The penicillins are derived from molds of the genus Penicillium ( eg, Penicillium notatum). The most widely used natural penicillin is penicillin G. From fermentation brews of Penicillium, 6-aminopenicillanic acid has been isolated on a large scale. This makes it possible to synthesize an almost unlimited variety of penicillin compounds by coupling the free amino group of the penicillanic acid to free carboxyl groups of different radicals.

All penicillins share the same basic structure (see 6-aminopenicillanic acid in Figure 1). A thiazolidine ring is attached to a β-lactam ring that carries a free amino group. The acidic radicals attached to the amino group can be split off by bacterial and other amidases. The structural integrity of the 6-aminopenicillanic acid nucleus is essential to the biologic activity of the compounds. If the β-lactam ring is enzymatically cleaved by β-lactamases (penicillinases), the resulting product, penicilloic acid, is devoid of antibacterial activity. However, it carries an antigenic determinant of the penicillins and acts as a sensitizing hapten when attached to carrier proteins.

Fig1. Structures of some penicillins. R, side chain.

The different-side chains attached to the aminopenicillanic acid determine the essential pharmacologic properties of the resulting drugs. The clinically important penicillins fall into five principal groups: (1) highest activity against Gram-positive organisms, spirochetes, and some others, natural penicillins are susceptible to hydrolysis by β-lactamases and are acid labile (eg, penicillin G); (2) relative resistance to β-lactamases but lower activity against Gram-positive organisms and inactivity against Gram-negative organisms (eg, nafcillin, methicillin, and oxacillin); (3) aminopenicillins have relatively high activity against both Gram-positive and Gram-negative organisms but are destroyed by β-lactamases (eg, ampicillin and amoxicillin); (4) ureidopenicillins possess activity against Pseudomonas species and other resistant Gram-negative rods (piperacillin); and (5) carboxypenicillins, which are no longer available in the United States (eg, car benicillin and ticarcillin). Most penicillins are dispensed as sodium or potassium salts of the free acid. Potassium penicillin G contains about 1.7 mEq of K+ per million units (2.8 mEq/g). Procaine salts and benzathine salts of penicillin provide repository forms for intramuscular injection. In dry form, penicillins are stable, but solutions rapidly lose their activity and must be prepared fresh for administration.

Antimicrobial Activity

 The initial step in penicillin action is binding of the drug to cell receptors. These receptors are PBPs, at least some of which are enzymes involved in transpeptidation reactions. From three to six (or more) PBPs per cell can be present. After penicillin molecules have attached to the receptors, peptidoglycan syn thesis is inhibited as final transpeptidation is blocked. A final bactericidal event is the removal or inactivation of an inhibitor of autolytic enzymes in the cell wall. This activates the auto lytic enzymes and results in cell lysis. Organisms with defective autolysin function are inhibited but not killed by β-lactam drugs, and they are said to be “tolerant.”

Because active cell wall synthesis is required for penicillin action, metabolically inactive microorganisms are not susceptible.

Penicillin G and penicillin V are often measured in units (1 million units = 0.6 g), but the semisynthetic penicillins are measured in grams. Whereas 0.002–1 μg/mL of penicillin G is lethal for a majority of susceptible Gram-positive organ isms, 10–100 times more is required to kill Gram-negative bacteria (except neisseriae).

Resistance

 Resistance to penicillins falls into several categories:

1. Production of β-lactamases by staphylococci, Gram-negative bacteria, Haemophilus sp., gonococci, and others. More than 50 different β-lactamases are known, most of them produced under the control of bacterial plasmids. Some β-lactamases are inducible by the newer cephalosporins.

 2. Lack of PBPs or altered PBPs (eg, pneumococci and enterococci) or inaccessibility of PBPs because of permeability barriers of bacterial outer membranes (more common in Gram-negative bacteria). These are often under chromosomal control.

 3. Efflux of drug out of the cell. Genes that encode these pumps are common in Gram-negative bacteria (eg, OprD in P. aeruginosa).

4. Failure to synthesize peptidoglycans, such as in mycoplasmas, L forms, or metabolically inactive bacteria.

 Absorption, Distribution, and Excretion

After intramuscular or intravenous administration, absorption of most penicillins is rapid and complete. After oral administration, absorption is variable and ranges from 15% to 80% depending on acid stability, binding to foods, presence of buffers, and so on. Amoxicillin is well absorbed. After absorption, penicillins are widely distributed in tissues and body fluids.

Special dosage forms have been designed for delayed absorption to yield drug levels for long periods. After a single intramuscular dose of benzathine penicillin, 1.5 g (2.4 million units), serum levels of 0.03 unit/mL are maintained for 10 days and levels of 0.005 unit/mL for 3 weeks. Procaine penicillin given intramuscularly yields therapeutic levels for 24 hours.

