Antimicrobial Chemotherapy, 4th Edition
The therapeutic use of antimicrobial agents
Topical use of antimicrobial
- C. B. Slack
The concept of applying drugs directly to clinical lesions is appealing: problems of absorption and pharmacokinetics do not apply and agents too toxic for systemic use may be safely applied to skin or mucous membranes. The major drawback is that, even in the most superficial skin lesion, there may be areas inaccessible to a topical approach. Furthermore, collections of pus may prevent the agent reaching the infecting organisms and for this reason the management of any abscess includes drainage of pus.
Although skin, the largest and most accessible organ of the body, is the most obvious target for topical antimicrobial agents, other sites are available for this approach to therapy: the mucous membranes of the mouth and vagina, and the external surfaces of eyes and ears. Direct application of antibiotics into normally sterile sites, such as joints, spinal fluid, or the urinary bladder, or instillation into surgical wounds prior to suture, may also be considered as a form of topical ther- apy, but will not be specifically dealt with in this chapter. Application of topical agents to mucous membranes or damaged skin may lead to considerable systemic absorption and the possibility of systemic toxicity should be borne in mind.
The chief reasons for using topical antimicrobial agents are:
- to achieve high drug concentrations at the site of infection
- to treat trivial infections where use of a systemic drug is unjustified
- to prevent infection in a susceptible site (e.g. burns)
- to enable the use of agents that are too toxic for systemic use
- cost: topical agents are generally cheaper than systemic drugs.
Disinfectant is a general term for chemicals that can destroy vegetative micro- organisms; those disinfectants that are sufficiently non-injurious to skin and
exposed tissues to be used topically are called antiseptics. In order to achieve adequate antimicrobial activity, high concentrations of antiseptics are required and this serves to distinguish them from antibiotics in Waksman's original sense of ‘substances produced by micro-organisms antagonistic to the growth or life of others in high dilution’. In many cases, true antibiotics are used topically in high concentration and might thus be classed as antiseptics. In fact, antiseptics and antibiotics are often used in exactly the same situations in dermatological practice and there has been some difference of opinion as to which class of agent to use in, for example, the treatment of infected ulcers or wounds. Antiseptics are usually cheaper and have the advantage that bacterial resistance rarely, if ever, develops. Preparations commonly employed include chlorhexidine, cetrimide, iodophors (non-irritant iodine complexes), triclosan and solutions liberating hypochlorite, such as Eusol or Dakin's solution.
Some concern has been expressed about the effect on tissue viability of many chemicals applied directly. There is some evidence in vitro of a direct toxic effect on epidermal cells and white blood cells of many antiseptics at concentrations well below those used topically.
Methods of application
Drugs which are dissolved in aqueous solutions (lotions) have the disadvantage of running off the skin and cooling it by evaporation. This method of delivering antimicrobial agents to the site of infection is inefficient and not often used, except as ear or eye drops. For use in eye infections, frequent application on to the cornea and conjunctiva is necessary, because the drug is only in contact for a short time and much of the active component runs down the cheek as an expensive tear! The value of aqueous preparations resides mainly in their irrigant and cleansing action and much of the therapeutic success may be due to these properties.
It is usual to apply drugs to the skin in a fat base, as either an oil and water cream, or a largely lipid ointment. Drug solubility affects the achievable concentration in each component, and availability at the lesion depends on diffusion from the applicant and absorption from the skin. Antibiotics which are lipid soluble and freely diffusible, for example fusidic acid, are at an advantage in this respect.
Sticky ointments may remain in contact with the infected site for a considerable time and application may be needed only once daily, but this obviously depends on the frequency of washing or removal of dressings.
Some of the commonly used topical preparations are listed in Table 32.1. Many of the formulations designed for topical use contain combinations of antimicrobial agents. Mixtures are intended to cover a wide antibacterial spectrum and to be compatible.
Table 32.1 Some of the most commonly used topical antimicrobial agents. The numerous topical antiseptics available are omitted
The results of laboratory tests may be helpful if adequate specimens are sent to the laboratory, but frequently colonizing microbes are isolated from the surface of deep lesions leaving the true underlying pathogen undetected. The clinician must be careful not to use a battery of antimicrobials to treat harmless commensals colonizing an unoccupied niche.
Conventional antimicrobial sensitivity testing is often irrelevant because susceptibility of organisms to antiseptics can usually be assumed. Moreover, laboratory criteria of susceptibility to antibiotics usually apply to systemic use, not the high concentrations achievable by topical application. Nevertheless, complete resistance in laboratory tests is a contra-indication to use of a particular agent. Regular monitoring of hospitalized patients with large skin lesions, such as ulcers and burns, is useful to determine the nature and prevalence of resistant organisms, as well as the extent of cross-infection.
