Azithromycin Treatment for Acne Vulgaris: A Case Report on the Risk of Infection

Background

Clostridioides difficile (C. difficile) is a gram-positive, anaerobic, spore-forming bacillus [1]. It is the main cause of antibiotic-associated diarrhea, and it can lead to pseudomembranous colitis [1]. C. difficile infection is commonly reported with use of some classes of antibiotics: in descending order – clindamycin, cephalosporins, carbapenems, fluoroquinolones, and penicillin [2,3]. Longer duration of antibiotics use is associated with a higher risk of C. difficile infection [1].

Azithromycin is an antimicrobial medication classified as a macrolide antibiotic [4]. It is considered a broad-spectrum antibiotic and has activity against gram-negative, gram-positive, and anaerobic bacteria, including Propionibacterium acnes [4]. It works by inhibiting the microorganism’s protein synthesis through blocking the ribosomal subunit [5]. In addition to its antimicrobial effect, azithromycin demonstrates an affinity to inflammatory tissue by inhibiting the production of proinflammatory factors like tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), and nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase (NOx) [6]. It also has immunomodulatory effects by reducing the production of PGE2 and interleukin-8 (IL-8) cytokines [6]. Azithromycin is known to be a safe antibiotic with few adverse effects, which include diarrhea, stomach pain, and constipation [5].

Based on the American Academy of Dermatology guidelines, macrolides are not the first-line treatment for acne vulgaris, and they are only used when traditional antibiotics cannot be used [7]. However, macrolides such as azithromycin are currently used in clinical practice for acne treatment due to its antimicrobial and anti-inflammatory activity, in addition to its good safety profile [6]. Using azithromycin in the treatment of acne vulgaris can be in different dosing regimens, from 3 times a week to 4 days a month, with a duration of 2–3 months [7]. Many studies that compared azithromycin and doxycycline showed doxycycline was more effective, especially in patients older than 18 years, but showed a similar effect when administered with topical treatments like tretinoin and adapalene gel [6]. A meta-analysis of randomized controlled trials comparing the efficacy of azithromycin with doxycycline in acne treatment found that doxycycline causes more adverse effects than azithromycin [4]. The reported adverse effects include diarrhea, nausea, epigastric pain, photosensitivity, vaginitis, abnormal blood cell count, and vertigo [4].

A few studies have linked macrolide use, including azithromycin, with C. difficile infection, but only in a low percentage of cases [8–11]. One study mentioned that azithromycin caused C. difficile infection with an odds ratio (OR) of 2.88 and confidence interval (CI) of 1.54–5.37, which was lower than with other antibiotics [9]. In addition, 2 meta-analyses have linked macrolide use with C. difficile infection, but only in a low percentage of cases and with no mention of a specific agent [10,11]. There are 2 published case reports of Moinuddin acne treatment with azithromycin [12,13]: the first used azithromycin 1 g/week for a patient with arthritis associated with acne [12], and the second report was of using azithromycin 500 mg/day for a patient with hidradenitis suppurativa (HS) [13].To the best of our knowledge, there are no reported cases that linked the use of azithromycin for the treatment of acne vulgaris with C. difficile-associated diarrhea.

Here, we report the case of a 41-year-old woman with acne vulgaris who developed C. difficile colitis following a second course of a 6-week course of azithromycin to treat her acne vulgaris.

Case Report

A 41-year-old woman presented to a dermatology clinic with a past medical history of severe acne vulgaris, hyperlipidemia, and migraine, with no past surgical history or prior hospitalization. She has been primarily treated with clindamycin 1% topical solution 2 times daily and azithromycin 250 mg by mouth 3 times weekly for 6 weeks based on her case and the dermatologist’s diagnosis. Eight months later, she had a dental implant in which she was prescribed amoxicillin/clavulanic acid 1 g by mouth for 10 days.

Ten months later, after completion of the first acne treatment regimen, the patient returned to the clinic with inflammatory acne vulgaris. The therapeutic plan was to reuse the previous regimen of azithromycin. Four days following her completion of the second course of azithromycin, she started to have mild abdominal pain, frequent soft stool (3 times a day) with abdominal gasses, and unusual stool odor. The pain was more frequent and kept worsening with softer bloody stool (around 5–6 times a day).

