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• Overview

  Cefradine (also known as cephradine), 7-[D-2-amino-2(1,4cyclohexadien1-yl) acetamido]-3-methyl-8-0x0-5thia-l-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid monohydrate (111 is a semi-synthetic cephalosporin antibiotic. used orally, intramuscularly, and intravenously. The structure of cephradine is similar to that of cephalexin, the only difference being in the six-membered ring. Cephalexin has three double bonds forming an aromatic system while cephradine has two double bonds in the same ring. The antibacterial activity of cephradine is similar to that of cephalexin^[1].
  
  Figure1 the chemical structure of cefradine;
  Cephradine is a white crystalline powder with a molecular weight of 349.4^[2]. The synthesis of cephradine has been discussed^[3]. Cephradine is freely soluble in aqueous solvents. It is a zwitterion, containing both an alkaline amino group and an acidic carboxyl group. In the pH range of 3-7, cephradine exists as an internal salt^[4]. Cephradine is stable for 24 hr at 25" within the pH range of 2-8. Since it is stable in acidic media, there is little loss of activity in the gastric fluid; losses of less than 7% have been reported^[5].
  Cephradine is weakly bound to human serum proteins. The drug was less than 20% bound to the serum proteins^[4]. At a serum concentration of 10-12 pg/ml, 6% of the total drug was in the protein-bound complex. Another study^[6] found that at a total concentration of 10 pg/ml, 28% of the drug was in the protein-bound state; at a total concentration of 100 pg/ml, 30% of the drug was in the protein-bound state. This study also showed that the addition of serum to cephradine decreased antibiotic activity. Another study^[2] showed that the protein binding of cephradine varied from 8 to 20%, depending on the concentration of the drug. However, a study by Gadebusch et al.^[5] found no change in the MIC of cephradine toward either Staphylococcus aureus or Escherichia coli after the addition of human serum.;

• Pharmacokinetic

  Little work has been performed on the pharmacokinetics of cephradine in subjects with normal and impaired kidney function. Further study is necessary to elucidate these parameters. A plot of cephradine serum concentration versus time indicates a bi-exponential decay. Therefore, fitting of the data for cephradine should be performed using a two-compartment open model. The effects of using a one-compartment open model analysis when a two-compartment open model is indicated were discussed previously. When the data for intravenous cephradine were fit to a two-compartment open model, the half-life was approximately 45 min. The volume of distribution was 22 liters, compared to 21-liters/1.73 m2 reported previously^[13]. A value of 17 f 3.9 lited1.73 m2 also was reported^[2].
  The pharmacokinetics of cephradine probably will be similar to those found for cephalexin due to the similarity of their structures. The protein binding of these two compounds is not significantly different, so the volume of distributions should be similar, as was found in the reanalysis of literature data. ;

