Gram-negative Folliculitis – Pathogenesis, Clinical and Treatment
First described by Fulton et al. in 1968 (1), gram-negative folliculitis (GNF) may occur in several clinical settings. It is seen as a complication of prolonged treatment of acne vulgaris with systemic antibiotics. Acne patients who have sudden flares of pustular or cystic lesions or who have acne that is resistant to standard antimicrobial therapy should be evaluated for the presence of GNF (3). Additionally, GNF may occur following the use of a hot tub and in patients with HIV.
In many regards, the pathogenesis of GNF is well understood. In most cases, the anterior nares serve as the reservoir for gram-negative organisms. Acne patients who are treated with oral antibiotics have a shift in their normal flora. In the nares, the number of Staphylococcus aureus organisms and diphtheroids decreases, while the number of coagulase-negative staphylococcal and enter-obacterial organisms increases (2). In patients with GNF, gram-negative flora may constitute up to 4% of the total bacterial flora, as opposed to 1% of flora detected in normal controls (5). In a small number of patients, this increased number of gram-negative organisms results in a transfer of organisms to neighboring areas of the face. The gram-negative bacteria can populate and exacerbate existing acne lesions and create new lesions (4).
Altered immunologic factors may also play a role in the pathogenesis of GNF (6). An assessment of hypersensitivity reactions to various microbial recall antigens and granulocyte functions was performed in 46 patients with GNF. In all patients, deviations in one or more immune parameters were detected, including lowered serum concentrations of immunoglobulin M and a1-antitrypsin and elevated levels of immunoglobulin E. The authors concluded that GNF might not simply be a complication of acne therapy, but rather its own entity as a result of derangements in underlying immunity.
Aside from the nares, other reservoirs, such as the auditory canal and loofah sponges, have been implicated. In 1979, Leyden et al. (7) identified three patients with sudden exacerbation of acne vulgaris who were shown to have GNF from Pseudomonas aeruginosa infection. In each patient, the source of the Pseudomonas was found to be an otitis externa infection. The anterior nares were not colonized. Unused loofah sponges undergo a shift in bacterial flora from sparse colonies of Bacillus spp. and Staphylococcus epidermidis to predom-inantly gram-negative spp. and may serve as a vehicle for the transmission of the pathogenic bacteria to the skin. Regular decontamination of loofah sponges with hypochlorite bleach may mitigate this problem (8).
The overall incidence of GNF is unclear. A study by Eady et al. (9) found that 15% of acne patients who failed to respond to antibiotic therapy had GNF. Sixty-five percent of nonresponders had no microbiological abnormality and 20% had resistant P. acnes. In general, the overall incidence of GNF is likely under-estimated due to poor sampling techniques including inadequate sampling, dried-out swabs, and long delays between sampling and arrival of specimen to the laboratory (10). Swabs should be taken from both the pustules and the nasal mucosa with sterile technique.
GNF is most likely to occur after the early teenage years, as this time period correlates with acne vulgaris patients who have been on oral antibiotics for a prolonged period of time. Patients oftentimes present with complaints of an acne flare. Typical acne patients with GNF are men with perioral and perinasal papules and pustules. They often give a history of prolonged treatment with oral and/or topical antibiotics (10).
There are two types of lesions that develop in GNF: superficial pap-ulopustular lesions without comedones, which occur in approximately 80% of patients. Pus is typically very viscous. These lesions are usually associated with a lactose-fermenting, gram-negative rod, including Klebsiella, Escherichia, and Serratia spp. Nodular lesions, seen in the other 20% of patients, are associated with Proteus sp. These species are motile and, thus, have the ability to invade more deeply, producing the large suppurative abscesses that result in deeper cystic lesions (3).
Histological differences between GNF lesions and acne lesions have also been appreciated. In contrast to typical acne lesions, lesions of GNF do not contain an extractable microcomedo. A minimal amount of keratinous material is present in an intrafollicular sea of pus. Segments of the follicular wall may be dissolved. Organisms are typically arranged 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 (i.e., gram-positive rods and cocci, gram-negative rods, budding yeasts) (3). Gram stain and culture are recommended to confirm diagnosis; however, history and physical exam are oftentimes adequate to make the correct diagnosis.
Pseudomonas organisms typically cause hot-tub folliculitis (19). P. aeru-ginosa is a ubiquitous gram-negative rod that is often implicated in this entity. Folliculitis develops in areas covered by swimsuits. Aeromonas hydrophila has also been found to cause hot-tub folliculitis and is associated with water sources, including an inflatable pool and poorly maintained home spa baths (11). Aci-netobacter baumannii, a known important cause of nosocomial infections, has also been implicated in GNF. Bachmeyer et al. (12) described a patient with AIDS who developed A. baumanii folliculitis of the face, neck, arms, and upper trunk. The bacterium was not found on healthy skin and the source of the infection remains unknown.
The mainstay of treatment of acne-related GNF is isotretinoin, which has largely replaced the use of systemic antibiotics. In general, gram-negative infection remits when factors altering the nasal and cutaneous flora are eliminated (6). It has been shown that isotretinoin can reduce sebum levels by up to 90% or more (13). How this affects GNF is not apparent. Isotretinoin is also thought to have anti-inflammatory effects (14). Isotretinoin does not possess antibacterial prop-erties and does not result in the direct killing of gram-negative organisms (18).
Several studies have shown that isotretinoin is the most effective treatment available for GNF, with low rates of recurrence and eradication of gram-negative bacteria from both the skin and the nares (15 17). Treatment may last anywhere from five months to one year, but clearance may be expected within two to three months. Recommended doses are 0.5 to 1.0 mg/kg/day. Follow-up cultures are recommended to ensure species eradication.
Systemic antibiotics were displaced as the treatment of choice for GNF. Topically, therapy is generally ineffective. However, in patients where iso-tretinoin is contraindicated, appropriate antibiotics may be supplemented. Ampicillin or trimethoprim-sulfamethoxazole for at least two weeks may be considered. Clearance of gram-negative bacteria from the anterior nares can aid in determining therapy duration.
Hot-tub folliculitis is typically self-limited in immunocompetent patients. A. bauniannii folliculitis in the setting of AIDS has responded to intravenous treatment with ticarcillin-clavulanic acid (12).
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