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The Cephalosporin Antibiotics
Symposium on Anti-Infective Therapy
The Cephalosporin Antibiotics JosephS. Bertino, Jr., Pharm. D.,* and William T. Speck, M.D.t
In 1945 Guiseppe Brotzu speculated that antibiotic-producing microorganisms were responsible for the good health of recreational bathers on the heavily polluted beaches of the Gulf of Cagliari on the southern coast of Sardinia. In support of this hypothesis he isolated a mold, Cephalosporium acremonium, from a local sewage effiuent and determined that this mold inhibited the growth of a number of microorganisms. Brotzu subsequently used extracts of his mold with apparent success to treat a variety of infections, including typhoid fever. 1 The major antibiotic produced by Brotzu's mold was identified in 1949 and named cephalosporin-N ("N" referring to the activity of this antibiotic against gram-negative microorganisms).1 In 1954 the structure of this compound was determined, and accordingly its name changed to penicillin-N. One year later Abraham and Newton isolated and characterized a minor fermentation product of Brotzu's mold, cephalosporin-C (Fig. 1), which, despite its limited intrinsic antibacterial activity, was resistant to hydrolysis by staphylococcal beta-lactamases and inhibited the growth of many penicillin-resistant gram-negative bacteria.1 Removal of the side chain of this molecule yielded a nucleus, 7aminocephalosporanic acid (Fig. 2), from which all subsequent cephalospo-
s R-C-NHD I II 0 ,
0
N
#
CH-R2
Figure 1.
Cephalosporin C.
COOH *Clinical Instructor, Department of Pediatrics, Division of Pediatric Pharmacology, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland Ohio tProfessor of Pediatrics and Chairman of Department of Pediatrics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio
Pediatric Clinics of North America-Vol. 30, No. 1, February 1983
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JOSEPH S. BERTINO, JR. AND WILLIAM
Figure 2.
T.
SPECK
7-Aminocephalosporic acid.
rins have been derived as semisynthetic compounds in a manner analogous to the development of the penicillins from 6-aminopenicillanic acid (Fig. 3). Structural manipulation of the cephalosporin nucleus has primarily involved two sites: the 7-acyl group of the beta-lactam ring with resultant change in the antibacterial spectrum of activity; and substitution in the third position on the dihydrothiazine ring, which changes the pharmacokinetic properties of the drug. 26 Chemical manipulation of the 7-aminocephalosporanic acid has resulted in the production of the oxa-beta-lactams. 26 More recently, another family of beta-lactam antibiotics has been discovered, the cephamycins (Fig. 4). Similar to the cephalosporins, these compounds differ by having a methoxy group in the 7-position of the betalactam ring and being produced naturally by actinomycetes rather than fungi. However like the cephalosporins, the cephamycins lend themselves to removal of the side-chain to provide a nucleus from which semisynthetic derivatives can be obtained. Antibacterial Activity Like the better-studied penicillins, the cephalosporins inhibit the latter stages of bacterial cell wall synthesis by interacting preferentially with one or more of the seven penicillin-binding proteins of the bacterial cell membrane. 35 Thus the intrinsic activity of a cephalosporin depends upon the ability of the antibiotic to penetrate the cell surface and its binding affinity to protein receptor molecules. The multiplicity of penicillin-binding proteins and the observation that most beta-lactam antibiotics bind only to one or two proteins suggest that beta-lactams that bind to different proteins may act synergistically when used in combination. 34 Microorganisms resist the antibacterial activity of the cephalosporins by several mechanisms acting alone or in combination. One major mecha-
5 Figure 3.
~,"----N--...._
o'
COOH
6-Aminopenicillanic acid.
19
THE CEPHALOSPORIN ANTIBIOTICS
COOH Figure 4.
Cephamycin C.
nism of resistance to this group of beta-lactams is by inhibiting uptake. Thus gram-negative bacteria are surrounded by an outer phospholipid membrane that retards the entry of various substrates, including cephalosporins. A second mechanism for resistance is the production of betalactamases, a group of enzymes that hydrolyze the beta-lactam ring of the cephalosporins and render the antibiotic ineffective. In general, gram-negative microorganisms produce a beta-lactamase that is more effective than that produced by gram-positive organisms. 21 Different cephalosporins vary in their sensitivity to hydrolysis by these enzymes; for example, cephalothin is the most resistant to gram-positive beta-lactamase, 21 while cefoxitin is the most resistant to gram-negative beta-lactamase. 5 • 21 Accordingly, the antibacterial properties of the various cephalosporins depend on a combination of factors acting simultaneously, which include the ability of the antibiotic to penetrate the bacteria and gain access to the target site, the affinity to bind to the proteins involved in cell wall synthesis, and the degree of resistance to beta-lactamases. Toxicity
The cephalosporins are remarkably free from significant toxicity. The local side effects of the cephalosporins are often trivial and include pain following intramuscular administration and thrombophlebitis following intravenous infusion. 21 Systemic reactions to the cephalosporins are uncommon, and include allergic, renal, hematologic, hepatic, and gastrointestinal manifestations. Hypersensitivity reactions (fever, rash, serum sickness, and eosinophilia) have been reported in 2 to 5 per cent of cephalosporin treated patients. 21 Cross-reactivity in patients with documented penicillin allergy ranges from 5 to 16 per cent, 21 and accordingly cephalosporins are avoided in patients with documented anaphylactic reactions due to penicillin.21 Renal manifestations are uncommon with the cephalosporins (cephaloridine is the exception); however, interstitial nephritis has been observed. 2 Hematologic side effects are also rare; however, positive Coombs test (3 per cent of patients) and reversible thrombocytopenia and leukopenia have been reported. 21 Hepatic and gastrointestinal side effects are uncommon and include hypoprothrombinemia responsive to vitamin K, transient liver enzyme elevations, and antabuse-like effect and pseudomembranous colitis. 7, s, 21. 21
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JOSEPH S. BERTINO, JR. AND WILLIAM
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FIRST GENERATION CEPHALOSPORINS The first generation cephalosporins (Table 1) have a similar spectrum of antibacterial activity and differ only in pharmacokinetic properties.16 Thus this group of cephalosporins is active against most streptococci, including S. pyogenes, S. pneumoniae, Group B streptococci, and the alpha· hemolytic streptococci of the viridans group. It is noteworthy that S. faecalis is resistant to all of the cephalosporins, although the nonenterococcal group D streptococci (for example, S. bovis) are usually quite sensitive. The staphylococci, including penicillinase-producing strains, are also sensitive to the first generation cephalosporins, however methicillin-resistant staphylococci are often resistant to them (methicillin-resistant staphylococci may appear sensitive by disc susceptibility testing, however, the minimal inhibitory concentration (MIC) of these microorganisms obtained by the tube dilution technique is often quite high). Gram-positive bacilli (Clostridum spp.) are quite sensitive; however, Listeria are of intermediate sensitivity. Among the non-hospital-acquired aerobic gram-negative enteric bacilli, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella, and Shigella spp. are usually sensitive. The Neisseria spp., Haemophilus injluenzae, and Bordetella pertussis are sensitive to high concentrations, while the indole-positive Proteus spp., Pseudomonas aeruginosa, and Serratia marcescens are invariably resistant. Despite good in vitro activity against many gram-positive and gram-negative anaerobic microorganisms, Bacteroides fragilis are resistant. The pharmacokinetic properties of these agents have similarities. In general, most of the first generation cephalosporins are completely eliminated by the kidney; however, two of the agents, cephalothin and cephapirin, are also deacetylated in the liver and then renally eliminated. 25 The first generation cephalosporins all achieve therapeutic concentrations in pleural, pericardia}, and synovial fluid, and in most tissue spaces, with the important exception of the central nervous system. Table 1.
