Advanced therapeutics

Acne
Foundation overview
1-Acne vulgaris is an inflammatory skin disorder of the pilosebaceous units of the skin.
Although most commonly seen on the face, acne can also present on the chest, back,
neck, and shoulders (1).

2-Acne is not just a self-limiting disorder of teenagers. The clinical course of acne can be
prolonged or recur, resulting in long-term physical complications, such as extensive
scarring and psychological distress (1).

3-The development of acne lesions results from four pathogenic factors:

excess sebum production, keratinization, bacterial growth, and inflammation (1).

A-Increased androgen levels, especially during puberty, can

cause production of abnormally high levels of sebum within the
sebaceous glands (1).

B-Keratinization (the sloughing of epithelial cells in the hair

follicle): In acne, hyperkeratinization occurs (1). Epithelial cells
adhere to each other, forming a dense keratinous plug. Sebum,
produced in increasing amounts, becomes trapped behind the
keratin plug and solidifies, contributing to comedone formation (2,
5)
. A closed comedones or “whitehead” appears when the opening
of the duct becomes blocked. If the follicular opening is dilated, the
keratin can darken and form an open comedones or “blackhead” (1).

C-Propionibacterium acnes (P. acnes), an anaerobic organism,

is also found in the normal flora of the skin. This bacterium
proliferates in the stagnant oil and can result in an inflammatory
response producing more severe acne lesions such as papules
(Solid, elevated lesion), pustules (Vesicles filled with purulent
fluid), nodules (Warm, tender, firm lesions) and cyst (Cysts:
Nodules that harden into larger, pus-filled lesions). Inflammatory
lesions may result in scarring if treated inadequately (1, 5).
4-The diagnosis of acne vulgaris is clinical (1). Acne vulgaris is
usually classified by the number, type and distribution of acne lesions.
Mild acne tends to consist of comedones, a few papules and pustules;
moderate acne has several papules, pustules and may contain a few
nodules; severe acne has numerous papules, pustules, multiple
nodules, cysts and
scarring (3).

Treatment
Desired Outcomes and Goals
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Goals of therapy are to (1) reduce the number and severity of existing
lesions, (2) prevent the development of new lesions and recurrence, and
(3) prevent long-term disfigurement and permanent scarring (1).

General Approach to Treatment

1-Acne treatment regimens should be based on acne severity and type
of acne lesion. Other factors such as response to previous treatment,
patient preference, cost, and adherence should also be considered (1).

2-Topical therapy is considered first-line for mild acne with oral

therapies added to topical therapy in moderate to severe acne
(1)
.

3-Using multiple topical agents that target different aspects of acne

pathogenesis is more effective, reduces adverse effects, and minimizes
treatment resistance (1).

4-Topical therapies should be applied to the entire area affected by

acne to prevent new lesions from developing (1).

5-Optimal management includes aggressive induction treatment

and maintenance therapy to prevent recurrence (1).

6-Improvement of symptoms following induction therapy occurs

gradually, sometimes taking 6 to 8 weeks for results to be
physically apparent. Patients need to be educated on continual
treatment compliance during this time and should not get discouraged if
acne lesions appear to worsen before getting better (1).

7-Maintenance therapy should begin after 12 weeks of induction

therapy and it was continued for 3 to 4 months in most clinical
trials. Due to frequent acne recurrences, clinical experience indicates
that a longer duration of maintenance therapy may be beneficial for
most patients (1). Topical retinoid alone or a retinoid plus benzoyl
peroxide fixed-dose combination is most commonly recommended (2).

Nonpharmacologic Therapy
1-Patients should be counseled to avoid aggressive skin washing
and to use a mild, noncomedogenic facial soap twice daily (1).

2-Excessive washing or use of harsh or abrasive cleansers can disrupt

the skin barrier and promote comedones and bacterial colonization (1).

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3-Manipulating or squeezing lesions should also be avoided to
minimize scarring (1).

