Antibiotics

This study sought to analyze the antimicrobial resistant phenotypes and genotypes as well as the virulence content of S. aureus isolates recovered from patients with diabetic foot infections (DFIs) in a Tunisian hospital. Eighty-three clinical samples of 64 patients were analyzed, and bacterial isolates were identified by MALDI-TOF. The antimicrobial resistance phenotypes were determined by the Kirby–Bauer disk diffusion susceptibility test. Resistance and virulence genes, agr profile, spa and SCCmec types were determined by PCR and sequencing. S. aureus was detected in 14 of the 64 patients (21.9%), and 15 S. aureus isolates were recovered. Six out of the fifteen S. aureus isolates were methicillin-resistant (MRSA, mecA-positive) (40%). The isolates harbored the following resistance genes (number of isolates): blaZ (12), erm(B) (2), erm(A) (1), msrA (2), tet(M) (2), tet(K) (3), tet(L) (1), aac(6′)-aph(2′′) (2), ant(4′′) (1) and fexA (1). The lukS/F-PV and tst genes were detected in three isolates. Twelve different spa-types were identified and assigned to seven clonal complexes with the predominance of agr-type III. Furthermore, the SCCmec types III, IV and V were found among the MRSA isolates. Moreover, one MSSA CC398-t571-agr-III isolate was found; it was susceptible to all antimicrobial agents and lacked luk-S/F-PV, tst, eta and etb genes. This is the first report on the prevalence and molecular characterization of S. aureus from DFIs and also the first detection of the MSSA-CC398-t571 clone in human infections in Tunisia. Our findings indicated a high prevalence S. aureus in DFIs with genetic diversity among the MSSA and MRSA isolates. Full article

An 8-year-old girl diagnosed with cardiofaciocutaneous syndrome presented to our department with gingival pain, inflammation, and bleeding. Her medical history included hypoplasia of the corpus callosum, intellectual disability, trichothiodystrophy, global developmental delay, myopia, laryngomalacia, hypothyroidism, and osteoporosis. A diagnosis was reached of “periodontitis as a direct manifestation of systemic diseases”. During 9 years of follow-up, there were exacerbation episodes with spontaneous gum bleeding, ulcers in the interdental papilla, tooth mobility, and progressive tooth loss. Some of these exacerbation episodes resolved clinically with the administration of amoxicillin and metronidazole. We therefore proposed an oral microbiome study (subgingival and saliva samples) before and after antibiotic therapy. The most abundant genera at the subgingival level before administering antibiotics were Prevotella, Streptococcus, Fusobacterium, Leptotrichia, and Aggregatibacter. Of the 94 genera sequenced, 57 were less abundant in the post-treatment state than at baseline, particularly certain Gram-negative periodontal pathogens such as Porphyromonas, Treponema, Aggregatibacter, Fusobacterium, and Campylobacter. In contrast, other genera related to oral health, such as Haemophilus, Granulicatella, and Abiotrophia, showed an increase after administering the antibiotic. In conclusion, periodontitis exacerbations as a direct manifestation of systemic disease can occasionally be controlled exclusively with systemic antibiotics, without the need for performing mechanical periodontal therapy. This clinical recovery is correlated to substantial changes in the oral microbiome, which lead to the recovery of eubiosis of the microbiota. Full article

Klebsiella pneumoniae is a multidrug-resistant opportunistic human pathogen related to various infections. As such, synthetic peptides have emerged as potential alternative molecules. Mo-CBP₃-PepI has presented great activity against K. pneumoniae by presenting an MIC₅₀ at a very low concentration (31.25 µg mL⁻¹). Here, fluorescence microscopy and proteomic analysis revealed the alteration in cell membrane permeability, ROS overproduction, and protein profile of K. pneumoniae cells treated with Mo-CBP₃-PepI. Mo-CBP₃-PepI led to ROS overaccumulation and membrane pore formation in K. pneumoniae cells. Furthermore, the proteomic analysis highlighted changes in essential metabolic pathways. For example, after treatment of K. pneumoniae cells with Mo-CBP₃-PepI, a reduction in the abundance of protein related to DNA and protein metabolism, cytoskeleton and cell wall organization, redox metabolism, regulation factors, ribosomal proteins, and resistance to antibiotics was seen. The reduction in proteins involved in vital processes for cell life, such as DNA repair, cell wall turnover, and protein turnover, results in the accumulation of ROS, driving the cell to death. Our findings indicated that Mo-CBP₃-PepI might have mechanisms of action against K. pneumoniae cells, mitigating the development of resistance and thus being a potent molecule to be employed in producing new drugs against K. pneumoniae infections. Full article

