Ampicillin

Chemical properties

White or almost white, crystalline powder.

Chemical properties

Ampicillin in anhydrous form occurs as crystals.

Originator

Polycillin,Bristol,US,1963

The Uses of Ampicillin

Commonly used to select for ampicillin resistance in mutated and transformed cells

The Uses of Ampicillin

Penicillin antibacterial.

What are the applications of Application

Ampicillin trihydrate is a penicillin derivative that inhibits bacterial cell-wall synthesis

Indications

Ampicillin may also be helpful in certain patients, particularly pregnant women with acne, for whom the use of tetracycline, erythromycin, and minocycline should be avoided. In resistant acne patients, culture may reveal a gram-negative bacteria responsive to ampicillin.

Definition

ChEBI: Ampicillin trihydrate is a hydrate. It contains an ampicillin.

Manufacturing Process

The known methods for the preparation of D-(-)-α-aminobenzylpenicillin by the acylation of 6-aminopenicillanic acid result in the preparation of aqueous mixtures which contain, in addition to the desired penicillin, unreacted 6- aminopenicillanic acid, hydrolyzed acylating agent, and products of side reactions such as the products of the acylating agent reacted with itself and/or with the desired penicillin, as well as other impurities.
The D-(-)-α-aminobenzylpenicitlin may then be recovered from the aqueous reaction mixture by concentration to small volume and recovering the product by filtration. However, due to the fact that anhydrous D-(-)-α- aminobenzylpenicillinis soluble in water to the extent of about 20-25 mg/ml at 20°-25°C, it is very difficult to recover the product in high yields. Furthermore, the recovered D-(-)-α-aminobenzylpenicillin may be obtained in the form of a monohydrate. The monohydrates (as well as the dihydrates) of D-(-)-α-aminobenzylpenicillin possess poor biological stability.
The trihydrate which is obtained in high yields, is relatively insoluble in water, possesses high biological stability and can be obtained by contacting, at a temperature not above 60°C, an acid addition salt of D-(-)-α- aminobenzylpenicillin with an amine in a water immiscible solvent containing at least 3 mols of water per mol of such penicillin.
The following is an example of the conduct of such a process. To a vigorously agitated mixture of 100 ml of methyl isobutyl ketone there are added at 25° to 30°C 15 ml of water and 10 ml of a mixture of secondary amines.
To this mixture there is then added slowly over a period of 30 minutes 10 grams of D-(-)-α-aminobenzylpenicillin α-naphthalenesulfonate. The mixture is agitated for 3 hours at 25-30°C. The product, D-(-)-α-aminobenzylpenicillin trihydrate precipitates and is collected by filtration. The filter cake of the product is washed several times with methyl isobutyl ketone and is dried at 40°C. The product is obtained in about a 90% yield and has a potency of 865 mcg/mg. It is determined by Karl Fischer analysis to have a moisture content of 13.4% by weight.

brand name

Amcill (Parke-Davis); Omnipen (Wyeth-Ayerst); Polycillin (Apothecon); Principen (Apothecon).

Therapeutic Function

Antibacterial

Antimicrobial activity

Ampicillin is slightly less active than benzylpenicillin against most Gram-positive bacteria but is more active against E. faecalis. MRSA and strains of Str. pneumoniae with reduced susceptibility to benzylpenicillin are resistant. Most group D streptococci, anaerobic Gram-positive cocci and bacilli, including L. monocytogenes, Actinomyces spp. and Arachnia spp., are susceptible. Mycobacteria and nocardia are resistant.
Ampicillin has similar activity to benzylpenicillin against N. gonorrhoeae, N. meningitidis and Mor. catarrhalis. It is 2–8 times more active than benzylpenicillin against H. influenzae and many Enterobacteriaceae, but β-lactamase-producing strains are resistant. Pseudomonas spp. are resistant, but Bordetella, Brucella, Legionella and Campylobacter spp. are often susceptible. Certain Gram-negative anaerobes such as Prevotella melaninogenica and Fusobacterium spp. are susceptible, but B. fragilis is resistant, as are mycoplasmas and rickettsiae.
Activity against molecular class A β-lactamase-producing strains of staphylococci, gonococci, H. influenzae, Mor. catarrhalis, certain Enterobacteriaceae and B. fragilis is enhanced by the presence of β-lactamase inhibitors, specifically clavulanic acid.
Its bactericidal activity resembles that of benzylpenicillin. Bactericidal synergy occurs with aminoglycosides against E. faecalis and many enterobacteria, and with mecillinam against a number of ampicillin-resistant enterobacteria.

