Chapter 11 Bacteriology of 11

Cristina Oprica, Carl Erik Nord

Key points Q Antibiotics do not cure the disease but they may relieve the symptoms through Q The pathogenesis of hidradenitis either an antibacterial or an anti- suppurativa (HS) is still poorly under- inflammatory effect stood and not yet clearly defined

Q A large variety of bacteria can be found in HS lesions and many of them belong to the normal flora of the skin #ONTENTS 11.1 Normal Microflora of the Skin ...... 86 Q In the studies using the bacteria prevalent on the surface of the lesions 11.2 BacteriaFoundinHSLesions ...... 87 there is possible contamination from 11.3 General Factors About Bacterial the resident flora of the skin InvolvementinHSPathogenicity ...... 90 11.4 The Role of Antibiotics in the Treatment 11 Q In cases of cultures obtained from the of HS ...... 91 deeper parts of HS, Staphylococcus 11.5 Possible Consequences aureus, coagulase-negative staphylo- forBacterialEcologydue cocci and anaerobic bacteria have toAntibioticTreatmentinHS ...... 92 commonly been isolated References ...... 92

Q The first event seems to be follicular occlusion by keratinized stratified 11.1 Normal Microflora of the Skin squamous epithelium in apocrine- bearing areas, with subsequent inflam- Normal human skin is colonized by a large vari- mation ety of organisms that live as commensals on its surface. There are quantitative differences Q The initial inflammatory change can be among different regions of the skin, related to produced by a pyogenic bacterial temperature difference, moisture content, and infection or by factors similar to those the presence of various amounts of skin lipids involved in that may be inhibitory or lethal for some micro- organisms. These differences characterize three Q In chronic lesions, bacteria represent a main regions of the skin: (1) axilla, perineum, risk factor for the destructive scarring and toe webs; (2) hands, face, and trunk; and (3) and extension of the disease and arms and legs [20]. The skin microflora reside secondary bacterial infections may on the skin surface and in the ducts of hair fol- occur licles and sebaceous glands [38]. Bacteriology of Hidradenitis Suppurativa Chapter 11 87

Table 11.1. The most important genera and species of bacteria normally found on the skin Genus Characteristics Most prevalent species

Coagulase-negative Aerobic, Gram-positive cocci S. hominis, S. haemolyticus Staphylococcus S. epidermidis Micrococcus Aerobic, Gram-positive cocci M. luteus, M. varians Corynebacterium Aerobic, Gram-positive pleomorphic rods C. bovis, C. minutissimum Propionibacterium Anaerobic, Gram-positive rods P. acnes, P. granulosum, P. avidum Acinetobacter Aerobic, Gram-negative coccobacilli A .calcoaceticus var. lwoffi and var. anitratus

