Exploring mechanisms of mupirocin resistance and hyper-resistance.

Mupirocin is a broad-spectrum antibiotic that acts predominantly against Gram-positive bacteria. It is produced by Pseudomonas fluorescens NCIMB 10586 and has been clinically used to treat primary and secondary skin infections and to eradicate nasal colonisation of methicillin-resistant Staphylococcus aureus strains. Mupirocin inhibits protein synthesis by blocking the active site of isoleucyl-tRNA synthetase (IleRS), which prevents the enzyme from binding isoleucine and ATP for Ile-tRNAIle synthesis. Two types of IleRS are found in bacteria - while IleRS1 is susceptible to mupirocin inhibition, IleRS2 provides resistance to cells. These two types belong to distinct evolutionary clades which likely emerged from an early gene duplication in bacteria. Resistance in IleRS2 is based on the loss of interactions that govern mupirocin binding to IleRS1, such as hydrogen bonding to the carboxylate moiety of mupirocin. IleRS2 enzymes with Ki in the millimolar range have recently been discovered. These hyper-resistant IleRS2 variants surprisingly have a non-canonical version of the catalytic motif, which serves as a signature motif of class I aminoacyl-tRNA synthetases to which IleRS belongs. The non-canonical motif, in which the 1st and 3rd positions are swapped, is key for hyper-resistance and can be accommodated without abolishing enzyme activity in IleRS2 but not in IleRS1. Clinical use of mupirocin led to the emergence of resistance in S. aureus. Low-level resistance arises by mutations of the housekeeping IleRS1, while high-level resistance develops by the acquisition of the resistant IleRS2 on a plasmid. There is no evidence that hyper-resistant variants have been found in clinical isolates.

New Synergistic Combination Therapy of Mupirocin and α-Pinene Against Multidrug-Resistant Clinical Strains of Methicillin-Resistant Staphylococcus aureus.

OBJECTIVE: Increased mupirocin use leads to mupirocin resistance and is associated with persistence of methicillin-resistant Staphylococcus aureus (MRSA) carriers, prolonged hospitalization, and significant economic burdens for health systems. The study aimed to investigate the antimicrobial activity of compounds of Salvia rosmarinus L. ("rosemary", formerly Rosmarinus officinalis), alone or in combination with mupirocin, against multidrug resistant MRSA using isolates obtained from pediatric patients. METHODS: The in vitro antibacterial activity of the monoterpene α-pinene (α-Pi), a rosemary essential oil constituent, alone and in combination with mupirocin, was evaluated by determining the minimum inhibitory concentrations and minimum bactericidal concentrations (MBCs) and the fractional inhibitory concentration indices (FICIs) and fractional bactericidal concentration indices against multidrug-resistant clinical MRSA strains. The in vivo efficacy of α-Pi, alone and in combination with mupirocin, to eradicate MRSA infection was determined using an optimized mouse model of MRSA-infected wounds. Mouse skin samples (obtained via biopsy) were assessed for toxicity, and rabbit skin samples for irritation. RESULTS: Both in vitro and in vivo, α-Pi was active against MRSA strains and acted synergistically with mupirocin against MRSA strains. Mupirocin-monoterpene combinations exhibited FICI values of 0.2 to 0.4, reducing the MBC of topical mupirocin 33-fold. A topical formulation containing α-Pi and mupirocin enhanced the efficacy of mupirocin in an in vivo MRSA-infected mouse skin model without significantly harming the skin of mice and rabbits. CONCLUSIONS: A topical formulation combining mupirocin and α-Pi may aid in the development of innovative agents for treating MRSA infections.

Review: the spectrum of antimicrobial resistance in bacteria isolated from wounds of patients with epidermolysis bullosa.

