Emily C. Keller, MD; Kenneth J. Tomecki, MD
Cleveland Clinic, Department of Dermatology, Cleveland, Ohio
Disclosure: The authors report no relevant conflicts of interest.
Abstract
Directed and preventive therapies for cutaneous infectious disease and infestation continue to evolve, providing physicians with new options for care. Common infectious diseases (e.g., genital herpes, herpes zoster, and head lice) occur in the outpatient and inpatient setting. This review of the literature highlights new therapies, including those still in development, such as novel drugs and vaccines, all of which should help to decrease the frequency and severity of common infectious diseases of the skin and subcutaneous tissues. (J Clin Aesthet Dermatol. 2011;4(12):18–24.)
Dermatologists encounter a plethora of infectious diseases in the inpatient and outpatient setting, most of which are treated with standard medications. Overuse and/or incorrect use may lead to decreased efficacy of the common drug as well as resistance. The introduction of novel topical and parenteral medications, as well as vaccines, allows for new treatment and preventive approaches to diseases, such as herpes zoster, genital herpes, head lice, and skin and soft tissue infections (SSTIs).
HERPES ZOSTER
Varicella zoster virus (VZV), an enveloped, double-stranded deoxyribonucleic acid (DNA) virus is the culprit of herpes zoster when reactivated in the sensory ganglia.[1] Approximately one million cases of zoster occur each year in the United States, with a lifetime risk of approximately 1 in 3.[2–4] One population-based study determined that 68 percent of herpes zoster occurred in persons aged 50 and older, with the incidence increasing one percent yearly in those 75 and older.4 The most common complication of zoster in healthy individuals is postherpetic neuralgia (PHN), defined as persistent pain for 30 days or more after the skin disease has resolved.[1] PHN occurs in 18 percent of affected adults. Incidence is five percent in those less than 60 years of age, but increases to 10 percent in those 60 to 69 years of age and to 20 percent in those 80 years of age or older.[4]
Zostavax. Zostavax (Merck & Co., Inc) is a live attenuated vaccine approved by the United States Food and Drug Administration (FDA) in 2006 for adults 60 years of age and older, with revised approval in 2011 for adults 50 years of age and older.[2,5,6] Administered as a single subcutaneous injection as a means to prevent or minimize zoster, Zostavax is indicated for healthy individuals with a known history of varicella.5 If a prior history of chickenpox is unknown, serological testing should be completed.[5] The vaccine is comparable to Varivax (Merck & Co., Inc), the varicella vaccine, but is 14 times more potent. Cost can be appreciable (i.e., $200–$400) and may not be covered by insurance.[7]
In the Shingles Prevention Study, Zostavax reduced the incidence of herpes zoster by 51.3 percent, the burden of illness secondary to herpes zoster by 61.1 percent, and the incidence of PHN by 66.5 percent.[2] The most common adverse effects were injection site reactions of erythema, pain or tenderness, swelling, and pruritus.[2] After 3.4 years, rates of hospitalization or death did not differ between those who received the vaccine and control groups.[8]
The personal impact of herpes zoster and PHN can be significant; 64 percent of patients experience sleep disturbance, 58 percent decreased “enjoyment of life,” and 53 percent alteration in general activities, the latter extending for 27 to 30 days in one study.[9] Physicians should encourage the use of Zostavax as routine vaccination for healthy individuals 50 years and older. Unfortunately, of the adults that should receive the vaccine, less than 10 percent do so. This could be secondary to physicians not strongly recommending the vaccine, not stocking the vaccine for easy accessibility, or upfront costs to the physician.[7,10]
HERPES SIMPLEX VIRUS
The herpes simplex virus (HSV) is pervasive worldwide, affecting approximately 536 million people aged 15 to 49 in 2003. Women are infected more often, and infection rates increase with age in both men and women.11 Prevention is the mainstay of treatment and many new products are in development.
