Chitosan-bovine serum albumin-Carbopol 940 nanogels for mupirocin dermal delivery: ex-vivo permeation and evaluation of cellular binding capacity via radiolabeling.

The goal of this study was to develop and examine the nanogel-based topical delivery system of mupirocin. Nanogels were prepared with chitosan and bovine serum albumin by ionic gelation and Carbopol 940 was added to improve the gelling/adhesive properties. Detailed characterization studies were performed and the cellular binding capacity of radiolabeled nanogels was investigated on CCD-1070Sk cell lines. Results indicate the successful formation of nanogels with particle size and zeta potential ranged between 341.920-603.320 nm and 13.120-24.300 mV, respectively. The mechanical and rheological studies proved pseudoplastic and strong elastic gel behavior (G' > G''). Mupirocin was successfully entrapped into nanogels with a ratio of more than 95% and the loaded drug was slowly released up to 93.89 ± 3.07% within 24 h. The ex vivo penetration and permeation percentages of mupirocin were very low (1.172 ± 0.202% and 0.161 ± 0.136%) indicating the suitability of nanogels for dermal use against superficial skin infections. The microbiological studies pointed out the effectiveness of nanogels against Staphylococcus aureus strains. Nanogels did not show toxicity signs and the cell binding capacity of radiolabeled formulations was found to be higher than [99mTc]NaTcO4 to CCD-1070Sk cell line. Overall, mupirocin nanogels might be considered as a potential and safe topical treatment option for bacterial skin infections.

Development of Emulgel Delivery of Mupirocin for Treatment of Skin Infection.

AIM: To design controlled release topical delivery of mupirocin for the treatment of skin infection. BACKGROUND: Mupirocin is an antibacterial drug. Mupirocin works to kill the bacteria, which include strains of Staphylococcus aureus and Streptococcus pyogenes. It is also used for the treatment of inflammation of a hair follicle. The half-life of mupirocin is only 20-40 min. It has very slight solubility in water. Patent literature had shown work on ointment, antibiotic composition, nasal and topical composition. Emulgel is a duel control release system for the topical delivery of hydrophobic drugs. OBJECTIVE: The objective was to formulate emulgel with controlled delivery of mupirocin using Sepineo P 600. METHODS: Soya oil, tween 80 and polyethylene glycol 400 (Oil:Surfactant:Cosurfactant) were used for emulsion formulation. Emulgel was optimized by 32 factorial design. Sepineo P 600 and hydroxy propyl methyl cellulose K4M were used as independent variables. Drug excipient compatibility analysis was carried out by FTIR, UV and DSC spectra. Emulgel was evaluated for its physical characterization, in vitro release, ex vivo release, antimicrobial and anti-inflammatory study. RESULTS: DSC, UV and FTIR analysis confirmed drug excipient compatibility. FE SEM showed a size range between 228-255 nm. Zeta potential was found to be -25.1 mV, which showed good stability of the emulsion. Design expert software showed F2 as an optimized batch. Release studies indicated that the controlled release of drugs forms Sepineo P 600 gel due to its higher gelling capacity. Batch F2 showed comparable results with marketed formulation against Staphylococcus aureus. For batch F2, 40 µg/ml was the minimal inhibitory concentration. CONCLUSION: Antimicrobial and anti-inflammatory study proved successful development of stably controlled release mupirocin emulgel.

Poly(hydroxybutyrate-co-hydroxyvalerate) microparticles embedded in κ-carrageenan/locust bean gum hydrogel as a dual drug delivery carrier.

A novel composite hydrogel was prepared as a dual drug delivery carrier. Poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) microparticles were prepared to encapsulate simultaneously ketoprofen and mupirocin, as hydrophobic drug models. These microparticles were embedded in a physically crosslinked hydrogel of κ-carrageenan/locust bean gum. This composite hydrogel showed for both drugs a slower release than the obtained release from microparticles and hydrogel separately. The release of both drugs was observed during a period of 7 days at 37 °C. Different kinetic models were analyzed and the results indicated the best fitting to a Higuchi model suggesting that the release was mostly controlled by diffusion. Also, the drug loaded microparticles were spherical with average mean particle size of 1.0 µm, mesoporous, and distributed homogeneously in the hydrogel. The composite hydrogel showed a thermosensitive swelling behavior reaching 183% of swelling ratio at 37 °C. The composite hydrogel showed the elastic component to be higher than the viscous component, indicating characteristics of a strong hydrogel. The biocompatibility was evaluated with in vitro cytotoxicity assays and the results indicated that this composite hydrogel could be considered as a potential biomaterial for dual drug delivery, mainly for wound healing applications.