The Cepha Antibiotics
FIRST GENERATION
Parenteral Cephalothin Cephaloridine Cefazolin Cephradine Cephapirin
Oral Cephaloglycin Cephalexin Cefadroxil Cephradine Cefadroxil
SECOND GENERATION
Cefamandol Cefoxitin Cefuroxime*
Cefaclor
THIRD GENERATION
Cefotaxime Moxalactam Cefoperazone* Cefsulodin * *Investigational.
Ceftizoxime* Ceftriaxone* Ceftazidime* Cefmenoxime*
THE CEPHALOSPORIN ANTIBIOTICS
21
Cephalothin. This was the first clinically available cephalosporin. Absorption following oral administration is minimal. Intramuscular injection of cephalothin is painful, and intravenous administration has been associated with thrombophlebitis. 22 In an effort to avoid this latter complication, buffering cephalothin to a pH of 7.0 with sodium bicarbonate has been attempted; however, no difference in the severity or incidence of thrombophlebitis has been noted.I 4 The short half-life necessitates a fourhour dosing schedule. Cephaloridine. The spectrum of activity of this cephalosporin is similar to cephalothin. The main disadvantage of cephaloridine is its potential for dose-related damage of the proximal tubules of the kidney. 2 There are a few, if any, indications for this agent. Cephapirin. This cephalosporin is similar to cephalothin in its spectrum of activity, pharmacokinetics, and toxicity. Clinical use in pediatric patients is limited, and cephapirin offers no advantages over cephalothin. Cephradine. This cephalosporin is similar in its spectrum of activity to cephalothin. Its major "advantage" is that it is the only cephalosporin commercially available in both oral and parenteral form. When used parenterally it offers no advantages over cephalothin. The pharmacokinetic properties and indications for oral use are identical to those of cephalexin (see below). Cefazolin. Although its spectrum of activity is similar to cephalothin its long half-life, higher serum and tissue concentrations, and the ease of administration-that is, better-tolerated intramuscular injection-make it the parenteral first generation cephalosporin of choice.2l, 25, 36 Cephalexin. The antibacterial spectrum of this oral agent is similar to that of cephalothin. Food interferes with the absorption of cephalexin, with reduced peak serum concentration (approximately 63 per cent) and an increase in the time necessary to achieve peak concentration (from 30 minutes to 60 minutes). 18 In infants less than six months of age cephalexin absorption is delayed with peak concentrations occurring up to three hours following oral administration. 25 This agent is excreted unchanged in the urine, where very high concentrations are found. 25 Cephalexin has been used extensively in treating pediatric patients with a variety of non-lifethreatening infections. 22 Cefadroxil. This is the newest of the first generation oral cephalosporins with an antibacterial spectrum similar to that of cephalexin. This agent is well absorbed even when administered with food. 9 The delayed urinary excretion of cefadroxil results in sustained serum and urine concentrations and permits administration on a twice daily basis. 9 In summary, the first generation cephalosporins have proven useful in the treatment of life-threatening non-central nervous system infections due to susceptible pathogens. The recent emergence of resistant gramnegative microorganisms precludes their use as single agents for the treatment of life-threatening infection due to an unknown pathogen. However, the combination of a first generation cephalosporin and an aminoglycoside provides satisfactory broad-spectrum coverage pending identification and susceptibility-testing of the responsible pathogen. The first generation cephalosporins also remain useful for prophylaxis in orthopedic and cardi-
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JOSEPHS. BERTINO, JR. AND WILLIAM
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SPECK
avascular surgery. 6 The oral first generation cephalosporins are valuable for treating non-life-threatening infections due to susceptible microorganisms, particularly in the penicillin-allergic child and for completing an antibiotic course in patients who have responded to initial parenteral treatment.
SECOND GENERATION CEPHALOSPORINS The second generation cephalosporins (Table 1) differ from the first generation agents in that they have an expanded spectrum of activity which includes many gram-negative microorganisms resistant to first generation cephalosporins and they are all very expensive. Like the first generation cephalosporins, these new agents are relatively nontoxic, efficacious in treating infections due to susceptible pathogens, do not cross the bloodbrain barrier consistently, and are all ineffective against Pseudomonas and enterococci. Cefamandole. This was the first of the second generation cephalosporins available in the United States. The activity of cefamandole against gram-positive microorganisms is equivalent to that of cephalothin; however, cefamandole is considerably more active against gram-negative microorganisms. 20 Thus this antibiotic is active against indole-positive Proteus spp., Enterobacter spp., Citrobacter spp., and Providencia spp. Cefamandole is also active against some strains of S . marcesens, and many cephalothin-resistant E. coli and Klebsiella. In addition, cefamandole has been successfully used to treat infections due to penicillinase-producing strains of N. gonorrhea and H. in.fluenzae. Cefamandole is administered parenterally with a six-hour dosage schedule. Cefaclor. This oral second generation cephalosporin has an antibacterial spectrum of activity similar to that of cefamandole. 19 In addition to its activity against gram-positive microorganisms, equivalent to cephalexin, this agent is more active than the oral first-generation cephalosporins against E. coli, Proteus spp., Klebsiella, and Enterobacter spp. Cefaclor is also active against H. in.fluenzae, including beta-lactamase-producing strains. Cefaclor is well absorbed when given with food and on an empty stomach. 9 Cefaclor finds its main pediatric use in the treatment of otitis media and only its high cost stands in the way of it totally replacing cephalexin. Cefoxitin. Cefoxitin is a parenteral cephamycin and accordingly differs structurally from the cephalosporins. The in vitro activity of cefoxitin is broader than cephalothin and the first generation cephalosporins except against gram-positive cocci where its in vitro activity is considerably less. Cefoxitin is extremely resistant to hydrolysis by beta-lactamases produced by gram-negative organisms and accordingly is active against many cephalothin-resistant gram-negative pathogens. 19 Thus cefoxitin is active against all gram-negative organisms susceptible to cefamandole, including some cefamandole-resistant E. coli and Klebsiella. Unlike cefamandole, cefoxitin has good activity against anaerobes, including B. fragilis .12 Pharmacokinetic properties resemble those of cephalothin, and accordingly the drug is often administered every four hours.
