Chapter 53: Penicillins, Cephalosporins, and Other β-Lactam Antibiotics

History. The history of the brilliant research that led to the discovery and development of penicillin is well chronicled. In 1928, while studying Staphylococcus variants in the laboratory at St. Mary's Hospital in London, Alexander Fleming observed that a mold contaminating one of his cultures caused the bacteria in its vicinity to undergo lysis. Broth in which the fungus was grown was markedly inhibitory for many microorganisms. Because the mold belonged to the genus Penicillium, Fleming named the antibacterial substance penicillin.

A decade later, penicillin was developed as a systemic therapeutic agent by the concerted research of a group of investigators at Oxford University headed by Florey, Chain, and Abraham. By May 1940, a crude preparation was found to produce dramatic therapeutic effects when administered parenterally to mice with streptococcal infections. Sufficient penicillin was accumulated by 1941 to conduct therapeutic trials in several patients desperately ill with staphylococcal and streptococcal infections refractory to all other therapy. At this stage, the crude, amorphous penicillin was only ~10% pure, and it required nearly 100 L of the broth in which the mold had been grown to obtain enough of the antibiotic to treat one patient for 24 hours. Bedpans actually were used by the Oxford group for growing cultures of Penicillium notatum. Case 1 in the 1941 report from Oxford was that of a policeman who was suffering from a severe mixed staphylococcal and streptococcal infection. He was treated with penicillin, some of which had been recovered from the urine of other patients who had been given the drug. It is said that an Oxford professor referred to penicillin as a remarkable substance grown in bedpans and purified by passage through the Oxford Police Force.

A vast research program soon was initiated in the U.S. During 1942, 122 million units of penicillin were made available, and the first clinical trials were conducted at Yale University and the Mayo Clinic, with dramatic results. By the spring of 1943, 200 patients had been treated with the drug. The results were so impressive that the surgeon general of the U.S. Army authorized a trial of the antibiotic in a military hospital. Soon thereafter, penicillin was adopted throughout the medical services of the U.S. Armed Forces.

The deep-fermentation procedure for the biosynthesis of penicillin marked a crucial advance in the large-scale production of the antibiotic. From a total production of a few hundred million units a month in the early days, the quantity manufactured rose to over 200 trillion units (nearly 150 tons) by 1950. The first marketable penicillin cost several dollars per 100,000 units; today, the same dose costs only a few cents.

Chemistry. The basic structure of the penicillins, as shown in Figure 53–1, consists of a thiazolidine ring (A) connected to a β-lactam ring (B) to which is attached a side chain (R). The penicillin nucleus itself is the chief structural requirement for biological activity; metabolic transformation or chemical alteration of this portion of the molecule causes loss of all significant antibacterial activity. The side chain (Table 53–1) determines many of the antibacterial and pharmacological characteristics of a particular type of penicillin. Several natural penicillins can be produced depending on the chemical composition of the fermentation medium used to culture Penicillium. Penicillin G (benzylpenicillin) has the greatest antimicrobial activity of these and is the only natural penicillin used clinically. For penicillin G, the side chain (R in Figure 53–1) is a phenyl-methyl substituent (Table 53–1).

Semisynthetic Penicillins. The discovery that 6-aminopenicillanic acid could be obtained from cultures of P. chrysogenum that were depleted of side-chain precursors led to the development of the semisynthetic penicillins. Side chains can be added that alter the susceptibility of the resulting compounds to inactivating enzymes (β-lactamases) and that change the antibacterial activity and the pharmacological properties of the drug. 6-Aminopenicillanic acid is now produced in large quantities with the aid of an amidase from P. chrysogenum (Figure 53–1). This enzyme splits the peptide linkage by which the side chain of penicillin is joined to 6-aminopenicillanic acid. Table 53–1 shows the variety of side chains that have been added to 6-aminopenicillanic acid to produce the medicinal penicillins in current use; the table also summarizes their major therapeutic properties (e.g., absorption following oral administration, resistance to penicillinase, and antimicrobial spectrum).

Unitage of Penicillin. The international unit of penicillin is the specific penicillin activity contained in 0.6 μg of the crystalline sodium salt of penicillin G. One milligram of pure penicillin G sodium thus equals 1667 units; 1.0 mg of pure penicillin G potassium represents 1595 units. The dosage and the antibacterial potency of the semisynthetic penicillins are expressed in terms of weight.

Mechanism of Action of the Penicillins and Cephalosporins. The β-lactam antibiotics can kill susceptible bacteria. Although knowledge of the mechanism of this action is incomplete, numerous researchers have supplied information that allows understanding of the basic phenomenon (Bayles, 2000; Ghuysen, 1991).

The cell walls of bacteria are essential for their normal growth and development. Peptidoglycan is a heteropolymeric component of the cell wall that provides rigid mechanical stability by virtue of its highly cross-linked latticework structure (Figure 53–2). In gram-positive microorganisms, the cell wall is 50-100 molecules thick, but it is only 1 or 2 molecules thick in gram-negative bacteria (Figure 53–3A). The peptidoglycan is composed of glycan chains, which are linear strands of two alternating amino sugars (N-acetylglucosamine and N-acetylmuramic acid) that are cross-linked by peptide chains.

The biosynthesis of the peptidoglycan involves ~30 bacterial enzymes and may be considered in three stages. The first stage, precursor formation, takes place in the cytoplasm. The product, uridine diphosphate (UDP)–acetylmuramyl-pentapeptide, accumulates in cells when subsequent synthetic stages are inhibited. The last reaction in the synthesis of this compound is the addition of a dipeptide, D-alanyl-D-alanine. Synthesis of the dipeptide involves prior racemization of L-alanine and condensation catalyzed by D-alanyl-D-alanine synthase. D-Cycloserine is a structural analog of D-alanine and acts as a competitive inhibitor of both the racemase and the synthase (Chapter 56).

During reactions of the second stage, UDP-acetylmuramyl-pentapeptide and UDP-acetylglucosamine are linked (with the release of the uridine nucleotides) to form a long polymer. The third and final stage involves completion of the cross-link. This is accomplished by peptidoglycan glycosyltransferases outside the cell membrane of gram-positive and within the periplasmic space of gram-negative bacteria (Figure 53–3B). The terminal glycine residue of the pentaglycine bridge is linked to the fourth residue of the pentapeptide (D-alanine), releasing the fifth residue (also D-alanine) (Figure 53–2). It is this last step in peptidoglycan synthesis that is inhibited by the β-lactam antibiotics and glycopeptide antibiotics such as vancomycin (by a different mechanism than the β-lactams; Chapter 54). Stereo models reveal that the conformation of penicillin is very similar to that of D-alanyl-D-alanine. The transpeptidase probably is acylated by penicillin; i.e., penicilloyl enzyme apparently is formed, with cleavage of the —CO—N— bond of the β-lactam ring. Although the transpeptidase activity has been targeted with the β-lactams and vancomycin, the glycosyltransferase is a relatively unexplored target for antibiotics (Lovering et al., 2007).

Although inhibition of the transpeptidase just described is demonstrably important, there are additional, related targets for the actions of penicillins and cephalosporins; these are collectively termed penicillin-binding proteins (PBPs). All bacteria have several such entities; e.g., S. aureus has four PBPs, whereas Escherichia coli has at least seven. The PBPs vary in their affinities for different β-lactam antibiotics, although the interactions eventually become covalent. The higher molecular weight PBPs of E. coli (PBPs 1a and 1b) include the transpeptidases responsible for synthesis of the peptidoglycan. Other PBPs in E. coli include those that are necessary for maintenance of the rod-like shape of the bacterium and for septum formation at division. Inhibition of the transpeptidases causes spheroplast formation and rapid lysis. However, inhibition of the activities of other PBPs may cause delayed lysis (PBP 2) or the production of long filamentous forms of the bacterium (PBP 3). The lethality of penicillin for bacteria appears to involve both lytic and nonlytic mechanisms. Penicillin's disruption of the balance between PBP-mediated peptidoglycan assembly and murein hydrolase activity results in autolysis. Non-lytic killing by penicillin may involve holin-like proteins in the bacterial membrane that collapse the membrane potential (Bayles, 2000).

Mechanisms of Bacterial Resistance to Penicillins and Cephalosporins. Although all bacteria with cell walls contain PBPs, β-lactam antibiotics cannot kill or even inhibit all bacteria because bacteria can be resistant to these agents by myriad mechanisms. The microorganism may be intrinsically resistant because of structural differences in the PBPs that are the targets of these drugs. Furthermore, a sensitive strain may acquire resistance of this type by the development of high-molecular-weight PBPs that have decreased affinity for the antibiotic. Because the β-lactam antibiotics inhibit many different PBPs in a single bacterium, the affinity for β-lactam antibiotics of several PBPs must decrease for the organism to be resistant. Altered PBPs with decreased affinity for β-lactam antibiotics are acquired by homologous recombination between PBP genes of different bacterial species. Four of the five high-molecular-weight PBPs of the most highly penicillin-resistant Streptococcus pneumoniae isolates have decreased affinity for β-lactam antibiotics as a result of interspecies homologous recombination events (Figure 53–4). In contrast, isolates with high-level resistance to third-generation cephalosporins contain alterations of only two of the five high-molecular-weight PBPs because the other PBPs have inherently low affinity for the third-generation cephalosporins. Penicillin resistance in Streptococcus sanguis and other viridans streptococci apparently emerged as a result of replacement of its PBPs with resistant PBPs from S. pneumoniae (Carratalá et al., 1995; Spratt, 1994). Methicillin-resistant S. aureus are resistant via acquisition of an additional high-molecular-weight PBP (via a transposon from an unknown organism) with a very low affinity for all β-lactam antibiotics. The gene (MecA) encoding this new PBP also is present in and responsible for methicillin resistance in the coagulase-negative staphylococci (Moran et al., 2006).

