¹Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
²Division of Dermatology, St. Paul’s Hospital, Vancouver, BC, Canada

Conflicts of interest:
None Reported.

ABSTRACT
Dermatologists have within their armamentarium numerous immunosuppressant agents, both traditional and new, that are useful in the treatment of chronic cutaneous disorders such as autoimmune bullous diseases and psoriasis. It is imperative that users of these agents are aware of potential sequelae from therapy, particularly infections. In this review, we summarize the most common immunosuppressant medications currently used in dermatology, and provide recommendations for infection screening prior to initiating treatment.

Key Words:
immunosuppression, infection, TNF-α inhibitors, IL-12/23 inhibitors, IL-17 inhibitors, clinical protocol, drug therapy, skin diseases

Introduction

Psoriasis, connective tissue diseases, and autoimmune bullous diseases such as bullous pemphigoid and pemphigus are but a few examples of the dermatological indications for which immunomodulatory/immunosuppressive therapy may be indicated. Treating patients with these inflammatory cutaneous diseases often involves one or more immunosuppressive agents, either sequentially or in combination, which increases the risk of infection-related morbidity and mortality. One of the main safety concerns for the dermatologist prior to initiating therapy is the risk of infection. Risk factors for infection include age, medical comorbidities, travel history, location of residence, occupation, as well as the type, duration and extent of immunosuppression. Although pretreatment infection-testing guidelines exist for the disciplines of gastroenterology, hepatology, rheumatology, and transplant medicine, no specific guidelines have been developed for the dermatologist wishing to begin immunosuppressive therapy. This discussion is timely and of interest within the dermatology literature, as multiple publications have emerged within the last 5 years.^1-3 The dermatologist has a therapeutic armamentarium of immunosuppressive drugs including traditional therapies such as systemic corticosteroids, methotrexate, cyclosporine, azathioprine, mycophenolate mofetil as well as novel therapeutics known as biologics. Within the last decade or so there has been an emergence of novel biologic therapeutics including inhibitors of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, CD20, p40 subunit of IL-12/23, and more recently IL-17. Herein, we discuss the current pre-treatment infection guidelines for the dermatologist prior to beginning immunosuppressive therapy.

Non-biologic immunosuppressive therapy

The non-biologic immunosuppressive therapies that will be discussed are corticosteroids, methotrexate, azathioprine, cyclosporine and mycophenolate mofetil (Table 1). Since their introduction in the 1950s, corticosteroids have revolutionized the management of inflammatory diseases.⁴ Corticosteroids are among the oldest immunosuppressants; their mechanism of action is through inhibition of gene transcription and downregulation of secreted inflammatory cytokines.^5,6 The risk of infection with corticosteroid use depends upon the patient’s underlying disease state, duration, dose and route of administration.⁷ A lower dose of corticosteroids as well as a shorter duration are associated with a reduction in infectious complications.⁸ Corticosteroid use in combination with other immunosuppressive agents, such as methotrexate or azathioprine, increases the risk of serious infections as evidenced in inflammatory bowel disease and rheumatoid arthritis.⁹ However, given the short half-life of systemic corticosteroids (e.g., prednisone plasma half-life is 60 minutes, prednisolone plasma half-life is 115-212 minutes), it is reasonable to start these medications, if needed, while awaiting infection screening results.

Azathioprine and its derivative 6-mercatopurine are structurally similar to the endogenous purines adenine and guanine. The exact mechanism of action of this immunosuppressive agent is unknown, however it is thought that the structural similarity to endogenous purines allows it to be incorporated into DNA and RNA with subsequent inhibition of purine metabolism and cell division. Azathioprine use is associated with increased bacterial, fungal and viral infections.¹⁰ Prior to initiating azathioprine, the dermatologist should ascertain whether the patient has been immunized or previously infected with varicella zoster virus and if not, immunization prior to commencing immunosuppression should be recommended.¹⁰ Furthermore, azathioprine in combination with prednisolone is associated with an increased risk of infection which can be fatal in the elderly.¹¹

Methotrexate is a potent competitive inhibitor of dihydrofolate reductase and a partially reversible inhibitor of thymidylate synthetase, which ultimately acts by inhibiting purine synthesis. However, the definitive mechanism of action of methotrexate is, to date, incompletely understood, as novel modes of action continue to be published; most recently its role as a Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway inhibitor has been described.¹² In patients receiving long-term treatment with methotrexate, hepatotoxicity is an important consideration and patients should be screened for hepatitis B and C infection prior to initiating treatment. In addition, untreated chronic tuberculosis and active tuberculosis infections are contraindications to treating with methotrexate.

Cyclosporine is postulated to act by inhibition of the intracellular enzyme calcineurin, resulting in reduced activity of the transcription factor nuclear factor of activated T-cells (NFAT-1). With decreased NFAT-1 activity, the transcription of a number of downstream cytokine genes, most notably IL-2, are suppressed. Furthermore, impaired production of IL-2 leads to a decline in the number of activated T-cells within the epidermis. Thus, cyclosporine results in decreased functional T-cell mediated immunity, leading to increased susceptibility to cytosolic microorganisms, including atypical Mycobacterium, and viruses.^13,14

Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid that inhibits inosine monophosphate dehydrogenase (IMPDH). Inhibition of this critical enzyme, IMPDH, subsequently deprives T- and B-cells of purine metabolites necessary for growth and replication. The net effect is selective immunosuppression. MMF is associated with an increased risk of infection especially when doses in excess of 2 g daily are used.^15,16 Serious infections are most common in renal and cardiac (2%) and hepatic (5%) transplant patients at doses of 2-3 g daily. Viral (herpes zoster, herpes simplex), bacterial, atypical mycobacterial and fungal infections have been reported in the literature.^17-20

Biologic Immunosuppressive Therapy

The biologics account for a relatively novel class of medications refered to as specialty drugs or specialty pharmaceuticals.²¹ Biologics are derived from living cells and are administered by injection, infusion or oral route, and are used to treat a variety of rare conditions. Biologic immunosuppressive therapies include TNF-α inhibitors (infliximab, adalimumab, etanercept), IL-12/23 inhibitors (ustekinumab), CD20 inhibitors (rituximab) and most recently the IL-17 pathway inhibitors (secukinumab, ixekizumab, brodalumab) (Table 2). Given the relative success of TNF-α inhibitors and ustekinumab in the treatment of psoriasis, there has been an emergence of biologics targeting various other cytokines. Inhibitors of IL-17 are the latest wave of therapeutics developed for the treatment of psoriasis and psoriatic arthritis, which deplete the Th17 population of T-cells. Other types of IL-17 inhibitors are currently in various phases of clinical trials for psoriasis and psoriatic arthritis.²² The clinical trials for these agents are currently ongoing and data pertaining to incidence and type of infections have not yet been published.

Rituximab, a biologic that targets the B-cell surface antigen CD20, can be used in several dermatologic conditions including pemphigus vulgaris. Rituximab became the first monoclonal antibody approved by the US FDA for the treatment of cancer. Since rituximab depletes CD20+ B-cells, it should not be administered to patients with active infections. Live vaccines should not be given to patients taking rituximab, and recombinant or killed vaccines should be given at least 4 weeks prior to initiating treatment. Patients should undergo screening for active and latent infections. Rituximab has been associated in particular with reactivation of hepatitis B virus (HBV).²³ The time from last rituximab dose to reactivation of HBV was 3 months, although 29% occurred >6 months after last rituximab. Patients with previous exposure to HBV should be screened prior to initiating rituximab. Carriers should be closely monitored for clinical and laboratory signs of infection as reactivation may lead to liver failure and death in the months following therapy. There is an argument for the consideration of prophylactic treatment in selected patients.²⁴ Reactivation of the JC virus (a type of human polyomavirus), leading to progressive multifocal leukoencephalopathy (PML) has also been associated with rituximab treatment.²⁵ Among human immunodeficiency virus (HIV)-negative patients, the median time to diagnosis of PML was 5.5 months following the last dose of rituximab and a 90% fatality was reported. These data warrant vigilant monitoring for new onset neurologic findings during and after the course of treatment.

Pretreatment Infection Workup

Recent publications within the dermatology literature have provided recommendations for an infection workup for the dermatologist prior to initiating immunosuppressive agents.^2,3 In general, the suggested steps apply to all immunosuppressants, whether non-biologic or biologic. Table 3 provides a summary of these and our recommendations.

Although the morbidity and mortality from infectious complications can be significant, careful patient selection and monitoring can mitigate risk and reduce potential harm. General recommendations include conducting a thorough history and physical exam, with particular focus on country of birth and residence, travel history, sexual and social risk factors and exposure to sick contacts. Vaccination records should be reviewed and, if feasible, age-appropriate vaccinations should be updated prior to initiating immunosuppressive therapy. Patients should be educated on the importance of general hygiene (i.e., handwashing), signs and symptoms of early infection and when they should seek urgent medical care. Likewise, the dermatologist should be vigilant for early signs and symptoms of infection, and have a low threshold to treat bacterial, fungal and viral illness. Physicians should assess patients at each visit for impetiginization and treat appropriately.

All patients should undergo HIV, HBV, and hepatitis C virus (HCV) testing. Furthermore, testing and diagnosis of tuberculosis should be undertaken as per Centers for Disease Control and Prevention (CDC) and Health Canada recommendations and CDC: http://www.cdc.gov/tb/topic/testing/).
Testing for parasitic infections, particularly Strongyloides stercoralis (S. stercoralis) should be considered and done on an individualized basis. Infection with S. stercoralis is usually chronic and asymptomatic in immunocompetent patients and may persist undetected for many years. In immunosuppressed patients, strongyloidiasis can cause hyperinfection and dessimination and carries a high mortality rate. It is reasonable to screen those who have resided in an endemic area for a prolonged period even if it was in the distant past (i.e., southeastern United States and subtropical areas, Europe) and those who possess other risk factors (i.e., occupation, activities). Unexplained hypereosinophilia should also trigger the physician to screen for Strongyloides. Conversely, the physician should be mindful that prolonged corticosteroid use can suppress hypereosinophilia. Stool microscopy for ova and parasites is currently the gold standard for diagnosis, however, up to seven collections may be required in order to reach a sensitivity of 100%.²⁶ A single stool sample collection has a low sensitivity of 30-75%.^27,28 Sensitivity for the enzyme-linked immunosorbent assay (ELISA) for S. stercoralis serology is 83-93% with 95-97% specificity.²⁹

Conclusion

We have provided an overview of some of the major immunosuppressant drugs used in dermatology and have presented a summary of recommendations prior to initiating these medications (Table 3). Regardless of the immunosuppressive agent used, the type of infections that the dermatologist needs to screen for and prevent are similar. Overall, the risk of infection is likely to be directly proportional to the dose and duration of immunosuppressant therapy.

References

1. Keith PJ, Wetter DA, Wilson JW, et al. Evidence-based guidelines for laboratory screening for infectious diseases before initiation of systemic immunosuppressive agents in patients with autoimmune bullous dermatoses. Br J Dermatol. 2014 Dec;171(6):1307-17.
2. Lehman JS, Wetter DA, Davis MD, et al. Anticipating and preventing infection in patients treated with immunosuppressive medications for dermatologic indications: a dermatologist’s checklist. J Am Acad Dermatol. 2014 Oct; 71(4):e125-6.
3. Lehman JS, Murrell DF, Camilleri MJ, et al. Infection and infection prevention in patients treated with immunosuppressive medications for autoimmune bullous disorders. Dermatol Clin. 2011 Oct;29(4):591-8.
4. Hench PS, Kendall EC, Slocumb CH, et al. Effects of cortisone acetate and pituitary ACTH on rheumatoid arthritis, rheumatic fever and certain other conditions. Arch Intern Med (Chic). 1950 Apr;85(4):545-666.
5. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. N Engl J Med. 2005 Oct 20;353(16):1711-23.
6. Buttgereit F, Straub RH, Wehling M, et al. Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action. Arthritis Rheum. 2004 Nov;50(11):3408-17.
7. Cutolo M, Seriolo B, Pizzorni C, et al. Use of glucocorticoids and risk of infections. Autoimmun Rev. 2008 Dec;8(2):153-5.
8. Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking glucocorticosteroids. Rev Infect Dis. 1989 Nov-Dec;11(6):954-63.
9. Stein RB, Hanauer SB. Comparative tolerability of treatments for inflammatory bowel disease. Drug Saf. 2000 Nov;23(5):429-48.
10. Meggitt SJ, Anstey AV, Mohd Mustapa MF, et al. British Association of Dermatologists’ guidelines for the safe and effective prescribing of azathioprine 2011. Br J Dermatol. 2011 Oct;165(4):711-34.
11. Wojnarowska F, Kirtschig G, Highet AS, et al. British Association of Dermatologists. Guidelines for the management of bullous pemphigoid. Br J Dermatol. 2002 Aug;147(2):214-21.
12. Thomas S, Fisher KH, Snowden JA, et al. Methotrexate Is a JAK/STAT Pathway Inhibitor. PLoS One. 2015 Jul 1;10(7):e0130078.
13. Amor KT, Ryan C, Menter A. The use of cyclosporine in dermatology: part I. J Am Acad Dermatol. 2010 Dec;63(6):925-46; quiz 47-8.
14. Ryan C, Amor KT, Menter A. The use of cyclosporine in dermatology: part II. J Am Acad Dermatol. 2010 Dec;63(6):949-72; quiz 73-4.
15. Beissert S, Mimouni D, Kanwar AJ, et al. Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebocontrolled trial. J Invest Dermatol. 2010 Aug;130(8):2041-8.
16. Powell AM, Albert S, Al Fares S, et al. An evaluation of the usefulness of mycophenolate mofetil in pemphigus. Br J Dermatol. 2003 Jul;149(1):138-45.
17. Murray ML, Cohen JB. Mycophenolate mofetil therapy for moderate to severe atopic dermatitis. Clin Exp Dermatol. 2007 Jan;32(1):23-7.
18. Benez A, Fierlbeck G. Successful long-term treatment of severe atopic dermatitis with mycophenolate mofetil. Br J Dermatol. 2001 Mar;144(3):638-9.
19. Rowin J, Amato AA, Deisher N, et al. Mycophenolate mofetil in dermatomyositis: is it safe? Neurology. 2006 Apr 25;66(8):1245-7.
20. Saha M, Black MM, Groves RW. Risk of herpes zoster infection in patients with pemphigus on mycophenolate mofetil. Br J Dermatol. 2008 Nov;159(5):1212-3.
21. Gleason PP, Alexander GC, Starner CI, et al. Health plan utilization and costs of specialty drugs within 4 chronic conditions. J Manag Care Pharm. 2013 Sep;19(7):542-8.
22. Mease PJ. Inhibition of interleukin-17, interleukin-23 and the TH17 cell pathway in the treatment of psoriatic arthritis and psoriasis. Curr Opin Rheumatol. 2015 Mar;27(2):127-33.
23. Evens AM, Jovanovic BD, Su YC, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol. 2011 May;22(5):1170-80.
24. Leung C, Tsoi E, Burns G, et al. An argument for the universal prophylaxis of hepatitis B infection in patients receiving rituximab: a 7-year institutional experience of hepatitis screening. Oncologist. 2011;16(5):579-84.
25. Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009 May 14;113(20):4834-40.
26. Sarubbi FA. Hyperinfection with Strongyloides during treatment of pemphigus vulgaris. Arch Dermatol. 1987 Jul;123(7):864-5.
27. Siddiqui AA, Berk SL. Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis. 2001 Oct 1;33(7):1040-7.
28. Cartwright CP. Utility of multiple-stool-specimen ova and parasite examinations in a high-prevalence setting. J Clin Microbiol. 1999 Aug;37(8):2408-11.
29. Centers for Disease Control and Prevention, Infectious Disease Society of America, American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep. 2000 Oct;49(RR-10):1-125, CE1-7.