THE CEPHALOSPORIN ANTIBIOTICS
23
In summary, the second generation cephalosporins offer improved activity against many of the gram-negative microorganisms resistant to first generation agents. The major advantage of some of these agents in pediatric patients is their activity against H. influenzae.
THIRD GENERATION CEPHALOSPORINS The third generation cephalosporins (Table 1) represent a successful attempt to expand the gram-negative spectrum of activity of the second generation cephalosporins. These new agents share with the older cephalosporins a wide therapeutic index, freedom from significant toxicity even at high concentrations, and a lack of activity against the enterococcus. 21, 28 These new third generation cephalosporins differ from the first and second generation cephalosporins in a number of important aspects, including a markedly increased resistance to gram-negative beta-lactamases and accordingly an expanded activity against gram-negative microorganisms; pharmacokinetic properties that include in some instances a prolonged serum half-life, an ability to reach bacteriocidal concentrations in the cerebrospinal fluid and their high cost-often exceeding 10 dollars per gram. The first of the third generation cephalosporins to reach the market was cefotaxime, which was approved by the FDA in March 1981, followed by moxalactam, which was released in October 1981. There are presently many third generation cephalosporins in various stages of clinical testing, and undoubtedly some of these will be approved for use in pediatric patients. It is important to recall that many of these new third generation cephalosporins are very similar, and clinical studies to date have failed to demonstrate the superiority of any single agent. The antimicrobial activity of these new cephalosporins is primarily directed at gram-negative microorganisms. 28 Thus these agents are active in vitro against most E. coli, Klebsiella, Enterobacter, Proteus spp., Provi· dencia spp., Citrobacter spp. and many Serratia, even when such organisms are resistant to cephalothin or aminoglycosides. These agents also demonstrate good activity against Sal11Wnella, Shigella spp., Neisseria, and H. influenzae. Although the third generation cephalosporins have in vitro activity against P. aeruginosa, in most cases their activity is comparable to that of ticarcillin and thus less than that of gentamicin.21• 33 Despite expanded activity against most gram-negative bacteria, these agents are less active than cephalothin or cefamandole against gram-positive cocci, and in some cases their anaerobic activity is less than that of cefoxitin. Like the first and second generation cephalosporins, none of the third generation cephalosporins are active against enterococcus and suprainfection with this microorganism has been reported in patients treated with third generation agents. 37 Cefotaxime. This was the first third generation cephalosporin available in the United States. The spectrum of activity against gram-negative microorganisms exceeds that of the second generation cephalosporins and includes activity against many strains of P. aeruginosa, including some carbenicillin-resistant strains. However, the antipseudomonal activity of ce-
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JOSEPH S. BERTINO, JR. AND WILLIAM
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SPECK
fotaxime is only moderate, and reports suggest that 30 to 60 per cent of clinical isolates are resistant. 13· 23 Clinical studies in patients with Pseudomonas infections have been disappointing. Cefotaxime is reasonably active against gram-positive cocci; however, this activity is less than that observed with cephalothin or cefamandole. Preliminary studies suggest that cerebrospinal fluid concentrations of cefotaxime may be adequate to treat some patients with nonpseudomonas gram-negative meningitis. 4 Cefotaxime is both renally and hepatically eliminated, with an average half-life of 1. 5 hours.1° Moxalactam. This agent is a 1-oxa-beta-lactam and is the first totally synthetic beta-lactam antibiotic. Technically, moxalactam is not a true cephalosporin. Moxalactam is highly active against many gram-negative microorganisms, including many resistant to first and second generation cephalosporins; however, its antipseudomonas activity is similar to that of cefotaxime. 28 This agent is active against anaerobic microorganisms, including B. fragilis. Moxalactam is less active than cefotaxime against staphylococci and streptococci. Recent reports suggest that this antibiotic achieves cerebrospinal fluid levels approximately 30 per cent of serum, which are satisfactory for treating many cases of nonpseudomonas gram-negative meningitis. 31 Moxalactam is renally eliminated, with an average half-life (non-neonates) of 1.5 hours. 29 Because its half-life is significantly prolonged in the neonate (4.5 to 7.6 hours), dosing intervals of 8 to 12 hours may be used. 31 Cefoperazone. This is a piperazine cephalosporin that is less active than moxalactam and cefotaxime against many gram-negative organisms. The hallmark of cefoperazone is a significant amount of biliary excretion. 24 It does not seem to offer an advantage over presently available agents. Cefsulodin. This is a narrow spectrum third generation antipseudomonal cephalosporin with poor activity against other gram-negative microorganisms. Cefsulodin activity against Pseudomonas is greater than that of carbenicillin and comparable to gentamicin. 11 Carbenicillin-resistant P. aeruginosa are generally sensitive to cefsulodin. 11 Ceftazidime. This third generation agent is the most potent antipseudomonal under investigation.15 Not only is ceftazidime significantly more active against P. aeruginosa than other third generation agents, but it is also more active than gentamicin and carbenicillin. 15 The role of ceftazidime remains to be determined in the clinical setting. Ceftriaxone. This cephalosporin shows promise as an agent useful in treatment of childhood meningitis because of its ability to cross the bloodbrain barrier and inhibit susceptible organisms at low concentrations. 17 In addition, ceftriaxone has a half-life of six to seven hours (facilitating twicea-day dosing). 32 In summary, the third generation cephalosporins exhibit increased gram-negative activity (often at the expense of gram-positive activity), with increased tissue penetration (in the central nervous system). At the present time the role of these agents in the clinical setting is not well defined and more data are necessary to define their indications. It is hard to believe that this all began with the observation of Giu-
I
THE CEPHALOSPORIN ANTIBIOTICS
25
seppe Brotzu that bathers in heavily polluted waters along the southern coast of Sardinia were in good health.