The sites affected by HS are, in order of fre- Propionibacteria are Gram-positive rod- quency: axillary, inguinal, perianal and perine- shaped anaerobic bacteria. Propionibacterium al, mammary and inframammary, buttock, pu- acnes and Propionibacterium granulosum are bic region, chest, scalp, retroauricular, and the associated with follicles that have large seba- eyelid [50]. ceous glands on the face and upper trunk and The major groups of microorganisms present they have a role in acne pathogenesis. Propioni- on the skin are various genera of bacteria and bacterium avidum is found in moist areas (axil- yeasts. The predominant bacteria of the skin are lae and groin) and it is not known if it has patho- as follows (Table 11.1) [20, 21]: genic potential [21]. Acinetobacter species are the only important Q Coagulase-negative staphylococci Gram-negative residents of the skin and are Q Micrococci found in the axillae and groin of 25% of the Q Saprophytic Corynebacterium species population [21]. (diphtheroids) In addition, any bacterial species that is found Q Propionibacterium species in nature or belongs to the normal flora on non- Q Acinetobacter species. cutaneous areas may temporarily be found on the skin [47]. Staphylococcus aureus is not nor- Various coagulase-negative staphylococci are mally considered a resident of normal skin, but found on the skin and some have special predi- it can be found on perineal skin, axillae, and in lection for some areas, for example Staphylococ- the toe cleft. Hemolytic streptococci may be cus hominis and Staphylococcus haemolyticus found as transients on different skin sites, more are found principally in areas where there are often in children [38]. Atypical mycobacteria numerous apocrine glands, such as axillae and may be found in genital and axillary regions the pubic region [20, 32]. Staphylococcus epider- and Bacillus species or different Gram-negative midis is also an important resident, colonizing bacilli such as Proteus, Pseudomonas, Entero- moist areas of the skin [21]. It is found preferen- bacter and Klebsiella are rarely found on the tially in the upper part of the body and repre- skin [20, 38]. sents over 50% of the resident staphylococci In conclusion, a large variety of bacteria are [47]. able to colonize the most affected areas in HS: Micrococcus species are found on the skin, axilla, perineum, and the groin. especially in women and children, and Micro- coccus luteus and Micrococcus varians are the prevailing species [20, 21]. These microorgan- 11.2 Bacteria Found in HS Lesions isms often colonize axilla, perineum, and groin [21]. Although the HS etiology is unknown, a large Different bacteria belonging to the genus variety of microorganisms can be isolated from Corynebacterium are associated, but not exclu- the lesions. The clinical picture of the disease sively, with moist areas of the skin [21]. resembles an infectious process and various 88 Cristina Oprica, Carl Erik Nord

Table 11.2. Studies describing the diversity of bacteria found in various HS lesions Investigator Bacteria found Area of the skin

Leach et al. [35] Staphylococcus aureus, anaerobic bacteria Axillae Brenner and Lookingbill [7] Staphylococcus aureus, Staphylococcus epidermidis Perirectal, groin, axillae Bacteroides fragilis, Bacteroides melaninogenicus Highet et al. [23] Streptococcus milleri Perineal Highet et al. [24] Streptococcus milleri, Staphylococcus aureus, Perineal anaerobic streptococci, Bacteroides species Finegold et al. [18] Biophila wadsworthia Axillae Bendahan et al. [5] Chlamydia trachomatis Perineal Jemec et al. [29] Staphylococcus aureus, Streptococcus milleri, Axillae, groin, breasts, Staphylococcus epidermidis, Staphylococcus hominis buttocks Brook and Frazier [8] Staphylococcus aureus, Streptococcus pyogenes, Axillae Pseudomonas aeruginosa; Peptostreptococcus species, Prevotella species, micro-aerophilic streptococci, Fusobacterium species, Bacteroides species Lapins et al. [33] Staphylococcus aureus, coagulase-negative Axillae and perineal staphylococci, enterococci, group B hemolytic streptococci, group C hemolytic streptococci, Bacillus cereus, diphtheroides, enterobacteriacae-; Peptostreptococcus species, Propionibacterium acnes, microaerophilic streptococci, Lactobacillus species, Bacteroides fragilis, other Bacteroides species, Prevotella species 11

bacteria are suspected as being responsible for streptococci, Fusobacterium species, and Bacte- the . The bacterial findings are roides species. considered by some authors as either contami- In most of the studies samples are collected nants from the normal skin flora or a result of from the surface of the lesions [22–24] and there secondary infection in a previously sterile pro- is a high risk of contamination with the resident cess [33]. skin flora. In these conditions the bacteriologi- Despite the volume of the discharge the HS cal results are difficult to interpret. Jemec et al. lesions are often found to be sterile [29, 33], but [29] have aspirated pus from the deeper parts of sometimes a large variety of microorganisms HS. Bacteria were found in half of active lesions: can be isolated from the sinuses, particularly Staphylococcus aureus and coagulase-negative staphylococci, streptococci, Gram-negative rods, staphylococci (Staphylococcus epidermidis and and anaerobic bacteria (Table 11.2). The bacte- Staphylococcus hominis) were most commonly rial flora are not consistent and may change un- isolated. An explanation for the large number of predictably [31]. Brook and Frazier [8] found, in negative cultures could be that it is difficult to a retrospective review of clinical and bacterio- localize the infected part using the aspiration logical data from patients with axillary disease, technique. It was found that the duration of the that the most prevalent aerobic bacteria were disease was shorter for those patients in whom Staphylococcus aureus, Streptococcus pyogenes, Staphylococcus aureus was detected as a possible and Pseudomonas aeruginosa and the most fre- etiological factor, indicating that this bacterium quent anaerobic bacteria were Peptostreptococ- may be involved early in the disease pathogene- cus species, Prevotella species, microaerophilic sis by causing anatomical changes in the hair Bacteriology of Hidradenitis Suppurativa Chapter 11 89