Conflict of interest disclosure:
None reported.

ABSTRACT
Efinaconazole 10% nail solution is a novel topical antifungal drug for the treatment of onychomycosis. Two Phase III trials were completed using efinaconazole 10% nail solution, where 17.8% and 15.2% of patients achieved complete cure, and 55.2% and 53.4%
achieved mycological cure. Several post hoc analyses were carried out using data from Phase III trials to determine the efficacy of efinaconazole with respect to disease duration, disease progression, and comorbidities of diabetes or tinea pedis with onychomycosis.
Efinaconazole produced higher efficacy rates with patients presenting onychomycosis in a small portion of the toenail (≤25%) for a shorter duration of time ( concurrent treatment, efficacy of efinaconazole increased from 16.1% to 29.4%, suggesting combination therapy improved results. Most interestingly, there was no difference in efinaconazole efficacy between diabetic and non-diabetic groups, indicating efinaconazole could be a safe and effective form of treatment for diabetics. Overall, efinaconazole 10% nail solution shows potential as an antifungal therapy for the treatment of onychomycosis.

Key Words:
antifungal agent, efinaconazole, fungal nail infection, Jublia^®, onychomycosis, topical triazole

Introduction

Onychomycosis is a fungal infection of the nail unit caused
by dermatophytes, yeasts, and nondermatophyte molds.¹
Onychomycosis affects toenails more frequently than fingernails
and accounts for 50% of nail disease.^2,3 Although this infection
can be perceived as merely a cosmetic issue of thickening and
discoloration of the nail plate, onychomycosis can result in
numerous side effects that can impede the use of shoes and make
walking difficult in general, leading to decreased quality of life.^4,5
Additional risks include bacterial infections, foot ulcers, and
gangrene.⁶ As a commonly occurring disease, it affects 2-13% of
the general population, with prevalence of up to 50% in patients
aged 70 years or higher.⁷ Along with advanced age, there are
several other risk factors including diabetes, peripheral arterial
disease, immunosuppression, and other pre-existing nail diseases
like psoriasis.⁸ Due to an increased chance of comorbidity with
onychomycosis, most recent investigational interests have focused
on topical antifungals, which have a lower risk of adverse effects
and drug-drug interactions.

The goal of onychomycosis treatment is restoring the nail to a
normal appearance and complete eradication of fungus. This
can be difficult to achieve as the nail plate acts as a barrier for
topical treatments, and poor circulation in the elderly can prevent
systemic treatments from reaching their target. Although some
therapies can result in complete clinical and mycological cure, the
rates are low (35-50%), and risk of relapse is high (10-53%).⁹
Currently, there are five classes of drugs approved for the
treatment of onychomycosis: allylamines, azoles, morpholines,
hydroxypyridinones, and benzoxaboroles.^10,11 Historically,
systemic therapies have been the most effective, with the oral
allylamine terbinafine being the current gold standard with a
complete cure rate of 38% and mycological cure rate of 74%.^12,13
The recommended dose of terbinafine for toenail onychomycosis
is 250 mg daily for 12 weeks. Patients who are high risk for adverse
effects from oral antifungals are prescribed topical agents. In the
US there are three topical therapies approved for the treatment
of onychomycosis: ciclopirox 8% nail solution, tavaborole 5%
solution, and efinaconazole 10% solution. Given the challenges of
transungual delivery, there is a need for novel topical antifungals
that can increase penetrance, are potent, and carry minimal side
effects.

Efinaconazole 10% solution is a novel topical antifungal of the
azole class that was US FDA approved for the treatment of toenail
onychomycosis in June 2014.¹⁴ Efinaconazole has demonstrated
a broad spectrum of activity against dermatophytes and yeasts
in vitro,¹⁵ and has uniquely low keratin affinity, allowing drug
release from keratin and enhanced penetration through the nail
plate compared to ciclopirox and amorolfine.¹⁶ Due to the unique
formulation of efinaconazole, both transungual and subungual
routes of delivery are achieved as the drug penetrates through
the nail plate into the underlying nail bed, as well as via spreading
around and under the nail plate through the air gap to reach
the fungal infection.^17,18 Recently, a human cadaver nail study
demonstrated that efinaconazole is able to penetrate the nail
even in the presence of nail polish,¹⁹ which may be a potential
advantage for patients concerned with hiding nail abnormalities
while at the same time using a topical treatment. Efinaconazole
works by inhibiting the synthesis of ergosterol, an essential
structural component of fungal cell membranes.^20,21 Its inhibition
results in a loss of cell membrane integrity, thus preventing fungal
cell growth.^20,21

Previously, two identical, randomized, double-blind, vehiclecontrolled
Phase III studies were performed using 1655
patients with mild to moderate toenail onychomycosis.²² The
treatment course was once daily application of efinaconazole
10% nail solution to the affected toenail and underside, as well
as surrounding skin, for 48 weeks followed by a 4 week washout
period.23 At week 52, 17.8% and 15.2% of patients achieved
complete cure, and 55.2% and 53.4% achieved mycological cure.²⁴
Interestingly, female patients demonstrated higher efficacies than
males (27.1% vs 15.8%, respectively, P=0.001), where the only
notable difference between genders were mean weight (73.3 kg
and 90.2 kg).²² Further subgroup analyses were completed using
Phase III data to elucidate the differences in treatment efficacy
in patients with concurrent tinea pedis or diabetes, as well as
duration and severity of disease.^25-28

Clinical Efficacy

Consistent with previous findings,²⁹ 21.3% (352/1655) of
patients from Phase III clinical trials reported onychomycosis
with concurrent tinea pedis, and 61.1% (215/352) underwent
concomitant treatment for tinea pedis with an investigatorapproved
topical antifungal.^26,30 Butenafine, luliconazole, and
ketoconazole were the most commonly used topical antifungal
agents for tinea pedis treatment; used by 64, 52, and 23 patients,
respectively.³⁰ With concomitant treatment of onychomycosis
(efinaconazole) and tinea pedis, complete and mycological cure
rates were 29.4% and 56.2%, respectively (7.8% and 26.6%
vehicle, P=0.003 and P<0.001, respectively). When tinea pedis
was left untreated, complete and mycological cure rates were
16.1% and 45.2% (0% and 12.5% vehicle, P=0.045 and P=0.007,
respectively). Efinaconazole treatment was superior to all vehicle
outcomes, and concurrent treatment for tinea pedis was superior
to untreated tinea pedis measures. Moreover, patients treated with
efinaconazole achieved a higher complete or almost complete
cure and higher treatment success, compared with vehicle (data
summarized in Table 1). Complete or almost complete cure was
defined as ≤5% clinical involvement of the target toenail plus
mycologic cure. Treatment success was defined as ≤10% clinical
involvement of the target toenail.

Of the 1655 patients from Phase III clinical trials, 112 patients
had coexistent onychomycosis and diabetes.²⁵ Only patients
whose diabetes was under control (N=96) were included in the
study. Diabetic (N=69) and non-diabetic (N=993) patients had
similar efficacies when treated with efinaconazole, with complete
cure rates of 13% and 18.8%, respectively and mycological
cure rates of 56.5% and 56.3%, respectively. These values were
significantly higher than vehicle (N=27) for complete cure (3.7%
and 4.7%, P P=0.016, and approximately 17.4%, P<0.001) for diabetic and
non-diabetic patients, respectively. Moreover, patients receiving
efinaconazole treatment had greater success achieving complete
or almost complete cures as well as treatment success at
week 52 (data summarized in Table 2). All secondary endpoints
were identical to those defined above.

Of all patients (1655) from Phase III trials, 1526 were categorized
based on disease duration: 5 years (770 patients).²⁷ Complete cure rates of
42.6%, 17.1%, and 16.2% were observed in efinaconazole-treated
patients with 5 years disease duration,
respectively. Complete cure rates with efinaconazole treatment
were significantly improved over vehicle for patients with baseline
disease durations of 1-5 years (17.1% vs. 4.4%, P<0.001) and >5
years (16.2% vs. 2.5%, P<0.001), however, this was not the case
for patients presenting with onychomycosis for vs. 16.7%, not significant). It is possible that non-significance
may be due to the small sample size (N=33 efinaconazole).
Furthermore, 66.0%, 59.0%, and 53.8% of patients achieved
mycological cure with disease duration of 5 years, respectively. Similar to complete cure, the latter two
durations were significantly different from vehicle (P <0.001).
Lastly, while not significant for any duration, patients receiving
efinaconazole treatment did show numerically higher complete
or almost complete cure rates, as well as treatment success, for
disease durations of 5 years (Figure 3). All secondary endpoints are identical to those
defined above.

Figure 1.Summary of cure rates for patients with baseline disease duration of 27

While cure rates are numerically higher for all efficacy outcomes, efinaconazole cure rates were not significantly greater than vehicle.

Figure 2.Summary of cure rates for patients with baseline disease duration of 1-5 years with efinaconazole.²⁷

^*

Figure 3.Summary of cure rates for patients with baseline disease duration of >5 years with efinaconazole.²⁷

^*P

Finally, effectiveness of efinaconazole based on disease severity
was measured using 414 patients with mild onychomycosis
(≤25% nail involvement), and 1237 patients with moderately
severe onychomycosis (>25% nail involvement).²⁸ Patients
presenting with mild onychomycosis had complete and
mycological cure rates of 25.8% and 58.2%, respectively, which are
significantly higher than vehicle cure rates of 11.3% (P=0.006)
and 25.0% (P<0.001), respectively. Patients with moderately
severe onychomycosis had complete and mycological cure rates
of 15.9% and 55.6%, respectively, again demonstrating significant
improvement over vehicle cure rates of 2.7% and 14.1% (P<0.001
for both), respectively. Moreover, all patients with efinaconazole
treatment had significantly higher complete or almost complete
cure rates and treatment success compare to vehicle (summarized
in Table 3, P to those defined above.

^a P<0.01; ^b P

Discussion

The data from two Phase III clinical trials have been analyzed and
the efficacy of efinaconazole with respect to concurrent treatment
for tinea pedis, diabetic patients, disease duration, and severity
of disease shows promise. Efficacies were highest among patients
with less severe (≤25% nail involvement) and shorter disease
duration.

Efinaconazole treatment was more effective than vehicle for the
treatment of onychomycosis with or without concurrent treatment
of tinea pedis. Since one-third of onychomycosis patients also
have tinea pedis, it is recommended that patients are examined
for concomitant dermatomycoses, and treatment for both fungal
infections (if present) be sought, as pathogens that cause tinea
pedis can also lead to onychomycosis.^29,30 Although concurrent
treatment for tinea pedis and onychomycosis (efinaconazole)
improved complete cure rates from 16.1% to 29.4%, there was
no information about the severity of tinea pedis, or the success
of tinea pedis treatment. Therefore, further testing would need
to be completed to confirm whether combination therapy could
increase treatment efficacy of both fungal infections.

Onychomycosis in diabetic patients is extremely difficult to treat
with traditional antifungals due to hyperglycemia and problematic
foot hygiene.³¹ Moreover, onychomycosis left untreated poses a
significant risk for further complications that can potentially lead
to loss of limb.^32,33 The findings that the efficacy of efinaconazole
was comparable between diabetic and non-diabetic patients
and cure rates for both groups were significantly higher than
respective vehicle groups, indicate that diabetics can now receive
safe and effective treatment for onychomycosis.

In summary, good responders to efinaconazole treatment are
more likely to be patients with mild (≤25% clinical toenail
involvement) onychomycosis and have a low number of nontarget
nail involvement,²⁸ with early or baseline onychomycosis
(27 who receive concurrent
treatment for tinea pedis (if present),^26,30 are female,²² and weigh
22 Most interestingly, whether patients were diabetic
or non-diabetic had no effect on the efficacy of efinaconazole
treatment.

Efinaconazole 10% topical solution is an effective topical
treatment for onychomycosis with favorable clinical and
mycological efficacies, low risk of drug-drug interactions, and a
minimal side effect profile.³⁴ With complete cure rates of 17.8%
and 15.2%,^22,34 and a favorable safety profile, efinaconazole also
looks promising for use in children and in combination therapy.
Moreover, since levels of efinaconazole reach a steady state in
the nail after 2 weeks of daily application, and remain at high
concentrations well above the minimum inhibitory concentration
for dermatophytes for at least 2 weeks off therapy,³⁵ it is possible
that efinaconazole may be used twice weekly as a maintenance
regime. This strategy may be considered after the completion of
the 48 week treatment period in order to prevent relapse; however,
maintenance studies have yet to be conducted. Taken together,
efinaconazole 10% topical solution is an easy to use, safe, and
effective therapy for the treatment of onychomycosis.

