Bacitracin Chemical Properties

Melting point:

221-225°C

Density 

1.0166 (rough estimate)

refractive index 

1.6700 (estimate)

storage temp. 

Keep in dark place,Inert atmosphere,2-8°C

solubility 

H₂O: 50 mg/mL, clear to very slightly hazy, deep yellow

form 

Powder

color 

white to faintly beige

Odor

odorless or acetic odor

Water Solubility 

soluble

Merck 

13,936

LogP

-0.050 (est)

EPA Substance Registry System

Bacitracin (1405-87-4)

Safety Information

Hazard Codes 

Xn

Risk Statements 

20/21/22

Safety Statements 

22-24/25-45-36

WGK Germany 

2

RTECS 

CP0175000

F 

21

TSCA 

Yes

HS Code 

29419090

Hazardous Substances Data

1405-87-4(Hazardous Substances Data)

Toxicity

LD50 oral in guinea pig: 2gm/kg

MSDS

• Language:English Provider:Bacitracin
• Language:English Provider:SigmaAldrich
• Language:English Provider:ACROS

Bacitracin Usage And Synthesis

Mode of action

The lipid carrier involved in transporting the cell wall building block across the membrane is a C55 isoprenyl phosphate. The lipid acquires an additional phosphate group in the transport process and must be dephosphorylated in order to regenerate the native compound for another round of transfer. Bacitracin as cyclic peptide antibiotics binds to the C55 lipid carrier. Bacitracin inhibits its dephosphorylation thus disrupting the lipid carrier cycle.

Description

Bacitracin is a mixture of similar peptides produced by fermentation of the bacterium Bacillus subtil is. The A-type component predominates. Its mode of action is to inhibit both peptidoglycan biosynthesis at a late stage (probably at the dephosphorylation of the phospholipid carrier step) and disruptions of plasma membrane function.

Chemical Properties

White to pale buff powder

Chemical Properties

Bacitracin is a white to light tan powder which is odorless or having a slight odor and very bitter taste.

Originator

Baciguent,Upjohn,US,1948

Uses

antibiotic agent effective against gram-positive organisms and spirochetes; in products for topieal treatment, ear medications and ophthalmie drugs

Uses

Polypeptide antibacterial.

Uses

Bacitracin is a peptide antibiotic effective against gram-postive bacteria. Bacitracin is an inhibitor of peptidoglycan synthesis. Bacitracin disrupts bacterial cell wall synthesis by inhibiting depho sphorylation of lipid pyrophosphate. Bacitracin also strongly inhibits proline endopeptidase from human muscle.

Definition

A complex of cyclic peptide antibiotic of known chemical structure isolated from the Tracy-I strain of Bacillus subtilis.

Indications

This polypeptide antibiotic, which is produced from Bacillus subtilis, interferes with bacterial cell wall growth and is bactericidal against many grampositive organisms such as streptococci, staphylococci, and pneumococci but is inactive against most gram-negative organisms. All anaerobic cocci, Neisseria, and the tetanus and diphtheria bacilli are also sensitive to bacitracin.
Resistance is rare, but some staphylococcal strains are inherently resistant. Hypersensitivity reactions are uncommon. Bacitracin is stable in petrolatum (but not water-miscible preparations) and is available as an ointment or as a component of antibiotic mixtures. Sensitization to bacitracin has been reported more recently, particularly in patients with leg ulcers.