REFERENCES 1. Abraham, E. P.: A Glimpse of the early history of the cephalosporins. Rev. Infect. Dis.: 1:99, 1979. 2. Appel, G. B., and Neu, H. C., The nephrotoxicity of antimicrobiol agents. New Engl. J. Med., 296:663, 722, 784, 1977. 3. Barza, M., and Miao, P. V. W.: Antimicrobial spectrum, Pharmacology and therapeutic use of antibiotics, Part 3:Cephalosporins. Am. J. Hosp. Pharm. 34:621, 1977. 4. Belohradsky, B. H., Bruch, K., Geiss, D., eta!.: Intravenous cefotaxime in children with . bacterial meningitis. Lancet, 1:61, 1980. 5. Davies, J.: General mechanisms of antimicrobial resistance. Rev. Infect. Dis., 1:23, 1979. 6. DiPiro, J. T., Record, K. E., Schanzenbach, K. S., eta!.: Antimicrobial prophylaxis in surgery. Am. J. Hosp. Pharm., 38:320, 487, 1981. 7. Fainstein, V., Elting, L., Bolivar, R., eta!.: Moxalactam and ticarillin or tobramycin for the treatment of neutropenic cancer patients. Twenty-First Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, November 4-6, 1981 (Abst. 317). 8. Foster, T. S., Raehl, C. L., and Wilson, H. D.: Disulfiram-like reaction associated with a parenteral cephalosporin. Am. J. Hosp. Pharm., 37:858, 1980. 9. Ginsburg, C. M., and McCracken, Jr., G. H.: Cefaclor and cefadroxil: A commentary on their properties and possible indications for use in pediatrics. J. Pediatr., 96:340, 1980. 10. Kafetzis, D. A., Brater, C. D., Kanarios, J. eta!.: Clinical pharmacology of cefotaxime in pediatric patients. Antimicrob Agents Chemother., 20:487, 1981. 11. King, A., Shannon, K., and Phillips, I.: In vitro activity of cefsulodin, an antipseudomonal cephalosporin to beta-lactamases, Antimicrob. Agents Chemother., 17:165, 1980. 12. Kirby, B. D., Busch, D. F., Cetron D. M., eta!.: Cefoxitin for treatment of infections due to anaerobic bacteria. Rev. Infect. Dis., 1:113, 1979. 13. Logast, H., Finner, S. H., and Klastersky, J.: Serum bactericidal activity ofmoxalactam and cetotaxime with and without tobramycin against Pseudomonas aeruginosa and Staphylococcus aureus. Antimicrob. Agents Chemother., 20:539, 1981. 14. Lipman, G. G.: Effect of buffering on the incidence and severity of cephalothin-induced phlebitis. Am. J. Hosp. Pharm., 31:266, 1974. 15. Livermore, D. M., Williams, R. J., and Williams, J. D., Comparison of the Beta-lactamase stability in the in-vitro activity of cefoperazone cefotaxime, cefsulodin, ceftazidime, moxalactam, and ceftriaxone against Pseudomonas aeruginosa. Antimicrob. Chemother., 8:323, 1981. 16. Mandell, G. L.: Cephalosporins. In Mandell, G. L., Douglas, R. G., Bennett, J. E. (eds.): Principles and Practice of Infectious Diseases. New York, John Wiley and Sons, 1979, p. 238. 17. Marchau, B., Tho, I. V., and Armengaud, M.: Diffusion of ceftriaxome (Ro 13-9904/001) in the cerebrospinal fluid. Chemotherapy, 27(Suppl. 1):37, 1981. 18. McCracken, Jr., G. H., Ginsburg, C. M., Clahsen, J., eta!.: Pharmacologic evaluation of orally administered antibiotics in infants and children: Effect of feeding on bioavailability. Pediatrics, 62:738, 1978. 19. McHenry, M. C., and Gavan, T. L.: Newer penicillin and cephalosporin antibiotics. Primary Care, 8:605, 1981. 20. Meyers, B. R., and Hirschman, S. Z.: Antibacterial activity of cefamandole in vitro. Infect. Dis. 137:525, 1978. 21. Murray, B. E., and Moellering, R. C.: Cephalosporins. Ann. Rev. Med., 32:559, 1981. 22. Nelson, J. D., Howard, J. B., and Shelton, S.: Oral antibiotic therapy for skeletal infections of children. J. Pediatr., eta!.: 92:131, 1978. 23. Neu, H. C., Aswaporez, N., Aswapokee, P., eta!.: HR 756, A new cephalosporin active against gram-positive and gram-negative aerobic and anaerobic bacteria. Antimicrob. Agents Chemother., 15:273, 1979.
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24. Neu, H. C.: A review and summary of the pharmacokinetics of cefoperazone: A new extended-spectrum beta-lactam antibiotic. Ther. Drug. Monitoring, 3:121, 1981. 25. Nightingale, C. H., Greene, D. S., and Quintiliani, R.: Pharmacokinetics and clinical of cephalosporin antibiotics. Pharm. Sci., 64:1899, 1975. 26. O'Callagban, C. H.: Description and classification of the newer cephalosporins and their relationships with the established compounds. J. Antimicrob. Chemother., 5:635, 1979. 27. Prince, A. S., and Neu, H. C.: Antibiotic associated pseudomembranous colitis in children. PEDIATR. CLIN. NORTH AM. 26:261, 1979. 28. Pulliam, L., Hadley, W. K., and Mills, J.: In vitro comparison of third-generation cephalosporins, piperacillin, dibekacin and other aminoglycosides against aerobic bacteria. Antimicrob. Agents Chemother., 19:490, 1981. 29. Reed, M. D., Bertino, Jr., J. S., Meyers, C. M., et al.: Pharmacokinetics ofmoxalactam in pediatric patients (abstract). Clin. Pharm. 31:268, 1982. 30. Richmond, M. H., (3-Lactam antibiotics and (3-lactamases: Two sides of a continuing story. Rev. Infect. Dis., 1:30, 1979. 31. Schaad, U. B., McCracken, Jr., G. H., Threlkeld, N., eta!.: Clinical evaluation of a new broad-spectrum oxa-beta-lactam antibiotic, moxalactam, in neonates and infants. J. Pediatr., 98:129, 1981. 32. Schaad, U. B, and Stoeckel, K.: Single-dose pharmacokinetics of ceftriaxone in infants and young children. Antimicrob. Agents Chemother., 21:248, 1982. 33. Shelton, S., Nelson, J. D., and McCracken, Jr., G. H.: In vitro susceptibility of gramnegative bacilli from pediatric patients to moxalactam, cefotaxime, Ro 13-9904, and other cephalosporins. Antimicrob. Agents Chemother., 18:476, 1980. 34. Sutherland, R., and Batchelor, F. R.: Synergistic activity of penicillins against penicillinase-producing gram-negative bacilli. Nature: 201:868, 1964. 35. Tomasz, A.: Penicillin-binding proteins in bacteria. Ann. Intern. Med., 96:502, 1982. 36. Weinstein, A. J.: The cephalosporins: Activity and clinical use. Drugs, 19:137, 1980. 37. Yu, V. K.: Enterococcal superinfection and colonization after therapy with moxalactam, a new broad spectrum antibiotic. Ann. Intern. Med., 94:784, 1981. Department of Pharmacy and Central Services The Mary Imogene Bassett Hospital Cooperstown, New York 13326
The Cephalosporin Antibiotics JosephS. Bertino, Jr., Pharm. D.,* and William T. Speck, M.D.t
In 1945 Guiseppe Brotzu speculated that antibiotic-producing microorganisms were responsible for the good health of recreational bathers on the heavily polluted beaches of the Gulf of Cagliari on the southern coast of Sardinia. In support of this hypothesis he isolated a mold, Cephalosporium acremonium, from a local sewage effiuent and determined that this mold inhibited the growth of a number of microorganisms. Brotzu subsequently used extracts of his mold with apparent success to treat a variety of infections, including typhoid fever. 1 The major antibiotic produced by Brotzu's mold was identified in 1949 and named cephalosporin-N ("N" referring to the activity of this antibiotic against gram-negative microorganisms).1 In 1954 the structure of this compound was determined, and accordingly its name changed to penicillin-N. One year later Abraham and Newton isolated and characterized a minor fermentation product of Brotzu's mold, cephalosporin-C (Fig. 1), which, despite its limited intrinsic antibacterial activity, was resistant to hydrolysis by staphylococcal beta-lactamases and inhibited the growth of many penicillin-resistant gram-negative bacteria.1 Removal of the side chain of this molecule yielded a nucleus, 7aminocephalosporanic acid (Fig. 2), from which all subsequent cephalospo-
s R-C-NHD I II 0 ,
0
N
#
CH-R2
Figure 1.