References

1. Scher RK, Rich P, Pariser D, et al. The epidemiology, etiology, and pathophysiology of onychomycosis. Semin Cutan Med Surg. 2013 Jun;32(2 Suppl 1):S2-4.
2. Gupta AK, Jain HC, Lynde CW, et al. Prevalence and epidemiology of onychomycosis in patients visiting physicians’ offices: a multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol. 2000 Aug;43(2 Pt 1):244-8.
3. Faergemann J, Baran R. Epidemiology, clinical presentation and diagnosis of onychomycosis. Br J Dermatol. 2003 Sep;149 Suppl 65:1-4.
4. Elewski BE. The effect of toenail onychomycosis on patient quality of life. Int J Dermatol. 1997 Oct;36(10):754-6.
5. Lubeck DP, Gause D, Schein JR, et al. A health-related quality of life measure for use in patients with onychomycosis: a validation study. Qual Life Res. 1999 8(1-2):121-9.
6. LaSenna CE, Tosti A. Patient considerations in the management of toe onychomycosis – role of efinaconazole. Patient Prefer Adherence. 2015 9:887-91.
7. Tabara K, Szewczyk AE, Bienias W, et al. Amorolfine vs. ciclopirox – lacquers for the treatment of onychomycosis. Postepy Dermatol Alergol. 2015 Feb;32(1):40-5.
8. Tosti A, Hay R, Arenas-Guzman R. Patients at risk of onychomycosis–risk factor identification and active prevention. J Eur Acad Dermatol Venereol. 2005 Sep;19(Suppl 1):13-6.
9. Epstein E. How often does oral treatment of toenail onychomycosis produce a disease-free nail? An analysis of published data. Arch Dermatol. 1998 Dec;134(12):1551-4.
10. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol. 2010 Mar 4;28(2):151-9.
11. Markham A. Tavaborole: first global approval. Drugs. 2014 Sep;74(13):1555-8.
12. LamisilÆ (terbinafine hydrochloride) tablets [Prescribing information]; revised
    August 2016. Novartis Pharmaceuticals Corporation, East Hanover, NJ. Available
    at: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/
    files/Lamisil_tablets.pdf. Accessed September 26, 2016.
13. Gupta AK, Paquet M, Simpson FC. Therapies for the treatment of onychomycosis. Clin Dermatol. 2013 Sep-Oct;31(5):544-54.
14. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013 Apr;68(4):600-8.
15. Jo Siu WJ, Tatsumi Y, Senda H, et al. Comparison of in vitro antifungal activities of efinaconazole and currently available antifungal agents against a variety of pathogenic fungi associated with onychomycosis. Antimicrob Agents Chemother. 2013 Apr;57(4):1610-6.
16. Sugiura K, Sugimoto N, Hosaka S, et al. The low keratin affinity of efinaconazole contributes to its nail penetration and fungicidal activity in topical onychomycosis treatment. Antimicrob Agents Chemother. 2014 Jul;58(7):3837-42.
17. Gupta AK, Pillai R. The presence of an air gap between the nail plate and nail bed in onychomycosis patients: treatment implications for topical therapy. J Drugs Dermatol. 2015 Aug;14(8):859-63.
18. Gupta AK, Simpson FC. Routes of drug delivery into the nail apparatus: Implications for the efficacy of topical nail solutions in onychomycosis. J Dermatolog Treat. 2016 27(1):2-4.
19. Zeichner JA, Stein Gold L, Korotzer A. Penetration of ((14)C)-efinaconazole topical solution, 10%, does not appear to be influenced by nail polish. J Clin Aesthet Dermatol. 2014 Sep;7(9):34-6.
20. Rodriguez RJ, Low C, Bottema CD, et al. Multiple functions for sterols in Saccharomyces cerevisiae. Biochim Biophys Acta. 1985 Dec 4;837(3):336-43.
21. Parks LW, Smith SJ, Crowley JH. Biochemical and physiological effects of sterol alterations in yeast–a review. Lipids. 1995 Mar;30(3):227-30.
22. Gupta AK, Elewski BE, Sugarman JL, et al. The efficacy and safety of efinaconazole 10% solution for treatment of mild to moderate onychomycosis: a pooled analysis of two phase 3 randomized trials. J Drugs Dermatol. 2014 Jul;13(7):815-20.
23. JUBLIA® (efinaconazole) topical solution, 10% [Prescribing information]; revised July 2014. Valeant Pharmaceuticals North America LLC, Bridgewater, NJ. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203567s000lbl.pdf. Accessed September 26, 2016.
24. Lipner SR, Scher RK. Efinaconazole in the treatment of onychomycosis. Infect
    Drug Resist. 2015 8:163-72.
25. Vlahovic TC, Joseph WS. Efinaconazole topical, 10% for the treatment of
    toenail onychomycosis in patients with diabetes. J Drugs Dermatol. 2014
    Oct;13(10):1186-90.
26. Lipner SR, Scher RK. Management of onychomycosis and co-existing tinea
    pedis. J Drugs Dermatol. 2015 May;14(5):492-4.
27. Rich P. Efinaconazole topical solution, 10%: the benefits of treating
    onychomycosis early. J Drugs Dermatol. 2015 Jan;14(1):58-62.
28. Rodriguez DA. Efinaconazole topical solution, 10%, for the treatment of mild and
    moderate toenail onychomycosis. J Clin Aesthet Dermatol. 2015 Jun;8(6):24-9.
29. Szepietowski JC, Reich A, Garlowska E, et al, Onychomycosis Epidemiology Study
    Group. Factors influencing coexistence of toenail onychomycosis with tinea
    pedis and other dermatomycoses: a survey of 2761 patients. Arch Dermatol. 2006
    Oct;142(10):1279-84.
30. Markinson B, Caldwell B. Efinaconazole topical solution, 10% efficacy in patients
    with onychomycosis and coexisting tinea pedis. J Am Podiatr Med Assoc. 2015
    Sep;105(5):407-11.
31. Tan JS, Joseph WS. Common fungal infections of the feet in patients with diabetes mellitus. Drugs Aging. 2004 21(2):101-12.
32. Gupta AK, Humke S. The prevalence and management of onychomycosis in diabetic patients. Eur J Dermatol. 2000 Jul-Aug;10(5):379-84.
33. Papini M, Cicoletti M, Fabrizi V, et al. Skin and nail mycoses in patients with diabetic foot. G Ital Dermatol Venereol. 2013 Dec;148(6):603-8.
34. Lipner SR, Scher RK. Efinaconazole 10% topical solution for the topical treatment of onychomycosis of the toenail. Expert Rev Clin Pharmacol. 2015 8(6):719-31.
35. Sakamoto M, Sugimoto N, Kawabata H, et al. Transungual delivery of efinaconazole: its deposition in the nail of onychomycosis patients and in vitro fungicidal activity in human nails. J Drugs Dermatol. 2014 Nov;13(11):1388-92.

¹School of Medicine, ² Department of Dermatology, The University of Texas Medical Branch, Galveston, TX, USA

ABSTRACT
Acute bacterial skin and skin-structure infections (ABSSSIs), often caused by aerobic gram-positive cocci, are most often mild-tomoderate infections that can easily be treated in an outpatient setting. With the rates of these infections substantially increasing in the past decade, owing in part to the emergence of community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), alternative options for the treatment of ABSSSIs are necessary. This editorial reviews the mechanism of action, efficacy, bacterial coverage, and potential side effect profiles for dalbavancin and oritavancin, both semisynthetic lipoglycopeptide antibiotics, and tedizolid, an oxazolidinone. Dalbavancin, oritavancin, and tedizolid have been extremely valuable additions to treatment options for ABSSSIs due to the convenient dosing regimen and the fact that there are fewer resistant organisms to these therapies at this time.

Key Words:
acute bacterial skin and skin-structure infections, antibiotics, glycopeptide, dalbavancin, oritavancin, tedizolid

Introduction

Acute bacterial skin and skin-structure infections (ABSSSIs), often caused by aerobic gram-positive cocci, are estimated to cause more than 15 million infections and 870,000 hospital admissions annually in the United States.1 SSSIs are most often mild-to-moderate infections that can easily be treated in an outpatient setting. Rates of these infections have substantially increased in the past decade, owing in part to the emergence of community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA).² The economic burden of SSSIs remains substantial and is driven by the high costs of hospitalization, which is often required for severe SSSIs since the agents used to treat these infections require daily intravenous (IV) administration for multiple days.³ Early clinical detection of severe or necrotizing SSSIs is difficult because the disease is often indistinguishable from its milder counterparts early in the disease course. Signs of a severe infection include pain disproportionate to the clinical findings, violaceous bullae, cutaneous hemorrhage, skin sloughing, skin anesthesia, rapid progression, and gas in the tissue.⁴ Additionally, it is recommended that patients with SSSIs accompanied by signs and symptoms of systemic toxicity, such as hypotension, fever, hypothermia, tachycardia, increased creatinine level, decreased serum bicarbonate, increased creatinine phosphokinase, marked left shift, or C-reactive protein >13 mg/L, be considered for hospitalization.⁴

Glycopeptide antibiotics, such as vancomycin, have been used in treatment of SSSIs for over half a century and are still used extensively today; however, reduced vancomycin susceptibility in CA-MRSA strains as well as difficulty in therapeutic drug monitoring compromise the clinical efficacy of vancomycin.^2,5 Second generation semisynthetic lipoglycopeptide derivatives such as dalbavancin and oritavancin, which possess a broader spectrum of activity and improved pharmacokinetic properties, will be discussed in this article. The new glycopeptide antibiotics provide efficacious alternatives for the treatment of complicated ABSSSIs.¹ A major benefit is management in an outpatient setting, which could significantly decrease or omit the costs and risks of hospitalization, as well as eliminating the need for laboratory monitoring.¹

Oxazolidinones are another important class of antibiotics used in the treatment of ABSSSIs, particularly vancomycin resistant Enterococcus(VRE) infections. Historically, linezolid has been the antibiotic of choice; however, tedizolid is a novel oxazolidinone that offers enhanced antimicrobial potency, low rates of bacterial resistance, and potential safety advantages. Additionally, the recommended dosing of once per day may be more convenient and is associated with higher compliance than twice per day dosing for linezolid.⁶

To maintain effectiveness of new antibiotics, their use should be limited to ABSSSIs where the bacteria are susceptible to the new medication and are resistant to other more cost effective options. Although tedizolid, dalbavancin, and oritavancin have been approved for SSSIs caused by MRSA, they probably should not be used as a first-line treatment when there are less expensive and more easily accessible antibiotics, such as trimethoprimsulfamethoxazole or doxycycline, that are very effective for MRSA infections.⁷

Glycopeptide Therapeutics – Dalbavancin and
Oritavancin

Dalbavancin is a long-acting IV semisynthetic lipoglycopeptide antibiotic with bactericidal activity against gram-positive cocci, including MRSA.^6-10 It is the first US FDA approved drug for adults with ABSSSIs that requires only 2 IV doses administered 1 week apart: the first dose is 1000 mg IV infused over 30 minutes, followed 1 week later by the second dose of 500 mg IV.^6-10

Dalbavancin is effective for treatment of adult patients with ABSSSI caused by susceptible isolates of gram-positive organisms. Susceptible gram-positive organisms include Staphylococcus aureus (S. aureus), including MRSA and MSSA, and Streptococcus groups (S. pyogenes, S. agalactiae, and S. anginosus).^6-11 In vitro studies suggest it may also be effective against vancomycinsusceptible Enterococcus faecium and Enterococcus faecalis (E. faecalis), as well as vancomycin-intermediate S. aureus; however, clinical importance has not been established.^6,11 The safety and efficacy in pediatric patients 18 years of age and younger has not been demonstrated.^8,11 However, vancomycin has been successfully used in treating these bacterial infections in the pediatric patient population.11 Dalbavancin is pregnancy category C meaning there has been some fetal toxicity in animals, but no adequate human studies.^6,8,11

The adverse effects most commonly experienced include nausea, diarrhea, and headaches, reported in 5% or less of patients.^6-8,10,11 Infrequent serious hypersensitivity reactions, including anaphylaxis, have been reported and caution should be exercised with patients who have a known allergy to other glycopeptides.^8,10 Additionally, rapid IV infusion could cause infusion-related reactions (pruritus, urticaria, and flushing).^6-8,10 Slowing or interrupting the infusion may be helpful if this occurs.⁷

Oritavancin is a long-acting IV semisynthetic lipoglycopeptide antibiotic with potent activity against gram-positive pathogens, including MRSA.³ Oritavancin is bactericidal and has an extended plasma half-life.^3,11,12 It is the first single-dose antibacterial drug approved by the US FDA for treatment of adult patients with ABSSIs.¹² The recommended single dose is 1200 mg IV infused over 3 hours.^7,11 Dose adjustment for advanced age, decreased renal function, or moderate hepatic impairment is not required.^3,7

Oritavancin is approved for use in adults with ABSSSIs caused by susceptible gram-positive microorganisms. Susceptible grampositive microorganisms include S. aureus (including MRSA and MSSA), various Streptococcus groups (S. pyogenes, S. agalactiae, S. dysgalactiae, and S. anginosus), and E. faecalis (vancomycinsusceptible isolates only).¹¹ The safety and efficacy have not been established in patients 18 years of age and younger.¹¹ Oritavancin is pregnancy category C.¹¹

The adverse effects most often reported include nausea, headache, vomiting and diarrhea, all occurring in less than 10% of patients.^3,7,11,12Osteomyelitis is a rare adverse event occurring in 0.3% of patients.^11,12 If osteomyelitis is suspected an antibacterial agent other than oritavancin should be used.^11,12 Infrequent reports of serious hypersensitivity reactions have occurred.^3,11 It is important to be aware of patients who have a history of allergies to other glycopeptides, including vancomycin.¹¹ Additionally, infusion-related reactions (pruritus, urticaria, flushing) have been experienced, as with other glycopeptides.^3,11,12 If this occurs, slowing or interrupting the infusion should be considered.¹¹

The current therapeutic options for the treatment of ABSSSIs require multidose and multiday regimens, with some patients requiring dosage adjustments for renal insufficiency or monitoring of plasma drug concentration.³ Multiday regimens may require patients to be hospitalized over their course of treatment, which increases the risk of nosocomial complications.³ Additionally, oral antibiotic regimens have an increased rate of noncompliance, which increases the potential for pathogen resistance. Oritavancin achieves a sustained clinical response with a single dose and does not require dosage adjustments for renal insufficiency. Oritavancin and dalbavancin could potentially reduce or eliminate hospital stays, improve treatment compliance, reduce utilization of health care resources, and add flexibility to the treatment of these serious infections. Despite the advantages, other more cost effective antibiotics with a history of effective use in treatment of ABSSSIs should be considered before deciding to treat with dalbavancin or oritavancin.