Antimicrobial drugs applied topically offer several advantages. However, the widespread use of antibiotics has led to increasing antimicrobial resistance. One interesting approach in the drug discovery process is drug repurposing. Disulfiram, which was originally approved as an anti-alcoholism drug, offers an attractive alternative to treat topical multidrug resistance bacteria in skin human infections. This study aimed to evaluate the biopharmaceutical characteristics of the drug and the effects arising from its topical application in detail. Microdilution susceptibility testing showed antibacterial activity against Gram-positive bacteria Staphylococcus aureus and Streptococcus pyogenes. Dermal absorption revealed no permeation in pig skin. The quantification of the drug retained in pig skin demonstrated concentrations in the stratum corneum and epidermis, enough to treat skin infections. Moreover, in vitro cytotoxicity and micro-array analyses were performed to better understand the mechanism of action and revealed the importance of the drug as a metal ion chelator. Together, our findings suggest that disulfiram has the potential to be repurposed as an effective antibiotic to treat superficial human skin infections. Full article

Low awareness of antibiotics and antibiotic resistance may lead to inappropriate antibiotic use and contribute to the problem of antibiotic resistance. This study explored levels and determinants of antibiotic awareness in a rural community in northern Vietnam, through a cross-sectional survey of 324 households in one commune of Ha Nam Province. Awareness and knowledge of antibiotics and antibiotic resistance and determinants were evaluated using structured questionnaires. Most respondents (232/323 (71.8%)) had heard of antibiotics, but fewer could name any antibiotic (68/323 (21.1%)) or had heard of antibiotic resistance (57/322 (17.7%)). In adjusted regression models, antibiotic awareness was lower among those who lived further from health facilities (Odds Ratio (OR): 0.08; 95% Confidence Interval (CI): 0.04–0.19) but higher among those who used interpersonal sources for health information (OR: 4.06; 95% CI: 1.32–12.46). Antibiotic resistance awareness was lower among those who used private providers or pharmacies as their usual health facility (OR: 0.14; 95% CI: 0.05–0.44) but higher among those with medical insurance (OR: 3.70; 95% CI: 1.06–12.96) and those with high media use frequency (OR: 9.54; 95% CI: 2.39–38.07). Awareness of Antimicrobial Resistance (AMR) was also higher among those who sought health information from official sources (OR: 3.88; 95% CI: 1.01–14.86) or had overall high levels of health information seeking (OR: 12.85; 95% CI: 1.63–101.1). In conclusion, communication interventions need to target frequently used media platforms, such as television, as well as key health information providers, such as health workers, as channels for increasing knowledge and changing community antibiotic use behaviour. Full article

Heterocyclic compounds are considered as one of the major and most diverse family of organic compounds. Nowadays, the demand for these compounds is increasing day-by-day due to their enormous synthetic and biological applications. These heterocyclic compounds have unique antibacterial activity against various Gram-positive and Gram-negative bacterial strains. This review covers the antibacterial activity of different heterocyclic compounds with nitrogen moiety. Some of the derivatives of these compounds show excellent antibacterial activity, while others show reasonable activity against bacterial strains. This review paper aims to bring and discuss the detailed information on the antibacterial activity of various nitrogen-based heterocyclic compounds. It will be helpful for the future evolution of diseases to synthesize new and effective drug molecules. Full article

