Penicillins

The original fermentation derived penicillins were produced by growth of the fungus Penicillium chrysogenum on complex solid media, with the result that they were mixtures differing from one another in the identity of the side-chain moiety. When a sufficient supply of phenylacetic acid is present in liquid media, this is preferentially incorporated into the molecule to produce mainly benzylpenicillin (penicillin G in the old nomenclature). Use of phenoxyacetic acid instead leads to phenoxymethyl penicillin (penicillin V). More than two dozen different penicillins have been made in this way, but these two are the only ones that remain in clinical use. The bicyclic penicillin nucleus itself is prepared biosynthetically via a complex process from an acylated cysteinyl valyl peptide.

Bacteria may exhibit resistance to penicillins and other β-lactam antibiotics by several mechanisms :
? Acquisition of penicillin-binding proteins (PBPs) with reduced affinity for penicillin. This is a frequent cause of resistance in Gram-positive bacteria such as staphylococci, pneumococci and enterococci. This mechanism may also be responsible for lowlevel penicillin resistance in H. influenzae and viridans streptococci.
? The production of a bacterial enzyme, β-lactamase, that opens the β-lactam ring, causing inactivation of the antibiotic.
? Modification of outer membrane proteins (porins) in Gram-negative bacteria, preventing passage of penicillins into the bacterial cell. Efflux mechanisms have been described in which bacteria pump out β-lactam antibiotics.
Bacteria frequently display more than one resistance mechanism – for example, methicillin-resistant staphylococci typically produce β-lactamase but demonstrate resistance primarily due to altered PBPs; Gram-negative bacteria may produce β-lactamases in organisms with efflux mechanisms or altered outer membrane proteins.
Methicillin-resistant strains of Staphylococcus aureus (MRSA) are considered to be resistant to all β-lactam antibiotics, with the exception of some newer cephalosporins, and are frequently multiresistant. The prevalence of MRSA is variable, with very low incidence in some countries of northern Europe, but high incidence in Japan and other countries. In the USA the frequency increased from 2.4% in 1975 to 64% in 2007. Although largely confined to hospitals, MRSA is increasingly seen in community settings.
When benzylpenicillin was introduced, all streptococci were sensitive to its action, and this situation remains largely unchanged. However, pneumococci exhibiting reduced susceptibility are now common, although the criteria for penicillin resistance differ in the USA and Europe .
The interpretive criteria for non-meningitis isolates defined by the FDA in 2008 is based on clinical experience showing that high doses of penicillin provide efficacious drug concentrations, except in cerebrospinal fluid (CSF). The EUCAST or FDA pre-2008 definitions are generally used for epidemiological purposes.
Until the 1980s, clinical isolates of Streptococcus pneumoniae were uniformly susceptible to penicillin, except for a few reports from South Africa and elsewhere. By 1998, 24% of invasive pneumococci isolated in the USA displayed reduced susceptibility to penicillin and often to other classes of antibiotics. The frequency of isolation of penicillin-resistant pneumococci in Europe was 51% in Hungary (1990) and 9% in the UK (1998). Introduction of the heptavalent pneumococcal vaccine in 2000 caused a dramatic decrease in isolates of pneumococci insusceptible to penicillin, especially in the elderly and young children, in countries with effective vaccination programs.
As with pneumococci, enterococci were initially perceived always to be susceptible to ampicillin and benzylpenicillin, but resistant strains are now common. Resistance is less prevalent among the most common species, Enterococcus faecalis, in which β-lactamase has been reported at a low frequency. In Enterococcus faecium, the next most common enterococcal species, high-level penicillin resistance due to modified PBPs is usual.

Natural penicillins remain the drugs of choice for a variety of bacteria, including group A beta-hemolytic streptococci, many grampositive anaerobes, spirochetes, gram-negative aerobic cocci, and some gram-negative aerobic bacilli. Generally, if a bacteria remains susceptible to a natural penicillin, either penicillin G or V is preferred for treating that infection as long as adequate penetration of the drug to the site of the infection occurs and the patient is not hypersensitive to penicillins.

Penicillins have been used for a wide range of infections in various species. See the dosage section for more information.

Penicillins have been used for a wide range of infections in various species. FDA-approved indications/species, as well as non-approved uses, are listed in the Uses/Indications and Dosage section for each drug.