Review Article Drugs 10: 81-111 (1975)
Antibacterial Drugs Today: IP A .P. Ball, l .A. Gray and r. McC. Murdo ch Infectious Diseases Unit , City Hospital, Edinburgh
Table of Contents Summary 12. Cephalosporins 12.1 Cephaloridine 12.1.1 Antibacterial Activity 12.1.2 Pharmacology 12.1.3 Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.1.4 Dosage 12.1.5 Side-Effects and Toxicity 12.2 Cephalothin 12.3 Cephalexin 12.4 Cephradine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.5 New Cephalosporin Derivatives 12.6 The Cephamycins 13. Peptide Antibiotics (Polymyxin B and Polymyxin E) 13.1 Antibacterial Activity 13.2 Pharmacology 13.3 Therapeutic Indications and Dosage 13.3.1 Topical Therapy 13.3.2 Parenteral Therapy 13.3.3 Intrathecal Therapy 13.3.4 Oral Therapy 13.4 Side-Effect s and Toxicity 13.4.1 Neurotoxicity 13.4 .2 Nephrotoxicity 14. The Aminoglycosides 14.1 Streptomycin 14.1.1 Antibacterial Activity 14.1.2 Pharmacology 14.1.3 Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Second of a 2-part review. Part I appeared in previous issue.
82 82 83 83 83 84 85 85 86 87 87 88 88 89 89 89 90 90 90 91 91 91 91 91 92 92 92 93 93
82
Antibacterial Drugs Today : II 14.1.4 Dosage 14.1.5 Side-Effects and Toxicity 14.2 Kanamycin . . . . . . . . . . . . . 14.2.1 Antibacterial Activity 14.2.2 Pharmacology .14.2.3 Indications . . . . . . . . . . . . . . . . . . 14.2.4 Dosage 14.2.5 Side-Effects and Toxicity 14.3 Gentamicin . . . . . . . . . . 14.3.1 Antibacte rial Activity . 14.3.2 Pharmacology . 14.3.3 Indication . 14.3.4 Dosage 14.3.5 Side-Effects and Toxicity 14.4 Tobramycin 14.4.1 Antibacterial Activity . . . . . . .. 14.4.2 Pharmacology 14.4.3 Indications 14.4.4 Dosage 14.4.5 Side-Effects and Toxicity 14.5 Neomycin, Framycetin and Paromomycin 14.5.1 Antibacterial Activity 14.5.2 Pharmacology 14.5.3 Indications . -. . . . . . . . . . 14.5.4 Side-Effects and Toxicity
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. 93 . 94 . 94 . 94 . . . . . . . . 95 . . . . . . . . 97 97 98 . . . . . . . 99 . . . . . . . . . . . . . .. 99 . . . . . . . . 100 . . . . . . . . 102 102 . 103 . 103 . 104 104 105 106 106 106 107 107 . . . . . . . 107 108
Summary Since the development of the sulphonamides in the 1930s and the subsequent development of antibiotics from the 1940s onwards , there have now been many drugs developed which are capable of chemotherapeutic activity in a patient infected by a susceptible micro-organism. This review is concerned with precise descriptions of important groups of antimicrobial drugs, with emphasis being placed on the more recently developed drugs. With each group of drugs the pharmacology, major therapeutic indications , dosages and adverse reactions are discussed. Part II of the review discusses the cephalosporins, polymyxins and aminoglycosides. The place of each in
. . . . . .
Key Words' Aminoglycosides Antibacterial drugs Cephalosporins Gentamicin Kanamycin Polymyxins Streptomycin Tobramycin therapy is defined .
12. Cephalosporins
It is now 30 years since Brotzu recovered the mould Cephalosporium acrimonium from Sardinian sewage. This produced a number of antibiotics, but 2 See subject index in each issue for further indexing terms .
Antibacterial Drugs Today : II
83
from the clinical standpoint, cephalosporin C and its chemical analogues are so far the most important to have been developed. The important cephalosporins at present available for parenteral use are cephaloridine and cephalothin. For oral use, cephalexin, cephaloglycin and cephradine are now available; the latter can also be given by the parenteral route . The cephalosporins are active against a wide range of organisms and are almost entirely excreted by the kidney. They are active against staphylococci with intrinsic resistance to penicillin and against penicillinase producing strains and may be used alone in the treatment of infections caused by these organisms. Apart from the differences in their route of administration there are also some differences in their degree of activity against the various Gram-positive and Gram-negative organisms, with the total exception of Mycobacterium tuberculosis and Pseudomonas aeruginosa. All cephalosporin derivatives act by inhibition of bacterial cell wall synthesis and are bactericidal. The drug level required to achieve a bactericidal effect in most cases is only 2 to 3 times that required for bacteriostasis. The basic structure , 7-aminocephalosporanic acid I (fig. 4) is similar to the 6-aminopenicillanic acid nucleus.
