Novel Microemulsion Containing Benzocaine and Fusidic Acid Simultaneously: Formulation, Characterization, and In Vitro Evaluation for Wound Healing.

Modern drug carrier technologies, such as microemulsions with small droplet sizes and high surface areas, improve the ability of low water solubility active ingredients to permeate and localize. The goal of this study was to create microemulsion formulations for wound healing that contained both fusidic acid (FA), an antibacterial agent, and benzocaine (BNZ), a local anesthetic. Studies on characterization were carried out, including viscosity, droplet size, and zeta potential. The drug-loaded microemulsion had a stable structure with -3.014 ± 1.265 mV of zeta potential and 19.388 ± 0.480 nm of droplet size. In both in vitro release and ex vivo permeability studies, the microemulsion was compared with Fucidin cream and oily BNZ solution. According to the drug release studies, BNZ release from the microemulsion and the BNZ solution showed a similar profile (p > 0.05), while FA release from the microemulsion had a higher drug release compared to Fucidin cream (p < 0.001). The microemulsion presented lower drug permeation (p > 0.05) for both active ingredients, on the other hand, provided higher drug accumulation compared to the control preparations. Moreover, according to the results of in vitro wound healing activity, the microemulsion indicated a dose-dependent wound healing potential with the highest wound healing activity at the highest concentrations. To the best of our knowledge, this developed BNZ- and FA-loaded microemulsion would be a promising candidate to create new opportunities for wound healing thanks to present the active ingredients, which have low water solubility, in a single formulation and achieved higher accumulation than control preparations.

A Nanocomposite Dynamic Covalent Cross-Linked Hydrogel Loaded with Fusidic Acid for Treating Antibiotic-Resistant Infected Wounds.

Methicillin-resistant Staphylococcus aureus (MRSA) is associated with high levels of morbidity and is considered a difficult-to-treat infection, often requiring nonstandard treatment regimens and antibiotics. Since over 40% of the emerging antibiotic compounds have insufficient solubility that limits their bioavailability and thus efficacy through oral or intravenous administration, it is crucial that alternative drug delivery products be developed for wound care applications. Existing effective treatments for soft tissue MRSA infections, such as fusidic acid (FA), which is typically administered orally, could also benefit from alternative routes of administration to improve local efficacy and bioavailability while reducing the required therapeutic dose. Herein, we report an antimicrobial poly(oligoethylene glycol methacrylate) (POEGMA)-based composite hydrogel loaded with fusidic acid-encapsulating self-assembled polylactic acid-b-poly(oligo(ethylene glycol) methyl ether methacrylate) (PLA-POEGMA) nanoparticles for the treatment of MRSA-infected skin wounds. The inclusion of the self-assembled nanoparticles (380 nm diameter when loaded with fusidic acid) does not alter the favorable mechanical properties and stability of the hydrogel in the context of its use as a wound dressing, while fusidic acid (FA) can be released from the hydrogel over ∼10 h via a diffusion-controlled mechanism. The antimicrobial studies demonstrate a clear zone of inhibition in vitro and a 1-2 order of magnitude inhibition of bacterial growth in vivo in an MRSA-infected full-thickness excisional murine wound model even at very low antibiotic doses. Our approach thus can both circumvent challenges in the local delivery of hydrophobic antimicrobial compounds and directly deliver antimicrobials into the wound to effectively combat methicillin-resistant infections using a fraction of the drug dose required using other clinically relevant strategies.

The anti-staphylococcal fusidic acid as an efflux pump inhibitor combined with fluconazole against vaginal candidiasis in mouse model.