• Pharmacodynamics

  Absorption
  Cephradine has been administered orally, intramuscularly, and intravenously and is well absorbed using these routes. This large degree of absorption is evidenced by recoveries of approximately 100% of the administered dose in the urine^{[4, 7-10]}. In one study^[4], tritiated cephradine was administered orally to human subjects in the form of a 250-mg capsule. Urine and feces were collected and assayed for the drug; 92% of the drug was present in the urine at the end of 24 hr, while minimal amounts were present in the feces at the end of 72 hr. These findings are evidence for the claim that cephradine is well absorbed orally and apparently not excreted in the bile.
  After oral administration of cephradine, the time of peak serum concentration was at 1 hr with peak concentration in the serum ranging from 6 to 7 pg/ml after a 250-mg capsule^{[4, 9, 10]}. After the administration of 500 mg of cephradine in the form of two 250-mg capsules, peak serum levels were in the range of 11-18 pg/ml^{[1, 4, 7-9]}. After the administration of 500 mg of cephradine as an oral suspension, a peak serum concentration of 19.5 pg/ml was found at 0.5 hr^[9]. When human subjects were given 1 g of cephradine, the peak levels ranged from 15 to 24 pg/ml^{[1, 9]}.
  After the administration of 1 g im, a peak level of 10.4 pg/ml at 2 hr was attained^[4]. While the peak concentration of cephradine after intramuscular injection was lower than that after oral administration, the areas under the curve were identical. One advantage of the intramuscular route over the oral route was that the concentration of the antibiotic in the serum was below 1 pg/ml at 4 hr after oral administration while the concentration after intramuscular administration was 6.8 pg/ml^[4].
  One study^[7] found that the rate of absorption after oral administration was influenced by the presence of food but that the extent of absorption was not affected. Serum levels at 30 min after administration were 7.9 pg/ml for non-fasting volunteers and 15.8 pg/ml for fasted volunteers. However, peak levels were not significantly different; values of 19.2 and 18.3 pg/ml were found for non-fasting and fasted volunteers, respectively. After intravenous administration of cephradine, the peak levels are reached immediately. In one study, a serum concentration of 56 pg/ml at 7 min after injection was attained after administration of 1 g^[11]. In another study^[4], the administration of 1 and 0.5 g of cephradine intravenously gave levels of 86.3 and 46.0 pg/ml, respectively, 5 min after injection. When cephradine was given as an intravenous constant infusion (0.166 g/hr), a steady-state level of 4.8 pg/ml was attained after 3 hr^[11].
  Distribution
  In a study performed with mice^[12], cephradine was widely distributed throughout the body. In this study, 50 mg/kg of tritiated cephradine was administered orally to mice and tissue levels were determined as a function of time. The levels in the stomach, small intestine, and kidneys were all above 100 pg/g of tissue. The liver had a level of more than 50 pg/g of tissue at 1 hr after administration. Almost all other body tissues had levels above l pg/g of tissue. The levels found in the brain were 0.8-2.2 pg/g of tissue in the 24-hr period of the study.
  The tissue levels of cephradine in humans after oral dosing were examined^[8]. The level in lung tissue 6 hr after administration of 500 mg PO was 0.46 pg/g of tissue (serum level was 0.58 pg/ml). Three hours after dosing, adipose tissue levels of 0.46-0.56 pg/g of tissue were found (serum level was 0.31-0.60 pg/ml). Cephradine levels for various other tissues were also given^[8]. The volume of distribution of cephradine was reported to be 21 liter/1.73 m2^[13].
  Metabolism and excretion
  A study in humans could not find any metabolites of cephradine^[4].
  When 500 mg of cephradine was administered orally to subjects having cholecystolithiasis^[8], the levels of cephradine in the bile ranged from 2.2 to 41.0 pg/ml at 3-7.5 hr after administration. The major route for the elimination of cephradine is renal excretion. Cephradine is removed from the body by the processes of glomerular filtration and tubular secretion^[4]. A study in which probenecid was co-administered with cephradine resulted in a prolonged half-life and elevated serum levels. The recovery of unchanged cephradine in the urine ranged from 78.3 to 95.9%^{[4, 7-9]}. The urinary concentration of cephradine in the first 2 hr after administration of 500 mg was between 1.1 and 3.2 mg/ml^{[4, 7-9]}.
  The half-lives of elimination of cephradine were 32 min^[11] after intravenous administration, 40-50 min after intramuscular administration^[4], and 42 min after oral administration^[9]. These studies were performed in patients having normal kidney function. During a constant infusion, patients having a creatinine clearance of 125 ml/min had serum and renal clearances of cephradine of 435 and 367 ml/ min, respectively^[13]. ;

• Indication

  Cephradine is active in vitro against a broad spectrum of gram-positive and gram-negative bacteria, including pathogenic organisms isolated in the clinic; the compound has been shown to be acid stable, and the addition of human serum had only a slight effect on the minimal inhibitory concentration (MIC) for the sensitive organisms. When given orally or subcutaneously to animals infected experimentally with a variety of pathogenic bacteria, cephradine offered effective protection^[16]. In the treatment of acute infective diseases, satisfactory clinical responses to cephradine therapy have been reported by a number of investigators^{[14, 15, 17-19]}. ;

