Cefotan

The first cephalosporin, known as cephalosporin C, was isolated fromthe fermentation products of a fungus, Cephatosporium acremonium. Hydrolysis of this compound produced aminocephalosporanic acid, which was modified with different side chains to create the whole family fo cephalosporin antibiotics.

To date, more than 20 cephalosporins have been approved by the U.S. Food and Drug Administration, and new ones continue to appear. Are all of these cephalosporins necessary, and to what extent are they clinically useful? The answers to these questions lie in the fact that the cephalosporins have an excellent safety profile and a basic structure that lends itself to numerous alternations, resulting in compounds that have widely different spectra of antimicrobial activity. The continuing emergence of resistant strains of bacteria necessitates the development of new antibiotics. This article reviews the pharmacology of the cephalosporins, establishing a rationale for their use in the management and prophylaxis of specific infections.

The cephalosporins, like other betalactam antibiotics, exert a "cidal" effect against susceptible bacteria by inhibiting cell wall synthesis. [1] These compounds bind to and inactivate a number of enzymes located on the cytoplasmic membrane. Known as penicillin-binding proteins, these enzymes are involved in the cross-linking of peptidoglycan strands and the reshaping of the cell wall during growth and division. Binding of the cephalosporins to these proteins inhibits transpeptidation of linear glycopeptide polymers, the final step in cell wall synthesis. This action triggers autolytic enzymes, resulting in cell lysis.

Structure

The cephalosporin molecule is composed of a nucleus and two side chains. The nucleus, 7-aminocephalosporanic acid, consists of a four-member beta-lactam ring fused to a six-member dihydrothiazine ring. By comparison, the penicillin nucleus, 7-aminopenicillanic acid, has a beta-lactam ring fused to a five-member thiazolidine ring (Figure 1).

The cephalosporin nucleus has two advantages over the penicillin nucleus. First, it is inherently more stable to beta-lactamases; bacteria that produce penicillinase are usually susceptible to cephalosporins. The second advantage is the presence of R2 substitutent. The penicillin molecule can be modified at only one site (R1), while the cephalosporin molecule has two sites (R1 and R2) for modification. Thus, compared with penicillins, the potential number of cephalosporins is considerably greater.

The presence of an intact beta-lactam ring is essential for the antimicrobial activity of the cephalosporins. Modifications of the R1 substituent, which is in close proximity to the beta-lactam ring, affect antibacterial activity by altering beta-lactamase stability and/or binding affinity for the penicillin-binding proteins.

Changes in the R2 substituent, which is attached to the dihydrothiazine ring, affect the pharmacokinetic properties of the drug. [2] Substitution of an acetoxy group ([-CH.sub.2]-O-CO[-CH.sub.3]) for R2 is associated with significant metabolism to desacetyl derivatives. This side chain is present in cephalothin (Keflin), cephapirin (Cefadyl) and cefotaxime (Claforan). The presence of an N-methylthiotetrazole group at this position is associated with two adverse reactions: hypoprothrombinemia and a disulfiram (Antabuse) effect. This side chain is present in cefamandole (Mandol), cefmetazole (Zefazone), cefotetan (Cefotan), cefoperazone (Cefobid) and moxalactam (Moxam).

The introduction of a methoxy group (-O[-CH.sub.3]) on the beta-lactam ring at position 7 is associated with a marked increase in both beta-lactamase stability and activity against anaerobes. [3] This side chain is present in cefoxitin (Mefoxin), cefmetazole, cefotetan and moxalactam. The parent compounds of cefoxitin, cefmetazole and cefotetan were derived from Streptomyces species, rather than C. acremonium. Strictly speaking, these three antibiotics are cephamycins rather than cephalosporins. Moxalactam is not a true cephalosporin, but a 1-oxa-beta-lactam, a totally synthetic compound. However, the cephamycins and moxalactam are sufficiently similar to the cephalosporins to justify the FDA's position that they should be considered in the same classification.

Mechanisms of Bacterial Resistance

The antimicrobial activity of the cephalosporins depends on their ability to penetrate the bacterial outer cell envelope, resist inactivation by beta-lactamases, and bind to and inactivate penicillin-binding proteins. The major mechanism of resistance to these agents is bacterial production of beta-lactamases, enzymes that cleave the C-N bond of the beta-lactam ring. Since an intact beta-lactam ring is an absolute requirement for interaction with the penicillin-binding proteins, cleavage of the ring destroys antibacterial activity.

