Role of topical nadifloxacin as an empirical treatment in patients with skin and soft-tissue infections in India: A review and consensus

Statement 1: Prevalence of SSTIs in India range from 17% to 25%

In India, only few studies have been done in a limited population. As per Abhilash and Varghese (2019), the incidence rate of SSTI in a tertiary care hospital in South India was 18.21/1000.^[9] In another study in Northern India, among 6–14-year-old school children, the prevalence of skin infections was 11.4%, among whom 64.4% had pyodermas, 25.4% fungal infections, 9.7% viral infections, and 0.4% had mycobacterial infections.^[19] Vasani and Medhekar reported that among superficial bacterial skin infections, furuncle was most common (59.70%), followed by folliculitis (4.4%).^[8] Similar findings were reported in other studies which revealed that furunculosis was the most common type of pyoderma (51%), followed by impetigo (21%), folliculitis (19%), sycosis barbae (5%), carbuncle (3%), and ecthyma (1%).^[20]

Statement 2: The most common microorganism causing SSTIs is S. aureus

Bacteria that colonize the skin can be broadly divided into two groups: Resident flora and transient flora. Resident flora includes Staphylococcus spp. such as Staphylococcus epidermidis, Staphylococcus saccharolyticus, Staphylococcus saprophyticus, and Staphylococcus anginosus; Streptococcus spp. such as Streptococcus mitis and Streptococcus mutans; and Propionibacterium granulosum, Propionibacterium acnes, etc. Whereas, the transient flora includes Gram-positive species such as S. aureus, Staphylococcus warneri, Streptococcus pyogenes, and Corynebacterium minutissimum, and Gram-negative species such as Escherichia coli, Proteus mirabilis, and Pseudomonas aeruginosa.^[1] SSTIs are largely caused by Staphylococcus spp. which form purulent lesions (e.g., abscesses), whereas, lesions caused by S. pyogenes are non-purulent (e.g., cellulitis and erysipelas).^[5]

Microbiology of pus cultures from SSTI lesions in Indian patients showed that the most common organisms were S. aureus, followed by E. coli, Streptococcus spp., Pseudomonas spp. and Coagulase negative staphylococci (CNS).^[9,21-26] [Table 2] shows the common isolates from SSTIs across India.

Statement 3: MRSA is now becoming a common cause of SSTIs in India with a prevalence ranging from 7.5% to 59%

Studies across India have reported prevalence of MRSA to be ranging from 7.5% to as high as 90.77% in isolates from SSTIs.^{[21-23,27-29]} MRSA infections are difficult to treat, as some strains produce biofilms.^[30] In fact, few studies have found the prevalence of biofilm-producing MRSA to be as high as 78.8%.^[31] These wide variations could be attributed to the differences in risk factors, infection control practices, prescription practices of antibiotics and antibiotic stewardship programs.

Statement 4: Risk factors for SSTIs include presence of systemic co-morbidities, malnutrition, vascular insufficiency, trauma, fungal infections, old age, obesity, drug abuse, poor skin hygiene

The presence of systemic comorbidities such as diabetes mellitus, peripheral vascular disease, malnutrition, HIV, and immunosuppression, may increase the risk of developing SSTIs.^[1] Local risk factors include anatomical alterations, fungal infections, infected wounds, inflammatory dermatoses, poor skin hygiene, pressure sores, repeated trauma, and vascular. Environmental risk factors include animal/human bite, close contact with infected person, invasive medical procedures, intravenous, or subcutaneous drug abuse.^[1,3] In developing countries like India, other aspects such as low socioeconomic status, malnutrition, overcrowding, and poor hygienic conditions, may predispose the individuals for the development of SSTIs.^[8,19] Hence, the experts recommended that meticulous assessment of pre-treatment risk factors is essential while treating patients presenting with SSTIs.