She presented to the gastroenterology clinic, and a complete blood count (CBC) test and C. difficile toxin A test were ordered, in addition to a colonoscopy. Her white blood count (WBC) as 9590 cells/µL (normal range: 4500–10 000 cells/µL) and the serum creatinine (SCr) was 0.6188 mg/dL (normal range: 0.59–1.04 mg/dL). The C. difficile toxin A test result came back positive. The colonoscopy revealed friable mucosa with white exudate extending from the rectum to the transverse colon, which is consistent with a C. difficile diagnosis (Figure 1). The 48-h stool culture revealed no growth of salmonella or shigella.

The patient was started on metronidazole 500 mg by mouth 3 times daily for 10 days. No improvement was noticed after completing the course. She still had mild abdominal pain and bloody diarrhea (3–4 times per day). As a result, the C. difficile toxin test was repeated, and the result came back positive. This time she was treated with vancomycin 125 mg by mouth 4 times daily for 10 days and her symptoms improved accordingly.

Discussion

We report the case of a woman diagnosed with C. difficile-associated diarrhea after recurrent use of azithromycin regimen for the treatment of severe acne vulgaris.

Acne vulgaris is a common cutaneous disorder characterized by inflammation of the pilosebaceous unit of a hair follicle and commonly caused by the anaerobic bacterium Propionibacterium acnes [14]. Many pharmacological options are very effective to reduce the inflammation of acne and improve the skin’s appearance, including topical oral and procedural therapies [7]. The selection is made based on the severity of acne vulgaris and patient preferences [7,15]. Based on the acne vulgaris treatment guideline, the first line of treatment for mild acne includes topical agents like benzoyl peroxide and retinoids, and topical antibiotics like clindamycin [7]. For moderate to severe cases, systemic agents can be used either alone or in combination with topical agents [7]. Systemic agents include isotretinoin and tetracyclines such as doxycycline. Macrolide can be used as an alternative treatment for those who cannot use doxycycline, such as pregnant women and children [7].

In our case, the patient was initially treated with clindamycin 1% topical solution 2 times daily and azithromycin 250 mg by mouth 3 times weekly for 6 weeks, which was not the first-line option in her case. Then, exactly the same course of azithromycin was repeated 10 months later, which might have increased her risk of C. difficile infection. In addition, between the 2 courses of azithromycin, she received another course of amoxicillin/clavulanic for her dental implant. As a result, after completing her second course of azithromycin, she was diagnosed with an initial episode of non-severe C. difficile infection based on her symptoms, colonoscopy, and laboratory data (WBC ≤15 000 cells/µL and SCr <1.5 mg/dl) [7]. The C. difficile infection was most likely due to the repeated course of the azithromycin regimen, since she had no risk factors such as history of colon disease or any gastrointestinal disease and she had not taken any laxatives for 48 h before her symptoms started.

Our patient was initially treated with metronidazole 500 mg by mouth 3 times daily for 10 days based on the hospital practice guidelines and had failed the treatment. Metronidazole treatment failure was unknown. However, she was re-treated successfully with vancomycin 125 mg by mouth 4 times daily for 10 days

Although azithromycin has a good safety profile and is rarely associated with reported cases of C. difficile, our case is a rare incidence that occurred after a repeated course of azithromycin to treat acne vulgaris. This case shows the importance of following the treatment guidelines carefully for managing acne vulgaris cases, and also highlights the role of infectious disease pharmacists in such decision-making for patient well-being and better health outcomes.

Conclusions

The acne vulgaris regimen of azithromycin of 250 mg 3 times weekly has been increasingly used in dermatology clinics for the treatment of acne vulgaris, despite being considered an alternative treatment based on the American Academy of Dermatology guidelines. A thorough assessment of the patient’s history, including the previous antibiotic regimen used and patient eligibility, needs to be considered before prescribing azithromycin for acne vulgaris. This report highlights the importance of managing patients with acne vulgaris according to current practice guidelines, and to report a link between the use of azithromycin as an acne regimen and the risk of C. difficile colitis occurrence.