Urinary Tract Infections (UTIs) are common outpatient and inpatient infections, often treated with empirical therapy. Enterococcus spp. is responsible for about 10% of UTIs. This study aimed to determine the necessity of changing the empirical treatment of UTIs caused by Enterococcus spp. The evaluation was performed for 542 Enterococcus strains isolated from urine samples in the years 2016–2021. We identified three Enterococcus species that were found: E. faecalis (389, 71.8%), E. faecium (151, 27.8%) and E. gallinarum (2, 0.4%). E. faecalis was the dominant species every year. Among E. faecalis, the most prevalent was resistance to norfloxacin (51.4%). Almost all E. faecium strains (150, 99.3%) were resistant to beta-lactams and norfloxacin. Eighty-three strains (55.0%) were resistant to vancomycin and 72 (47.7%) to teicoplanin. E. faecium strains showed a significantly higher percentage of resistance mechanisms GRE (Glicopeptide-Resistant Enterococcus) (72, 48.7%) and VRE (Vancomycin-Resistant Enterococcus) (11, 7.3%), while only five strains of E. feacalis showed a VRE mechanism (1.3%). In the therapy of E. faecalis UTIs, ampicillin and imipenem still remain effective. However, the above-mentioned antibiotics, as well as fluoroquinolones, are not recommended in the treatment of UTIs of E. faecium etiology. Full article

Bacterial resistance to antibiotics continues to be a global public health problem. The choice of the most effective antibiotic and the use of an adapted dose in the initial phase of the infection are essential to limit the emergence of resistance. This will depend on (i) the isolated bacteria and its resistance profile, (ii) the pharmacodynamic (PD) profile of the antibiotic used and its level of toxicity, (iii) the site of infection, and (iv) the pharmacokinetic (PK) profile of the patient. In order to take account of both parameters to optimize the administered treatment, a minimal inhibitory concentration (MIC) determination associated with therapeutic drug monitoring (TDM) and their combined interpretation are required. The objective of this narrative review is thus to suggest microbiological, pharmacological, and/or clinical situations for which this approach could be useful. Regarding the microbiological aspect, such as the detection of antibiotic resistance and its level, the preservation of broad-spectrum β-lactams is particularly discussed. PK-PD profiles are relevant for difficult-to-reach infections and specific populations such as intensive care patients, cystic fibrosis patients, obese, or elderly patients. Finally, MIC and TDM are tools available to clinicians, who should not hesitate to use them to manage their patients. Full article

Chronic tonsillitis (CT) is a global health issue which can impair patient’s quality of life and has an important socioeconomic impact due to the nonrational use of antibiotics, increased antimicrobial resistance and frequent need for surgical treatment. In order to isolate and identify the causing agents of CT, a total of 79 postoperative palatine and adenoid tissue samples were obtained from the ENT Clinic, KBC Zvezdara, Belgrade, Serbia. Culture identification was performed by MALDI-TOF MS and the Staphylococcus aureus isolates were tested for biofilm forming capability and antibiotic susceptibility. Additionally, a histological examination of palatine and adenoid tissue was performed in order to detect the presence of CT-causing bacteria. The slight majority of participants were females with median age of 28 years for adult patients (group I) and 6 years for children (group II). Analysis of the incidence of bacteria isolated from tissue samples in both groups showed the highest prevalence of S. aureus, Streptococcus oralis and Streptococcus parasanquinis. In addition to interfollicular hyperplasia, colonies of species S. aureus were detected in histological material. The presence of biofilm might be the reason for the recurrence of infection. Therefore, searching for a new treatment of CT is of great importance. Full article

Helicobacter pylori infection (H. pylori) is mainly managed at the primary care level. Our group previously performed a study demonstrating that providing specific counselling (SC) to primary care practitioners (PCPs) who requested a urea breath test (UBT) improved treatment management but not indications for H. pylori tests. SC was given in the form of a personal letter addressed to PCPs with UBT results which contained information about accepted UBT indications and a Helicobacter pylori treatment algorithm. The purpose of the present study was to evaluate the effect of training sessions (TS) on UBT indications, antibiotic prescriptions and eradication rates. This was a quasi-experimental study performed at primary care centres (PCCs). Phase I included 399 patients diagnosed with H. pylori infection after providing SC to PCPs. Phase II included 400 H. pylori-positive patients after giving TS to PCPs who had already received SC (100 from PCCs with TS and 300 from PCCs without TS). An improved trend in the appropriate indication of H. pylori diagnosis was observed between Phase I and PCCs with TS in Phase II (57.5% vs. 67%; p = 0.06). TS improved appropriate prescriptions in PCCs with TS compared to PCCs that only received SC in Phase I and II (94% vs. 75.3%, p = 0.01; 94% vs. 85.6%, p = 0.04, respectively). Eradication rates showed no differences between groups. In conclusion, training sessions after specific counselling improved antibiotic prescription appropriateness but not eradication rates. Full article