There are many beta-lactamases that can be distinguished on the basis of substrate specificity, gene location (chromosome or plasmid) and inducibility. [4] Various beta-lactamases differ structurally from one another in one or more amino acid residues.

Ingram-positive bacteria, such as staphylococci, the beta-lactamase is secreted extracellularly. In gram-negative bacteria, however, the beta-lactamase is cell bound, retained in the periplasmic space that lies between the cytoplasmic and outer memberanes. Thus, the enzyme is strategically located to destroy the beta-lactam compound before it reaches the penicillin-binding proteins on the cytoplasmic membrane. As a group, the cephalosporins are quite resistant to inactivation by the beta-lactamases secreted by staphylococci, but they are variably stable to inactivation by the beta-lactamases of gram-negative bacilli.

In some bacteria, resistance to cephalosporins is due to impermeability (i.e., inability of the drug to reach the penicillin-binding proteins). To reach its target, the cephalosporin molecule must cross the outer cell envelope. In gram-positive bacteria, the outer cell envelope consists of one or more peptidoglycan layers, which are not effective barriers against small molecules such as those of the cephalosporins. [5] In contrast, the outer cell envelope of gram-negative bacteria includes a membrane composed of lipopolysaccharide and lipoprotein that is exterior to the peptidoglycan layer. Penetration through this membrane is made possible by transmembrane channels formed by proteins called porins. [6,7] The ease with which cephalosporins diffuse through the porin channels varies according to their size, charge and hydrophilic properties. Some species of bacteria, such as Pseudomonas aeruginosa, have an outer membrane that is relatively impermeable to most cephalosporins.

A third mechanism of resistance to cephalosporins is alteration of the target penicillin-binding protein, resulting in reduced binding affinity for the cephalosporin molecule. This mechanism accounts for the resistance of gram-positive species, such as methicillin-resistant staphylococci, to these compounds. [8]

Antimicrobial Spectrum

Based on their spectrum of activity against gram-negative bacteria, cephalosporins are classified into three generations. The various cephalosporins are listed by generation in Table 1. [9] Compounds within a generation differ from one another primarily in pharmacokinetic properties, although they may also differ significantly in their activity against certain organisms. It should be emphasized that the generation classification does not correlate with gram-positive antibacterial activity.

First-generation cephalosporins are hydrolyzed by many of the beta-lactamases produced by gram-negative bacteria and therefore have a relatively narrow gram-negative spectrum. Second-generation compounds have greater beta-lactamase stability and, thus, a broader spectrum of activity against gram-negative organisms. Third-generation cephalosporins are relatively resistant to hydrolysis by beta-lactamases and, as a result, have a very broad gram-negative spectrum. [10]

The three generations of cephalosporins differ from one another not only in spectrum of activity but also in potency against gram-negative bacilli. Against susceptible gram-negative bacteria, second-generation cephalosporins are four to eight times more potent than first-generation compounds. Similarly, third-generation cephalosporins are approximately ten times more active than the second-generation cephalosporins.

GRAM-POSITIVE BACTERIA

First-generation cephalosporins have excellent activity against Staphylococcus aureus and coagulase-negative staphylococci, including strains that procedure penicillinase. Methicillin-resistant strains, however, are resistant to first-generation and other cephalosporins. These compounds do not have an affinity for the altered penicillin-binding protein in methicillin-resistant staphylococci. First-generation cephalosporins are active against various Streptococcus species, including Streptococcus pneumoniae. Listeria monocytogenes and enterococci, including Streptococcus faecalis and Streptococcus faecium, are resistant to all cephalosporins.