Purpose: Cutaneous infection in epidermolysis bullosa (EB) can cause significant morbidity, mortality, and dangerous sequelae. This review article aims to delve into the known epidemiology of EB, highlight the disease's primary causative agents and their antimicrobial resistance spectrum.Materials and methods: A thorough literature search was conducted using Medline, EMBASE, JBI and PubMed to gather data on the microbial landscape of EB wounds. The focus was on identifying the most common bacteria associated with EB infections and assessing their antimicrobial resistance profiles.Results: The analysis revealed that Staphylococcus aureus is the most frequently identified bacterium in EB wounds, with a notable prevalence of methicillin-resistant strains (MRSA). Specific studies on mupirocin resistance further indicated rising rates of mupirocin-resistant Staphylococcus aureus, with one study reporting rates as high as 16.07%. Additionally, high resistance to other antibiotics, such as levofloxacin and trimethoprim/sulfamethoxazole, was observed in MRSA isolates.Conclusions: The findings highlight the critical need for regular resistance surveillance and the prudent use of mupirocin to manage infections effectively in EB. The multi-drug resistant nature of pathogens in EB presents a significant challenge in treatment, highlighting the importance of antimicrobial stewardship. Ultimately, given the sparse literature and the rarity of large-scale studies, further longitudinal research on the antimicrobial resistance profile of bacteria isolated from EB wounds is essential.

Emergence and spread of a mupirocin-resistant variant of the European epidemic fusidic acid-resistant impetigo clone of Staphylococcus aureus, Belgium, 2013 to 2023.

BackgroundAntimicrobial resistance to mupirocin and fusidic acid, which are used for treatment of skin infections caused by Staphylococcus aureus, is of concern.AimTo investigate resistance to fusidic acid and mupirocin in meticillin-susceptible S. aureus (MSSA) from community-acquired skin and soft tissue infections (SSTIs) in Belgium.MethodsWe collected 2013-2023 data on fusidic acid and mupirocin resistance in SSTI-associated MSSA from two large Belgian laboratories. Resistant MSSA isolates sent to the Belgian Staphylococci Reference Centre were spa-typed and analysed for the presence of the eta and etb virulence genes and the mupA resistance gene. In addition, we whole genome sequenced MSSA isolates collected between October 2021 and September 2023.ResultsMupirocin resistance increased between 2013 and 2023 from 0.5-1.5% to 1.7-5.6%. Between 2018 and 2023, 91.4% (64/70) of mupirocin-resistant isolates were co-resistant to fusidic acid. By September 2023, between 8.9% (15/168) and 10.1% (11/109) of children isolates from the two laboratories were co-resistant. Of the 33 sequenced isolates, 29 were sequence type 121, clonal and more distantly related to the European epidemic fusidic acid-resistant impetigo clone (EEFIC) observed in Belgium in 2020. These isolates carried the mupA and fusB genes conferring resistance to mupirocin and fusidic acid, respectively, and the eta and etb virulence genes.ConclusionWe highlight the spread of a mupirocin-resistant EEFIC in children, with a seasonal trend for the third quarter of the year. This is of concern because this variant is resistant to the two main topical antibiotics used to treat impetigo in Belgium.

Synthesis and characterization of mupirocin-LDH/PVA nanofibrous composite as a dual-carrier drug release system.

Nowadays, nanofibrous structures based on organic and inorganic materials are considered a drug delivery system for the controlled release of antibiotics and other antibacterial agents. The main goal of this research is a combination of the special properties of nanofibrous structure and Mupirocin-loaded Layered double hydroxide (LDH) to obtain a dual-carrier drug release system to provide long term antibacterial properties in wound healing process. Regards, unloaded layered double hydroxide (LDH) and Mupirocin-loaded LDH, which were synthesized by co-precipitation method, were added to Polyvinyl alcohol (PVA) solution in different mass ratio and electrospun using different processing conditions. The physico-chemical characterizations were performed using SEM, FTIR and tensile strength tests. The biological properties of the fabricated nanocomposites were evaluated using antibacterial test and in vitro cell culturing followed by MTT assay. The SEM results showed a bead-less and uniform morphology of nanofibrous composite containing Mupirocin(2.3 wt%)-LDH(15 wt%)/PVA with an average fiber diameter of about 270 ± 58 nm. According to the release study, the maximum release of the mupirocin drug was about 54 % in the first 6 h. The antibiogram analysis exhibited good antibacterial activity of mupirocin-loaded nanocomposite against both bacteria, especially gram-positive one. Finally, MTT assay approved the biocompatibility of the mupirocin-loaded nanocomposite. Overall, the produced nanofibrous composites would be a promising dual-carrier system for controlled release of antibiotic.