Table 11.3. Possible factors responsible for coagulase- crease the pathogenic properties of these other- negative staphylococci pathogenicity in HS lesions wise harmless members of the normal flora. Factors Effect Lapins et al. [33] have often found coagulase- negative staphylococci as the sole bacteria in the deep portion of the lesions and suggested that Sinus formation Enhances the the abnormally structural tissue in HS due to in HS lesions pathogenic properties of the bacteria [33] sinus formation can provide a medium similar to the presence of a foreign body and the result Bacterial capacity Protects against antibiotics of biofilm formation and from attacks by the will be enhancement of the pathogenic proper- immune system [42] ties of coagulase-negative staphylococci. Gener- ally, the pathogenic potential of coagulase-nega- Bacterial production Persistence in the host. of lipases, proteases, Tissue degradation [42] tive staphylococci is mainly due to their capacity and other exoenzymes to form biofilms on medical devices [42]. The Toxin production Invasion properties sinus formation in HS may be an ideal place for [35, 36] biofilm formation and this microbiologic prin- ciple may be applicable to coagulase-negative Production of PAS- Obstructs the delivery positive extracellular of sweat to the skin staphylococci in HS. Many coagulase-negative polysaccharide substance surface [37] staphylococci produce several lipases, proteases, and other exoenzymes, which possibly contrib- ute to the persistence of coagulase-negative staphylococci in the host and may degrade host follicles. These modifications may later predis- tissue [42]. Here, the bacteria find protection pose to inflammation independently of the against antibiotics and from attacks by the im- presence of bacteria [29]. mune system. The biofilm model was recently Lapins et al. [33] circumvented problems proposed to be involved in acne pathogenesis, both of contamination and of missing the active where glycocalyx polymer secreted by Propioni- area of infection by using a carbon dioxide bacterium acnes as a biofilm may explain the (CO2) laser surgical method to evaporate the immunogenicity of the organism as well as the diseased tissue level by level from the surface unpredictable course of the disease [11]. There downwards. This allows sampling for bacterio- are also some lines of evidence that under cer- logical cultures from each level without the risk tain conditions they may produce similar toxins of contamination with bacteria from the level to Staphylococcus aureus and could cause inva- above. By using this method, bacteria were sive diseases [36, 56]. found even in the deeper and closed parts of HS. Mowad et al. [37] showed that periodic-acid- Staphylococcus aureus and coagulase-negative Schiff- (PAS-) positive extracellular polysaccha- staphylococci were also the most commonly ride substance produced by Staphylococcus epi- found species. After the Staphylococcus species dermidis obstructs the delivery of sweat to the the most commonly cultured bacteria were the skin surface and these strains are involved in anaerobic species found in the deeper levels: the pathogenesis of . It was speculated Peptostreptococcus species and Propionibacteri- that a similar mechanism could be involved um acnes. The aerobic bacteria were found in in HS pathogenesis [33]. It is known that the 60% of positive cultures at deep levels. pathogenic potential of coagulase-negative The clinical significance of coagulase-nega- staphylococci varies according to species [33]. tive staphylococci is unclear because while they Staphylococcus haemolyticus and Staphylococ- are part of the normal microflora [29, 33] they cus saprophyticus have well-known pathogenic have also gained attention as pathogens (Table potential and Staphylococcus lugdunesis, Staph- 11.3). Coagulase-negative staphylococci are as- ylococcus schleiferi or Staphylococcus caprae are sociated with infections in those with intravas- considered emerging pathogens [56]. Staphylo- cular catheters [46] and prosthetic devices [14] coccus lugdunesis was found in axillary lesions where the presence of the foreign body will in- diagnosed as HS [54]. 90 Cristina Oprica, Carl Erik Nord