12.1 Cephaloridine Cephaloridine has been in use clinically in the United Kingdom for approximately 10 years and has been well documented (Murdoch , 1965 ; Eykyn, 1971; Leading Article, 1973). 12.1.1 Antibacterial Activity Cephaloridine is actively bactericidal against a wide range of Gram-positive and Gram-negative bacteria but is ineffective against Pseudomonas aeruginosa, enterobacter, indole-positive proteus and bacteroides. Its use is also limited against Haemophilus influenzae and Streptococcus faecalis. 12.1.2 Pharmacology
Since cephaloridine is not absorbed from the upper intestinal tract, parenteral administration is necessary. After intramuscular injection of 500mg, peak serum levels of more than 12/1g/rnl are reached within 30 minutes and adequate levels are maintained for up to 8 hours. Protein binding in the serum is slight (20%) and the drug is largely excreted unchanged by the kidneys, mainly by glomerular filtration. High concentrations in the urine are therefore achieved. The antibiotic penetrates well into inflamed muscle but very little appears in the bile or normal cerebrospinal fluid.
84
Antibacterial Drugs Today : II
12.1.3 Indications Gram-Positive Infections Cephaloridine is very active against Streptococcus pneumoniae , Staphylococcus aureus, Streptococcus viridans, Streptococcus pyogenes and Corynebacterium diphtheriae. If the patient gives a clear cut history of allergy to the penicillins, cephaloridine should be considered as the primary treatment for severe infections caused by these organisms. Even in the patient with pneumococal meningitis which is not responding to high doses of benzylpenicillin after 48 hours of treatment, a change to parenteral cephaloridine can be effective (Murdoch, 1965). Cephaloridine alone can be effective in the treatment of acute staphylococcal endocarditis but it cannot always be relied upon in this condition and combination with another antibiotic such as gentamicin may be necessary. Gram-Negative Infections Because cephaloridine is active against Escherichia coli, Neisseria gonorrhoeae, Clostridium septicum, Salmonella , typhi, Salmonella paratyphi,
a
O
~ CH-C-NH-eH-CH I NH2
Cepha lexin
Cephalothin
I
..
a
S
Antibacterial Drugs Today: IP A .P. Ball, l .A. Gray and r. McC. Murdo ch Infectious Diseases Unit , City Hospital, Edinburgh
Table of Contents Summary 12. Cephalosporins 12.1 Cephaloridine 12.1.1 Antibacterial Activity 12.1.2 Pharmacology 12.1.3 Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.1.4 Dosage 12.1.5 Side-Effects and Toxicity 12.2 Cephalothin 12.3 Cephalexin 12.4 Cephradine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.5 New Cephalosporin Derivatives 12.6 The Cephamycins 13. Peptide Antibiotics (Polymyxin B and Polymyxin E) 13.1 Antibacterial Activity 13.2 Pharmacology 13.3 Therapeutic Indications and Dosage 13.3.1 Topical Therapy 13.3.2 Parenteral Therapy 13.3.3 Intrathecal Therapy 13.3.4 Oral Therapy 13.4 Side-Effect s and Toxicity 13.4.1 Neurotoxicity 13.4 .2 Nephrotoxicity 14. The Aminoglycosides 14.1 Streptomycin 14.1.1 Antibacterial Activity 14.1.2 Pharmacology 14.1.3 Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Second of a 2-part review. Part I appeared in previous issue.
82 82 83 83 83 84 85 85 86 87 87 88 88 89 89 89 90 90 90 91 91 91 91 91 92 92 92 93 93
82
Antibacterial Drugs Today : II 14.1.4 Dosage 14.1.5 Side-Effects and Toxicity 14.2 Kanamycin . . . . . . . . . . . . . 14.2.1 Antibacterial Activity 14.2.2 Pharmacology .14.2.3 Indications . . . . . . . . . . . . . . . . . . 14.2.4 Dosage 14.2.5 Side-Effects and Toxicity 14.3 Gentamicin . . . . . . . . . . 14.3.1 Antibacte rial Activity . 14.3.2 Pharmacology . 14.3.3 Indication . 14.3.4 Dosage 14.3.5 Side-Effects and Toxicity 14.4 Tobramycin 14.4.1 Antibacterial Activity . . . . . . .. 14.4.2 Pharmacology 14.4.3 Indications 14.4.4 Dosage 14.4.5 Side-Effects and Toxicity 14.5 Neomycin, Framycetin and Paromomycin 14.5.1 Antibacterial Activity 14.5.2 Pharmacology 14.5.3 Indications . -. . . . . . . . . . 14.5.4 Side-Effects and Toxicity
. . . .