Liposomal mupirocin holds promise for systemic treatment of invasive Staphylococcus aureus infections.

Staphylococcus aureus is a major cause of severe invasive infections. The increasing incidence of infections caused by antibiotic-resistant strains such as methicillin-resistant S. aureus (MRSA), calls for exploration of new approaches to treat these infections. Mupirocin is an antibiotic with a unique mode of action that is active against MRSA, but its clinical use is restricted to topical administration because of its limited plasma stability and rapid degradation to inactive metabolites. Mupirocin was identified by a machine learning approach to be suitable for nano-liposome encapsulation. The computational predictions were verified experimentally and PEGylated nano-liposomal formulation of mupirocin (Nano-mupirocin) was developed. The aim of this study was to investigate the efficacy of this formulation when administered parenterally for the treatment of S. aureus invasive infections. Nano-mupirocin exhibited prolonged half-life of active antibiotic and displayed superior antimicrobial activity against S. aureus than free mupirocin in the presence of plasma. Parenteral application of Nano-mupirocin in a murine model of S. aureus bloodstream infection resulted in improved antibiotic distribution to infected organs and in a superior therapeutic efficacy than the free drug. Parenterally administered Nano-mupirocin was also more active against MRSA than free mupirocin in a neutropenic murine lung infection model. In addition, Nano-mupirocin was very efficiently taken up by S. aureus-infected macrophages via phagocytosis leading to enhanced delivery of mupirocin in the intracellular niche and to a more efficient elimination of intracellular staphylococci. The outcome of this study highlights the potential of Nano-mupirocin for the treatment of invasive MRSA infections and support the further clinical development of this effective therapeutic approach.

Development, characterization and pharmacokinetics of mupirocin-loaded nanostructured lipid carriers (NLCs) for intravascular administration.

Mupirocin is a promising broad-spectrum antibiotic that is effective in treating MRSA infections. However, due to its rapid elimination and hydrolysis following injection and high protein binding, current therapeutic use is limited to topical administration. Nanotechnology-driven innovations provide hope for patients and practitioners in overcoming the problem of drug degradation by encapsulation. The objective of this research is to develop and characterize Mupirocin-Loaded Nanostructured Lipid Carriers (M-NLC) for intravascular administration. The MNLC was produced by a combination of high shear homogenization and high pressure homogenization of solid (cetyl palmitate) and liquid (caprylic/caprylic acid) biocompatible lipids in 5 different ratios. The mean particle size, polydispersity index (PDI) and the zeta potential (ZP) of the MNLC formulations were between 99.8 and 235 nm, PDI lower than 0.164, ZP from -25.96 to -19.53 and pH ranging from 6.28-6.49. The MNLC formulation also enhances the anti-bacterial activity of mupirocin. All formulation showed sustained drug release and good physical characteristics for three months storage under 25 °C. It also revealed that the MNLC 1 is safe at 250 mg/kg dose in rats. The MNLC 1 also showed a significant increase in plasma concentration in rabbits following IV administration thus, demonstrating an enhancement on its pharmacokinetic profile as compared to free mupirocin.

TXA497 as a topical antibacterial agent: comparative antistaphylococcal, skin deposition, and skin permeation studies with mupirocin.

TXA497 is representative of a new class of guanidinomethyl biaryl compounds that exhibit potent bactericidal behavior against methicillin-resistant Staphylococcus aureus (MRSA). In this study, we compared the anti-staphylococcal, skin deposition, and skin permeation properties of TXA497 and the topical anti-MRSA antibiotic mupirocin. The results of minimum inhibitory concentration (MIC) assays revealed that TXA497 retains potent activity against MRSA that is highly resistant to mupirocin. Using Franz diffusion cells, compound deposition into human cadaver skin was evaluated, and the results showed the skin deposition of TXA497 to be significantly greater than that of mupirocin. Moreover, unlike mupirocin, TXA497 does not pass through the entire skin layer, suggesting a minimal potential for the systemic absorption of the compound upon topical administration. Additionally, antibacterial concentrations of TXA497 showed no significant toxicity to primary human keratinocytes. Given the rising levels of mupirocin resistance among MRSA populations, our results are significant in that they highlight TXA497 as a potentially useful alternative therapy for treating MRSA skin infections that are resistant to mupirocin.