Cephalosporin C.
COOH *Clinical Instructor, Department of Pediatrics, Division of Pediatric Pharmacology, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland Ohio tProfessor of Pediatrics and Chairman of Department of Pediatrics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio
Pediatric Clinics of North America-Vol. 30, No. 1, February 1983
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JOSEPH S. BERTINO, JR. AND WILLIAM
Figure 2.
T.
SPECK
7-Aminocephalosporic acid.
rins have been derived as semisynthetic compounds in a manner analogous to the development of the penicillins from 6-aminopenicillanic acid (Fig. 3). Structural manipulation of the cephalosporin nucleus has primarily involved two sites: the 7-acyl group of the beta-lactam ring with resultant change in the antibacterial spectrum of activity; and substitution in the third position on the dihydrothiazine ring, which changes the pharmacokinetic properties of the drug. 26 Chemical manipulation of the 7-aminocephalosporanic acid has resulted in the production of the oxa-beta-lactams. 26 More recently, another family of beta-lactam antibiotics has been discovered, the cephamycins (Fig. 4). Similar to the cephalosporins, these compounds differ by having a methoxy group in the 7-position of the betalactam ring and being produced naturally by actinomycetes rather than fungi. However like the cephalosporins, the cephamycins lend themselves to removal of the side-chain to provide a nucleus from which semisynthetic derivatives can be obtained. Antibacterial Activity Like the better-studied penicillins, the cephalosporins inhibit the latter stages of bacterial cell wall synthesis by interacting preferentially with one or more of the seven penicillin-binding proteins of the bacterial cell membrane. 35 Thus the intrinsic activity of a cephalosporin depends upon the ability of the antibiotic to penetrate the cell surface and its binding affinity to protein receptor molecules. The multiplicity of penicillin-binding proteins and the observation that most beta-lactam antibiotics bind only to one or two proteins suggest that beta-lactams that bind to different proteins may act synergistically when used in combination. 34 Microorganisms resist the antibacterial activity of the cephalosporins by several mechanisms acting alone or in combination. One major mecha-
5 Figure 3.
~,"----N--...._
o'
COOH
6-Aminopenicillanic acid.
19
THE CEPHALOSPORIN ANTIBIOTICS
COOH Figure 4.
Cephamycin C.
nism of resistance to this group of beta-lactams is by inhibiting uptake. Thus gram-negative bacteria are surrounded by an outer phospholipid membrane that retards the entry of various substrates, including cephalosporins. A second mechanism for resistance is the production of betalactamases, a group of enzymes that hydrolyze the beta-lactam ring of the cephalosporins and render the antibiotic ineffective. In general, gram-negative microorganisms produce a beta-lactamase that is more effective than that produced by gram-positive organisms. 21 Different cephalosporins vary in their sensitivity to hydrolysis by these enzymes; for example, cephalothin is the most resistant to gram-positive beta-lactamase, 21 while cefoxitin is the most resistant to gram-negative beta-lactamase. 5 • 21 Accordingly, the antibacterial properties of the various cephalosporins depend on a combination of factors acting simultaneously, which include the ability of the antibiotic to penetrate the bacteria and gain access to the target site, the affinity to bind to the proteins involved in cell wall synthesis, and the degree of resistance to beta-lactamases. Toxicity
The cephalosporins are remarkably free from significant toxicity. The local side effects of the cephalosporins are often trivial and include pain following intramuscular administration and thrombophlebitis following intravenous infusion. 21 Systemic reactions to the cephalosporins are uncommon, and include allergic, renal, hematologic, hepatic, and gastrointestinal manifestations. Hypersensitivity reactions (fever, rash, serum sickness, and eosinophilia) have been reported in 2 to 5 per cent of cephalosporin treated patients. 21 Cross-reactivity in patients with documented penicillin allergy ranges from 5 to 16 per cent, 21 and accordingly cephalosporins are avoided in patients with documented anaphylactic reactions due to penicillin.21 Renal manifestations are uncommon with the cephalosporins (cephaloridine is the exception); however, interstitial nephritis has been observed. 2 Hematologic side effects are also rare; however, positive Coombs test (3 per cent of patients) and reversible thrombocytopenia and leukopenia have been reported. 21 Hepatic and gastrointestinal side effects are uncommon and include hypoprothrombinemia responsive to vitamin K, transient liver enzyme elevations, and antabuse-like effect and pseudomembranous colitis. 7, s, 21. 21
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FIRST GENERATION CEPHALOSPORINS The first generation cephalosporins (Table 1) have a similar spectrum of antibacterial activity and differ only in pharmacokinetic properties.16 Thus this group of cephalosporins is active against most streptococci, including S. pyogenes, S. pneumoniae, Group B streptococci, and the alpha· hemolytic streptococci of the viridans group. It is noteworthy that S. faecalis is resistant to all of the cephalosporins, although the nonenterococcal group D streptococci (for example, S. bovis) are usually quite sensitive. The staphylococci, including penicillinase-producing strains, are also sensitive to the first generation cephalosporins, however methicillin-resistant staphylococci are often resistant to them (methicillin-resistant staphylococci may appear sensitive by disc susceptibility testing, however, the minimal inhibitory concentration (MIC) of these microorganisms obtained by the tube dilution technique is often quite high). Gram-positive bacilli (Clostridum spp.) are quite sensitive; however, Listeria are of intermediate sensitivity. Among the non-hospital-acquired aerobic gram-negative enteric bacilli, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella, and Shigella spp. are usually sensitive. The Neisseria spp., Haemophilus injluenzae, and Bordetella pertussis are sensitive to high concentrations, while the indole-positive Proteus spp., Pseudomonas aeruginosa, and Serratia marcescens are invariably resistant. Despite good in vitro activity against many gram-positive and gram-negative anaerobic microorganisms, Bacteroides fragilis are resistant. The pharmacokinetic properties of these agents have similarities. In general, most of the first generation cephalosporins are completely eliminated by the kidney; however, two of the agents, cephalothin and cephapirin, are also deacetylated in the liver and then renally eliminated. 25 The first generation cephalosporins all achieve therapeutic concentrations in pleural, pericardia}, and synovial fluid, and in most tissue spaces, with the important exception of the central nervous system. Table 1.