Other instances of bacterial resistance to the β-lactam antibiotics are caused by the inability of the agent to penetrate to its site of action (Jacoby and Munoz-Price, 2005) (Figure 53–5). In gram-positive bacteria, the peptidoglycan polymer is very near the cell surface (Figure 53–3). Some gram-positive bacteria have polysaccharide capsules that are external to the cell wall, but these structures are not a barrier to the diffusion of the β-lactams; the small β-lactam antibiotic molecules can penetrate easily to the outer layer of the cytoplasmic membrane and the PBPs, where the final stages of the synthesis of the peptidoglycan take place. The situation is different with gram-negative bacteria. Their surface structure is more complex, and their inner membrane, which is analogous to the cytoplasmic membrane of gram-positive bacteria, is covered by the outer membrane, lipopolysaccharide, and capsule (Figure 53–3). The outer membrane functions as an impenetrable barrier for some antibiotics (Nakae, 1986). Some small hydrophilic antibiotics, however, diffuse through aqueous channels in the outer membrane that are formed by proteins called porins. Broader-spectrum penicillins, such as ampicillin and amoxicillin, and most of the cephalosporins diffuse through the pores in the E. coli outer membrane significantly more rapidly than can penicillin G. The number and size of pores in the outer membrane vary among different gram-negative bacteria. An extreme example is P. aeruginosa, which is intrinsically resistant to a wide variety of antibiotics because it lacks the classical high-permeability porins (Nikaido, 1994). Active efflux pumps serve as another mechanism of resistance, removing the antibiotic from its site of action before it can act (Nikaido, 1998) (Figure 53–5). This is an important mechanism of β-lactam resistance in P. aeruginosa, E. coli, and Neisseria gonorrhoeae.

Bacteria also can destroy β-lactam antibiotics enzymatically. β-Lactamases are capable of inactivating certain of these antibiotics and may be present in large quantities (Figures 53–1 and 53–3). Different microorganisms elaborate a number of distinct β-lactamases, although most bacteria produce only one form of the enzyme. The substrate specificities of some of these enzymes are relatively narrow, and these often are described as either penicillinases or cephalosporinases. Other "extended-spectrum" enzymes are less discriminant and can hydrolyze a variety of β-lactam antibiotics. β-Lactamases are grouped into four classes: A through D. Class A β-lactamases include the extended-spectrum β-lactamases (ESBLs) that degrade penicillins, some cephalosporins, and, in some instances, carbapenems. Perhaps most worrisome of the class A enzymes is the KPC carbapenemase that is rapidly emerging in the Enterobacteriaceae. This enzyme confers resistance to carbapenems, penicillins, and all of the extended-spectrum cephalosporins (Jones et al., 2008). Some class A and D enzymes are inhibited by the commercially available β-lactamase inhibitors, such as clavulanate and tazobactam. Class B β-lactamases are Zn²⁺-dependent enzymes that destroy all β-lactams except aztreonam, whereas class C β-lactamases are active against cephalosporins. Class D includes cloxacillin-degrading enzymes (Bush, 2001; Jacoby and Munoz-Price, 2005; Walsh, 2008).

In general, gram-positive bacteria produce and secrete a large amount of β-lactamase (Figure 53–3A). Most of these enzymes are penicillinases. The information for staphylococcal penicillinase is encoded in a plasmid, and this may be transferred by bacteriophage to other bacteria. The enzyme is inducible by substrates, and 1% of the dry weight of the bacterium can be penicillinase. In gram-negative bacteria, β-lactamases are found in relatively small amounts but are located in the periplasmic space between the inner and outer cell membranes (Figure 53–3A). Because the enzymes of cell wall synthesis are on the outer surface of the inner membrane, these β-lactamases are strategically located for maximal protection of the microbe. β-Lactamases of gram-negative bacteria are encoded either in chromosomes or in plasmids, and they may be constitutive or inducible. The plasmids can be transferred between bacteria by conjugation. These enzymes can hydrolyze penicillins, cephalosporins, or both (Bush, 2001; Jacoby and Munoz-Price, 2005; Walsh, 2008). However, there is an inconsistent correlation between the susceptibility of an antibiotic to inactivation by β-lactamase and the ability of that antibiotic to kill the microorganism.

Other Factors That Influence the Activity of β-Lactam Antibiotics. Microorganisms adhering to implanted prosthetic devices (e.g., catheters, artificial joints, prosthetic heart valves, etc.) produce biofilms. Bacteria in biofilms produce extracellular polysaccharides and, in part owing to decreased growth rates, are much less sensitive to antibiotic therapy (Donlan, 2001). The density of the bacterial population and the age of an infection influence the activity of β-lactam antibiotics. The drugs may be several thousand times more potent when tested against small bacterial inocula than when tested against a dense culture. Many factors are involved. Among these are the greater number of relatively resistant microorganisms in a large population, the amount of β-lactamase produced, and the phase of growth of the culture. The clinical significance of this effect of inoculum size is uncertain. The intensity and duration of penicillin therapy needed to abort or cure experimental infections in animals increase with the duration of the infection. The primary reason is that the bacteria are no longer multiplying as rapidly as they do in a fresh infection. These antibiotics are most active against bacteria in the logarithmic phase of growth and have little effect on microorganisms in the stationary phase, when there is no need to synthesize components of the cell wall.

The presence of proteins or other constituents of pus, low pH, or low O₂ tension does not appreciably decrease the ability of β-lactam antibiotics to kill bacteria. However, bacteria that survive inside viable cells of the host generally are protected from the action of the β-lactam antibiotics.

Whereas most strains of S. aureus were highly sensitive to penicillin G when this agent was first employed therapeutically, >90% of strains of staphylococci isolated from individuals inside or outside of hospitals are now resistant to penicillin G (and nearly half are methicillin-resistant). Most strains of S. epidermidis also are resistant to penicillin. Unfortunately, penicillinase-producing strains of gonococci that are highly resistant to penicillin G have become widespread. With rare exceptions, meningococci are quite sensitive to penicillin G.

Although the vast majority of strains of Corynebacterium diphtheriae are sensitive to penicillin G, some are highly resistant. The presence of chromosomally encoded β-lactamase in Bacillus anthracis is the reason that penicillin was not used for prophylaxis of anthrax exposure, although most isolates are susceptible. Most anaerobic microorganisms, including Clostridium spp., are highly sensitive. Bacteroides fragilis is an exception, displaying resistance to penicillins and cephalosporins by virtue of expressing a broad-spectrum cephalosporinase. Some strains of Prevotella melaninogenicus also have acquired this trait. Actinomyces israelii, Streptobacillus moniliformis, Pasteurella multocida, and L. monocytogenes are inhibited by penicillin G. Most species of Leptospira are moderately susceptible to the drug. One of the most exquisitely sensitive microorganisms is Treponema pallidum. Borrelia burgdorferi, the organism responsible for Lyme disease, also is susceptible. None of the penicillins is effective against amebae, plasmodia, rickettsiae, fungi, or viruses.

Absorption

Oral Administration of Penicillin G. About one-third of an orally administered dose of penicillin G is absorbed from the intestinal tract under favorable conditions. Gastric juice at pH 2 rapidly destroys the antibiotic. The decrease in gastric acid production with aging accounts for better absorption of penicillin G from the gastrointestinal (GI) tract of older individuals. Absorption is rapid, and maximal concentrations in blood are attained in 30-60 minutes. The peak value is ~0.5 unit/mL (0.3 μg/mL) after an oral dose of 400,000 units (~250 mg) in an adult. Ingestion of food may interfere with enteric absorption of all penicillins, perhaps by adsorption of the antibiotic onto food particles. Thus, oral penicillin G should be administered at least 30 minutes before a meal or 2 hours after. Despite the convenience of oral administration of penicillin G, this route should be used only in infections in which clinical experience has proven its efficacy.

Oral Administration of Penicillin V. The virtue of penicillin V in comparison with penicillin G is that it is more stable in an acidic medium and therefore is better absorbed from the GI tract. On an equivalent oral-dose basis, penicillin V (K⁺ salt) yields plasma concentrations two to five times greater than those provided by penicillin G. The peak concentration in the blood of an adult after an oral dose of 500 mg is nearly 3 μg/mL. Once absorbed, penicillin V is distributed in the body and excreted by the kidney in a manner similar to that of penicillin G.

Parenteral Administration of Penicillin G. After intramuscular injection, peak concentrations in plasma are reached within 15-30 minutes. This value declines rapidly because the t_1/2 of penicillin G is 30 minutes.

Many means for prolonging the sojourn of the antibiotic in the body and thereby reducing the frequency of injections have been explored. Probenecid blocks renal tubular secretion of penicillin, but it is used rarely for this purpose. More commonly, repository preparations of penicillin G are employed. The compound currently favored is penicillin G benzathine (bicillin l-a, permapen), which releases penicillin G slowly from the area in which it is injected and produces relatively low but persistent concentrations of antibiotic in the blood. Penicillin G benzathine suspension is the aqueous suspension of the salt obtained by the combination of 1 mol of an ammonium base and 2 mol of penicillin G to yield N,N′-dibenzylethylenediamine dipenicillin G. The salt itself is only 0.02% soluble in water. The long persistence of penicillin in the blood after a suitable intramuscular dose reduces cost, need for repeated injections, and local trauma. The local anesthetic effect of penicillin G benzathine is comparable with that of penicillin G procaine.

Penicillin G benzathine is absorbed very slowly from intramuscular depots and produces the longest duration of detectable antibiotic of all the available repository penicillins. For example, in adults, a dose of 1.2 million units given intramuscularly produces a concentration in plasma of 0.09 μg/mL on the first, 0.02 μg/mL on the fourteenth, and 0.002 μg/mL on the thirty-second day after injection. The average duration of demonstrable antimicrobial activity in the plasma is ~26 days. It is administered once monthly for rheumatic fever prophylaxis and can be given in a single injection to treat streptococcal pharyngitis.

Distribution. Penicillin G is distributed widely throughout the body, but the concentrations in various fluids and tissues differ widely. Its apparent volume of distribution is ~0.35 L/kg. Approximately 60% of the penicillin G in plasma is reversibly bound to albumin. Significant amounts appear in liver, bile, kidney, semen, joint fluid, lymph, and intestine.

Although probenecid markedly decreases the tubular secretion of the penicillins, this is not the only factor responsible for the elevated plasma concentrations of the antibiotic that follow its administration. Probenecid also produces a significant decrease in the apparent volume of distribution of the penicillins.

Penetration into Cerebrospinal Fluid. Penicillin does not readily enter the CSF when the meninges are normal. However, when the meninges are acutely inflamed, penicillin penetrates into the CSF more easily. Although the concentrations attained vary and are unpredictable, they are usually in the range of 5% of the value in plasma and are therapeutically effective against susceptible microorganisms.

Penicillin and other organic acids are secreted rapidly from the CSF into the bloodstream by an active transport process. Probenecid competitively inhibits this transport and thus elevates the concentration of penicillin in CSF. In uremia, other organic acids accumulate in the CSF and compete with penicillin for secretion; the drug occasionally reaches toxic concentrations in the brain and can produce convulsions.