Oxazolidinone Therapeutic – Tedizolid Phosphate

The oxazolidinones are a synthetic class of agents now commonly relied on for the treatment of ABSSSIs, including more serious infections like MRSA and VRE.¹³ With increasing utilization of linezolid, resistant pathogens have begun to emerge.¹³ Tedizolid phosphate is a second-generation oxazolidinone antibiotic that offers enhanced antimicrobial potency and low rates of bacterial resistance.^13-15 Available in both IV and oral forms, tedizolid exhibits bacteriostatic activity by binding the 50S subunit of the bacterial ribosome, resulting in inhibition of bacterial protein synthesis.^11,13-15 The recommended dosage is 200 mg once daily for 6 days,^6,7,14,16 which may offer increased convenience and compliance when compared to twice daily linezolid.

Clinical studies have proven tedizolid phosphate to be effective against susceptible isolates of gram-positive organisms including S. aureus (including MRSA and MSSA), various Streptococcus groups (S. pyogenes, S. agalactiae, and S. anginosus), and E. faecalis (including VRE).^6,7,11,13-16 In vitro studies have suggested it may also exhibit activity against some strains of Staphylococci and Enterococci that are not susceptible to vancomycin or linezolid; however, the clinical importance of this data has not been established.^{6,11,13,14,16} The safety and effectiveness in pediatric patients 18 years of age or younger has not been demonstrated; whereas, linezolid is indicated for use in pediatric patients.^11,16 Tedizolid phosphate is pregnancy category C.^6,11,16

Structural differences between tedizolid and linezolid are thought to contribute to tedizolid’s decreased rates of resistance and enhanced potency.^13,14 Bacteria confer resistance to linezolid by acquiring the chloramphenicol-florfenicol resistance gene, which can be horizontally transferred.^13,15 However, because of structural distinctions, tedizolid has decreased vulnerability to this resistance mechanism.^13,15 Interactions with the ribosomal subunit are thought to contribute to the increased potency of tedizolid.^13,15

Another potential advantage of tedizolid compared to linezolid is an improved safety profile.^14,15 The most common adverse effects are similar to those seen with linezolid and include nausea, headache, diarrhea, vomiting, and dizziness, each occurring in less than 8% of patients.^6,7,14-16 Toxicity linked to duration of treatment with linezolid includes peripheral and optic neuropathy as well as hematologic toxicity and thrombocytopenia.^13,16 Tedizolid has not had reports of peripheral and optic neuropathy.^13,16 Although tedizolid exposure has been limited to 21 days or less in patients, a rat study using tedizolid doses up to 10-fold greater than human doses did not induce a neuropathy.¹³ This data indicates a possible safety advantage of tedizolid. Additionally, at recommended doses, tedizolid has not been associated with hematologic toxicity or thrombocytopenia¹³; however, higher doses or longer treatment durations might increase the risk. Linezolid has been associated with the occurrence of myelosuppression, especially in patients who have underlying hematologic abnormalities or renal insufficiency, which requires complete blood counts to be monitored weekly.¹³ An additional concern exists for the oxazolidinone class, which has been shown to act as weak, reversible monoamine oxidase (MAO) inhibitors in some in vitro studies.^6,13 However, based on two randomized, double-blind, placebo-controlled crossover studies, as well as another study including both humans and animals, tedizolid failed to interact with serotonergic drugs, adrenergic agents, or result in MAO inhibitor activity.^6,13,16 Data from post marketing experience will be beneficial to confirm the encouraging results that are currently available.

Conclusion

Dalbavancin, oritavancin, and tedizolid have been extremely valuable additions to treatment options for ABSSSIs due to the convenient dosing regimen and the fact that there are fewer resistant organisms to therapy at this time. In practice, other antibiotics with a history of effective use for ABSSSIs, which also cost less, should be considered first in order to prevent bacterial resistance.

References

1. Chambers HF. Pharmacology and the treatment of complicated skin and skin-structure infections. N Engl J Med. 2014 Jun 5;370(23):2238-9.
2. Holmes NE, Howden BP. What’s new in the treatment of serious MRSA infection? Curr Opin Infect Dis. 2014 Dec;27(6):471-8.
3. Corey GR, Kabler H, Mehra P, et al. Single-dose oritavancin in the treatment of acute bacterial skin infections. N Engl J Med. 2014 Jun 5;370(23):2180-90.
4. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005 Nov 15;41(10):1373-406.
5. Tacconelli E, Kern WV. New antibiotics for skin and skin-structure infections. Lancet Infect Dis. 2014 Aug;14(8):659-61.
6. Two new drugs for skin and skin structure infections. Med Lett Drugs Ther. 2014 Aug 18;56(1449):73-5.
7. New MRSA drugs: tedizolid, dalbavancin, and oritavancin. Duke Antimicrobial Stewardship Outreach Network (DASON): Infection Prevention News. 2014 Aug; 2(8).
8. Dalvanceô (dalbavancin) for injection, for intravenous use [Prescribing information]. Chicago, IL: Durata Therapeutics U.S. Limited; revised May 2014.
9. Dalvanceô for acute bacterial skin and skin structure infections (ABSSSI). J Drugs Dermatol. 2014 Jun;13(6):772.
10. Boucher HW, Wilcox M, Talbot GH, et al. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med. 2014 Jun 5; 370(23):2169-79.
11. Hussar DA, Nguyen A. Dalbavancin, tedizolid phosphate, oritavancin diphosphate, and vedolizumab. J Am Pharm Assoc (2003). 2014 Nov-Dec; 54(6):658-62.
12. Markham A. Oritavancin: first global approval. Drugs. 2014 Oct;74(15):1823-8.
13. Rybak JM, Marx K, Martin CA. Early experience with tedizolid: clinical efficacy, pharmacodynamics, and resistance. Pharmacotherapy. 2014 Nov; 34(11):1198-208.
14. Moran GJ, Fang E, Corey GR, et al. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2014 Aug;14(8):696-705.
15. O’Riordan W, Green S, Mehra P, et al. Tedizolid phosphate for the management of acute bacterial skin and skin structure infections: efficacy summary. Clin Infect Dis. 2014 Jan;58 Suppl 1:S43-50.
16. Sivextro^® (tedizolid phosphate) for injection, for intravenous use; tablet, for oral use [Prescribing information]. Lexington, MA: Cubist Pharmaceuticals U.S; revised March 2015.

Section of Dermatology, Department of Surgery & Department of Obstetrics and Gynecology, Dartmouth Medical School, Hanover, NH, USA

ABSTRACT

Vulvovaginal diseases commonly are inadequately diagnosed and treated. Most are dermatologic, but can be atypical in presentation in the warm, moist genital area. There is limited training or education for medical caregivers for these conditions. The first step is correct diagnosis, which requires time and knowledge of the normal anatomy, and careful examination. Dermatologists are invaluable for management as they recognize skin problems and can correct barrier function, control inflammation, and address itching and pain.

Key Words:
examination, lichen planus, lichen sclerosus, pruritus, vagina, vulva

The consequential effects of vulvovaginal diseases being rarely taught is that they are frequently missed or mismanaged by medical and surgical caregivers, leaving both patients and physicians floundering. Women hide and scratch, enduring pain, engendering significant debility and sexual dysfunction, and wasting millions of dollars on “yeast treatments”. The general unfamiliarity with the normal anatomy and the atypical appearance of common dermatological conditions represent a considerable clinical challenge. Dermatologists, who are accustomed to instant visual diagnosis, need to take extra time to apply their knowledge of morphology and recognize the normal anatomy when treating vulvovaginal disorders. We are uniquely qualified to help^1,2 in assessing the pathology, identifying etiology, correcting barrier function, limiting inflammation, and addressing cutaneous itching and pain.

Anatomy

Recognizing normal variants is essential. The appearance of the vulva varies depending on age, ethnicity, and hormonal factors. A good diagram is invaluable – anatomical familiarity is important not only for the caregiver, but also for the patient. A suitable figure is available on the website of the International Society for the Study of Vulvovaginal Disease at www.ISSVD.org.

The vulva becomes flattened with loss of normal architecture in lichen sclerosus. Without an understanding of the normal architecture, subtle scarring in this condition may be unrecognized. The prepuce may be slightly swollen and adherence to the clitoris is easily missed. Scarring is a nonspecific sign associated with many erosive and inflammatory skin conditions in the vulvar area. It is important to make sure all architectural features are intact. Both digital and speculum examinations of the vagina are important to rule out erosions, synechiae, and scarring in the vagina, as can be seen in erosive lichen planus.³

Because common variations in vulvar anatomy may be unfamiliar, recognizing these is important. Vulvar papillomatosis shows small monomorphous papules on the vulvar trigone that can be easily confused with genital warts. Normal sebaceous glands (Fordyce spots) are at times quite prominent and can appear worrisome. These lesions are soft, asymptomatic, and harmless. Also, common benign blood vessel growths on the labia majora (angiokeratomas) can appear black and sinister.³

History

A thorough and accurate patient history is essential, including details of previous treatments and response to therapy. Inquire about all the various products the patient is using, particularly cleansers, lubricants, and menstrual products. Do not always accept the chief complaint at face value. The patient may complain of itching or burning, but her real concern is about infidelity, cancer, or sexually transmitted infection. Always ask about incontinence, both urinary and fecal, as 10% of women over 50 years of age have urinary incontinence.⁴ Women seldom, if ever, volunteer this information to their treating physician. Furthermore, fecal incontinence is very common and almost never mentioned. Schlosser et al. ³ provide a detailed approach.

Physical Examination

A thorough examination requires good visualization with proper lighting, avoiding glare. Proper exposure is mandatory. Examination can be in the frog-leg position or in stirrups. The latter is preferred as one can then visualize the entire area including the anus. A close look, preferably with magnification, is mandatory. Not infrequently a patient will complain bitterly of pain and burning from an apparently trivial lesion. Painful fissures and erosions can be very subtle or invisible in poor light. Concomitant vulvar conditions are common. It is not unusual to see the patient with lichen sclerosus, contact dermatitis from incontinence, and atrophy from lack of estrogen. Occasionally, squamous cell carcinoma may also be seen. Examine the rest of the skin and the oral cavity. About 60% of patients with oral lichen planus have vulvar or vaginal disease.^5,6 Always investigate the possibility of more than one problem. Iatrogenic disease is common. One can see steroid atrophy with thigh striae or herpes simplex flaring in an area of lichen sclerosus being treated with a superpotent topical steroid. Vaginal disease must be considered to be associated with the vulvar condition or contributing to it. It is worth noting that about 60% of vulvar lichen planus cases have vaginal disease. Chronic vaginitis discharge from any vaginitis can cause or worsen a vulvar condition.^1,3

Biopsies

Biopsies are always important, especially if the patient will need lifetime treatment as in lichen sclerosus. However, a biopsy of lichen sclerosus is not generally recommended for children. A pain-free biopsy is ideal, and can be accomplished using a topical anesthetic (e.g., 2.5% lidocaine with 2.5% prilocaine in a cream base). This is applied liberally to the modified mucous membrane area for 20 minutes, or for 60 minutes for keratinized skin. Local anesthesia with 2% lidocaine with adrenaline is then injected slowly using a 30-gauge needle. If there is any question, do multiple biopsies at a single sitting. A typical problem is vulvar melanosis. There are often several sites that look suspect and it is best to biopsy all of them at one visit. Biopsies, particularly from vulvar or vaginal lichen planus, can be nonspecific. Differentiated squamous cell carcinoma of the vulva can be read as lichen simplex chronicus. Therefore, a dermatopathologist who is clinically familiar with these conditions is invaluable.

Education and Support

Before starting therapy it is important to understand that for almost all vulvovaginal conditions there are psychological, social, and sexual repercussions. Loss of intimacy not uncommonly results in low self-esteem, frustration, depression, anger, or hostility. Frequently, some combination of patient ignorance, guilt, embarrassment, and anxiety further complicate vulvovaginal problems. Consequently, good education, support, and counseling are imperative. More than with any other area of the body, the vulvar patient needs to be recognized as a person and treated gently and with respect. Take extra time for patient education by addressing the disease process, discussing available therapies, and managing expectations. Precise treatment details must be conveyed. As well, use the encounter for an educational vulvar examination. Handouts are very helpful to demystify the disorder and improve compliance. High-quality clinical photographs are essential for patient education and documentation.

Treatment

The goal of therapy is to correct barrier function, thereby reducing or eliminating inflammation, itching, and pain.