Statement 5: SSTIs are more common in upper (25.2%) and lower extremities (23.7%)

SSTIs are found to affect all parts of the body, especially the limbs. Stahlman et al. (2017) reported that the upper extremity was most frequently affected (25.2%), especially the arm (50.6%) and finger (40.1%). Lower extremities were affected in 23.7% of the cases.^[32] This is in contrast to a study done by Abhilash and Varghese (2019), who reported that lower limb (75.07%) was the most common site, followed by gluteal/perianal/genital regions (8.50%); trunk (7.08%); upper limb (4.82%); and head and neck regions (4.53%).^[9] Various other studies reported the most common site to be the lower extremities^[20,33] and face.^[34]

Statement 6: In cases where superficial SSTIs are associated with co-morbid conditions, we need to treat them as moderate SSTIs

The Infectious Disease Society of America (IDSA) 2014 has classified SSTIs based on the degree of severity into three categories. Mild infections are those with superficial involvement. Moderate Class A includes erysipelas, cellulitis, purulent skin and soft infections and traumatic wounds, whereas moderate Class B additionally includes systemically unwell patients. Severe category involves sepsis, life threatening, and necrotizing infections.^[35] Patients with systemic co-morbidities need special treatment as such conditions may impact the progression and the course of SSTIs. The presence of fever, hypotension, tachycardia, site of lesion, and altered mental status represent systemic toxicity.^[2]

Statement 7: Mild SSTIs are mostly treated by topical antimicrobials, whereas moderate and severe SSTIs require both systemic and topical antimicrobial agents

Topical antimicrobials render several advantages over systemic agents such as availability of high local drug concentration, less systemic absorption and toxicity, reduced risk of development of antibiotic resistance, and higher likelihood of compliance.^[36,37] They may also be used to hasten the healing process, minimize the spread of infection and to prevent re-infection.^[8] Evidence supports the use of topical antibiotics for infected ischemic wounds and burn wounds which have no vascular supply, in persistent wounds for removal of biofilms and to eradicate multidrug resistant organisms.^[38]

Superficial uncomplicated SSTIs (impetigo, localized infected eczemas, and acne vulgaris), staphylococcal nasal carriage and post-operative surgical wounds^[39] can be managed with topical antibiotic agents, heat packs or incision and drainage.^[1] Whereas, systemic antibiotic therapy is required if the lesions are deep (furunculosis and carbunculosis) or generalized, with involvement of regional lymph nodes, and presence of systemic toxicity.^[8,40]

According to the guidelines developed by IDSA, for diabetic foot infections, the use of topical antibiotics is recommended in mildly infected open wounds and superficial SSTIs such as venous stasis ulcers, low-grade pressure ulcers, abrasions, limited surgical wounds, inflammatory skin disorders (e.g., eczema), or limited thermal burns.^[35] Thus, experts proposed the use of topical agents either as primary therapy for superficial mild infections or as supportive therapy to systemic antibiotics for moderate or severe infections. [Figure 1] shows the management of SSTIs based on the degree of severity of disease.^[8,35,41]

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Figure 1:

Management of SSTIs based on the degree of severity of disease. I and D: Incision and Drainage, MRSA: Methicillin resistant Staphylococcus aureus, MSSA: Methicillin sensitive Staphylococcus aureus, TMP/SMX: Trimethoprim/Sulfamethoxazole, UTI: Urinary tract infections.

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Statement 8: Mupirocin resistance is increasing in India

Mupirocin is regularly prescribed in the prevention and treatment of SSTIs caused by S. aureus.^[42] In India, Mupirocin alone and in combination with topical corticosteroids is approved for treating atopic and inflammatory dermatitis with secondary bacterial infections.^[17] However, there has been emergence of antimicrobial resistance to Mupirocin in many parts of the world due to its increased usage.^[15,37,43] Low level Mupirocin resistance results from a point mutation in the native isoleucyl RNA synthetase gene, IleRS and high-level Mupirocin resistance is mediated by the mupA (ileS-2) gene.^[44] Various studies have also reported the increasing Mupirocin resistance in India^[10-14] [Table 3].

