INTRODUCTION:

Antimicrobial drugs are classified as either antibiotics or chemotherapeutics based on whether they cause microorganisms to die or simply inhibit their proliferation.^1,2 Previously, biologically derived or naturally occurring compounds were termed as antibiotics, whereas chemotherapeutic was termed for chemicals synthesised in laboratories.³ Some antibiotics can chemically modified and synthesised based on the understanding of their chemical structures. Concerns about the quality and efficacy of medicines drive intensive research in quality control laboratories occurred worldwide.⁴ It is well understood that the incorrect analytical data can leads to conflicts in decisions and may also leads to irreversible financial loss.^5,6,7, As a result.

All analytical methods used in therapeutic drug monitoring and/or drug production must have certain characteristics (i.e. sensitivity, accuracy, precision, and robustness).⁸

Fusidic acid (FA) was isolated from the fungus Fusidium coccineum in 1960. Other yeast sources that have been reported include Acremonium fusidioides and Calcarisporium arbuscula, Cephalosporium lamellaecula, C. acremonium, Mucor ramannianus, Epidermophyton floccosum, Gabarnaudia tholispora, and Paecilomyces.^9,10,11 The term "fusidic acid" refers to both fusidic acid (constituent of the cream) and sodium fusidate (constituent of the ointment and tablets), because the active principle (fusidate) is the same for both compounds after absorption.¹² FA is the most important member of the fusidane group, which can be structurally classified as 29-nor protostano triterpenes.^13,9 These are classified as steroid compounds and have a cyclopentanoperhydrophenanthrene ring system.^14,15,16 Fusidic acid has been available as an antibiotic for dermatological use for many years, first as tablets in 1962, then as a suspension in 1963, an ointment in 1965, and a cream in 1982.^17,18 It has been shown to be effective in the treatment of primary and secondary skin infections, particularly those caused by Staphylococcus aureus.^19,20 Its functionality is enhanced further by the availability of combination formulations: fusidic acid/hydrocortisone ointment since 1967, fusidic acid/betamethasone cream since 1987 for the treatment of infected eczema lesions,²¹ and a new lipid-rich formulation of fusidic acid/betamethasone cream, introduced in 2007 for the treatment of infected eczema lesions where a more lipid rich formulation is preferred by doctors or patients.^22,23 FA was identified as α, β -unsaturated carboxylic acid with the molecular formula C31H48O6 which contain a acetoxyl group and two hydroxyl groups.^24,25 The FA is a weak acid with a pKa of 5.7 that is mostly ionised in plasma and tissue at the physiological pH of 7.4.²⁶ FA is a white crystalline powder slightly hygroscopic in nature and is insoluble in water, ether and hexane, and is soluble in 96 percent ethanol, acetone, chloroform, pyridine, dioxane, and acetonitrile.^27,28 Furthermore, the drug has no cross-resistance with other antibiotics used in clinical practise (-lactams, aminoglycosides, and macrolides), which is likely due to the fact that these antibiotic classes have different chemical structures.^29,9 Unlike most recent antibiotics, such as broad-spectrum linezolid and daptomycin, the FA has maintained its effectiveness consistent activity against multiresistant strains.³⁰ Fusidic acid is the only commercially available member of the fusidane antibiotic group. It acts by inhibiting bacterial protein synthesis through interference with elongation factor G in the translocation step. The FA has steroid-like structure which provide certain advantages, such as good skin penetration and also have good skin permeability.^31,32,33,23

The topical administration of FA produces much higher local concentrations than systemic administration, as the fusidic acid has strong absorption properties.^33,34 Fusidic acid has high antibacterial activity against S. aureus, including methicillin-resistant strains (MRSA) and S. epidermidis.^35,36 It is also active against some Corynebacterium species and has been applied for the treating mild to moderately severe primary and secondary skin and soft tissue infections (SSTIs) which is caused by sensitive organisms.^37,38

Table 1. Minimum inhibitory concentration (MIC) values for fusidic acid for common pathogens in skin infections

Organism	MIC (µg/ml)
Staphylococcus aureus	0.25
MRSA	0.25
Staphylococcus epidermidis	0.25
Corynebacterium minutissimum	0.06
Propionibacterium acnes	1
Streptococcus pyogenes	8