Barrier Function

Common causes of altered skin barrier in the vulvovaginal area are contact dermatitis (particularly from overzealous hygiene), atopic dermatitis, atrophy from lack of estrogen, psoriasis, or other ‘rashes’ and, less commonly, tumors. To provide the optimal environment for maintenance of a functioning skin barrier, it is important to limit the exposure to harmful factors (e.g., excessive hygiene, heat, sweat, vaginal secretion, urine, feces, clothing washed in enzyme-containing detergents, and friction) that can cause or exacerbate any skin condition. Sweat, heat, and moisture promote maceration, epithelial breakdown, and infection. Women have a tendency to over wash using facecloths and caustic cleansers. For cleansing, little to no soap is best. Dove for Sensitive Skin® (fragrance free) or Cetaphil Gentle Cleanser® can be used for cleansing with bare hands only. A hand-held shower on a gentle setting can be a good choice, especially for women with physical limitations. The area is patted dry and hairdryers should never be used. Clothing should be ventilated, fit well, and be laundered in enzyme-free detergent. Avoid thongs, girdles, and tight jeans. Urinary and fecal incontinence need to be addressed. For urinary incontinence, an appropriate incontinence pad (not a menstrual panty liner) should be used. For fecal cleansing, consider Cetaphil Gentle Cleanser® or mineral oil. Pelvic floor rehabilitation and/or help from a urologist should be considered.

The concept of ‘soak and seal’ is the same on the vulva as elsewhere. Soaks provide symptomatic relief, gentle debridement, and restore a moist environment for healing. A plain water soak in a tub or sitz bath for 5-10 minutes can be used. Occasionally, water will sting very raw skin. Normal saline does not sting, so it can be used by mixing 1 teaspoon of salt in
4 cups of water. After the soak, to seal in the moisture, a petrolatum-based product is best, but this can be messy, sticky, and can even trap sweat. A hypoallergenic product, such as Vanicream™, can be very useful. For very raw skin, plain white petrolatum is recommended. Always perform cultures and treat any associated infection caused by Candida and bacteria, usually Staphylococcus and Streptococcus. For acute severe candidiasis use fluconazole 150mg on day 1, 3 and 7. For suppression use fluconazole 150mg per week for up to 6 months. If the patient exhibits a poor response, re-culture to rule out an azole resistant Candida (e.g., Candida Glabrata), which would require treatment with 600mg boric acid vaginal suppositories nightly for 14 days.

Inflammation Reduction

Topical Corticosteroids

Too often topical corticosteroids are not effectively used in the vulvovaginal area. It must be appreciated that the vulvar vestibule is relatively treatment resistant to topical corticosteroids, in contrast to the labiocrural folds, perineum, perianal area, and thighs (which can easily be thinned and develop striae). For thick, scaly vulvar conditions, such as lichen sclerosus, lichen planus, or lichen simplex chronicus, a superpotent steroid (e.g., clobetasol or halobetasol 0.05% in an ointment base) is advisable. Daily treatment may be needed for 8-12 weeks to gain adequate control. Education is very important here. The patient needs to know exactly where to apply the ointment and how much. A diagram is very useful and a clinical photograph of the female patient’s affected area is even better. Limit the use of superpotent corticosteroids in the steroid sensitive areas to 2-3 weeks. Limit the amount prescribed to 15g. For long-term use consider intermittent application, such as treatment on Monday, Wednesday and Friday, or switch to a low potency steroid. A typical therapeutic regimen for vulvar lichen sclerosus would be clobetasol 0.05% ointment daily for 12 weeks, then decrease to 3 times a week. If there is concern about recurrent yeast infections prescribe oral fluconazole 150mg weekly for suppression.

Topical Calcineurin Inhibitors (TCIs)

TCIs can be used to avoid corticosteroid-induced side-effects. Pimecrolimus 1% cream and tacrolimus 0.03% and 0.1% ointments have been reported to be very helpful for lichen sclerosus, lichen planus, lichen simplex chronicus, and a number of the bullous diseases, or even Crohn’s disease.7 Unfortunately, because TCIs can cause localized burning they are often poorly tolerated. Overall, both TCIs are less effective than topical potent and superpotent steroids for treating vulvovaginal skin disorders. There is controversy regarding their safety in lichen sclerosus and lichen planus. In addition, their cost can be prohibitive.

Intralesional Corticosteroids

For a nonresponsive area of lichen sclerosus or lichen planus, triamcinolone acetonide 10mg/mL diluted to a concentration of 3.3-5mg/mL can overcome the failure of topicals. The area injected will depend on the individual case. To avoid pain, preanesthetize the area. Treatment can cause atrophy and must be used intermittently with caution.⁸

Systemic Corticosteroids

Systemic steroids can be very useful for intractable itching and inflammation. Classically, prednisone is recommended, but it too often causes gastrointestinal upset, anxiety, and agitation. Systemic prednisone is very useful for a quick burst without a taper for 7-10 days when treating an acute, limited skin condition, such as simple contact dermatitis. For longer-term management of inflammation, intramuscular (IM) triamcinolone (Kenalog®-40) can be an excellent choice. It is very well tolerated and best given deep into the muscle of the mid-anterior thigh. In obese women, injection into the fat results in subcutaneous atrophy, slow absorption, and a poor response. One milligram per kilogram, up to 80mg/dose, is recommended. IM triamcinolone does not have the side-effects of anxiety and agitation that are common with prednisone. Its main side-effect is occasional irregular bleeding in premenopausal women. It is an ideal therapeutic option for lichen simplex chronicus and lichen planus, administered as one dose monthly for 1-3 months, limiting the number of treatments to four times a year. Although the list of generic side-effects of triamcinolone include pituitary axis suppression, infection, cataracts and worsening glaucoma, irregular menses, and rarely allergy, these are much less prevalent than with prednisone.⁸

Vaginal Corticosteroids

Vaginal corticosteroids are imperative for the management of vaginal lichen planus and bullous diseases, however, there are no commercially available products. The simplest treatment is with clobetasol or halobetasol 0.05% ointment or cream using a Premarin® applicator and inserting 1-2g in the vagina at night. Commonly, hydrocortisone acetate is used. A 25mg suppository is available, but the dose is usually too low for effective treatment of significant disease. A 100mg suppository can be compounded. For more severe disease 10% hydrocortisone acetate is compounded in a vaginal cream and 3-5g (300-500mg) are inserted nightly for 2 weeks and then decreased to Monday, Wednesday and Friday. There are no safety data on these products and local atrophy may occur. Yeast infection must be suppressed using fluconazole 150mg weekly. Adrenal axis suppression can occur.⁸

Vulvar Pruritus

Up to 10% of women present with vulvar pruritus.⁹ Itching is one of the most distressing vulvar symptoms and patients can find it more difficult to manage than pain. Start by identifying the underlying cause or disease for targeted treatment. Pruritus is often an ongoing clinical challenge. Management involves not only pharmacologic intervention, but also nonspecific measures, such as patient support and education. All potential irritants, including excessive body hygiene (over washing), must be stopped. Infection with Candida and bacteria must be eliminated. Cooling the area can be helpful. Use cool gel packs, not ice packs that can further injure the skin. Cool soaks or sitz baths and bland emollients can soothe fissured or eroded skin. Inflammation can be controlled with topical and systemic steroids. Sedation is often imperative to stop scratching. For nighttime sedation, hydroxyzine or doxepin starting at 10mg/dose can be slowly increased to 100mg. During the day a selective serotonin reuptake inhibitor (citalopram 20-40mg in the morning), can be helpful. For neuropathic pruritus, a tricyclic antidepressant (amitriptyline, doxepin, or nortriptyline) can be considered. Begin with a low dose and increase gradually. Gabapentin can be of benefit, start at 300mg/dose up to a maximum of 3600mg/day.^10,11

Vulvar Pain

Vulvar pain may be due to any one of a number of vulvar disorders or attributable to idiopathic pain (i.e., vulvodynia). Topical anesthetics are commonly recommended (e.g., 2-5% lidocaine in a gel or ointment base or 2.5% lidocaine with 2.5% prilocaine in a cream base). These can be applied several times a day if the treatment is not too irritating. Never use benzocaine as it is very caustic and allergenic. The range of pain medications is beyond the scope of this article. Typically, tricyclic agents (e.g., amitriptyline or nortriptyline), anticonvulsants (e.g., gabapentin or pregabalin), and/or antidepressants (e.g., duloxetine or venlafaxine) are used. For these medications, start low and go slow. Treatment for vulvodynia is most effective with a multidisciplinary approach using medications, pelvic floor physiotherapy, cognitive pain therapy, nerve blocks, and more.^12,13

Nonresponders

For patients not responding consider noncompliance, an incorrect diagnosis, infection, trauma due to aggressive hygiene, contact dermatitis, or squamous cell carcinoma. Factors that can contribute to noncompliance include fear of steroids, vulvar ignorance, miscommunication, secondary gain (e.g., to avoid sexual activity), and physical impairment, such that the obese or arthritic patient cannot reach the area. Always look for concomitant conditions (e.g., lichen sclerosus plus contact dermatitis plus infection). Patients showing a poor response to treatment should be reassessed, biopsied, and re-biopsied.

Conclusion

Dermatologists can play an important role in the management of vulvovaginal disease. We are ideally trained to recognize any skin changes and the multiple, often confusing, combinations of these conditions. In addition, familiarity with managing chronic and complex cutaneous conditions requiring long-term maintenance therapy provides an invaluable clinical advantage.

References

1. Margesson LJ. Vulvar disease pearls. Dermatol Clin 24(2):145-55, v (2006 Apr).
2. Edwards L. Vulvovaginal dermatology. Preface. Dermatol Clin 28(4):xi-xii (2010 Oct).
3. Schlosser BJ, Mirowski GW. Approach to the patient with vulvovaginal complaints. Dermatol Ther 23(5):438-48 (2010 Sep-Oct).
4. Nygaard I, Barber MD, Burgio KL, et al. Prevalence of symptomatic pelvic floor disorders in US women. JAMA 300(11):1311-6 (2008 Sep 17).
5. Belfiore P, Di Fede O, Cabibi D, et al. Prevalence of vulval lichen planus in a cohort of women with oral lichen planus: an interdisciplinary study. Br J Dermatol 155(5):994-8 (2006 Nov).
6. Di Fede O, Belfiore P, Cabibi D, et al. Unexpectedly high frequency of genital involvement in women with clinical and histological features of oral lichen planus. Acta Derm Venereol 86(5):433-8 (2006).
7. Goldstein AT, Thaci D, Luger T. Topical calcineurin inhibitors for the treatment of vulvar dermatoses. Eur J Obstet Gynecol Reprod Biol 146(1):22-9 (2009 Sep).
8. McPherson T, Cooper S. Vulval lichen sclerosus and lichen planus. Dermatol Ther 23(5):523-32 (2010 Sep-Oct).
9. Margesson LJ, Danby FW. Anogenital pruritus. In: Bope E, Rakel R, Kellerman R (eds). Conn’s Current Therapy 2010. 2010 ed. Philadelphia: Elsevier, p882-4 (2010).
10. Lynch PJ. Lichen simplex chronicus (atopic/neurodermatitis) of the anogenital region. Dermatol Ther 17(1):8-19 (2004).
11. Stewart KM. Clinical care of vulvar pruritus, with emphasis on one common cause, lichen simplex chronicus. Dermatol Clin 28(4):669-80 (2010 Oct).
12. Danby CS, Margesson LJ. Approach to the diagnosis and treatment of vulvar pain. Dermatol Ther 23(5):485-504 (2010 Sep-Oct).
13. Groysman V. Vulvodynia: new concepts and review of the literature. Dermatol Clin 28(4):681-96 (2010 Oct).

¹The University of Texas Medical School at Houston, Houston, TX, USA

²Center for Clinical Studies, Houston, TX, USA

³Department of Dermatology, University of Texas Health Sciences Center, Houston, TX, USA

ABSTRACT

In atopic dermatitis (AD), the stratum corneum of patients appears to have alterations that predispose them to colonization and invasion by various bacteria, most notably Staphylococcus aureus (S. aureus). This bacterial co-existence is accepted to be an important factor in AD disease activity. Exactly when to initiate antimicrobial treatment is controversial, but such intervention, when warranted, has repeatedly been demonstrated to improve the course of AD. However, the increase in antibiotic resistance presents a therapeutic challenge in the management of AD patients, which highlights the need for novel mechanism topical antibacterial agents. Retapamulin is a relatively new pleuromutilin antibiotic designed for topical use. In vitro studies have demonstrated its low potential for the development of antibacterial resistance and high degree of potency against Gram-positive bacteria found in skin infections, including many S. aureus strains that are resistant to methicillin, fusidic acid, and mupirocin. Clinical studies exploring the treatment of secondarily infected dermatitis reveal that the efficacy of topical retapamulin is comparable to a 10-day course of oral cephalexin or to topical fusidic acid. Retapamulin appears to be a much needed antimicrobial option for treating the AD population due to their common carriage of bacterial pathogens and frequency of infectious complications.