Fusidic acid is another commonly used topical agent for skin infections. In India, Fusidic acid is approved as eye drops for treating bacterial infections but there is no regulatory approval in the public domain for its usage in treating skin infections. Although its combination with corticosteroids is approved in treating dermatoses with secondary infection; and in acute and chronic infected eczematous dermatitis.^[17] Increase in antimicrobial resistance of Fusidic acid has also been noted due to its increased utilization ranging from 0.4% to 57%.^[37] In India, Nagarajan et al. (2012) isolated S. aureus strains from skin infections and found that 3.7% of total isolates were Fusidic acid resistant S. aureus and harbored the fusC gene.^[28]

Nadifloxacin is a broad-spectrum antibiotic, which has been approved in India as an anti-acne agent and in treating superficial localized bacterial skin infections. A combination of Nadifloxacin and corticosteroids is approved in bacterial infections of the skin including contact dermatitis, seborrheic dermatitis, infective eczema, and mixed infections of the skin.^[17] Studies on Nadifloxacin have shown no increase in resistance to P. acnes, Methicillin Sensitive S. aureus (MSSA), MRSA, and S. epidermidis.^[45-49] This is due to its unique dual mechanism of action. Figure 2 shows the mechanism of action of Nadifloxacin.^[50-52]

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Figure 2:

Mechanism of action of Nadifloxacin. NF: Nadifloxacin, IL: Interleukin, TNF: Tumor necrosis factor.

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Statement 9: Efficacy of Nadifloxacin is equivalent to Mupirocin and Fusidic acid. Safety is also well established

Although there are meager studies comparing the efficacy of Nadifloxacin with other antimicrobials such as Mupirocin and Fusidic acid, they have shown promising results ^[6,8,53-55] [Table 4a]. It was equally efficacious and as safe as Mupirocin and Fusidic acid in the treatment of SSTI in the Indian population. Few of the experts suggested that topical Nadifloxacin could be used as an effective, low-cost option in treating bacterial nail infections.

Safety of Nadifloxacin is also well documented. Muto et al. (1990) reported that the peak plasma concentration was only 1.6 ng/ml, 8 h after percutaneous application of 10 g of Nadifloxacin 1% cream, in healthy volunteers, indicating extremely low systemic absorption.^[56] There have been no reports on the occurrence of allergic contact dermatitis to Nadifloxacin. Only one case report of contact dermatitis was reported in a patient who used lysozyme chloride ointment, 1% Nadifloxacin cream, 1% sulfadiazine silver cream, and 0.25% tretinoin tocoferil ointment, for the treatment of livido reticularis. He was diagnosed with allergic contact dermatitis due to methylparaben and propylparaben present in lysozyme chloride ointment and not due to Nadifloxacin cream.^[57]

Statement 10: Nadifloxacin MIC is least as compared to other topical antimicrobials

Nadifloxacin is effective against Gram positive, Gram negative, and anaerobic bacteria, including MRSA and MSSA^[53,54] [Figure 3]. When the effectiveness of Nadifloxacin, Erythromycin, Clindamycin, and Tetracycline against P. acnes and CNS isolates from inflammatory lesions were compared, the MIC for Nadifloxacin was ≤1 μg/mL and resistance was shown at MIC level ≥4 μg/mL.^[58] Compared to Ciprofloxacin, Erythromycin, and Clindamycin, Nadifloxacin demonstrated better activity against P. acnes as the MIC50 and MIC90 values were lesser compared to those of other antimicrobials.^[45] Biswal et al. (2016) demonstrated that the MIC50 and MIC90 values for Nadifloxacin (0.25 and 1μg/ mL) were lower than those for Ciprofloxacin (0.5 and 1μg/ mL).^[59] Nishijima et al. (1996) reported that Nadifloxacin did not induce cross-resistance to other fluoroquinolones, but suggested cross-resistance among the fluoroquinolone group as a whole.^[48] Hence, there is a need to watch for the development of cross-resistance to other organisms with the use of Nadifloxacin, such as in systemic antibiotic therapy.