In-vitro resistance to FA was first observed in 1984, and has remained at very low levels despite the drug's widespread use.^9,39,40 This review will provide information regarding the properties, along with the studies on clinical efficacy of fusidic acid in skin and soft-tissue infections. It will also include information on the analytical methods used to detect the presence of FA in biological samples and pharmaceutical formulations. This review summarises the available evidence for fusidic acid's clinical efficacy in dermatology and new data on shifting resistance patterns. This review includes all randomised trials that investigated the clinical efficacy of fusidic acid in dermatology in comparative trials that were discovered.

Pharmacological Properties:

Since 1962, FA has been used in the treatment of various systemic and topical staphylococcal infection like coagulase negative Staphylococcus and strains which are resistant to other antimicrobial agents, which make it a good alternative for the treatment of MRSA-related diseases.^41,9 FA can be used to treat a variety of clinical conditions, including bacterial conjunctivitis, cystic fibrosis, respiratory issues, leprosy, surgical prophylaxis, ophthalmic and neurological conditions, bone and joint infections, and soft-tissue infections, due to its activity against a wide range of gram-positive bacteria.⁴² Many dermatologists use topical FA to treat staphylococcus and streptococcus skin infections, as well as other microorganisms sensitive to this drug.^43,44 Boils, anthrax, and carbuncles are the most common symptoms associated with staphylococcus and streptococcus microorganism.⁴⁵

FA is a bacteriostatic antibiotic with the potential for bactericidal activity at high concentrations.⁴⁶ FA is an G(EF-G) that prevents EF-G translocation.^47,48 During protein synthesis EF-G protein is required for ribosome translocation after a peptide bond is formed. ⁴⁹ In the ribosome FA binds to EF-G accompanied by inactive guanosine diphosphate or active triphosphate guanosine (GTP) that inhibits EF-GTPase G's function, preventing further elongation.^50,51 EF-2 is the drug-sensitive elongation factor in prokaryotes, and the functions of EF-2 in eukaryotic cells can be performed by other elongation factors, such as EF-Tu and EF1.^52,53

Fusidic Acid in Management of Psoriasis:

Psoriasis is a chronic inflammatory autoimmune disease which is associated with hyperproliferation and abnormal epidermal differentiation at typical body sites. ⁵⁴ It mostly effects the external surfaces of the elbows, knees, natal cleft, umbilicus, scalp, and nails.⁵⁵ The most common form of psoriasis which is generally characterized by redness, thickness, and scaling of the skin is chronic plaque psoriasis.^56,57 Various risk factors that influence the repetition of psoriasis are genetic changes, infections, local trauma, duration of treatment, sunlight exposure, alcohol intake, smoking, endocrine factors and stress.^58,59 It is a chronic inflammatory skin condition which leads to cause imbalance in the immune system and affect it by increasing epidermal proliferation. Psoriasis is an autoimmune disease which do not have permanent cure and characterised by white or red colour patches on skin surface.^60,61

The topical treatment is preferred as the first-line therapy for diseases associated with skin. Anti-psoriatic agents are used for the management of psoriasis, the bacterial cause of disease can be tackled by the administration of antibiotics.⁶² Fusidic acid (FA) is derived from the fungus Fusidium coccineum is a steroidal bacteriostatic agent. It is administered to the patient to manage the skin, ocular, and orthopedic infections. The antipsoriatic potential of FA was investigated in 1970 during the preliminary stage of clinical trials.⁶³ FA is available in the market in the form of oral, parenteral, and topical formulations for the treatment or management of various infections; however, the oral and parenteral routes have been linked to a number of health risks such as GIT discomfort, liver upset, hepatotoxicity, phlebitis, diarrhoea, and rhabdomyolysis.⁶⁴ These negative effects are due to FA's widespread systemic distribution and absorption into various body organs, which may reduce its therapeutic efficacy at the target site.⁶⁵ Certain obstacles, such as local irritation, poor dermal penetration, and suboptimal topical drug delivery efficacy, can be overcome by developing a nanocarrier of dosage form.⁶⁵

