MRSA carrier decolonization.14 The proportion of resistance of the community-acquired MRSA (Ca-MRSA) is also increasing. In the USA, mupirocin resistance as high as 30% has been reported in children with SSTIs.14 A retrospective study looked at 358 S. aureus isolates from 249 children in an outpatient setting in New York City between May 2012 and September 2013.14 The study demonstrated that 19.3% of patients had mupirocinresistant S. aureus isolates at the time of their first culture and that 22.1% of patients with S. aureus infection had a mupirocinresistant isolate at some time during the study period. Of all S. aureus isolates collected during the study period, 31.3% were resistant to mupirocin.14 The study further revealed that prior mupirocin usage was strongly correlated (P<0.001) with mupirocin resistance. Of the MRSA isolates, 67.7% stemmed from atopic patients, from which 68% were mupirocin resistant versus 28% resistance in non-atopic patients.14
In Greece, the emergence of a new community-associated methicillin-susceptible Staphylococcus aureus (MSSA) clone has led to an alarming increase in the resistance rate to mupirocin, with a 7-fold increase in 3 years, being 4.2% in 2013 and 37.7% in 2016. For the same clone, an increase in resistance to fusidic acid from 26.8% to 51.9% has been reported.15 The prevalence of mupirocin resistance in different countries varied; in South Korea, the overall percentage of MSSA and MRSA resistance to mupirocin was 13.6%, in the USA, 1.2 % in the community, 12.2% in nursing homes, 11%, and in the UK 0.8%, respectively.32 In countries where a restriction on OTC use of topical antibiotics has been implemented, the percentages of mupirocin resistance decreased, for instance, New Zeeland from 28% (2006) to 11% (2014) and Australia from 18% to 0.3% in the same period.32
Resistance to Retapamulin
Retapamulin is a derivative of pleuromutilin, a component of a mushroom called Clitopilus scyphoides, which selectively binds the 50S bacterial ribosomal subunit and inhibits protein synthesis.33 Despite that in the prescribing information of retapamulin 1% ointment, the product is indicated for methicillinsusceptible S. aureus only, in the USA (2013), out of 155 MRSA isolates, only 2.6% were resistant to retapamulin.33 However, in 2014, decreased susceptibilities to retapamulin, mupirocin, and chlorhexidine among Staphylococcus aureus isolates, causing skin and soft tissue infections in otherwise healthy children, were reported.34 Of 200 S. aureus isolates from pediatric patients in Houston, TX from otherwise healthy children with S. aureus SSTI, such as impetigo, furunculosis, abscess, pustulosis, and cellulitis, 9.5% of isolates were resistant to retapamulin, and 9.8% resistance to mupirocin was observed.34
Resistance to Fusidic Acid
In the E.U., some impetigo outbreaks due to fusidic acidresistant clones of S. aureus have been reported. Compared to other topical antibiotic agents, fusidic acid retains its high concentration at deeper layers of the skin. Resistance to fusidic acid has been reported in various countries. In Taiwan, the resistance of MRSA isolates to fusidic acid increased from 3.2% in 2002 to 18.1% in 2012.35
In 2017, 32.1% of MRSA isolates were shown to be resistant to fusidic acid in Egypt,36 and in 2018 a Danish study of atopic dermatitis patients showed resistance of S. aureus colonization to fusidic acid as high as 41.0%.13 Further studies within Sweden demonstrated that in 2010, 33% of S. aureus isolates were resistant to fusidic acid in impetigo and 12% in secondarily infected A.D.14 In a case-control study conducted in the U.K., fusidic acid resistance was shown to be significantly associated with A.D., and bacterial isolates showed three acquired resistance genes: fusA, fusB, and fusC2.32
Topical Hydrogen Peroxide
A rationale for the use of topical hydrogen peroxide is to limit the usage of antibiotics. A 2012 Cochrane review showed no superiority of fusidic acid but a lack of evidence for antiseptic use in impetigo.37 However, the UK-based National Institute for Health and Care Excellence (NICE) guidelines suggest it is a valid option in some instances.38
Ozenoxacin
Before the introduction of ozenoxacin in December 2017, the last approved topical antibiotic for impetigo was retapamulin (April 2007).10,39 Ozenoxacin (Xepi in the U.S. and Ozanex or Dubine in other countries) is a non-fluorinated quinolone antibiotic that is active on susceptible and resistant strains of S. aureus and S. pyogenes, causal agents of the majority of SSTIs.40-43 Ozenoxacin cream 1% was developed for the first-line treatment of impetigo in patients aged two months and older and has been studied in seventeen clinical trials up to date.19,40,44-47 Fifteen studies in phase 1 and 2 have been conducted, and two pivotal phase 3 studies in both adult and pediatric patients with impetigo have been completed.44-46 In these studies, twice daily ozenoxacin treatment for five days demonstrated superior clinical and bacteriologic outcomes versus matching vehicle control.19,44-47