Excretion. Under normal conditions, penicillin G is eliminated rapidly from the body mainly by the kidney but in small part in the bile and by other routes. Approximately 60-90% of an intramuscular dose of penicillin G in aqueous solution is eliminated in the urine, largely within the first hour after injection. The remainder is metabolized to penicilloic acid. The t_1/2 for elimination of penicillin G is ~30 minutes in normal adults. Approximately 10% of the drug is eliminated by glomerular filtration and 90% by tubular secretion. Renal clearance approximates the total renal plasma flow. The maximal tubular secretory capacity for penicillin in the normal adult male is ~3 million units (1.8 g) per hour.

Clearance values are considerably lower in neonates and infants because of incomplete development of renal function; as a result, after doses proportionate to surface area, the persistence of penicillin in the blood is several times as long in premature infants as in children and adults. The t_1/2 of the antibiotic in children <1 week of age is 3 hours; by 14 days of age it is 1.4 hours. After renal function is fully established in young children, the rate of renal excretion of penicillin G is considerably more rapid than in adults.

Anuria increases the t_1/2 of penicillin G from a normal value of 0.5 hour to ~10 hours. When renal function is impaired, 7-10% of the antibiotic may be inactivated each hour by the liver. Patients with renal shutdown who require high-dose therapy with penicillin can be treated adequately with 3 million units of aqueous penicillin G followed by 1.5 million units every 8-12 hours. The dose of the drug must be readjusted during dialysis and the period of progressive recovery of renal function. If, in addition to renal failure, hepatic insufficiency also is present, the t_1/2 will be prolonged even further.

Therapeutic Uses

Pneumococcal Infections. Penicillin G remains the agent of choice for the management of infections caused by sensitive strains of S. pneumoniae. However, strains of pneumococci resistant to usual doses of penicillin G are being isolated more frequently in several countries, including the U.S. (Fiore et al., 2000).

Pneumococcal Pneumonia. Until it is highly likely or established that the infecting isolate of pneumococcus is penicillin-sensitive, pneumococcal pneumonia should be treated with a third-generation cephalosporin or with 20-24 million units of penicillin G daily by constant intravenous infusion. If the organism is sensitive to penicillin, then the dose can be reduced (Medical Letter, 2007). For parenteral therapy of sensitive isolates of pneumococci, penicillin G is favored. Although oral treatment with 500 mg penicillin V given every 6 hours for treatment of pneumonia owing to penicillin-sensitive isolates has been used with success in this disease, it cannot be recommended for routine initial use because of the existence of resistance. Therapy should be continued for 7-10 days, including 3-5 days after the patient's temperature has returned to normal.

Pneumococcal Meningitis. Until it is established that the infecting pneumococcus is sensitive to penicillin, pneumococcal meningitis should be treated with a combination of vancomycin and a third-generation cephalosporin (Catalan et al., 1994; John, 1994). Dexamethasone given at the same time as antibiotics was associated with an improved outcome (de Gans and van de Beek, 2002). Prior to the appearance of penicillin resistance, penicillin treatment reduced the death rate in this disease from nearly 100% to ~25%. The recommended therapy is 20-24 million units of penicillin G daily by constant intravenous infusion or divided into boluses given every 2-3 hours. The usual duration of therapy is 14 days.

Streptococcal Infections. Streptococcal Pharyngitis (Including Scarlet Fever). This is the most common disease produced by S. pyogenes (group A β-hemolytic streptococcus). Penicillin-resistant isolates have yet to be observed for S. pyogenes. The preferred oral therapy is with penicillin V, 500 mg every 6 hours for 10 days. Penicillin therapy of streptococcal pharyngitis reduces the risk of subsequent acute rheumatic fever; however, current evidence suggests that the incidence of glomerulonephritis that follows streptococcal infections is not reduced to a significant degree by treatment with penicillin.

Streptococcal Toxic Shock and Necrotizing Fascitis. These are life-threatening infections associated with toxin production and are treated optimally with penicillin plus clindamycin (to decrease toxin synthesis) (Bisno and Stevens, 1996; Brown, 2004).

Streptococcal Pneumonia, Arthritis, Meningitis, and Endocarditis. Although uncommon, these conditions should be treated with penicillin G when they are caused by S. pyogenes; daily doses of 12-20 million units are administered intravenously for 2-4 weeks. Such treatment of endocarditis should be continued for a full 4 weeks.

Infections Caused by Other Streptococci. The viridans group of streptococci are the most common cause of infectious endocarditis. These are nongroupable α-hemolytic microorganisms that are increasingly resistant to penicillin G (minimum inhibitory concentration [MIC] >0.1 μg/mL). Because enterococci also may be α-hemolytic, and certain other α-hemolytic strains may be relatively resistant to penicillin, it is important to determine quantitative microbial sensitivities to penicillin G in patients with endocarditis. Patients with penicillin-sensitive viridans group streptococcal endocarditis can be treated successfully with daily doses of 12-20 million units of intravenous penicillin G for 2 weeks in combination with gentamicin 1 mg/kg every 8 hours. Some physicians prefer a 4-week course of treatment with penicillin G alone.

Enterococcal endocarditis is one of the few diseases treated optimally with two antibiotics. The recommended therapy for penicillin- and aminoglycoside-sensitive enterococcal endocarditis is 20 million units of penicillin G or 12 g ampicillin daily administered intravenously in combination with a low dose of gentamicin. Therapy usually should be continued for 6 weeks, but selected patients with a short duration of illness (<3 months) have been treated successfully in 4 weeks (Wilson et al., 1984).

Infections with Anaerobes. Many anaerobic infections are caused by mixtures of microorganisms. Most are sensitive to penicillin G. An exception is the B. fragilis group, in which up to 75% of strains may be resistant to high concentrations of this antibiotic. Pulmonary and periodontal infections (with the exception of β-lactamase-producing Prevotella melaninogenica) usually respond well to penicillin G, although a multicenter study indicated that clindamycin is more effective than penicillin for therapy of lung abscess (Levison et al., 1983). Mild-to-moderate infections at these sites may be treated with oral medication (either penicillin G or penicillin V 400,000 units [250 mg] four times daily). More severe infections should be treated with 12-20 million units of penicillin G intravenously. Brain abscesses also frequently contain several species of anaerobes, and most authorities prefer to treat such disease with high doses of penicillin G (20 million units per day) plus metronidazole or chloramphenicol. Some physicians add a third-generation cephalosporin for activity against aerobic gram-negative bacilli.

Staphylococcal Infections. The vast majority of staphylococcal infections are caused by microorganisms that produce penicillinase (Swartz, 2004). Hospital-acquired methicillin-resistant staphylococci are resistant to penicillin G, all the penicillinase-resistant penicillins, and the cephalosporins. Isolates occasionally may appear to be sensitive to various cephalosporins in vitro, but resistant populations arise during therapy and lead to failure. Vancomycin, linezolid, quinupristin-dalfopristin, and daptomycin are active for infections caused by these bacteria, although reduced susceptibility to vancomycin has been observed. Community-acquired methicillin-resistant S. aureus (MRSA) in many cases retains susceptibility to trimethoprim-sulfamethoxazole, doxycycline, and clindamycin (Medical Letter, 2007).

Meningococcal Infections. Penicillin G remains the drug of choice for meningococcal disease. Patients should be treated with high doses of penicillin given intravenously, as described for pneumococcal meningitis. Penicillin-resistant strains of N. meningitides have been reported in Britain and Spain but are infrequent at present. The occurrence of penicillin-resistant strains should be considered in patients who are slow to respond to treatment. Penicillin G does not eliminate the meningococcal carrier state, and its administration thus is ineffective as a prophylactic measure.

Gonococcal Infections. Gonococci gradually have become more resistant to penicillin G, and penicillins are no longer the therapy of choice, unless it is known that gonococcal strains in a particular geographic area are susceptible. Uncomplicated gonococcal urethritis is the most common infection, and a single intramuscular injection of 250 mg ceftriaxone is the recommended treatment (Handsfield and Sparling, 2005).

Gonococcal arthritis, disseminated gonococcal infections with skin lesions, and gonococcemia should be treated with ceftriaxone 1 g daily given either intramuscularly or intravenously for 7-10 days. Ophthalmia neonatorum also should be treated with ceftriaxone for 7-10 days (25-50 mg/kg per day intramuscularly or intravenously).

Syphilis. Therapy of syphilis with penicillin G is highly effective. Primary, secondary, and latent syphilis of <1-year duration may be treated with penicillin G procaine (2.4 million units per day intramuscularly) plus probenecid (1.0 g/day orally) for 10 days or with 1-3 weekly intramuscular doses of 2.4 million units of penicillin G benzathine (three doses in patients with HIV infection). Patients with late latent syphilis, neurosyphilis, or cardiovascular syphilis may be treated with a variety of regimens. Because the latter two conditions are potentially lethal and their progression can be halted (but not reversed), intensive therapy with 20 million units of penicillin G daily for 10 days is recommended. There are no proven alternatives for treating syphilis in pregnant women, so penicillin-allergic individuals must be acutely desensitized to prevent anaphylaxis (Centers for Disease Control and Prevention, 2006).

Infants with congenital syphilis discovered at birth or during the postnatal period should be treated for at least 10 days with 50,000 units/kg daily of aqueous penicillin G in two divided doses or 50,000 units/kg of procaine penicillin G in a single daily dose (Tramont, 2005).

Most patients (70-90%) with secondary syphilis develop the Jarisch-Herxheimer reaction. This also may be seen in patients with other forms of syphilis. Several hours after the first injection of penicillin, chills, fever, headache, myalgias, and arthralgias may develop. The syphilitic cutaneous lesions may become more prominent, edematous, and brilliant in color. Manifestations usually persist for a few hours, and the rash begins to fade within 48 hours. It does not recur with the second or subsequent injections of penicillin. This reaction is thought to be due to release of spirochetal antigens with subsequent host reactions to the products. Aspirin gives symptomatic relief, and therapy with penicillin should not be discontinued.

Actinomycosis. Penicillin G is the agent of choice for the treatment of all forms of actinomycosis. The dose should be 10-20 million units of penicillin G intravenously per day for 6 weeks. Some physicians continue therapy for 2-3 months with oral penicillin V (500 mg four times daily). Surgical drainage or excision of the lesion may be necessary before cure is accomplished.

Diphtheria. There is no evidence that penicillin or any other antibiotic alters the incidence of complications or the outcome of diphtheria; specific antitoxin is the only effective treatment. However, penicillin G eliminates the carrier state. The parenteral administration of 2-3 million units per day in divided doses for 10-12 days eliminates the diphtheria bacilli from the pharynx and other sites in practically 100% of patients. A single daily injection of penicillin G procaine for the same period produces comparable results.