Streptococcus milleri, a microaerophilic mi- and Cahn [49] were able to reproduce HS lesions croorganism frequently causing pyogenic infec- by applying atropine-impregnated adhesive tape tions [17] that often colonizes the gastrointesti- to a manually depilated axillary region. They nal tract and female genital tract, was found by noticed subsequent dilatation, inflammation, some investigators to be a major pathogen in and bacterial invasion of the apocrine duct and perineal HS. Furthermore, the presence of this concluded that HS is a bacterial infection of an bacterium correlated with the disease activity obstructed apocrine with the caus- and its elimination by appropriate antibiotic ative bacteria deriving from the normal flora of therapy was accompanied by marked clinical the skin. improvements [23, 24]. Microaerophilic strepto- However, today it is largely accepted that cocci were found by Brunsting in 1939 in a apocrine gland involvement is not essential to group of patients with HS [9]. Streptococcus mil- the pathogenesis, and that the inflammatory leri, Staphylococcus aureus, anaerobic strepto- processes and involvement of apocrine glands cocci, or Bacteroides species were frequently are secondary events [6, 28]. The disease starts isolated in a group of 32 patients with active with follicular hyperkeratosis and dilatation of perineal HS [24]. Other authors could not find the infundibula and most authors believe that Streptococcus milleri in any of the specimens the bacterial contribution is a secondary event [41]. in the disease process [27, 48]. The retention of In perianal forms of HS, Escherichia coli, keratin in follicles and chronic sinusoids is sub- Klebsiella and Proteus strains as well as anaero- ject to subsequent bacterial infection. Follicular bic bacteria were isolated [27]. Brenner and occlusion leads to dilatation followed by rupture Lookingbill [7] have recovered Bacteroides spe- and spillage of the keratin and bacteria into the cies from perirectal, groin and axillae and the dermis. This induces a strong chemotactic re- patients responded well to a suitable antibiotic sponse with an inflammatory cellular infiltrate treatment regimen. They suggest that the pres- consisting of neutrophils, lymphocytes, and ence of anaerobic bacteria may reflect the chro- histiocytes [50]. In chronic lesions, bacteria can 11 nicity of pre-existing local infection. Anaerobic be found in and around the glands and lym- bacteria were also isolated by Leach et al. from phatics [34]. In later stages of HS, bacterial in- recurrent axillary lesions of HS [35]. fection is a risk factor for extension of the le- Bilophila wadsworthia is a Gram-negative sions. Sinus tracts are formed in the dermis and anaerobic rod found as part of the normal flora subcutis from the ruptured follicular epithelium in feces and, occasionally, in saliva and in the in an attempt by the tissue to confine the in- vagina; in one case of HS it was isolated together flammation, and there is a high risk for second- with other anaerobic bacteria of the Prevotella ary infections [34, 50]. species [4, 18]. Systemic infections such as bacterial menin- Bendahan et al. [5] found an association be- gitis, bronchitis or pneumonia are possible, due tween perineal HS lesions and Chlamydia tra- to the spread of microorganisms [27]. In the case chomatis infection, but it was not clear whether of coagulase-negative staphylococci, the recent- the latter was a direct cause or a predisposing ly found inflammatory peptides called phenol- factor. These findings have not been confirmed soluble modulins (microbial products that stim- by other authors. ulate cytokine production in host cells) play a role in the pathogenesis and systemic manifes- tations of sepsis [42]. 11.3 General Factors About Bacterial Polypeptides from Propionibacterium acnes Involvement in HS Pathogenicity were found to stimulate a specific immune re- sponse in acne patients [26]. Jemec et al. [29] The series of events in HS pathogenesis are un- tried to detect a specific serologic response to a clear and the exact role of bacteria in the etiol- possible staphylococcal or streptococcal infec- ogy of the disease remains controversial. Shelley tion but the results were inconclusive. Bacteriology of Hidradenitis Suppurativa Chapter 11 91

