Combining of Antibacterial Agents

Q85 The combination of antibacterial agents in co-trimoxazole presents a synergistic activity. Co-trimoxazole is associated with rare but serious side-effects. 

A number of different combinations of antibacterial agents have been found to possess enhanced activity against Ps. aeruginosa. A brief account of some of these follows ... 

Quinolone-Gephalosporin Godrugs. Quinolones have been covalently linked to cephalosporins in order to generate a codmg containing one molecule of each type of antibacterial agent. An example is the fleroxacin—cefotaxime [63527-52-6] combination, Ro 23-9424 [115622-58-7] (23). 

In essence, the cephalosporin acts as a carrier (63) for the quinolone. The quinolone is replaced in the bacterial ceU after the action of P-lactamase on the cephalosporin portion of the molecule. This codmg combination represents a relatively new class of antibacterial agents which appear to offer advantages over the separated components (64). A good introductory discussion of these exciting agents can be found (65) (see also Antibiotics P-lactams ... 

As mentioned in the Introduction, bacterial resistance to currently used antibacterial agents poses a major threat to their continued effectiveness [2]. Interestingly, a number of enzymes are involved in the development of antibacterial resistance via several mechanisms. For example, there are enzymes that catalyze the inactivation of antibacterial agents [47], 3-Lactamases are the best-known examples of this class of enzymes and have been studied extensively as targets for new inhibitors that are used in combination with 3-lactams to prevent their inactivation [48], Several [3-lactamase inhibitors have been developed and are used in combination with [3-lactams (e.g., amoxicillin/clavulanic acid, piperacillin/tazo-bactam, and others) [49,50],... 

There are four possible justifications as to the use of antibacterial agents in combination. 

Nitrofurathiazide. 6-Acetylamino-3,-4-dihydro-3-(5-nitro-2-furanyl)-2JT-l,2,4-benzothiadiazine 1,1-dioxide, nitrofurathiazide, is synthesized from 4-acetylanaino-2-aniinobenzenesulfonaniide with 5-nitro-2-furancarboxaldehyde (45). The product has been employed as an antibacterial agent for humans and, in combination with other dmgs, has been used for acute or chronic otitis externa of dogs and cats. 

There are hundreds of topical steroid preparations that are available for the treatment of skin diseases. In addition to their aforementioned antiinflammatory effects, topical steroids also exert their effects by vasoconstriction of the capillaries in the superficial dermis and by reduction of cellular mitosis and cell proliferation especially in the basal cell layer of the skin. In addition to the aforementioned systemic side effects, topical steroids can have adverse local effects. Chronic treatment with topical corticosteroids may increase the risk of bacterial and fungal infections. A combination steroid and antibacterial agent can be used to combat this problem. Additional local side effects that can be caused by extended use of topical steroids are epidermal atrophy, acne, glaucoma and cataracts (thus the weakest concentrations should be used in and around the eyes), pigmentation problems, hypertrichosis, allergic contact dermatitis, perioral dermatitis, and granuloma gluteale infantum (251). 

Deoxyribonuclease (DNAase), an enzyme that degrades deoxyribonucleic acid, has been used in patients with chronic bronchitis, and found to produce favorable responses presumably by degrading the DNA, contributed by cell nuclei, to inflammatory mucus (213). Lysozyme [9001 -63-2] hydrolyzes the mucopeptides of bacterial cell walls. Accordingly, it has been used as an antibacterial agent, usually in combination with standard antibiotics. Topical apphcations are also useful in the debridement of serious bums, cellulitis, and dermal ulceration. 

Retinoids, which are highly effective in the treatment of acne, stimulate epithelial cell turnover and aid in unclogging blocked pores. Retinoids also exhibit anti-inflammatory properties through the inhibition of neutrophil and monocyte chemotaxis.8 Because of these comedolytic and antiinflammatory effects, topical retinoids are recommended as first-line treatment for mild to moderate comedonal and inflammatory acne.3 While success is seen with monotherapy, using a retinoid in combination with benzoyl peroxide or topical antibacterials is also an appropriate and effective therapeutic treatment option.3 Tretinoin, adapalene, and tazarotene are topical retinoids available for use in the treatment of acne. Table 62-2 describes the strengths and formulations of these agents. 

The type of antibacterial therapy used is important. No effect need be expected from the use of a single chemotherapeutic agent. Successful use has been made of a triple combination of sulfonamide, chloramphenicol, and chlortetracycline (A8). It would seem advisable to avoid neomycin (FI, J2), since this can itself cause a malabsorption syndrome. 

Co-amoxiclav consists of the combination of amoxicillin (penicillin antibacterial agent) and clavulanic acid (beta-lactamase inhibitor) which is associated with a risk of crystalluria in patients with renal impairment who are receiving high doses, particularly during parenteral therapy. 

Docusate sodium is a preparation used for softening ear wax before removal. Hydrocortisone is a corticosteroid, whereas gentamicin, neomycin and clioquinol are antibacterial agents. Otitis externa may be managed by the use of antibacterial preparations used alone or in combination with topical corticosteroids. 

Blepharitis is a topical inflammation of the eyelid margins that should be treated using topical antibacterial agents. Gentamicin eye ointment is preferred to the fusidic acid drops since the ointment is a better formulation to be used where the condition involves the eyelid margins. Chloramphenicol eye drops is the third option since it is an antibiotic with a wider spectrum of activity. A combination of corticosteroid and antibiotic is not recommended because of the side-effects associated with the steroid. The use of oral tablets is not usually recommended since blepharitis can easily be managed with topical drops. The use of dexamethasone eye drops, monotherapy steroid, could clear the inflammation but mask persistence of infection. 

In many therapeutic situations the drug combinations are completely misused (12). Adding another drug to a combination does not reduce the need for sound clinical judgement in therapy. Although there are many disease situations in which the use of more than one antibacterial agent may be justified, generalizations about various combinations of bactericidal or bacteriostatic antibiotics or admixtures have not proven valid. Basically, antibiotic combinations should be avoided as a common practice unless they have shown a clear increase in effectiveness as reported in the literature. 

Triclosan is retained in dental plaque for at least 8 hours, which in addition to its broad antibacterial property could make it suitable for use as an antiplaque agent in oral care preparations. However, the compound is rapidly released from oral tissues, resulting in relatively poor antiplaque properties as assessed in clinical studies of plaque formation. This observation is further corroborated by a poor correlation between minimal inhibitory concentration values generated in vitro and clinical plaque inhibitory properties of triclosan. Improvement of substantivity was accomplished by incorporation of triclosan in a polyvinyl methyl ether maleic acid copolymer (PVM/MA, Gantrez). With the combination of PVM/MA copolymer and triclosan, the substantivity of the triclosan was increased to 12 hours in the oral cavity. 

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