Anthrax. Strains of Bacillus anthracis resistant to penicillin have been recovered from human infections. When penicillin G is used, the dose should be 12-20 million units per day.

Clostridial Infections. Penicillin G is the agent of choice for gas gangrene; the dose is in the range of 12-20 million units per day given parenterally as an adjunct to the antitoxin. Adequate debridement of the infected areas is essential. Antimicrobial drugs probably have no effect on the ultimate outcome of tetanus. Débridement and administration of human tetanus immune globulin may be indicated. Penicillin is administered, however, to eradicate the vegetative forms of the bacteria that may persist.

Fusospirochetal Infections. Gingivostomatitis, produced by the synergistic action of Leptotrichia buccalis and spirochetes that are present in the mouth, is readily treatable with penicillin. For simple "trench mouth," 500 mg penicillin V given every 6 hours for several days is usually sufficient to clear the disease.

Rat-Bite Fever. The two microorganisms responsible for this infection, Spirillum minor in the Far East and Streptobacillus moniliformis in America and Europe, are sensitive to penicillin G, the therapeutic agent of choice. Because most cases due to Streptobacillus are complicated by bacteremia and, in many instances, by metastatic infections, especially of the synovia and endocardium, the dose should be large; a daily dose of 12-15 million units given parenterally for 3-4 weeks has been recommended.

Listeria Infections. Ampicillin (with gentamicin for immunosuppressed patients with meningitis) and penicillin G are the drugs of choice in the management of infections owing to L. monocytogenes. The recommended dose of ampicillin is 1-2 g intravenously every 4 hours. The recommended dose of penicillin G is 15-20 million units parenterally per day for at least 2 weeks. When endocarditis is the problem, the dose is the same, but the duration of treatment should be no less than 4 weeks.

Lyme Disease. Although a tetracycline is the usual drug of choice for early disease, amoxicillin is effective; the dose is 500 mg three times daily for 21 days. Severe disease is treated with a third-generation cephalosporin or up to 20 million units of intravenous penicillin G daily for 10-14 days.

Erysipeloid. The causative agent of this disease, Erysipelothrix rhusiopathiae, is sensitive to penicillin. The uncomplicated infection responds well to a single injection of 1.2 million units of penicillin G benzathine. When endocarditis is present, penicillin G, 12-20 million units per day, has been found to be effective; therapy should be continued for 4-6 weeks.

Pasteurella multocida. Pasteurella multocida is the cause of wound infections after a cat or dog bite. It is uniformly susceptible to penicillin G and ampicillin and resistant to penicillinase-resistant penicillins and first-generation cephalosporins (Goldstein et al., 1988). When the infection causes meningitis, a third-generation cephalosporin is preferred because the MICs are slightly lower than for penicillin.

Prophylactic Uses of the Penicillins. The demonstrated effectiveness of penicillin in eradicating microorganisms was followed quickly and quite naturally by attempts to prove that it also was effective in preventing infection in susceptible hosts. As a result, the antibiotic has been administered in almost every situation in which a risk of bacterial invasion has been present. As prophylaxis has been investigated under controlled conditions, it has become clear that penicillin is highly effective in some situations, useless and potentially dangerous in others, and of questionable value in still others (Chapter 48).

Streptococcal Infections. The administration of penicillin to individuals exposed to S. pyogenes affords protection from infection. The oral ingestion of 200,000 units of penicillin G or penicillin V twice a day or a single injection of 1.2 million units of penicillin G benzathine is effective. Indications for this type of prophylaxis include outbreaks of streptococcal disease in closed populations, such as boarding schools or military bases. Patients with extensive deep burns are at high risk of severe wound infections with S. pyogenes; "low-dose" prophylaxis for several days appears to be effective in reducing the incidence of this complication.

Recurrences of Rheumatic Fever. The oral administration of 200,000 units of penicillin G or penicillin V every 12 hours produces a striking decrease in the incidence of recurrences of rheumatic fever in susceptible individuals. Because of the difficulties of compliance, parenteral administration is preferable, especially in children. The intramuscular injection of 1.2 million units of penicillin G benzathine once a month yields excellent results. In cases of hypersensitivity to penicillin, sulfisoxazole or sulfadiazine, 1 g twice a day for adults, also is effective; for children weighing <27 kg, the dose is halved. Prophylaxis must be continued throughout the year. The duration of such treatment is an unsettled question. It has been suggested that prophylaxis should be continued for life because instances of acute rheumatic fever have been observed in the fifth and sixth decades. However, the necessity for such prolonged prophylaxis has not been established and may be unnecessary for young adults judged to be at low risk for recurrence (Berrios et al., 1993).

Syphilis. Prophylaxis for a contact with syphilis consists of a course of therapy as described for primary syphilis. A serological test for syphilis should be performed at monthly intervals for at least 4 months thereafter.

Surgical Procedures in Patients with Valvular Heart Disease. About 25% of cases of subacute bacterial endocarditis follow dental extractions. This observation, together with the fact that up to 80% of persons who have teeth removed experience a transient bacteremia, emphasizes the potential importance of chemoprophylaxis for those who have congenital or acquired valvular heart disease of any type and need to undergo dental procedures. Since transient bacterial invasion of the bloodstream occurs occasionally after surgical procedures (e.g., tonsillectomy and genitourinary and GI procedures) and during childbirth, these, too, are indications for prophylaxis in patients with valvular heart disease. Whether the incidence of bacterial endocarditis actually is altered by this type of chemoprophylaxis remains to be determined.

Detailed recommendations for adults and children with valvular heart disease have been formulated (Wilson et al., 2007).

Pharmacological Properties. The isoxazolyl penicillins are potent inhibitors of the growth of most penicillinase-producing staphylococci. This is their valid clinical use. Dicloxacillin is the most active, and many strains of S. aureus are inhibited by concentrations of 0.05-0.8 μg/mL. Comparable values for cloxacillin (not currently marketed in the U.S.) and oxacillin are 0.1-3 and 0.4-6 μg/mL, respectively. These differences may have little practical significance, however, because dosages are adjusted accordingly. These agents are, in general, less effective against microorganisms susceptible to penicillin G, and they are not useful against gram-negative bacteria.

These agents are absorbed rapidly but incompletely (30-80%) from the GI tract. Absorption of the drugs is more efficient when they are taken on an empty stomach; preferably they are administered 1 hour before or 2 hours after meals to ensure better absorption. Peak concentrations in plasma are attained by 1 hour and ~5-10 μg/mL after the ingestion of 1 g oxacillin. Slightly higher concentrations are achieved after the administration of 1 g cloxacillin, whereas the same oral dose of dicloxacillin yields peak plasma concentrations of 15 μg/mL. There is little evidence that these differences are of clinical significance. All these congeners are bound to plasma albumin to a great extent (~90-95%); none is removed from the circulation to a significant degree by hemodialysis.

The isoxazolyl penicillins are excreted rapidly by the kidney. Normally, ~50% of a dose of these drugs is excreted in the urine in the first 6 hours after oral administration. There also is significant hepatic elimination of these agents in the bile. The half-lives for all are between 30 and 60 minutes. Intervals between doses of oxacillin, cloxacillin, and dicloxacillin do not have to be altered for patients with renal failure. The differences just noted in plasma concentrations produced by the isoxazolyl penicillins are related mainly to differences in rate of urinary excretion and degree of resistance to degradation in the liver.

Nafcillin. This semisynthetic penicillin is highly resistant to penicillinase and has proven effective against infections caused by penicillinase-producing strains of S. aureus. Its structural formula is shown in Table 53–1.

Pharmacological Properties. Nafcillin is slightly more active than oxacillin against penicillin G–resistant S. aureus (most strains are inhibited by 0.06–2 μg/mL). Although it is the most active of the penicillinase-resistant penicillins against other microorganisms, it is not as potent as penicillin G. The peak plasma concentration is ~8 μg/mL 60 minutes after a 1-g intramuscular dose. Nafcillin is ~90% bound to plasma protein. Peak concentrations of nafcillin in bile are well above those found in plasma. Concentrations of the drug in CSF appear to be adequate for therapy of staphylococcal meningitis.

Pharmacological Properties. Ampicillin (principen, others) is stable in acid and is well absorbed after oral administration. An oral dose of 0.5 g produces peak concentrations in plasma of ~3 μg/mL at 2 hours. Intake of food prior to ingestion of ampicillin diminishes absorption. Intramuscular injection of 0.5 or 1 g sodium ampicillin yields peak plasma concentrations of ~7 or 10 μg/mL, respectively, at 1 hour; these decline exponentially, with a t_1/2 of ~80 minutes. Severe renal impairment markedly prolongs the persistence of ampicillin in the plasma. Peritoneal dialysis is ineffective in removing the drug from the blood, but hemodialysis removes ~40% of the body store in ~7 hours. Adjustment of the dose of ampicillin is required in the presence of renal dysfunction. Ampicillin appears in the bile, undergoes enterohepatic circulation, and is excreted in appreciable quantities in the feces.

Peak plasma concentrations of amoxicillin (amoxil, others) are 2-2.5 times greater for amoxicillin than for ampicillin after oral administration of the same dose; they are reached at 2 hours and average ~4 μg/mL when 250 mg is administered. Food does not interfere with absorption. Perhaps because of more complete absorption of this congener, the incidence of diarrhea with amoxicillin is less than that following administration of ampicillin. The incidence of other adverse effects appears to be similar. Although the t_1/2 of amoxicillin is similar to that for ampicillin, effective concentrations of orally administered amoxicillin are detectable in the plasma for twice as long as with ampicillin, again because of the more complete absorption. About 20% of amoxicillin is protein bound in plasma, a value similar to that for ampicillin. Most of a dose of the antibiotic is excreted in an active form in the urine. Probenecid delays excretion of the drug.

Therapeutic Indications for the Aminopenicillins

Upper Respiratory Infections. Ampicillin and amoxicillin are active against S. pyogenes and many strains of S. pneumoniae and H. influenzae, which are major upper respiratory bacterial pathogens. The drugs constitute effective therapy for sinusitis, otitis media, acute exacerbations of chronic bronchitis, and epiglottitis caused by sensitive strains of these organisms. Amoxicillin is the most active of all the oral β-lactam antibiotics against both penicillin-sensitive and penicillin-resistant S. pneumoniae. Based on the increasing prevalence of pneumococcal resistance to penicillin, an increase in dose of oral amoxicillin (from 40-45 up to 80-90 mg/kg per day) for empirical treatment of acute otitis media in children is recommended (Dowell et al., 1999). Ampicillin-resistant H. influenzae may be a problem in many areas. The addition of a β-lactamase inhibitor (amoxicillin-clavulanate or ampicillin-sulbactam) extends the spectrum to β-lactamase-producing H. influenzae and Enterobacteriaceae. Bacterial pharyngitis should be treated with penicillin G or penicillin V because S. pyogenes is the major pathogen.