11.4 The Role of Antibiotics Table 11.4. Anti-inflammatory and immunomodulatory in the Treatment of HS properties of antibiotics used in the treatment of HS Antibiotic Mechanisms Despite the fact that the clinical response to an- tibiotics is poor and that bacteria are found in only 50% of lesions, the recommendation for Tetracyclines – Inhibition of metalloproteases – Inhibition of free radicals systemic antibiotics is clear and this is derived – Modulation of IL-1α from empirical attempts to control the disease. – Inhibition of lipases Also, it is reasonable to try antibiotic treatment, and proteases as various bacteria are suspected as having a – Inhibition of nitric oxide role in the inflammatory process and in de- synthetase and caspase 1 structive scarring in HS patients. Approximate- and 3 production ly 10% of patients have some benefit from the – Modulation of cytokine expression use of systemic antibiotics [57]. – Reduction in the production If the drainage from lesions is available, bac- of free radicals secreted by poly- terial cultures and antibiotic sensitivity should morphonuclear leukocytes be performed and the antibiotic treatment – Reduction in the formation should be tailored according to these results. of inflammatory granuloma Collaboration between the dermatologist and Clindamycin – Suppression of complement- the bacteriologist is an important factor in find- derived chemotaxis of poly- ing the best treatment option. Acute episodes morphonuclear leukocytes and relapses are treated as bacterial infections for a 2-week period [21]. Oral antibiotics such as minocycline, erythromycin in combination are known as good candidates for the treatment with metronidazole, ciprofloxacin, cephalospo- of inflammatory disorders. The anti-inflamma- rins or semisynthetic penicillins may be used tory properties are enumerated in Table 11.4 [7, 19, 21]. Bukley and Sarkany [10] reported a [43, 44]. case of severe HS who improved after systemic Hindle et al. treated seven patients with a clindamycin treatment. combination therapy of clindamycin (300 mg Long-term administration of tetracyclines or twice daily) and rifampicin (300 mg twice daily) erythromycin may be used in regimens similar for a 10-week period [25]. Three patients did not to acne vulgaris and seems to prevent episodic tolerate the combination, two because of diar- flares [19, 21]. rhea associated with Clostridium difficile, and Topical clindamycin was found to be superior three of them responded well and remained to placebo in a randomized double-blind clini- clear at 12 months. The combination of rifampi- cal trial [12] and Jemec and Wendelboe did not cin and clindamycin was also successfully used find any difference between systemic tetracy- for two other chronic and difficult-to-treat con- cline and topical clindamycin in another ran- ditions: decalvans [45] and acne ke- domized clinical trial [30]. However, after with- loidalis nuchae [25]. Clindamycin is a lincos- drawal of antibiotic treatment, HS very often amide antibiotic active against Gram-positive relapses [3, 13]. cocci (except enterococci) and most anaerobic As is the case with acne vulgaris, it is not bacteria [52]. Rifampicin is a broad spectrum known whether the most important factor in antibacterial agent that inhibits the growth of the treatment of HS is antibacterial or anti-in- the majority of Gram-positive bacteria as well as flammatory. Lincosamides and tetracyclines many Gram-negative microorganisms [55]. It is have been known for their immunomodulatory highly active against both Staphylococcus aureus effects. Clindamycin suppresses the comple- and coagulase-negative staphylococci. Rapid ment-derived chemotaxis of polymorphonucle- emergence of resistance when the drug was used ar leukocytes in vitro, thereby reducing the alone has limited the use except in association inflammation potential [43, 52]. Tetracyclines with another anti-staphylococcal drug [2]. The 92 Cristina Oprica, Carl Erik Nord