BACKGROUND: Candida albicans is the most common fungus that causes vaginal candidiasis in immunocompetent women and catastrophic infections in immunocompromised patients. The treatment of such infections is hindered due to the increasing emergence of resistance to azoles in C. albicans. New treatment approaches are needed to combat candidiasis especially in the dwindled supply of new effective and safe antifungals. The resistance to azoles is mainly attributed to export of azoles outside the cells by means of the efflux pump that confers cross resistance to all azoles including fluconazole (FLC). OBJECTIVES: This study aimed to investigate the possible efflux pump inhibiting activity of fusidic acid (FA) in C. albicans resistant isolates and the potential use of Fusidic acid in combination with fluconazole to potentiate the antifungal activity of fluconazole to restore its activity in the resistant C. albicans isolates. METHODS: The resistance of C. albicans isolates was assessed by determination of minimum inhibitory concentration. The effect of Fusidic acid at sub-inhibitory concentration on efflux activity was assayed by rhodamine 6G efflux assay and intracellular accumulation. Mice model studies were conducted to evaluate the anti-efflux activity of Fusidic acid and its synergistic effects in combination with fluconazole. Impact of Fusidic acid on ergosterol biosynthesis was quantified. The synergy of fluconazole when combined with Fusidic acid was investigated by determination of minimum inhibitory concentration. The cytotoxicity of Fusidic acid was tested against erythrocytes. The effect of Fusidic acid on efflux pumps was tested at the molecular level by real-time PCR and in silico study. In vivo vulvovaginitis mice model was used to confirm the activity of the combination in treating vulvovaginal candidiasis. RESULTS: Fusidic acid showed efflux inhibiting activity as it increased the accumulation of rhodamine 6G, a substrate for ABC-efflux transporter, and decreased its efflux in C. albicans cells. The antifungal activity of fluconazole was synergized when combined with Fusidic acid. Fusidic acid exerted only minimal cytotoxicity on human erythrocytes indicating its safety. The FA efflux inhibitory activity could be owed to its ability to interfere with efflux protein transporters as revealed by docking studies and downregulation of the efflux-encoding genes of both ABC transporters and MFS superfamily. Moreover, in vivo mice model showed that using fluconazole-fusidic acid combination by vaginal route enhanced fluconazole antifungal activity as shown by lowered fungal burden and a negligible histopathological change in vaginal tissue. CONCLUSION: The current findings highlight FA's potential as a potential adjuvant to FLC in the treatment of vulvovaginal candidiasis.

New fusidane-type nortriterpenoids from the Arctic marine-derived fungus Simplicillium lamellicola culture medium with their inhibitory effect on benign prostatic hyperplasia.

Three new fusidane-type nortriterpenoids, simplifusinolide A, 24-epi simplifusinolide A, and simplifusidic acid L (1-3), were isolated from the EtOAc extract of the Arctic marine-derived fungus Simplicillium lamellicola culture medium, together with fusidic acid (4) and 16-O-deacetylfusicid acid (5). The structures of the isolated compounds were elucidated by NMR and MS analyses. The absolute configurations of compounds 1-3 were established by the quantum mechanical calculations of electronic circular dichroism and gauge-including atomic orbital NMR chemical shifts, followed by DP4 + analysis. Benign prostatic hyperplasia (BPH) is a major urological disorder in men worldwide. The anti-BPH potentials of the isolated compounds were evaluated using BPH-1 and WPMY-1 cells. Treatment with simplifusidic acid L (3) and fusidic acid (4) significantly downregulated the mRNA levels of the androgen receptor (AR) and its downstream effectors, inhibiting the proliferation of BPH-1 cells. Specifically, treatment with 24-epi simplifusinolide A (2) significantly suppressed the cell proliferation of both BPH-1 and DHT-stimulated WPMY-1 cells by inhibiting AR signaling. These results suggest the potential of 24-epi simplifusinolide A (2), simplifusidic acid L (3) and fusidic acid (4) as alternative agents for BPH treatment by targeting AR signaling.

The origin of sequence type 72 community-associated methicillin-resistant Staphylococcus aureus (MRSA) and fusidic acid (FA) resistant sequence type 5 MRSA: Analysis of FA resistance and spa type in a single center in South Korea.

INTRODUCTION: We investigated the prevalence of fusidic acid (FA) resistance in MSSA and MRSA stratified by sequence (ST) and spa types, and determined the prevalence of FA resistance mechanisms. METHODS: From August 2014 to April 2020, S. aureus blood isolates were collected in Asan Medical Center, Seoul, South Korea. Antimicrobial susceptibility tests were performed using broth microdilution and interpreted according to EUCAST's FA criteria. We performed spa typing for fusA mutation presence and acquired FA resistance determinants (fusB, fusC, and fusD) by PCR. RESULTS: Of the 590 MRSA isolates, 372 were FA resistant, and among 425 MSSA isolates, 136 were resistant. Of the 380 ST5-MRSA isolates, 350 were FA resistant, whereas only 1 of 14 ST5-MSSA isolates was FA resistant. Conversely, of the 163 ST72-MRSA isolates, only 8 were resistant, whereas 37 of 42 ST72-MSSA were resistant. The fusA mutation (80%) was the most common determinant. The one FA resistant ST5-MSSA isolate belonged to the t2460 spa type, the most common spa type (24 of 35 isolates) of FA resistant ST5-MRSA. In addition, t324 and t148, which are minor spa types of ST72-MSSA, were susceptible to FA, in contrast to other ST72-MSSA spa types, and the major spa type of ST72-MRSA (110 of 163 isolates). CONCLUSIONS: FA resistance was common in ST5-MRSA and ST72-MSSA, and rare in ST5-MSSA and ST72-MRSA. Our findings suggest that minor clones of ST5-MSSA isolates, with the fusA mutation and minor clones of ST72-MSSA susceptible to FA, may have evolved to harbor the mecA gene.