In many tissues, penicillin concentrations are simi lar to those in serum. Lower levels occur in the eyes, the prostate, and the CNS. However, in meningitis, penetration is enhanced, and levels of 0.5–5 μg/mL occur in the cerebrospinal fluid (CSF) with a daily parenteral dose of 12 g.

Most of the penicillins are rapidly excreted by the kidneys. About 10% of renal excretion is by glomerular filtration and 90% by tubular secretion. The latter can be partially blocked by probenecid to achieve higher systemic and CSF levels. In newborns and in persons with renal failure, penicillin excretion is reduced and systemic levels remain elevated longer. Some penicillins (eg, nafcillin) are eliminated mainly by nonrenal mechanisms.

Clinical Uses

Penicillins are the most widely used antibiotics, particularly in the following areas.

Penicillin G is the drug of choice in most infections caused by streptococci, susceptible pneumococci, meningococci, spirochetes, clostridia, aerobic Gram-positive rods, non penicillinase-producing staphylococci, and actinomycetes.

Penicillin G is inhibitory for enterococci (E. faecalis), but for bactericidal effects (eg, in enterococcal endocarditis), an aminoglycoside must be added. Penicillin G in ordinary doses is excreted into the urine in sufficiently high concentrations to inhibit some Gram-negative organisms unless they produce a large amount of β-lactamases.

Benzathine penicillin G is a salt of very low solubility given intramuscularly for low but prolonged drug levels. A single injection of 1.2 million units (0.7 g) is satisfactory treatment for group A streptococcal pharyngitis and primary syphilis. The same injection once every 3–4 weeks is satisfactory prophylaxis against group A streptococcal reinfection in patients with rheumatic fever.

Infection with β-lactamase-producing staphylococci is the only indication for the use of penicillinase-resistant penicillins (eg, nafcillin and oxacillin). Cloxacillin or dicloxacillin by mouth can be given for milder staphylococcal infections. Staphylococci resistant to oxacillin and nafcillin have the mecA gene and make a low-affinity penicillin-binding protein, 2a.

Oral amoxicillin is better absorbed than ampicillin and yields higher levels. Amoxicillin given together with clavulanic acid is active against β-lactamase-producing H. influenzae. Piperacillin is more effective against aerobic Gram-negative rods, especially pseudomonads. Piperacillin combined with the β-lactamase inhibitor tazobactam has increased activity against some β-lactamase-producing Gram-negative rods. The piperacillin–tazobactam combination, however, is no more active against P. aeruginosa than piperacillin alone.

Side Effects

Penicillins possess less direct toxicity than most of the other antimicrobial drugs. Most serious side effects are caused by hypersensitivity.

All penicillins are cross-sensitizing and cross-reacting. Any material (including milk or cosmetics) containing penicillin may induce sensitization. The responsible antigens are degradation products (eg, penicilloic acid) bound to host protein. Skin tests with penicilloyl-polylysine, with alkaline hydrolysis products, and with undegraded penicillin identify many hypersensitive persons. Among positive reactors to skin tests, the incidence of major immediate allergic reactions is high. Such reactions are associated with cell-bound immunoglobulin E (IgE) antibodies. IgG antibodies to penicillin are common and are not associated with allergic reactions other than rare cases of hemolytic anemia. A history of a penicillin reaction in the past is not reliable, but the drug must be administered with caution to such persons, or a substitute drug should be chosen.

Allergic reactions may occur as typical anaphylactic shock; typical serum sickness-type reactions (urticaria, joint swelling, angioneurotic edema, pruritus, respiratory embarrassment within 7–12 days of penicillin dosage); and as a variety of skin rashes, fever, nephritis, eosinophilia, vasculitis, and so on. The incidence of hypersensitivity to penicillin is negligible in children but may be 1–5% among adults in the United States. Acute anaphylactic life-threatening reactions are very rare (0.5%). Corticosteroids can sometimes suppress allergic manifestations to penicillins.

Very high doses may produce CNS concentrations that are irritating. In patients with renal failure, smaller doses may produce encephalopathy, delirium, and seizures. With such doses, direct cation toxicity (K+) may also occur. Nafcillin occasionally causes granulocytopenia. Oral penicillins can cause diarrhea. High doses of penicillins may cause a bleeding tendency. Some penicillins have become obsolete because of their enhanced toxicities. Methicillin too frequently causes interstitial nephritis. Carbenicillin too frequently decreases normal platelet aggregation, which can lead to clinically significant bleeding.

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