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provided by Elsevier - Publisher Connector J Infect Chemother (2011) 17 (Suppl 1):72–76 DOI 10.1007/s10156-010-0143-8

GUIDELINES

Chapter 2-5-3a. Anaerobic (individual fields): and soft tissue infections

Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2011. Open access under the Elsevier OA license.

Introduction is described in detail in other sections. The skin and underlying soft tissues are comprised of the epidermis (in external contact), dermis, subcutaneous fat Classification (adipose) tissue, fascia and muscles. Since anaerobes are that grow in -free (anaerobic) environ- with gas-generating anaerobes (gas ) ments, as to skin and soft tissue infections, these bacteria are involved in infections of fascia and muscle at deep sites is classified into infections with of the skin, where oxygen concentrations are lower than in (clostridial type) and those with bacteria other than superficial sites. Clostridium (non-clostridial type) [2]. The frequency of clostridial gas gangrene was previously high, but in recent years that of non-clostridial gas gangrene has tended to Pathogenesis increase [3].

No definite systematic classification of skin and soft tissue Clostridial gas gangrene This disease is a clostridial infections with anaerobic bacteria has yet been established. infection with gas-generating , and is also called In a narrow sense, however, these infections are classified ‘‘clostridial myonecrosis’’ [4]. There are 6 species of into two types according to the presence/absence of aerosis, causative bacteria: C. perfringens (Welch ), i.e., gas gangrene and necrotizing fasciitis. The former C. novyi, C. histolyticum, C. sporogenes, C. septicum and condition is classified into infection with Clostridium C. fallax. The incidence of infection with C. perfringens is (clostridial type) versus bacteria other than Clostridium the highest (80–95%) [2]. (non-clostridial type) according to causative bacteria [1]. With regard to predisposing factors, the majority of Necrotizing fasciitis is classified into type I (polymicrobial these diseases are due to trauma; the disease manifests necrotizing fasciitis), i.e., mixed infections with anaerobic secondary to an operative, dermal sutures removal or bacteria, and type II due to group A b-hemolytic Strepto- contaminated wound, and also after tonsillectomy or coccus (Table 1). In actuality, there are some cases with abortion [3]. The latent period is 6 h to 2 days. The com- both gas gangrene and necrotizing fasciitis (double cases). mon sites of occurrence are the lower extremities. These The main causative bacteria are C. perfringens, Pepto- infections can also develop in the upper extremities, gluteal anaerobius and fragilis. Cul- region, external pudendal region and the neck. tures yielding a single type of anaerobic bacteria are rare. Clinical symptoms include severe pain at the affected Genus Staphylococcus and genus Streptococcus show site as a local finding, redness, swelling, dark purple dis- symbiosis with anaerobic bacteria, and mixed infection of coloration, , fluctuation and blistering. Subcutane- either genus Staphylococcus or genus Streptococcus with ous crepitation is palpable. When gas is present at a anaerobes occurs in most cases. shallow skin site, rattles and fine crackles are recognizable.

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Table 1 Classification of skin and soft tissue infections with anaerobic bacteria Gas gangrene Necrotizing fasciitis Clostridial Non-clostridial Type I (polymicrobial Type II (streptococcal fasciitis) gangrene)

Causative bacteria Mixed infections with Mixed infections with Bacteroides Obligate and facultative Group A b-hemolytic Clostridium species and species, Escherichia coli, anaerobes Streptococcus other bacteria Streptococcus species, etc., which include anaerobic bacteria Underlying diseases Trauma (contaminated mellitus in many cases Diabetes mellitus, Absence of underlying wound, etc.) in most cases obesity, , diseases in many cases etc. Progression of Rapid Slow Slow Rapid symptoms Inflammatory tissue Myositis, muscular necrosis Fascia, skin and subcutaneous tissue Fascia, muscles Skin and subcutaneous morphology tissue, fascia, muscles Dermal symptoms Local pain, redness, Local pain, redness, swelling, Local pain, redness, Marked , marked swelling, blister formation, dark purple swelling, blister , blister, formation, discoloration, necrosis, and formation, dark purple hemorrhage, well- dark purple discoloration, fluctuation discoloration and demarcated necrosis, necrosis, and fluctuation necrosis ulcer Fine crackles and ++ -- crepitation Properties of / Serous, smell of putrid flesh Purulent, putrid smell Purulent, malodorous (+) Serous, malodorous (-) malodorous Bacterial microscopic Gram-positive Gram-negative bacilli and Gram- Gram-positive cocci Gram-positive cocci findings positive cocci Blood examination Anemia, jaundice, General inflammatory findings, General inflammatory General inflammatory and hemoglobinuria, elevated Diabetes mellitus findings findings, elevated anti- urinalysis findings creatine phosphokinase streptolysin O (ASO) (CPK) X-ray findings Aerosis shows feathering Image of subcutaneous aerosis Gas (-) Gas (-) pattern in the muscle layer on imaging Hyperbaric oxygen Markedly effective Ineffective Ineffective Ineffective therapy

