CASE #1: Gram-negative folliculitis

Gram-negative folliculitis (GNF) is one of the most common mimics and complications of acne and acne rosacea. First described by Fulton in 1968,1 GNF in acne patients is a relatively rare complication of prolonged antibiotic therapy and should be considered in acne and acne rosacea patients who have flare-ups of pustules or cysts after prolonged courses of such antibiotics as doxycycline and minocycline.

The differential diagnoses of GNF when acne and acne rosacea are excluded include: eosinophilic pustular folliculitis (especially if the patient is HIV-positive); Malassezia (Pityrosporum) folliculitis; chloracne; and drug-induced pustular eruption caused by corticosteroids, epidermal growth factor receptor inhibitors, cyclosporine, anticonvulsants, antipsychotics, antidepressants, tumor necrosis factor-alpha inhibitors, anabolic steroids, danazol (Danocrine), anti-TB drugs, quinidine, azathioprine (Azasan, Imuran), and testosterone. Molluscum contagiosum, coccidioidomycosis, secondary syphilis (syphilids), tuberculids, and perioral dermatitis are not true mimics of GNF.

The key epidemiologic factor in the development of GNF is the presence of acne or acne rosacea treated with the tetracycline class antibiotics.2 There is no sexual or racial predilection for the development of GNF. Teenagers seem to suffer less frequently than older persons because they have had less exposure to tetracycline antibiotics.


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The basis for GNF is not fully understood. Gram-negative organisms require a sufficiently moist environment to survive and proliferate.3 It is thought that antibiotics—tetracycline in particular—change the normal florae of the skin, allowing gram-negative bacteria that colonize the anterior nares to spread to the facial skin.4 In addition, the presence of seborrheic dermatitis is thought to increase the risk of GNF because facial seborrheic dermatitis traps moisture and promotes the survival of gram-negative bacteria; therefore, the presence of excessive seborrhea may predispose an individual to GNF. Occlusion and maceration have also been suggested as factors that increase the incidence of GNF.

Immune factors likely influence the development of GNF. A study of 46 patients with GNF evaluated hypersensitivity reactions to various microbial recall antigens as well as granulocyte functions. Serum levels of immunoglobulin (Ig) M, G, A, and E, total complement activity, complement factors C3 and C4, and alpha 1-antitrypsin were measured and found deviations of one or more immune parameters, including lowered serum concentrations of IgM and alpha-1-antitrypsin and elevated levels of IgE in all patients.2

While acne is a disease of closed and open comedones, red papules, pustules, and cysts, GNF is a disease primarily of pustules (and to a lesser extent, cysts). That is, GNF causes acneiformlike dermatoses, which are follicular eruptions rather than a true acne eruption of comedones. Approximately 80% of patients with GNF have Type 1 disease, which manifests as superficial, fragile pustules without comedones. Type 2 GNF results in deeper nodules and cysts. GNF occurs most commonly on the cheeks, chin, paranasal areas, and less commonly, the forehead. GNF does usually occur on the back.

GNF was reported in 4% of patients who received broad-spectrum antibiotics for treatment of acne;5 however, this occurrence rate in acne patients may be considered underestimated because clinicians rarely perform culture. GNF may also occur in the setting of hot-tub immersion and in people infected with HIV.6,7

GNF has a distinct clinical appearance, so a diagnosis can be established based on the clinical history (failure of oral tetracycline) and a physical exam showing numerous fragile pustules. To confirm the diagnosis of GNF, promptly perform Gram stain and culture of a fresh pustule with an erythematous base, as Gram-negative organisms are more sensitive to desiccation than staph. Gram stain may show a mixture of gram-positive rods, gram-positive cocci, gram-negative rods, and budding yeasts. Biopsy is not recommended to diagnose GNF.

The assessment of samples is complex. Such selective medium-containing dyes as methylene blue allow selective growth of gram-negative organisms while inhibiting growth of gram-positive organisms. The organisms that produce colonies on eosin-methylene blue agar are classified as either lactose-fermenting gram-negative rods or Proteus species by their cultural characteristics and their ability to ferment lactose.

GNF is caused by a variety of gram-negative bacterium, including: Escherichia coli, Serratia marcescens, K. pneumoniae, K. oxytoca, and Proteus mirabilis. Pseudomonas aeruginosa is a ubiquitous gram-negative rod that can also cause GNF.8,9 Aeromonas species are ubiquitous, facultative, anaerobic, gram-negative flagellated rods mainly found in aquatic ecosystems worldwide. Interestingly, Pseudomonas aeruginosa and Aeromonas can cause hot-tub folliculitis.6 Citrobacter diversus (koseri) has been noted to be a cause of GNF and scalp folliculitis.10

The classical treatment of GNF calls for isotretinoin 0.5-1.0 mg/kg for five months.11 Antibiotic regimens involving double-strength TMP/SMX can be successful if used for two to four months. Although it seems that topical treatment with benzoyl peroxide or azelaic acid would be helpful, GNF requires oral medication. Children, persons with diabetes, and immunodeficient patients may be more susceptible to gram-negative infections and may require treatment with a second- or third-generation cephalosporin in addition to conventional therapies.

At the patient’s one-month follow-up visit, most of his pustules had disappeared. Two months later all of the pustules were gone.