PRO 2000, SAMMA. Topical microbicides include PRO 2000, cellulose sulfate, and polystyrene, all sulfonated polysaccharides that form complexes with glycoprotein B to inhibit HSV from binding, penetrating, and spreading between cells.[12,13] These microbicides are applied intravaginally before sexual intercourse and, in vitro, inhibit HSV infection 10,000-fold.[12] Human trials have shown that PRO 2000 gel (Indevus), a synthetic naphthalene sulfonic acid polymer, inhibits human immunodeficiency virus (HIV) and HSV by at least 1,000-fold.[14]
SAMMA, a mandelic acid condensation polymer, targets glycoprotein B-2, but does not contain sulfur.[15] In vitro SAMMA blocks the binding of HIV and HSV and has shown activity against Neisseria gonorrhoeae and Chlamydia trachomatis.[15]
Invisible condom. The invisible condom is yet another microbicide, a polyoxyethylene-polyocypropylene block copolymer that is in Phase 2/3 trials.[16] It is safe to use in healthy women once or twice daily for 14 days as well as their male sexual partners. Common adverse reactions were erythema (27%), itching (56%), dryness (34%), and burning (29%).[17]
Glycoprotein D vaccine. Glycoprotein D vaccine, administered intramuscularly at 0, 1, and 6 months, has been studied in women with and without a history of HSV. Efficacy in women seronegative for HSV-1 and HSV-2 was 38 percent and 42 percent in women seropositive for either HSV-1 or HSV-2. As such, there was no significant protection in either group, but a trend toward protection in those who were seronegative for both HSV-1 and HSV-2. The vaccine was not efficacious in men or in those women who were seropositive for HSV-1 and seronegative for HSV-2.[18]
HUMAN PAPILLOMAVIRUS
Human papillomavirus (HPV), a nonenveloped, double-stranded DNA virus, is the cause of external genital warts (EGWs), the most common sexually transmitted infection. HPV serotypes 6 and 11 are responsible for most genital warts and HPV 16 and 18 for most invasive cervical cancers.[19] HPV 16 accounts for 54 percent of cases and HPV 18 for 17 percent of invasive cervical cancer cases worldwide.[20,21] EGWs affect approximately one percent of the sexually active population, with the highest prevalence in women aged 20 to 24 and men aged 25 to 29.[22,23]
Human papillomavirus bivalent (types 16 and 18) vaccine, recombinant (Cervarix, GlaxoSmithKline) and human papillomavirus quadrivalent (types 6, 11, 16, and 18) vaccine, recombinant (Gardasil, Merck & Co., Inc). Human papillomavirus quadrivalent (types 6, 11, 16, and 18) vaccine, recombinant protects against HPV serotypes 6, 11, 16, and 18, and human papillomavirus bivalent (types 16 and 18) vaccine, recombinant protects against HPV 16 and 18—both are highly effective measures to prevent HPV infection. Approved by the FDA in 2009, Cervarix is indicated for women 10 to 25 years of age. Approved in 2006, Gardasil is indicated for men and women 9 to 26 in the prevention of EGWs and/or cervical cancer in women.[24,25] The Advisory Committee on Immunization Practices (ACIP) recommends Gardasil as routine vaccination for women 11 to 26 years of age, though the series can be started at age nine. The ACIP does not recommend Gardasil as a routine vaccination for males. Either vaccine can be administered in women, regardless of HPV history, abnormal Pap smears, or history and/or presence of genital warts.[26,27] The most common adverse reactions for both vaccines were those of headache, dizziness, and pain/erythema/edema at the injection site.[24,25] Gardasil is administered intramuscularly at 0, 2, and 6 months, whereas Cervarix is administered intramuscularly at 0, 1, and 6 months.[24,25,28,29]
The FUTURE I trial (Females United to Unilaterally Reduce Endo/Ectocervical Disease), a study of Gardasil in women without a history of HPV disease, found the vaccine to be 100-percent effective at preventing anogenital warts, vulvar or vaginal intraepithelial neoplasia, and vaginal or perianal disease.[29] FUTURE II trials yielded 98-percent efficacy in preventing HPV 16- and 18-related cervical intraepithelial neoplasia grade 2 or 3 and adenocarcinoma in situ in women without a prior history of HPV disease and 44-percent efficacy in women with or without a prior history of HPV disease.[30] Trials with Cervarix showed an efficacy of 90.4 percent in protecting against cervical intraepithelial neoplasia 2+ in those without a history of HPV disease.[28] A separate trial in women seropositive for HPV disease showed no evidence of increased viral clearance or therapeutic effect.[31] Prior infection with one serotype did not influence the vaccine effectiveness against other types.[32] After 4.5 years, 98 percent of those vaccinated with the bivalent vaccine were seropositive for antibodies against HPV 16 and 18, with an added effect of cross-protection against HPV 31 and 45.[33]