Staphylococcus aureus resistente a la meticilina y a descolonizadores habituales con reservorio en un trabajador sanitario en un hospital de tercer nivel / Antibiotic ointments and methicillin-resistant Staphylococcus aureus with a reservoir in a healthcare worker in a tertiary hospital

INTRODUCCIÓN: Staphylococcus aureus resistente a la meticilina (SARM) es un patógeno nosocomial, con reservorio en portadores o infectados y que tiene como principal mecanismo de transmisión el contacto con las manos del personal. Métodos Se puso en marcha una investigación epidemiológica y se realizaron determinaciones de laboratorio para abordar el estudio de la situación provocada por la aparición de nuevos casos de SARM resistente a los descolonizadores habituales. Resultados Desde septiembre de 2010 a febrero de 2012, en nuestro centro, 16 pacientes y una trabajadora tuvieron un aislamiento de SARM resistente a los descolonizadores habituales (mupirocina y ácido fusídico). Se detectaron casos esporádicos no relacionados, y a su vez brotes epidémicos relacionados con la ubicación de la actividad del personal sanitario portador de SARM. El análisis mediante electroforesis en campo pulsado de las muestras de pacientes y de la trabajadora puso de manifiesto la clonalidad de las cepas, lo que sugiere que el reservorio pudiera ser la trabajadora afectada. La descontaminación con antibióticos sistémicos no tuvo éxito y la trabajadora fue adscrita a otro puesto de trabajo sin contacto directo con pacientes, con lo que se consiguió que no aparecieran más casos hasta el momento actual (septiembre de 2012). Conclusiones Este trabajo ilustra el riesgo de transmisión nosocomial relacionada con la atención prestada por los trabajadores sanitarios

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) has become an important hospital acquired pathogen, with transfer of the organism from a carrier or infected patient to uninfected patients by the hands or clothing of staff as the main mode of transmission. METHODS: Investigation of a cluster of new cases of MRSA resistant to mupirocin and fusidic acid, using epidemiological and microbiological resources. RESULTS: From September 2010 to February 2012, sixteen patients had at least one culture positive for MRSA resistant to mupirocin and fusidic acid. Some not apparently related cases and outbreaks appeared. By analysing cultures taken from patients and staff using pulsed-field. CONCLUSION: This report illustrates the risk of nosocomial transmission linked to care delivered by healthcare workers

An intranasal irritation assessment of antibacterial ointment alone or in combination with mupirocin versus Bactroban Nasal in rabbits.

The purpose of this study was to evaluate the potential irritating effects and the systemic exposure level of an antibacterial ointment containing REP8839 as a single agent or in combination with mupirocin versus Bactroban Nasal in rabbits. Additionally, the reversibility of REP8839 effects during a 14-day recovery period was assessed. Five treatment groups of six male and six female New Zealand White rabbits received dose levels of 1%, 2%, and 4% REP8839, 2% Bactroban Nasal, or 2% REP8839/2% mupirocin combination. One additional group of six animals/sex served as the control and received the vehicle, Petrolatum/Softisan 649. The test article or vehicle was administered to all groups via topical administration to the external nares, twice a day (approx. 8h intervals between the doses) for 21 consecutive days, at a dose volume of 100 microL per nare/dose for a total of 400 microL per day (200 microL per nare). Two animals/sex/group were maintained for a 14-day recovery period. The external nares were reflected back and the mucosal lining was evaluated and scored for erythema and edema within 30-60 min following the first dose each day. Blood samples were collected from all animals at designated time points on Day 21 of the study to assess systemic exposure levels. Cross-sectioning of the nasal tract was conducted in all the groups for microscopic evaluation. Mucosal scoring of the nares did not reveal any edema or erythema in any of the dose groups with the antibacterial alone, with the combination product, or with Bactroban Nasal. Mean body weights and food consumption were not adversely impacted by the test articles. Minimal plasma exposure was observed in the rabbits (<5 ng/mL). The REP8839 groups did appear to have dose-responsive exposure (from below the limit of quantitation to 5 ng/mL with 1%, 2%, and 4% REP8839, respectively). Microscopic changes on the nasal sectioning noted in these animals were infrequent and considered incidental findings unrelated to administration of the test articles. In conclusion doses of up to 4% of REP8839 ointment as a single agent or 2% in the combination product, as well as 2% Bactroban Nasal, were not found to induce mucosal irritation when applied topically to the external nares twice a day for 21 consecutive days. Additionally, no delayed effects were observed in the recovery animals.

The bioavailability of mupirocin in nasal secretions in vitro.