The Cepha Antibiotics
FIRST GENERATION
Parenteral Cephalothin Cephaloridine Cefazolin Cephradine Cephapirin
Oral Cephaloglycin Cephalexin Cefadroxil Cephradine Cefadroxil
SECOND GENERATION
Cefamandol Cefoxitin Cefuroxime*
Cefaclor
THIRD GENERATION
Cefotaxime Moxalactam Cefoperazone* Cefsulodin * *Investigational.
Ceftizoxime* Ceftriaxone* Ceftazidime* Cefmenoxime*
THE CEPHALOSPORIN ANTIBIOTICS
21
Cephalothin. This was the first clinically available cephalosporin. Absorption following oral administration is minimal. Intramuscular injection of cephalothin is painful, and intravenous administration has been associated with thrombophlebitis. 22 In an effort to avoid this latter complication, buffering cephalothin to a pH of 7.0 with sodium bicarbonate has been attempted; however, no difference in the severity or incidence of thrombophlebitis has been noted.I 4 The short half-life necessitates a fourhour dosing schedule. Cephaloridine. The spectrum of activity of this cephalosporin is similar to cephalothin. The main disadvantage of cephaloridine is its potential for dose-related damage of the proximal tubules of the kidney. 2 There are a few, if any, indications for this agent. Cephapirin. This cephalosporin is similar to cephalothin in its spectrum of activity, pharmacokinetics, and toxicity. Clinical use in pediatric patients is limited, and cephapirin offers no advantages over cephalothin. Cephradine. This cephalosporin is similar in its spectrum of activity to cephalothin. Its major "advantage" is that it is the only cephalosporin commercially available in both oral and parenteral form. When used parenterally it offers no advantages over cephalothin. The pharmacokinetic properties and indications for oral use are identical to those of cephalexin (see below). Cefazolin. Although its spectrum of activity is similar to cephalothin its long half-life, higher serum and tissue concentrations, and the ease of administration-that is, better-tolerated intramuscular injection-make it the parenteral first generation cephalosporin of choice.2l, 25, 36 Cephalexin. The antibacterial spectrum of this oral agent is similar to that of cephalothin. Food interferes with the absorption of cephalexin, with reduced peak serum concentration (approximately 63 per cent) and an increase in the time necessary to achieve peak concentration (from 30 minutes to 60 minutes). 18 In infants less than six months of age cephalexin absorption is delayed with peak concentrations occurring up to three hours following oral administration. 25 This agent is excreted unchanged in the urine, where very high concentrations are found. 25 Cephalexin has been used extensively in treating pediatric patients with a variety of non-lifethreatening infections. 22 Cefadroxil. This is the newest of the first generation oral cephalosporins with an antibacterial spectrum similar to that of cephalexin. This agent is well absorbed even when administered with food. 9 The delayed urinary excretion of cefadroxil results in sustained serum and urine concentrations and permits administration on a twice daily basis. 9 In summary, the first generation cephalosporins have proven useful in the treatment of life-threatening non-central nervous system infections due to susceptible pathogens. The recent emergence of resistant gramnegative microorganisms precludes their use as single agents for the treatment of life-threatening infection due to an unknown pathogen. However, the combination of a first generation cephalosporin and an aminoglycoside provides satisfactory broad-spectrum coverage pending identification and susceptibility-testing of the responsible pathogen. The first generation cephalosporins also remain useful for prophylaxis in orthopedic and cardi-
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avascular surgery. 6 The oral first generation cephalosporins are valuable for treating non-life-threatening infections due to susceptible microorganisms, particularly in the penicillin-allergic child and for completing an antibiotic course in patients who have responded to initial parenteral treatment.
SECOND GENERATION CEPHALOSPORINS The second generation cephalosporins (Table 1) differ from the first generation agents in that they have an expanded spectrum of activity which includes many gram-negative microorganisms resistant to first generation cephalosporins and they are all very expensive. Like the first generation cephalosporins, these new agents are relatively nontoxic, efficacious in treating infections due to susceptible pathogens, do not cross the bloodbrain barrier consistently, and are all ineffective against Pseudomonas and enterococci. Cefamandole. This was the first of the second generation cephalosporins available in the United States. The activity of cefamandole against gram-positive microorganisms is equivalent to that of cephalothin; however, cefamandole is considerably more active against gram-negative microorganisms. 20 Thus this antibiotic is active against indole-positive Proteus spp., Enterobacter spp., Citrobacter spp., and Providencia spp. Cefamandole is also active against some strains of S . marcesens, and many cephalothin-resistant E. coli and Klebsiella. In addition, cefamandole has been successfully used to treat infections due to penicillinase-producing strains of N. gonorrhea and H. in.fluenzae. Cefamandole is administered parenterally with a six-hour dosage schedule. Cefaclor. This oral second generation cephalosporin has an antibacterial spectrum of activity similar to that of cefamandole. 19 In addition to its activity against gram-positive microorganisms, equivalent to cephalexin, this agent is more active than the oral first-generation cephalosporins against E. coli, Proteus spp., Klebsiella, and Enterobacter spp. Cefaclor is also active against H. in.fluenzae, including beta-lactamase-producing strains. Cefaclor is well absorbed when given with food and on an empty stomach. 9 Cefaclor finds its main pediatric use in the treatment of otitis media and only its high cost stands in the way of it totally replacing cephalexin. Cefoxitin. Cefoxitin is a parenteral cephamycin and accordingly differs structurally from the cephalosporins. The in vitro activity of cefoxitin is broader than cephalothin and the first generation cephalosporins except against gram-positive cocci where its in vitro activity is considerably less. Cefoxitin is extremely resistant to hydrolysis by beta-lactamases produced by gram-negative organisms and accordingly is active against many cephalothin-resistant gram-negative pathogens. 19 Thus cefoxitin is active against all gram-negative organisms susceptible to cefamandole, including some cefamandole-resistant E. coli and Klebsiella. Unlike cefamandole, cefoxitin has good activity against anaerobes, including B. fragilis .12 Pharmacokinetic properties resemble those of cephalothin, and accordingly the drug is often administered every four hours.