Manufacturing Process

The early patent, US Patent 2,498,165 first disclosed bacitracin and described a process for preparing bacitracin, comprising cultivating Bacillus subtilis Tracy I in a nutritive medium, at substantially pH 7 and 37°C, for more than three days, extracting the antibiotic from the resulting medium with a low molecular weight alcohol, concentrating the resulting alcoholic solution in vacuo, acidifying the resulting concentrate, extracting the antibiotic from the resulting solution, and precipitating the antibiotic from the resulting solution, with a precipitating agent for the antibiotic, selected from the group consisting of Reinecke's salt, phosphotungstic acid, phosphomolybdic acid, molybdic acid, picric acid, ammonium rhodanilate, and azobenzene-p-sulfonicacid.
A subsequent patent, US Patent 2,828,246 described a commercial process for bacitracin production. A 1,230 gallon portion of a medium containing 10% soybean oil meal, 2.50% starch and 0.50% calcium carbonate having a pH of 7.0 was inoculated with a culture of bacitracin-producing bacteria of the Bacillus subtilis group and the inoculated medium incubated for a period of 24 hours with aeration such that the superficial air velocity was 12.1. An assay of the nutrient medium following the fermentation revealed a yield of bacitracin amounting to 323 units/ml. This was more than twice the yields previously obtained.
Then, a patent, US Patent 2,834,711 described the purification of bacitracin. In this process for purifying bacitracin, the steps comprise adding a watersoluble zinc salt to a partially purified aqueous solution of bacitracin, adjusting the pH to from 5 to 9, recovering the precipitate which forms, dissolving the precipitate in water at a pH not substantially in excess of 4, and removing the zinc ion by passing the aqueous solution through a cation exchange resin and drying the resulting solution to obtain dry solid bacitracin.
Another patent, US Patent 2,915,432describes a process of recovering and concentrating bacitracin from aqueous filtered fermentation broth containing on the order of 3% protein-aceous solids which comprises intimately contacting the broth with a synthetic organic cation exchange resin having as its functional groups nuclear sulfonic acids and having a crosslinkage of the order of 1 to 2%, with the resin being in the hydrogen form, and eluting the adsorbed bacitracin from the resin with a weak base.
Bacitracin recovery is described in US Patents 3,795,663 and 4,101,539.

brand name

Ziba (X Gen).

Therapeutic Function

Antibacterial

General Description

The organism from which Johnson et al. produced bacitracinin 1945 is a strain of B. subtilis. The organism hadbeen isolated from debrided tissue from a compound fracturein 7-year-old Margaret Tracy, hence the name “bacitracin.”Bacitracin is now produced from the licheniformisgroup (B. subtilis). Like tyrothricin, the first useful antibioticobtained from bacterial cultures, bacitracin is a complex mixture of polypeptides. So far, at least 10 polypeptideshave been isolated by countercurrent distribution techniques:A, A1, B, C, D, E, F1, F2, F3, and G. The commercialproduct known as bacitracin is a mixture of principallyA, with smaller amounts of B, D, E, and F1–3.The official product is a white to pale buff powder that isodorless or nearly so.
The activity of bacitracin is measured in units per milligram.The potency per milligram is not less than40 units/mg except for material prepared for parenteral use,which has a potency of not less than 50 units/mg. It is a bactericidalantibiotic that is active against a wide variety ofGram-positive organisms, very few Gram-negative organisms,and some others. It is believed to exert its bactericidaleffect through inhibition of mucopeptide cell wall synthesis.Its action is enhanced by zinc. Although bacitracin hasfound its widest use in topical preparations for local infections,it is quite effective in several systemic and local infectionswhen administered parenterally. It is not absorbedfrom the GI tract; accordingly, oral administration is withouteffect, except for the treatment of amebic infectionswithin the alimentary canal.

Hazard

Poison; moderately toxic; mutagen.

Pharmaceutical Applications

A mixture of peptides produced by Bacillus licheniformis. Bacitracin A is the major constituent of commercial preparations. The more stable zinc salt is used in topical formulations. It has been widely used as a growth promoter in animals, but has been banned for that purpose in the European Union.
It is highly active against many Gram-positive bacteria and is mainly used as a component of topical preparations. Although strains of Staph. aureus are usually susceptible, they are rather less so than most other Gram-positive bacteria. Streptococcus pyogenes is so much more susceptible than other hemolytic streptococci that bacitracin susceptibility is used as a screening test for identification. Clostridium difficile and Actinomyces spp. are susceptible, but enterobacteria and Pseudomonas spp. are resistant. Entamoeba histolytica is inhibited by 0.6–10 mg/L.
Resistance is uncommon, but has been detected in Staph. aureus following topical treatment.
It is nephrotoxic and unsuitable for parenteral use. Systemic toxicity from application to skin or ulcerated areas is rare, but it may cause allergic reactions and occasional anaphylaxis has been described. It is found in many ointments and ophthalmic preparations, usually together with other components, including polymyxins, neomycin and corticosteroids.
Bacitracin is not absorbed by mouth but oral preparations have been used for suppression of gut flora, including C. difficile.

Mechanism of action

Bacitracin interferes with bacterial cell wall formation by inhibiting peptidoglycan synthesis, the major cell wall component in Gram positive bacteria. The lipid C-55-isoprenyl pyrophosphate (IPP) normally carries peptidoglycan units across the bacterial cell membrane. Upon delivery, the IPP is dephosphorylated by a membrane-associated pyrophosphatase to C-55-isoprenyl phosphate (IP). This enables the lipid to bind new cargo. Mediated by a metal ion, bacitracin forms a complex with IPP that inhibits its dephosphorylation to IP. Consequently, the amount of IP decreases, whereby the formation of the bacterial cell wall is hindered. Bacitracin is also thought to damage the bacterial cytoplasmic membrane. It may be either bactericidal or bacteriostatic, depending on the susceptibility of the infecting organism and local drug concentration.