A comparison of Cervarix and Gardasil found the mean titers of antibodies were 2.3 to 4.8 higher against HPV 16 and 6.8 to 9.1 higher against HPV 18 with Cervarix than Gardasil.[34] The difference in response might be secondary to different formulations: Cervarix is produced in Trichoplusia Rix 4446 cell substrate formulated with Adjuvant System 04; Gardasil is produced in the yeast Saccharomyces cerevisiae formulated with amorphous aluminum hydroxyphosphate sulfate salt.[29]
Sinecatechins 15% ointment. Treatment of EGWs is challenging and many therapies exist, such as podophyllotoxin, imiquimod, curettage, cryotherapy, trichloroacetic acid, and laser. Success rates, regardless of treatment, are approximately 50 to 60 percent and recurrence rates can be as high as 90 percent. Appreciable recurrence may be secondary to treatments that target visible disease, not subclinical disease or the virus itself.[35] Such standard treatment often incurs significant expense and repeated physician visits can total $436 by one estimate.[23]
The newest treatment approved for EGWs is a botanical drug, sinecatechins 15% ointment (Veregen, PharmaDerm, a division of Nycomed US Inc., Melville, New York), also known as Polyphenon E in Europe (MediGene AG, Martinsried, Germany). Veregen, approved by the FDA in 2006, is indicated for the treatment of EGW in men and women 18 years and older. The ointment needs to be applied three times daily for up to 16 weeks and does not need to be washed off. It is composed of eight catechins derived from the extract of green tea, Camellia sinensis, of which the lead catechin is (-)-epigallocatechin gallate (EGCG).[36,37] The mode of action is via the stimulation of the immune system, upregulation of inflammatory cytokines, such as interleukin-1 and tumor necrosis factor-alpha, and inhibition of the pathways of HPV oncogenes.[37,38] EGCG also inhibits HPV-induced cervical cancer via regulation of gene expression, cell cycle arrest, and apoptosis.[39]
A Phase 2/3 study comparing the efficacy of Polyphenon E 15% ointment to Polyphenon 10% cream yielded complete clearance rates of 61 percent (males) and 56.8 percent (females) with 15% ointment, 53.8 percent (males) and 39.5 percent (females) with 10% cream, and 40.5 percent (males) and 34.1 percent (females) with the vehicle.[40] Recurrence rates at 12 weeks following treatment were 10.6 percent with ointment, 11.8 percent with cream, and 10.3 percent with the vehicle. Local adverse reactions occurred in approximately 30 percent of individuals treated with ointment or cream and consisted of erythema, itching, and burning. The adverse reactions reached a maximum by two weeks, all of which gradually declined. In another study comparing Polyphenon E ointment 15% and 10% applied three times daily for 16 weeks, complete clearance was 52.6 percent with the 15% ointment and 50.8 percent with the 10% ointment, and recurrence rates were 5.9 percent and 4.1 percent, respectively. In this study, women did better than men: 60 percent of women achieved complete clearance versus 45 percent of men.[37] Another study reported ~55 percent complete clearance for 15% and 10% ointments.[41,42] Both studies differed in regard to improved clearance in men versus women—the difference attributed to the increased keratinized tissue in men.[40,41]
Veregen is expensive, but cost effective. In one analysis, comparing average wholesale price (AWP) and assessing efficacy, the total cost of Veregen was $631.72 and the total cost of Imiquimod was $781.13 for a 16-week treatment period, a difference of $149.41.[38]
HEAD LICE
Head lice, Pediculus humanus capitis, is an infestation disease spread by direct contact. The louse, an obligate human parasite 2 to 3mm in size, feeds on the blood of the host every 4 to 6 hours and lays 5 to 10 eggs per day.[43] Current treatment, and those used in the past, includes lindane, malathion, and permethrin. Due to its neurotoxic effects, lindane is a second-line treatment, a dictate established by an FDA advisory warning in 2003.[44] The treatment-of-choice is permethrin 1% lotion (Nix, Pfizer Consumer Health Care Group, New York, New York), based upon the recommendations by the American Academy of Pediatrics.[45] First introduced in 1986, permethrin has encountered increasing resistance, approximately 50 percent in some studies.[43,46,47] Newer therapies with proven efficacy include benzyl alcohol lotion 5% (Ulefsia, Shionogi Inc., Florham Park, New Jersey), malathion 0.5% lotion and gel (Ovide, Taro Pharmaceuticals U.S.A., Inc., Hawthorne, New York), and spinosad 0.9% creme rinse (NatrOVA, ParaPRO, LLC, Carmel, Indiana).
