Gram-negative folliculitis, first described by Fulton et al in 1968,[1] is an infection caused by gram-negative organisms. The infection may occur as a complication in patients with acne vulgaris and rosacea and usually develops in patients who have received systemic antibiotics for prolonged periods.[2] Gram-negative folliculitis should be considered in patients with acne who have a flare-up of pustular or cystic lesions and in patients whose acne is resistant to treatment. Gram-negative folliculitis may also occur in the setting of hot-tub immersion and in people infected with HIV. Note the image below.
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Pseudomonas folliculitis. Courtesy of Hon Pak, MD.
The anterior nares serve as a reservoir of gram-negative organisms. Prolonged systemic antibiotic treatment can alter the relative prevalence of bacterial flora carried in the nasal passages. An inverse relationship has been demonstrated between the presence of gram-positive organisms and gram-negative organisms in the pharyngeal, axillary, and toe-web flora. In patients with acne who are treated with oral antibiotics, the number of Staphylococcus aureus organisms and diphtheroids decreases and the number of coagulase-negative staphylococcal and enterobacterial organisms increases in the nose. Usually, gram-negative bacteria constitute less than 1% of the total bacterial flora in the nose. In patients with gram-negative folliculitis, enterobacteria constitute approximately 4% of the total bacterial flora.
The antibiotic-induced increase in gram-negative organisms usually does not result in adverse effects, and once antibiotic treatment is discontinued, the nasal flora reverts to its previous state. However, in a small number of patients, the increased number of gram-negative organisms results in a transfer of organisms to neighboring areas of the face. The bacteria populate existing acne lesions and can also cause pustules to arise de novo.
In addition to the need for suppression of interspecies interference, gram-negative organisms require a sufficiently moist environment to survive and proliferate. The presence of excessive seborrhea may promote the survival of gram-negative bacteria by trapping moisture in the face. The effectiveness of isotretinoin in the treatment of gram-negative folliculitis has been attributed to its ability to make the skin and the mucous membranes dry as a result of the marked reduction in sebaceous gland secretion.
Another factor has been implicated in the pathogenesis of gram-negative folliculitis. An assessment of hypersensitivity reactions to various microbial recall antigens and granulocyte functions was performed. Lowered serum concentrations of immunoglobulin M (IgM) and alpha1-antitrypsin and elevated levels of immunoglobulin E (IgE) were found, suggesting that altered immunologic factors may play a critical role in the pathogenesis of gram-negative folliculitis.
Systemic antibiotics, such as tetracyclines, can alter the nasal flora. The resultant overgrowth of gram-negative bacteria can lead to folliculitis.
Type 1 lesions are usually associated with a lactose-fermenting, gram-negative rod, including Klebsiella, Escherichia, and Serratia species. Cases associated with Citrobacter and Morganella species, other organisms of the Enterobacteriaceae family, have also been described.[3, 4, 5]
Type 2 lesions are associated with Proteus species. These species are motile and, thus, have the ability to invade more deeply, producing the large suppurative abscesses that result in deeper cystic lesions.
Folliculitis caused by Pseudomonas organisms is typically associated with immersion in hot tubs and swimming pools, resulting in a generalized folliculitis.[6] Aeromonas hydrophila has also been associated with water sources, including an inflatable pool.[7, 8] Home spas have also been implicated in causing gram-negative folliculitis. In the reported patients who were swimmers, a sudden unmanageable flare-up of facial acne associated with chronic bilateral otitis externa was reported. A case of Acinetobacter baumannii folliculitis of the face, neck, arms, and upper part of the trunk has been reported in a patient with AIDS.[9]
Gram-negative folliculitis is a relatively uncommon complication of prolonged antibiotic therapy. In two studies, approximately 4% of patients with acne vulgaris who were under treatment with broad-spectrum antibiotics reported this infection. However, the frequency of this infection is probably generally underestimated because clinicians rarely perform correct sampling and bacteriology.
Race
No racial predilection is documented for gram-negative folliculitis.
Sex
No sexual predilection is documented for gram-negative folliculitis.
Age
Although gram-negative folliculitis is largely a complication of acne vulgaris and thus is expected to follow the age distribution of that entity, a slightly increased age at onset has been observed. The tendency for gram-negative folliculitis to begin after the early teenage years is most likely because most patients who develop gram-negative folliculitis have undergone treatment of acne with a broad-spectrum antibacterial agent for a prolonged period.
Gram-negative folliculitis has no associated increase in mortality. Morbidity is related to local pain and to the unwanted cosmetic effect of the folliculitis. Complete remission of the gram-negative folliculitis results with isotretinoin use. If antibiotic therapy is used, long-term suppression is required.