4-Use of an oil-free, noncomedogenic moisturizer daily may

improve the tolerability of topical drug therapy (1).

Pharmacologic Therapy
Topical Agents
A-Retinoids
1-Topical retinoids are the foundation of first-line therapy for
induction and maintenance regimens in all forms of acne (1).

2-Although success is seen with monotherapy in comedonal acne, using

topical retinoids in combination with benzoyl peroxide, topical
antibacterial agents, or oral antibacterial agents is preferred for
inflammatory acne lesions (1).

3-Retinoids normalize epithelial cell turnover, which in turn promotes

clearing of obstructed follicles and prevents comedones formation.
Retinoids also exhibit anti-inflammatory (1).

4-Available topical retinoids include tretinoin, adapalene, tazarotene

and trifarotene. Adapalene, available by prescription and over-the-
counter, is considered the drug of first choice because it has similar
efficacy and a lower incidence of adverse effects (1).

5-Newer topical retinoid formulations [e.g. using a microsphere gel

(Retin-A Micro)] gradually release the active ingredient over time and
may also cause less initial skin discomfort (1).

6-Retinoids should be applied at night, a half hour after cleansing

(starting with every other night for 1–2 weeks to adjust to irritation) (2),
beginning with a low-potency formulation. Increased strengths are then
initiated according to treatment results and tolerance (1). Gels and
creams are less irritating than solutions (2).

7-Patients should be advised that a worsening of acne symptoms

generally occurs in the first few weeks of therapy, with lesion
improvement occurring in 3 to 4 months (1).
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8-The safety and efficacy of topical retinoids in children younger than 12
years of age and in pregnant women is not well established (1). However;
trifarotene is approved in the United States for treatment of
acne in patients aged 9 years and older (2).

B-Benzoyl Peroxide
1-Benzoyl peroxide is easy to use and is recommended as an alternative
to, or in combination with, topical retinoids, topical antibacterial agents,
or oral antibacterial agents in the treatment of acne of all severities (1).

2-It has a rapid onset and may decrease the number of inflamed
lesions within 5 days (2).

3-Benzoyl peroxide has a comedolytic. It also has antibacterial activity

against P. acnes, which appears to be the main reason for its
effectiveness (1).

4-Some data suggest that lower strengths offer similar efficacy to

higher strengths. Beginning benzoyl peroxide treatment regimen
with the lowest strength and titrating to higher effective strengths
over several weeks, if needed, will reduce the incidence of localized
adverse effects (1).

5-Newer formulations of benzoyl peroxide are combined with

moisturizers to help decrease skin redness and irritation (1).

6-Gel preparations are the most potent dosage form. Patients

with dry or overly sensitive skin should try a cream, lotion, or facial
wash first (1).

7-If severe irritation or an allergic reaction develops, benzoyl peroxide

should be discontinued (1). It may bleach hair, clothing, and towels
(2)
.

C-Antibacterials
1-Topical antibacterials directly suppress P. acnes and are first-line agents used in
combination with benzoyl peroxide, topical retinoids, or azelaic acid for the treatment of
mild to moderate inflammatory acne (1).

2-To reduce the likelihood of bacterial resistance, topical antibiotics should

never be used as monotherapy or as long-term maintenance
therapy (1).

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3-Clindamycin is currently the preferred topical antibiotic for acne
therapy (1) due to better efficacy, lack of systemic absorption (2) and increased bacterial
resistance to erythromycin preparations (1),

4-Applied once or twice daily for 3 months, these agents are available in various
formulations and combinations with benzoyl peroxide and topical retinoids (1).

D-Clascoterone
1-Clascoterone cream, an androgen receptor inhibitor, decreases sebum production and
inflammation that in turn reduces follicular plugging. This novel mechanism is the first
antiandrogen therapy that can be used in both males and females (1).

2-Clascoterone has demonstrated efficacy and a favorable safety profile in males and
nonpregnant females with moderate-severe facial acne (1) (12 years of age and older) (2).