Adverse Reactions:

According to preliminary research, FA is least toxic, with the most common side effects being gastrointestinal discomfort, diarrhoea, and headache.⁶⁶ Since 1972, Hepatotoxicity has been mentioned in case reports, but according to a retrospective investigation, this effect is reversible and is primarily associated with intravenous administration.^67,68 Intravenous(IV) administration of fusidic acid should be done slowly to avoid thrombophlebitis.⁶⁹ In patients with hepatic dysfunction, intravenous administration of FA is not prohibited, but should be done with caution.⁷⁰ In the treatment of bacterial conjunctivitis, fusidic acid can cause eye burning, these are rarely reported.^71,9 Skin reactions such as itching, rashes, dryness, and allergic reactions are extremely rare. In comparison with other topical and systemic antibacterial therapies, FA has a low incidence of adverse reactions.^72,18,73

Drug Interactions:

Albendazole metabolism can be slowed when combined with Fusidic acid. Fusidic acid may reduce the rate of Atropine excretion, resulting in a higher serum level.^74,75 When combined with Fusidic acid, Benzylpenicillin excretion can be reduced. When combined with Fusidic acid, the metabolism of Betamethasone can be slowed. When combined with Fusidic acid, the metabolism of Betamethasone phosphate can be slowed.^27,39When combined with Fusidic acid, Buprenorphine metabolism can be slowed.⁷⁶ Cephalexin metabolism can be slowed when combined with Fusidic acid. When Fusidic acid is combined with Chloroquine, its metabolism can be slowed. When Fusidic acid is combined with Chlorpromazine, its metabolism can be slowed.^77,78 Clindamycin metabolism can be slowed when combined with Fusidic acid. Diazepam metabolism can be slowed when combined with Fusidic acid. Fusidic acid may reduce the excretion rate of Diclofenac, resulting in a higher serum level. Clomipramine metabolism can be slowed when combined with fusidic acid.^79,80 Corticotropin metabolism can be slowed when combined with Fusidic acid. When Fusidic acid is combined with Cyclosporine, its metabolism can be slowed. When Fusidic acid is combined with Dexamethasone, its metabolism is increased. When fusidic acid is combined with Dimethyl sulfoxide, its metabolism is slowed.^81,82 Domperidone metabolism can be slowed when combined with fusidic acid. When Doxycycline is combined with fusidic acid, its metabolism can be slowed. When Enalapril is combined with Fusidic acid, the risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased.^83,84 Fusidic acid may decrease Erythromycin excretion, resulting in a higher serum level. When combined with Fusidic acid, the metabolism of Estradiol acetate can be slowed. When combined with Fusidic acid, the metabolism of Estradiol benzoate can be slowed.^75,85

Studies on efficacy and safety:

Systemic formulations:

In SSTIs, fusidic acid is at least as effective as other oral antibiotics and has comparable or better tolerability. Some studies compared the effects of different doses of fusidic acid. At doses greater than 250mg twice daily (BID), cure rates did not increase significantly, and there were more adverse events.^86,6 The most common side effects of systemic fusidic acid are gastrointestinal issues like nausea and diarrhoea. Response rates with fusidic acid and the comparator were comparable in studies comparing it to flucloxacillin, pristinamycin, ciprofloxacin, and erythromycin.^87,72 Fusidic acid's tolerability was either comparable to or significantly better than the comparator, owing to fewer gastrointestinal adverse events. In general, systemic fusidic acid is well tolerated, with only a few minor side effects.^88,72

Table 3. Studies on healing rates and times with fusidic acid cream (a) and ointment (b) in skin and soft tissue infections