Carriage of methicillin-resistant Staphylococcus aureus in children <6 years old: a retrospective follow-up study of the natural course and effectiveness of decolonization treatment.

BACKGROUND: Decolonization treatment of MRSA carriers is recommended in Denmark, except in households with MRSA-positive children <2 years old (wait-and-see approach). OBJECTIVES: To investigate a wait-and-see approach in children 2-5 years old, and the effect of decolonization treatment of MRSA carriage in all children <6 years old. PATIENTS AND METHODS: In this retrospective follow-up study, we included MRSA carriers <6 years old in the Capital Region of Denmark from 2007 to 2021. Data were collected from laboratory information systems and electronic patient records. We divided children into age groups of <2 years or 2-5 years and decolonization treatment versus no treatment. Treatment was chlorhexidine body washes and nasal mupirocin, sometimes supplemented with systemic antibiotics. Children were followed until becoming MRSA free, or censoring. The probability of becoming MRSA free was investigated with Cox regression (higher HRs indicate faster decolonization). RESULTS: Of 348 included children, 226 were <2 years old [56/226 (25%) received treatment] and 122 were 2-5 years old [90/122 (74%) received treatment]. Multivariable analyses did not show a larger effect of decolonization treatment versus no treatment in <2-year-olds (HR 0.92, 95% CI 0.52-1.65) or 2-5-year-olds (HR 0.54, 95% CI 0.26-1.12). Without treatment, 2-5-year-olds tended to clear MRSA faster than <2-year-olds (HR 1.81, 95% CI 0.98-3.37). CONCLUSIONS: We did not find a larger effect of decolonization treatment versus no treatment in children <6 years old, and 2-5-year-olds tended to become MRSA free faster than <2-year-olds. These results support a wait-and-see approach for all children <6 years old, but further studies are needed.

The Hybrid Antibiotic Thiomarinol A Overcomes Intrinsic Resistance in Escherichia coli Using a Privileged Dithiolopyrrolone Moiety.

An impermeable outer membrane and multidrug efflux pumps work in concert to provide Gram-negative bacteria with intrinsic resistance against many antibiotics. These resistance mechanisms reduce the intracellular concentrations of antibiotics and render them ineffective. The natural product thiomarinol A combines holothin, a dithiolopyrrolone antibiotic, with marinolic acid A, a close analogue of mupirocin. The hybridity of thiomarinol A converts the mupirocin scaffold from inhibiting Gram-positive bacteria to inhibiting both Gram-positive and -negative bacteria. We found that thiomarinol A accumulates significantly more than mupirocin within the Gram-negative bacterium Escherichia coli, likely contributing to its broad-spectrum activity. Antibiotic susceptibility testing of E. coli mutants reveals that thiomarinol A overcomes the intrinsic resistance mechanisms that render mupirocin inactive. Structure-activity relationship studies suggest that the dithiolopyrrolone is a privileged moiety for improving the accumulation and antibiotic activity of the mupirocin scaffold without compromising binding to isoleucyl-tRNA synthetase. These studies also highlight that accumulation is required but not sufficient for antibiotic activity. Our work reveals a role of the dithiolopyrrolone moiety in overcoming intrinsic mupirocin resistance in E. coli and provides a starting point for designing dual-acting and high-accumulating hybrid antibiotics.

Antimicrobial susceptibilities and genomic characteristics of methicillin-resistant Staphylococcus aureus resistant to mupirocin in Stockholm, Sweden.