Choice, if not based on microbiological evidence, must include agents active against all likely pathogens. Topical antiseptics and hydroxyquinolines are to be preferred to antibiotics on microbiological grounds of avoidance of resistance, but many users prefer antibiotics because it is claimed that a quicker response is generally obtained. Tetracyclines are often recommended by clinicians, but not by microbiologists, who point to the prevalence of tetracycline resistance and the readiness with which such prevalence increases under selective pressure. Combinations of antibiotics, such as bacitracin and neomycin, or bacitracin, neomycin, and polymyxin are often used, and a corticosteroid is sometimes added for good measure. These antibiotics are not usually used for systemic therapy, so possible problems of compromising the activity of systemically useful agents by encouraging the emergence of resistance are minimized (see below). Nevertheless, it should be remembered that the topical use of neomycin might generate strains of bacteria cross-resistant to other aminoglycosides such as gentamicin.
One antibiotic, mupirocin (pseudomonic acid), has been marketed solely for topical use. The spectrum of activity of this agent is virtually restricted to Gram-positive cocci. Mupirocin is unsuitable for systemic use since it is quickly metabolized in the body (see p. 44). It has a unique mode of action (on protein synthesis) and cross-resistance is not a problem.
In practice, one of the most important limitations to choice is the availability of a particular drug as a topical product. Manufacturers are well aware that it makes little commercial sense to market a relatively cheap topical formulation if it is going to encourage resistance which diminishes the usefulness of more expensive parenteral forms of the drug. Here, at least, the interests of industry and the consumer coincide.
Bacterial skin infections
Trivial skin sepsis, often due to staphylococci, is common, but usually self-limiting in healthy individuals. Impetigo is frequently a more severe and widespread condition which may involve both Streptococcus pyogenes and Staphylococcus aureus. In general, mild infections of the skin respond to local measures involving cleansing of the crusted areas and application of topical agents, such as fusidic acid or mupirocin, to the raw surfaces. More severe staphylococcal and streptococcal skin lesions may require systemic therapy and this is discussed in Chapter 24.
In recurrent sepsis with Staph. aureus it may be necessary to attempt to eradicate the organism from the body. This is also desirable in patients and staff colonized with antibiotic-resistant strains, particularly methicillin-resistant Staph. aureus (MRSA) which can cause serious cross-infection problems. The external surface of the skin can be washed in antiseptics, but nasal carriage of staphylococci is often resistant to this treatment. For this purpose, nasal creams should be applied at least twice a day for 5 days. Chlorhexidine/neomycin cream (Naseptin) has been widely used, but does not appear to be as effective as mupirocin in the eradication of nasal carriage of MRSA. The normal dermatological preparation of mupirocin, which is in a macrogol (polyethylene glycol) excipient, is unsuitable for nasal application and a paraffin-based ointment should be used for this purpose.
The role of bacteria in the pathogenesis of acne vulgaris is still under debate, although commensal diphtheroids, such as Propionibacterium acnes, are thought to play some part. Systemic antibiotics, including tetracycline and erythromycin, do improve severe intractable cases and success has also been claimed for topical antimicrobial agents, in particular for clindamycin. Treatment with any of these agents needs to be prolonged and is an adjunct to other measures aimed at improving the condition.
The treatment of burns is an enormous specialized topic that cannot be covered adequately in this chapter. However, topical agents do have definite value in the prevention of infection in patients with burns so it is appropriate that their use should be mentioned.
Initially, a thermal burn renders the skin sterile, but bacterial colonization is inevitable, even with scrupulous aseptic technique. Indeed, infection, usually with Str. pyogenes, Staph. aureus, or Pseudomonas aeruginosa, is an important determinant in the outcome of extensive burns, since it is a major cause of delay in skin healing and of death.
Prophylaxis with topical antibiotics and antiseptics has been shown signifi-cantly to reduce colonization and sepsis. Mafenide, a sulphonamide derivative, was widely used, but has been largely replaced in the UK by silver sulphadi-azine or chlorhexidine. None of these agents will reliably prevent infection by multiresistant Gram-negative rods, especially Ps. aeruginosa (an organism that has replaced Str. pyogenes as the major scourge of burns units), or fungi. Aggressive surgical approaches of early wound closure by skin grafting after debridement has reduced the requirement for topical applications to burned surfaces.
In cases in which infection becomes established, systemic drugs will often have to be employed, the choice being dictated by laboratory tests. However, since the penetration of antibiotics to surface lesions with a poor blood supply may be inadequate, topical dressings are additionally required.
Urinary and respiratory infections are commonly encountered in the burned patient, as is septicaemia, which has a poor prognosis. These infections require, of course, systemic therapy, but choice may be limited by bacterial resistance since many burns units are notorious for the prevalence of highly resistant strains, especially of Ps. aeruginosa.
Ulceration of the skin of the leg or the area overlying the sacrum may arise from a variety of pathological states and infection is usually a sequela, not an initiating event. Disorders of the circulation, including obliterative arterial disease, small-vessel damage consequent on diabetes mellitus, and varicose veins are the most common underlying conditions; correction of the underlying cause is essential to the healing of any ulcer. Continuous pressure is another common factor in the formation of a break in the skin, particularly in the bed-ridden. Such pressure sores (bed sores) are difficult to prevent without scrupulous nursing care. This problem has led to the development of special air beds and cushions to minimize local vascular occlusion to the skin overlying bony areas such as the sacrum.
