Antibiotics I

Isao Kawamoto

• Publisher: CRC Press
• Year: 2020
• Print ISBN: 9782881248559
• eBook ISBN: 9781000674408
• Topic: Medicine
• Subtopic: Chemistry
• Index: Chemistry

This book reviews more recent studies of antibiotics in Japan. It describes ?-lactams and other antimicrobial agents according to the following categories: parenteral cephems and related compounds, oral cephalosporins, penems and carbapenems, monobactams, aminoglycosides, and macrolides.

CHAPTER 1

Introduction

It is well known that the discovery of penicillin by Alexander Fleming in 1929, which led to the isolation and development of penicillin in the mid-1940s, was the beginning of an era of β-lactam antibiotics that continues to this day. In Japan, cefazolin was produced by Fujisawa in 1969, the first of a number of cephalosporins in which the acetoxy group was replaced by a heterocyclic thiol group. Cefazolin was also one of the first-generation cephalosporins as were cephalotin and cephaloridine. Table 1 lists the major β-lactam antibiotics developed in Japan. The 1970s saw the appearance of the second-generation of semisynthetic cephalosporins, with higher resistance to hydrolysis by a considerable number of β-lactamases than the first-generation cephalosporins.

Table 1. Major β-lactam antibiotics developed in Japan.

Antibiotic	Abbreviation	Company	Year discovered	Year marketed
Cefazolin	CEZ	Fujisawa	1969	1971
Piperacilin	PIPC	Toyama	1976	1980
Cefmetazole	CMZ	Sankyo	1976	1980
Cefotiam	CTM	Takeda	1977	1981
Cefoperazone	CPZ	Toyama	1978	1981
Latamoxef	LMOX	Shionogi	1978	1981
Cefmenoxime	CMX	Takeda	1978	1983
Ceftizoxime	CZX	Fujisawa	1978	1983
Cefotetan	CTT	Yamanouchi	1979	1983
Cefuzonam	CZON	Lederle-Takeda	1981	1987
Cefixime	CFIX	Fujisawa	1982	1987
Cefteram
pivoxil	CFTM-PI	Toyama	1984	1987
Carumonam	CRMN	Takeda	1983	1988
Flomoxef	FMOX	Shionogi	1983	1988
Cefpodoxime
proxetil	CPDX-PR	Sankyo	1985	1989

Cefoxitin, the first synthetic cephamycin, from Merck Sharp & Dohme, is a 7-α-methoxy cephalosporin with a thienylacetoamido group at C-7 and a carbamoyloxymethyl group at C-3. Two years after the discovery of cephamycin C by the Merck group, Sankyo scientists discovered cephamycin C, and modifications at the C-3 and C-7 positions of cephamycin led to cefmetazole in 1976, which has a cyanomethylthioacetoamido group at C-7 and a N-methyltetrazolylthiomethyl group at C-3. Cefotiam, having a 2-amino thiazole group, was synthesized during an attempted synthesis of 7-β-ketoacylamino cephalosporins at Takeda in 1977. These cephalosporins, including cefuroxime from Glaxo, are so-called second-generation cephalosporins. The potential value of replacing the sulfur in the cephamycin dihydrothiazin ring by oxygen was assessed at Shionogi laboratories. Latamoxef was discovered in 1978. It was the first oxacephem antibiotic having a p-hydroxyphenylacetoamido group at C-7 and a N-methylterazolylthiomethyl group at C-3, and it was resistant to penicillinase-type and cephalosporinase-type β-lactamase. Cefotaxime, with a 2-aminothiazolyl-methoxyiminoacetoamido group in the 7-side chain, from Hoechst-Roussel Uclaf, shows an exceptionally wide spectrum of activity compared to the second-generation cephalosporins; it is a so-called third-generation cephalosporin. In Japan, cefmenoxime (Takeda, 1977), ceftizoxime (Fujisawa, 1979), cefuzonam (Lederle-Takeda, 1981), and flomoxef (Shionogi, 1983) were discovered in rapid succession. These β-lactam antibiotics were marketed in 1983 to 1988. Despite the large number of cepalosporin antibiotics available, there has been continued interest in finding agents that would have better antibacterial activity or pharmacology than those currently available.

On the other hand, there has been continued interest in the development of oral cephalosporins since the discovery of cephaloglycin as the first oral cephalosporin in 1962. Cephalexin (Lilly) was marketed in 1970 and cefaclor (Lilly) was marketed in 1982 in Japan. Both oral cephalosporins have been used widely to treat infections caused by Gram-positive and Gram-negative bacteria. Oral cephalosporins on the market are quite few compared with parenteral cephalosporins. Their value for the treatment of a number of Gramnegative infections has been limited. Therefore, oral cephalosporins with a wider spectrum than cephalexin and cefactor were desired for use in Gram-negative infections. In general, β-lactam antibiotics, such as cephalosporins, are classified as poorly absorptive drugs from the pKa value of their carboxylic acid group. Amino-β-lactams such as cephalexin and cefaclor, are exceptionally absorbed by the carrier-mediated mechanism. Ester-type prodrugs of cephalosporins have been studied for improving the oral absorption of drugs containing a carboxylic acid group, and now the ester-type prodrug approach has become one of the important fields of β-lactam antibiotics. Recently, novel oral cephalosporins corresponding to the third-generation cephalosporins were extensively studied. Cefixime (Fujisawa), cefteram pivoxil (Toyama), and cefpodoxime proxetil (Sankyo) were marketed in succession from 1987 to 1989.

Nonclassical β-lactam antibiotics, penems and carbapenems, have received extensive attention since the pioneering synthesis of penems by Woodward and the discovery of thienamycin by Merck. Among penems, FCE 22891, a new orally active penem antib...

Table of contents

• Cover
• Half Title
• Series Page
• Title Page
• Copyright Page
• Table of Contents
• Preface to the Series
• Preface
• 1. Introduction
• 2. Parenteral Cephems and Related Compounds
• 3. Oral Cephalosporins
• 4. Penems and Carbapenems
• 5. Monobactams
• 6. Aminoglycosides
• 7. Macrolides
• References
• Author Index
• Subject Index