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Background: Systemic antibiotics are an effective treatment for acne vulgaris. However, intolerable side effects may invariably
occur.
Objective: To determine whether probiotics reduce the side effects imparted by systemic antibiotics while working
synergistically with the latter in treating inflammatory acne.
Methods: Forty-five 18- to 35-year-old females were randomly assigned to one of three arms in this prospective, open-label
study. Group A received probiotic supplementation, whereas group B received only minocycline. Group C was treated with both
probiotic and minocycline. Clinical and subjective assessments were completed at baseline and during the 2-, 4-, 8-, and 12-week
follow-up visits.
Results: All patients demonstrated a significant improvement in total lesion count 4 weeks after treatment initiation (p < .001),
with continued improvement seen with each subsequent follow-up visit (p < .01 ). At the 8- and 12-week follow-up visits, group C had
a significant decrease in total lesion count versus groups A (p < .001) and B (p < .01). Two patients (13%) from group B failed to
complete the study secondary to vaginal candidiasis.
Conclusion: Probiotics may be considered a therapeutic option or adjunct for acne vulgaris by providing a synergistic
antiinflammatory effect with systemic antibiotics while also reducing potential adverse events secondary to chronic antibiotic use.
Contexte: Les antibiotiques à action générale sont efficaces contre l'acné vulgaire, mais ils peuvent toujours produire des effets
indésirables intolérables.
Objectif: L'étude visait à déterminer si les probiotiques diminuaient les effets indésirables des antibiotiques à action générale,
tout en agissant en synergie avec ces derniers dans le traitement de l'acné inflammatoire.
Méthode: Quarante-cinq femmes, âgées de 18 à 35 ans, ont été dirigées au hasard vers l'un des trois groupes de traitement,
formés dans le cadre de cet essai prospectif, mené au su des parties; le groupe A a reçu un supplément probiotique; le groupe B, de la
minocycline seule; et le groupe C, le supplément probiotique et la minocycline. Il y a eu une évaluation clinique et subjective au
départ, puis à la 2e, 4e, 8e, et 12e semaine de suivi.
Résultats: Une diminution sensible du nombre total de lésions a été observée chez tous les sujets, 4 semaines après le début du
traitement (p < .001), diminution qui a été constatée à chacune des visites ultérieures de suivi (p < .01). Aux visites de la 8e et de la
12e semaine, une diminution importante du nombre total de lésions a été notée dans le groupe C comparativement aux groupes A (p
< .001) et B (p < .01). Deux patientes (13%) dans le groupe B n'ont pas terminé l'étude en raison d'une candidose vaginale.
Conclusions: Les probiotiques peuvent être envisagés comme formule thérapeutique ou appoint thérapeutique dans l'acné
vulgaire en produisant un effet anti-infiammatoire synergique avec celui des antibiotiques à action générale, en plus de diminuer les
effets indésirables possibles de l'emploi prolongé des antibiotiques.
From the Division of Dermatology and Cutaneous Sciences, Department Address reprint requests to: Jaggi Rao, MD, FRCPC, Division of
of Medicine, University of Alberta, Edmonton, AB; Shape MD, Dermatology and Cutaneous Sciences, Department of Medicine,
Edmonton, AB; Acne Clinics of Canada, Edmonton, AB; and University Dermatology Centre, 2-125 Clinical Sciences Bldg, Edmonton,
Dermatology and Cosmetic Laser Associates of La ¡olla. La Jolla, CA. ^ ^^^^ 2G3; e-mail: jrao@ualberta.ca.
The results of this study were presented at the 70th Annual Meeting of the ^ ^ ^ 10.2310/7750.2012.12026
American Academy of Dermatology, March 16-20, 2012, San Diego, CA. © 2013 Canadian Dermatology Association
DECKEI^
114 Canadian Dermatology Association I journal of Cutaneous Medicine and Surgery, Vol 17, No 2 (March/April), 2013: pp 114-122
Acne Treatment with Minocycline and/or Probiotics
CNE VULGARIS is one of the most common antiinflammatory mechanisms while imparting other health
A dermatologie diseases affecting Western societies and benefits when administered in adequate amounts.^ However,
typically presents during the adolescent period.' Although a review of the literature failed to identify studies assessing
not life-threatening, acne causes significant morbidity, both the effects of probiotics with antibiotics on acne vulgaris.
physically and psychologically. Specifically, severe acne has The purpose of this study was to determine whether
been associated with high levels of anxiety, major depres- probiotics reduced the side effects imparted by systemic
sion, social isolation, aggressive behavior, and suicidal antibiotics while working synergistically with the latter in
ideation.^ Furthermore, poorly controlled acne can lead to treating inflammatory acne.
irreversible disfigurement.