The antibiotic spectrum is not reflected in conventional antimicrobial metrics. Days of antibiotic spectrum coverage (DASC) is a novel quantitative metric for antimicrobial consumption developed with consideration of the antibiotic spectrum. However, there were no data regarding disease and pathogen-specific DASC. Thus, this study aimed to evaluate the DASC trend in patients with bloodstream infections (BSIs). DASC and days of therapy (DOT) of in-patients with positive blood culture results during a 2-year interval were evaluated. Data were aggregated to calculate the DASC, DOT, and DASC/DOT per patient stratified by pathogens. During the 2-year study period, 1443 positive blood culture cases were identified, including 265 suspected cases of contamination. The overall DASC, DASC/patient, DOT, DOT/patient, and DASC/DOT metrics were 226,626; 157.1; 28,778; 19.9; and 7.9, respectively. A strong correlation was observed between DASC and DOT, as well as DASC/patient and DOT/patient. Conversely, DASC/DOT had no correlation with other metrics. The combination of DASC and DOT would be a useful benchmark for the overuse and misuse evaluation of antimicrobial therapy in BSIs. Notably, DASC/DOT would be a robust metric to evaluate the antibiotic spectrum that was selected for patients with BSIs. Full article

Knowledge of antibiotics and awareness of microbial resistance are essential for appropriate antibiotic consumption. This study aimed to develop and validate a measure of antibiotic knowledge and consumption (AKCT) and to make it available in the Arabic language and context. The tool was developed and applied on individuals ≥ 18 years, with mastery of Arabic or English. Exploratory factor analysis using principal-component analysis tested the psychometric properties of the items. AKCT scores were compared with the Infectious Numeracy Test (INT) scores to establish convergent validity. Cronbach’s α >0.7 measured reliability. Three hundred-eighty-six participants completed the questionnaire, achieving a 95.3% response rate. Five components were retained after factor analysis: Side-effects and resistance, Access to antibiotics, Recovery after use, Antibiotics use indications, and Body response. Cronbach’s α = 0.85. The mean ± SD of AKCT = 9.82 ± 3.85 (range = 7–20); lowest scores were related to “Side-effects and resistance” (2.32 ± 2.00, max = 7) and “Antibiotic use indications” (1.61 ± 1.29, max = 5). Scores on the AKCT and INT positively correlated. The AKCT is a valuable, valid, and reliable tool developed for measurement of antibiotic knowledge and consumption behaviors to identify specific areas needing improvements; hence, targeted interventions are devised. Full article

Infectious diseases caused by various nosocomial microorganisms affect worldwide both immunocompromised and relatively healthy persons. Bacteria and fungi have different tools to evade antimicrobials, such as hydrolysis damaging the drug, efflux systems, and the formation of biofilm that significantly complicates the treatment of the infection. Here, we show that myrtenol potentiates the antimicrobial and biofilm-preventing activity of conventional drugs against S. aureus and C. albicans mono- and dual-species cultures. In our study, the two optical isomers, (-)-myrtenol and (+)-myrtenol, have been tested as either antibacterials, antifungals, or enhancers of conventional drugs. (+)-Myrtenol demonstrated a synergistic effect with amikacin, fluconazole, and benzalkonium chloride on 64–81% of the clinical isolates of S. aureus and C. albicans, including MRSA and fluconazole-resistant fungi, while (-)-myrtenol increased the properties of amikacin and fluconazole to repress biofilm formation in half of the S. aureus and C. albicans isolates. Furthermore, myrtenol was able to potentiate benzalkonium chloride up to sixteen-fold against planktonic cells in an S. aureus–C. albicans mixed culture and repressed the adhesion of S. aureus. The mechanism of both (-)-myrtenol and (+)-myrtenol synergy with conventional drugs was apparently driven by membrane damage since the treatment with both terpenes led to a significant drop in membrane potential similar to the action of benzalkonium chloride. Thus, due to the low toxicity of myrtenol, it seems to be a promising agent to increase the efficiency of the treatment of infections caused by bacteria and be fungi of the genus Candida as well as mixed fungal–bacterial infections, including resistant strains. Full article

