IMP, PA-003, bla_VIM, PA-014, bla_GES, and PA-017, bla_NDM) by reducing the bacterial loads by 5.1 log₁₀~8.9 log₁₀. Conclusions: The title compound 5 exhibited inhibitory activity against NDM-1 as well as the efflux pump of P. aeruginosa, and the combined inhibitory activity resulted in synergistical potentiation of ATM. It should be noted that most CPPA isolates tested were sensitized to 8 mg/L of ATM upon combination with 4~8 mg/L of 5. Full article

(This article belongs to the Special Issue Antibiotics Resistance in Gram-Negative Bacteria, 2nd Edition)

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23 pages, 4785 KiB

Open AccessReview

Dynamic In Vitro PK/PD Infection Models for the Development and Optimisation of Antimicrobial Regimens: A Narrative Review

by Yalew M. Wale, Jason A. Roberts and Fekade B. Sime

Antibiotics 2024, 13(12), 1201; https://doi.org/10.3390/antibiotics13121201 - 10 Dec 2024

Abstract

The antimicrobial concentration–time profile in humans affects antimicrobial activity, and as such, it is critical for preclinical infection models to simulate human-like dynamic concentration–time profiles for maximal translatability. This review discusses the setup, principle, and application of various dynamic in vitro PK/PD infection [...] Read more.

The antimicrobial concentration–time profile in humans affects antimicrobial activity, and as such, it is critical for preclinical infection models to simulate human-like dynamic concentration–time profiles for maximal translatability. This review discusses the setup, principle, and application of various dynamic in vitro PK/PD infection models commonly used in the development and optimisation of antimicrobial treatment regimens. It covers the commonly used dynamic in vitro infection models, including the one-compartment model, hollow fibre infection model, biofilm model, bladder infection model, and aspergillus infection model. It summarises the mathematical methods for the simulation of the pharmacokinetic profile of single or multiple antimicrobials when using the serial or parallel configurations of in vitro systems. Dynamic in vitro models offer reliable pharmacokinetic/pharmacodynamic data to help define the initial dosing regimens of new antimicrobials that can be developed further in clinical trials. They can also help in the optimisation of dosing regimens for existing antimicrobials, especially in the presence of emerging antimicrobial resistance. In conclusion, dynamic in vitro infection models replicate the interactions that occur between microorganisms and dynamic antimicrobial exposures in the human body to generate data highly predictive of the clinical efficacy. They are particularly useful for the development new treatment strategies against antimicrobial-resistant pathogens. Full article

(This article belongs to the Special Issue Strategies for Combatting Multidrug-Resistant and Extensively Drug-Resistant Bacteria, 2nd Edition)

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15 pages, 2001 KiB

Open AccessArticle

Effectiveness of Cooking Procedures in Reducing Antibiotic Residues in Bivalves

by Hugo Bastos, André M. P. T. Pereira, Angelina Pena, Andreia Freitas, Marta Leite and Liliana J. G. Silva

Antibiotics 2024, 13(12), 1200; https://doi.org/10.3390/antibiotics13121200 - 9 Dec 2024

Abstract

Background/Objectives: The widespread use of antibiotics, which wastewater treatment plants (WWTPs) cannot fully remove, in human and veterinary medicine leads to their release into wastewater, resulting in the contamination of aquatic environments. Bivalves can accumulate these antibiotics, posing a risk to shellfish consumers, [...] Read more.

Background/Objectives: The widespread use of antibiotics, which wastewater treatment plants (WWTPs) cannot fully remove, in human and veterinary medicine leads to their release into wastewater, resulting in the contamination of aquatic environments. Bivalves can accumulate these antibiotics, posing a risk to shellfish consumers, including potential antimicrobial resistance. This study aimed to assess how three cooking methods—marinating, steaming, and grilling—affect the concentration of 33 different antibiotics in bivalves fortified at the level of maximum residue limit (MRL) and twice the MRL (2MRL). Results: The data show the percentage of antibiotic remaining after cooking: 100% indicates stability or no reduction; values above 100% show an increase in concentration, and values below 100% reflect a decrease in antibiotic concentration. In general, all culinary procedures removed part of the added antibiotics. However, the most effective method was marinating (47%), followed by steaming (60%) and finally grilling (92%). It was also found that, overall, the fortification level, MRL or 2MRL, did not impact antibiotic removal in each cooking method. Moreover, different antibiotics’ classes presented diverse removals when cooked, ranging between 0% for penicillins and 73% for sulphonamides. Furthermore, the results showed a great diversity of responses to cooking within some antibiotic classes. Methods: After cooking, the analysis was based on solid–liquid extraction followed by liquid chromatography–quadrupole time-of-flight mass spectrometry (UHPLC-ToF-MS). Conclusions: The ongoing monitoring of antibiotic levels is essential, and further research is needed to understand how cooking affects these substances and their metabolites. This will help assess the real risk to consumers and guide risk-mitigation measures. Full article

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