Educate patients that gram-negative folliculitis is a different disease entity and that the treatment of the primary disease (acne or rosacea) is causing the gram-negative folliculitis. If antibiotic therapy is used, make patients aware that treatment is usually only suppressive.
A history is helpful in suggesting the diagnosis of gram-negative folliculitis.
Patients usually have been receiving a course of antibiotics for a prolonged period. Patients with gram-negative folliculitis may present with one of two histories.
A history of apparent acne, usually of the nodulocystic form, may be present. The acne has not been responding to antimicrobial therapy or other therapy. A history of acne that has responded well to therapy and suddenly flares may be present.
Because gram-negative folliculitis usually occurs in patients with existing acne, the development of this new process is often mistaken as an exacerbation of acne.
The morphology of the lesions is as follows:
Type 1 (approximately 80% of patients) - Superficial pustular lesions without comedones
Type 2 (approximately 20% of patients) - Deep, nodular, and cystic lesions
The distribution of the lesions is extending from the infranasal area to the chin and the cheeks.
Complications of gram-negative folliculitis are largely limited to expansion of infection, as well as potential permanent scarring. Of note, however, is the high potential for this condition to be missed when a diagnosis is attempted through telemedicine or direct-to-consumer telemedicine websites and smartphone apps.[10]
As history is the primary method by which a diagnosis is made, advancements and increases acceptance of direct-to-consumer telemedicine and apps have resulted in this condition being a particular diagnosis at risk of being missed. Additional consideration should be given to patients presenting with self-diagnosed and treated acne with flare for gram-negative folliculitis.[11]
The diagnosis of gram-negative folliculitis can often be made based on the history and the physical examination findings alone. However, confirmation with Gram stain and culture is recommended.
In confirming the diagnosis with Gram stain and culture, use special care in culturing. Gram-negative organisms are sensitive to desiccation; samples must be taken quickly and cultured as soon as possible. The pustule that is sampled should also be fresh. A small pustule on an erythematous base is preferable for culturing purposes.
Culture pustules in any patient with acne who is in their late teens or older and has been on long-term antibiotics and develops a pustular form of the disease.
Gram-negative organisms cannot be recovered from every pustule but will be found on cultures of the anterior nares.
Selective medium-containing dyes, such 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. Lactose-fermenting, gram-negative rods produce small, dark, discreet, metallic colonies. Proteus species produce rapidly spreading, translucent, and odorous colonies.
In patients with facial folliculitis that presents a diagnostic challenge, a potassium hydroxide mount (10-20% potassium hydroxide is used to stain a sample on a slide and look for possible fungal elements) and a skin biopsy specimen may be of value.
In contrast to typical acne lesions, lesions of gram-negative folliculitis do not contain a comedonal core. A minimal amount of keratinous material is present in an intrafollicular sea of pus. Occasionally, segments of the follicular wall may be dissolved. Organisms are located in nests around clumps of keratinous material, around hairs, and in phagocytes. In contrast to the predominant gram-negative rod recovered on culture, Gram stain of the tissue section may show a mixed flora (ie, gram-positive rods and cocci, gram-negative rods, budding yeasts).
Treatment of gram-negative folliculitis includes the use of isotretinoin and systemic antibiotics.[12]
Isotretinoin offers the most effective cure for gram-negative folliculitis.[13, 14, 15] It is a synthetic beta-carotene derivative that is highly effective when used in patients with severe nodulocystic acne unresponsive to conventional therapy. Studies in patients with gram-negative folliculitis have demonstrated effective eradication of facial lesions and nasal carriage with isotretinoin, with an average clearance time of approximately 2-3 months. A low incidence of recurrence has been reported with this therapy. Isotretinoin has no antibiotic effect against the organisms causing gram-negative folliculitis. Several mechanisms have been proposed for its action, including sebum suppression, because all patients with this disease have severe seborrhea prior to isotretinoin treatment, and drying out of the mucous membranes, including the nasal mucosa, which is the reservoir for the organisms.
Systemic antibiotics were the mainstay of therapy for gram-negative folliculitis prior to the development of isotretinoin; the choice of antibiotic was dictated by antibiotic sensitivities. Topical therapy rarely works. The most effective antibiotics have come from the bacteriostatic group, which includes ampicillin and trimethoprim-sulfamethoxazole. Reports have conflicted concerning the degree to which these medications can eradicate the carriage of gram-negative organisms and induce remission. Most studies describe recurring infection after therapy is discontinued, making antibiotic use largely a suppressive modality.