Neutrophil-targeted combinatorial nanosystems for suppressing bacteremia-associated hyperinflammation and MRSA infection to improve survival rates.

There is currently no specific and effective treatment for bacteremia-mediated sepsis. Hence, this study engineered a combinatorial nanosystem containing neutrophil-targeted roflumilast-loaded nanocarriers and non-targeted fusidic acid-loaded nanoparticles to enable the dual mitigation of bacteremia-associated inflammation and methicillin-resistant Staphylococcus aureus (MRSA) infection. The targeted nanoparticles were developed by conjugating anti-lymphocyte antigen 6 complex locus G6D (Ly6G) antibody fragment on the nanoparticulate surface. The particle size and zeta potential of the as-prepared nanosystem were about 200 nm and -25 mV, respectively. The antibody-conjugated nanoparticles showed a three-fold increase in neutrophil internalization compared to the unfunctionalized nanoparticles. As a selective phosphodiesterase (PDE) 4 inhibitor, the roflumilast in the nanocarriers largely inhibited cytokine/chemokine release from the activated neutrophils. The fusidic acid-loaded nanocarriers were vital to eliminate biofilm MRSA colony by 3 log units. The nanoparticles drastically decreased the intracellular bacterial count compared to the free antibiotic. The in vivo mouse bioimaging demonstrated prolonged retention of the nanosystem in the circulation with limited organ distribution and liver metabolism. In the mouse bacteremia model, the multifunctional nanosystem produced a 1‒2 log reduction of MRSA burden in peripheral organs and blood. The functionalized nanosystem arrested the cytokine/chemokine overexpression greater than the unfunctionalized nanocarriers and free drugs. The combinatory nanosystem also extended the median survival time from 50 to 103 h. No toxicity from the nanoformulation was found based on histology and serum biochemistry. Furthermore, our data proved that the active neutrophil targeting by the versatile nanosystem efficiently alleviated MRSA infection and organ dysfunction caused by bacteremia. STATEMENT OF SIGNIFICANCE: Bacteremia-mediated sepsis poses a significant challenge in clinical practice, as there is currently no specific and effective treatment available. In our study, we have developed a novel combinatorial nanosystem to address this issue. Our nanosystem consists of neutrophil-targeted roflumilast-loaded nanocarriers and non-targeted fusidic acid-loaded nanoparticles, enabling the simultaneous mitigation of bacteremia-associated inflammation and MRSA infection. Our nanosystem demonstrated the decreased neutrophil activation, effective inhibition of cytokine release, elimination of MRSA biofilm colonies, and reduced intracellular bacterial counts. In vivo experiments showed prolonged circulation, limited organ distribution, and increased survival rates in a mouse bacteremia model. Importantly, our nanosystem exhibited no toxicity based on comprehensive assessments.

Synthesis and structure-activity relationship studies of fusidic acid derivatives as anti-inflammatory agents for acute lung injury.

