ACTA FAC. MED. NAISS. 2003; 20 (2): 131-136

Review article

CEPHALOSPORINS

Pešić Gordana, Jović Zorica, Oputa Karin

Department of Pharmacology and Toxicology, Faculty of Medicine Nis

INTRODUCTION

The cephalosporins and their 7-methoxy analogs, the cephamycins such as cefoxitis, cefotetan and cefmetazole are b-lactam antibiotics that are closely related to penicillins. Most cephalosporins are produced semi-synthetically by the attachment of side chains to 7-aminocephalosporanic acid.

Mechanism of action

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

Resistance

Mechanisms of bacterial resistance to the cephalosporins are essentially the same as those for penicillins.

Classification

Cephalosporins may be classified by their antimicrobial spectrum into four generations (7), although some authors divide cephalosporins in seven groups (table 1).

The first generation cephalosporins have good activity against gram-positive bacteria and relatively modest activity against gram-negative bacteria. Streptococci and pneumococci are susceptible. Some species of Staphylococci are sensitive to this generation, but not methicillin-resistant S. aureus and S. epidermidis. Enterococci are resistant too. Activity against Moraxella catarrhalis, E. coli, K. pneumoniae and P. mirabilis is good. Most oral cavity anaerobes are sensitive.

The second generation cephalosporins have increased activity against gram-negative bacteria, but are less active than third-generation agents. Cefoxitin, cefotetan and cefmetazole are active as well against B. fragilis group.

The third generation cephalosporins are generally less active than first-generation agents against gram-positive cocci, but they are much more active against Enterobacteriaceae, including b-lactamase-producing strains (1).

Ceftazidime and cefoperazone are active against P. aeruginosa, but less active than the rest third-generation agents against gram-positive cocci.

The fourth generation cephalosporins such as cefepime and cefpirom have an extended spectrum of activity compared to the third-generation and have increased stability to b-lactamase-producing bacteria (table 2).

table 1. Cephalosporins-generations and routes of administration

Table 2. Groups of cephalosporins

Pharmacokinetics

ADMINISTRATION

All the cephalosporins (except cephalexin, cefprozil, cefaclor, cefixime, cephradine, loracarbef, cefprozil, cefpodoxime and ceftibuten) must be administered parentally because of their poor oral absorption. All the cephalosporins distribute very well into body fluids. Some of them such as cephoperazone, cefuroxime, cefotaxime, ceftriaxone, cefepime and ceftizoxime penetrate into cerebrospinal fluid and achieve sufficient concentrations to be useful for treatment of meningitis. Cephalosporins are found in synovial and pericardial fluid and aqueous humor of the eye after systemic administration. These antibiotics also cross the placenta. The cephalosporins do not undergo appreciable biotransformation in liver except cephalothin, cephapirin and cefotaxime. Thus, they are eliminated by kidney in unchanged form by glomerular filtration and tubular secretion. Dosage must be adjusted in patients with renal insufficiency.

Cefoperazone and ceftriaxone are excreted through the bile into the feces and are frequently used in patients with renal failure.

THERAPEUTIC USES

Oral Cephalosporins

Generally, oral cephalosporins are indicated for treatment of respiratory infections, recurrent urinary infections, skin infections, infections of soft tissues or bones caused by gram-negative bacteria or when patients are allergic to penicillins.

Cephalexine is very effective against gram-positive bacteria, but less active against gram-negative bacteria. It is recommended for treatment of urinary infections in pregnant women if they do not react to other drugs. Oral therapy is effective after a dose of 0,5 g every 3-4 times a day.

Cefaclor is used orally and is very active against Branhamella catarrhalis and H. influenza. Recommended dosage is 0,5 g every 3-4 times a day.

Cefpodoxime belongs to a third-generation cephalosporin for oral administration with similar antibacterial spectrum such as cefixime, except that it is less active against S. aureus. Cefpodoxime is the most active oral cephalosporin for treatment of infections of upper and lower respiratory tract. The dose is 0,1-0,2 g during 5 days for upper respiratory tract infections, while infections of the lower respiratory tract must be treated during the period of 7 to14 days.