Urinary Tract Infections. Most uncomplicated urinary tract infections are caused by Enterobacteriaceae, and E. coli is the most common species; ampicillin often is an effective agent, although resistance is increasingly common. Enterococcal urinary tract infections are treated effectively with ampicillin alone.

Meningitis. Acute bacterial meningitis in children is most frequently due to S. pneumoniae or N. meningitidis. Because 20-30% of strains of S. pneumoniae now may be resistant to this antibiotic, ampicillin is not indicated for single-agent treatment of meningitis. Ampicillin has excellent activity against L. monocytogenes, a cause of meningitis in immunocompromised persons. Thus, the combination of ampicillin and vancomycin plus a third-generation cephalosporin is a rational regimen for empirical treatment of suspected bacterial meningitis.

Salmonella Infections. Disease associated with bacteremia, disease with metastatic foci, and the enteric fever syndrome (including typhoid fever) respond favorably to antibiotics. A fluoroquinolone or ceftriaxone is considered by some to be the drug of choice, but the administration of trimethoprim-sulfamethoxazole or high doses of ampicillin (12 g/day for adults) also is effective. In some geographic areas, resistance to ampicillin is common. The typhoid carrier state has been eliminated successfully in patients without gallbladder disease with ampicillin, trimethoprim-sulfamethoxazole, or ciprofloxacin.

Preparations of carbenicillin may cause adverse effects in addition to those that follow the use of other penicillins. Congestive heart failure may result from the administration of excessive Na⁺. Hypokalemia may occur because of obligatory excretion of cation with the large amount of nonreabsorbable anion (carbenicillin) presented to the distal renal tubule. The drug interferes with platelet function, and bleeding may occur because of abnormal aggregation of platelets.

Therapeutic Indications. Piperacillin and related agents are important agents for the treatment of patients with serious infections caused by gram-negative bacteria. Such patients frequently have impaired immunological defenses, and their infections often are acquired in the hospital. Therefore, these penicillins find their greatest use in treating bacteremias, pneumonias, infections following burns, and urinary tract infections owing to microorganisms resistant to penicillin G and ampicillin; the bacteria especially responsible include P. aeruginosa, indole-positive strains of Proteus, and Enterobacter spp. Because Pseudomonas infections are common in neutropenic patients, therapy for severe bacterial infections in such individuals should include a β-lactam antibiotic such as piperacillin with good activity against these microorganisms.

Ticarcillin. This semisynthetic penicillin (Table 53–1) is very similar to carbenicillin, but it is two to four times more active against P. aeruginosa. Ticarcillin is inferior to piperacillin for the treatment of serious infections caused by Pseudomonas. Ticarcillin is only marketed in combination with clavulanate (timentin) in the U.S.

Mezlocillin. This ureidopenicillin is more active against Klebsiella than is carbenicillin; its activity against Pseudomonas in vitro is similar to that of ticarcillin. It is more active than ticarcillin against E. faecalis. Mezlocillin sodium has been discontinued in the U.S.

Hypersensitivity reactions may occur with any dosage form of penicillin; allergy to one penicillin exposes the patient to a greater risk of reaction if another is given. But the occurrence of an untoward effect does not necessarily imply repetition on subsequent exposures. Hypersensitivity reactions may appear in the absence of a previous known exposure to the drug. This may be caused by unrecognized prior exposure to penicillin in the environment (e.g., in foods of animal origin or from the fungus-producing penicillin). Although elimination of the antibiotic usually results in rapid clearing of the allergic manifestations, they may persist for 1-2 weeks or longer after therapy has been stopped. In some cases, the reaction is mild and disappears even when the penicillin is continued; in others, immediate cessation of penicillin treatment is required. In a few instances, it is necessary to interdict the future use of penicillin because of the risk of death, and the patient should be so warned. It must be stressed that fatal episodes of anaphylaxis have followed the ingestion of very small doses of this antibiotic or skin testing with minute quantities of the drug.

Penicillins and their breakdown products act as haptens after covalent reaction with proteins. The most abundant breakdown product is the penicilloyl moiety (major determinant moiety [MDM]), which is formed when the β-lactam ring is opened. A large percentage of immunoglobulin (Ig)E-mediated reactions are to the MDM, but at least 25% of reactions are to other breakdown products, and the severities of the reactions to the various components are comparable. These products are formed in vivo and can be found in solutions of penicillin prepared for administration. The terms major and minor determinants refer to the frequency with which antibodies to these haptens appear to be formed. They do not describe the severity of the reaction that may result. In fact, anaphylactic reactions to penicillin usually are mediated by IgE antibodies against the minor determinants.

Antipenicillin antibodies are detectable in virtually all patients who have received the drug and in many who have never knowingly been exposed to it. Recent treatment with the antibiotic induces an increase in major-determinant-specific antibodies that are skin sensitizing. The incidence of positive skin reactors is three to four times higher in atopic than in nonatopic individuals. Clinical and immunological studies suggest that immediate allergic reactions are mediated by skin-sensitizing or IgE antibodies, usually of minor-determinant specificities. Accelerated and late urticarial reactions usually are mediated by major-determinant–specific skin-sensitizing antibodies. The recurrent-arthralgia syndrome appears to be related to the presence of skin-sensitizing antibodies of minor-determinant specificities. Some maculopapular and erythematous reactions may be due to toxic antigen-antibody complexes of major-determinant-specific IgM antibodies. Accelerated and late urticarial reactions to penicillin may terminate spontaneously because of the development of blocking antibodies.

Skin rashes of all types may be caused by allergy to penicillin. Scarlatiniform, morbilliform, urticarial, vesicular, and bullous eruptions may develop. Purpuric lesions are uncommon and usually are the result of a vasculitis; thrombocytopenic purpura may occur very rarely. Henoch-Schönlein purpura with renal involvement has been a rare complication. Contact dermatitis is observed occasionally in pharmacists, nurses, and physicians who prepare penicillin solutions. Fixed-drug reactions also have occurred. More severe reactions involving the skin are exfoliative dermatitis and exudative erythema multiforme of either the erythematopapular or vesiculobullous type; these lesions may be very severe and atypical in distribution and constitute the characteristic Stevens-Johnson syndrome. The incidence of skin rashes appears to be highest following the use of ampicillin, at ~9%; rashes follow the administration of ampicillin in nearly all patients with infectious mononucleosis. When allopurinol and ampicillin are administered concurrently, the incidence of rash also increases. Ampicillin-induced skin eruptions in such patients may represent a "toxic" rather than a truly allergic reaction. Positive skin reactions to the major and minor determinants of penicillin sensitization may be absent. The rash may clear even while administration of the drug is continued.

The most serious hypersensitivity reactions produced by the penicillins are angioedema and anaphylaxis. Angioedema, with marked swelling of the lips, tongue, face, and periorbital tissues, frequently accompanied by asthmatic breathing and "giant hives," has been observed after topical, oral, or systemic administration of penicillins of various types.

Acute anaphylactic or anaphylactoid reactions induced by various preparations of penicillin constitute the most important immediate danger connected with their use. Among all drugs, the penicillins are most often responsible for this type of untoward effect. Anaphylactoid reactions may occur at any age. Their incidence is thought to be 0.004-0.04% in persons treated with penicillins (Kucers and Bennett, 1987). About 0.001% of patients treated with these agents die from anaphylaxis. It has been estimated that at least 300 deaths per year are due to this complication of therapy. About 70% have had penicillin previously, and one-third of these reacted to it on a prior occasion. Anaphylaxis most often has followed the injection of penicillin, although it also has been observed after oral ingestion of the drug and even has resulted from the intradermal instillation of a very small quantity for the purpose of testing for the presence of hypersensitivity. The clinical pictures that develop vary in severity. The most dramatic is sudden, severe hypotension and rapid death. In other instances, bronchoconstriction with severe asthma; abdominal pain, nausea, and vomiting; extreme weakness and a fall in blood pressure; or diarrhea and purpuric skin eruptions have characterized the anaphylactic episodes.

Serum sickness varies from mild fever, rash, and leukopenia to severe arthralgia or arthritis, purpura, lymphadenopathy, splenomegaly, mental changes, electrocardiographic abnormalities suggestive of myocarditis, generalized edema, albuminuria, and hematuria. It is mediated by IgG antibodies. This reaction is rare, but when it occurs, it appears after penicillin treatment has been continued for 1 week or more; it may be delayed, however, until 1 or 2 weeks after the drug has been stopped. Serum sickness caused by penicillin may persist for a week or longer.

Vasculitis of the skin or other organs may be related to penicillin hypersensitivity. The Coombs reaction frequently becomes positive during prolonged therapy with a penicillin or cephalosporin, but hemolytic anemia is rare. Reversible neutropenia may occur. It is not known if this is truly a hypersensitivity reaction; it has been noted with all the penicillins and has been seen in up to 30% of patients treated with 8-12 g nafcillin for >21 days. The bone marrow shows an arrest of maturation.

Fever may be the only evidence of a hypersensitivity reaction to the penicillins. It may reach high levels and be maintained, remittent, or intermittent; chills occur occasionally. The febrile reaction usually disappears within 24-36 hours after administration of the drug is stopped but may persist for days.

Eosinophilia is an occasional accompaniment of other allergic reactions to penicillin. At times, it may be the sole abnormality, and eosinophils may reach levels of ≥10-20% of the total number of circulating white blood cells.

Penicillins rarely cause interstitial nephritis; methicillin has been implicated most frequently. Hematuria, albuminuria, pyuria, renal cell and other casts in the urine, elevation of serum creatinine, and even oliguria have been noted. Biopsy shows a mononuclear infiltrate with eosinophilia and tubular damage. IgG is present in the interstitium. This reaction usually is reversible.

