Route of Acid Binding ^-Lactamase Spectrum of Antipseudomonal
Cephalosporin Generation Admin. Resistant (%) Resistance Activity Activity
Cephalexin, 7a-(d-amino-a-phenylacetamido)-3-methyl-cephemcarboxylic acid (Keflex, Keforal), was designed purposely as an orally active, semisynthetic cephalosporin. The oral inactivation of cephalosporins has been attributed to two causes: instability of the jS-lactam ring to acid hydrolysis (cephalothin and cephaloridine) and solvolysis or microbial transformation of the 3-methylacetoxy group (cephalothin, cephaloglycin). The a-amino group of cephalexin renders it acid stable, and reduction of the 3-acetoxymethyl to a methyl group circumvents reaction at that site.
Cephalexin occurs as a white crystalline monohydrate. It is freely soluble in water, resistant to acid, and absorbed well orally. Food does not interfere with its absorption. Because of minimal protein binding and nearly exclusive renal excretion, cephalexin is recommended particularly for the treatment of urinary tract infections. It is also sometimes used for upper respiratory tract infections. Its spectrum of activity is very similar to those of cephalothin and cephaloridine. Cephalexin is somewhat less potent than these two agents after parenteral administration and, therefore, is inferior to them for the treatment of serious systemic infections.
Cephradine (Anspor, Velosef) is the only cephalosporin derivative available in both oral and parenteral dosage forms. It closely resembles cephalexin chemically (it may be regarded as a partially hydrogenated derivative of cephalexin) and has very similar antibacterial and pharmacokinetic properties.
It occurs as a crystalline hydrate that is readily soluble in water. Cephradine is stable to acid and absorbed almost completely after oral administration. It is minimally protein bound and excreted almost exclusively through the kidneys. It is recommended for the treatment of uncomplicated urinary tract and upper respiratory tract infections caused by susceptible organisms. Cephradine is available in both oral and parenteral dosage forms.
Cefadroxil (Duricef) is an orally active semisynthetic derivative of 7-ADCA, in which the 7-acyl group is the d-
hydroxylphenylglycyl moiety. This compound is absorbed well after oral administration to give plasma levels that reach 75% to 80% of those of an equal dose of its close structural analog cephalexin. The main advantage claimed for ce-fadroxil is its somewhat prolonged duration of action, which permits once-a-day dosing. The prolonged duration of action of this compound is related to relatively slow urinary excretion of the drug compared with other cephalosporins, but the basis for this remains to be explained completely. The antibacterial spectrum of action and therapeutic indications of cefadroxil are very similar to those of cephalexin and cephra-dine. The d-p-hydroxyphenylglycyl isomer is much more active than the l-isomer.
Cefaclor (Ceclor) is an orally active semisynthetic cephalosporin that was introduced in the American market in 1979. It differs structurally from cephalexin in that the 3-methyl group has been replaced by a chlorine atom. It is synthesized from the corresponding 3-methylenecepham sulfoxide ester by ozonolysis, followed by halogenation of the resulting jS-ketoester.82 The 3-methylenecepham sulfoxide esters are prepared by rearrangement of the corresponding 6-acylaminopenicillanic acid derivative. Cefaclor is moderately stable in acid and achieves enough oral absorption to provide effective plasma levels (equal to about two-thirds of those obtained with cephalexin). The compound is apparently unstable in solution, since about 50% of its antimicrobial activity is lost in 2 hours in serum at 37°C.83 The antibacterial spectrum of activity is similar to that of cephalexin, but it is claimed to be more potent against some species sensitive to both agents. Currently, the drug is recommended for the treatment of non-life-threatening infections caused by H. influenzae, particularly strains resistant to ampicillin.
Cefprozil (Cefzil) is an orally active second-generation cephalosporin that is similar in structure and antibacterial spectrum to cefadroxil. Oral absorption is excellent (oral bioavailability is about 95%) and is not affected by antacids or histamine H2-antagonists. Cefprozil exhibits greater in vitro activity against streptococci, Neisseria spp., and S. aureus than does cefadroxil. It is also more active than the first-generation cephalosporins against members of the Enterobacteriaceae family, such as E. coli, Klebsiella spp.,
P. mirabilis, and Citrobacter spp. The plasma half-life of 1.2 to 1.4 hours permits twice-a-day dosing for the treatment of most community-acquired respiratory and urinary tract infections caused by susceptible organisms.