THE CEPHALOSPORIN ANTIBIOTICS
23
In summary, the second generation cephalosporins offer improved activity against many of the gram-negative microorganisms resistant to first generation agents. The major advantage of some of these agents in pediatric patients is their activity against H. influenzae.
THIRD GENERATION CEPHALOSPORINS The third generation cephalosporins (Table 1) represent a successful attempt to expand the gram-negative spectrum of activity of the second generation cephalosporins. These new agents share with the older cephalosporins a wide therapeutic index, freedom from significant toxicity even at high concentrations, and a lack of activity against the enterococcus. 21, 28 These new third generation cephalosporins differ from the first and second generation cephalosporins in a number of important aspects, including a markedly increased resistance to gram-negative beta-lactamases and accordingly an expanded activity against gram-negative microorganisms; pharmacokinetic properties that include in some instances a prolonged serum half-life, an ability to reach bacteriocidal concentrations in the cerebrospinal fluid and their high cost-often exceeding 10 dollars per gram. The first of the third generation cephalosporins to reach the market was cefotaxime, which was approved by the FDA in March 1981, followed by moxalactam, which was released in October 1981. There are presently many third generation cephalosporins in various stages of clinical testing, and undoubtedly some of these will be approved for use in pediatric patients. It is important to recall that many of these new third generation cephalosporins are very similar, and clinical studies to date have failed to demonstrate the superiority of any single agent. The antimicrobial activity of these new cephalosporins is primarily directed at gram-negative microorganisms. 28 Thus these agents are active in vitro against most E. coli, Klebsiella, Enterobacter, Proteus spp., Provi· dencia spp., Citrobacter spp. and many Serratia, even when such organisms are resistant to cephalothin or aminoglycosides. These agents also demonstrate good activity against Sal11Wnella, Shigella spp., Neisseria, and H. influenzae. Although the third generation cephalosporins have in vitro activity against P. aeruginosa, in most cases their activity is comparable to that of ticarcillin and thus less than that of gentamicin.21• 33 Despite expanded activity against most gram-negative bacteria, these agents are less active than cephalothin or cefamandole against gram-positive cocci, and in some cases their anaerobic activity is less than that of cefoxitin. Like the first and second generation cephalosporins, none of the third generation cephalosporins are active against enterococcus and suprainfection with this microorganism has been reported in patients treated with third generation agents. 37 Cefotaxime. This was the first third generation cephalosporin available in the United States. The spectrum of activity against gram-negative microorganisms exceeds that of the second generation cephalosporins and includes activity against many strains of P. aeruginosa, including some carbenicillin-resistant strains. However, the antipseudomonal activity of ce-
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JOSEPH S. BERTINO, JR. AND WILLIAM
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fotaxime is only moderate, and reports suggest that 30 to 60 per cent of clinical isolates are resistant. 13· 23 Clinical studies in patients with Pseudomonas infections have been disappointing. Cefotaxime is reasonably active against gram-positive cocci; however, this activity is less than that observed with cephalothin or cefamandole. Preliminary studies suggest that cerebrospinal fluid concentrations of cefotaxime may be adequate to treat some patients with nonpseudomonas gram-negative meningitis. 4 Cefotaxime is both renally and hepatically eliminated, with an average half-life of 1. 5 hours.1° Moxalactam. This agent is a 1-oxa-beta-lactam and is the first totally synthetic beta-lactam antibiotic. Technically, moxalactam is not a true cephalosporin. Moxalactam is highly active against many gram-negative microorganisms, including many resistant to first and second generation cephalosporins; however, its antipseudomonas activity is similar to that of cefotaxime. 28 This agent is active against anaerobic microorganisms, including B. fragilis. Moxalactam is less active than cefotaxime against staphylococci and streptococci. Recent reports suggest that this antibiotic achieves cerebrospinal fluid levels approximately 30 per cent of serum, which are satisfactory for treating many cases of nonpseudomonas gram-negative meningitis. 31 Moxalactam is renally eliminated, with an average half-life (non-neonates) of 1.5 hours. 29 Because its half-life is significantly prolonged in the neonate (4.5 to 7.6 hours), dosing intervals of 8 to 12 hours may be used. 31 Cefoperazone. This is a piperazine cephalosporin that is less active than moxalactam and cefotaxime against many gram-negative organisms. The hallmark of cefoperazone is a significant amount of biliary excretion. 24 It does not seem to offer an advantage over presently available agents. Cefsulodin. This is a narrow spectrum third generation antipseudomonal cephalosporin with poor activity against other gram-negative microorganisms. Cefsulodin activity against Pseudomonas is greater than that of carbenicillin and comparable to gentamicin. 11 Carbenicillin-resistant P. aeruginosa are generally sensitive to cefsulodin. 11 Ceftazidime. This third generation agent is the most potent antipseudomonal under investigation.15 Not only is ceftazidime significantly more active against P. aeruginosa than other third generation agents, but it is also more active than gentamicin and carbenicillin. 15 The role of ceftazidime remains to be determined in the clinical setting. Ceftriaxone. This cephalosporin shows promise as an agent useful in treatment of childhood meningitis because of its ability to cross the bloodbrain barrier and inhibit susceptible organisms at low concentrations. 17 In addition, ceftriaxone has a half-life of six to seven hours (facilitating twicea-day dosing). 32 In summary, the third generation cephalosporins exhibit increased gram-negative activity (often at the expense of gram-positive activity), with increased tissue penetration (in the central nervous system). At the present time the role of these agents in the clinical setting is not well defined and more data are necessary to define their indications. It is hard to believe that this all began with the observation of Giu-
I
THE CEPHALOSPORIN ANTIBIOTICS
25
seppe Brotzu that bathers in heavily polluted waters along the southern coast of Sardinia were in good health.