The aim of this study was to investigate antimicrobial susceptibilities and genomic characteristics of mupirocin-resistant MRSA isolates in Stockholm, Sweden. In total, 44 non-duplicate mupirocin-resistant MRSA isolates detected in Stockholm during 2010-2022 were investigated. Antimicrobial susceptibility testing was performed using broth microdilution method and further tested for high-level mupirocin-resistance (MuH) and rifampicin by Etest®. All isolates were subjected to whole genome sequencing. 41 isolates presented MuH with MICs ≥1024 mg/L whilst three isolates displayed low-level mupirocin resistance (MuL). mupA-gene was detected in all MuH isolates. Point mutations in ileS gene leading to N213D and V588F were identified in the three MuL isolates. Mutation in rpoB (H481N) was detected in a rifampicin-resistant isolate. Among the isolates, 15 multi-locus sequence types (MLST) were identified, with the four most common sequence types (ST22, ST72, ST8, and ST125) accounting for 66% of the isolates. Mupirocin-resistant MRSA in Stockholm was uncommon, with a percentage of <0.5% among MRSA cases during 2010-2022. In the present study, most mupirocin-resistant isolates were MuH and mupA-positive, predominantly linked to ST22 or ST72 isolates. MuL-resistance was associated with a point mutation in the IleS protein. A multidrug-resistant ST1-MRSA-IV strain was resistant to both mupirocin and rifampicin.

Fabrication of geraniol nanophytosomes loaded into polyvinyl alcohol: A new product for the treatment of wounds infected with methicillin-resistant Staphylococcusaureus.

The current study was conducted to evaluate the effectiveness of geraniol nanophytosomes in accelerating the healing process of wounds infected with Methicillin-resistant Staphylococcus aureus (MRSA) in a mouse model. The physicochemical properties confirmed physical properties and successful synthesis of the nanophytosomes. Wounds were induced and mice (n = 90) were treated with a base ointment (negative control group) and/or mupirocin (positive control) and also formulations prepared from geraniol (GNL), geraniol nanophytosomes (NPhs-GNL), and PVA/NPhs-GNL. Wound contraction, total bacterial count, pathological parameters and the expressions of bFGF, CD31 and COL1A were also assessed. The results showed that topical administration of mupirocin and PVA/NPhs/GNL increased wound contraction, fibroblast and epithelization and also the expressions of bFGF, CD31 and COL1A while decreased the expression of total bacterial count and edema compared with negative control mice (P = 0.001). The results also showed that PVA/NPhs-GNL and mupirocin could compete and PVA/NPhs-GNL formulation was safe. In conclusion, the prepared formulations accelerated the wound healing process by modulation in proliferative genes. Geraniol nanophytosomes loaded into PVA could improve the healing in infected full-thickness wounds healing process and can be used for the treatment of infected wounds after future clinical studies.

Chitosan and α-cellulose-based mupirocin topical film-forming spray: Optimization, in vitro characterization, antimicrobial studies and wound healing activity.

The study aimed to develop a biopolymer-based mupirocin film-forming spray (MUP-FFS) for wound healing using chitosan and α-cellulose. MUP-FFS formulation was optimized by box-Behnken design, wherein the amount of chitosan, glycerol, and microfluidizer cycles showed a significant effect on the drying time and sprayability, but drug release remained unaffected. The optimized MUP-FFS formulation prepared by 13 microfluidizer cycles containing chitosan (0.125 %), glycerol (2.76 %) was quickly sprayable with 235 s drying time. The viscosity, spray uniformity and occlusive potential were found optimum for MUP-FFS. MUP-FFS released 98.066 % of MUP, 2-fold and 4-fold greater than the marketed ointment and MUP-API. The transmission electron microscopy displayed a homogeneous fibrous network, and scanning electron microphotographs showed uniform drug distribution on the MUP-film surface. The antimicrobial study revealed the efficacy of MUP-FFS against S.aureus and E.coli, wherein the former was more susceptible to formulation than the later. MUP-FFS indicated better wound contraction and healing than other groups on 7th and 14th day in rats. On Day-21, MUP-FFS could regress TGF-ß1 to a normal level similar to the marketed formulation, which was also reflected in histopathological observations. Therefore, MUP-FFS can be a treatment option for chronic wounds, applied without touch and with minimal mechanical pressure.

Exploring alternative strategies for Staphylococcus aureus nasal decolonization: insights from preclinical studies.