Condition	Fusidic Acid			Comparator				Reference
	N	CRR	TD (days)		N	CRR	TD
(a)Fusidic acid cream
Skin infection	19	95%	14	Dicloxacillin 500 mg BID	19	89%	14	94
Acute skin sepsis	104	95%	7	Mupirocin	102	98%	7	95
Superficial bacterial infections of skin	34	78%	14	Trimethoprim-polymixin	30	84%	14	96
Pyodermas	50	47%	14	Trimethoprim-polymixin	50	73%	14	96
Erythrasma	31	87%	14	Erythromycin tablets	31	77%	14	97
Facial impetigo	93	97%	7	Mupirocin	84	98%	7	95,98
Impetigo	128	82%	12.4	Hydrogen peroxide cream	128	72%	14	99
Impetigo	78	95%	14	Povidone/iodine	82	86%	14	100
(b) Fusidic acid ointment
Bacterial skin infection	101	93%	6	Oral/intramuscular penicillin	58	96% oral, 98% i.m.	5	101
Erythrasma	66	89%	5	6% benzoic acid + 3% salicylic acid	61	90%	5	102
Soft tissue infections	49	100%	7	Oral antibiotics	4	83%	10	103
Skin infections	30	93%	4-7	Oral amoxicillin Oral amoxicillin + fusidic acid ointment	30	97% 90%	4-7 4-7	104
acute skin infection	191	86%	7	Mupirocin	163	86%	7	105,106
Superficial skin infections	138	93%	7	Mupirocin	275	97%	7	105,107
Primary and secondary skin infections	35	94%	7	Mupirocin	35	94%	7	105,108
Primary pyodermas	50	84%	7	Mupirocin	50	90%	7	105,109
Impetigo	172	90%	7	Retapamulin	345	95%	7	110

N= patient treated; BID: two times day; CRR: clinical response rate; TD: treatment duration; i.m.: intramuscular

Analytical Methods:

Various methods are used for determining FA in biological fluids and other dosage forms which are described below:

· Spectrophotometry is an analytical method used to make analytical determinations in a variety of fields. First derivative UV spectrophotometry was used to determine the concentrations of FA and sodium fusidate (SF) in capsules and ointments.^9,117 Another spectrophotometric study was conducted to identify these two drugs in tablets and suspensions using a colorimetric reaction in the visible absorption region. ¹¹⁸

· A mass spectrometry study of FA dissociative ionisation by electron impact was performed, and the products formed as a result of thermolysis were identified.^119,120

· A method for determining FA levels in dermatological creams using atomic absorption spectrometry was also developed. The drug was introduced into a reaction with silver nitrate, copper acetate, and iron chloride in order to form solid complexes.^121,122

· A surfactant-dye binding method was used to determine the levels of FA and SF in tablets, ointments, and creams. The analysis was based on varying the concentration of the cationic surfactant didodecyldimethylammonium bromide (DDABr) while binding with the anionic dye. G Coomassie Brilliant Blue (CBBG), which results in DDABr-CBBG, which was determined by changes in the dye's spectral properties.^123,124 The degree of surfactant-dye binding is reduced by addition of these antibiotics to aqueous mixtures containing DDABr-CBBG complex, which promotes the formation of DDABr–drug aggregates.⁹ Thus, the surfactant to dye binding degree (SDBD) method provides significant advantages over traditional methods which are used for quality control of both drugs, exhibiting higher sensitivity, selectivity, accuracy, rapidity, and cost reduction.^125,126

· High-Performance Liquid Chromatography (HPLC) was used to confirm FA's physical and chemical stability. In this study, samples of FA in intravenous infusions with erythromycin and methylprednisolone were frozen and thawed using a microwave for 12 months. ¹²⁷ No significant loss in any of the samples, indicating that the three drugs are stable under these conditions of analysis.^128,129,9 Researchers used a reversed-phase mode with UV detection in HPLC methods because it provided the best reliability and reproducibility, as well as shorter analysis times.¹³⁰

· In order to investigate the physical and chemical properties of FA, other analytical methods were used. In 1962, the first elemental analysis was performed to characterise the chemical structure of FA and the location of its functional groups, as well as to identify a large number of them.^130,131 Polymorphs were characterised using differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), intrinsic dissolution rate (IDR), X-ray diffraction (XRD), and polarising hot-stage microscopy (HSM). This study can be used to identify and characterise two unknown FA polymorphic compounds.^132,133,134

· Separation of FA from serum in combination with other antibiotics has also been described, as has electrophoretic separation followed by a microbiological assay. Some papers use agar diffusion assays to determine the potency of FA.^135,136