Key Words:
antibacterial, atopic dermatitis, retapamulin, skin infections

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease that affects approximately 20% of children and 1-3% of adults; incidence is on the rise due to modern environmental factors in addition to genetic predisposition.^1-5 AD is a condition that encompasses eczematous changes within the epidermis, consisting of a multifaceted underlying etiology including, but not limited to, epidermal barrier dysfunction, atopic diathesis, and an increased incidence of secondary infections.^3,4,6 Acute lesions are characterized by erythema, oozing, and crusting, whereas chronic lesions can feature papules and lichenification. Affected individuals experience a decreased quality of life that is secondary to intermittent skin eruptions and difficult-to-control pruritus.^7,8

One of the main factors in the pathogenesis of AD involves a compromised function of the natural skin barrier. AD patients are deficient in ceramides, the sphingolipid constituents of protective and potently antimicrobial lamellar sheets in the stratum corneum.^9,10 A second factor is a reduced amount of antimicrobial peptides in the skin of AD patients.^4,5,10 Keratinocytes produce 2 major classes of innate antimicrobials: Β-defensins and cathelicidins; both are essential to defend the skin against bacterial invasion. In AD, the high concentrations of interleukin-10 and T2 helper cytokines cause a down regulation in the production of these antimicrobial peptides. Furthermore, the skin of AD patients has decreased moisture content. Together, these alterations in the microenvironment of the skin predispose AD patients to widespread microbial colonization and infection. For instance, it has been reported that AD patients have a 200- fold increase in S. aureus colonization when compared with individuals with healthy skin.^4,11 On both lesional and nonlesional skin, >90% of AD patients are colonized by S. aureus, whereas the prevalence is only 5-20% in non-AD individuals.^7,8,12 Among AD patients, the mean colonization density of S. aureus is markedly higher within the atopic lesions.^4,8,11 The presence of such a high microbial load is associated with increased disease severity.^1,2,8

Overview of Standard Treatment

Standard AD care includes topical glucocorticoids as firstline agents, followed by newer options, such as calcineurin inhibitors and anti-IgE antibodies.⁵ With regard to secondary infections, antimicrobial therapy can either be administered orally or topically. Topical antimicrobials are preferentially given due to the fact that administration can be directly targeted to the infected area, therefore reducing the potential for systemic side-effects, such as gastrointestinal distress and undesired drug interactions.¹³ Until recently, topical antimicrobials have been limited in availability; the main options include fusidic acid (introduced in 1962) and mupirocin (introduced in 1985). Recent reports indicate that multiple bacterial organisms have successfully developed resistance to these 2 drugs.^14,15 This rising prevalence increasingly limits their use to specific conditions, e.g., systemic fusidic acid for severe bone infections and topical mupiricin to eradicate nasal methicillin-resistant Staphylococcus aureus (MRSA).¹⁴ However, due to the aforementioned phenomena of increased susceptibility to colonization with microorganisms, combined with a compromised ability to defend against them, the addition of antimicrobial therapy to the standard care regimen of AD is recommended in certain clinical circumstances, which include:⁴

a) early signs of secondary bacterial infection;

b) AD exacerbation that cannot be otherwise explained; and

c) AD that is poorly controlled by monotherapy with topical anti-inflammatories.

Topical Retapamulin

Retapamulin ointment 1% (Altabax^®/Altargo^®, GlaxoSmithKline) is the first approved pleuromutilin antimicrobial for the treatment of uncomplicated superficial skin infections caused by staphylococcal, streptococcal, and anaerobic Grampositive organisms; it is not substantially effective against Gram-negative organisms.^16,17 Currently, it is approved for use in the EU for patients with impetigo or small infected wounds, and in the US for impetigo. Retapamulin has not received US FDA approval for MRSA skin infections. However, based on in vitro studies and incidental clinical trials data, it holds promise in the treatment of bacterial skin infections owing to its high in vitro potency against many common skin pathogens, low potential for development of bacterial resistance, and targeted application to the sites of involvement without significant systemic exposure.^13,16,18

Retapamulin is a semisynthetic pleuromutilin derivative isolated from Clitopilus scyphoides (an edible mushroom) and functions by selectively targeting the 50S subunit of bacterial ribosomes to inhibit protein synthesis.¹⁴ It acts at a site distinct from other available drugs; therefore, crossresistance is not yet a concern. The in vitro minimum inhibitory concentration required to suppress the growth of 90% of organisms (MIC90) by retapamulin was 0.12g/ml against S. aureus, including methicillin- and mupirocinresistant, and Staphylococcus Epidermidis isolates. Retapamulin was also shown to be very active against Streptococcus Pyogenes (S. Pyogenes), approximately 1000 times as potent as mupiricin or fusidic acid.¹⁵

A large study of over 6500 bacterial isolates, including staphylococcus and streptococcus from 13 countries, obtained from both hospital and community settings, further demonstrated the in vitro efficacy of retapamulin against these bacteria. Between 2005-2006, this Global Surveillance Program found retapamulin to also be effective against strains of S. aureus with resistance to methicillin, mupirocin, and fusidic acid^19-21. Other in vitro studies have reported similar findings.¹⁸ In addition to Gram-positive coverage,²¹ retapamulin has shown mixed antimicrobial activity against anaerobes^14,22 and exhibited very minimal efficacy against enterococci and Gram-negative bacteria. Despite this in vitro data, clinical studies thus far have focused on Gram-positive skin infections. A low potential for the development of bacterial resistance has also been reported with retapamulin, and if resistance does develop, it does so very gradually and by mechanisms distinct from those known to occur against other available antimicrobial options.^23,24 The main mechanisms of resistance are twofold and include mutations in the retapamulin ribosomal binding site and a non-target-specific efflux mechanism.^25-27 These results have been reproduced in both single-step and multistep passage studies.^14,23,24

Efficacy of Retapamulin

The overall findings from multiple trials indicate that retapamulin is a safe therapeutic alternative and it is at least as effective as conventional treatment options.

Impetigo

One of the initial retapamulin trials consisted of 7 days of treatment with topical retapamulin 1% vs. placebo for impetigo in 210 patients. Clinical success rates were significantly higher for the retapamulin-treated group as compared with placebo (85.6% vs. 52.1%). Microbiological success rates were even higher for retapamulin vs. placebo (91.2% vs. 50.9%).²⁸

A multicenter trial of noninferiority comparison of retapamulin ointment 1% twice daily for 5 days with sodium fusidate ointment 2% 3 times daily for 7 days was completed. Over 500 adults and children ≥9 months of age with impetigo were treated in this randomized, observer-blinded phase 3 study. The group treated with retapamulin exhibited a 99% clinical success rate vs. 94% in the sodium fusidate treated arm. Cases of MRSA isolated at baseline were treated in the retapamulin group (n=8) and in the sodium fusidate group (n=2); both agents were 100% effective in treating these cases of MRSA impetigo.¹³

Secondarily Infected Traumatic Lesions

For the treatment of secondarily infected traumatic lesions, over 1900 patients participated in 2 identical, randomized, double-blind, controlled, multicenter trials of retapamulin 1% ointment twice daily for 5 days vs. oral cephalexin 500mg twice daily for 10 days.²⁹ Retapamulin was approximately 90% effective in successfully treating these skin infections compared with 92% for cephalexin. Compliance rates were significantly higher in the retapamulin group. Another randomized, double-blind, double-dummy noninferiority trial with 547 adults and children ≥9 months of age with secondarily infected dermatitis (SID) was performed with retapamulin.¹⁶ Patients with SID were randomized to treatment with retapamulin ointment 1% twice daily for 5 days or oral cephalexin 500mg twice daily for 10 days. Clinical success rates were 86% and 90%, respectively.

Potential Side-Effects of Retapamulin

The most common adverse event with the use of retapamulin ointment was localized application site irritation (e.g., pruritis), which was reported by less than 2% of all patients. Additionally, there exist 2 newly published case reports detailing allergic contact dermatitis as a result of retapamulin usage.^30,31 These patients ranged in age from 6 to 79 years and were all diagnostically worked up via patch testing, which identified retapamulin as the cause and excluded other ingredients in the formulation. While this has been reported as an extremely rare occurrence, no detailed studies have yet been conducted to estimate its true incidence. Nonetheless, a limited duration regimen of topical retapamulin can still ease AD progression and increase compliance vs. other longer term topical treatments or oral regimens. Improved treatment compliance may also contribute to decreased resistance.

The Use of Antibiotics in AD Treatment

Conflicting data exists with regard to the role of antibiotic therapy in the treatment of AD. One controlled study showed that systemic cloxacillin or erythromycin cleared S. aureus with at least 6 months of sustained clinical improvement.³² However, a second study among patients with no overt signs of infection indicated that there was no improvement after flucloxacillin treatment.³³ Numerous open and doubleblinded placebo-controlled experiments have since evaluated the combination of corticosteroids with topical antimicrobials in AD treatment. The majority of findings from these studies have shown significant benefit (1 of these studies specified benefit only in the case of severe disease), which included decreased colonization density and at least partial improvement of skin lesions. However, 1 study showed only marginal improvement and 2 showed no benefit.^7,8,10,34-37

Bacterial Decolonization

A meta-analysis by Birnie et al. investigated whether or not interventions to decrease S. aureus colonization in AD patients should be prescribed.¹ They looked at 21 studies and analyzed different eradication mechanisms, and concluded that treatment simply to decrease the colony load of S. aureus in AD patients without an overt infection was not recommended. However, the study team stated that this conclusion is limited by multiple factors, such as poor study design, improper reporting of results, and failure to include outcome findings related to quality of life and longterm improvement. The investigators do recommend further research in this area.

Conclusion

Finite topical antimicrobial therapy (for approximately 2 weeks) can be an important addition to the standard treatment of AD in many instances, especially when there are overt signs of a secondary infection or if manifestations cannot be well controlled with anti-inflammatories alone. Data is conflicting as to exactly when antimicrobials should be introduced for the treatment of AD, but following their use, overall improvement in disease course has been shown in multiple studies. Considering that resistance to current topical antimicrobials is increasing, leading to further challenges in treating skin infections, the need for new treatment options is very real. The advent of retapamulin offers a safe, effective, and distinct alternative to its predecessors, and can serve as an adjunctive therapeutic option in specified AD patients. While no clinical trials with retapamulin have been performed specifically for AD, its safety and efficacy are proven in uncomplicated superficial skin infections involving the same bacterial isolates, notably S. aureus, MRSA, and S. pyogenes.

References

1. Birnie AJ, Bath-Hextall FJ, Ravenscroft JC, et al. Interventions to reduce Staphylococcus aureus in the management of atopic eczema. Cochrane Database Syst Rev (3):CD003871 (2008).
2. Gilani SJ, Gonzalez M, Hussain I, et al. Staphylococcus aureus re-colonization in atopic dermatitis: beyond the skin. Clin Exp Dermatol 30(1):10-3 (2005 Jan).
3. Katoh N. Future perspectives in the treatment of atopic dermatitis. J Dermatol 36(7):367-76 (2009 Jul).
4. Lin YT, Wang CT, Chiang BL. Role of bacterial pathogens in atopic dermatitis. Clin Rev Allergy Immunol 33(3):167-77 (2007 Dec).
5. Novak N. New insights into the mechanism and management of allergic diseases: atopic dermatitis. Allergy 64(2):265-75 (2009 Feb).
6. Komine M. Analysis of the mechanism for the development of allergic skin inflammation and the application for its treatment: keratinocytes in atopic dermatitis – their pathogenic involvement. J Pharmacol Sci 110(3):260-4 (2009 Jul).
7. Breuer K, HÄussler S, Kapp A, et al. Staphylococcus aureus: colonizing features and influence of an antibacterial treatment in adults with atopic dermatitis. Br J Dermatol 147(1):55-61 (2002 Jul).
8. Gong JQ, Lin L, Lin T, et al. Skin colonization by Staphylococcus aureus in patients with eczema and atopic dermatitis and relevant combined topical therapy: a double-blind multicentre randomized controlled trial. Br J Dermatol 155(4):680-7 (2006 Oct).
9. Arikawa J, Ishibashi M, Kawashima M, et al. Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patients with atopic dermatitis to colonization by Staphylococcus aureus. J Invest Dermatol 119(2):433-9 (2002 Aug).
10. Biedermann T. Dissecting the role of infections in atopic dermatitis. Acta Derm Venereol 86(2):99-109 (2006).
11. Kedzierska A, Kapinska-Mrowiecka M, Czubak-Macugowska M, et al. Susceptibility testing and resistance phenotype detection in Staphylococcus aureus strains isolated from patients with atopic dermatitis, with apparent and recurrent skin colonization. Br J Dermatol 159(6):1290-9 (2008 Dec).
12. Hauser C, Wuethrich B, Matter L, et al. Staphylococcus aureus skin colonization in atopic dermatitis patients. Dermatologica 170(1):35-9 (1985).
13. Oranje AP, Chosidow O, Sacchidanand S, et al. Topical retapamulin ointment, 1%, versus sodium fusidate ointment, 2%, for impetigo: a randomized, observer-blinded, noninferiority study. Dermatology 215(4):331-40 (2007).
14. Yang LP, Keam SJ. Retapamulin: a review of its use in the management of impetigo and other uncomplicated superficial skin infections. Drugs 68(6):855-73 (2008).
15. Rittenhouse S, Biswas S, Broskey J, et al. Selection of retapamulin, a novel pleuromutilin for topical use. Antimicrob Agents Chemother 50(11):3882-5 (2006 Nov).
16. Parish LC, Jorizzo JL, Breton JJ, et al. Topical retapamulin ointment (1%, wt/wt) twice daily for 5 days versus oral cephalexin twice daily for 10 days in the treatment of secondarily infected dermatitis: results of a randomized controlled trial. J Am Acad Dermatol 55(6):1003-13 (2006 Dec).
17. Yang LP, Keam SJ. Spotlight on retapamulin in impetigo and other uncomplicated superficial skin infections. Am J Clin Dermatol 9(6):411-3 (2008).
18. Woodford N, Afzal-Shah M, Warner M, et al. In vitro activity of retapamulin against Staphylococcus aureus isolates resistant to fusidic acid and mupirocin. J Antimicrob Chemother 62(4):766-8 (2008 Oct).
19. Scangarella-Oman NE, Shawar RM, Bouchillon S, et al. Microbiological profile of a new topical antibacterial: retapamulin ointment 1%. Expert Rev Anti Infect Ther 7(3):269-79 (2009 Apr).
20. Jones RN, Fritsche TR, Sader HS, et al. Activity of retapamulin (SB-275833), a novel pleuromutilin, against selected resistant gram-positive cocci. Antimicrob Agents Chemother 50(7):2583-6 (2006 Jul).
21. Pankuch GA, Lin G, Hoellman DB, et al. Activity of retapamulin against Streptococcus pyogenes and Staphylococcus aureus evaluated by agar dilution, microdilution, E-test, and disk diffusion methodologies. Antimicrob Agents Chemother 50(5):1727-30 (2006 May).
22. Odou MF, Muller C, Calvet L, et al. In vitro activity against anaerobes of retapamulin, a new topical antibiotic for treatment of skin infections. J Antimicrob Chemother 59(4):646-51 (2007 Apr).
23. Kosowska-Shick K, Clark C, Credito K, et al. Single- and multistep resistance selection studies on the activity of retapamulin compared to other agents against Staphylococcus aureus and Streptococcus pyogenes. Antimicrob Agents Chemother 50(2):765-9 (2006 Feb).
24. Gentry DR, Rittenhouse SF, McCloskey L, et al. Stepwise exposure of Staphylococcus aureus to pleuromutilins is associated with stepwise acquisition of mutations in rplC and minimally affects susceptibility to retapamulin. Antimicrob Agents Chemother 51(6):2048-52 (2007 Jun).
25. Davidovich C, Bashan A, Auerbach-Nevo T, et al. Induced-fit tightens pleuromutilins binding to ribosomes and remote interactions enable their selectivity. Proc Natl Acad Sci U S A 104(11):4291-6 (2007 Mar 13).
26. Champney WS, Rodgers WK. Retapamulin inhibition of translation and 50S ribosomal subunit formation in Staphylococcus aureus cells. Antimicrob Agents Chemother 51(9):3385-7 (2007 Sep).
27. Yan K, Madden L, Choudhry AE, et al. Biochemical characterization of the interactions of the novel pleuromutilin derivative retapamulin with bacterial ribosomes. Antimicrob Agents Chemother 50(11):3875-81 (2006 Nov).
28. Koning S, van der Wouden JC, Chosidow O, et al. Efficacy and safety of retapamulin ointment as treatment of impetigo: randomized double-blind multicentre placebo-controlled trial. Br J Dermatol 158(5):1077-82 (2008 May).
29. Free A, Roth E, Dalessandro M, et al. Retapamulin ointment twice daily for 5 days vs oral cephalexin twice daily for 10 days for empiric treatment of secondarily infected traumatic lesions of the skin. Skinmed 5(5):224-32 (2006 Sep-Oct).
30. Schalock PC. Allergic contact dermatitis to retapamulin ointment. Contact Dermatitis 61(2):126 (2009 Aug).
31. Warshaw EM, Toby Mathias CG, Baker DR. Allergic contact dermatitis from retapamulin ointment. Dermatitis 20(4):220-1 (2009 Aug).
32. Dhar S, Kanwar AJ, Kaur S, et al. Role of bacterial flora in the pathogenesis & management of atopic dermatitis. Indian J Med Res 95:234-8 (1992 Sep).
33. Ewing CI, Ashcroft C, Gibbs AC, et al. Flucloxacillin in the treatment of atopic dermatitis. Br J Dermatol 138(6):1022-9 (1998 Jun).
34. Hjorth N, Schmidt H, Thomsen K. Fusidic acid plus betamethasone in infected or potentially infected eczema. Pharmatherapeutica 4(2):126-31 (1985).
35. Huang JT, Abrams M, Tlougan B, et al. Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics 123(5):e808-14 (2009 May).
36. Leyden JJ, Kligman AM. The case for steroid–antibiotic combinations. Br J Dermatol 96(2):179-87 (1977 Feb).
37. Wachs GN, Maibach HI. Co-operative double-blind trial of an antibiotic/corticoid combination in impetiginized atopic dermatitis. Br J Dermatol 95(3):323-8 (1976 Sep).