Nasal decolonization of Staphylococcus aureus with the antibiotic mupirocin is a common clinical practice before complex surgical procedures, to prevent hospital acquired infections. However, widespread use of mupirocin has led to the development of resistant S. aureus strains and there is a limited scope for developing new antibiotics for S. aureus nasal decolonization. It is therefore necessary to develop alternative and nonantibiotic nasal decolonization methods. In this review, we broadly discussed the effectiveness of different nonantibiotic antimicrobial agents that are currently not in clinical practice, but are experimentally proved to be efficacious in promoting S. aureus nasal decolonization. These include lytic bacteriophages, bacteriolytic enzymes, tea tree oil, apple vinegar, and antimicrobial peptides. We have also discussed the possibility of using photodynamic therapy for S. aureus nasal decolonization. This article highlights the importance of further large scale clinical studies for selecting the most suitable and alternative nasal decolonizing agent.

Antiseptics and mupirocin resistance in clinical, environmental, and colonizing coagulase negative Staphylococcus isolates.

BACKGROUND: Coagulase-Negative Staphylococci (CoNS) are opportunistic and nosocomial pathogens. The excessive use of antimicrobial agents, including antiseptics, represents one of the world's major public health problems. This study aimed to test the susceptibility of CoNS to antiseptics. METHODS: Out of 250 specimens collected from different sections of the hospital, 55 samples were identified as CoNS, categorized into three groups based on their sources: environmental samples (n = 32), healthcare worker carriers samples (n = 14), and clinical infection samples (n = 9). Isolates were examined for susceptibility to antibiotics and antiseptics, such as benzalkonium chloride (BC), cetyltrimethylammonium bromide (CTAB), and chlorhexidine digluconate (CHDG). Mupirocin and antiseptic resistance genes, as well as the mecA gene, were detected using polymerase chain reaction. CoNS isolates with notable resistance to antiseptics and antibiotics were identified using the API-Staph system. RESULTS: A high frequency of multidrug resistance among CoNS clinical infection isolates was observed. Approximately half of the CoNS isolates from healthcare workers were susceptible to CHDG, but 93% were resistant to BC and CTAB. The frequency of antiseptics and antibiotics resistance genes in CoNS isolates was as follows: qacA/B (51/55; 92.7%), smr (22/55; 40.0%), qacG (1/55; 1.8%), qacH (6/55; 10.9%), qacJ (4/55; 7.3%), mecA (35/55; 63.6%), mupB (10/55; 18.2%), and mupA (7/55; 12.7%). A significant difference in the prevalence of smr gene and qacJ genes between CoNS isolates from healthcare workers and other isolates was reported (P value = 0.032 and ˂0.001, respectively). Four different CoNS species; S. epidermidis, S. chromogene, S. haemolyticus, and S. hominis, were identified by API. CONCLUSIONS: CoNS isolates colonizing healthcare workers showed a high prevalence of antiseptic resistance genes, while clinical infection samples were more resistant to antibiotics. CHDG demonstrated greater efficacy than BC and CTAB in our hospital.

Mupirocin loaded core-shell pluronic-pectin-keratin nanofibers improve human keratinocytes behavior, angiogenic activity and wound healing.

In the current study, a core-shell nanofibrous wound dressing based on Pluronic-F127 (F127) containing 2 wt% mupirocin (Mup) core and pectin (Pec)-keratin (Kr) shell was fabricated through coaxial electrospinning technique, and the blended nanofibers were also fabricated from the same materials. The fiber diameter and specific surface area of the blended nanofibers were about 101.56 nm and 20.16 m2/g, while for core-shell nanofibers they were about 97.32 nm and 25.26 m2/g, respectively. The resultant blended and core-shell nanofibers experienced a degradation of 27.65 % and 32.28 % during 7 days, respectively. The drug release profile of core-shell nanofibers revealed a sustained release of Mup over 7 days (87.66 %), while the blended F127-Pec-Kr-Mup nanofibers had a burst release within the first few hours (89.38 % up to 48 h) and a cumulative release of 91.36 % after 7 days. Due to the controlled release of Mup, the core-shell structure significantly improved the human keratinocytes behavior, angiogenic potential and wound healing in a rat model compared to the blended structure. In conclusion, the F127-Mup/Pec-Kr core-shell nanofibrous wound dressing appears to be a promising candidate for the prevention of infection, and can potentially accelerate the recovery and healing of chronic and ischemic wounds.

Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif.

