Antimicrobial Chemotherapy, 4th Edition
The therapeutic use of antimicrobial agents
Skin and soft-tissue infections
- J. Wilkinson
At birth the skin of the baby rapidly becomes colonized with bacteria from the mother, other handlers, and the environment. Some of these essentially non-pathogenic microbes, including coryneforms, coagulase-negative staphylococci, micrococci, and propionibacteria become established as the resident flora of the normal skin. In intact skin, these micro-organisms usually prevent potential pathogens such asStaphylococcus aureus and Streptococcus pyogenes (haemolytic streptococci of Lancefield group A) from becoming established. However, if the skin is broken by accidental or surgical trauma, burns, a foreign body, or a primary skin disease (psoriasis, atopic dermatitis), these pathogens may not only become established as resident organisms; they may also give rise to infection of the skin and subcutaneous tissue.
Other bacteria from, for example, faeces or the environment can briefly colonize the skin as transient flora; they are readily removed by washing, whereas resident organisms will persist in moderate numbers despite even the most thorough skin disinfection. If introduced through, for example, a dirty wound or compound fracture, transient micro-organisms can also give rise to skin and soft-tissue infection. Such infections are often polymicrobial (mixed).
The general condition of the patient, including factors such as underlying immunodeficiency, diabetes mellitus, or systemic or topical treatment with corticosteroids, can also predispose to skin infection. Treatment with broad-spectrum antibiotics, which disrupts the resident flora, can give rise to cutaneous candidiasis (thrush). In one of the commonest skin infections—a boil or furuncle—there is usually no evident breach in the skin nor any other predisposing factor.
Many different micro-organisms, including bacteria, fungi, and some viruses, may be involved in skin and soft-tissue infections. The commonest bacterial causes are Staph. aureus, Str. pyogenes, Clostridium perfringens, and Bacteroides
species. Thrush is usually caused by the yeast Candida albicans, and cold sores by the virus herpes simplex.
Staph. aureus is the commonest cause of infection of traumatic wounds (accidental or surgical), burns, and skin diseases. The adult intact skin does not readily accept Staph. aureus except as transient flora, whereas the skin of the newborn is readily colonized. However, approximately one in four people, and more in a hospital environment, carry the organism in their nostrils. Other sites of skin carriage of this species are the perineum and axilla.
Skin infection with Staph. aureus may involve the hair follicles or the surface, and the lesions produced may be pustular or exfoliative.
Such lesions of the skin are by far the commonest bacterial infection in man and include:
- folliculitis (pimples), where the infection is confined to hair follicles and does not involve the surrounding skin or subcutaneous tissue; such infections are usually mild and self limiting, and do not need medical attention
- furuncles (boils), where the folliculitis has spread deeper and is surrounded by an area of cellulitis
- carbuncles, where several furuncles have coalesced and extended into subcutaneous fat to form a large, indurated, painful lesion that contains loculated pus with multiple drainage points.
These involve the superficial layers of the skin and are characterized by stripping of the epidermis as a result of the action of an exfoliative toxin produced by certain phage types of Staph. aureus. When such lesions are localized and limited the condition is known as impetigo, but this form may also be caused by Str. pyogenes (see below) or by both organisms. In the newborn the more pronounced lesions may give rise to large flaccid blisters, or bullous impetigo, which occasionally may spread in an epidemic form in baby nurseries or neonatal units.
Rarely, in the very young or the immunosuppressed adult, extensive, continuous lesions affect large areas of the body. The patient is generally ill with fever and skin tenderness, and the epidermis may separate in sheets in response to gentle stroking (Nikolsky's sign). Various names have been given to this generalized skin infection, such as scalded skin syndrome, toxic epidermal necrolysis, Ritter's disease, and pemphigus neonatorum. Staph. aureus may not be found in the skin
lesions and the infection may be at a remote site (e.g. the conjunctiva) from where the toxin causing the generalized skin lesions is absorbed.