ABSTRACT

Young adult populations (18-25 years of age) throughout the world have latched onto the mainstream trend of body piercing. Best health care practices for these individuals involves the knowledge of proper procedural techniques, postsite care, common complications, and treatment modalities.

Key Words:
blood transfusions, body art, body piercings, infective endocarditis, piercing infections, scarring, skin trauma

Creativity and ubiquity are the only constants of body piercing.^1,2 Yet, no matter what one’s opinion is about body piercings, don’t become distracted by them and delay important medical care.³ Body piercing has been around for centuries in various societies as part of ritualistic or cultural practices, and now it is rapidly becoming a worldwide mainstream fashion trend, especially among young adults aged 18-25 years. According to Armstrong et al., body piercing is defined as the insertion of a needle to create a fistula-like opening (into either cartilage or skin) for the introduction of decorative ornaments, which can include insertion of jewelry, plastic or wood plugs, beads, or pearls.¹ Current US body piercing rates are approximately 36%,⁵ and those figures are similar for smaller studies^2,6 that also excluded ear lobe piercings. Women tend to report obtaining body piercings more so than men do.

Body Piercing Regulated Environment

An actual body piercing procedure only takes a few moments, but given the invasive technique of the procedure, an earlier study⁶ cited frequent infections (45%) and skin irritations (39%) as prevalent piercing site problems, often because no aftercare instructions for proper skin treatment were provided. Now, considering the overall amount of body piercing worldwide and the presence of a better (but certainly not perfect) regulated body art environment,⁷ the number of self-reported complications remain around 17%-35%.⁸ While most body piercings are not problematic, the potential for localized infections, as well as associated systemic diseases, is present so long as the piercing site remains open.^1,9,10 These infections may become an even more invasive problem with the emergence of community acquired methicillin resistant Stapthylococcus aureus (CA-MRSA).³

Blood transfusions have also been affected by the increase in body piercing.¹¹ For many years, individuals with new piercings could not donate blood for at least 1 year following the piercing. In 2005, the Canadian Blood Services reduced their deferral period from 12 to 6 months, and the US has reduced their deferral period (which varies from state to state) if body art was obtained in regulated areas. Current evidence indicates disease transmission has not increased with these new regulations, and Spain is currently examining a deferral period reduction to 4 months.

Pierced Seeking Prompt Treatment

Many individuals with body piercings do not perceive their body art as “permanent”; frequently they say, “If I don’t like it, I can remove it.” They are often aware of the procedural risks; however, when initial site irritation, pain, or oozing occurs, most skin problems may be dismissed or self-treated.¹² Other times, individuals are “embarrassed,” thinking the infection could be their fault, and/or “fear” that the jewelry needs to be removed. Additionally, findings from recent studies^13-15 suggest that these individuals look to the internet or return to the piercer for assistance, instead of seeing their health care provider, due to the clinicians’ lack of adequate knowledge, judgmental perspectives about body art, and limited educational resources about piercings.

Piercing History Helps Determine Your Diagnosis

Where was the piercing obtained?

Stores/kiosks in shopping malls provide ear lobe and high rim ear piercings using piercing guns, and sell benzalkonium chloride solution as their after-care product of choice. This solution does not have adequate microbicidal activity against Pseudomonas aeruginosa infections and has been frequently mentioned in outbreaks of auricular chondritis.^16-19 Additionally, limited employee training and supervision, along with inadequate quality control measures have also been reported.

What type of after-care was done?

Diminished skin integrity is greater with newly acquired body piercings, especially from procedures obtained during warm weather months.¹² In a regulated body art environment, piercing artists emphasize conscientious care of the piercing site following the procedure with careful monitoring of the site until it is completely healed.^7,10,20-21 While healing times are dependent on site location, facial piercings usually heal within 2 months, and covered areas can take up to 6 months. Yet, a completely healed site requires judicious care of the piercing site for at least 1 year until the skin epithelializes, “toughening up” the area for the adjustment of wearing various piercing inserts.¹

What kind of jewelry was placed in the site?

Due to the overall increase in jewelry containing nickel, there has been a marked increase in contact dermatitis related to nickel allergy,²² especially if it is purchased in shopping malls. Carefully selecting piercing jewelry (comprised of niobium, titanium, 300 grade surgical steel, or gold) that is found in piercing studios helps avoid allergen exposure, scarring, and risks of delayed infection.^9,21

Should jewelry be removed or not?

Retaining the jewelry at the site when an infection initially occurs, allows for better drainage and epidermal healing, whereas removal can potentiate abscess formation in deeper skin structures. However, if there is not resolution within 5-7 days, the jewelry should be removed, followed by surgical incision and drainage, and possible hospitalization with intravenous antibiotic therapy, especially for high ear-rim piercing infections.^16-19

Local Complications

Secondary trauma from body piercings (Table 1)¹² can occur frequently at the naval (40%), ear (35%), nose (12%), tongue, chin, eyebrows, genitals (8%), and nipple (5%). Common complications include bleeding, bacterial or viral infections, mechanical tissue tearing, keloid scarring, nerve impairment, and allergies. These complications can arise from the body piercing procurement and/or limited procedural after-care. Embedded earrings are also frequently seen.²³ Exposed wounds from piercing inserts can also occur from physical assaults, motor vehicle accidents, or aggressive contact sports.¹² Additionally, as more people retain their body art for longer periods of time, other effects can evolve, which may involve further invasive, corrective procedures from a specialist.

Management of Infections

Bacterial skin infections at or near the site are considered the most commonly reported complication of body piercings, with causative organisms primarily consisting of 2 gram-positive bacteria: Staphylococcus, and group A Beta-hemolytic Streptococcus, and 1 gram-negative bacteria: Pseudomonas.²⁴ Ideally, pharmacological interventions would be pathogen-specific, based on cultures of the affected site. However, due to the length of time cultures take to be processed, it is not always reasonable to delay treatment, as a more severe infection can ensue if left untreated.

Current infectious disease guidelines²⁴ recommend that the majority of minor skin and soft-tissue infections may be treated with penicillins, first-generation or second-generation oral cephalosporins, macrolides, or clindamycin. Of note, though, is that there is growing resistance of MRSA strains to clindamycin, in the range of approximately 50%. CA-MRSA strains showed continued responsiveness to trimethoprim-sulfamethoxazole and tetracycline. Ideally, after initiation of antibiotic therapy, patient follow-up at 24-48 hours is important. If the patient is not demonstrating a positive response to therapy, the clinician should strongly consider that the progression of infection may be a result of resistance or a sign of a more severe infection.²⁴ In the event that the infection causes the formation of skin abscesses, the clinician should consider a more aggressive combination approach to therapy, including antibiotics and possible incision and drainage of related skin abscesses.¹¹

Systemic Infections from Piercing

Although rare, systemic infections, such as infective endocarditis (IE) or sepsis, can also occur.²⁵ These are thought to be “triggered either by normal flora at the puncture site, microorganism colonization around the jewelry, or by a localized site infection that stimulates episodes of transient bacteremia, that can seed various areas of the heart.”²⁵ More than 25 IE cases in the past decade have come from tongue, navel, earlobe, lower lip, and nipple piercings. If an individual with a new piercing (i.e., up to 4 months), with or without a history of congenital heart disease, presents with unexplained fever, night chills, weakness, myalgia, arthralgia, lethargy, or malaise, IE should be considered, especially as body piercing continues to increase. Prophylactic antibiotic regimens have been suggested since 1999, but the treatment is still being debated.²⁴

Conclusion

While piercers are knowledgeable regarding the techniques and procedures of body piercing, treatment for health concerns and complications related to piercings should be provided by knowledgeable clinicians. Non-judgmental, informative care is crucial when complications arise.^1,20 Yet, as you work with those who have piercing complications, remember that removing a piercing does not remove the individual’s motive or rationale for obtaining the piercing. Often, within about 6 months they will obtain another,^1,2,20 so applicable education about piercing care remains vital for preventing further or repeated sequelae.

Recommendations for care of a new piercing as defined by the Association of Professional Piercers include:²²

• Instruct patients to wash the piercing site with soap and water or a diluted saline solution (1/8 tsp of salt to 8 oz of water) twice per day, because piercing tracts can become portals or reservoirs for viruses and bacteria.
• Recommend the use of antiseptic mouthwash (alcohol-free) for oral piercings.
• Instruct individuals with oral piercings to use ice chips or other cool fluids to reduce swelling and ease discomfort during the initial healing phase.
• Advise against the use of alcohol, Hibiclens® (Mölnlyke Healthcare), hydrogen peroxide, Bactine® (Bayer Healthcare), and Betadine® (Purdue Products LP) in piercing care.
• Encourage patients to search the Association of Professional Piercers website21 for further educational material regarding each type of piercing.

References

1. Armstrong ML, Koch JR, Saunders JC, et al. The hole picture: risks, decision making, purpose, regulations, and the future of body piercing. Clin Dermatol 25(4):398-406 (2007 Jul-Aug).
2. Armstrong ML, Roberts AE, Owen DC, et al. Toward building a composite of college student influences with body art. Issues Compr Pediatr Nurs 27(4):277-95 (2004 Oct-Dec).
3. Centers for Disease Control and Prevention. National MRSA Education Initiative: Preventing MRSA skin infections. At: www.cdc.gov/mrsa/mrsa_initiative/skin_infection/index.html. Accessed Aug 2009.
4. DeBoer S, Amundson T, Angel E. Managing body jewelry in emergency situations: misconceptions, patient care, and removal techniques. J Emerg Nurs 32(2):159-64 (2006 Apr).
5. Pew Research Center For the People & the Press: How young people view their lives, futures and politics: A portrait of Generation Next (2007). At: www.people=press.org. Accessed May 2008.
6. Greif J, Hewitt W, Armstrong ML. Tattooing and body piercing: body art practices among college students. Clin Nurs Research 8(4):238-44 (1999 Nov).
7. Armstrong ML. Tattooing, body piercing, and permanent cosmetics: A historical and current view of state regulations, with continuing concerns. J Enviro Health 67(8):38-43. (2005 Apr).
8. Mayers L, Chiffriller S. Sequential survey of body piercing and tattooing prevalence and medical complication incidence among college students. Arch Pediatr Adolesc Med 161(12):1219-20 (2007 Dec).
9. Beers MS, Meires J, Loriz L. Body piercing: coming to a patient near you. Nurse Pract 32(2):55-60 (2007 Feb).
10. Meltzer DI. Complications of body piercing. Am Fam Physician 72(10):2029-34 (2005 Nov).
11. Goldman M, Xi G, Yi QL, et al. Reassessment of deferrals for tattooing and piercing. Transfusion 49(4):648-54 (2009 Apr).
12. Kuchinski A, Pereira P, Armstrong ML. Caring for Pierced Patients: Attitudes, Secondary Trauma, and Forensic Evidence. Mosby’s Nursing Consult. At: http://www.nursingconsult.com/das/stat/view/138582404-2/cup. Accessed May 2009.
13. Caliendo C, Armstrong ML, Roberts AE. Self-reported characteristics of women and men with intimate body piercings. J Adv Nurs 49(5):474-84 (2005 Mar).
14. Young C, Armstrong ML. What nurses need to know when caring for women with genital piercings. Nurs Womens Health 12(2):129-38 (2008 Apr).
15. Young C, Armstrong ML, Roberts AE, et al. A triad of evidence for care of women with genital piercings. J Am Acad Nurs Pract (in press).
16. Widick MH, Coleman J. Perichondrial abscess resulting from a high ear-piercing–case report. Otolaryngol Head Neck Surg 107(6 Pt 1):803-4 (1992 Dec).
17. Hanif J, Frosh A, Marnane C, et al. Lesson of the week: “High” ear piercing and the rising incidence of perichondritis of the pinna. BMJ 322(7291):906-7 (2001 Apr).
18. Keene WE, Markum AC, Samadpour M. Outbreak of Pseudomonas aeruginosa infections caused by commercial piercing of upper ear cartilage. JAMA 291(8):981-5 (2004 Feb).
19. More DR, Seidel JS, Bryan PA. Ear-piercing techniques as a cause of auricular chondritis. Pediatr Emerg Care 15(3):189-92 (1999 Jun).
20. Stirn A. Body piercing: medical consequences and psychological motivations. Lancet 361(9376):1205-15 (2003 Apr).
21. The Association of Professional Piercers. Suggested aftercare of body piercings. At: www.safepiercing.org. Accessed May 2009.
22. Copeland SD, DeBey S, Hutchison D. Nickel allergies: implications for practice. Dermatol Nurs 19(3):267-8, 288 (2007 Jun).
23. Timm N, Iyer S. Embedded earrings in children. Pediatr Emerg Care 24(1):31 (2008 Jan).
24. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 41(10):1373-406 (2005 Nov).
25. Armstrong ML, DeBoer S, Cetta F. Infective endocarditis after body art: a review of the literature and concerns. J Adolesc Health 43(3):217-25 (2008 Sep).
26. The American Red Cross. (2009). Donor Eligibility. At: www.redcross.org/en/eligibility. Updated August 31, 2009.