Clinical Use

Bacitracin is predominantly active against Gram-positive microorganisms, and parenteral use is limited to IM injection for infants with pneumonia and empyema caused by staphylococci resistant to other agents. It is rather neuro- and nephrotoxic and, therefore, is used in this manner with caution. Bacitracin also is widely employed topically to prevent infection in minor cuts, scrapes, and burns.

Clinical Use

Bacitracin is mainly used topically for the treatment of skin, eye and ear infections, and the prevention of wound infections. It is especially employed for minor skin injuries, such as cuts, scrapes, or burns. Although it has been in use for almost half a century, it has only quite recently been recognized as a potent sensitizer, with occasional anaphylaxis. Thus, bacitracin should be used with caution. The value of bacitracin in the prevention of wound infections following clean surgical procedures is doubtful. A randomized, doubleblind study that evaluated approximately 1200 surgical wounds and compared bacitracin with white petrolatum for postoperative dressings demonstrated petrolatum to be equally as effective for postoperative wound care as bacitracin. The important advantage of white petrolatum over bacitracin was that its application led to a significantly lower rate of contact allergy. Other studies that have compared topical antimicrobial agents for use on clean surgical wounds have confirmed that such protocols do not improve healing or reduce the infection rate.

Toxicology

Nephrotoxicity (tubular and glomerular necrosis) and thrombophlebitis are the main toxic effects of bacitracin if it is administered systemically or intramuscularly. The renal toxicity of this drug may be largely due to the fact that it causes renal vasoconstriction. Nephrotoxicity usually does not occur in infants. Since the nephrotoxic effects may be additive, the concurrent or sequential use of systemic bacitracin with other nephrotoxic drugs should be avoided. Other adverse reactions include hypersensitivity reactions, anaphylaxis, hypotension, facial edema, urticaria, rash, diaphoresis, and blood dyscrasias, such as eosinophilia. When it is taken orally, it can induce anorexia, nausea, vomiting, and diarrhea. Cases of bacitracin-associated paresthesias, fever, and bone marrow toxicity, have also been described. Respiratory paralysis may occur in patients with a neuromuscular disease, such as myasthenia gravis. The use of bacitracin can result in overgrowth of nonsusceptible organisms, such as Candida spp. Bacitracin is classified as a Food and Drug Administration (FDA) pregnancy risk factor C agent, which means either that studies in animals have revealed adverse effects on the fetus (teratogenic, embryocidal, or other) or that there are no controlled studies in women, or that studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

Safety Profile

A poison by intraperitoneal and intravenous routes. Moderately toxic by ingestion and subcutaneous routes. Mutation data reported.

Potential Exposure

Bacitracin is used as an ingredient in antibiotic ointments to treat or prevent topical or eye infections. Commercial Bacitracin is a mixture of at least 9 bacitracins. Also used as a feed and drinking water additive for animals; as a food additive for human consumption.

First aid

In case of large-scale exposure, the directions formedicines (nonspecific, n.o.s.) would be applied as follows:Move victim to fresh air; call emergency medical care. Ifnot breathing, give artificial respiration. If breathing is diffi

storage

Color Code—Green: General storage may be used.

Shipping

UN 3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1—Poisonous materials.

Purification Methods

Bacitracin has been purified by carrier displacement using n-heptanol, n-octanol and n-nonanol as carriers and 50% EtOH in 0.1 N HCl. The pure material gives one spot with RF ~0.5 on paper chromatography using AcOH:n-BuOH:H2O (4:1:5). [Porath Acta Chem Scand 6 1237 1952.] It has also been purified by ion-exchange chromatography. It is a white powder soluble in H2O and EtOH but insoluble in Et2O, CHCl3 and Me2CO. It is stable in acidic solution but unstable in base. It is a strong antibacterial. [Abraham & Bewton Biochem J 47 257 1950, Synthesis: Munekata et al. Bull Chem Soc Jpn 46 3187, 3835 1973, Beilstein 27 III/IV 5746.]

Incompatibilities

Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides.

Waste Disposal

It is inappropriate and possibly dangerous to the environment to dispose of expired or waste pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

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