Toxic shock syndrome
Certain phage types of Staph. aureus produce toxins that cause a multi-system disease characterized by the sudden onset of fever, myalgia, vomiting, diarrhoea, hypotension and an erythematous rash: the toxic shock syndrome. Originally thought to affect only menstruating women who used a particular type of tampon, it is now known to be a rare sequel of any type of staphylococcal infection.
Management of staphylococcal infections
Large pustular lesions
Minor, well localized staphylococcal skin lesions usually resolve without medical attention. Larger boils, carbuncles, and infected wounds may need surgical drainage and systemic antimicrobial therapy, which may have little effect on the local lesion, but prevents local extension or metastatic infection. This is particularly important when lesions are on the face: retrograde spread along the emissary veins can give rise to cavernous sinus thrombosis, so that antibiotic treatment of even small lesions around the nose and lips is justified.
Most isolates of Staph. aureus produce β-lactamase and therefore require treatment with a β-lactamase-stable penicillin such as flucloxacillin. Cephalosporins such as cefuroxime and cephradine are also stable to β-lactamases and effective, but have a broader spectrum of activity which is not needed to treat purely staphylococcal or streptococcal infection. Erythromycin or clindamycin are suitable alternatives for patients who are allergic to penicillin. Locally applied antimicrobials in ointments, powders, or sprays diffuse unevenly to the site of all but the most super-ficial skin infections, and are not recommended for treatment (see Chapter 32).
To prevent spread through the bloodstream, antibiotic treatment should be started before any drainage procedure and in high-risk situations should be given parenterally. Treatment should continue until the acute inflammation has subsided. A sample of pus should be sent for bacterial culture and determination of the antibiotic sensitivities of the causal bacteria, which may be found to have multiple antibiotic resistances (e.g. a multi-resistant strain of Staph. aureus) or to be an organism other than Staph. aureus.
The management of patients with recurrent boils poses a special problem. Any one episode is treated in the standard way, but to prevent further episodes the site of staphylococcal carriage (which may involve another person, partner, or family member) should be determined and steps taken to eradicate the source of infection (see p. 372).
The minor pustular lesions of acne and rosacea are not bacterial in origin, although commensal bacteria may contribute to their persistence and tetracyclines may help to keep the lesions under control. Topical clindamycin is also useful in acne, and topical metronidazole gel in rosacea.
Very superficial lesions such as impetigo may be controlled by topical agents only (see Chapter 32), but if Str. pyogenes is involved, systemic penicillin should be given for at least 10 days to eradicate the organisms from skin lesions and thereby avoid the possible risk of post-streptococcal glomerulonephritis. Erythromycin is suitable for patients who are allergic to penicillin.
Extensive impetigenous or bullous lesions, as well as staphylococcal scalded skin syndrome and toxic shock syndrome, are potentially life-threatening and require urgent medical attention. They should be treated parenterally with an antistaphylococcal agent such as flucloxacillin or erythromycin.
Streptococcal skin infections
Str. pyogenes does not form part of the normal skin flora and primary streptococcal skin infections are now far less common than those due to Staph. aureus in communities in which good hygiene is practised. Streptococci probably enter the skin through minor cuts, scratches, or puncture wounds, or become superimposed on some pre-existing skin disease.
Streptococcal impetigo is very similar to the non-bullous form of staphylococcal impetigo, except that regional lymphadenopathy is commoner with the streptococcal variety. Characteristically, a pre-school child develops lesions around the mouth and nostrils, or on the extremities. In some outbreaks of impetigo the causative streptococcal strains are nephritogenic and in certain parts of the world impetigo is now the commonest form of streptococcal infection to precede acute glomeru-lonephritis. It is therefore advisable to treat all cases with systemic antibiotics, preferably a penicillin, and to limit topical antimicrobial agents to patients with small numbers of lesions or as supplemental therapy. Antibiotic treatment is also justified as a public health measure to decrease the reservoir of pyogenic streptococci in a population and to limit the spread of potentially nephritogenic strains.
