Ampicillin

Ampicillin
IUPAC name	(2S,5R,6R)-6-([(2R)-2-amino-2-phenylacetyl]amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
Tradename	Principen, others
CAS number	69-53-4
DrugBank	DB00415
PubChem	6249
ChemSpider	6013
UNII	7C782967RD
ChEBI	28971
ATC prefix	J01
ATC suffix	CA01
Legal status	Rx-only
Routes of administration	Oral, intravenous, intramuscular

Ampicillin is a broad-spectrum beta-lactam antibiotic within the aminopenicillin class, derived from the core penicillin structure. It was developed in the early 1960s by scientists at the Beecham Research Laboratories in the United Kingdom, representing a significant advancement over earlier penicillin G by exhibiting activity against many Gram-negative bacteria. The drug works by inhibiting the synthesis of the bacterial cell wall, leading to cell lysis and death, and is commonly used to treat infections such as respiratory tract infections, urinary tract infections, meningitis, and salmonellosis.

History

The discovery of ampicillin was a landmark achievement in the field of antibacterial chemotherapy. Following the isolation of the penicillin nucleus, 6-aminopenicillanic acid, by researchers at the Beecham Research Laboratories, a team led by scientists including Frank P. Doyle and J. H. C. Nayler synthesized the compound. It was introduced for medical use around 1961, offering a crucial advantage over penicillin V by its ability to penetrate the cell envelope of many Gram-negative organisms, such as Escherichia coli and Proteus mirabilis. Its development occurred during a period of intense competition in the pharmaceutical industry, with rival firms like Bristol-Myers also pursuing similar aminopenicillin agents, and it quickly became a widely prescribed antibiotic globally.

Medical uses

Ampicillin is indicated for a variety of bacterial infections caused by susceptible organisms. It is a first-line agent for the treatment of Listeria infections, including meningitis and septicemia, and is often used in combination with aminoglycosides like gentamicin for enterococcal endocarditis. Common applications include combating Haemophilus influenzae in respiratory tract infections, treating urinary tract infections caused by Escherichia coli and Proteus mirabilis, and managing salmonellosis and shigellosis. It is also a component of the standard regimen, alongside sulbactam or clavulanic acid, to overcome beta-lactamase-mediated resistance in conditions like intra-abdominal infections.

Mechanism of action

As a beta-lactam antibiotic, ampicillin exerts its bactericidal effect by interfering with the final stage of peptidoglycan synthesis in the bacterial cell wall. It binds covalently to penicillin-binding proteins (PBPs), which are enzymes located on the inner surface of the cytoplasmic membrane responsible for cross-linking the peptidoglycan strands. This binding irreversibly inhibits the transpeptidase activity of these PBPs, preventing the formation of a stable, rigid cell wall. The resulting weakened structure cannot withstand the high internal osmotic pressure of the bacterium, leading to cell lysis and death, particularly during active growth and division.

Resistance

Bacterial resistance to ampicillin is a major clinical concern and can occur through several mechanisms. The most common is the production of beta-lactamase enzymes, such as TEM-1 and SHV-1, which hydrolyze the beta-lactam ring, rendering the antibiotic inactive. This resistance is often plasmid-encoded, facilitating rapid spread among species like Escherichia coli and Klebsiella pneumoniae. Other mechanisms include alterations in the target penicillin-binding proteins, as seen in methicillin-resistant Staphylococcus aureus (MRSA), and reduced permeability of the outer membrane in Gram-negative bacteria due to changes in porin channels. The widespread use of ampicillin in settings like hospitals and agriculture has significantly contributed to the prevalence of resistant strains.

Side effects

The most frequent adverse effects associated with ampicillin are related to the gastrointestinal tract, including diarrhea, nausea, and vomiting. As with other penicillins, hypersensitivity reactions ranging from mild skin rashes to severe anaphylaxis can occur; cross-reactivity is possible in patients allergic to cephalosporins. A notable side effect is the development of a characteristic non-allergic maculopapular rash in patients with EBV-induced infectious mononucleosis. Prolonged use can lead to C. difficile-associated diarrhea or pseudomembranous colitis, and, rarely, hematologic disturbances such as leukopenia or thrombocytopenia.

Chemical properties

Ampicillin is a semisynthetic aminopenicillin with the chemical formula C₁₆H₁₉N₃O₄S. It differs from penicillin G by the presence of an amino group on the phenylacetyl side chain, which confers its enhanced Gram-negative spectrum and stability in gastric acid, allowing for oral administration. The compound exists as a white, crystalline powder that is sparingly soluble in water and more soluble in dimethyl sulfoxide. Its beta-lactam ring is susceptible to hydrolysis, particularly under alkaline conditions or in the presence of beta-lactamase enzymes. The stereochemistry at the 6-position of the penam nucleus is crucial for its antibacterial activity.

Category:Beta-lactam antibiotics Category:World Health Organization essential medicines Category:Antibiotics