Second-generation cephalosporins differ in their activity against gram-positive bacteria. Cefuroxime (Kefurox, Zinacef) and cefamandole are nearly as active as first-generation cephalosporins against Staphylococcus and Streptococcus species. Other second-generation compounds, including cefonicid (Monocid), ceforanide (Preced) and the cephamycins (cefoxitin, cefmetazole, cefotetan), are significantly less active against these organisms. Of the second-generation cephalosporins, cefotetan is the least active against gram-positive organisms. [11]

Third-generation cephalosporins are less active than first-generation agents against S. auereus and coagulase-negative staphylococci. In descending order of anti-staphylococcal activity, these agents are ranked as follows: (1) cefotaxime, (2) ceftizoxime (Cefizox) and ceftriaxone (Rocephin), (3) cefoperazone, (4) ceftazidime (Fortaz, Tazicef, Tazidime) and 95) moxalactam. Cefotaxime, which has the greatest activity against coagulase-negative staphylococci, is two to four times less potent against these organisms than the first-generation cephalosporins. Ceftazidime and moxalactam have poor anti-staphylococcal activity. Cefixime (Suprax), the only currently available orally administered third-generation cephalosporin, does not have clinically significant activity against S. aureus. [12]

Third-generation cephalosporins, with the exception of ceftazidime and moxalactam, are more active than first-generation cephalosporins against Streptococcus species, including S. pneumoniae and beta-hemolytic and viridans streptococci. [13,14] Ceftazidime and moxalactam are slightly less potent than the first-generation compounds.

GRAM-NEGATIVE BACTERIA

First-generation cephalosporins have a narrow spectrum of activity against gram-negative organisms. Most strains of Escherichia coli, Proteus mirabilis and Citrobacter diversus, as well as Klebsiella species, are susceptible to these agents. Other

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gram-negative bacteria, including Haemophilus influenzae, gonococci and meningococci, are resistant to the first-generation cephalosporins.

Second-generation cephalosporins are active against Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella catarrhalis (previously known as Branhamella catarrhalis) and H. influenzae, including strains that produce beta-lactamase. Cefuroxime and cefonicid have greater activity against H. influenzae than other second-generation cephalosporins. Cefamandole has poor activity against H. influenzae strains that produce beta-language.

Second-generation cephalosporins have a broader spectrum of activity against enteric gram-negative bacilli than first-generation compounds. As a group, the second-generation compounds are more potent against Klebsiella species, E. coli, P. mirabilis and C. diversus. Moreover, their antimicrobial spectra include a variable percentage of strains of Proteus vulgaris, Morganella and Providencia species, Serratia marcescens (more susceptible to cefoxitin and cefotetan) and Enterobacter aerogenes (more susceptible to cefuroxime, cefonicid and cefotetan). [15] Cefotetan is the most active second-generation cephalosporin against gram-negative enteric bacilli.

Third-generation cephalosporins are highly active against N. gonorrheoae, N. meningitidis, M. catarrhalis and H. influenzae, including strains that produce beta-lactamase. [13,14] The spectrum of activity and the potency of the third-generation cephalosporins against enteric gram-negative bacilli are markedly superior to those of the second-generation compounds. all enteric gram-negative bacteria, except some strains of Enterobacter cloacae and Citrobacter freundii, are usually quite sensitive to third-generation cephalosporins. [13,14,16-20] However, with increasing use of these compounds, resistant strains of various gram-negative species are being encountered in many hospitals. Except for cefoperazone, which is slightly less active in vitro, the third-generation agents have comparable activity against gram-negative enteric bacilli.

Third-generation cephalosporins, except for ceftazidime and cefoperazone, have poor activity against Pseudomonas species. Ceftazidime is the most active cephalosporin against P. Aeruginosa; cefoperazone is two to four times less active. [21,22] Pseudomonas cepacia is inhibited by ceftazidime, but not by other third-generation compounds. Xanthomonas maltophilia and Acinetobacter calcoaceticus are usually resistant to all cephalosporins.

ANAEROBES

The activity of cephalosporins against anaerobes does not correlate with the generation classification. All of the cephalosporins are active against various anaerobic bacteria, including Peptococcus and Peptostreptococcus species, Clostridium perfringens, Fusobacterium species, and Bacteroides species other than Bacteroides fragilis. Ceftazidime has poor activity against these organisms. The cephamycins (cefoxitin, cefmetazole, cefotetan) are the most active cephalosporins against anaerobes; approximately 80 to 90 percent of B. fragilis strains are also susceptible to these compounds. [23] Of the third-generation cephalosporins, moxalactam and ceftizoxime are the most active against B. fragilis.