Gram-negative folliculitis caused by Pseudomonas organisms in whirlpools usually subsides spontaneously within 10 days without recurrence. In patients with facial folliculitis caused by Pseudomonas organisms associated with acne vulgaris, the infection clears when the source of the organism, external otitis, is cured. Acinetobacter baumannii folliculitis in the setting of AIDS has responded to intravenous treatment with ticarcillin-clavulanic acid.
Most patients have ordinary acne in addition to gram-negative folliculitis. Once the folliculitis has responded, residual acne must be treated by other methods, including retinoic acid, benzoyl peroxide, cryotherapy, and other therapies.
Gram-negative folliculitis is relatively uncommon, and the general benefit from antibiotics far outweighs the occasional complication of folliculitis.
Clinical Context:
An oral agent that treats serious dermatologic conditions, isotretinoin is synthetic 13-cis isomer of naturally occurring tretinoin (trans-retinoic acid). Both agents are structurally related to beta-carotene. Isotretinoin decreases sebaceous gland size and sebum production. It may inhibit sebaceous gland differentiation and abnormal keratinization.
A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.
Female patients must sign an informed consent that they will use contraceptives during treatment course and for 30 days after discontinuing therapy.
Clinical Context:
Ampicillin has bactericidal activity against susceptible organisms. It is an alternative to amoxicillin if the patient is unable to take medication orally.
Clinical Context:
This drug combination inhibits the biosynthesis of cell wall mucopeptide and is effective during the stage of active growth. It consists of an antipseudomonal penicillin plus a beta-lactamase inhibitor and provides coverage against most gram positives, most gram negatives, and most anaerobes.
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Antibiotic selection should be guided by blood culture sensitivity whenever feasible.
Clinical Context:
Benzoyl peroxide is an oxidizing agent that possesses antibacterial properties and is comedolytic. The antibacterial activity results from the release of active or free-radical oxygen that can oxidize bacterial proteins. Benzoyl peroxide is oxidized into benzoic acid with contact to the skin. It is available over the counter and by prescription. It may be used to treat residual acne once the folliculitis has responded,
Acne products are used for the treatment of mild to moderate acnes vulgaris. These agents may have antibacterial and comedolytic properties. In severe cases the agents may be used as an adjunct in therapeutic regimens.
What is gram-negative folliculitis?What is the pathophysiology of gram-negative folliculitis?What causes gram-negative folliculitis?What is the prevalence of gram-negative folliculitis?What are the racial predilections of gram-negative folliculitis?What are the sexual predilections of gram-negative folliculitis?Which age groups have the highest prevalence of gram-negative folliculitis?What is the prognosis of gram-negative folliculitis?What is included in patient education about gram-negative folliculitis?Which clinical history findings are characteristic of gram-negative folliculitis?Which physical findings are characteristic of gram-negative folliculitis?What are the possible complications of gram-negative folliculitis?What are the differential diagnoses for Gram-Negative Folliculitis?How is gram-negative folliculitis diagnosed?What is the role of lab tests in the workup of gram-negative folliculitis?Which histologic findings are characteristic of gram-negative folliculitis?How is gram-negative folliculitis treated?What is the role of medications in the treatment of gram-negative folliculitis?Which medications in the drug class Acne Agents, Topical are used in the treatment of Gram-Negative Folliculitis?Which medications in the drug class Antibiotics, Other are used in the treatment of Gram-Negative Folliculitis?Which medications in the drug class Retinoid-like Agents are used in the treatment of Gram-Negative Folliculitis?
Mordechai M Tarlow, MD, Clinical Assistant Professor of Dermatology, University of Pennsylvania School of Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Michael Wiederkehr, MD, Consulting Staff, Livingston Dermatology Associates; Consulting Staff, Comprehensive Dermatology and Laser Center
Disclosure: Nothing to disclose.
Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School
Disclosure: Nothing to disclose.
Sofia Piela, MD, Head, Department of Dermatology, Rzeszow Regional Health Center, Poland
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Rosalie Elenitsas, MD, Herman Beerman Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System
Disclosure: Received royalty from Lippincott Williams Wilkins for textbook editor.
Chief Editor
William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine
Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.
Additional Contributors
Andrea Leigh Zaenglein, MD, Professor of Dermatology and Pediatrics, Department of Dermatology, Hershey Medical Center, Pennsylvania State University College of Medicine
Disclosure: Received consulting fee from Galderma for consulting; Received consulting fee from Valeant for consulting; Received consulting fee from Promius for consulting; Received consulting fee from Anacor for consulting; Received grant/research funds from Stiefel for investigator; Received grant/research funds from Astellas for investigator; Received grant/research funds from Ranbaxy for other; Received consulting fee from Ranbaxy for consulting.
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