Benzyl alcohol lotion 5% (Ulefsia). Benzyl alcohol lotion 5% is a pediculicide with asphyxiation as its mode of action. The product “stuns” open the louse’s spiracles, the external entry points of the breathing apparatus, and penetrates the “honeycomb” respiratory apparatus. Phase 2 and 3 studies, in which benzyl alcohol lotion 5% is applied to the hair and scalp for 10-minute intervals one week apart, have shown success rates of 92.2 percent after the second treatment and 75 percent at 22 days in participants aged 6 months to 70 years.[48] The decrease in success rates was thought to be secondary to re-infestation rather than treatment failure. Benzyl alcohol lotion 5% can be used in those as young as six months of age as well as in pregnant women. Adverse reactions include application site irritation (2.3%), pain (1.0%), and application site anesthesia (2.0%), which were no worse in the younger participants. Symptoms of pruritus, excoriation, and erythema decreased throughout the treatment process.
Malathion (Ovide). Malathion (Ovide, Taro Pharmaceuticals U.S.A., Inc.), an organophosphate, is a known and effective pediculicide, which has received increased attention and use secondary to permethrin resistance. A randomized, investigator-blinded evaluation compared the efficacy of 0.5% malathion (Ovide lotion) applied to dry hair for 20 minutes to 1% permethrin (Nix Crème Rinse) applied to towel-dried hair for 10 minutes.[46] Treatment success at Day 15 was 90 percent with 0.5% malathion versus 55 percent with 1% permethrin. Of note, 40 percent of the Nix patients required a second application and had a 33-percent re-infestation rate. Another study comparing the efficacy of 0.5% malathion gel to 0.5% malathion lotion (Ovide) and 1% permethrin (Nix Crème Rinse) as the treatment for head lice showed significant success rates for both malathion vehicles compared to 1% permethrin.[47] In that study, 70 percent of Nix participants required retreatment. The same study revealed that a 30-minute application of 0.5% malathion gel was as effective as the 8- to 12-hour application of malathion lotion, with less odor and greater ease of application.
Spinosad 0.9% creme rinse (Natroba). Spinosad 0.9% crème rinse (Natroba, ParaPRO, LLC, Carmel, Indiana), a derivative of the actinomycete Saccharopolyspora spinosa, was approved by the FDA in January 2011 for the treatment of head lice in patients four years of age and older. The drug’s target is the nicotinic receptor of acetylcholine and gamma-aminobutyric acid (GABA)-gated chloride channel, creating excitation of the nervous system and resulting in paralysis of the louse.[49,50] Natroba has similar efficacy against body lice and head lice, and efficacy is independent of resistance to permethrin.[51,52] Label instructions require saturating the scalp and hair and leaving the creme rinse in for 10 minutes, followed by rinsing and shampooing as usual.53 Unlike permethrin, nit combing is not required because the medication is not ovicidal.[45] Two Phase 3 studies compared 0.9% spinosad without nit combing to 1% permethrin with combing and found that 85 percent of the spinosad patients were lice free 14 days after the last treatment compared to 43 percent of the permethrin patients.[53] The majority of spinosad patients required only one treatment, whereas permethrin participants required two. As such, spinosad is more user friendly, less time consuming, and has fewer side effects than permethrin.
SKIN and SOFT TISSUE INFECTIONS
Cutaneous infections are common and relatively easy to treat, often without the need for systemic antibiotics. Complicated skin and soft tissue infections (cSSTIs), such as extensive cellulitis, diabetic foot infections, or infections in patients with major comorbidities, require systemic antibiotics, even hospitilization.[54] The majority of cSSTIs are secondary to Staphylococcus aureus, still the most common pathogen in hospitalized patients.[55,56]
Daptomycin (Cubicin). Daptomycin (Cubicin, Cubist Pharmaceuticals, Inc., Lexington, Massachusetts) is a lipopeptide that induces cell death by inserting its lipophilic tail into the cell membrane, allowing potassium to enter the cell via a calcium-dependent mechanism.[57,58] Approved in 2003, the drug is active against Gram-positive bacteria, including Methicillin-resistant S. aureus (MRSA).[59,60] With resistance to S. aureus increasing, the use of daptomycin for cSSTI is growing, even in the outpatient setting.[61,62]
