Bacitracins toxicity

Although tyrothricia is too toxic for parenteral therapy, it was formerly sold in the United States as oral lo2enges. Modem tyrothricin formulations are composed of 70—80% tyrocidines and 30—20% linear gramicidins. Tyrocidines are not as active as linear gramicidins and are too toxic for any therapeutic use by themselves. The bactericidal linear gramicidins are used in the United States solely as an ophthalmic solution in combination with polymyxin B sulfate and neomycin sulfate. The linear gramicidin is used in this aqueous product as a substitute for bacitracin, which lacks stabiUty under such conditions. 

Because of its highly toxic nature when administered parenterally, bacitracin is normally restricted to external usage. 

Bacitracin (Fig. 4) is a cyclic peptide antibiotic. The lipid II molecule involved in the bacterial cell wall biosynthesis has a C55 isoprenyl pyrophosphate moiety that must be dephosphorylated so that it can reparticipate in another round of lipid II transfer. Bacitracin binds to the isoprenyl pyrophosphate and prevents the dephosphorylation which, in turn, blocks cell wall growth by interfering with the release of the muropeptide subunits to the outside of the bacterial cell membrane. Bacitracin inhibits similar reactions in eukaryotic cells. So, it is systemically toxic but is an effective and widely used topical antibiotic. 

Bacitracin and gramicidin are polypeptide antibiotics with activity against gram-positive organisms and against most anaerobic cocci. Systemic toxicity for bacitracin is rare because of poor absorption through the skin. Gramicidin is used only topically... 

Bacitracin is primarily a topical antibiotic. Previously, it was administered intramuscularly, but the toxicity associated with its parenteral administration has precluded systemic use. The bacitracins are not absorbed from the gastrointestinal tract following oral administration. 

Bacitracin is highly nephrotoxic when administered systemically and is only used topically (Chapter 62). Bacitracin is poorly absorbed. Topical application results in local antibacterial activity without systemic toxicity. Bacitracin, 500 units/g in an ointment base (often combined with polymyxin or neomycin), is indicated for the suppression of mixed bacterial flora in surface lesions of the skin, in wounds, or on mucous membranes. Solutions of bacitracin containing 100-200 units/mL in saline can be used for irrigation of joints, wounds, or the pleural cavity. 

The use of bacitracin in the anterior nares may temporarily decrease colonization by pathogenic staphylococci. Microbial resistance may develop following prolonged use. Bacitracin-induced contact urticaria syndrome, including anaphylaxis, occurs rarely. Allergic contact dermatitis occurs frequently, and immunologic contact urticaria rarely. Bacitracin is poorly absorbed through the skin, so systemic toxicity is rare. 

Gramicidin is available only for topical use, in combination with other antibiotics such as neomycin, polymyxin, bacitracin, and nystatin. Systemic toxicity limits this drug to topical use. The incidence of sensitization following topical application is exceedingly low in therapeutic concentrations. 

Peptide antibiotics are not often the drags of first choice for systemic therapy of important human disease. However, the World Health Organization, which chooses drags especially for Third World use based on efficacy, safety, quality, price, and availability, includes as essential such peptide antibiotics as bleomycin, dactinomycin, and bacitracin (as an ointment containing neomycin), plus several /8-lactams. See also Antibiotics, Antibiotics -Lactams. Systemic use of peptide antibiotics is many times limited by nephroloxicity and other toxicities. Semisynthesis or complete chemical synthesis of analogues of peptide antibiotics has most often not resulted in improved drags. 

Most biologically active natural peptides are linear, but bacitracin is a leading member of the so-called cyclic peptide type of antibiotics. The commercial material, extracted from Bacillus subtilis, is a mixture of several compounds in which bacitracin A predominates. It exerts its action by inhibiting peptidoglycan synthesis and membrane function. Bacitracin has been a useful antibiotic since the 1960s, but its systemic use results in a number of toxic side effects, including nephrotoxicity. One cannot be sure which components of the mixture are responsible for the toxicity, and separation of natural constituents is complex and difficult. For this reason, an efficient synthesis of bacitracin A would be useful. 

Unfortunately, bacitracin causes nephrotoxicity [36] and so its use as a suitable adjuvant to overcome the enzymatic barrier is quite questionable. Interestingly, it was demonstrated recently that bacitracin, when covalently linked to a mucoadhesive polymer, still displays its inhibitory activity [30]. The immobilization to an unabsorbable drug carrier matrix is believed to lead to an exclusion of systemic toxic side effects, but detailed toxicological studies are necessary to prove this hypothesis. 

Bacitracin is markedly nephrotoxic if administered systemically, producing proteinuria, hematuria, and nitrogen retention. Hypersensitivity reactions (eg, skin rashes) are rare. Because of its marked toxicity when used systemically, it is limited to topical use. Bacitracin is poorly absorbed. Topical application results in local antibacterial activity without significant systemic toxicity. The small amounts of bacitracin that are absorbed are excreted by glomerular filtration. 

Owing to their significant toxicity with systemic administration, polymyxins are now restricted to topical use. Ointments containing polymyxin B, 0.5 mg/g, in mixtures with bacitracin or neomycin... 

Topical antibiotics with a narrow spectrum of action and low toxicity (eg, bacitracin and mupirocin) can be used for temporary control of bacterial growth and are generally preferred to antiseptics. Methenamine mandelate releases formaldehyde in a low antibacterial concentration at acid pH and can be an effective urinary antiseptic for long-term control of urinary tract infections. 

A number of zinc compounds with organic constituents (e.g., zinc salts of organic acids) have therapeutic uses. These include antidandruff zinc pyridinethione, antifungal zinc undecylenate used to treat athlete s foot, zinc stearate and palmitate (zinc soap), and antibacterial zinc bacitracin. Zinc naphthenate is used as a low-toxicity wood preservative, and zinc phenolsulfonate has insecticidal properties and was once used as an intestinal antiseptic. The inhalation of zinc soaps by infants has been known to cause acute fatal pneumonitis characterized by lung lesions similar to, but more serious than, those caused by talc. Zinc pyridine thione (zinc 2-pyridinethiol-l-oxide) has been shown to cause retinal detachment and blindness in dogs this is an apparently species-specific effect because laboratory tests at the same and even much higher dosages in monkeys and rodents do not show the same effect. 

Unless specifically requested, topically administered antimicrobial agents are not tested. System-ically toxic antimicrobial agents, such as pol)rmixin B, bacitracin and mupirocin, are often not included... 

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