Acute lung injury (ALI) are severe forms of diffuse lung disease that impose a substantial health burden all over the world. In the United States, approximately 190,000 cases per year of ALI each year, with an associated 74,500 deaths per year. Anti-inflammatory therapy has become a reasonable approach for the treatment of patients with ALI. In this study, fusidic acid derivatives were used to design new anti-inflammatory compounds with high pharmacological activity and low toxicity. A total of 30 new fusidic acid derivatives were discovered, synthesized, and screened for their anti-inflammatory activity against lipopolysaccharide (LPS)-treated RAW264.7 cells. Of them, b2 was found to be the most active, with a higher efficiency compared with fusidic acid and celecoxib in 10 µM. In vitro, we further measured b2 inhibited inflammatory factor NO (IC50 = 5.382 ± 0.655 µM), IL-6 (IC50 = 7.767 ± 0.871 µM), and TNF-α (IC50 = 7.089 ± 0.775 µM) and b2 inhibited inflammatory cytokines COX-2 and iNOS, ROS production, NF-κB/MAPK and Bax/Bcl-2 signaling pathway pathway. In vivo,b2 attenuated ALI pathological changes and inhibited inflammatory cytokines COX-2 and iNOS in lung tissue and NF-κB/MAPK and Bax/Bcl-2 signaling pathway. In conclusion, b2 may be a promising anti-inflammatory lead compound.

Identification and validation of fusidic acid and flufenamic acid as inhibitors of SARS-CoV-2 replication using DrugSolver CavitomiX.

In this work, we present DrugSolver CavitomiX, a novel computational pipeline for drug repurposing and identifying ligands and inhibitors of target enzymes. The pipeline is based on cavity point clouds representing physico-chemical properties of the cavity induced solely by the protein. To test the pipeline's ability to identify inhibitors, we chose enzymes essential for SARS-CoV-2 replication as a test system. The active-site cavities of the viral enzymes main protease (Mpro) and papain-like protease (Plpro), as well as of the human transmembrane serine protease 2 (TMPRSS2), were selected as target cavities. Using active-site point-cloud comparisons, it was possible to identify two compounds-flufenamic acid and fusidic acid-which show strong inhibition of viral replication. The complexes from which fusidic acid and flufenamic acid were derived would not have been identified using classical sequence- and structure-based methods as they show very little structural (TM-score: 0.1 and 0.09, respectively) and very low sequence (~ 5%) identity to Mpro and TMPRSS2, respectively. Furthermore, a cavity-based off-target screening was performed using acetylcholinesterase (AChE) as an example. Using cavity comparisons, the human carboxylesterase was successfully identified, which is a described off-target for AChE inhibitors.

Persistence of the Staphylococcus aureus epidemic European fusidic acid-resistant impetigo clone (EEFIC) in Belgium.

OBJECTIVES: In August 2018, a public health alert was issued in Belgium regarding clusters of impetigo cases caused by the epidemic European fusidic acid-resistant impetigo clone (EEFIC) of Staphylococcus aureus. As a result, the Belgian national reference centre (NRC) was commissioned to update the epidemiology of S. aureus causing community-onset skin and soft tissues infection (CO-SSTI) to assess the proportion of EEFIC among them. METHODS: For 1 year, Belgian clinical laboratories were asked to send their first three S. aureus isolated from CO-SSTI each month. Isolates were tested for antimicrobial susceptibility to oxacillin, mupirocin and fusidic acid. Resistant isolates were also spa typed and tested for the presence of the genes encoding the Panton-Valentine leucocidin, the toxic shock syndrome toxin and the exfoliatins A and B. MLST clonal complexes were deduced from the spa types. RESULTS: Among the 518 S. aureus strains analysed, 487 (94.0%) were susceptible to oxacillin. Of these, 79 (16.2%) were resistant to fusidic acid, of which 38 (48.1%) belonged to the EEFIC. EEFIC isolates were mostly isolated from young patients with impetigo and showed a seasonal late summer peak. CONCLUSIONS: These results suggest the persistence of EEFIC in Belgium. Furthermore, its prevalence may lead to reconsideration of the treatment guidelines for impetigo.

Clonal Spreading of ST42 Staphylococcus haemolyticus Strains Occurs Possibly Due to fusB and tetK Resistant Genes and Capsule-Related Genes.