· Physico-chemical methods are widely used in the pharmaceutical industry as they are highly accurate and are suitable for determining impurities as well as degradation of products.^137,138 This method may be incapable of indicating the true biological activity of antibacterial.¹³⁹ When the results of microbiological assays are compared to those of physicochemical methods different results are frequently obtained. As a result, the microbiological assay is required and indispensable for determining antibiotic potency in manufacturing processes and quality control.¹⁴⁰

CONCLUSION:

FA is a steroidal compound which have been used in clinical practice for treatment of infections caused by gram positive microorganism particularly against MRSA strain, which is due to the fact that the drug has low toxicity and has no cross-resistance with other antibiotics. FA is used in the treatment of SSTs and also in management of psoriasis by tackling bacterial cause of disease. The HPLC has been widely used for analysis of FA among various analytical methods in biological and pharmaceutical matrices. The efficacy of FA in systemic, topical, combination have been studied which also indicate that the fusidic acid-steroid combination has high clinical and bacteriological efficacy.

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Received on 08.04.2022 Modified on 07.06.2022

Asian J. Research Chem. 2022; 15(5):372-380.

DOI: 10.52711/0974-4150.2022.00066

Fusidic acid				Comparator				Reference
Dose	N = points treated	TD (days)	Response rate	Dose	n=pts treated	TD (days)	Response rate
250mg BID 500mg BID	N =181	5 10	93.2% 91% (5) 94.5% (10)	Flucloxacillin 500 mg TID	178	5 10	90.8% 92.6%	89
500mg/d 1g/d	N =90	9	92% 99%	Pristinamycin 2 g/d	93	9	96%	90
250 mg BID	N =94	5 or 10	86.6%	Ciprofloxacin 250 mg BID	92	5 or 10	91.5%	91
250 mg BID	N =240	5 or 10	75.8%	Flucloxacillin 250 mg QDS	233	5(39% of pts) 10(61% of pts)	81.1%	90
250 mg BID	N =255	5 or 10	85.3%	Erythromycin 1g BID	229	5 or 10	87.3%	92
500 mg BID	N =158	7	79.7%	Pristinamycin 1g BID	155	10	76.1%	93

Fusidic acid combination N		Comparator N		Treatment duration (days)	Result	Reference
Fusidic acid 2%/and hydrocortisone 1% cream (F)	9	Miconazole 2%/ hydrocortisone 1% cream (M) n = 102	102	7	Response rates: F 69.5%, M 68.6% Faster healing with F (p = 0.04) Bacteriological efficacy: F 97.9%, M 83.0% (p = 0.04)	114
Fusidic acid 2%/ and betamethasone 0.1% cream (F)	45	Neomycin - 0.5% betamethasone - 0.1% cream (N) n = 46	46	14	Response rates: F 95%, N 90% Bacteriological efficacy: F 91%, N 88%	113
Fusidic acid 2% and betamethasone 0.1% cream (F)	27	Neomycin - 0.5%/ betamethasone - 0.1% cream (N) n = 32	32	7-10	Response rates: F 85%, N 81% Bacteriological efficacy: F 78%, N 72%	22
Fusidic acid 2% and betamethasone valerate 0.1% cream	50	Gentamicin - 0.1%/ betamethasone valerate - 0.1% cream (G), n = 49	49	7-12	Response rates: F 98%, G 90% Bacteriological efficacy: F 86%, G 86%	113,115
Fusidic acid 2% and betamethasone 0.1% cream	58	Clioquinol - 3%/ betamethasone - 0.1% cream (C) n = 62	62	Up to 28	Response rates: F 57.9%, C 60.4% Patients finding cosmetic acceptability good: F 90.6%, C 29.6% Bacteriological efficacy: F 92.3%, C 55.2% (p < 0.005)	116
Fusidic acid 2% and betamethasone 0.1% cream and Fusidic acid 2%/ betamethasone 0.1% lipid cream	275 258	Lipid cream vehicle n = 88	88	14	Response rate: cream 84.0%, lipid cream, 83.5%, vehicle NR Bacteriological efficacy: Cream 89.6%, lipid cream 89.7%, vehicle 25.0%	22,113