E-Azelaic Acid / F-Dapsone/ G-Keratolytics [Exfoliants

(Peeling Agents)]
Further reading 1

Oral Agents
A-Antibacterials
1-Oral antibiotics are indicated for use in patients with moderate to severe acne and
forms of inflammatory acne that are resistant to topical therapy (1).

2-When used, oral antibiotics should be combined with a topical retinoid and/or
benzoyl peroxide (1).

3-Because of the ability to decrease P. acnes colonization, oral antibiotics can prevent acne
lesions from developing. Use of oral antibiotics should be limited to short periods of
time, ideally 3 to 4 months, or less (1).

4-Assessment of response to oral antibiotics after 6 to 8 weeks of therapy is

recommended (1).
5-After inflammatory lesions have stopped emerging, oral antibiotics should be
discontinued and replaced with topical retinoid or benzoyl peroxide containing
maintenance regimens (1).
6-As with topical antibiotics, oral antibiotics should never be used as monotherapy or
as long-term maintenance therapy (1).

7-Additionally, the use of topical antibiotics in combination with oral antibiotics

should be avoided due to increased risk of bacterial resistance (1).

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8-Tetracycline, doxycycline, and minocycline are the most commonly prescribed oral
antibiotics for acne. Doxycycline and minocycline are more effective than tetracycline,
but neither is superior to each other (1).

9-Sarecycline, a recently approved tetracycline, displays a more narrow spectrum of

activity designed to target skin bacterium with the potential for fewer gastrointestinal
adverse effects (1).

10-Erythromycin, azithromycin, and trimethoprim (± sulfamethoxazole) are

appropriate second-line agents for use when patients cannot tolerate or have developed
resistance to tetracycline or its derivatives (1).

11-Although effectiveness is similar to the tetracyclines, erythromycin use is often limited

due to potential adverse outcomes and increased bacterial resistance (1).

12-The incidence of significant adverse effects with oral antibiotic use is low. Vaginal
candidiasis may complicate use of all oral antibiotics (2).
Isotretinoin.
1-Isotretinoin works on the four pathogenic factors that contribute to acne development
and can produce acne remission rates of up to several years (1) (Isotretinoin is the only
drug treatment for acne that produces prolonged remission) (2).

2-Oral isotretinoin is Food and Drug Administration (FDA)-approved for patients with
severe recalcitrant nodular acne unresponsive to other topical and oral treatment
regimens (1).

3-Additional evidence suggest that oral isotretinoin may be useful in treatment resistant
moderate acne or acne that is producing physical scarring or psychosocial distress (1).

4-Some expert clinicians suggest that oral isotretinoin therapy may be used as first-line
therapy in patients with severe nodular acne due to clinical effectiveness, prevention of
scarring, and quick improvements in patient’s quality of life (1).

5-Adverse effects with the use of isotretinoin are frequent and generally dose related.
A-Cheilitis, dryness of the nose, eyes, and mouth, peeling, pruritus, and drying of the
face and skin, alopecia, acne flair up at start of therapy.
B-Teratogenicity C-Depression/suicidality. D-Musculoskeletal pain.
E-Increased serum lipids, creatine phosphokinase, and blood glucose
F-Photosensitivity (1).

6-Because of teratogenicity, two different forms of contraception must be started in

female patients of childbearing potential beginning 1 month before therapy, continuing
throughout treatment, and for up to 4 months after discontinuation of therapy (2).

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7-Two negative pregnancy tests prior to initiating therapy and one negative pregnancy
test each month thereafter must be obtained before a prescription can be dispensed to
female patients of child-bearing potential (1).
8-Treatment with oral isotretinoin should be continued for 4 to 6 months, but may be
extended for patients with an insufficient response (1).

Hormonal Agents
1-Oral contraceptives and anti-androgens are valuable second-line treatment options for
moderate to severe inflammatory acne in female patients (1).

2-Hormonal agents primarily work by decreasing androgen production resulting in

reduced sebum formation. It takes several months to see the full effect of hormonal agents
(1)
.