Aerosols generated through volatilization and subsequent recondensation of oil vapors have been used as obscurant (smoke) screens during military operations since the early twentieth century. Specifically, a petroleum middle distillate known as the fog oil (FO) has been used in US military battlefields to create obscurant smoke screens. During a study on the feasibility of replacing petroleum-derived FO with vegetable oil-derived esters such as methyl soyate (MS), it was observed that that FO and MS aerosols and vapors did not exhibit detectable mutagenic activity but were lethal to Ames strains bacteria even after very short exposure periods. These results opened the potential use of oil-derived vapors as antimicrobial agents. Subsequent studies showed that optimal aerosol/vapor production conditions could further enhance disinfectant efficiency. For this purpose, we examined the antimicrobial activities of mineral oils and biogenic oil ester aerosols/vapors against a wide range of Gram-positive and Gram-negative bacteria. The results of the study showed that the aerosols/vapors obtained from mineral oil or vegetable oil ester under proper conditions can serve as an excellent antibacterial disinfectant. Full article

The effects of bismuth toxicity on the kidney—the main organ responsible for blood filtration—were systematically reviewed. This review was motivated by availability of several sources of bismuth in contact with humans including environmental, medications, dental materials, and cosmetics, potentially leading to kidney filtration of this chemical. No previous studies have systematically reviewed the literature considering this association. A total of 22 studies with a total of 46 individuals met the inclusion criteria, 19 being case reports with only one patient enrolled. The included studies publication dates ranged from 1961 to 2021 and the countries of publication were the United States of America, United Kingdom, Germany, Turkey, Switzerland, and Canada. Bismuth sources affecting the kidneys were uniquely reported as from medical purposes and mostly associated to overdoses with several symptoms, apparently with dose-dependent consequences. Patient history of renal impairment seemed to affect the outcome of the case. Several therapies were conducted following bismuth intoxication, and few studies performed renal biopsies describing its histological findings. It is crucial to reconsider the nephrotoxicity of bismuth compounds, mainly in patients with previous history of renal impairment. Full article

The emergence and spread of multidrug resistant Enterobacterales (MDR-E) are a global public health issue. This problem also concerns urinary tract infections (UTI), which are the second most frequent infections after respiratory infections. The objective of this study was to determine MDR-E frequency and to characterize MDR-E isolates from patients with community-acquired UTIs in Djibouti, Republic of Djibouti. From 800 clinical urinary samples collected at the Mer Rouge Laboratory, Djibouti, from January to July 2019, 142 were identified as Enterobacterales (age range of the 142 patients mean age is 42 years.) Mass spectrometry analysis of these isolates identified 117 Escherichia coli, 14 Klebsiella pneumoniae, 2 Proteus mirabilis, 4 Enterobacter spp., 4 Providencia stuartii and 1 Franconibacter helveticus. Antibiotic susceptibility testing (disk diffusion method) of these 142 isolates detected 68 MDR-E (68/142 = 48%): 65 extended-spectrum bêta lactamase- (ESBL), 2 carbapenemase- (one also ESBL), and 1 cephalosporinase-producer. Multiplex PCR and sequencing showed that the 65 ESBL-producing isolates carried genes encoding CTX-M enzymes (CTX-M-15 in 97% and CTX-M-9 in 3% of isolates). Two isolates harboured a gene encoding the OXA-48-like carbapenemase, and one the gene encoding the AmpC CMY-2 cephalosporinase. Genes implicated in resistance to quinolones (qnrB, aac (6′)-Ib-cr, qnrD, oqxA and B) also were detected. Among the E. coli phylogroups, B2 was the most common phylogenetic group (21% of MDR-E isolates and 26% of non-MDR-E isolates), followed by A (14% and 12%), B1 (9% and 7%), D (3% and 3%), F (3% and 3%) and E (2% and 2%). This study highlights the high frequency of ESBL producers and the emergence of carbapenemase-producers among Enterobacterales causing community-acquired UTIs in Djibouti. Full article