Acne treatment, consisting of topical, systemic, and
light and laser therapies, is individualized and dependent Methods
on the number and type of lesions a patient has. Oral
Subject Population
antibiotics have been used to treat a significant number of
acne patients with inflammatory disease, with the tetra- From May 2010 to April 2011, otherwise healthy,
cycline family being the most widely used.^ The tetra- nonpregnant female patients, 18 to 35 years of age with
cyclines alter the course of acne lesions via its bacteriostatic Fitzpatrick skin types I to III, were enrolled in this
action against Propionibacterium acnes by inhibiting prospective, randomized, open-label study. Only subjects
bacterial protein synthesis.* In addition, antibiotics have with mild to moderate acne vulgaris, with a score of 2 or 3
antiinflammatory properties through modulation of via the Global Acne Assessment Scale (Table 1) and 20 to
cytokine and reactive oxygen species production and 50 total lesions (with at least 10 inflammatory lesions),
reduction of leukocyte chemotaxis.^ Although effective, were included. The face was divided into five regions:
with a 22 to 91% and 23 to 75% reduction of forehead, nose, chin, right cheek, and left cheek.
inflammatory lesions after treatment with minocycline Patients were excluded from the trial if they had active
and doxycycline,^ respectively, side effects from such localized or generalized infections, a history of auto-
medications may occur, some of which may lead to immune disease, or a history of mental illness. Pregnant or
decreased compliance and/or discontinuation of the breastfeeding patients were also excluded from the study.
antibiotic. Such adverse effects include gastrointestinal Patients who smoked more than one pack per day, drank
disturbance, candidiasis, dizziness, lethargy, headaches, more than three alcoholic beverages per day, were
blue staining of the teeth in pédiatrie patients, and concurrently using isotretinoin, or changed their oral
photosensitivity and photo-onycholysis.^ contraceptive therapy within the past 3 months were not
The side effects of antibiotic treatment may be reduced included in the trial. Those with a history of probiotic use
via concomitant use of probiotics. Such live microorganisms (supplement and/or food enhanced) within the month
have been used for decades to alleviate abdominal symptoms prior to starting the study were excluded. Finally, subjects
via maintenance of commensal intestinal organisms and with excessive facial hair or scars, which could interfere
Grade Description
Normal, clear skin with no evidence of acne vulgaris
Skin is almost clear; rare noninflammatory lesions present, with rare noninflamed papules (papules must be resolving and
may be hyperpigmented, although not pink-red), requiring no further treatment in the investigator's opinion
Some noninflammatory lesions are present, with few inflammatory lesions (papules/pustules only; no nodulocystic lesions)
Noninflammatory lesions predominate, with multiple inflammatory lesions evident; several to many comedones and
papules/pustules, and there may or may not be one small nodulocystic lesion
Inflammatory lesions are more apparent; many comedones and papules/pustules; there may or may not be a few
nodulocystic lesions
Highly inflammatory lesions predominate: variable number of comedones, many papules/pustules and nodulocystic lesions
The Global Acne Assessment Scale used to categorize patients as mild, moderate, or severe acne vulgaris in the current study. To qualify for the study,
subjects were to have mild to moderate acne as determined by the investigative staff (defined as a score of 2 or 3) in addition to having between 20 and 50
total lesions with at least 10 inflammatory lesions.
' Canadian Dermatology Association I Journal of Cutaneous Mediane and Surgery, Vol 17, No 2 (March/April), 2013: pp 114-122 115
Jung et at
with clinical assessments, and those who had any facial study. Ethics approval was granted by the Health Research
cosmetic procedures completed within the 3 months prior Ethics Board (Biomédical Panel) of the University of
to study initiation were excluded. Alberta on April 9, 2010.
