Beta Lactam Compounds: Penicillins

BETA LACTAM COMPOUNDS

PENICILLINS

The penicillins share features of chemistry, mechanism of action, pharmacology, and immunologic characteristics with cephalosporins, monobactams, carbapenems, and β-lactamase inhibitors. All are β-lactam compounds, so named because of their four-memberedlactam ring.

Chemistry

All penicillins have the basic structure shown in Figure 43–1. A thiazolidine ring (A) is attached to a β-lactam ring (B) that carries a secondary amino group (RNH–). Substituents (R; examples shown in Figure 43–2) can be attached to the amino group. Structural integrity of the 6-aminopenicillanic acid nucleus (rings A plus B) is essential for the biologic activity of these compounds.Hydrolysis of the β-lactam ring by bacterial β-lactamases yields penicilloic acid, which lacks antibacterial activity.

A. Classification

Substituents of the 6-aminopenicillanic acid moiety determine the essential pharmacologic and antibacterial properties of the result-ing molecules. Penicillins can be assigned to one of three groups (below). Within each of these groups are compounds that are rela-tively stable to gastric acid and suitable for oral administration, eg, penicillin V, dicloxacillin, and amoxicillin. The side chains of some representatives of each group are shown in Figure 43–2, with a few distinguishing characteristics.

1. Penicillins (eg, penicillin G)—These have greatest activityagainst gram-positive organisms, gram-negative cocci, and non-β-lactamase producing anaerobes. However, they have little activ-ity against gram-negative rods, and they are susceptible to hydrolysis by β-lactamases.

2. Antistaphylococcal penicillins (eg, nafcillin)—Thesepenicillins are resistant to staphylococcal β-lactamases. They are active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and gram-negative cocci and rods.

3. Extended-spectrum penicillins (ampicillin and the antipseudomonal penicillins)— These drugs retain the anti-bacterial spectrum of penicillin and have improved activity againstgram-negative organisms. Like penicillin, however, they are rela-tively susceptible to hydrolysis by β-lactamases.

B. Penicillin Units and Formulations

The activity of penicillin G was originally defined in units. Crystalline sodium penicillin G contains approximately 1600 units per mg (1 unit = 0.6 mcg; 1 million units of penicillin = 0.6 g). 

Semisynthetic penicillins are prescribed by weight rather than units. The minimum inhibitory concentration (MIC) of any penicillin (or other antimicrobial) is usually given in mcg/mL. Most penicillins are formulated as the sodium or potassium salt of the free acid. Potassium penicillin G contains about 1.7 mEq of K⁺ per million units of penicillin (2.8 mEq/g). Nafcillin contains Na⁺, 2.8 mEq/g. Procaine salts and benzathine salts of penicillin G provide repository forms for intramuscular injection. In dry crystalline form, penicillin salts are stable for years at 4°C. Solutions lose their activity rapidly (eg, 24 hours at 20°C) and must be prepared fresh for administration.

Mechanism of Action

Penicillins, like all β-lactam antibiotics, inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cellwall synthesis. The cell wall is a rigid outer layer unique to bacte-rial species. It completely surrounds the cytoplasmic membrane (Figure 43–3), maintains cell shape and integrity, and prevents cell lysis from high osmotic pressure. The cell wall is composed of complex, cross-linked polymer of polysaccharides and polypeptides, peptidoglycan (also known as murein or mucopep-tide). The polysaccharide contains alternating amino sugars,

N-acetylglucosamine and N-acetylmuramic acid (Figure 43–4). Afive-amino-acid peptide is linked to the N-acetylmuramic acid sugar. This peptide terminates in D-alanyl-D-alanine. Penicillin-binding protein (PBP, an enzyme) removes the terminal alanine in the process of forming a cross-link with a nearby peptide. Cross-links give the cell wall its structural rigidity. Beta-lactam antibiot-ics, structural analogs of the natural D-Ala-D-Ala substrate, covalently bind to the active site of PBPs. This inhibits the trans-peptidation reaction (Figure 43–5), halting peptidoglycan synthe-sis, and the cell dies. The exact mechanism of cell death is not completely understood, but autolysins and disruption of cell wall morphogenesis are involved. Beta-lactam antibiotics kill bacterial cells only when they are actively growing and synthesizing cell wall.