AIM: To determine the bioavailability of mupirocin in human nasal secretions and to assess whether the contents of nasal secretions interact appreciably with this antibiotic. METHODS: The comparative bioavailability of mupirocin and chlorhexidine in nasal secretions was determined by bioassay after one, four, and eight hours of incubation with pooled secretions from three subjects. The interaction of mupirocin with nasal secretions was characterised by matrix assisted laser desorption time of flight mass spectrometry (MALDI-TOF). RESULTS: MALDI-TOF analysis showed that mupirocin was not absorbed by the main fraction of pooled nasal secretions and should remain active. In bioassay, mupirocin retained 100% of its antistaphylococcal activity in nasal secretions, whereas chlorhexidine was significantly reduced from 100 mg/litre to 1.5 mg/litre and from 1000 mg/litre to 38.5 mg/litre, irrespective of incubation time. CONCLUSIONS: The high bioavailability of mupirocin in nasal secretions results from the lack of appreciable molecular interactions.

Intranasal mupirocin for outbreaks of methicillin-resistant Staphylococcus aureus.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of mupirocin are reviewed. Mupirocin is a naturally occurring antibiotic produced by submerged fermentation of Pseudomonas fluorescens. It inhibits bacterial protein synthesis by binding reversibly and specifically to isoleucyl-tRNA synthetase. Organisms resistant to other antimicrobials are not simultaneously resistant to mupirocin. Mupirocin is highly active against Staphylococcus aureus and other staphylococci and streptococci. When mupirocin ointment is applied topically, local concentrations exceed the inhibitory concentrations for staphylococci and remain detectable for up to 72 hours. Placebo-controlled studies demonstrate the ability of mupirocin to eliminate nasal carriage of S. aureus in health care workers. Observational studies suggest that mupirocin is efficacious in treating methicillin-resistant S. aureus (MRSA) outbreaks. Preliminary studies show that mupirocin might have a role in preventing infections in high-risk patients. Although mupirocin seems to be well tolerated, mild to moderate adverse events have been reported, including respiratory problems and effects confined to the nose--erythema, swelling, burning or stinging, pruritus, and dryness. Mupirocin calcium ointment has FDA-approved labeling for the eradication of nasal MRSA colonization in adult patients and health care workers as part of comprehensive infection-control programs to reduce the risk of infection during institutional outbreaks. The recommended dosage is 0.5 g inserted into each nostril twice daily for five days. Intranasal mupirocin ointment appears to be a useful addition to infection-control programs designed to reduce the risk of infection among patients during MRSA outbreaks.

Development of a new CSF-shunt with sustained release of an antimicrobial broad-spectrum combination.

The use of Cerebro-Spinal-Fluid-shunts (CSF-shunts) is often associated with infectious complications, because bacteria tend to colonize plastic material. The use of plastic materials with antibacterial activity may reduce catheter related bacterial colonization. A novel CSF-shunt impregnated with a broad-spectrum antimicrobial combination was designed in order to meet two requirements; lack of toxicity and persistence of antimicrobial efficacy. Incorporation of three antibiotics up to 10% (wt/wt) into the shunt material (polydimethyl-siloxane) was required for sustained release for more than 100 days, measured by HPLC. The combination of antimicrobials showed additive and synergistical effects as measured by the checker-board and time kill technique. These antimicrobial combinations prevented mutations in resistance inducing experiments with several S. epidermidis and S. aureus strains. Using large challenge doses of S. aureus in a catheter colonization model, antimicrobially modified catheters were protected against bacterial colonization for more than 14 days. Using a C3a-des-Arg-ELISA-test and a CH50-hemolysis test the modified catheter was as biocompatible as the unmodified shunt material. These encouraging results indicate that such antibiotic-bonded catheters substantially reduce the incidence and magnitude of catheter-related bacterial colonization and may substantially reduce CSF-shunt infection.

Comparative killing kinetics of methicillin-resistant Staphylococcus aureus by bacitracin or mupirocin.

The in vitro activities of bacitracin and mupirocin were compared for seven different strains of methicillin-resistant Staphylococcus aureus. Six of seven strains showed bacitracin minimum inhibitory concentrations (MICs) of 0.5 to 1.0 units/mL, and all seven had mupirocin MICs of 0.5 to 2 micrograms/mL. Time-kill studies revealed 2.6- to 4.5-log reduction in 24 hours with strains susceptible to bacitracin (4 units/mL) and 0 to 2.2 reduction with mupirocin (16 micrograms/mL). Bacitracin should be considered further for in vivo studies because of enhanced bacteriocidal effect and lower cost.