Cefixime is less active against gram-positive cocci, but very active against Enterobacteriaceae and b-lactamase-producing H. influenza, M. catarrhalis and N. gonorrhoeae. It has poor activity against S. aureus. Cefixime has been utilized for respiratory infections and for treatment of uncomplicated urinary infections. Cefixime is the only oral cephalosporin that may be administered once a day in a dose of 0,4 g during  the period of 5 to 15 days.

Ceftibuten is similar to cefixime and cefaclor, but is less active against pneumococci.

Parenteral cephalosporins

Parenteral cephalosporins are very useful for the treatment of:

1.      infections in patients that are allergic to penicillins, but in such situations  great caution must be taken.

2.      intra-hospital acquired infections caused by gram-negative bacteria such as pneumonia, sepsis and other.

3.      mixed bacterial infections whose etiology is unknown.

4.      Surgical prophylaxis during gastrointestinal, pelvic or orthopedic procedures.

5.      Meningitis caused by gram-positive bacteria and gram-negative bacteria.

6.      gonorrhea, since  gonococci frequently produce b-lactamases.

The first and the second generation cephalosporins are not widely used now, except for cefazolin that has a high activity against Staphylococci. Due to that fact, cefazolin is a drug of choice for surgical prophylaxis and for treatment of postoperative infections as well.

Cefamandole is active against Enterobacter species, indol-positive Proteus species and Klebsiella species. H. influenza and N. gonorrhea are sensitive to cefomandole and cefuroxime.

Cefoxitin and cefotetan are cephamycins showing good activity against anaerobes, particularly Bacteroides fragilis. This drug is useful in patients with intra-abdominal sepsis, and against gynecological sepsis including pelvic inflammatory diseases (10).

Cefuroxime has longer half-life than similar agents. Crossing the blood brain barrier, cefuroxime can be used for community-acquired bronchitis or pneumonia in both elderly and in patients who are immunocompromised. The drug is effective for treatment of meningitis caused by H. influenzae, N. meningitidis and S. pneumoniae (15).

Cefoperazone has a good activity against penicillin-resistant Streptococci and gram-negative bacteria including P. aeruginosa. Most of the drug is eliminated by biliary excretion and concentrations of cefoperazone in bile are higher than those achieved with other cephalosporins.

Ceftazidime has an excellent activity against P. aeruginosa and other gram-negative bacteria.

Ceftriaxone is used for the treatment of meningitis (5) once or twice a day. For other infections, ceftriaxone can be used once a day. A single dose of this agent (125 to 250 mg) effective in the treatment of urethral, cervical, rectal or pharyngeal gonorrhea including disease caused by penicillinase-producing microorganisms (2,12).

Cefotaxime is highly resistant to many of the bacterial b-lactamases and has good activity against many gram-positive and gram-negative aerobic bacteria. In serious infections cefotaxime should be administered every 4 to 8 hours. Cefotaxime is used for meningitis caused by H. influenza, penicillin-sensitive S. pneumoniae and N. meningitidis (8).

Ceftizoxime has a similar spectrum of activity like cefotaxime, except that it is less active against S. pneumoniae and more active against B. fragilis. This drug can be administered every 8 to 12 hours for serious infections.

          Generally, parenteral cephalosporins with good activity against Enterobacteriaceae and Pseudomonas compete with amino-glycosides which have widespread uses. In spite of their high cost, cephalosporins are less toxic and do not require blood level controls such as amino-glycosides.

FOURTH GENERATION CEPHALOSPORINS

Cefepime and cefpirome are the newest cephalosporins that belong to the Fourth generation cephalosporins (4).

Cefepime is semi-synthetic cephalosporin effective against Staphylococci (but not against methicillin-resistant Staphylococci), Enterobacteriaceae that are resistant to other cephalosporins. Cefepime has higher activity against H. influenzae, N. gonorrhoeae and N. meningitidis compared with cefotaxime. For P. aeruginosa, cefepime has comparable activity to ceftazidime, but it is less active than ceftazidime for other Pseudomonas species. Cefepime has greater activity against Streptococci and methicillin-sensitive S. aureus (13) than ceftazidime and cefotaxime.

Cefepime is almost 100% renally excreted and doses should be adjusted in renal failure. Cefepime easily crosses the blood-brain barrier when meninges are inflamed and into the bile (3.)