Loracarbef (Lorabid) is the first of a series of carbacephems prepared by total synthesis to be introduced.84 Carbacephems are isosteres of the cephalosporin (or A3-cephem) antibiotics in which the 1-sulfur atom has been replaced by a methylene (CH2) group. Loracarbef is isosteric with cefaclor and has similar pharmacokinetic and microbiological properties. Thus, the antibacterial spectrum of activity resembles that of cefaclor, but it has somewhat greater potency against H. influenzae and M. catarrhalis, including ß-lactamase-producing strains. Unlike cefaclor, which undergoes degradation in human serum, loracarbef is chemically stable in plasma. It is absorbed well orally. Oral absorption is delayed by food. The half-life in plasma is about 1 hour.
Cephalothin sodium (Keflin) occurs as a white to off-white, crystalline powder that is practically odorless. It is freely soluble in water and insoluble in most organic solvents. Although it has been described as a broad-spectrum antibacterial compound, it is not in the same class as the tetra-cyclines. Its spectrum of activity is broader than that of penicillin G and more similar to that of ampicillin. Unlike ampicillin, cephalothin is resistant to penicillinase produced by S. aureus and provides an alternative to the use of penicillinase-resistant penicillins for the treatment of infections caused by such strains.
is relatively nontoxic and acid stable. It is excreted rapidly through the kidneys; about 60% is lost within 6 hours of administration. Pain at the site of intramuscular injection and thrombophlebitis following intravenous injection have been reported. Hypersensitivity reactions have been observed, and there is some evidence of cross-sensitivity in patients noted previously to be penicillin sensitive.
Cefazolin Sodium, Sterile
Cefazolin (Ancef, Kefzol) is one of a series of semisynthetic cephalosporins in which the C-3 acetoxy function has been replaced by a thiol-containing heterocycle—here, 5-methyl-2-thio-1,3,4-thiadiazole. It also contains the somewhat unusual tetrazolylacetyl acylating group. Cefazolin was released in 1973 as a water-soluble sodium salt. It is active only by parenteral administration.
Cefazolin provides higher serum levels, slower renal clearance, and a longer half-life than other first-generation cephalosporins. It is approximately 75% protein bound in plasma, a higher value than for most other cephalosporins. Early in vitro and clinical studies suggest that cefazolin is more active against Gram-negative bacilli but less active against Gram-positive cocci than either cephalothin or cephaloridine. Occurrence rates of thrombophlebitis following intravenous injection and pain at the site of intramuscular injection appear to be the lowest of the parenteral cephalosporins.
Cephapirin Sodium, Sterile
Cephapirin (Cefadyl) is a semisynthetic 7-ACA derivative released in the United States in 1974. It closely resembles cephalothin in chemical and pharmacokinetic properties. Like cephalothin, cephapirin is unstable in acid and must be administered parenterally in the form of an aqueous solution of the sodium salt. It is moderately protein bound (45%-50%) in plasma and cleared rapidly by the kidneys. Cephapirin and cephalothin are very similar in antimicrobial spectrum and potency. Conflicting reports concerning the relative occurrence of pain at the site of injection and thrombophlebitis after intravenous injection of cephapirin and cephalothin are difficult to assess on the basis of available clinical data.
Cephalothin is absorbed poorly from the GI tract and must be administered parenterally for systemic infections. It
Cefamandole (Mandol) nafate is the formate ester of cefamandole, a semisynthetic cephalosporin that incorporates d-mandelic acids as the acyl portion and a thiol-containing heterocycle (5-thio-1,2,3,4-tetrazole) in place of the acetoxyl function on the C-3 methylene carbon atom. Esterification of the a-hydroxyl group of the d-mandeloyl function overcomes the instability of cefamandole in solid-state dosage forms85 and provides satisfactory concentrations of the parent antibiotic in vivo through spontaneous hydrolysis of the ester at neutral to alkaline pH. Cefamandole is the first second-generation cephalosporin to be marketed in the United States.