Standard dosing is 4mg/kg/day for 7 to 14 days for cSSTI, though recent trials have used higher doses (i.e., 6–10mg/kg/day), and excretion is via the kidneys.[60,63–65] The Cubicin Outcomes Registry and Experience (CORE) has reported success rates of 93 percent for patients with complicated skin and skin structure infections (cSSSIs) as a first-line drug or a subsequent antibiotic. Post-marketing experience from CORE showed success rates of 97 percent (patient was improved or cured), whereas other studies have shown clinical success rates approximating 90 percent.[66–69]
A comparison of daptomycin to vancomycin as treatement for cSSSIs found that treatment with intravenous daptomycin significantly reduced the median number of treatment days and shortened hospitalization, a savings of $2,800.[70] Daptomycin was again compared to vancomycyin, but in the treatment of cellulitis and erysipelas, and no stastitical difference in efficacy was revealed.[71]
The most clinically significant adverse reaction of Cubicin is elevated creatine phosphokinase (CPK).[60] Elevated CPK has been shown in three percent of patients treated with standard dosing and 5 to 8 percent of patients who received doses of 6 to 10mg/kg.[63–65,72] More common reactions occur in 5 to 6 percent of patients and include constipation, nausea, injection site reactions, headache, and diarrhea.[72]
Retapamulin (Altabax). Retapamulin (Altabax, GlaxoSmithKline) is the first new topical antibiotic in 20 years. Retapamulin was FDA approved in 2007 for the treatment of impetigo and superficially infected wounds with Streptococcus pyogenes and methicillin-susceptible S. aureus. Labeled use is twice daily for five days, with a maximum surface area of 100cm2 in adults or two percent of total body surface in children aged nine months or older.[73]
Retapamulin is a pleuromutilin derived from the edible mushroom Clitopilus passeckerianus.[73] Its mode of action is unique, enhancing its use against resistant bacteria. It inhibits bacterial growth via three mechanisms: hinders activity of peptidyl transferase, blocks binding of initiator tRNA substrate to the ribosomal p-site, and inhibits the formation of the ribosomal 50s subunit at the domain V of 23s rRNA.[74–78] At present, pleuromutilins exhibit no cross-resistance to antibacterials, including oxacillin, erythromycin, and mupirocin.[75]
A randomized, controlled trial compared retapamulin twice daily for five days to cephalexin 500mg twice daily for 10 days, as treatment of secondarily infected dermatitis. Treatment success rates after 7 to 9 days were 85.9 percent for retapamulin and 89.7 percent for cephalexin.[79] Another study comparing retapamulin to placebo for the treatment of impetigo yielded a success rate of 85.6 percent, compared to 52.1 percent for placebo. The most common adverse effect was application site pruritus.[80]
Ceftaroline fosamil (Teflaro). Ceftaroline fosamil (Teflaro, Forest Laboratories, Inc., New York, New York) is a new parenteral cephalosporin approved by the FDA in 2010 for the treatment of acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP). Ceftaroline, the active metabolite of ceftaroline fosamil, binds to penicillin-binding proteins (PBP) to inhibit cell wall synthesis.[81] Its mode of action is unique—it binds to PBP 2a, a novel PBP created by the mecA gene, a product of MRSA.[82]
Ceftaroline is active against methicillin-sensitive and methicillin-resistant Staphylococcus epidermidis, MRSA, vancomycin-intermediate and vancomycin-resistant S. aureus, linezolid-resistant S. aureus, and daptomycin-nonsusceptible S. aureus.[83–88] Unlike many other antibiotics, ceftaroline has a low tendency for resistance against susceptible pathogens.[89] Additionally, drug-drug interactions are negligible because the CYP450 metabolic pathway is not heavily involved.[83]
The CANVAS (Ceftaroline versus Vancomycin in Skin and Skin-Structure Infections) trials compared the safety and efficacy of ceftaroline 600mg intravenously every 12 hours to vancomycin 1g intravenously plus aztreonam 1g intravenously every 12 hours for 5 to 14 days in adults with cSSSIs. Efficacy was 91.6 percent for ceftaroline and 92.7 percent for vancomycin plus aztreonam, and more specifically, 93.4 percent and 94.3 percent, respectively, in patients with MRSA.[85] In patients with comorbidities (i.e., diabetes mellitus and peripheral vascular disease), clinical cure rates were comparable.[86] The most common adverse effects were nausea, headache, diarrhea, pruritus, and rash, affecting 3 to 6 percent of participants.[85,90] Hypersensitivity reactions, rash, allergic dermatitis, and urticaria occurred more frequently in the vancomycin plus aztreonam group than in the ceftaroline group.[90]
Conclusion
Cutaneous infections and infestations are common maladies in the general population. The authors reviewed and highlighted some of the newer drugs that should be helpful to physicians treating such affected patients.
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