Cellulitis is an acute spreading infection of the skin and subcutaneous tissues and is usually streptococcal in origin, though it can be staphylococcal or polymicrobial,
particularly after operations on the intestinal or female genital tracts, when spreading infections with mixed aerobic and anaerobic bacteria of gut or genital origin can occur. Erysipelas, a more superficial form of cellulitis that usually affects the face or lower limbs, is almost always caused by Str. pyogenes. In the neonate erysipelas may develop from an infection of the umbilical stump.
Previous trauma (accidental or surgical) or a pre-existent skin lesion are the usual predisposing factors in cellulitis. Rarely, however, blood-borne bacteria may localize in subcutaneous tissue, or an underlying osteomyelitis may present as cellulitis.
If material for bacteriological examination is difficult to obtain because there is no exudate or superficial skin lesion, clinical appearances may help to differentiate staphylococcal from streptococcal cellulitis. The involved lymphatic ducts may be seen as red streaks that extend towards the regional lymph nodes, which are enlarged and tender. A secondary bacteraemia can arise.
Although various kinds of haemolytic streptococci other than Str. pyogenes may be involved, benzylpenicillin remains the treatment of choice. Staphylococcal cellulitis requires flucloxacillin or erythromycin, which will provide cover for both organisms if the bacterial aetiology is in doubt.
Non-streptococcal cellulitic infection
Haemophilus influenzae type b can cause cellulitis in infants under the age of 3, although its incidence has been greatly reduced in countries in which immunization with the H. influenzae conjugate vaccine has been introduced. Facial swelling, often of the cheek or peri-orbital region, is a common presenting feature and blood cultures are usually positive. In such cases, a parenteral, broad-spectrum cephalosporin such as cefotaxime or ceftriaxone should be given initially, followed by an oral agent such as cefuroxime axetil, co-amoxiclav, or (if sensitive) amoxycillin. Chloramphenicol, although effective, has been superseded on account of its toxicity. Benzylpenicillin is not effective against H. influenzae and should not be used in such cases.
Anthrax, an animal disease that occasionally spreads to workers who handle animal hides, wool, or animal products contaminated with the spores of Bacillus anthracis, may present as an oedematous cellulitis. Characteristically, a large, painless necrotic lesion (malignant pustule) develops on the face, neck or arm over 2–3 days and can lead to septicaemia which is sometimes fatal. The characteristic lesion and the patient's occupation should alert the doctor to this rare condition. Parenteral penicillin is the treatment of choice; a tetracycline or macrolide is suitable for those allergic to penicillin.
The classification of necrotizing, subcutaneous infections is confusing and controversial. Necrotizing fasciitis (streptococcal gangrene) is a rapidly spreading and life-threatening form of cellulitis that involves skin, subcutaneous tissue, and fascia. Most cases are caused by Str. pyogenes either alone or in combination with other bacteria, including Staph. aureus, coliform bacilli, and anaerobes. The initial cellulitis advances aggressively and the patient becomes toxic. Blood cultures are often positive and streptococci can also be isolated from the bullous lesions.
Progressive synergistic bacterial gangrene usually complicates surgical abdominal wounds. It starts as an ulcer near the wound and can spread to much of the anterior abdominal wall. Micro-aerophilic streptococci, together with Staph. aureus and, occasionally, coliform bacilli are typically isolated from such lesions.
The management of these rare conditions is primarily surgical, with radical debridement of all necrotic tissue, intensive life-support therapy, and the treatment of shock. Antibiotics are initially of only secondary importance, but should nevertheless be given as indicated by bacteriological results. Suitable regimens include: ampicillin with ciprofloxacin and metronidazole; clindamycin with ceftazidime; meropenem; and the combination of piperacillin and tazobactam.