Resistance

Resistance to penicillins and other β-lactams is due to one of four general mechanisms: (1) inactivation of antibiotic by β-lactamase,modification of target PBPs, (3) impaired penetration of drug to target PBPs, and (4) efflux. Beta-lactamase production is the most common mechanism of resistance. Hundreds of different β-lactamases have been identified. Some, such as those produced by Staphylococcus aureus, Haemophilus influenzae, and Escherichia coli, are relatively narrow in substrate specificity, preferring penicillins to cephalosporins. 

Other β-lactamases, eg, AmpC β-lactamase pro-duced by Pseudomonas aeruginosa and Enterobacter sp, and extended-spectrum β-lactamases (ESBLs), hydrolyze both cephalosporins and penicillins. Carbapenems are highly resistant to hydrolysis by peni-cillinases and cephalosporinases, but they are hydrolyzed by metallo-β lactamase and carbapenemases.

Altered target PBPs are the basis of methicillin resistance in staphylococci and of penicillin resistance in pneumococci and enterococci. These resistant organisms produce PBPs that have low affinity for binding β-lactam antibiotics, and consequently, they are not inhibited except at relatively high, often clinically unachievable, drug concentrations.

Resistance due to impaired penetration of antibiotic to target PBPs occurs only in gram-negative species because of their imper-meable outer cell wall membrane, which is absent in gram-positive bacteria. Beta-lactam antibiotics cross the outer membrane and enter gram-negative organisms via outer membrane protein channels called porins. Absence of the proper channel or down-regulation of its production can greatly impair drug entry into the cell. Poor penetration alone is usually not sufficient to confer resistance because enough antibiotic eventually enters the cell to inhibit growth. However, this barrier can become important in the presence of a β-lactamase, even a relatively inactive one, as long as it can hydrolyze drug faster than it enters the cell. Gram-negative organisms also may produce an efflux pump, which consists of cytoplasmic and periplasmic protein components that efficiently transport some β-lactam antibiotics from the periplasm back across the outer membrane.

Pharmacokinetics

Absorption of orally administered drug differs greatly for different penicillins, depending in part on their acid stability and protein binding. Gastrointestinal absorption of nafcillin is erratic, so it is not suitable for oral administration. Dicloxacillin, ampicillin, and amoxicillin are acid-stable and relatively well absorbed, producing serum concentrations in the range of 4–8 mcg/mL after a 500-mg oral dose. Absorption of most oral penicillins (amoxicillin being an exception) is impaired by food, and the drugs should be admin-istered at least 1–2 hours before or after a meal.

Intravenous administration of penicillin G is preferred to the intramuscular route because of irritation and local pain from intra-muscular injection of large doses. Serum concentrations 30 minutes after an intravenous injection of 1 g of a penicillin (equivalent to approximately 1.6 million units of penicillin G) are 20–50 mcg/ mL. Only a small amount of the total drug in serum is present as free drug, the concentration of which is determined by protein binding. Highly protein-bound penicillins (eg, nafcillin) generally achieve lower free-drug concentrations in serum than less protein-bound penicillins (eg, penicillin G or ampicillin). Protein binding becomes clinically relevant when the protein-bound percentage is approximately 95% or more. Penicillins are widely distributed in body fluids and tissues with a few exceptions. They are polar mol-ecules, so intracellular concentrations are well below those found in extracellular fluids.

Benzathine and procaine penicillins are formulated to delay absorption, resulting in prolonged blood and tissue concentra-tions. A single intramuscular injection of 1.2 million units of benzathine penicillin maintains serum levels above 0.02 mcg/mL for 10 days, sufficient to treat β-hemolytic streptococcal infection. After 3 weeks, levels still exceed 0.003 mcg/mL, which is enough to prevent β-hemolytic streptococcal infection. A 600,000 unit dose of procaine penicillin yields peak concentrations of 1–2 mcg/ mL and clinically useful concentrations for 12–24 hours after a single intramuscular injection.

Penicillin concentrations in most tissues are equal to those in serum. Penicillin is also excreted into sputum and milk to levels 3–15% of those in the serum. Penetration into the eye, the prostate, and the central nervous system is poor. However, with active inflammation of the meninges, as in bacterial meningitis, penicillin concentrations of 1–5 mcg/mL can be achieved with a daily par-enteral dose of 18–24 million units. These concentrationsare sufficient to kill susceptible strains of pneumococci and meningococci.