Management of the Patient Potentially Allergic to Penicillin. Evaluation of the patient's history is the most practical way to avoid the use of penicillin in patients who are at the greatest risk of adverse reaction. Most patients who give a history of allergy to penicillin should be treated with a different type of antibiotic. Unfortunately, there is no totally reliable means to confirm a history of penicillin allergy (Romano et al., 2003). Skin testing for IgE-mediated immediate-type responses is compromised by the lack of a commercially available minor-determinant mixture. A National Institute of Allergy and Infectious Diseases (NIAID) multicenter study used major and minor determinants for skin testing. Of 726 patients with a history of penicillin allergy, 566 had negative skin tests. Of those, only 7 of 566 (1.2%) had possibly IgE-mediated immediate or accelerated penicillin allergy when given penicillin (Sogn et al., 1992). Radioallergosorbent tests (RASTs) for IgE antipenicilloyl determinants suffer from the same limitations as skin tests (Weiss and Adkinson, 2005).

Occasionally, desensitization is recommended for penicillin-allergic patients who must receive the drug. This procedure consists of administering gradually increasing doses of penicillin in the hope of avoiding a severe reaction and should be performed only in an intensive care setting. This may result in a subclinical anaphylactic discharge and the binding of all IgE before full doses are administered. Penicillin may be given in doses of 1, 5, 10, 100, and 1000 units intradermally in the lower arm, with 60-minute intervals between doses. If this is well tolerated, then 10,000 and 50,000 units may be given subcutaneously. Desensitization also may be accomplished by the oral administration of penicillin. When full doses are reached, penicillin should not be discontinued and then restarted because immediate reactions may recur (see Weiss and Adkinson, 2005, for details). The patient should be observed constantly during the desensitizing procedure, an intravenous line must be in place, and epinephrine and equipment and expertise for artificial ventilation must be on hand. It must be emphasized that this procedure may be dangerous, and its efficacy is unproven.

Patients with life-threatening infections (e.g., endocarditis or meningitis) may be continued on penicillin despite the development of a maculopapular rash, although alternative antimicrobial agents should be used whenever possible. The rash often resolves as therapy is continued, perhaps owing to the development of blocking antibodies of the IgG class. The rash may be treated with antihistamines or glucocorticoids, although there is no evidence that this therapy is efficacious. Rarely, exfoliative dermatitis with or without vasculitis develops in these patients if therapy with penicillin is continued.

Other Adverse Reactions. The penicillins have minimal direct toxicity. Apparent toxic effects that have been reported include bone marrow depression, granulocytopenia, and hepatitis. The last-named effect is rare but is seen most commonly following the administration of oxacillin and nafcillin. The administration of penicillin G, carbenicillin, piperacillin, or ticarcillin has been associated with a potentially significant defect of hemostasis that appears to be due to an impairment of platelet aggregation; this may be caused by interference with the binding of aggregating agents to platelet receptors (Fass et al., 1987).

Most common among the irritative responses to penicillin are pain and sterile inflammatory reactions at the sites of intramuscular injections—reactions that are related to concentration. Serum transaminases and lactic dehydrogenase may be elevated as a result of local damage to muscle. In some individuals who receive penicillin intravenously, phlebitis or thrombophlebitis develops. Many persons who take various penicillin preparations by mouth experience nausea, with or without vomiting, and some have mild to severe diarrhea. These manifestations often are related to the dose of the drug.

When penicillin is injected accidentally into the sciatic nerve, severe pain occurs and dysfunction in the area of distribution of this nerve develops and persists for weeks. Intrathecal injection of penicillin G may produce arachnoiditis or severe and fatal encephalopathy. Because of this, intrathecal or intraventricular administration of penicillins should be avoided. The parenteral administration of large doses of penicillin G (>20 million units per day, or less with renal insufficiency) may produce lethargy, confusion, twitching, multifocal myoclonus, or localized or generalized epileptiform seizures. These are most apt to occur in the presence of renal insufficiency, localized lesions of the central nervous system (CNS), or hyponatremia. When the concentration of penicillin G in CSF exceeds 10 μg/mL, significant dysfunction of the CNS is frequent. The rapid intravenous administration of 20 million units of penicillin G potassium, which contains 34 mEq of K⁺, may lead to severe or even fatal hyperkalemia in persons with renal dysfunction.

Injection of penicillin G procaine may result in an immediate reaction, characterized by dizziness, tinnitus, headache, hallucinations, and sometimes seizures. This is due to the rapid liberation of toxic concentrations of procaine. It has been reported to occur in 1 of 200 patients receiving 4.8 million units of penicillin G procaine to treat venereal disease.

Reactions Unrelated to Hypersensitivity or Toxicity. Regardless of the route by which the drug is administered, but most strikingly when it is given by mouth, penicillin changes the composition of the microflora in the GI tract by eliminating sensitive microorganisms. This phenomenon is usually of no clinical significance, and normal microflora are typically reestablished shortly after therapy is stopped. In some persons, however, superinfection results from pathological changes to the flora. Pseudomembranous colitis, related to overgrowth and production of a toxin by Clostridium difficile, has followed oral and, less commonly, parenteral administration of penicillins.

Chemistry. Cephalosporin C contains a side chain derived from D-α-aminoadipic acid, which is condensed with a dihydrothiazine β-lactam ring system (7-aminocephalosporanic acid). Compounds containing 7-aminocephalosporanic acid are relatively stable in dilute acid and highly resistant to penicillinase regardless of the nature of their side chains and their affinity for the enzyme.

Cephalosporin C can be hydrolyzed by acid to 7-aminocephalosporanic acid. This compound subsequently has been modified by the addition of different side chains to create a whole family of cephalosporin antibiotics. It appears that modifications at position 7 of the β-lactam ring are associated with alteration in antibacterial activity and that substitutions at position 3 of the dihydrothiazine ring are associated with changes in the metabolism and pharmacokinetic properties of the drugs.

The cephamycins are similar to the cephalosporins but have a methoxy group at position 7 of the β-lactam ring of the7-aminocephalosporanic acid nucleus. The structural formulas of representative cephalosporins and cephamycins are shown in Table 53–2, along with dosages schedules and half-lives.

Mechanism of Action. Cephalosporins and cephamycins inhibit bacterial cell wall synthesis in a manner similar to that of penicillin.

Classification. The large number of cephalosporins makes a system of classification most desirable. Although cephalosporins may be classified by their chemical structure, clinical pharmacology, resistance to β-lactamase, or antimicrobial spectrum, the well-accepted system of classification by "generations" is very useful, although admittedly somewhat arbitrary (Table 53–3). It is important to remember that none of the cephalosporins has activity against MRSA, listeria, or enterococci.

Classification by generations is based on general features of antimicrobial activity (Andes and Craig, 2005). The first-generation cephalosporins, epitomized by cephalothin (discontinued in the U.S.) and cefazolin, have good activity against gram-positive bacteria and relatively modest activity against gram-negative microorganisms. Most gram-positive cocci (with the exception of enterococci, methicillin-resistant S. aureus, and S. epidermidis) are susceptible. Most oral cavity anaerobes are sensitive, but the B. fragilis group is resistant. Activity against Moraxella catarrhalis, E. coli, K. pneumoniae, and P. mirabilis is good. The second-generation cephalosporins have somewhat increased activity against gram-negative microorganisms but are much less active than the third-generation agents. A subset of second-generation agents (cefoxitin, cefotetan, and cefmetazole, which have been discontinued in the U.S.) also is active against the B. fragilis group. Third-generation cephalosporins generally are less active than first-generation agents against gram-positive cocci; these agents are much more active against the Enterobacteriaceae, although resistance is dramatically increasing due to β-lactamase-producing strains. A subset of third-generation agents (ceftazidime and cefoperazone, which are discontinued in the U.S.) also is active against P. aeruginosa but less active than other third-generation agents against gram-positive cocci. Fourth-generation cephalosporins, such as cefepime, have an extended spectrum of activity compared with the third generation and have increased stability from hydrolysis by plasmid and chromosomally mediated β-lactamases (but not the KPC class A β-lactamases). Fourth-generation agents are useful in the empirical treatment of serious infections in hospitalized patients when gram-positive microorganisms, Enterobacteriaceae, and Pseudomonas all are potential etiologies. It is important to remember that none of the cephalosporins has reliable activity against the following bacteria: penicillin-resistant S. pneumoniae, MRSA, methicillin-resistant S. epidermidis and other coagulase-negative staphylococci, Enterococcus, L. monocytogenes, Legionella pneumophila, L. micdadei, C. difficile, Xanthomonas maltophilia, Campylobacter jejuni, KPC-producing Enterobacteriaceae, and Acinetobacter spp.

The most prevalent mechanism of resistance to cephalosporins is destruction of the cephalosporins by hydrolysis of the β-lactam ring. Many gram-positive microorganisms release relatively large amounts of β-lactamase into the surrounding medium. Although gram-negative bacteria seem to produce less β-lactamase, the location of their enzyme in the periplasmic space may make it more effective in destroying cephalosporins because they diffuse to their targets on the inner membrane, as is the case for the penicillins. The cephalosporins have variable susceptibility to β-lactamase. For example, of the first-generation agents, cefazolin is more susceptible to hydrolysis by β-lactamase from S. aureus than is cephalothin (no longer marketed). Cefoxitin, cefuroxime, and the third-generation cephalosporins are more resistant to hydrolysis by the β-lactamases produced by gram-negative bacteria than first-generation cephalosporins. Third-generation cephalosporins are susceptible to hydrolysis by inducible, chromosomally encoded (type I) β-lactamases. Induction of type I β-lactamases by treatment of infections owing to aerobic gram-negative bacilli (especially Enterobacter spp., Citrobacter freundii, Morganella, Serratia, Providencia, and P. aeruginosa) with second- or third-generation cephalosporins and/or imipenem may result in resistance to all third-generation cephalosporins. The fourth-generation cephalosporins, such as cefepime, are poor inducers of type I β-lactamases and are less susceptible to hydrolysis by type I β-lactamases than are the third-generation agents. They are, however, susceptible to degradation by KPC and metallo-β-lactamases (Jacoby and Munoz-Price, 2005; Jones et al., 2008; Walsh, 2008).

Cephalexin is available for oral administration, and it has the same antibacterial spectrum as the other first-generation cephalosporins. However, it is somewhat less active against penicillinase-producing staphylococci. Oral therapy with cephalexin results in peak concentrations in plasma of 16 μg/mL after a dose of 0.5 g; this is adequate for the inhibition of many gram-positive and gram-negative pathogens. The drug is not metabolized, and 70-100% is excreted in the urine.