The d-mandeloyl moiety of cefamandole appears to confer resistance to a few jS-lactamases, since some j-lactamase-producing, Gram-negative bacteria (particularly Enterobacteriaceae) that show resistance to cefazolin and other first-generation cephalosporins are sensitive to cefamandole. Additionally, it is active against some ampi-cillin-resistant strains of Neisseria and Haemophilus spp. Although resistance to S-lactamases may be a factor in determining the sensitivity of individual bacterial strains to cefamandole, an early study86 indicated that other factors, such as permeability and intrinsic activity, are frequently more important. The l-mandeloyl isomer is significantly less active than the d-isomer.
Cefamandole nafate is very unstable in solution and hydrolyzes rapidly to release cefamandole and formate. There is no loss of potency, however, when such solutions are stored for 24 hours at room temperature or up to 96 hours when refrigerated. Air oxidation of the released formate to carbon dioxide can cause pressure to build up in the injection vial.
Cefonicid Sodium, Sterile
Cefonicid Sodium (Monocid) is a second-generation cephalosporin that is structurally similar to cefamandole, except that it contains a methane sulfonic acid group attached to the N-1 position of the tetrazole ring. The antimicrobial spectrum and limited S-lactamase stability of cefonicid are essentially identical with those of cefamandole.
Cefonicid is unique among the second-generation cephalosporins in that it has an unusually long serum halflife of approximately 4.5 hours. High plasma protein binding coupled with slow renal tubular secretion are apparently responsible for the long duration of action. Despite the high fraction of drug bound in plasma, cefonicid is distributed throughout body fluids and tissues, with the exception of the cerebrospinal fluid.
Cefonicid is supplied as a highly water-soluble disodium salt, in the form of a sterile powder to be reconstituted for injection. Solutions are stable for 24 hours at 25°C and for 72 hours when refrigerated.
Ceforanide (Precef) was approved for clinical use in the United States in 1984. It is classified as a second-generation cephalosporin because its antimicrobial properties are similar to those of cefamandole. It exhibits excellent potency against most members of the Enterobacteriaceae family, especially K. pneumoniae, E. coli, P. mirabilis, and Enterobacter cloacae. It is less active than cefamandole against H. influenzae, however.
The duration of action of ceforanide lies between those of cefamandole and cefonicid. It has a serum half-life of about 3 hours, permitting twice-a-day dosing for most indications. Ceforanide is supplied as the sterile, crystalline disodium salt. Parenteral solutions are stable for 4 hours at 25°C and for up to 5 days when refrigerated.
Cefoperazone Sodium, Sterile
Cefoperazone (Cefobid) is a third-generation, anti-pseudomonal cephalosporin that resembles piperacillin chemically and microbiologically. It is active against many strains of P. aeruginosa, indole-positive Proteus spp., Enterobacter spp., and S. marcescens that are resistant to cefamandole. It is less active than cephalothin against Gram-positive bacteria and less active than cefamandole against most of the Enterobacteriaceae. Like piperacillin, cefoperazone is hydrolyzed by many of the S-lactamases that hydrolyze penicillins. Unlike piperacillin, however, it is resistant to some (but not all) of the S-lactamases that hydrolyze cephalosporins.
Cefoperazone is excreted primarily in the bile. Hepatic dysfunction can affect its clearance from the body. Although only 25% of the free antibiotic is recovered in the urine, urinary concentrations are high enough to be effective in the management of urinary tract infections caused by susceptible organisms. The relatively long half-life (2 hours) allows dosing twice a day. Solutions prepared from the crystalline sodium salt are stable for up to 4 hours at room temperature. If refrigerated, they will last 5 days without appreciable loss of potency.
Cefoxitin Sodium, Sterile
Cefoxitin (Mefoxin) is a semisynthetic derivative obtained by modification of cephamycin C, a 7a-methoxy-substituted cephalosporin isolated independently from various Streptomyces by research groups in Japan87 and the United States. Although it is less potent than cephalothin against Gram-positive bacteria and cefamandole against most of the Enterobacteriaceae, cefoxitin is effective against certain strains of Gram-negative bacilli (e.g., E. coli, K. pneumoniae, Providencia spp., S. marcescens, indole-positive Proteus spp., and Bacteroides spp.) that are resistant to these cephalosporins. It is also effective against penicillin-resistant S. aureus and N. gonorrhoeae.