Acquired resistance

β-Lactamase-producing pathogens, including most clinical isolates of Staph. aureus, are resistant. Strains of pneumococci, enterococci, gonococci and H. influenzae with altered PBPs have reduced susceptibility to ampicillin. Isolates of N. gonorrhoeae and H. influenzae with a TEM plasmid- mediated β-lactamase (which are more common) are fully resistant. Resistance among H. influenzae is often linked with resistance to chloramphenicol, erythromycin or tetracycline, due to plasmid-encoded resistance markers that are co-transferred with the gene for the TEM enzyme. However, at least 70% of current H. influenzae isolates remain susceptible to ampicillin worldwide.
The widespread use of ampicillin and other aminopenicillins has led to resistance becoming common in formerly susceptible species of enteric pathogens as a result of the widespread dissemination of plasmid-mediated β-lactamases. Surveillance data from North America and Europe indicate less than 50% susceptibility to ampicillin in Esch. coli. At least 90% of current isolates of Mor. catarrhalis are β-lactamaseproducing strains. Ampicillin-resistant strains of salmonellae, notably S. enterica serotypes Typhi and Typhimurium (many of which are also resistant to chloramphenicol, sulfonamides and tetracyclines) present a serious problem in Africa, Asia and South America. Multiresistant strains of shigellae also predominate in many parts of the world.

General Description

Odorless white microcrystalline powder with a bitter taste. A 0.25% solution in water has a pH of 3.5 to 5.5.

Air & Water Reactions

Slightly soluble in water.

Reactivity Profile

Ampicillin absorbs insignificant amounts of moisture at 77° F and relative humidities up to approximately 80%, but under damper conditions Ampicillin absorbs significant amounts. A pH-rate profile reveals specific-acid- and specific-base- catalyzed hydrolysis. The pH of maximum stability is 5.8.

Fire Hazard

Flash point data for Ampicillin are not available; however, Ampicillin is probably combustible.

Contact allergens

Ampicillin caused contact dermatitis in a nurse also sensitized to amoxicillin (with tolerance to oral phenoxymethylpenicillin) and in a pharmaceutical factory worker. Systemic drug reactions are common. Crossreactivity is regular with ampicillin and can occur with other penicillins.

Biochem/physiol Actions

A β-lactam antibiotic with an amino group side chain attached to the penicillin structure. Penicillin derivative that inhibits bacterial cell-wall synthesis (peptidoglycan cross-linking) by inactivating transpeptidases on the inner surface of the bacterial cell membrane. Bactericidal only to growing Escherichia coli . Mode of resistance: Cleavage of β-lactam ring of ampicillin by β-lactamase. Antimicrobial spectrum: Gram-negative and Gram-positive bacteria.

Pharmacokinetics

Oral absorption: 30–40%
C_max 500 mg oral: 3.2 mg/L after c. 2 h
500 mg intramuscular: 5–15 mg/L after 1 h
500 mg intravenous infusion: 12–29 mg/L
Plasma half-life: 1–1.5 h
Volume of distribution: 0.38 L/kg
Plasma protein binding: 20%
Absorption and distribution
Ampicillin is highly stable to acid: in 2 h at pH 2 and 37°C, only 5% of activity is lost. Absorption is impaired when it is given with meals. It is distributed in the extracellular fluid. Adequate concentrations are obtained in serous effusions. Effective CSF levels are obtained only in the presence of inflammation, variable peak concentrations around 3 mg/L being found in the first 3 days of treatment in patients receiving 150 mg/kg per day. It accumulates and persists in the amniotic fluid. Metabolism and excretion
A small proportion is converted to penicilloic acid. About 34% of an oral dose and 60–80% of parenteral doses are recoverable from the urine, where concentrations around 250–1000 mg/L appear. Excretion is partly in the glomerular filtrate and partly by tubular secretion, which can be blocked by probenecid. Impairment of renal function reduces the rate of excretion, the plasma half-life rising to 8–9 h in anuric patients.
Although excretion is mainly renal, up to 50 times the corresponding serum level may be attained in the bile. There is a degree of enterohepatic recirculation and significant quantities appear in the feces. Bioavailability may be affected in severe liver disease.

Clinical Use

Isolates should be tested for susceptibility before use, especially for serious infections. For oral therapy, amoxicillin is preferable to ampicillin.
Urinary tract infections
Bacterial meningitis
Respiratory tract infections
Gastrointestinal infections, including typhoid fever and bacillary dysentery Enterococcal endocarditis and septicemia (in combination with an aminoglycoside)
Listeriosis (in combination with an aminoglycoside)