Pharmacokinetics

ORAL ADMINISTRATION

Three first-generation cephalosporins (cephalexin [Keflex, Keftab], cephradine [Anspor, Velosef] and cefadroxil [Duricef, Ultracef]), two second-generation cephalosporins (cefaclor [Ceclor] and cefuroxime axetil [Ceftin]) and one third-generation cephalosporin (cefixime) are acid-stable and are well absorbed after oral administration. Cefuroxime axetil, an ester of cefuroxime, does not have antimicrobial activity; it is a prodrug that is rapidly hydrolyzed to cefuroxime after absorption.

The rate of absorption and the peak serum concentration of cefadroxil are not affected when the drug is administered with food. The absorption of cefuroxime axetil is increased when it is given with or shortly after food; the bioavailability of the drug, which is 36 percent when it is administered in the fasting state, increases to 52 percent when it is administered with food. Gastrointestinal absorption of the other oral cephalosporins is delayed by the presence of food in the stomach, resulting in lower and delayed peak serum concentrations; however, the total amount of drug absorved is not affected. The average bioavailability of orally administered cefixime is approximately 45 percent.

PARENTERAL ADMINISTRATION

Four first-generation cephalosporins (cephalothin, cefazolin [Ancef, Kefzol], cephapirin and cephradine), seven second-generation agents (cefamandole, cefuroxime, ceforanide, cefonicid, cefoxitin, cefmetazole and cefotetan) and six third-generation cephalosporins (cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime and moxalactam) are available for parenteral administration. Although all of these drugs are absorved following intramuscular injection, they are usually given intravenously because of the pain associated with intramuscular administration. Those administered once or twice daily, such as ceftriaxone and cefonicid, are more suitable for intramuscular injection.

PROTEIN BINDING

In the blood, cephalosporins bind reversibly to serum proteins, primarily albumin. The percentage of drug bound to proteins is characteristic of each compound (Table 1). Only the unbound drug can leave the vascular compartment and penetrate into tissues. Moreover, only the unbound drug binds to penicillin-binding proteins.

The cephalosporins with longer half-lives generally have greater serum protein binding. Cefonicid is 90 percent protein-bound; ceftriaxone is 85 to 95 percent protein-bound. Ceftriaxone, cefoperazone and cefmetazole display concentration-dependent protein binding (i.e., the extent of protein binding decreases at higher serum concentrations due to saturation of the binding sites). [24]

Since antimicrobial activity is a function of the unbound antibiotic, high protein binding would theoretically reduce efficacy. This relationship, however, is not clear.

DISTRIBUTION

Cephalosporins penetrate well into most tissues and body fluids. However, only cefuroxime and the third-generation cephalosporins penetrate the cerebrospinal fluid in high enough concentrations to treat meningitis caused by susceptible organisms. [10,25]

Biliary concentrations of the cephalosporins are in the therapeutic range if biliary obstruction is not present. Due to significant biliary excretion, cefoperazone and ceftriaxone attain very high biliary concentrations.

Cephalosporins readily cross the placenta, and the fetal serum concentration may be 10 percent or more of the maternal serum concentration. Cephalosporins are distributed in low concentrations in breast milk.

ELIMINATION

Most cephalosporins are excreted primarily by the kidneys in an active, unchanged form. However, they differ significantly in their rates of elimination.

Metabolism plays a role in the elimination of cephalothin, cephapirin and cefotaxime. For these drugs, 20 to 30 percent of the administered dose is metabolized in the liver to desacetyl derivatives, which have some antibacterial activity and are excreted by the kidneys. In patients with liver disease, the half-lives of the cephalosporins are slightly increased; however, compensatory renal elimination prevents drug accumulation. Because of hepatic metabolism, the elimination half-lives of these gents are only modestly increased in anuric patients (Table 1).