3-Oral contraceptives may improve acne for many women with clinical and laboratory
findings of hyperandrogenism and in women without these findings (2).

4-Cyproterone (anti-androgen) combined with ethinyl estradiol (in the form of an oral
contraceptive) has been found effective in the treatment of acne in females (2).

3-While not FDA-approved, spironolactone, at higher doses, is effective for acne through
anti-androgenic properties (1).

Other Agents.
Although use is infrequent, several other agents are available as second- or third-line
treatment options for acne when first-line therapies fail (1).
1-Corticosteroids:
A-Oral corticosteroids in high doses used for short courses may provide temporary
benefit in patients with severe inflammatory acne. Low-dose prednisone (5–15 mg
daily) given alone or with high estrogen-containing combination oral contraceptives
has shown efficacy for acne and seborrhea. Long-term adverse effects preclude oral
corticosteroid use as a primary therapy for acne (2).

B-Intralesional triamcinolone injections are effective for large individual

inflammatory nodules. Intralesional injections may produce rapid improvement and
decreased pain but may also be associated with local skin atrophy (2).

2-Surgical Comedone extraction (1): Comedone extraction results in immediate cosmetic

improvement but has not been widely tested in clinical trials (2).

3-Phototherapy (1): Light therapies are believed to work by killing P. acnes and by
damaging and shrinking sebaceous glands, reducing sebum output with few or temporary
adverse effects (2).

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4-Laser treatments (1). Current guidelines prefer drug therapy to light and laser
therapies because there are less stringent clinical testing for devices compared to
medications (4).

Figure 1 shows useful algorithms for the effective treatment of the various stages of acne
(1)
.

Figure 1. Algorithms for acne treatment. The double asterisks (**) indicate that the drug may be
prescribed as a fixed combination product or as separate component. (BP, benzoyl peroxide.) (1).

Outcome evaluation (1).

1-Depending on severity, complete resolution of acne lesions may take weeks to months.
Monitor patients every 4 to 8 weeks during pharmacologic therapy to assess for
efficacy.
 Decreased number of lesions
 Decreased severity of lesions
 Presence of scarring
 Psychological effects
 Medication adherence

2-If no improvement is reported after 6 weeks of drug therapy or if symptoms have

worsened, patients should be reevaluated and a change to an alternative drug regimen may
be necessary.

3-Educate patients on potential adverse effects of drug therapy. Consider changing therapy
if a patient experiences effects that are not tolerated or are a compromise to their health.

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References
1-Marie A. Chisholm-Burns .Pharmacotherapy Principles & Practice. 6th edition. 2022.
2-Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 12 th
Edition. 2023.
3-Canadian pharmacists association. Therapeutic choices. 2019.
4-Zeind, Caroline S and Carvalho, Michael G. Applied Therapeutics: The clinical use of
drugs, 12th ed., 2024.
5-Community pharmacy.

E-Azelaic Acid
With antibacterial and anti-inflammatory properties, and the ability to stabilize
keratinization, azelaic acid is an effective alternative in the treatment of mild to
moderate acne in patients who cannot tolerate benzoyl peroxide or topical retinoids (1)
(has limited
efficacy compared with other therapies) (2).

F-Dapsone
Dapsone gel, a sulfone drug, has antimicrobial and anti-inflammatory properties. Dapsone
gel may be used as an alternative agent for inflammatory acne as monotherapy or in
combination with topical or oral agents (1).

G-Keratolytics [Exfoliants (Peeling Agents)]

1-Sulfur, resorcinol, and salicylic acid have limited evidence available to support
efficacy, but can be used as second-line therapies in the treatment of mild to moderate acne
(1)
.
2-Although these agents may cause less skin irritation than benzoyl peroxide or the topical
retinoids, several disadvantages exist. Sulfur preparations produce an unpleasant odor
when applied to the skin, whereas resorcinol may cause brown scaling (1).