When the wound is incised, serous and/or bouillon-like pus To investigate causative bacteria, Gram staining and is recognized. It has a specific strong putrid flesh smell. microscopy of smear preparations from pus and necrotic Remarkable generalized symptoms, as follows, are tissue must be conducted immediately as bacteriological associated with this disease: hyperthermia, arthralgia, tests. The presence of spores with Gram-positive bacilli muscle pain, nausea/, general malaise, delirium strongly suggests the clostridial type. Since anaerobic and . The clostridial type produces leading culture takes several days, treatment should be started early to thrombus formation, and can cause disseminated intra- without waiting for culture results. vascular coagulation (DIC) and shock. Some reports have shown the mortality rate to be 7–25% On examination, gas bubbles in tissue is demonstrated [2, 4]. by X-ray or computed tomography (CT). Gas bubbles in the deep muscle layer produces a feather-like invasion Non-clostridial gas gangrene This is gas gangrene due to pattern on X-ray images [2]. Clinical laboratory data show non-clostridial infections with anaerobes. The causative leukocytosis with a nuclear shift to the left, extremely bacteria are obligate anaerobes including B. fragilis, increased C-reactive protein (CRP), increased blood sedi- Porphyromonas asaccharolytica, an- mentation, and liver dysfunction. The spread of inflam- aerobius and Eggerthella lenta. In mixed infections with mation from fascia to muscles lead to increasing CPK or facultative anaerobes, , Escherichia aldorase value, and , DIC and shock may develop coli, Klebsiella species, Proteus species and Staphylococ- from renal failure due to rhabdomyolysis [5]. cus aureus are included.

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Diabetes mellitus is associated with diseases due to Anaerobic infections without characteristic gas generation these pathogens in many cases, with a frequency of 60% among all cases. Other conditions associated with these Necrotizing fasciitis (for details, refer to other sec- pathogens include decubitus ulcers, carcinomas, pilonidal tions) This is the most serious infection leading to sinus and hidradenitis suppurativa [6]. These infectious necrosis of the skin and soft tissue with cardiovascular diseases also develop in many patients with liver disturbances. It is classified into type I (polymicrobial cirrhosis. fasciitis: causative bacteria are obligate and facultative The local findings and general symptoms are generally anaerobes) and type II [streptococcal gangrene: severe similar to those of clostridial gas gangrene; the disease infection with group A b-hemolytic Streptococcus leading spreads rapidly to reach the deep fascia. Superficial to sudden , DIC, adult respiratory distress swelling, fine crackles and crepitation manifest. When the syndrome (ARDS), and multiple organ failure] [1, 8]. wound is incised, gas bubbles are revealed. The discharge obtained by incision and drainage is purulent. In the case of infection with B. fragilis, the discharge smells like Causative bacteria feces. In the case of infection with P. anaerobius, the discharge is a yellowish pus which smells like fetid mud The main causative bacteria of skin and soft tissue anaer- [3]. obic infections are listed in Table 2. Examination findings of the disease are also similar to Bacteroides species includes small anaerobic Gram- those for clostridial gas gangrene, but gas bubbles rarely negative bacilli. B. fragilis is an anaerobe with relatively spreads to muscles in non-clostridial gas gangrene. Mixed high aerotolerance, and even when left untreated for infections with Streptococcus species may lead to the 3 days, some cells remain alive [7]. This resistance to rapid spread of phlegmon and cause streptococcal oxygen (the aerotolerant state) is considered to be related to gangrene. the pathogenicity of Bacteroides species. In a manner similar to that for clostridial gas gan- Clostridium species includes obligate anaerobic Gram- grene, Gram staining and microscopy of smear prepara- positive bacilli. They exist in soil and animal feces, and tions from pus and necrotic tissue must be conducted most are non-pathogenic. Most infections with these bac- immediately to identify the causative bacteria. When the teria develop after injury. The bacteria frequently cause causative bacteria are members of genus Bacteroides, infections from the and skin at the which are small Gram-negative bacilli, being overlooked injury site. Infections with these bacteria develop from is likely because they blend into the background [7]. intramuscular injections, surgical and dermal sutures-out Since culture takes at least 2 days, treatment should be wounds, after abortion, with rectal cancer, and from foreign started immediately in suspected cases without waiting bodies in the rectum [4]. Six species of clostridia, C. per- for culture results. fringens (Welch bacillus), C. novyi, C. histolyticum, The prognosis of this disease is considered to be worse C. sporogenes, C. septicum and C. fallax, are believed to than that of clostridial gas gangrene; the morbidity rate is possess pathogenicity. C. perfringens is among the resident believed to be 30–40%. flora of the lower gastrointestinal tract. C. perfringens