Penicillin is rapidly excreted by the kidneys; small amounts are excreted by other routes. About 10% of renal excretion is by glomerular filtration and 90% by tubular secretion. The normal half-life of penicillin G is approximately 30 minutes; in renal failure, it may be as long as 10 hours. Ampicillin and the extended-spectrum penicillins are secreted more slowly than penicillin G and have half-lives of 1 hour. For penicillins that are cleared by the kidney, the dose must be adjusted according to renal function, with approximately one fourth to one third the normal dose being administered if creatinine clearance is 10 mL/min or less (Table 43–1).

Nafcillin is primarily cleared by biliary excretion. Oxacillin, dicloxacillin, and cloxacillin are eliminated by both the kidney and biliary excretion; no dosage adjustment is required for these drugs in renal failure. Because clearance of penicillins is less efficient in the newborn, doses adjusted for weight alone result in higher sys-temic concentrations for longer periods than in the adult.

Clinical Uses

Except for oral amoxicillin, penicillins should be given 1–2 hours before or after a meal; they should not be given with food to minimize binding to food proteins and acid inactivation. Blood levels of all penicillins can be raised by simultaneous administra-tion of probenecid, 0.5 g (10 mg/kg in children) every 6 hours orally, which impairs renal tubular secretion of weak acids such as β-lactam compounds. Penicillins should never be used for viralinfections and should be prescribed only when there is reasonable suspicion of, or documented infection with, susceptible organisms.

A. Penicillin

Penicillin G is a drug of choice for infections caused by streptococci, meningococci, some enterococci, penicillin-susceptible pneumo-cocci, non-β-lactamase-producing staphylococci, Treponemapallidum and certain other spirochetes, Clostridium species,

Actinomyces and certain other gram-positive rods, and non-β-lactamase-producing gram-negative anaerobic organisms. Depend-ing on the organism, the site, and the severity of infection, effective doses range between 4 and 24 million units per day administered intravenously in four to six divided doses. High-dose penicillin G can also be given as a continuous intravenous infusion.

Penicillin V, the oral form of penicillin, is indicated only in minor infections because of its relatively poor bioavailability, the need for dosing four times a day, and its narrow antibacterial spectrum. Amoxicillin  is often used instead.

Benzathine penicillin and procaine penicillin G for intramus-cular injection yield low but prolonged drug levels. A single intra-muscular injection of benzathine penicillin, 1.2 million units, is effective treatment for β-hemolytic streptococcal pharyngitis; given intramuscularly once every 3–4 weeks, it prevents reinfec-tion. Benzathine penicillin G, 2.4 million units intramuscularly once a week for 1–3 weeks, is effective in the treatment of syphilis. Procaine penicillin G, formerly a work horse for treating uncom-plicated pneumococcal pneumonia or gonorrhea, is rarely used now because many strains are penicillin-resistant.

B. Penicillins Resistant to Staphylococcal Beta Lactamase (Methicillin, Nafcillin, and Isoxazolyl Penicillins)

These semisynthetic penicillins are indicated for infection by β-lactamase-producing staphylococci, although penicillin-susceptible strains of streptococci and pneumococci are also suscep-tible to these agents. Listeria monocytogenes, enterococci, and methicillin-resistant strains of staphylococci are resistant. In recent years the empirical use of these drugs has decreased substantially because of increasing rates of methicillin-resistance in staphylo-cocci. However, for infections caused by methicillin-susceptible and penicillin-resistant strains of staphylococci, these are consid-ered the drugs of choice.

An isoxazolyl penicillin such as oxacillin, cloxacillin, or dicloxacil-lin, 0.25–0.5 g orally every 4–6 hours (15–25 mg/kg/d for children), is suitable for treatment of mild to moderate localized staphylococcal infections. All are relatively acid-stable and have reasonable bioavail-ability. However, food interferes with absorption, and the drugs should be administered 1 hour before or after meals.

For serious systemic staphylococcal infections, oxacillin or nafcillin, 8–12 g/d, is given by intermittent intravenous infusion of 1–2 g every 4–6 hours (50–100 mg/kg/d for children).

C. Extended-Spectrum Penicillins (Aminopenicillins, Carboxypenicillins, and Ureidopenicillins)

These drugs have greater activity than penicillin against gram-negative bacteria because of their enhanced ability to penetrate the gram-negative outer membrane. Like penicillin G, they are inacti-vated by many β lactamases.