. . . . -. . . . . .
. . . .
. . . .
. . . .
. . . . . .
. . . . . .
. 93 . 94 . 94 . 94 . . . . . . . . 95 . . . . . . . . 97 97 98 . . . . . . . 99 . . . . . . . . . . . . . .. 99 . . . . . . . . 100 . . . . . . . . 102 102 . 103 . 103 . 104 104 105 106 106 106 107 107 . . . . . . . 107 108
Summary Since the development of the sulphonamides in the 1930s and the subsequent development of antibiotics from the 1940s onwards , there have now been many drugs developed which are capable of chemotherapeutic activity in a patient infected by a susceptible micro-organism. This review is concerned with precise descriptions of important groups of antimicrobial drugs, with emphasis being placed on the more recently developed drugs. With each group of drugs the pharmacology, major therapeutic indications , dosages and adverse reactions are discussed. Part II of the review discusses the cephalosporins, polymyxins and aminoglycosides. The place of each in
. . . . . .
Key Words' Aminoglycosides Antibacterial drugs Cephalosporins Gentamicin Kanamycin Polymyxins Streptomycin Tobramycin therapy is defined .
12. Cephalosporins
It is now 30 years since Brotzu recovered the mould Cephalosporium acrimonium from Sardinian sewage. This produced a number of antibiotics, but 2 See subject index in each issue for further indexing terms .
Antibacterial Drugs Today : II
83
from the clinical standpoint, cephalosporin C and its chemical analogues are so far the most important to have been developed. The important cephalosporins at present available for parenteral use are cephaloridine and cephalothin. For oral use, cephalexin, cephaloglycin and cephradine are now available; the latter can also be given by the parenteral route . The cephalosporins are active against a wide range of organisms and are almost entirely excreted by the kidney. They are active against staphylococci with intrinsic resistance to penicillin and against penicillinase producing strains and may be used alone in the treatment of infections caused by these organisms. Apart from the differences in their route of administration there are also some differences in their degree of activity against the various Gram-positive and Gram-negative organisms, with the total exception of Mycobacterium tuberculosis and Pseudomonas aeruginosa. All cephalosporin derivatives act by inhibition of bacterial cell wall synthesis and are bactericidal. The drug level required to achieve a bactericidal effect in most cases is only 2 to 3 times that required for bacteriostasis. The basic structure , 7-aminocephalosporanic acid I (fig. 4) is similar to the 6-aminopenicillanic acid nucleus.
12.1 Cephaloridine Cephaloridine has been in use clinically in the United Kingdom for approximately 10 years and has been well documented (Murdoch , 1965 ; Eykyn, 1971; Leading Article, 1973). 12.1.1 Antibacterial Activity Cephaloridine is actively bactericidal against a wide range of Gram-positive and Gram-negative bacteria but is ineffective against Pseudomonas aeruginosa, enterobacter, indole-positive proteus and bacteroides. Its use is also limited against Haemophilus influenzae and Streptococcus faecalis. 12.1.2 Pharmacology
Since cephaloridine is not absorbed from the upper intestinal tract, parenteral administration is necessary. After intramuscular injection of 500mg, peak serum levels of more than 12/1g/rnl are reached within 30 minutes and adequate levels are maintained for up to 8 hours. Protein binding in the serum is slight (20%) and the drug is largely excreted unchanged by the kidneys, mainly by glomerular filtration. High concentrations in the urine are therefore achieved. The antibiotic penetrates well into inflamed muscle but very little appears in the bile or normal cerebrospinal fluid.
84
Antibacterial Drugs Today : II
12.1.3 Indications Gram-Positive Infections Cephaloridine is very active against Streptococcus pneumoniae , Staphylococcus aureus, Streptococcus viridans, Streptococcus pyogenes and Corynebacterium diphtheriae. If the patient gives a clear cut history of allergy to the penicillins, cephaloridine should be considered as the primary treatment for severe infections caused by these organisms. Even in the patient with pneumococal meningitis which is not responding to high doses of benzylpenicillin after 48 hours of treatment, a change to parenteral cephaloridine can be effective (Murdoch, 1965). Cephaloridine alone can be effective in the treatment of acute staphylococcal endocarditis but it cannot always be relied upon in this condition and combination with another antibiotic such as gentamicin may be necessary. Gram-Negative Infections Because cephaloridine is active against Escherichia coli, Neisseria gonorrhoeae, Clostridium septicum, Salmonella , typhi, Salmonella paratyphi,
a
O
~ CH-C-NH-eH-CH I NH2
Cepha lexin
Cephalothin
I
..
a
S