The presence of infection in a skin ulcer may be detected by odour, local cellulitis, and appearance of pus, which in the case of pseudomonas infection may be characteristically green. Gas in the tissues, detected as crepitus on palpation, may indicate anaerobic infection. Swab reports showing the presence of potential pathogens do not prove infection since colonization of a large raw skin area is inevitable. Staph. aureus, environmental, and gut bacteria are the organisms most
commonly found in these sites. Ps. aeruginosa is frequently found in longstanding ulcers because of its intrinsic resistance to many antibiotics and chemical agents used as antiseptics. In some cases infection is sufficiently invasive to warrant systemic treatment and metronidazole should be given to patients in whom Bacteroides fragilis infection is suspected.
Local therapy with antiseptics, combined with measures to improve the nutrition of the site, are the mainstays of management of skin ulcers. Chlorine- or iodine-containing compounds (especially iodophors, which are iodine complexes that do not stain the skin and are less irritant) are often used, but older remedies such as honey, sugar, and vinegar may be as effective as modern antiseptics. In addition, topical antibiotics such as tetracycline are often used in severe infected ulcers which do not respond to conservative management. Many weeks of regular dressing combined with bed rest may be required to heal large ulcers; admission to hospital often speeds up the process. Skin grafting is frequently used for the most recalcitrant cases.
Superficial fungal infections
Confirmation of the diagnosis of superficial fungal infections such as ringworm and tinea pedis of the skin, or thrush of the mouth or vagina, depends on laboratory investigation of appropriate specimens from the affected area (nail, hair, skin scrapings, swabs of lesions of mucous membranes). Microscopy alone will be sufficient to establish a fungal cause in most cases, but culture is necessary to identify the aetiological agent. Susceptibility testing presents technical difficulties, but dermatophytes may usually be assumed to be susceptible to appropriate agents (see Table 4.1, p. 60). Candida albicans may acquire resistance to some drugs, but this is of great importance only in invasive candidiasis.
The limiting factor in treating dermatophyte infections is penetration of the agent. For superficial skin infections old-fashioned remedies, such as benzoic acid-containing ointments (e.g. Whitfield's ointment) are perfectly effective, but for hair and nail infections agents which penetrate into keratinized tissue are needed. Oral griseofulvin is uniquely suited to this purpose, since it is absorbed from the gastrointestinal tract and is perferentially concentrated in keratin. Because of the slow turnover of nail and hair, treatment for several months may be required; indeed, fungal infections of toenails may not completely clear even after a year's treatment with griseofulvin, despite susceptibility of the infecting fungus. In such cases terbinafine (p. 64) may be successful.
Thrush responds in most cases to an appropriate antifungal agent, applied topically (e.g. nystatin or an imidazole), but precipitating factors, such as diabetes or antibiotic therapy, must also be corrected if they are present. If there is clinical evidence for invasive infection, as, for example, Candida oesophagitis, appropriate systemic drugs, such as amphotericin B, 5-fluorocytosine, fluconazole, ketoconazole, or itraconazole must be added.
Disadvantages of topical therapy
Topical therapy is not without its hazards. Although the direct toxic effects of drugs given systemically are reduced, exposed tissues and mucous membranes offer a fairly efficient site for drug absorption. For example, aminoglycoside ototoxicity has been reported following local application of neomycin, especially in the newborn. A more frequently observed effect is sensitization to the agent so that subsequent use of the drug, either topically or parenterally, produces a hypersensitivity reaction. Penicillin, in particular, is prone to sensitize the host and because of possible anaphylactic reactions it is not advisable to use any β-lactam antibiotic on the skin. A further hazard of topical therapy is that local irritation may lead to a delay in wound healing, even though the actual infection is controlled.
Superinfection with resistant bacteria or with fungi is a common consequence of using any topical antibiotic for a prolonged period. Widespread use of one particular agent will lead to a larger reservoir of resistant organisms and the possibility of cross-infection. This is particularly likely to occur in burns units and dermatology wards, where there are many patients with large open skin lesions. Prevention of infection and cross-infection by aseptic methods is desirable, but often difficult in practice.
Of equal concern is the development of bacterial resistance during therapy. It has been shown that topical neomycin can select resistantStaphylococcus epider-midis strains, which can transfer resistance to Staph. aureus on the skin. The emergence of gentamicin-resistant Ps. aeruginosa and coliforms has been associated with topical use of that aminoglycoside, particularly on leg ulcers. In some instances the resistance is plasmid mediated. In this manner, topical agents select multiresistant organisms which may subsequently cause systemic infection in the patient or, by cross-infection, others. This is the most powerful argument against the indiscriminate use of topical antibiotics, and since antiseptics lack this disadvantage they are to be preferred wherever possible.