116 Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 17, No 2 (March/April), 2013: pp 114-122
Acne Treatment with Minocycline and/or Probiotics
40 n
showed a significant degree of improvement fi-om the noninflamed lesion counts from baseline (p < .001) with no
previous visit (p = .001 for group B; p < .001 for groups A significant difference between groups (p > .05) (see
and C). Again, group C showed a significantly reduced Figure 2). All arms also experienced a significant improve-
total lesion count than both groups A (p < .001) and B (p ment from week 4 to week 8 (p = .003 for group A; p < .001
< .001) at week 12 (see Figure 1). for groups B and C). By week 12, all groups again showed a
significant degree of improvement from the previous visit (p
= .02 for group B; p < .001 for groups A and C). In
Noninflamed Lesion Count
addition. Figure 2 illustrates that group C experienced a
At baseline, patients in the probiotic-only arm had a mean significantly lower total noninflamed lesion count than both
noninflamed lesion count of 19.8 (range 10-26). Groups B groups A (p = .03) and B (p = .001) at 12 weeks.
and C had average total noninflamed lesion counts of 19.2
(range 13-23) and 20.7 (range 15-28), respectively (Figure 2).
Inflamed Lesion Count
The percent decreases in noninflamed lesion count from
baseline for each group are presented in Table 2. By week 4, Group A had an average total inflamed lesion count of 10.7
all three groups showed a significant improvement in (range 5-15), whereas groups B and C had mean total
Table 2. Percent Decrease in Total, Noninflamed, and Inflamed Lesion Counts from Baseline
Decrease in Total Lesion Count from Decrease in Noninflamed Lesion Decrease in Inflamed Lesion Count from
Baseline (%) Count from Baseline (%) Baseline (%)
Week Group A Group B Group C Group A Group B Group C Group A Group B Group C
4 38 33 41 46 40 38 46* 40* 38
8 52 56 67 59 56 62 59 56 62
12 67 67 82 70 65 77 70 65 77
Group A = probiotic only; group B = minocycline only; group C = probiotic and minocycline.
*Not significant (p > .05).
/^
' Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 17, No 2 (March/April), 2013: pp 114-122 117
Jung et al
inflamed lesion counts of 10.8 (range 2-15) and 12.3 skin roughness, mottled pigmentation, sallowness, dullness,
(range 6-19), respectively (Figure 3). inflammation, and irritation (p < .001) (Figure 4). A
The percent decreases in inflamed lesion count lrom significant improvement with regard to facial skin peeling,
baseline for each group are presented in Table 2. By week 4, itching, burning, oiliness, scaling, dryness, and erythema
only group C achieved a significant reduction in inflamed acne was also demonstrated in all three groups at the 12-week
lesions from baseline {p < .001) (see Figure 3), which was a follow-up visit (p < .001) (see Figure 4). Furthermore,
significant improvement versus group B {p = .04) (see Figure following 12 weeks of treatment with their appointed
3). By week 8, groups A and B also achieved significant regimens, compared to patients in groups A and B, subjects
improvement from baseline [p < .001), whereas group C in group C revealed a significant decrease in facial skin
continued to experience improvement from week 4 (p < dullness (mean difference 0.73 [p < .001] and 0.59 [p =
.001). At 8 weeks, group B demonstrated significanfly more .004], respectively), inflammation (mean difference 0.79 [p
improvement than group A (p = .04), whereas group C < .001] and 0.64 [p = .001], respectively), and erythema
showed significanfly more improvement compared to the (mean difterence 0.86 [p < .001] and 0.68 [p = .001],
other two arms (p < .001 versus group A; p = .006 versus respectively).