Table 2 Main anaerobic Clostridium species C. perfringens (Welch bacillus) bacteria causing skin and soft tissue infections C. novyi C. histolyticum C. sporogenes C. septicum C. fallax Anaerobic bacteria other than Clostridium species Bacteroides fragilis Porphyromonas asaccharolytica Peptostreptococcus anaerobitus Feingoldia magna Eggerthella lenta Prevotella species Fusobacterium species

123 J Infect Chemother (2011) 17 (Suppl 1):72–76 75 produces exotoxins, i.e., toxins a, j, l and h (phospholi- Oxygen under high pressure (OHP) therapy pase C, hemolytic action, , hyaluronidase), and thereby induces , hematogenous disorders and Since anaerobic bacteria are harmed by oxygen, oxygen is tissue damage. The most important is toxin a [4]. very effective for gas gangrene. Oxygen is essential for the P. anaerobius is a Gram-positive anaerobic coccus. treatment of clostridial gas gangrene, while it is less Other bacteria, which are involved in the pathogenesis effective for non-clostridial gas gangrene [4]. Transporta- of this disease, include (Finegoldia magna), tion of patients with clostridial infections to institutions Parvimonas (Parvimonas micra, previously Micromonas), equipped with OHP should also be considered. Peptoniphilus (Peptoniphilus asaccharolyticus), Prevotella species and Fusobacterium species. Antimicrobial therapy

Treatment When causative bacteria are identified by Gram staining and anaerobic culture, the antimicrobial drugs used are re- The important therapeutic methods for skin and soft tissue examined, and changed to other agents to which the iso- infections with anaerobic bacteria are: Management of lated bacteria are susceptible. With regard to skin and soft general condition; ` wound opening and removal tissue infections with anaerobic bacteria, it is rare for these () of necrotic tissue; and ´ administration of infections to involve a single type of anaerobe. Most of antimicrobial agents. The antimicrobial agents will be these infections involve multiple bacteria. It is therefore described later. desirable to administer antimicrobial drugs with broad spectra, covering these bacteria [10]. Skin and soft tissue Management of general condition infections with anaerobic bacteria are serious diseases with a high possibility of taking a fatal course. The drugs are At the intensive care unit (ICU), etc., where general con- frequently administered by non-approved dosage regimens. ditions can be managed, a route is secured for fluid Fundamentally, many anaerobic bacteria isolated from replacement. Vital signs are checked, and respiration, skin and soft tissue infections are sensitive to the penicil- heartbeat and blood pressure are constantly monitored. lins. Therefore, are effective against these bacteria. High dose administration of PCG is suggested. In Wound opening and removal (debridement) of necrotic actual clinical settings, piperacillin (PIPC) is administered tissue at a dose of 2 g, 4 times, and a tazobactam/piperacillin (TAZ/PIPC) combination, at a dose of 4.5 g, also 4 times. When progression is rapid and the patient’s general con- In the presence of mixed infections, second-generation dition is poor, surgical treatment by debridement is per- cephems with broad antibacterial spectra are used formed under anesthesia in the operating room to rapidly additionally. counter this condition. Debridement begins with a longi- tudinal incision [9]. According to the affected sites and Clostridial gas gangrene depths of infection, plastic , surgery and orthopedic, as well as , consultations are required. It is PIPC (2 g 9 4/day) and a TAZ/PIPC combination (4.5 g 9 important to remove the environment fostering anaerobic 4/day) are administered intravenously. For C. perfringens multiplication and to thoroughly remove the necrotic tis- infections, ampicillin (ABPC) (2 g 9 4/day) or sulbactam/ sue, pus and any foreign bodies in the wound. Adminis- ampicillin (SBT/ABPC) combination (3 g 9 4/day) is tration of antimicrobial agents, regional cleansing with administered intravenously. physiological saline solutions including antiseptic solu- tions, and discharge with a drain inserted are necessary for Non-clostridial gas gangrene wound management. When the wound is stable, skin grafting is undertaken at the affected site 1–2 weeks after For P. anaerobicus infections, PIPC (2 g 9 4/day) and a these procedures. TAZ/PIPC combination (4.5 g 9 4/day) are administered intravenously. B. fragilis shows natural resistance to Administration of antimicrobial agents aminoglycosides and cotrimoxazoles, and the efficacy of fluoroquinolones is also low when these bacteria are Details of antimicrobial drug administration will be the causative . Therefore, SBT/ABPC described later. (3 g 9 4/day), as well cefmetazole (CMZ), flomoxef