Antibiotics target key biological processes that include protein synthesis. Bacteria respond by developing resistance, which increases rapidly due to antibiotics overuse. Mupirocin, a clinically used natural antibiotic, inhibits isoleucyl-tRNA synthetase (IleRS), an enzyme that links isoleucine to its tRNAIle for protein synthesis. Two IleRSs, mupirocin-sensitive IleRS1 and resistant IleRS2, coexist in bacteria. The latter may also be found in resistant Staphylococcus aureus clinical isolates. Here, we describe the structural basis of mupirocin resistance and unravel a mechanism of hyper-resistance evolved by some IleRS2 proteins. We surprisingly find that an up to 103-fold increase in resistance originates from alteration of the HIGH motif, a signature motif of the class I aminoacyl-tRNA synthetases to which IleRSs belong. The structural analysis demonstrates how an altered HIGH motif could be adopted in IleRS2 but not IleRS1, providing insight into an elegant mechanism for coevolution of the key catalytic motif and associated antibiotic resistance.

Antibiotic susceptibility and clonal distribution of Staphylococcus aureus from pediatric skin and soft tissue infections: 10-year trends in multicenter investigation in China.

Background: Skin and Soft Tissue Infections (SSTIs) Surveillance Network of S. aureus In Pediatrics in China was established in 2009 to routinely report epidemiological changes. We aimed to monitor the present antibiotic sensitivity and molecular characteristics of S. aureus and methicillin-resistant S. aureus (MRSA) from SSTIs in children nationwide and track the changes over the past decade. Methods: Patients diagnosed with SSTIs from the dermatology departments of 22 tertiary pediatric hospitals in seven geographical regions of China were recruited continuously from May 2019 to August 2021. S. aureus was isolated, and its sensitivity to 15 antimicrobials was evaluated using the broth microdilution method. The molecular characteristics of the MRSA isolates were determined through multilocus sequence typing (MLST) and staphylococcal cassette chromosome mec (SCCmec) typing. The presence of the Panton-Valentine leukocidin gene (pvl) was determined. Results: The detection rate of S. aureus was 62.57% (1379/2204), among which MRSA accounted for 14.79% (204/1379), significantly higher than the result in previous study in 2009-2011 (2.58%, 44/1075). Compared with previous study, the sensitivity to cephalosporins and fusidic acid decreased to varying degrees, while that to chloramphenicol, ciprofloxacin, clindamycin, erythromycin, gentamicin, penicillin, and tetracycline increased significantly. The sensitivity to mupirocin, trimethoprim/sulfamethoxazole (TRISUL), and rifampicin still maintained at a high level (97.90%, 99.35% and 96.66% respectively). The leading multidrug resistance pattern of MRSA and methicillin-sensitive S. aureus (MSSA) were erythromycin-clindamycin-tetracycline (55.84%; 43/77) and erythromycin-clindamycin-chloramphenicol (27.85%, 44/158) respectively. 12 high-level mupirocin-resistant strains were detected, and notable differences in geographical distribution and seasonal variation were observed. The main types of MRSA were ST121 (46.08%, 94/204), followed by ST59 (19.61%, 40/204). SCCmec V (65.69%, 134/204) and SCCmec IV (31.86%, 65/204) were dominant epidemic types. ST121-V, ST59-IV, and ST22-V were the most prevalent clones nationwide. The detection rate of pvl had increased markedly from 9.09% (4/44) in 2009-2011 to 22.55% (46/204) in 2019-2021 (P<0.05). Conclusion: The antibiotic sensitivity and molecular characteristics of S. aureus from pediatric SSTIs has changed significantly over the past decade. To standardize medical care, provide timely and reasonable clinical treatment, and effectively manage infection control, Chinese pediatric SSTIs guidelines are urgently needed.

Mupirocin enhances the biofilm formation of Staphylococcus epidermidis in an atlE-dependent manner.