Biliary excretion plays a significant role in the elimination fo cefoperazone, ceftriaxone and cefixime. Approximately 70 percent of cefoperazone is excreted unchanged into the bile. The elimination half-life of this drug is essentially unchanged in patients with renal failure, but it is two to four times higher in patients with impaired hepatic function. Approximately 40 percent of ceftriaxone is excreted unchanged into the bile. The elimination half-life of ceftriaxone increases slightly in patients with renal failure; however, since the drug is administered every 12 to 24 hours, there is little accumulation and, thus, no need to adjust the dosage. In patients with impaired hepatic function, renal excretion of ceftriaxone increases, and the half-life is not appreciably prolonged. In patients with both hepatic and renal dysfunction, the dosages of both cefoperazone and ceftriaxone should be adjusted. [26] About 25 percent of cefixime is excreted unchanged into the bile.

Adverse Effects

Allergic reactions are the most significant adverse effects encountered with the use of cephalosporins. Immediate reactions, such as anaphylaxis, bronchospasm, angioedema and urticaria (which are mediated by IgE antibodies), may occur minutes to hours after administration. More commonly, patients develop a maculopapular rash, usually after several days of therapy. Approximately 5 to 10 percent of patients who are allergic to penicillins also prove to be allergic to cephalosporins. A history of delayed allergic reactions to penicillins is only a relative contra-indication to the cautious administration of cephalosporins. However, if immediate reactions to penicillins have occurred or if patients have a positive skin test to penicillin antigens, cephalosporins should not be used. No skin testing materials are available to test for cephalosporin allergy. Allergic interstitial nephritis is a rate complication that may occur with any of the cephalosporins.

Hypoprothrombinemia may occur with cefamandole, cefmatazole, cefotetan, cefoperazone and moxalactam; it is related to the presence of an N-methylthiotetrazole side chain. [27,28] Weekly administration of vitamin K will prevent this complication and is therefore recommended when these cephalosporins are used for prolonged periods in seriously ill patients. Moxalactam may also interfere with platelet aggregation; this drug has been implicated in clinically significant bleeding more often than any other cephalosporin.

A positive Coombs' reaction may occur in patients receiving large doses of cephalosporins. Hemolysis is not usually associated with this phenomenon, although it has occasionally been reported. Rare cases of granulocytopenia and thrombocytopenia have also been reported.

Diarrhea may occur with use of any of the cephalosporins, but it is more common with cefixime, cefoperazone and ceftriaxone, which are all excreted in high concentrations into the bile. Diarrhea occurs in 13 to 17 percent of patients receiving oral cefixime and in 3.5 percent of patients treated with ceftriaxone. Clostridium difficile colitis has been reported with all cephalosporins. High doses of ceftriaxone (2 g every 12 hours), which

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are used to treat meningitis, may produce biliary sludge (pseudolithiasis) and symptoms resembling those of cholelithiasis.

A disulfiram-like reaction may occur in patients who ingest alcohol while receiving cefamandole, cefmetazole, cefotetan, cefoperazone and moxalactam. The N-methylthiotetrazone side chain in these compounds, which is structurally similar to disulfiram, [2] causes this reaction by binding to, and interfering with, the action of aldehyde dehydrogenase, the enzyme that metabolizes the acetaldehyde breakdown product of ethanol to water and carbon dioxide. Accumulation of acetaldehyde product of ethanol to water and is thought to cause the symptoms.

Superinfection with resistant organisms may occur during therapy with third-generation cephalosporins. Resistant organisms most commonly include enterococci and E. cloacae, as well as Acinetobacter, Pseudomonas and Candida species.

Clinical Use

The cephalosporins of choice for selected infections are given in Table 2.

FIRST-GENERATION CEPHALOSPORINS

First-generation cephalosporins are alternatives to penicillins for treating staphylococcal and streptococcal infections in patients who cannot tolerate penicillins. They are also effective in infections caused by susceptible strains of Klebsiella, E. coli and P. mirabilis. Cephalothin, cephapirin and cephradine are nearly identical. Because cefazolin has a longer elimination half-life, it has emerged as the most popular parenteral first-generation cephalosporin.

None of the cephalosporins are effective in the treatment of infections caused by methicillin-resistant staphylococci. Even when combined with an aminoglycoside, cephalosporins are not useful in the treatment of enterococcal infections.