Cephradine is similar in structure to cephalexin, and its activity in vitro is almost identical. Cephradine is not metabolized and, after rapid absorption from the GI tract, is excreted unchanged in the urine. Cephradine can be administered orally, intramuscularly, or intravenously. When administered orally, it is difficult to distinguish cephradine from cephalexin; some authorities believe these two drugs can be used interchangeably. Because cephradine is so well absorbed, the concentrations in plasma are nearly equivalent after oral or intramuscular administration.

Cefadroxil is the para-hydroxy analog of cephalexin. Concentrations of cefadroxil in plasma and urine are at somewhat higher levels than are those of cephalexin. The drug may be administered orally once or twice a day for the treatment of urinary tract infections. Its activity in vitro is similar to that of cephalexin.

Cefoxitin is a cephamycin produced by Streptomyces lactam durans. It is resistant to some β-lactamases produced by gram-negative rods. This antibiotic is less active than the first-generation cephalosporins against gram-positive bacteria. Cefoxitin is more active than other first- or second-generation agents (except cefotetan) against anaerobes, especially B. fragilis. After an intramuscular dose of 1 g, concentrations in plasma are ~22 μg/mL. The t_1/2 is ~40 minutes. Cefoxitin's special role seems to be for treatment of certain anaerobic and mixed aerobic-anaerobic infections, such as pelvic inflammatory disease and lung abscess.

Cefaclor is used orally. The concentration in plasma after oral administration is ~50% of that achieved after an equivalent oral dose of cephalexin. However, cefaclor is more active against H. influenzae and Moraxella catarrhalis, although some β-lactamase-producing strains of these organisms may be resistant.

Loracarbef is an orally administered carbacephem, similar in activity to cefaclor, that is more stable against some β-lactamases. The serum t_1/2 is 1.1 hours.

Cefuroxime is similar to loracarbef with broader gram-negative activity against some Citrobacter and Enterobacter spp. Unlike cefoxitin, cefmetazole (discontinued in the U.S.), and cefotetan, cefuroxime lacks activity against B. fragilis. The t_1/2 is 1.7 hours, and the drug can be given every 8 hours. Concentrations in CSF are ~10% of those in plasma, and the drug is effective (but inferior to ceftriaxone) for treatment of meningitis owing to H. influenzae (including strains resistant to ampicillin), N. meningitidis, and S. pneumoniae (Schaad et al., 1990).

Cefuroxime axetil is the 1-acetyloxyethyl ester of cefuroxime. Between 30% and 50% of an oral dose is absorbed, and the drug then is hydrolyzed to cefuroxime; resulting concentrations in plasma are variable.

Cefprozil is an orally administered agent that is more active than first-generation cephalosporins against penicillin-sensitive streptococci, E. coli, P. mirabilis, Klebsiella spp., and Citrobacter spp. It has a serum t_1/2 of ~1.3 hours.

Ceftizoxime has a spectrum of activity in vitro that is very similar to that of cefotaxime, except that it is less active against S. pneumoniae and more active against B. fragilis (Haas et al., 1995). The t_1/2 is somewhat longer, 1.8 hours, and the drug thus can be administered every 8-12 hours for serious infections. Ceftizoxime is not metabolized, and 90% is recovered in urine.

Ceftriaxone has activity in vitro very similar to that of ceftizoxime and cefotaxime. A t_1/2 of ~8 hours is the outstanding feature. Administration of the drug once or twice daily has been effective for patients with meningitis, whereas dosage once a day has been effective for other infections. About half the drug can be recovered from the urine; the remainder appears to be eliminated by biliary secretion. A single dose of ceftriaxone (125-250 mg) is effective in the treatment of urethral, cervical, rectal, or pharyngeal gonorrhea, including disease caused by penicillinase-producing microorganisms.

Cefpodoxime proxetil is an orally administered third-generation agent that is very similar in activity to the fourth-generation agent cefepime except that it is not more active against Enterobacter or Pseudomonas spp. It has a serum t_1/2 of 2.2 hours.

Cefditoren pivoxil is a prodrug that is hydrolyzed by esterases during absorption to the active drug, cefditoren. Cefditoren has a t_1/2 of ~1.6 hours and is eliminated unchanged in the urine. The drug is active against methicillin-susceptible strains of S. aureus, penicillin-susceptible strains of S. pneumoniae, S. pyogenes, H. influenzae, H. parainfluenzae, and Moraxella catarrhalis. Cefditoren pivoxil is only indicated for the treatment of mild-to-moderate pharyngitis, tonsillitis, uncomplicated skin and skin structure infections, and acute exacerbations of chronic bronchitis.

Cefixime is an oral third-generation cephalosporin with clinical efficacy against urinary tract infections caused by E. coli and P. mirabilis, otitis media caused by H. influenza and S. pyogenes, pharyngitis due to S. pyogenes, and uncomplicated gonorrhea. It is available as an oral suspension (suprex, others). Cefixime has a plasma t_1/2 of 3–4 hours and is both excreted in the urine and eliminated in the bile. The standard dose for adults is 400 mg/day for 5-7 days, and for a longer interval in patients with S. pyogenes. Doses must be reduced in patients with renal impairment (300 mg/day for creatinine clearance between 20 and 60 mL/minute, and 200 mg day for <20 mL/minute). Pediatric dosing varies with patient weight.

Ceftibuten is an orally effective cephalosporin with a t_1/2 of 2.4 hours. It is less active against gram-positive and gram-negative organisms than cefixime, with activity limited to S. pneumonia and S. pyogenes, H. influenzae, and M. catarrhalis. Ceftibuten is only indicated for acute bacterial exacerbations of chronic bronchitis, acute bacterial otitis media, pharyngitis, and tonsillitis. It lacks useful activity against S. aureus.

Cefdinir is effective orally, with a t_1/2 of ~1.7 hours; it is eliminated primarily unchanged in the urine. Cefdinir has greater activity than the second-generation agents for facultative gram-negative bacteria but lacks anaerobic activity. It is also inactive against Pseudomonas and Enterobacter spp.

Third-Generation Cephalosporins with Good Activity Against Pseudomonas

Ceftazidime is one-quarter to one-half as active by weight against gram-positive microorganisms as is cefotaxime. Its activity against the Enterobacteriaceae is very similar, but its major distinguishing feature is excellent activity against Pseudomonas and other gram-negative bacteria. Ceftazidime has poor activity against B. fragilis. Its t_1/2 in plasma is ~1.5 hours, and the drug is not metabolized. Ceftazidime is more active in vitro against Pseudomonas than piperacillin is (Edmond et al., 1999).

Against the fastidious gram-negative bacteria (H. influenzae, N. gonorrhoeae, and N. meningitidis), cefepime has comparable or greater in vitro activity than cefotaxime. For P. aeruginosa, cefepime has comparable activity to ceftazidime, although it is less active than ceftazidime for other Pseudomonas spp. and X. maltophilia. Cefepime has higher activity than ceftazidime and comparable activity to cefotaxime for streptococci and methicillin-sensitive S. aureus. It is not active against methicillin-resistant S. aureus, penicillin-resistant pneumococci, enterococci, B. fragilis, L. monocytogenes, Mycobacterium avium complex, or M. tuberculosis. Cefepime is excreted almost 100% renally, and doses should be adjusted for renal failure. Cefepime has excellent penetration into the CSF in animal models of meningitis. When given at the recommended dosage for adults of 2 g intravenously every 12 hours, peak serum concentrations in humans range from 126 to 193 μg/mL. The serum t_1/2 is 2 hours.

Adverse Reactions. Hypersensitivity reactions to the cephalosporins are the most common side effects, and there is no evidence that any single cephalosporin is more or less likely to cause such sensitization. The reactions appear to be identical to those caused by the penicillins, perhaps related to the shared β-lactam structure of both groups of antibiotics. Immediate reactions such as anaphylaxis, bronchospasm, and urticaria are observed. More commonly, maculopapular rash develops, usually after several days of therapy; this may or may not be accompanied by fever and eosinophilia.

Because of the similar structures of the penicillins and cephalosporins, patients who are allergic to one class of agents may manifest cross-reactivity to a member of the other class. Immunological studies have demonstrated cross-reactivity in as many as 20% of patients who are allergic to penicillin, but clinical studies indicate a much lower frequency (~1%) of such reactions. There are no skin tests that can reliably predict whether a patient will manifest an allergic reaction to the cephalosporins.

Patients with a history of a mild or a temporally distant reaction to penicillin appear to be at low risk of rash or other allergic reaction following the administration of a cephalosporin. However, patients who have had a recent severe, immediate reaction to a penicillin should be given a cephalosporin with great caution, if at all. A positive Coombs reaction appears frequently in patients who receive large doses of a cephalosporin. Hemolysis usually is not associated with this phenomenon, although it has been reported and has been associated with fatalities. Cephalosporins have produced rare instances of bone marrow depression, characterized by granulocytopenia.

The cephalosporins have been implicated as potentially nephrotoxic agents, although they are not nearly as toxic to the kidney as the aminoglycosides or the polymyxins. Renal tubular necrosis has followed the administration of cephaloridine in doses >4 g/day; this agent is no longer available in the U.S. Other cephalosporins are much less toxic and, when used by themselves in recommended doses, rarely produce significant renal toxicity. High doses of cephalothin (no longer available in the U.S.) have produced acute tubular necrosis in certain instances, and usual doses (8-12 g/day) have caused nephrotoxicity in patients with preexisting renal disease. There is good evidence that the concurrent administration of cephalothin and gentamicin or tobramycin act synergistically to cause nephrotoxicity, especially in patients >60 years of age. Diarrhea can result from the administration of cephalosporins and may be more frequent with cefoperazone, perhaps because of its greater biliary excretion. Intolerance to alcohol (a disulfiram-like reaction) has been noted with cephalosporins that contain the methylthiotetrazole (MTT) group, including cefotetan, cefamandole, moxalactam, and cefoperazone (the latter three are no longer available in the U.S.). Serious bleeding related either to hypoprothrombinemia owing to the MTT group, thrombocytopenia, and/or platelet dysfunction has been reported with several β-lactam antibiotics.

The first-generation cephalosporins are excellent agents for skin and soft tissue infections owing to S. pyogenes and methicillin-susceptible S. aureus. A single dose of cefazolin just before surgery is the preferred prophylaxis for procedures in which skin flora are the likely pathogens (Medical Letter, 2006). For colorectal surgery, where prophylaxis for intestinal anaerobes is desired, the second-generation agent cefoxitin is preferred.