The pathogenicity of Staphylococcus epidermidis is largely attributed to its exceptional ability to form biofilms. Here, we report that mupirocin, an antimicrobial agent widely used for staphylococcal decolonization and anti-infection, strongly stimulates the biofilm formation of S. epidermidis. Although the polysaccharide intercellular adhesin (PIA) production was unaffected, mupirocin significantly facilitated extracellular DNA (eDNA) release by accelerating autolysis, thereby positively triggering cell surface attachment and intercellular agglomeration during biofilm development. Mechanistically, mupirocin regulated the expression of genes encoding for the autolysin AtlE as well as the programmed cell death system CidA-LrgAB. Critically, through gene knockout, we found out that deletion of atlE, but not cidA or lrgA, abolished the enhancement of biofilm formation and eDNA release in response to mupirocin treatment, indicating that atlE is required for this effect. In Triton X-100 induced autolysis assay, mupirocin treated atlE mutant displayed a slower autolysis rate compared with the wild-type strain and complementary strain. Therefore, we concluded that subinhibitory concentrations of mupirocin enhance the biofilm formation of S. epidermidis in an atlE dependent manner. This induction effect could conceivably be responsible for some of the more unfavourable outcomes of infectious diseases.

Chronicity of high and low level mupirocin resistance in Staphylococcus aureus from 30 Indian hospitals.

Mupirocin is one of the most effective topically used antibiotic for the treatment of dermatitis, nasal carriage, decolonization of methicillin susceptible Staphylococcus aureus and eradication of methicillin resistant Staphylococcus aureus. Extensive use of this antibiotic has resulted in mupirocin resistance in Staphylococcus aureus which is a matter of concern. This study was conducted to evaluate the high and low level of mupirocin resistance in Staphylococcus aureus collected from various Indian hospitals. A total of 600 samples, of which 436 were pus specimens and 164 wound site swabs were collected from 30 Indian hospitals. Disc diffusion and agar dilution methods were used to test mupirocin susceptibility in methicillin resistant Staphylococcus aureus. Out of 600 Staphylococcus aureus isolates, 176 isolates (29.33%) were found to be methicillin resistant Staphylococcus aureus (MRSA). Out of 176 non-duplicate MRSA strains, 138 isolates were found to be mupirocin sensitive, 21 isolates had high level resistance whereas 17 isolates had low level resistance to mupirocin, which contributed 78.41%, 11.93% and 9.66% respectively. Multidrug resistant susceptibility was tested for all the MRSA with Cefuroxime, Cotrimoxazole and Vancomycin antibiotics. All the high and low level resistant strain were subjected to genome screening for mupA ileS gene respectively. mupA gene was found positive in all the high level resistant strain and out of 17 low level resistant strain, 16 strain were found point mutation in V588F of ileS gene. Overall, high rate of mupirocin resistance was found in the studied samples which might be a result of indiscriminate use of mupirocin in the population of studied region. This data emphasizes the urgent need for formulation of a well-defined and regulated guidelines for mupirocin use. Moreover, continuous surveillance is needed for the use of mupirocin and routine test should be performed to detect MRSA in patients and health care personnel to prevent MRSA infections.

Exploiting Broad-Spectrum Chimeric Lysin to Cooperate with Mupirocin against Staphylococcus aureus-Induced Skin Infections and Delay the Development of Mupirocin Resistance.

Staphylococcus aureus often leads to severe skin infections. However, S. aureus is facing a crisis of antibiotic resistance. The combination of phage and antibiotics is effective for drug-resistant S. aureus infections. Therefore, it is worth exploiting novel antibacterial agents to cooperate with antibiotics against S. aureus infections. Herein, a novel chimeric lysin ClyQ was constructed, which was composed of a cysteine- and histidine-dependent amidohydrolase/peptidase (CHAP) catalytic domain from S. aureus phage lysin LysGH15 and cell wall-binding domain (CBD) from Enterococcus faecalis phage lysin PlyV12. ClyQ had an exceptionally broad host range targeting streptococci, staphylococci, E. faecalis, and E. rhusiopathiae. ClyQ combined with mupirocin (2.64 log reduction) was more effective at treating S. aureus skin infections than ClyQ (0.46 log reduction) and mupirocin (2.23 log reduction) alone. Of equal importance, none of S. aureus ATCC 29213 or S3 exposed to ClyQ developed resistance, and the combination of ClyQ and mupirocin delayed the development of mupirocin resistance. Collectively, chimeric lysin ClyQ enriches the reservoirs for treating S. aureus infections. Our findings may provide a way to alleviate the current antibiotic resistance crisis. IMPORTANCE Staphylococcus aureus, as an Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) pathogen, can escape the elimination of existing antibiotics. At present, phages and phage lysins against S. aureus infections are considered alternative antibacterial agents. However, the development of broad-spectrum chimeric phage lysins to cooperate with antibiotics against S. aureus infections remains at its initial stage. In this study, we found that the broad-host-range chimeric lysin ClyQ can synergize with mupirocin to treat S. aureus skin infections. Furthermore, the development of S. aureus resistance to mupirocin is delayed by the combination of ClyQ and mupirocin in vitro. Our results bring research attention toward the development of chimeric lysin that cooperates with antibiotics to overcome bacterial infections.