Multi-drug resistant Staphylococcus haemolyticus is a frequent nosocomial invasive bacteremia pathogen in hospitals. Our previous analysis showed one of the predominant strains, ST42 originated from ST3, had only one multilocus sequence typing (MLST) variation among seven loci in SH1431; yet no significant differences in biofilm formation observed between ST42 and ST3, suggesting that other factors influence clonal lineage change. Whole genome sequencing was conducted on two isolates from ST42 and ST3 to find phenotypic and genotypic variations, and these variations were further validated in 140 clinical isolates. The fusidic acid- and tetracycline-resistant genes (fusB and tetK) were found only in CGMH-SH51 (ST42). Further investigation revealed consistent resistant genotypes in all isolates, with 46% and 70% of ST42 containing fusB and tetK, respectively. In contrast, only 23% and 4.2% ST3 contained these two genes, respectively. The phenotypic analysis also showed that ST42 isolates were highly resistant to fusidic acid (47%) and tetracycline (70%), compared with ST3 (23% and 4%, respectively). Along with drug-resistant genes, three capsule-related genes were found in higher percentage distributions in ST42 than in ST3 isolates. Our findings indicate that ST42 could become endemic in Taiwan, further constitutive surveillance is required to prevent the spread of this bacterium.

Prevalence and genetic characteristics of fusidic acid resistant Staphylococcus aureus clinical isolates: Emergence of t030 strains carrying fusB in Tehran, Iran.

The literature on fusidic acid resistant Staphylococcus aureus strains is scarce in Iran, although the emergence of these strains in health care settings is increasing. This descriptive cross-sectional study was conducted on 68 fusidic acid resistant S. aureus strains to learn about the molecular characteristics and antimicrobial resistance of strains isolated from hospitalized patients. In the present study, the prevalence of resistance to fusidic acid in S. aureus isolates was 15.1%. Fusidic acid resistance determinative factors (fusB, fusC and fusD) were identified by multiplex PCR assay. To detect the existence of fusA and fusE determinants and their mutation status, amplifications and sequencing were performed. Molecular characterization of fusidic acid resistant isolates was investigated by SCCmec and spa typing methods. All strains were MRSA and multi drug resistant. Two (2.9%) and 31 (45.6%) isolates were resistant to vancomycin and mupirocin respectively. The SCCmec type IV was highly prevalent representing 50% followed by types III (51.5%), and SCCmec types II (13.2%). fusB, was the most predominant acquired gene (66.2%) followed by fusC (19.1%), and fusA (14.7%). The mutations in fusA were present in 10 isolates with 5 (50%) having L461K mutation showing fusidic acid MIC values of ≥256 µg ml-1 followed by H457Y (40%), and H457Q (10%) showing fusidic acid MIC values of 128 and 64 µg ml-1 respectively. Isolates were allocated to ten particular t030 (22.1%), t037 (14.6%), t408 (11.8%), t064 (11.8%), t008 (10.3%), t002 (8.8%), t005 (5.9%), t790 (5.9%), t318 (4.4%), and t018 (4.4%) spa types. fusA positive isolates were assigned to particular spa types t002 (60%), and t005 (40%). There may be be a spreading of fusidic acid resistance among MRSA, creating worrying public concern. This research notes the importance of adequate data of local prevalence of FA-resistant MRSA in Iran for taking appropriate measures to treat, control and reduce the incidence of these isolates.

Fusidic Acid and Its Major Active Metabolite Penetration into Cerebrospinal Fluid for Assessing Treatment of Intracranial Infections.

Fusidic acid (FA) had excellent antimicrobial effects due to its unique mechanism of action. Since 1962, FA has been widely used in the systemic and topical treatment of staphylococcal infections and exhibits a well-characterized potency against methicillin-susceptible Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and methicillin-resistant coagulase-negative Staphylococci. In view of the spectrum of activity, no cross-resistance with other clinically used antibiotics, and potential penetration into brain tissue, FA was used to treat possible gra-positive bacteria in 3 patients with intracranial infections in the present report. FA and its active metabolite (3-keto FA) were measured in plasma and cerebrospinal fluid (CSF) to assess the treatment of FA, and the results indicated that 1,500 mg per day of FA was sufficient to achieve therapeutic concentrations in both plasma and CSF in intracranial infection patients, while the dosage did not experience unexpected regimen-related toxicity.

Egg yolk oil accelerates wound healing in streptozotocin induced diabetic rats.