Objectives: To perform a pharmacokinetic/pharmacodynamic (PK/PD) analysis of continuous-infusion (CI) fosfomycin combined with extended-infusion (EI) cefiderocol or CI ceftazidime-avibactam in a case series of severe difficult-to-treat Pseudomonas aeruginosa (DTR-PA) infections. Methods: A single-center retrospective study of patients who were treated with CI fosfomycin plus EI cefiderocol or CI ceftazidime-avibactam for severe DTR-PA infections and who underwent therapeutic drug monitoring (TDM), from 1 September 2021 to 30 June 2022 was performed. Concentrations were measured at steady-state (C_ss) for CI fosfomycin and ceftazidime-avibactam and at trough (C_min) for EI cefiderocol. Joint PK/PD targets of combination therapy were analyzed (thresholds: area-under-the curve to minimum inhibitory concentration (AUC/MIC) ratio > 40.8 for fosfomycin; ceftazidime C_ss/MIC ratio ≥ 4 coupled with avibactam C_ss > 4 mg/L for ceftazidime-avibactam; C_min/MIC ratio ≥ 4 for cefiderocol). Joint PK/PD targets of the combination therapy were analyzed and defined as optimal when both were achieved, quasi-optimal if only one of the two was achieved, and suboptimal if none of the two was achieved). The relationship between joint PK/PD target attainment and microbiological response was assessed. Results: Six patients (three pneumonia, two BSI + pneumonia, and one BSI) were included. The joint PK/PD targets were optimal in four cases and quasi-optimal in the other two. Microbiological eradication (ME) occurred in 4/4 of patients with optimal joint PK/PD targets and in one of the two patients with quasi-optimal joint PK/PD targets. Conclusions: Attaining optimal joint PK/PD targets with a combo-therapy of CI fosfomycin plus EI cefiderocol or CI ceftazidime-avibactam could represent an effective strategy for granting favorable microbiological outcomes in patients with DTR-PA pneumonia and/or BSI. Full article

A well-known class of antibacterials, 14- and 15-membered macrolides are widely prescribed to treat upper and lower respiratory tract infections. Azithromycin is a 15-membered macrolide antibiotic possessing a broad spectrum of antibacterial potency and favorable pharmacokinetics. Bacterial resistance to marketed antibiotics is growing rapidly and represents one of the major global hazards to human health. Today, there is a high need for discovery of new anti-infective agents to combat resistance. Recently discovered conjugates of azithromycin and thiosemicarbazones, the macrozones, represent one such class that exhibits promising activities against resistant pathogens. In this paper, we employed an approach which combined LC-SPE/cryo NMR, MS/MS and molecular modeling for rapid separation, identification and characterization of bioactive macrozones and their diastereomers. Multitrapping of the chromatographic peaks on SPE cartridges enabled sufficient sample quantities for structure elucidation and biological testing. Furthermore, two-dimensional NOESY NMR data and molecular dynamics simulations revealed stereogenic centers with inversion of chirality. Differences in biological activities among diastereomers were detected. These results should be considered in the process of designing new macrolide compounds with bioactivity. We have shown that this methodology can be used for a fast screening and identification of the macrolide reaction components, including stereoisomers, which can serve as a source of new antibacterials. Full article

Although Ag nanoparticles (NPs) have been widely applied in daily life and in biomedical and industrial fields, there is a demand for Ag-based bimetallic nanoalloys (NAs), such as AgCu and AgFe, due to their enhanced antibacterial efficacy and reduced Ag consumption. In this work, we present a comparison study on the antibacterial efficacy and cytotoxicity rates of Ag NPs and AgCu and AgFe NAs to L929 mouse fibroblast cells using the CCK-8 technique based on the relative cell viability. The concept of the minimum death concentration (MDC) is introduced to estimate the cytotoxicity to the cells. It is found that the minimum inhibitory concentrations (MICs) of the NPs against E. coli and S. aureus decrease with the addition of both Cu and Fe. There is a strong correlation between the MDC and MIC, implying that the mechanisms of both antibacterial efficacy and cytotoxicity are similar. The enhanced antibacterial efficacy to bacteria and cytotoxicity toward the cell are attributed to Ag⁺ release. The following order is found for both the MIC and MDC: AgFe < AgCu < Ag NPs. However, there is no cytotoxicity to the L929 cells for AgFe and AgCu NAs at their MIC Ag concentrations against S. aureus. Full article