Topical delivery of mupirocin calcium nanostructured lipid carriers using a full-thickness excision wound healing model.

OBJECTIVE: Treatment of contaminated wounds represents a significant challenge in healthcare and there is a need to develop approaches maximising skin retention to maintain therapeutic concentrations of anti-infectives at the wound site. The objective of the present study was to develop and evaluate mupirocin calcium nanolipid emulgels to enhance wound healing performance and patient acceptability. METHODS: Nanostructured lipid carriers (NLCs) of mupirocin calcium were prepared by the phase inversion temperature method using Precirol ATO 5 (Gattefosse, India) and oleic acid as lipids and Kolliphor RH 40 (BASF, India) as surfactant and further incorporated into a gel base for topical delivery. RESULTS: The particle size, polydispersity index and zeta potential of mupirocin NLCs were found to be 128.8±1.25nm, 0.283±0.003 and -24.2±0.56mV, respectively. In vitro release studies from developed emulgel showed sustained drug release over 24 hours. Ex vivo drug permeation studies through excised rat abdominal skin showed better skin permeation (1712.38±15. 57µg/cm2) from developed emulgel compared to marketed ointment (827.92±21.42µg/cm2) after 8 hours, which was in agreement with in vitro antibacterial activity. Studies on Wistar rats indicated the nonirritant potential of developed emulgels. Further, mupirocin emulgels showed improved efficacy in percent wound contraction of acute contaminated open wounds in Wistar rats using a full-thickness excision wound healing model. CONCLUSION: The emulgels of mupirocin calcium NLCs appear to be effective in the treatment of contaminated wounds due to increased skin deposition and sustained release, thereby enhancing the wound healing potential of existing molecules.

A bilayer mupirocin/bupivacaine-loaded wound dressing based on chitosan/poly (vinyl alcohol) nanofibrous mat: Preparation, characterization, and controlled drug release.

An infected skin wound caused by external injury remains a serious challenge. Electrospun drug-loaded nanofibers with antibacterial properties based on biopolymers have been widely explored for wound healing. In this study, the double-layer CS/PVA/mupirocin (CPM) + CS/PVA/bupivacaine (CPB) mats were prepared by electrospinning method (20 % polymer weight) and then crosslinked with glutaraldehyde (GA) to optimize the water-resistant and biodegradation properties for wound dressing applications. The morphology of mats was characterized as defect-free and interconnected nanofibers by Scanning Electron Microscope (SEM) and Atomic Force Microscopy (AFM). Fourier Transform Infrared Spectrometry (FTIR) analysis also assessed the chemical structural properties. The porosity, surface wettability, and swelling degree of the dual-drug loaded mats were improved by about 20 %, 12°, and 200 % of the CS/PVA sample to provide a moist environment for efficient wound breathing and repairing. This highly porous mat facilitated the wound exudates absorption and air permeability excellently, reducing the chance of bacterial infections by inhibiting the growth of S. aureus bacterial colonies with a zone of 71.3 mm diameter. In vitro drug release results showed a high-burst release of 80 % and a continuous release profile for bupivacaine and mupirocin, respectively. MTT assay and in vivo tests indicated >90 % of cell viability and improvement in cell proliferation. It triply accelerated wound closure compared to the control group, reaching nearly full closure after 21 days as a potential clinical wound treatment.