combination therapy was introduced to prevent Table 11.5. Effects of antibiotic administration on the resistance development against rifampicin and ecological balance of human microflora to cover a broad antibacterial spectrum. – Disturbances in the balance between host and normal flora from the intestinal tract, skin, oropharyngeal tract, and vagina 11.5 Possible Consequences – Altered colonization resistance (growth control for Bacterial Ecology due of opportunistic bacteria) to Antibiotic Treatment in HS – Overgrowth of pathogenic bacteria or yeasts The drawback to the usefulness of long-term – The emergence of antimicrobial resistance in the normal flora antibiotic treatments is concern about the effect on microbial ecology (Table 11.5). The normal – Possible transfer of resistance to pathogenic bacteria microflora act as a barrier against colonization by potentially pathogenic bacteria and the con- trol of growth of opportunistic bacteria is called colonization resistance. The normal equilibri- cocci on the skin, Staphylococcus aureus in the um between host and microorganisms may be nares, streptococci in the oral cavity, and en- disturbed by a number of factors, but commonly terobacteria in the gut [16]. and essentially by antibiotic therapy. To what Topical clindamycin will increase carriage of extent disturbances occur depends of numerous Propionibacterium acnes and Staphylococcus factors: the spectrum of the antibiotic, the dose, epidermidis resistant strains on skin and there is the route of administration, pharmacokinetic a risk of transfer of resistance to other patho- and pharmacodynamic properties and in vivo genic bacteria, Staphylococcus aureus and Strep- inactivation of the drug [53]. tococcus species [15]. The skin and conjunctivae Clindamycin administration results in major flora from untreated sites will also be affected ecological disturbances in intestinal and oro- by transfer of antibiotic [16]. 11 pharyngeal microflora: the numbers of entero- In conclusion, antibacterial drugs represent coccal species increase and those of all anaer- an adjuvant treatment in HS. They are not cura- obes decrease [39, 51]. A possible complication tive but they reduce odor and discharge, and of clindamycin treatment is pseudomembra- diminish pain. Antibiotics represent a palliative nous colitis, which occurs when antibiotics such therapy that may control the disease in early as clindamycin, ampicillin and third-generation stages and can reduce the inflammation before cephalosporins suppress the normal flora, al- and after surgery [28] but clinicians should be lowing Clostridium difficile to grow and produce aware about the downside of taking them. toxins [40]. Rifampicin treatment was shown to lead to a decrease in total aerobic and anaerobic oral bacteria in healthy volunteers [1]. References The emergence of antimicrobial resistance is strongly associated with the clinical use of the 1. Appelbaum PC, Spangler SK, Potter CR, et al (1986) antibiotics and a balanced microflora prevents Reduction of oral flora with rifampin in healthy vol- establishment of resistant strains of bacteria unteers. Antimicrob Agents Chemother 29:576–578 [53]. It is well known that oral antibiotics select 2. Arditi M, Yogev R (1989) In vitro interaction between rifampin and clindamycin against pathogenic co- for resistant bacteria at all body sites where there agulase-negative staphylococci. Antimicrob Agents is a normal flora: skin, conjunctivae, oral cavity, Chemother 33:245–247 nasopharynx, upper respiratory tract, intestinal 3. Banerjee AK (1992) Surgical treatment of hidradeni- tract, and vagina [16]. A therapy administered tis suppurativa. Br J Surg 79:863–866 for a long period, as was recommended in HS 4. Baron EJ, Curren M, Henderson G, et al (1992) Bi- treatment [25], will exert a high pressure for the lophila wadsworthia isolates from clinical specimens. development of the resistant strains of Propioni- J Clin Microbiol 30:1882–1884 bacterium acnes, coagulase-negative staphylo- Bacteriology of Hidradenitis Suppurativa Chapter 11 93

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