REFERENCES 1. Abraham, E. P.: A Glimpse of the early history of the cephalosporins. Rev. Infect. Dis.: 1:99, 1979. 2. Appel, G. B., and Neu, H. C., The nephrotoxicity of antimicrobiol agents. New Engl. J. Med., 296:663, 722, 784, 1977. 3. Barza, M., and Miao, P. V. W.: Antimicrobial spectrum, Pharmacology and therapeutic use of antibiotics, Part 3:Cephalosporins. Am. J. Hosp. Pharm. 34:621, 1977. 4. Belohradsky, B. H., Bruch, K., Geiss, D., eta!.: Intravenous cefotaxime in children with . bacterial meningitis. Lancet, 1:61, 1980. 5. Davies, J.: General mechanisms of antimicrobial resistance. Rev. Infect. Dis., 1:23, 1979. 6. DiPiro, J. T., Record, K. E., Schanzenbach, K. S., eta!.: Antimicrobial prophylaxis in surgery. Am. J. Hosp. Pharm., 38:320, 487, 1981. 7. Fainstein, V., Elting, L., Bolivar, R., eta!.: Moxalactam and ticarillin or tobramycin for the treatment of neutropenic cancer patients. Twenty-First Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, November 4-6, 1981 (Abst. 317). 8. Foster, T. S., Raehl, C. L., and Wilson, H. D.: Disulfiram-like reaction associated with a parenteral cephalosporin. Am. J. Hosp. Pharm., 37:858, 1980. 9. Ginsburg, C. M., and McCracken, Jr., G. H.: Cefaclor and cefadroxil: A commentary on their properties and possible indications for use in pediatrics. J. Pediatr., 96:340, 1980. 10. Kafetzis, D. A., Brater, C. D., Kanarios, J. eta!.: Clinical pharmacology of cefotaxime in pediatric patients. Antimicrob Agents Chemother., 20:487, 1981. 11. King, A., Shannon, K., and Phillips, I.: In vitro activity of cefsulodin, an antipseudomonal cephalosporin to beta-lactamases, Antimicrob. Agents Chemother., 17:165, 1980. 12. Kirby, B. D., Busch, D. F., Cetron D. M., eta!.: Cefoxitin for treatment of infections due to anaerobic bacteria. Rev. Infect. Dis., 1:113, 1979. 13. Logast, H., Finner, S. H., and Klastersky, J.: Serum bactericidal activity ofmoxalactam and cetotaxime with and without tobramycin against Pseudomonas aeruginosa and Staphylococcus aureus. Antimicrob. Agents Chemother., 20:539, 1981. 14. Lipman, G. G.: Effect of buffering on the incidence and severity of cephalothin-induced phlebitis. Am. J. Hosp. Pharm., 31:266, 1974. 15. Livermore, D. M., Williams, R. J., and Williams, J. D., Comparison of the Beta-lactamase stability in the in-vitro activity of cefoperazone cefotaxime, cefsulodin, ceftazidime, moxalactam, and ceftriaxone against Pseudomonas aeruginosa. Antimicrob. Chemother., 8:323, 1981. 16. Mandell, G. L.: Cephalosporins. In Mandell, G. L., Douglas, R. G., Bennett, J. E. (eds.): Principles and Practice of Infectious Diseases. New York, John Wiley and Sons, 1979, p. 238. 17. Marchau, B., Tho, I. V., and Armengaud, M.: Diffusion of ceftriaxome (Ro 13-9904/001) in the cerebrospinal fluid. Chemotherapy, 27(Suppl. 1):37, 1981. 18. McCracken, Jr., G. H., Ginsburg, C. M., Clahsen, J., eta!.: Pharmacologic evaluation of orally administered antibiotics in infants and children: Effect of feeding on bioavailability. Pediatrics, 62:738, 1978. 19. McHenry, M. C., and Gavan, T. L.: Newer penicillin and cephalosporin antibiotics. Primary Care, 8:605, 1981. 20. Meyers, B. R., and Hirschman, S. Z.: Antibacterial activity of cefamandole in vitro. Infect. Dis. 137:525, 1978. 21. Murray, B. E., and Moellering, R. C.: Cephalosporins. Ann. Rev. Med., 32:559, 1981. 22. Nelson, J. D., Howard, J. B., and Shelton, S.: Oral antibiotic therapy for skeletal infections of children. J. Pediatr., eta!.: 92:131, 1978. 23. Neu, H. C., Aswaporez, N., Aswapokee, P., eta!.: HR 756, A new cephalosporin active against gram-positive and gram-negative aerobic and anaerobic bacteria. Antimicrob. Agents Chemother., 15:273, 1979.
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24. Neu, H. C.: A review and summary of the pharmacokinetics of cefoperazone: A new extended-spectrum beta-lactam antibiotic. Ther. Drug. Monitoring, 3:121, 1981. 25. Nightingale, C. H., Greene, D. S., and Quintiliani, R.: Pharmacokinetics and clinical of cephalosporin antibiotics. Pharm. Sci., 64:1899, 1975. 26. O'Callagban, C. H.: Description and classification of the newer cephalosporins and their relationships with the established compounds. J. Antimicrob. Chemother., 5:635, 1979. 27. Prince, A. S., and Neu, H. C.: Antibiotic associated pseudomembranous colitis in children. PEDIATR. CLIN. NORTH AM. 26:261, 1979. 28. Pulliam, L., Hadley, W. K., and Mills, J.: In vitro comparison of third-generation cephalosporins, piperacillin, dibekacin and other aminoglycosides against aerobic bacteria. Antimicrob. Agents Chemother., 19:490, 1981. 29. Reed, M. D., Bertino, Jr., J. S., Meyers, C. M., et al.: Pharmacokinetics ofmoxalactam in pediatric patients (abstract). Clin. Pharm. 31:268, 1982. 30. Richmond, M. H., (3-Lactam antibiotics and (3-lactamases: Two sides of a continuing story. Rev. Infect. Dis., 1:30, 1979. 31. Schaad, U. B., McCracken, Jr., G. H., Threlkeld, N., eta!.: Clinical evaluation of a new broad-spectrum oxa-beta-lactam antibiotic, moxalactam, in neonates and infants. J. Pediatr., 98:129, 1981. 32. Schaad, U. B, and Stoeckel, K.: Single-dose pharmacokinetics of ceftriaxone in infants and young children. Antimicrob. Agents Chemother., 21:248, 1982. 33. Shelton, S., Nelson, J. D., and McCracken, Jr., G. H.: In vitro susceptibility of gramnegative bacilli from pediatric patients to moxalactam, cefotaxime, Ro 13-9904, and other cephalosporins. Antimicrob. Agents Chemother., 18:476, 1980. 34. Sutherland, R., and Batchelor, F. R.: Synergistic activity of penicillins against penicillinase-producing gram-negative bacilli. Nature: 201:868, 1964. 35. Tomasz, A.: Penicillin-binding proteins in bacteria. Ann. Intern. Med., 96:502, 1982. 36. Weinstein, A. J.: The cephalosporins: Activity and clinical use. Drugs, 19:137, 1980. 37. Yu, V. K.: Enterococcal superinfection and colonization after therapy with moxalactam, a new broad spectrum antibiotic. Ann. Intern. Med., 94:784, 1981. Department of Pharmacy and Central Services The Mary Imogene Bassett Hospital Cooperstown, New York 13326