group B) (see Figure 3). By week 12, all groups again showed a
significant degree of improvement in inflamed lesion counts
Quality of Life Assessment
fi-om the previous visit (p = .001 for group A; p = .007 for
group B; p < .001 for group C). Furthermore, group B showed At the 12-week follow-up visit, patients from all three
significanfly more improvement versus group A (p = .02), groups were significantly happier with their appearance,
whereas group C showed significanfly more improvement more comfortable around others, less likely to avoid
compared to both groups A (p < .001) and B (p < .001). people, less hopeless about their skin, and less frustrated
about their acne (Table 3). Patients in groups A and B were
Skin Tolerabüity less discouraged about their acne at the 12-week follow-up
appointment, whereas those in groups A and C were less
Over the 12-week study period, patients from all three humiliated and those in groups B and C were less upset
groups established a significant improvement in their facial about their acne (see Table 3). Finafly, patients in the
Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 17, No 2 (March/April), 2013: pp 114-122
Acne Treatment with Minocycline and/or Probiotics
16 -1
combination minocycline-probiotic arm of the study were of the host's natural flora with antibiotic treatment can occur,
found to be more self-confident, more attractive to others, possibly resulting in intolerable gastrointestinal side effects
less self-conscious around others, less embarrassed, and and affecting patient compliance. Although no subjects
less ugly at the end of the treatment period. Such findings experienced gastrointestinal disturbances in the current
were not identified in the minocycline-only and probiotic- study, a meta-analysis of 19 studies found a reduction of
only arms (see Table 3). 52% (p < .001) in antibiotic-associated diarrhea with
probiotic use.^° Song and colleagues further found that
certain strains of Lactobacillus significantly maintained a
Discussion patient's bowel habits versus placebo when given during a
In recent decades, the characterization of specific probiotic course of antibiotics for a respiratory tract infection." Hence,
strains in preventing and treating infections and allergic antibiotic treatment of acne with concurrent administration
and inflammatory disorders has progressed significantly. of probiotics may reduce intolerable gastrointestinal adverse
Such beneficial health effects are believed to stem from the effects, improving patient compliance.
symbiotic relationship between the intestinal microbiota The vaginal microflora, consisting predominantly of
with the gut epithelium and mucosa. Specifically, the Lactobacillus species, may also be disrupted following
commensal flora has been found to extract nutrients from antibiotic use, leading to bacterial or fungal infections.
otherwise indigestible carbohydrates, compete with patho- Although the mechanism of gastrointestinal to vaginal
genic organisms for residence within the host's intestine, transmission is unclear, exogenous Lactobacillus species used
and modulate the deleterious effects of the mucosal innate on a consistent basis have been shown to colonize the female
and adaptive immune systems.^ More importantly, just as genital tract.^^'^^ Hence, it seems possible that speciflc
different antibiotics generate unique effects, different probiotics used in conjunction with antibiotics may reduce
probiotic strains provide specific health benefits, which the risk of disrupting a healthy vaginal ecosystem and
may include a role in acne therapeutics. populating the vaginal vault with pathogenic organisms.
Tetracyclines are effective and frequent therapeutic This was supported by the current study as 13% of subjects
options for inflammatory acne. Unfortunately, disturbance in the antibiotic-only arm developed vaginal candidiasis, an
• Canadian Dermatology Association I journal of Cutaneous Medicine and Surgery, Vol 17, No 2 (March/April), 2013: pp ¡14-122 119
Jung et al
'120 Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 17, No 2 (March/April), 2013: pp 114-122
Acne Treatment with Minocycline and/or Prohiotics
Mean Difference of Patient Quality of Life Responses from Baseline to the 12-Week Follow-up Visit*
With respect to your acne, do you feel Mean Difference* p Value Mean Difference* p Value Mean Difference* p Value
Unhappy with your appearance? 1.2 0.005 1.4 0.004 2.3 < .001
Uncomfortable around others? 0.9 0.029 0.7 0.041 1.5 < .001
Angry? 0.2 NS 0.4 NS 0.5 NS
Less self-confident? 0.5 NS 0.8 NS 1.4 .002
Self-conscious around others? 0.3 NS 0.7 NS 1.4 < .001
Uneasy? -0.1 NS 0.1 NS 0.4 NS
Discouraged? 1.8 < .001 2.2 < .001 3.3 NS
Like you want to avoid people? 1.9 < .001 2.5 < .001 2.9 < .001
Sad or down? -0.4 NS 0.3 NS 0.3 NS
Humiliated? 1.0 .005 1.1 NS 2.4 < .001
Embarrassed? -0.1 NS 0.1 NS 0.5 .024
Upset? 0.5 NS 0.6 .031 1.2 < .001
Hopeless about your skin? 1.9 < .001 2.2 < .001 3.3 < .001
Unattractive to others? 0.5 NS 0.9 NS 1.3 .008
Frustrated? 1.5 < .001 1.2 < .001 2.1 < .001
Ugly? 0.5 NS 0.9 NS 1.5 .002
Uncomfortable? -0.1 NS -0.1 NS -0.1 NS
NS = not significant.
*Quality of life questions were based on a 7-point scale (1, 2 = not at all; 3, 4, 5 = sometimes; 6, 7 = extremely), with the mean difference calculated from
the baseline visit response to the 12-week follow-up visit response for each group.
' Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 17, No 2 (March/April), 2013: pp 114—122 121
Jung et al
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