Clinical Use

Ampicillin, 6-[D-α-aminophenylacetamido]penicillanic acid,D-α-aminobenzylpenicillin (Penbritn, Polycillin, Omnipen,Amcill, Principen), meets another goal of the research onsemisynthetic penicillins—an antibacterial spectrum broaderthan that of penicillin G. This product is active against thesame Gram-positive organisms that are susceptible to otherpenicillins, and it is more active against some Gram-negativebacteria and enterococci than are other penicillins.Obviously, the α-amino group plays an important role in thebroader activity, but the mechanism for its action isunknown. It has been suggested that the amino group confersan ability to cross cell wall barriers that are impenetrableto other penicillins. D-(－)-Ampicillin, prepared from D-(－)-α-aminophenylacetic acid, is significantly more active thanL-(＋)-ampicillin.
Ampicillin is water soluble and stable in acid. Theprotonated α-amino group of ampicillin has a pKa of 7.3,46and thus it is protonated extensively in acidic media, whichexplains ampicillin’s stability to acid hydrolysis and instabilityto alkaline hydrolysis. It is administered orally andis absorbed from the intestinal tract to produce peak plasmaconcentrations in about 2 hours. Oral doses must be repeatedabout every 6 hours because it is excreted rapidly andunchanged through the kidneys. It is available as a white, crystalline, anhydrous powder that is sparingly soluble inwater or as the colorless or slightly buff-colored crystallinetrihydrate that is soluble in water. Either form may be usedfor oral administration, in capsules or as a suspension.Earlier claims of higher plasma levels for the anhydrousform than for the trihydrate following oral administrationhave been disputed. The white, crystalline sodium salt isvery soluble in water, and solutions for injections should beadministered within 1 hour after being made.

Side Effects

Ampicillin is generally free from severe toxicity and, apart from gastrointestinal intolerance, the only significant side effects seen have been rashes. In common with other semisynthetic penicillins, it appears to be less likely than benzylpenicillin to elicit true allergic reactions. However, it is more likely to cause rashes, which are found in approximately 9% of treated patients and which occur more frequently in patients receiving large doses or in renal failure. Rashes occur in 95% of patients with infectious mononucleosis or other lymphoid disorders. This unusual susceptibility disappears when the disease resolves. In keeping with a toxic rather than an allergic origin, skin tests to ampicillin and to mixed-allergen moieties of benzylpenicillin are negative. Since the typical maculopapular rash of ampicillin does not have an allergic origin, its development does not indicate penicillin allergy and is not a contraindication to the use of other penicillins.
Gastrointestinal side effects are relatively common (around 10%) in patients treated with oral ampicillin, and occur in 2–3% of patients given the drug parenterally, presumably as a result of drug entering the gut through the bile. The very young and the old are most likely to suffer. Diarrhea can be sufficiently severe to require withdrawal of treatment and pseudomembranous colitis may occur. Interference with the bowel flora, which is presumably implicated in diarrhea, can also affect enterohepatic recirculation of steroids, and the derangement can be sufficient to impair the absorption of oral contraceptives and affect the interpretation of estriol levels.

Safety Profile

Mildly toxic by ingestion. An experimental teratogen. Other experimental reproductive effects. When heated to decomposition it emits toxic fumes of SO,xand NOx.

Synthesis

Ampicillin, [2S-[2α,5α,6β(S)]]-3,3-dimethyl-7-oxo-6-(2-amino-2-phenylacetamido)-4-thia-azabicylco[3.2.0]-heptan-2-carboxylic acid (32.1.1.16), is synthesized in various ways using different methods of protection of amino group in the starting phenylglycine. One of the most widely used methods uses the benzyl chloroformate. Reacting this with phenylglycine initially forms benzyloxycarbonylphenylglycine (32.1.1.13). Treating this with ethyl chloroformate in the presence of triethylamine gives a mixed anhydride (32.1.1.14) with a protected amino group that easily reacts with 6-APA in the presence of sodium bicarbonate, to form the sodium salt of the N-benzyloxycarbonyl-protected ampicillin (32.1.1.15). Removing the protecting group by hyrogenolysis using a palladium on barium carbonate catalyst gives the desired ampicillin (32.1.1.16).

Another method of making ampicillin is analogous to the method described above, and it differs in the method of protecting the α-amino group in the initial phenylglycine. In order to do this, acetoacetic ester is reacted with the sodium salt of phenylglycine, which forms an intermediate—aminocrontonic ester (32.1.1.17). Subsequent transformation of this product to the mixed anhydride (32.1.1.18) followed by a reaction with 6-APA in the presence of sodium bicarbonate gives ampicillin (32.1.1.16) in the form of a sodium
salt.

A method of directly acylating 6-APA with phenylglycine chloride hydrochloride also has been proposed.

Potential Exposure

Used as an antibiotic.

Drug interactions

Potentially hazardous interactions with other drugs
Ciclosporin: may increase ciclosporin levels.
Reduces excretion of methotrexate (increased risk of toxicity).

Metabolism

Ampicillin is metabolised to some extent to penicilloic acid which is excreted in the urine.
Renal clearance of ampicillin occurs partly by glomerular filtration and partly by tubular secretion; it is reduced by probenecid. About 20-40% of an oral dose and 60-80% of an IV dose may be excreted unchanged in the urine in 6 hours. High concentrations are reached in bile; it undergoes enterohepatic recycling and some is excreted in the faeces.

Shipping

UN3077 Environmentally hazardous substances, solid, n.o.s., Hazard class: 9; Labels: 9-Miscellaneous hazardous material, Technical Name Required.

Incompatibilities

May be 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.