Gas gangrene (clostridial myositis) is a life-threatening, invasive infection that can be caused by several species of Clostridium, principallyC. perfringens. These bacteria are part of the normal intestinal flora of man and animals, and clostridial spores are common in soil. Gas gangrene develops when impaired blood supply, tissue necrosis, or the presence of foreign bodies produce a low oxygen tension in the tissues and thus create conditions in which the spores can germinate. Extensive soft-tissue injury contaminated with soil or dirt, for example a compound fracture in a road accident, or a bullet or shrapnel wound, all carry an increased risk of gas gangrene. Gas gangrene may rarely complicate surgical wounds, particularly after intestinal or biliary surgery, or be a complication of septic abortion. Clostridial anaerobic cellulitis occurs under similar circumstances, but exploration of the wound usually reveals that the muscle is spared.
Prevention of gas gangrene
Patients undergoing above-knee amputation for peripheral vascular disease are at risk of developing gas gangrene from faecal clostridia that contaminate the buttocks, and should be given penicillin prophylaxis (see p. 217).
Management of gas gangrene
A clinical diagnosis is made on the basis of palpable (crepitus) or radiological signs of a spreading, gas-producing infection in a toxic patient with the above risk factors. Immediate and extensive surgical excision of all involved tissues and the removal of any foreign body are essential, and may mean hysterectomy (after septic abortion), excision of subcutaneous tissue and muscle of the abdominal wall, or even amputation of a limb. Parenteral benzylpenicillin should also be given promptly in high dosage. For patients allergic to penicillin, metronid-azole may be used. Some authorities also advocate local irrigation with penicillin and hydrogen peroxide, or the use of hyperbaric oxygen.
Despite these desperate and mutilating measures, the mortality remains high. Antitoxin therapy has no place in the management of gas gangrene, whereas in tetanus and botulism, the other important clostridial diseases caused by C. tetani and C. botulinum respectively, antitoxin is much more important than antibiotic therapy.
Anaerobes other than clostridia
Bacteroides fragilis and other non-sporing, Gram-negative anaerobes form a major part of the normal bacterial flora of the upper respiratory, gastrointestinal, and female genital tracts. These organisms and anaerobic streptococci are often found with coliform bacilli in mixed infections in intra-abdominal sepsis following appendicectomy, abdominal, ano-rectal, and gynaecological surgery.
In the elderly, diabetic, or obese patient, post-operative infection or infected pressure sores may give rise to a rapidly spreading infection that involves deeper tissues, including muscle, to produce synergistic necrotizing cellulitis, a variant of necrotizing fasciitis. Fournier's gangrene, another form of necrotizing fasci-itis that involves the perineum, scrotum, or penis, is also associated with mixed organisms including anaerobes. Infection may spread to the anterior abdominal wall. The incidence of post-operative infection following certain types of abdominal operation is high, but is very substantially reduced by antimicrobial prophylaxis (see Chapter 19).
For established infection, surgical intervention is the most important treatment and antimicrobial therapy plays a supportive role. Metronidazole should be given to provide activity against anaerobes, but therapy must cover coliform bacilli as well. Appropriate choices include an expanded-spectrum cephalosporin (e.g. cefotaxime or ceftazidime); an aminoglycoside (e.g. gentamicin) plus ampicillin; or ciprofloxacin. Alternatively, a carbapenem, such as meropenem, can be used alone.
A wide variety of organisms, alone or in combination, may occasionally give rise to infection of, for example, human or animal bites, or gangrenous lesions in diabetics. Wounds close to bones or joints may extend to involve these structures. A definitive bacteriological diagnosis should be sought and appropriate treatment given on the basis of laboratory results.
Viral infections of the skin, such as herpes simplex and varicella zoster, are discussed in Chapter 28. Superficial fungal infections usually respond to topical therapy (see p. 374) although dermatophyte infections of finger- or toenails may require oral treatment with terbinafine for up to 3 months, or with griseofulvin for a year or more. These agents are deposited in newly formed keratin and the prolonged treatment is needed to allow healthy nail to replace the diseased tissue. Even so, treatment of chronic infections of toenails may be unsuccessful, although terbinafine is more reliable in this respect than griseofulvin.