Recommended doses for adults are 2 g intravenously every 12 hours.

Cefpirome has similar antibacterial activity such as cefotaxime, but in vitro, it is more effective against Staphylococci, enterococci, some species of Enterobacteriaceae and Pseudomonas aeruginosa.

Cefepime is indicated for the empirical treatment of nosocomial infections where antibiotic resistance due to extended-spectrum b-lactamases or chromosomally induced b-lactamases are anticipated. Cefepime has superior activity against nosocomial isolates of Enterobacter, Citrobacter and Serratia species compared to ceftazidime and piperacillin.

Cefpirome is used for treatment of urinary infections, infections of lower part of respiratory tract, skin infections, sepsis and infections in neutropenic patients. Cefpirome dosage for adults are 1 to 2 grams intravenously (injection or infusion) every 12 hours. It is not recommended for children under 12 years.

During the last decade numerous clinical studies confirmed that cefepime and cefpirome were very useful for treatment of serious infections that poorly responded to other antibiotics caused by multi-resistant microorganisms, especially in hospitals (intra-hospital pneumonia caused by resistant bacteria). The infections caused by penicillin-resistant S.pneumoinae can be treated by cefepime and cefpirome.

Cefpirome in vitro has good activity against anaerobic bacteria and thus in surgical infections some antibiotic active against anaerobic bacteria should be administered.

Cefepime and cefpirome have modest activity against Pseudomonas and because of that, infections caused by this bacteria must be treated in combination with amino-glycosides, especially in neutropenic patients.

Cefepime and cefpirome are reserve antibiotics.

Adverse effects of cefepime and cefpirome

Adverse effects of cefepime and cefpirome are pain after intravenous administration (flebitis, pain and/or inflammation), colitis including pseudomembranosa, diarrhea, vomiting, temperature, headache, oral candidiasis, pruritus, urticaria, vaginitis, etc (incidence < 1%) (11).

Adverse effects of cephalosporins

The cephalosporins produce modest and reversible adverse effects. Incidence of adverse effects of cephalosporins compared with incidence adverse effects of other antibiotics is low; thus, this group of antibiotics is actually a very safe group of drugs.

1.      Hypersensitivity reactions to the cephalosporins are the most common side effects. The reactions are similar to those caused by the penicillins. Generally, allergic reactions show cross-sensitivity with penicillins (about 5 to 15%). In contrast, the incidence of allergic reactions to cephalosporins is 1-2% in patients without the history of allergy to penicillins.

2.      Renal tubular necrosis has followed the administration of cephaloridine in doses greater than 4g a day; other cephalosporins are much less toxic and rarely produce renal toxicity, except cephalothin which produces tubular necrosis in high doses (9).

3.      Diarrhea appears after administration of cephalosporins and may be more frequent with cefoperazone, perhaps due to its greater biliary excretion.

4.      Intolerance to alcohol (a disulfiram-like reaction) can result from the administration of cefamandole, cefotetan, moxalactam and cefoperazone.

5.      Serious bleeding due to hypoprothrombinemia and/or platelet dysfunction has been reported with several b-lactam antibiotics.

6.      Cephalothin and cephapirin cause pain when given by intramuscular injection and are therefore usually used only intravenously.

OTHER b-LACTAM ANTIBIOTICS

CARBAPENEMS

Carbapenems are synthetic b-lactam antibiotics that differ from the penicillins in that sulfur atom of the thiazolidinedione ring has been externalized and replaced by a carbon. Imipenem is the only drug of this group currently available.

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

Imipenem kills susceptible microorganisms in a similar manner as the penicillins. It is very resistant to hydrolysis by most b-lactamases.

Antimicrobial activity of imipenem includes Streptococci, Enterococci (excluding Enterococcus faecium and non-b-lactamase-producing penicillin-resistant strains), Staphylococci (including penicillinase-resistant strains) and Lysteria. Enterobacteriaceae are very susceptible and most strains of Pseudomonas and Actino-bacter. Anaerobes, including B. fragilis, are highly susceptible.

Imipenem is active only after intravenous administration is combined with cilastatin that blocks renal dipeptidase found in the brush boarder of the proximal renal tubule.