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(FMOX) and ceftazidime (CAZ), administered at a dose of 3. Takahashi H. Infection syndrome, bacterial infections, subcuta- 2 g, 3–4 times a day, are effective. neous tissue infections, and anaerobic phlegmon due to bacteria 9 other than Clostridium. Jpn J Clin Med (Supplement volume) As combined therapy, (CLDM) (600 mg Infect Syndr I 1999; 587–8. (Japanese). 4/day) or minocycline (MINO) (200 mg 9 2/day) is also 4. Shimazu T, Tanaka R, Hashiguchi N, Sugimoto H. Infection administered intravenously. syndrome, bacterial infections, subcutaneous tissue infections, Regardless of the types of causative bacteria, carbapen- and gas-gangrene myositis. Jpn J Clin Med (Supplement volume) Infect Syndr I 1999; 593–6. (Japanese). ems, i.e., a combination of imipenem/cilastain (IPM/CS) 5. Hino H. Dermatology Seminarium, dermatological bacterial (0.5 g 9 2–3/day or 1 g 9 3/day), is administered intra- infections, and general bacterial infections of the skin. Jpn J venously for severe cases. Meropenem (MEPM) is admin- Dermatol. 2005;115:985–94. (Japanese). istered intravenously (0.5 g or 1 g 9 3/day). 6. Jousimies-Somer HR, Summanen P, Citron D, Baron E, Wexler H, Finegold S. Wadsworth-KTL anaerobic bacteriology manual. 6th When infection with methicillin-resistant Staphylococcus ed. CA: Star Publishing Co; 2002. p. 1–22. aureus (MRSA) is suspected, vancomycin (VCM) is 7. Fujimoto T. Resident manual for infections. Tokyo: Igaku-Shoin; administered (1 g 9 2/day) [11]. 2004. p. 298–300. (Japanese). 8. Swartz MN. Clinical practice. . N Engl J Med. 2004;350:904–12. 9. Nanko H, Ohara A. , necrotizing fascitis and gas gangrene. In: Honda M, editor. Medical examination and treat- References ment practice in dermatology. 1. Therapeutic strategy for dermal infections. Tokyo: Bunkodo; 1998. p. 24–9. (Japanese). 1. DiNubile MJ, Lipsky BA. Complicated infection of skin and skin 10. Shinagawa N. Cellulitis, and necrotizing fascitis and similar structures: when the infection is more than skin deep. J Anti- diseases. In: Arata J, editor. Dermatology MOOK 17 bacterial microb Chemother. 2004;53(Suppl 2):ii37–50. infections. Tokyo: Kanehara & Co., Ltd; 1990. p. 103–10. 2. Takahashi H. Infection syndrome, bacterial infections, subcuta- Japanese. neous tissue infections, and clostridial phlegmon. Japanese 11. Konno M. Infections of the skin and muscle. The approach to anti- Journal of Clinical Medicine (Supplement volume) Infection microbial drug therapy, vol. 3. Antimicrobial drug therapy from the Syndrome I 1999; 585–6. (Japanese). aspect of clinical diagnoses. Osaka; 2003. p. 282–305. (Japanese).

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