Impaired diabetic wound healing causes foot ulcers. We investigated egg yolk oil for skin wound healing in streptozotocin (STZ) induced diabetic rats. Rats were allocated into three groups of six. Group 1, nondiabetic control group, was treated topically with 2% fusidic acid ointment. Group 2, STZ diabetic control, was treated topically with 2% fusidic acid ointment. Group 3, STZ diabetic group, was treated topically with egg yolk oil. Three days after STZ injection, two full thickness excisional skin wounds were created on the back of each animal. Wound diameter was measured for 14 days and wound contraction was calculated. Re-epithelization time also was determined. Three rats from each group were sacrificed on experimental day 7 and the remaining rats on day 14. Wound samples were examined using hematoxylin and eosin, periodic acid-Schiff, Masson's trichrome, Taenzer-Unna orcein and toluidine blue staining. Expression of endoglin (CD105), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) were investigated using immunohistochemistry. Egg yolk oil increased the proliferation of epithelial cells and angiogenesis, and stimulated collagen deposition in the lesion area. Egg yolk oil increased CD105, EGF and VEGF expression in blood vessels, and EGF and VEGF expression in epidermis of the lesions. The predominant fatty acids in egg yolk oil are oleic, palmitic and linoleic, which likely were responsible for the beneficial effects of egg yolk oil on diabetic wound healing. Egg yolk oil appears to be a promising therapeutic agent for healing of diabetic wounds.

Discovery of fusidic acid derivatives as novel STING inhibitors for treatment of sepsis.

Sepsis is often caused by systemic inflammatory responses. Stimulator of interferon genes (STING) could be a promising treatment target for sepsis. In this study, we report the design and synthesis of a new series of fusidic acid derivatives. Among the synthesized derivatives, the promising compound 30 inhibited lipopolysaccharide (LPS)-induced nitric oxide production in macrophages with an IC50 of 1.15 µM. Compound 30 was then identified as a STING inhibitor that suppressed LPS-induced inflammatory responses and inhibited the abnormal activation of the TBK1, IRF3, and NF-κB signaling pathways by targeting STING. In vivo treatment with compound 30 significantly inhibited the inflammatory response and ameliorated the histopathological changes of the liver, and the mechanism of its anti-inflammatory effect in vivo was the same as that in vitro. Our studies identified compound 30 as a potent STING inhibitor, laying the groundwork for future drug development of anti-inflammatory agents for the treatment of sepsis.

[Susceptibility of drug-resistant staphylococci isolated from different parts of the ocular anterior segment to common ophthalmic antibiotics].

Objectie To investigate the susceptibility of drug-resistant staphylococci isolated from different parts of the anterior segment to levofloxacin, tobramycin, cefazolin sodium, fusidic acid and clindamycin. Methods: Experimental Study. A total of 67 patients with anterior segment infection (33 cases of conjunctivitis, 6 cases of bacterial keratitis, 7 cases of blepharitis, 9 cases of neonatal dacryocystitis, 9 cases of neonatal dacryocystitis, 1 case of adult dacryocystitis and 11 cases of other infectious eye diseases) were collected from the conjunctival sac, cornea, eyelid margin and lacrimal sac. Minimum inhibitory concentration (MIC) determination of methicillin-resistant Staphylococcus (MRS) strains and ß-lactamase-producing (ß-Lac) strains by a micro-liquid-based method, according to the M100 standard of the American Institute for Clinical and Laboratory Standardization Susceptibility and resistance determinations were made. Data were statistically analyzed using Chi-square or Fisher's exact test. Results: Thirty-five MRS, 30 ß-Lac and 2 ß-Lac MRS isolates were identified from 67 multidrug-resistant Staphylococcus . There were 3, 9, 4, and 19 MRS isolates isolated from the lacrimal sac, cornea, eyelid margin and conjunctival sac, accounting for 3/4, 9/12, 4/8, 19/43 (44.2%) of the isolated sites respectively. There were 1, 3, 3, and 23 ß-Lac isolates, accounting for 1/4, 3/12, 3/8 and 23/43 (53.5%) of the isolated sites, respectively. The highest proportion of ß-Lac isolates isolated from patients with a diagnosis of conjunctivitis was 17 (25.3%) from the conjunctival sac. Among the MRS strains isolated from the cornea and lacrimal sac, 5 (7.5%) and 3 (4.5%) were from patients diagnosed with bacterial keratitis and neonatal tear, respectively. The number of MRS strains and ß-Lac isolates isolated from patients with a diagnosis of blepharitis were both 3 (4.5%) from the lid margin.Among the strains isolated from the eyelid margin and the conjunctival sac, drug-resistant Staphylococcus epidermidis was the main strain, the drug-resistant Staphylococcus aureus was the major isolates in lacrimal sac and cornea. Among the 35 MRS isoaltes, 25, 24, 12, 12, and 11 were sensitive to cefazolin sodium, fusidic acid, levofloxacin, clindamycin and tobramycin, and the sensitivity rates were 71.4%, 68.6%, 34.3%, 34.3% and 31.4%, the difference was statistically significant (χ2=22.756, P<0.001), The sensitivity rates of levofloxacin, tobramycin, cefazolin sodium, fusidic acid and clindamycin against MRS isolates from the anterior segment were both statistically significant differences (χ2=18.493, 11.594, 8.906, 9.841, 16.059; all P<0.05). The susceptibility rates of MRS isolates against five antibiotics was statistically significant differences (χ2=33.080, P<0.001). Among the 30 ß-Lac isolates, 27, 22, 19, 16, and 8 were sensitive to cefazolin sodium, fusidic acid, levofloxacin, tobramycin and clindamycin, and the sensitivity rates were 90.0 % , 73.3%, 63.3%, 53.3% and 26.7%, the difference was statistically significant (χ2=28.280, P<0.001). The sensitivity rates of five antibiotics against ß-Lac isolates from the anterior segment were both statistically significant differences (χ2=50.971, 24.543, 48.147, 44.899, 18.676; all P<0.001). The susceptibility rates of ß-Lac isolates against five antibiotics was statistically significant differences (χ2=23.383, P<0.001). The sensitivity of cefazolin sodium and fusidic acid against ß-Lac isolates were higher than MRS isolates. Conclusions: Cefazolin sodium and fusidic acid may be the best choice for the treatment of drug-resistant Staphylococcus isolated from anterior conjunctival sac, cornea, eyelid margin and lacrimal sac, especially for ß-Lac-producing drug-resistant Staphylococcus infection.