inactivation of some of these enzymes. Cefotetan is reported to synergize with ¡-lactamase-sensitive ¡-lactams but, unlike cefoxitin, does not appear to cause antagonism.90
The activity of cefoxitin and cephamycins, in general, against resistant bacterial strains is because of their resistance to hydrolysis by ¡-lactamases conferred by the 7a-methoxyl substituent.88 Cefoxitin is a potent competitive inhibitor of many ¡-lactamases. It is also a potent inducer of chromosom-ally mediated ¡-lactamases. The temptation to exploit the ¡-lactamase-inhibiting properties of cefoxitin by combining it with ¡-lactamase-labile ¡-lactam antibiotics should be tempered by the possibility of antagonism. In fact, cefoxitin antagonizes the action of cefamandole against E. cloacae and that of carbenicillin against P. aeruginosa.89 Cefoxitin alone is essentially ineffective against these organisms.
The pharmacokinetic properties of cefoxitin resemble those of cefamandole. Because its half-life is relatively short, cefoxitin must be administered 3 or 4 times daily. Solutions of the sodium salt intended for parenteral administration are stable for 24 hours at room temperature and 1 week if refrigerated. 7a-Methoxyl substitution stabilizes, to some extent, the ¡-lactam to alkaline hydrolysis.
The principal role of cefoxitin in therapy seems to be for the treatment of certain anaerobic and mixed aerobic-anaerobic infections. It is also used to treat gonorrhea caused by ¡-lactamase-producing strains. It is classified as a second-generation agent because of its spectrum of activity.
Cefotetan (Cefotan) is a third-generation cephalosporin that is structurally similar to cefoxitin. Like cefoxitin, cefotetan is resistant to destruction by ¡-lactamases. It is also a competitive inhibitor of many ¡-lactamases and causes transient
The antibacterial spectrum of cefotetan closely resembles that of cefoxitin. It is, however, generally more active against S. aureus, and members of the Enterobacteriaceae family sensitive to both agents. It also exhibits excellent potency against H. influenzae and N. gonorrhoeae, including ¡-lactamase-producing strains. Cefotetan is slightly less active than cefoxitin against B. fragilis and other anaerobes. Enterobacter spp. are generally resistant to cefotetan, and the drug is without effect against Pseudomonas spp.
Cefotetan has a relatively long half-life of about 3.5 hours. It is administered on a twice-daily dosing schedule. It is excreted largely unchanged in the urine. Aqueous solutions for parenteral administration maintain potency for 24 hours at 25°C. Refrigerated solutions are stable for 4 days.
Cefotetan contains the MTT group that has been associated with hypoprothrombinemia and alcohol intolerance. Another cephalosporin that lacks these properties should be selected for patients at risk for severe bleeding or alcoholism.
Cefmetazole (Zefazone) is a semisynthetic, third-generation, parenteral cephalosporin of the cephamycin group. Like other cephamycins, the presence of the 7a-methoxyl group confers resistance to many ¡-lactamases. Cefmetazole exhibits significantly higher potency against members of the Enterobacteriaceae family but lower activity against Bacteroides spp. than cefoxitin. It is highly active against N. gonorrhoeae, including ¡-lactamase-producing strains. In common with other cephamycins, cefmetazole is ineffective against indole-positive Proteus, Enterobacter, Providencia, Serratia, and Pseudomonas spp. Cefmetazole has the MTT moiety associated with increased bleeding in certain high-risk patients. It has a plasma half-life of 1.1 hours.
Cefuroxime (Zinacef) is the first of a series of a-methoximi-noacyl-substituted cephalosporins that constitute most of the third-generation agents available for clinical use. A syn alkox-imino substituent is associated with ¡-lactamase stability in these cephalosporins.78 Cefuroxime is classified as a second-generation cephalosporin because its spectrum of antibacterial activity more closely resembles that of cefamandole. It is, however, active against ß-lactamase-producing strains that are resistant to cefamandole, such as E. coli, K. pneumoniae, N. gonorrhoeae, and H. influenzae. Other important Gramnegative pathogens, such as Serratia, indole-positive Proteus spp., P. aeruginosa, and B. fragilis, are resistant.
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