The high activity on MRSA and other resistant strains is an important point that favors ozenoxacin.10,40-47 Since its introduction, there is no data on bacterial resistance.10,39,42,43
Antibiotic resistance in S. aureus poses a rapidly increasing global problem.48 Antimicrobial stewardship is critical to optimize patient outcomes and to prevent the development of resistance.10
In Greece, the emergence of a new community-associated methicillin-susceptible Staphylococcus aureus (MSSA) clone has led to an alarming increase in the resistance rate to mupirocin, with a 7-fold increase in 3 years, being 4.2% in 2013 and 37.7% in 2016. For the same clone, an increase in resistance to fusidic acid from 26.8% to 51.9% has been reported.15 The prevalence of mupirocin resistance in different countries varied; in South Korea, the overall percentage of MSSA and MRSA resistance to mupirocin was 13.6%, in the USA, 1.2 % in the community, 12.2% in nursing homes, 11%, and in the UK 0.8%, respectively.32 In countries where a restriction on OTC use of topical antibiotics has been implemented, the percentages of mupirocin resistance decreased, for instance, New Zeeland from 28% (2006) to 11% (2014) and Australia from 18% to 0.3% in the same period.32
Resistance to Retapamulin
Retapamulin is a derivative of pleuromutilin, a component of a mushroom called Clitopilus scyphoides, which selectively binds the 50S bacterial ribosomal subunit and inhibits protein synthesis.33 Despite that in the prescribing information of retapamulin 1% ointment, the product is indicated for methicillinsusceptible S. aureus only, in the USA (2013), out of 155 MRSA isolates, only 2.6% were resistant to retapamulin.33 However, in 2014, decreased susceptibilities to retapamulin, mupirocin, and chlorhexidine among Staphylococcus aureus isolates, causing skin and soft tissue infections in otherwise healthy children, were reported.34 Of 200 S. aureus isolates from pediatric patients in Houston, TX from otherwise healthy children with S. aureus SSTI, such as impetigo, furunculosis, abscess, pustulosis, and cellulitis, 9.5% of isolates were resistant to retapamulin, and 9.8% resistance to mupirocin was observed.34
Resistance to Fusidic Acid
In the E.U., some impetigo outbreaks due to fusidic acidresistant clones of S. aureus have been reported. Compared to other topical antibiotic agents, fusidic acid retains its high concentration at deeper layers of the skin. Resistance to fusidic acid has been reported in various countries. In Taiwan, the resistance of MRSA isolates to fusidic acid increased from 3.2% in 2002 to 18.1% in 2012.35
In 2017, 32.1% of MRSA isolates were shown to be resistant to fusidic acid in Egypt,36 and in 2018 a Danish study of atopic dermatitis patients showed resistance of S. aureus colonization to fusidic acid as high as 41.0%.13 Further studies within Sweden demonstrated that in 2010, 33% of S. aureus isolates were resistant to fusidic acid in impetigo and 12% in secondarily infected A.D.14 In a case-control study conducted in the U.K., fusidic acid resistance was shown to be significantly associated with A.D., and bacterial isolates showed three acquired resistance genes: fusA, fusB, and fusC2.32
Topical Hydrogen Peroxide
A rationale for the use of topical hydrogen peroxide is to limit the usage of antibiotics. A 2012 Cochrane review showed no superiority of fusidic acid but a lack of evidence for antiseptic use in impetigo.37 However, the UK-based National Institute for Health and Care Excellence (NICE) guidelines suggest it is a valid option in some instances.38
Ozenoxacin
Before the introduction of ozenoxacin in December 2017, the last approved topical antibiotic for impetigo was retapamulin (April 2007).10,39 Ozenoxacin (Xepi in the U.S. and Ozanex or Dubine in other countries) is a non-fluorinated quinolone antibiotic that is active on susceptible and resistant strains of S. aureus and S. pyogenes, causal agents of the majority of SSTIs.40-43 Ozenoxacin cream 1% was developed for the first-line treatment of impetigo in patients aged two months and older and has been studied in seventeen clinical trials up to date.19,40,44-47 Fifteen studies in phase 1 and 2 have been conducted, and two pivotal phase 3 studies in both adult and pediatric patients with impetigo have been completed.44-46 In these studies, twice daily ozenoxacin treatment for five days demonstrated superior clinical and bacteriologic outcomes versus matching vehicle control.19,44-47
The high activity on MRSA and other resistant strains is an important point that favors ozenoxacin.10,40-47 Since its introduction, there is no data on bacterial resistance.10,39,42,43
Antibiotic resistance in S. aureus poses a rapidly increasing global problem.48 Antimicrobial stewardship is critical to optimize patient outcomes and to prevent the development of resistance.10
LIMITATIONS
Due to COVID-19, the review process of the algorithm and the