Preclinical development of sodium fusidate antibiotic cutaneous spray based on water-free lipid formulation system.

Topical antibiotics are a key component in the management of mild to moderate skin and soft tissue infections. There are, however, concerns about the emerging bacterial resistance against topical antibacterial agents such as fusidic acid, due to the prolonged treatment period of its marketed dosage forms. Improving the efficacy of topical formulations could potentially shorten the treatment period and avoid the resistance growth. To provide a more effective drug delivery, a water-free lipid-based formulation system (AKVANO®) which can be applied by spraying, has been developed. In the current paper, different formulations containing sodium fusidate were evaluated for their in vitro skin permeability using artificial skin mimicking membranes and antibacterial properties using ex vivo and in vivo skin wound infection models. The novel formulations containing sodium fusidate showed a much higher skin permeation (up to 60% of nominal amount) than the commercially available Fucidin® cream (3%). These formulations also gave a significantly stronger antibacterial effect than Fucidin cream showing a clear dose-response relationship for the sodium fusidate content. A spray product based on the described formulation technology would therefore require a shorter treatment time and thereby lower the risk for the development of bacterial resistance. Spray administration of these formulations provides an even layer on the skin surface from which the solvent quickly evaporates and thereby facilitates a non-touch application where no rubbing is required.

Fusidic acid in a tertiary hospital: an observational study focusing on prescriptions, tolerance and susceptibility of Staphylococcus and Cutibacterium spp. strains from bone samples.

Adverse drug reactions of broad-spectrum fluoroquinolones or rifampicin are not uncommon during osteomyelitis and orthopaedic implant infections (OOII). Thus, we made an overview (i) of the prescription of fusidic acid (FA) and (ii) of FA susceptibility of Staphylococcus sp. and Cutibacterium sp. strains isolated from bone samples. All prescriptions of FA and all bone samples with positive culture for Staphylococcus sp. or Cutibacterium sp. (Reims University Hospital June 2017-May 2021) were included. All Staphylococcus aureus strains were considered as significant, whereas Coagulase-negative Staphylococcus and Cutibacterium spp. strains were not if these strains grew only on one sole sample. The antibiotic susceptibility of Staphylococcus sp. strains and the susceptibility to FA of Cutibacterium sp. strains had been determined using disk diffusion methods, as described for Staphylococcus sp. in the CASFM/EUCAST guidelines. The mean FA consumption was 0.6 daily defined doses/1000 patient days. FA was prescribed for OOII due to Staphylococcus sp. and Cutibacterium sp. in 24 and 2 cases, respectively. Among 401 Staphylococcus sp. strains, there were 254 S. aureus (63.3%), 84 methicillin-resistant (20.9%) and 333 FA-susceptible (83.0%) strains. S. aureus and methicillin-sensitive strains were more likely to be susceptible to FA (p < 0.001). Among 39 Cutibacterium sp. strains, the FA inhibition zone diameter geometric mean was 28.6 mm (24-35 mm), suggesting that all these strains could be considered as susceptible to FA. These data suggested that FA could be more frequently used in OOII due to Staphylococcus sp. and Cutibacterium sp., subject to the absence of other resistant bacteria.