The aminopenicillins, ampicillin and amoxicillin, have nearly identical spectrums of actiity, but amoxicillin is better absorbed orally. Amoxicillin, 250–500 mg three times daily, is equivalent to the same amount of ampicillin given four times daily. Amoxacillin is given orally to treat urinary tract infections, sinusitis, otitis, and lower respiratory tract infections. Ampicillin and amoxicillin are the most active of the oral β-lactam antibiotics against pneumo-cocci with elevated MICs to penicillin and are the preferred β-lactam antibiotics for treating infections suspected to be causedby these strains. Ampicillin (but not amoxicillin) is effective for shigellosis. Its use to treat uncomplicated salmonella gastroenteritis is controversial because it may prolong the carrier state.

Ampicillin, at dosages of 4–12 g/d intravenously, is useful for treating serious infections caused by susceptible organisms, includ-ing anaerobes, enterococci, L monocytogenes, and β-lactamase-negative strains of gram-negative cocci and bacilli such as E coli, and Salmonella sp. Non-β-lactamase producing strains of H influenzae are generally susceptible, but strains that are resistant because of altered PBPs are emerging. Many gram-negative species produce β lactamases and are resistant, precluding use of ampicillin for empir-ical therapy of urinary tract infections, meningitis, and typhoid fever. Ampicillin is not active against Klebsiella sp, Enterobacter sp, P aeruginosa, Citrobacter sp, Serratia marcescens, indole-posi-tive proteus species, and other gram-negative aerobes that are commonly encountered in hospital-acquired infections. These organisms produce β lactamase that inactivates ampicillin.

Carbenicillin, the first antipseudomonal carboxypenicillin, is no longer used in the USA, as there are more active, better toler-ated alternatives. A carboxypenicillin with activity similar to that of carbenicillin is ticarcillin. It is less active than ampicillin against enterococci. The ureidopenicillins, piperacillin, mezlocillin, and azlocillin, are also active against selected gram-negative bacilli, such as Klebsiella pneumoniae. Although supportive clinical data are lacking for superiority of combination therapy over single-drug therapy, because of the propensity of P aeruginosa to develop resistance during treatment, an antipseudomonal penicillin is fre-quently used in combination with an aminoglycoside or fluoro-quinolone for pseudomonal infections outside the urinary tract.

Ampicillin, amoxicillin, ticarcillin, and piperacillin are also available in combination with one of several β-lactamase inhib-itors: clavulanic acid, sulbactam, or tazobactam. The addition of a β-lactamase inhibitor extends the activity of these penicil-lins to include β-lactamase-producing strains of S aureus as well as some β-lactamase-producing gram-negative bacteria (see Beta-Lactamase Inhibitors).

Adverse Reactions

The penicillins are generally well tolerated, and unfortunately, this encourages their misuse and inappropriate use. Most of the serious adverse effects are due to hypersensitivity. All penicillins are cross-sensitizing and cross-reacting. The antigenic determinants are degradation products of penicillins, particularly penicilloic acid and products of alkaline hydrolysis bound to host protein. A his-tory of a penicillin reaction is not reliable; about 5–8% of people claim such a history, but only a small number of these will have an allergic reaction when given penicillin. Less than 1% of persons who previously received penicillin without incident will have an allergic reaction when given penicillin. Because of the potential for anaphylaxis, however, penicillin should be administered with cau-tion or a substitute drug given if the person has a history of serious penicillin allergy. The incidence of allergic reactions in young children is negligible.

Allergic reactions include anaphylactic shock (very rare—0.05% of recipients); serum sickness-type reactions (now rare—urticaria, fever, joint swelling, angioneurotic edema, intense pruritus, and respiratory compromise occurring 7–12 days after exposure); and a variety of skin rashes. Oral lesions, fever, interstitial nephritis (an autoimmune reaction to a penicillin-protein complex), eosino-philia, hemolytic anemia and other hematologic disturbances, and vasculitis may also occur. Most patients allergic to penicillins can be treated with alternative drugs. However, if necessary (eg, treat-ment of enterococcal endocarditis or neurosyphilis in a patient with serious penicillin allergy), desensitization can be accomplished with gradually increasing doses of penicillin.

In patients with renal failure, penicillin in high doses can cause seizures. Nafcillin is associated with neutropenia; oxacillin can cause hepatitis; and methicillin causes interstitial nephritis (and is no longer used for this reason). Large doses of penicillins given orally may lead to gastrointestinal upset, particularly nausea, vomiting, and diarrhea. Ampicillin has been associated with pseudomembranous colitis. Secondary infections such as vaginal candidiasis may occur. Ampicillin and amoxicillin can cause skin rashes that are not allergic in nature. These rashes frequently occur when aminopenicillins are inappropriately prescribed for a viral illness.