• Mode of action

  Cefradine is a first generation cephalosporin antibiotic with a spectrum of activity similar to cefalexin. Cefradine, like the penicillins, is a beta-lactam antibiotic. By binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, it inhibits the third and last stage of bacterial cell wall synthesis. Bacterial cell wall autolytic enzymes such as autolysins further mediate cell lysis; it is possible that cefradine interferes with an autolysin inhibitor. ;

• References

  1. J. F. Scholand, G. R. Hodges, R. J. Fass, and S. Saslaw, Amer. J. Med. Sci., 267, lll (1974).
  2. “Anspor Product Information,” AN-L2, Smith Kline and French Laboratories, Philadelphia, Pa., 1974.
  3. J. E. Dolfini, H. E. Applegate, G. Bach, H. Basch, J. Bernstein, J. Schwartz, and F. L. Weisinborn, J. Med. Chem., 14. 117(1971).
  4. E. S. Neiss, J. Ir. Med. Ass. 66,1(1973).
  5. H. H. Gadebusch, G. J. Miraglia, H. I. Basch, C. Goodwin, S. Pan, and K. Renz, “Advances in Antimicrobial and Antineoplastic Chemotherapy,” Vol. 1, Proceedings of the VIIth International Congress of Chemotherapy-1971, Prague, Czechoslovakia, 1972, p. 1059.
  6. G. Renzini, G. Ravagnan, and B. Oliva, Quad. Antibiot., 1972,l.
  7. C. Harvengt, P. DeSchepper, F. Lamy, and J. Hansen, J. Clin. Pharmacol., 13,36(1973).
  8. G. Renzini, G. Ravagnan, B. Oliva, E. Salvetti, and R. Auriti, Quad. Antibiot., 1972, 17.
  9. A. Zaki, E. C. Schreiber, I. Weliky, J. R. Knill, and J. A. Hubsher, J. Clin. Pharmacol., 14,118(1974).
  10. J. Klastersky, D. Daneau, and D. Weerts, Chemotherapy (Easel), 18.191(1973).
  11. C. Simon, V. Malerczyk, E. Brahnstaedt, and W. Toeller, Deut. Med. Wochenschr., 98,2448(1973).
  12. I. Weliky, H. H. Gadebusch, K. Kripalani, P. Arnow, and E. C. Schreiber, Antimicrob. Ag. Chemother. 5.49(1974).
  13. I. Weliky and A. Zoki, Eighth International Congress of Chemotherapy, Athens, Greece, 1973.
  14. de Mendonca, J. S., G. W. Oselka, G. C. Levi, V. A. Neto, and H. V. Lopes. 1972. Observacoes preliminares sobre an atividade terapeutica da Cefradina, nova cefalosporina, administrada por via oral. Rev. Brasil. Clin. Terap. 1:207-210.
  15. Estrada, F. A., B. D. Alora, and S. L. Lansang. 1972. A clinical trial of cephradine, a new cephalosporin derivative. J. Philippine Med. Ass. 48:250-254.
  16. Gadebusch, H., G. Miraglia, H. Basch, C. Goodwin, S. Pan, and K. Renz. 1972. Cephradine: a new orally absorbed cephalosporin antibiotic. Advan. Antimicrob. Antineoplastic Chemother. 1:1059-1062.
  17. Landa, L. 1972. Cephradine in the treatment of intestinal infections caused by Shigella or Salmonella organisms. Curr. Ther. Res. Clin. Exp. 14:496-502.
  18. Limson, B. M., R. E. Siasoco, and F. P. Dial. 1972. A new cephalosporin derivative, cephradine, in the treatment of acute infective diseases. Curr. Ther. Res. Clin. Exp. 14:101-106.
  19. Mitelman, A. 1972. Cefradina: una nueva cefalosporina de sintesis. Evaluacion clinicobacteriologica. Dia Med. 44:152-153.
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