The second-generation cephalosporins generally have been displaced by third-generation agents. They have inferior activity against penicillin-resistant S. pneumoniae compared with either the third-generation agents or ampicillin and therefore should not be used for empirical treatment of meningitis or pneumonia. The oral second-generation cephalosporins can be used to treat respiratory tract infections, although they are suboptimal (compared with oral amoxicillin) for treatment of penicillin-resistant S. pneumoniae pneumonia and otitis media. In situations where facultative gram-negative bacteria and anaerobes are involved, such as intra-abdominal infections, pelvic inflammatory disease, and diabetic foot infection, cefoxitin and cefotetan both are effective.

The third-generation cephalosporins, with or without aminoglycosides, have been considered to be the drugs of choice for serious infections caused by Klebsiella, Enterobacter, Proteus, Providencia, Serratia, and Haemophilus spp. Ceftriaxone is the therapy of choice for all forms of gonorrhea and for severe forms of Lyme disease. The third-generation cephalosporins cefotaxime or ceftriaxone are used for the initial treatment of meningitis in nonimmunocompromised adults and children >3 months of age (in combination with vancomycin and ampicillin pending identification of the causative agent) because of their antimicrobial activity, good penetration into CSF, and record of clinical success. They are the drugs of choice for the treatment of meningitis caused by H. influenzae, sensitive S. pneumoniae, N. meningitidis, and gram-negative enteric bacteria. Cefotaxime has failed in the treatment of meningitis owing to resistant S. pneumoniae; thus vancomycin should be added (Quagliarello and Scheld, 1997). Ceftazidime plus an aminoglycoside is the treatment of choice for Pseudomonas meningitis. Third-generation cephalosporins, however, lack activity against L. monocytogenes and penicillin-resistant pneumococci, which may cause meningitis. The antimicrobial spectra of cefotaxime and ceftriaxone are excellent for the treatment of community-acquired pneumonia, i.e., pneumonia caused by some pneumococci (achievable serum concentrations exceed MICs for many or most penicillin-resistant isolates), H. influenzae, or S. aureus.

The fourth-generation cephalosporins are indicated for the empirical treatment of nosocomial infections where antibiotic resistance owing to extended-spectrum β-lactamases or chromosomally induced β-lactamases are anticipated. For example, cefepime has superior activity against nosocomial isolates of Enterobacter, Citrobacter, and Serratia spp. compared with ceftazidime and piperacillin. However KPC- or metallo-β-lactamase expressing strains are resistant to cefepime.

Imipenem. Imipenem is marketed in combination with cilastatin, a drug that inhibits the degradation of imipenem by a renal tubular dipeptidase.

Imipenem is derived from a compound produced by Streptomyces cattleya. The compound thienamycin is unstable, but imipenem, the N-formimidoyl derivative, is stable.

Antimicrobial Activity. Imipenem, like other β-lactam antibiotics, binds to penicillin-binding proteins, disrupts bacterial cell wall synthesis, and causes death of susceptible microorganisms. It is very resistant to hydrolysis by most β-lactamases.

The activity of imipenem is excellent in vitro for a wide variety of aerobic and anaerobic microorganisms. Streptococci (including penicillin-resistant S. pneumoniae), enterococci (excluding E. faecium and non-β-lactamase-producing penicillin-resistant strains), staphylococci (including penicillinase-producing strains), and Listeria all are susceptible. Although some strains of methicillin-resistant staphylococci are susceptible, many strains are not. Activity was excellent against the Enterobacteriaceae until the emergence of KPC carbapenemase-producing strains (Jones et al., 2008; Walsh, 2008). Most strains of Pseudomonas and Acinetobacter are inhibited. S. maltophilia is resistant. Anaerobes, including B. fragilis, are highly susceptible.

Pharmacokinetics and Adverse Reactions. Imipenem is not absorbed orally. The drug is hydrolyzed rapidly by a dipeptidase found in the brush border of the proximal renal tubule. Because concentrations of active drug in urine were low, cilastatin, an inhibitor of the dehydropeptidase, was synthesized. A preparation has been developed that contains equal amounts of imipenem and cilastatin (primaxin).

After the intravenous administration of 500 mg imipenem and cilastatin, peak concentrations in plasma average 33 μg/mL. Both imipenem and cilastatin have a t_1/2 of ~1 hour. When administered concurrently with cilastatin, ~70% of administered imipenem is recovered in the urine as the active drug. Dosage should be modified for patients with renal insufficiency.

Nausea and vomiting are the most common adverse reactions (1-20%). Seizures also have been noted in up to 1.5% of patients, especially when high doses are given to patients with CNS lesions and to those with renal insufficiency. Patients who are allergic to other β-lactam antibiotics may have hypersensitivity reactions when given imipenem.

Therapeutic Uses. Imipenem–cilastatin is effective for a wide variety of infections, including urinary tract and lower respiratory infections; intra-abdominal and gynecological infections; and skin, soft tissue, bone, and joint infections. The drug combination appears to be especially useful for the treatment of infections caused by cephalosporin-resistant nosocomial bacteria, such as Citrobacter freundii and Enterobacter spp. (with the exception of the increasingly common KPC-producing strains). It would be prudent to use imipenem for empirical treatment of serious infections in hospitalized patients who have recently received other β-lactam antibiotics because of the increased risk of infection with cephalosporin- and/or penicillin-resistant bacteria. Imipenem should not be used as monotherapy for infections owing to P. aeruginosa because of the risk of resistance developing during therapy.

Meropenem. Meropenem (merrem iv) is a dimethylcarbamoyl pyrolidinyl derivative of thienamycin. It does not require co-administration with cilastatin because it is not sensitive to renal dipeptidase. Its toxicity is similar to that of imipenem except that it may be less likely to cause seizures (0.5% for meropenem; 1.5% for imipenem). Its in vitro activity is similar to that of imipenem, with activity against some imipenem-resistant P. aeruginosa but less activity against gram-positive cocci. Clinical experience with meropenem demonstrates therapeutic equivalence with imipenem.

Doripenem. Doripenem (doribax) has a spectrum of activity thatis similar to that of imipenem and meropenem, with greateractivity against some resistant isolates of Pseudomonas (Medical Letter, 2008).

Ertapenem. Ertapenem (invanz) differs from imipenem and meropenem by having a longer t_1/2 that allows once-daily dosing and by having inferior activity against P. aeruginosa and Acinetobacter spp. Its spectrum of activity against gram-positive organisms, Enterobacteriaceae, and anaerobes makes it attractive for use in intra-abdominal and pelvic infections (Solomkin et al., 2003).

Aztreonam. Aztreonam (azactam) is a monocyclic β-lactam compound (a monobactam) isolated from Chromobacterium violaceum (Sykes et al., 1981).

Aztreonam interacts with penicillin-binding proteins of susceptible microorganisms and induces the formation of long filamentous bacterial structures. The compound is resistant to many of the β-lactamases that are elaborated by most gram-negative bacteria, including the metallo-β-lactamases but not the KPC β-lactamases (Jones et al., 2008; Walsh, 2008).

The antimicrobial activity of aztreonam differs from those of other β-lactam antibiotics and more closely resembles that of an aminoglycoside. Aztreonam has activity only against gram-negative bacteria; it has no activity against gram-positive bacteria and anaerobic organisms. However, activity against Enterobacteriaceae is excellent, as is that against P. aeruginosa. It is also highly active in vitro against H. influenzae and gonococci.

Aztreonam is administered either intramuscularly or intravenously. Peak concentrations of aztreonam in plasma average nearly 50 μg/mL after a 1-g intramuscular dose. The t_1/2 for elimination is 1.7 hours, and most of the drug is recovered unaltered in the urine. The t_1/2 is prolonged to ~6 hours in anephric patients.

Aztreonam generally is well tolerated. Interestingly, patients who are allergic to penicillins or cephalosporins appear not to react to aztreonam, with the exception of ceftazidime.

The usual dose of aztreonam for severe infections is 2 g every 6-8 hours. This should be reduced in patients with renal insufficiency. Aztreonam has been used successfully for the therapy of a variety of infections. One of its notable features is little allergic cross-reactivity with β-lactam antibiotics, with the possible exception of ceftazidime (Perez Pimiento et al., 1998), with which it has considerable structural similarity. Aztreonam is therefore quite useful for treating gram-negative infections that normally would be treated with a β-lactam antibiotic were it not for the history of a prior allergic reaction.

Amoxicillin plus clavulanate is effective in vitro and in vivo for β-lactamase-producing strains of staphylococci, H. influenzae, gonococci, and E. coli. Amoxicillin-clavulanate plus ciprofloxacin has been shown to be an effective oral treatment for low-risk febrile patients with neutropenia from cancer chemotherapy (Freifeld et al., 1999; Kern et al., 1999). It also is effective in the treatment of acute otitis media in children, sinusitis, animal or human bite wounds, cellulitis, and diabetic foot infections. The addition of clavulanate to ticarcillin (timentin) extends its spectrum such that it resembles imipenem to include aerobic gram-negative bacilli, S. aureus, and Bacteroides spp. There is no increased activity against Pseudomonas spp. The dosage should be adjusted for patients with renal insufficiency. The combination is especially useful for mixed nosocomial infections and is used often with an aminoglycoside.

Sulbactam is another β-lactamase inhibitor similar in structure to clavulanic acid. It may be given orally or parenterally along with a β-lactam antibiotic. It is available for intravenous or intramuscular use combined with ampicillin (unasyn, others). Dosage must be adjusted for patients with impaired renal function. The combination has good activity against gram-positive cocci, including β-lactamase-producing strains of S. aureus, gram-negative aerobes (but not resistant strains of E. coli or Pseudomonas), and anaerobes; it also has been used effectively for the treatment of mixed intra-abdominal and pelvic infections.

Tazobactam is a penicillanic acid sulfone β-lactamase inhibitor. In comparison with the other available inhibitors, it has poor activity against the inducible chromosomal β-lactamases of Enterobacteriaceae but has good activity against many of the plasmid β-lactamases, including some of the extended-spectrum class. It has been combined with piperacillin as a parenteral preparation (zosyn).

The combination of piperacillin and tazobactam does not increase the activity of piperacillin against P. aeruginosa because resistance is due to either chromosomal β-lactamases or decreased permeability of piperacillin into the periplasmic space. Because the currently recommended dose (3 g piperacillin per 375 mg tazobactam every 4-8 hours) is less than the recommended dose of piperacillin when used alone for serious infections (3-4 g every 4-6 hours), concern has been raised that piperacillin-tazobactam may prove ineffective in the treatment of some P. aeruginosa infections that would have responded to piperacillin. The combination of piperacillin plus tazobactam should be equivalent in antimicrobial spectrum to ticarcillin plus clavulanate.