First-generation cephalosporins, especially cefazolin, are widely used for prophylaxis in cardiovascular, orthopedic, biliary, pelvic and gastric surgical procedures. For this purpose, they are usually preferable to second-generation cephalosporins, because they are as effective, cost less and have a narrower antimicrobial spectrum. Due to cefazolin's longer elimination half-life, it is usually considered the agent of choice for prophylaxis.

SECOND-GENERATION CEPHALOSPORINS

Cefuroxime, due to its excellent activity against S. pneumoniae and H. influenzae, is commonly used in the treatment of community-acquired pneumonia when a specific pathogen is not detected by sputum examination. For this purpose, it is superior to cefamandole, which has poor activity against H. influenzae strains that produce beta-lactamase. Cefuroxime axetil is used to treat a variety of mild to moderate infections, including otitis media, bronchitis and urinary tract infections.

The cephamycins (cefoxitin, cefmetazone, cefotetan) are valuable for treating mixed aerobic-anaerobic infections, including intra-abdominal infections, pelvic infections, nosocomial aspiration pneumonia and foot infections in patients with diabetes. [29-32] These drugs are also effective prophylactic agents for colorectal surgery and other procedures in which anaerobic infections are potential complications. Cefotetan, which has a long elimination half-life (allowing a dosing schedule of every 12 hours), is frequently used as a replacement for cefoxitin in the hospital formulary. Cefonicid, because of its long half-life, is used in a once-daily regimen to treat a variety of mild to moderate infections.

THIRD-GENERATION CEPHALOSPORINS

Infections caused by multidrug-resistant gram-negative bacilli are the primary indication for the use of third-generation cephalosporins. These agents are effective in the treatment of gram-negative bacteremia, nosocomial pneumonia, bone and joint infections, nosocomial urinary tract infections, intra-abdominal infections, and skin and soft tissue infections. In intra-abdominal infections, a companion drug, such as metronidazole (Flagyl), which is active against B. fragilis, is usually given. For infections involving P. aeruginosa, ceftazidime is the third-generation agent of choice.

Third-generation cephalosporins are also useful in the treatment of meningitis caused by susceptible bacteria. Ceftriaxone (or cefotaxime) is considered the drug of choice for empiric treatment of bacterial meningitis in children and for H. influenzae meningitis. [33] A combination of ceftriaxone and ampicillin is as effective as the conventional ampicillin and gentamicin (Garamycin) regimen in neonatal meningitis. [34] Third-generation cephalosporins, especially cefotaxime, ceftriaxone and ceftazidime, are also excellent for treating meningitis caused by susceptible gram-negative bacilli. [35-37] For the treatment of brain abscess, cefotaxime or ceftriaxone combined with metronidazole is an alternative to the penicillin and chloramphenicol (Chloromycetin) combination. [38] Ceftriaxone is also the drug of choice for treating the central nervous system complications of Lyme disease. [39, 40]

Ceftazidime is effective monotherapy for the empiric treatment of febrile neutropenic patients. [41 Once therapy is started, the patient must be monitored closely for nonresponse, the emergence of secondary infections and the development of drug-resistant organisms. Although the initial response to monotherapy may be good, modification is required with sufficient frequency to warrent initial therapy with drug combinations, such as ceftazidime plus an aminoglycoside.

Because of the increasing prevalence of penicillin-resistant strains of N. gonorrhoeae, ceftriaxone has become the drug of choice for treating uncomplicated urethral, anorectal and pharyngeal gonorrhea. Ceftriaxone is an alternative to erythromycin for the treatment of chancroid.

Third-generation cephalosporins are an alternative to chloramphenicol, ampicillin and trimethoprim-sulfamethoxazole (Bactrim, Septra) for the treatment of enteric fever and other salmonelloses. [42]

Cefixime may be used to treat otitis media in children and nosocomial urinary tract infections. Since this drug does not have clinically useful activity against S. aureus, it should not be used to treat cellulitis.

Third-generation cephalosporins are not recommended for prophylaxis. Although these highly potent drugs would be effective for this purpose, it is best to limit their use to the treatment of difficult infections.

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JOSEPH R. DIPALMA, M.D., coordinator of this series, is emeritus professor of pharmacology and medicine at Hahnemann University School of Medicine, Philadelphia.

COPYRIGHT 1991 American Academy of Family Physicians
COPYRIGHT 2004 Gale Group