Therapeutic uses of impinem-cilastatin are widespread (6: infections of the urinary tract; lower respiratory infections; intra-abdominal and gynecological infections; skin, soft-tissue, bone and joint infections. The drug combination appears to be especially useful for the treatment of infections caused by cephalosporin-resistant nosocomial bacteria such as Citrobacter freundii and Enterobacter spp. It is recommended that imipenem be used for serious infections in hospitalized patients who have recently received other b-lactam antibiotics.

Nausea and vomiting are the most common adverse reactions; seizures are very rare adverse reactions, especially when patients have central nervous system lesions or renal failure.

MEROPENEM

Meropenem is a dimethyl-carbonyl pyrrolidine derivate of thienamycin and this drug is not sensitive to renal dipeptidase. Thus, this antibiotic is not combined with cilastatin. Its in vitro activity is similar to that of imipenem, with activity against some imipenem-resistant P. aeruginosa, but less activity against gram-positive cocci. Clinical experience with meropenem is similar with imipenem.

AZTREONAM

Aztreonam is a monocyclic b-lactam compound (a monobactam) the drug is resistant to many of the b-lactamases that are produced by most gram-negative bacteria. The antimicrobial spectrum of activity is very similar to that of amino-glycosides. Gram-positive bacteria and anaerobic bacteria are quite resistant. Activity against Enterobacteriaceae is excellent as is that against Pseudomonas aeruginosa, H. influenza and gonococci.

Aztreonam is administered parenterally (intramuscularly or intravenously). The usual dose of this drug for severe infections is 2g every 6 to 8 hours. This antibiotic is especially useful for treatment of gram-negative infections that normally would be treated with a b-lactam antibiotic.

Aztreonam generally is well tolerated. It is very interesting that patients who are allergic to penicillins or cephalosporins appear not to react to aztreonam (14).
 

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2.      Barradell, L.B., and  Bryson, H.M. Cefepime: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs, 1994, 47:471-505.

3.      Brogden, R.N., and Ward, A. Ceftriaxone: a reappraisal of its antibacterial activity and pharmacokinetic properties, and an update on its therapeutic use with particular reference to once-daily administration. Drugs, 1998, 35:604-645.

4.      Bryskier A. New concepts in the field of cephalosporins: C-3’ quarternary ammonium cephems (group IV). Clin. Microbiol. Infect.,1997: (suppl. 1): S1-61.

5.      del Rio, M.A., Chrane, D., Shelton, S., McCracken, G.H., Jr., and Nelson, J.D. Ceftriaxone versus ampicillin and chloramphenicol for treatment of bacterial meningitis in children. Lancet, 1983, 1:1241-1244.

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8.      Mullaney, D.T., and John, J.F. Cefotaxime therapy. Evaluation of its effect on bacterial meningitis, CSF drug levels, and bactericidal activity. Arch.Intern. Med., 1983, 143:1705-1708.

9.      Pasternack, D.P., and Stephens, B.G. Reversible nephrotoxicity associated with caphalotin therapy. Arch. Intern. Med., 1975, 135:599-602.

10.    Phillips, I., Wise, R., and Leigh, D.A. Cetotetan: a new cephamycin. J. Antimicrob. Chemother., 1983, 11 (suppl.):1-239.

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12.    Rajan, V.S., Sng, E.H., Thirumoorthy, T., and Goh, C.L. Ceftriaxone in the treatment of ordinary and penicillinase-producing strains of Neisseria gonorrhea. Br. J. Vener. Dis., 1982, 58:314-316.

13.    Sanders C.S. Cefepime: the next generation? Clin. Infect. Dis., 1993, 17:369-379.

14.    Saxon, A., Hassner, A., Swabb, E.A., Wheller, B. and Adkinson, N.F. Lack of cross-reactivity between aztreonam, a monobactam antibiotic, and penicillin in penicillin-allergic subjects. J. Infect. Dis., 1984, 149: 16-22.

15.    Smith, B.R., and LeFrock, J.L. Cefuroxime: antimicrobial activity, pharmacology, and clinical efficacy. Ther. Drug Monit., 1983, 5:149-160.