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Figure 3:

Spectrum of activity of Topical Nadifloxacin.

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Statement 11: Nadifloxacin is beneficial in managing MRSA infections

Several studies have demonstrated the efficacy of Nadifloxacin against MRSA. Nishijima et al. compared the in vitro susceptibility of MRSA and MSSA isolates from skin infections to other fluoroquinolones from 1991 to 1994. Nadifloxacin exhibited the lowest MIC for both MSSA and MRSA (0.012–1.56 μg/ml). There were also no resistant S. aureus, neither MSSA and MRSA, to Nadifloxacin, whereas other fluoroquinolones developed resistance quickly during the study period.^[46,48] The effects of Nadifloxacin cream on atopic dermatitis (AD) with MRSA was assessed by Kimata (1999) in 35 young children (<1-syear-old). After 4 weeks, MRSA was eradicated in all patients, and AD was significantly improved in the Nadifloxacin group.^[60]

Most of the other antimicrobials do not effectively treat intracellular infections due to poor penetration and reduced action in intracellular acidic environment. A formulation of polyhexamethylene biguanide and Nadifloxacin could kill intracellular MRSA in keratinocytes, prevent bacterial re-growth, and also helped in the recovery of infected keratinocytes.^[51,61] Thus, Nadifloxacin can be used not only against planktonic MRSA, but is also effective against intracellular MRSA.

Statement 12: Combination of Nadifloxacin and Adapalene has shown promising results in the management of acne vulgaris

The efficacy and safety of Nadifloxacin as an anti-acne agent, has already been proved through various in vitro and clinical studies^[50,62-69] [Table 4b]. Combination of Nadifloxacin and Adapalene was approved in India for the topical treatment of acne vulgaris in 2006.^[17] This combination has shown superior efficacy compared to Nadifloxacin used alone.^[70] Moreover, it also minimizes the emergence of antibiotic-resistant bacterial strains.^[71] Thus, experts suggested that such a combination therapy could be a useful means by which further resistance development towards Nadifloxacin can be avoided along with better clinical efficacy.

Statement 13: Nadifloxacin has a unique property of penetrating the biofilm and henceforth less resistance has developed over the years

Biofilms are the main cause for the persistence of chronic skin infections. Due to their presence, the susceptibility of the microorganisms to antimicrobials and immune defenses is decreased.^[72] They need higher drug concentration to be inhibited.^[73] Sharma and Gupta (2016) reported that among the S. aureus and CNS isolates from pus samples of patients with SSTIs, 32.03% were biofilm producers, MRSA (54.83%) showing higher biofilm production than MR CNS (38.46%).^[26] Biofilms may result in dispersal of bacterial cells leading to the spread of infection to secondary sites.^[72] Topical agents such as Mupirocin and Fusidic acid were less effective in removing biofilms compared to Povidone iodine;^[74] Gentamicin;^[75] Ceftarolin, Daptomycin, Fosfomycin, Ofloxacin, Rifampicin, and Vancomycin.^[76] A study demonstrated that sub-inhibitory concentrations of Mupirocin promoted biofilm formation of S. aureus, in particular the MRSA USA300 clone. However, the antibiofilm effect of Mupirocin was seen at the higher concentrations (near or above MIC).^[77] Thus, experts suggested that the correct use of this drug should be done at optimal concentration.

Nadifloxacin effectively penetrate biofilms and displays improved bactericidal activity under low pH biofilm environments.^[78] Tellis et al. (2019) demonstrated that Levonadifloxacin showed ≥90% bacterial kill rate against biofilm-embedded organisms, while vancomycin and linezolid displayed inconsistent activity. This might be attributed to its lipophilic nature, which aids in permeation of the drug in biofilm polymer matrices.^[79]