A fusidic acid-resistant (PVL+) clone is associated with the increase in methicillin-resistant Staphylococcus aureus in New Caledonia.

OBJECTIVES: Since 2014, Staphylococcus aureus methicillin resistance has been rapidly increasing in New Caledonia and is associated with potential serious clinical repercussions. In the present study, we investigated the epidemiology of methicillin-resistant S. aureus (MRSA) in New Caledonia and the possible emergence of a particular clonal strain. METHODS: An overview of the distribution of MRSA in New Caledonia in 2019 is presented. We collected and analysed 171 clinical MRSA isolates from New Caledonia medical laboratories during August and September 2019. Among this collection, 49 representative isolates were analyzed by the French National Reference Center for Staphylococci using the StaphyType DNA microarray, allowing genetic characterization of the isolates. RESULTS: Among the 1144 S. aureus isolated over the year 2019, 442 isolates (39%) were resistant to methicillin, and 62% of these isolates were resistant to fusidic acid (FA). During the inclusion period, FA resistance rate was similar (60%). Genetic characterization evidenced CC6 as the predominant clonal complex (70%) with 26 isolates (53%) identified as CC6-MRSA-[IV+fus] (PVL+). CONCLUSIONS: These findings demonstrated a low diversity of MRSA in New Caledonia, with the dominance of a clonal complex not reported previously. The frequent fusidic acid (FA) resistance in MRSA was associated with a high prevalence of fusC gene, suggesting that FA misuse contributed to driving the selection of this clone. Our findings suggest the recommendation to stop the topical use of FA to control the emergence of this severe MRSA clone and decrease the rate of MRSA in New Caledonia.

The effect of dilution of fusidic acid cream and betamethasone dipropionate cream in complex extemporaneous mixes on formulation performance.

The Aron regimen is an unconventional therapy which entails frequent applications of an extemporaneously prepared three component system (a topical antibiotic, a corticosteroid and an emollient), with the intention of decolonising the skin of S. aureus whilst treating atopic dermatitis. The impact of heavily diluting these topical medicinal products, to differing extents, on formulation performance is not well understood thus was investigated in this study. Following a single application of a range of compounded Aron mixes (fusidic acid and betamethasone dipropionate diluted to varying extents in an emollient base), significant reductions in the expected drug flux across silicone membrane, ex vivo percutaneous absorption and skin retention of both drugs relative to the marketed products were observed. This was attributed to a number of complex formulation effects making such changes difficult to predict in a clinical setting. Further investigations are required to evaluate the impact of frequent applications of the Aron mix to widespread areas on clinical efficacy, antimicrobial resistance and long term side effects.

The cyclic octapeptide antibiotic argyrin B inhibits translation by trapping EF-G on the ribosome during translocation.

Argyrins are a family of naturally produced octapeptides that display promising antimicrobial activity against Pseudomonas aeruginosa. Argyrin B (ArgB) has been shown to interact with an elongated form of the translation elongation factor G (EF-G), leading to the suggestion that argyrins inhibit protein synthesis by interfering with EF-G binding to the ribosome. Here, using a combination of cryo-electron microscopy (cryo-EM) and single-molecule fluorescence resonance energy transfer (smFRET), we demonstrate that rather than interfering with ribosome binding, ArgB rapidly and specifically binds EF-G on the ribosome to inhibit intermediate steps of the translocation mechanism. Our data support that ArgB inhibits conformational changes within EF-G after GTP hydrolysis required for translocation and factor dissociation, analogous to the mechanism of fusidic acid, a chemically distinct antibiotic that binds a different region of EF-G. These findings shed light on the mechanism of action of the argyrin-class antibiotics on protein synthesis as well as the nature and importance of rate-limiting, intramolecular conformational events within the EF-G-bound ribosome during late-steps of translocation.