• Stop the bleeding
• Clean the wound
• Homecare for scrapes and cuts
• Options for closing wounds
• Prevent infection
• Promote healing
• Identifying secondary infections
• Medical help for secondary infections

Stop the bleeding

Stopping the bleeding

The first priority is to stop the wound bleeding. Follow these simple steps:

• Try to calm and reassure the injured person.
• Apply firm pressure directly to the wound, ideally using a clean cloth or towel. You can also use a finger if nothing else is available.
• If the blood seeps through the cloth or towel, add more pressure.
• Remove pressure when the bleeding stops, usually in five to ten minutes.

When your patient should seek medical help

Your patient may need to seek medical help to stop the bleeding. They should seek immediate medical attention if:

• The bleeding does not stop in ten minutes.
• You see bright red and spurting blood (this means that an artery has been severed).

Clean the wound

Cleaning the wound

It’s very important to carefully clean a wound. Proper cleaning removes any foreign material, reduces the risk of secondary infection and minimizes any potential scarring.

To clean the wound:

• Rinse the wound with clear water. Running tap water can be used.
• Remove any foreign material in the wound (such as dirt, gravel or glass) by using tweezers if necessary.
• Ideally, clean the wound with a sterile gauze.
• Avoid using cotton wool.
• If the bleeding restarts, apply firm pressure.

Most first aid kits include sterile or antiseptic wipes which can be used to clean the wound.

When your patient should seek medical help

If your patient is unable to remove all foreign objects, they should seek medical help in thoroughly cleaning the wound.

Homecare for scrapes and cuts

Most scrapes and cuts can be cared for at home.

Scrapes often cover large areas, but they are superficial. When caring for a scrape, make sure to remove any embedded grit or dirt.

Small cuts can be cared for at home if the edges of the cut are close together. Make sure to remove any foreign material from the cut, stop the bleeding and cover the cut with a bandage or dressing.

When your patient should seek medical help

Your patient may need to seek medical attention for a cut or scrape if:

• The wound needs sutures. A wound needs sutures if it is deep, if fat protrudes from it, if the wound is over half an inch long or if it is a gaping wound.
• Your patient is unable to remove dirt, debris or dead tissue.
• Your patient can’t stop the bleeding.
• The wound is a puncture.
• The wound occurs on the face, eyelids, lips, or neck.
• The edges of the wound are badly torn
• A tetanus shot is required.
• Your patient is uncomfortable or unable to deal with the situation.

Options for closing wounds

There are many ways to close wounds, and the best option will depend on the type and severity of the wound itself.

Skinstrips are tape-like strips that hold the skin together. These are appropriate for small cuts that occur on parts of the body where there is very little tension or movement that could pull the wound apart (e.g. torso, thigh).

For deeper cuts, stitches (or sutures) are used to sew the edges of the cut together. They are very useful for closing wounds that have occurred on parts of the body where there is a lot of movement (e.g. hands).

Steri-strips are used to close wounds on the face in those instances where stitches may leave a scar. Steri-strips or butterfly strips are thin and sticky, and usually fall off after a few days.

Skin glue is a special adhesive that sticks together the edges of the wound and seals the skin for protection. Skin glue is not as effective on areas where there is a significant amount of skin movement.

Prevent infection

Once you have stopped the bleeding and cleaned the wound, you will want to prevent infections from developing. The most effective strategy is to apply a topical antibiotic to the wound and cover it with a dressing.

You can help prevent infection by:

• Applying a topical antibiotic, such as Bactroban, Fucidin or Polysporin to the wound. Topical antibiotics should be applied with each dressing change, or two to three times a day if the wound is left uncovered.
• Cover the wound to keep it moist and to protect the topical antibiotic.

Studies show that applying a topical antibiotic can promote healing in eight days, as opposed to 13 days for wounds left untreated. The use of mercurochrome and tincture of iodine was not as effective. These products resulted in healing over 13 and 15 days respectively.

Promote healing

You can promote healing and minimize the potential for scarring by covering the wound. Scientific studies show that keeping an injured area moist:

• promotes the growth of new tissue
• lessens the potential for infection
• minimizes scarring
• lessens the chance of further injury to the cut or scrape

Many different sizes and types of wound dressings are available. Dressings should be changed daily or when they become wet or dirty.

Although covering a wound is generally the best choice, there are times when it’s appropriate to leave a wound uncovered. A scrape on a knee or elbow, for example, can often be left to heal uncovered after cleaning and applying a topical antibiotic.

Identifying secondary infection

You should examine the wound carefully to ensure that secondary infection has not developed. Signs of infection generally emerge a few days after the injury and include:

• red, swollen or warm skin surrounding the wound
• discharge and pus from the cut or scrape
• a red line moving up the limb from the wound
• fever

If your patients suspect secondary infection, they should seek medical help.

Medical help for secondary infections

If your patient seeks medical attention for a secondary infection of a cut or scrape, the doctor may swab the wound for bacteria.

Staph infections are the most common bacterial infections, and can lead to impetigo elsewhere on the skin. Prescription and over-the-counter topical antibiotics have been shown to be as effective at treating localized infections as oral antibiotics – and they have fewer side effects.

Strep infections are often indicated by a red line (lymphangitis) leading from the wound. Strep infections can also produce cellulitis, which is a tender swollen redness on the skin. Oral antibiotics provide an effective treatment.

This is a superficial chronic infection caused by a bacteria called Corynebacterium minutissimus. It is most commonly seen in the groin, armpits and in the folds. There are fairly well defined large brown patches with some fine scale wrinkling on the surface. Initially there is a light red colour which became brownish in time. There are usually no symptoms associated with this. The diagnosis can be confirmed by examination of the skin with Woods light. This is ultraviolet A which identifies the infected area by a bright coral red fluorescent colour.

Treatment: Anti-bacterial soaps as well as topical antibiotics can clear this problem.

Pitted keratolysis

This is most commonly seen on the undersurface of the feet. It is common. Well defined erosions are seen on the surface of the skin. This appears to be because the bacteria eat away at the keratin surface of the skin producing small craters and erosions. There is no inflammation associated with this. It usually does not produce any symptoms.

Treatment: Usually drying the skin with anti-perspirants can be very beneficial Topical antibiotics can also be of benefit.

Trichomycosis acillaris

This is a superficial bacterial infection in the hair of the armpits and the pubic area. There are small nodules or thickened cylinders attached to the hair which can be seen quite easily. They are usually yellow, sometimes red or brown. This may cause some discolouration on clothing. It is produced by a Corynebacterium.

Treatment: Using antibacterial soaps usually clears the problem. Oral antibiotics such as erythromycin may also be used.

This is a common superficial skin infection which is very contagious and is seen mostly in children. It can be either blistering or non-blistering. It is most commonly caused by staphylococcal infection although streptococcus pyogenes is sometimes a cause. It is spread easily by direct contact. It is more common in warm climates with high humidity and is often associated with mild skin trauma. The bullous form of impetigo is caused by staph aureus, usually Phage II Type 71. This causes blistering. This most commonly occurs in young infants or neonates and may be associated with fever. It starts as a small blister particularly on the face, trunk or buttocks. The blister will slowly enlarge to rupture leaving shiny skin which then becomes eroded. There is often a surrounding scale. The non-blistering or non-bullous form, which makes up the majority of infections, is usually caused by staph aureus but occasionally strep pyogenes. This commonly occurs at sites of minor trauma to the skin such as insect bites, reactions, abrasions, cuts, and hand burns. It usually starts with small reddish patches measuring about 2-4mm. They evolve to form small pustules or tiny blisters. These become easily crusted with a typical yellow or honey crust. It spreads by direct extension. It is most commonly seen on the face around the nose, mouth and also the extremities. The diagnosis is usually clear by examination of the skin. If left untreated this may resolve itself.

Treatment: The application of topical antibiotics such as mupirocin cream or ointment (Bactroban) is very effective. Fusidic acid (Fucidin) is also used. If the infection is more extensive oral antibiotics such as Cloxacillin or Cephalexin are used as well as those in the erythromycin family.

Ecthyma

This is a deeper form of impetigo. It occurs in the epidermis as well as in the dermis, producing a superficial ulcer that becomes secondarily crusted. It usually occurs secondary to trauma and is most commonly seen with poor hygiene. The lesions will often last for many weeks becoming essentially ulcerated and may even scar the skin. Secondary cellulitis and osteomyelitis are very uncommon developments.

Treatment: Oral antibiotics such as Cloxacillin or Keflex are often required

Folliculitis

This is an infection in the hair follicles. It is inclined to be on surface of the opening of the pore or deeper in the tissue. This is most commonly caused by staphylococcus aureus. It is seen on the face, upper trunk, arms and on buttocks. Deeper involvement can produce large red papules and sometimes pustules.

Treatment: Topical antibiotics such as Bacitracin or mupirocin cream or ointment (Bactroban) or fusidic acid (Fucidin) can be used. Chronic staphylococcal carriage in the nose should be looked for and be treated with mupirocin cream or ointment (Bactroban).

Staphylococcal Scalded Skin Syndrome

This has also been called Ritter’s disease. This condition is caused by a toxin produced by staphylococcus and is similar to that producing bullous impetigo or the toxic shock syndrome. It is usually seen in young children. It is occasionally seen in adults who are immune suppressed or have renal failure. There are usually associated symptoms such as fatigue, fever and irritability. The skin is very tender. There may be associated runny nose and conjunctivitis. This often starts on the head but then spreads to involve much of the body. The skin develops redness and a wrinkling appearance over soft blisters. Within days these loosen the surface to leave moist open areas. This is followed by scaling and peeling off of the skin. Recovery usually occurs within about two weeks. It is interesting that swabs of the skin are negative for staph aureus. This bacteria can be identified often in the eyes and throat.

Treatment: If this condition is extensive hospitalization will be required and treatment with systemic antibiotics.

Toxic Shock Syndrome

This is caused by a toxin produced by staphylococcus. It was first observed in the late 1970’s. Most commonly it was seen in young women who were menstruating. It was also observed following surgical procedures. It is also associated with deep skin infections such as abscesses and post-partum. A source of entry can also be the site of infusion sites for insulin pumps. This starts suddenly with high fevers, diarrhea, headaches, sore throats and aches and pains. It progresses to a state of shock. Initially there is diffusa redness that starts on the trunk and spreads outwards. There is swelling on the palms and soles. The mouth and tongue become red as do the eyes. There is often general swelling of these areas. This is followed by peeling of skin particularly on the palms and soles after one to three weeks.

Treatment: Intensive care is required to support the blood pressure and the organs. Any source of infection such as tampons must be removed. Oral antibiotics are required.

• Anterior nares
• Axilla, groin, perineum, rectum
• Dermatic skin, skin ulcers
• I.V. sites
• Indwelling catheters
• Tracheostomy tubes
• Feeding tubes

Antibiotic Resistance Profiles of MRSA:1

• All B-lactam antibiotics
• 94% resistant to clindamycin and erythomycin
• 89% resistant to ciprofloxacin
• 56% resistant to trimethoprimsulfamethoxazole
• 33% resistant to tetracycline
• 3% resistant to rifampin
• 3% resistant to fusidic acid
• 2% resistant to mupirocin

Antibiotic resistance varies from region to region in Canada

Suggestions for office practice involving MRSA patients:

• Hand hygiene
• When dealing with open wound:

– Gloves, Mask, Gown

– Contact isolation

– Barrier precautions

• Book MRSA patients at the end of the clinic day
• Educate patient about MRSA at home
• Educate office staff about reducing MRSA spread

Practical Points in Wound Care:

• Open wounds always contain bacteria
• Don’t try to eliminate bacteria from a wound
• Don’t try to decolonize the nares, if there is an open wound
• Don’t use oral antibiotics to “treat” wound colonization or wound contamination
• Don’t try to prevent wound infection with antibiotics
• Discontinue antibiotics when symptoms and signs of infection improve
• Do not let the presence of MRSA affect your decision about the diagnosis of infection

MRSA Treatment Flowchart

1 Andrew E. Simor, Marianna Ofner-Agostini, Elizabeth Bryce, Karen Green, Allison McGeer, Michael Mulvey, and Shirley Paton. The evolution of methicillin-resistant Staphylococcus aureus in Canadian hospitals: 5 years of national surveillance. Can. Med. Assoc. J. Jul 2001;165:21-26.

Click here to download a PDF with all the above information on MRSA.