A new oral cephem, cefdinir: its structure-activity relationships and biological profile]

This article reviews structure-activity relationships and biological properties of a new oral cephem, cefidinir (CFDN). It also describes a hypothesis concerning the absorption mechanism from the intestine. Antibacterial activities and the oral absorption efficiencies were studied with regard to 3-vinyl cephalosporins with various 7-acyl side chains. From the study, 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetyl group was selected and various 3-substituents were screened. As a result, it was found that the vinyl compound, CFDN, showed excellent antibacterial activity and good oral absorption in rats. In vitro and in vivo antibacterial activities, the affinity for PBPs and the stability to beta-lactamases revealed that CFDN had well balanced antimicrobial activities against Gram-positive and Gram-negative bacteria and good biological properties. The pharmacokinetics of CFDN in healthy volunteers showed that serum concentration and half life were good enough to make CFDN an effective therapeutic agent. The mechanism of intestinal absorption of CFDN and related oral cephems are discussed and a hypothesis for molecular recognition by the carrier protein in the intestine is proposed.     

Studies on beta-lactam antibiotics. VII. Effect on antibacterial activity of the oxime O-substituents with various functional groups in the 7 beta-[(Z)-2-(2-amino-4-thiazolyl)-2-oxyiminoacetamido]cephalosporins

The synthesis and in vitro activity of the 7-[O-substituted oxyiminoacetamido]cephalosporins (I) without substitution at 3-position of a cephem nucleus are described. Effect of changing the oxime O-substituents (R1) with various functional groups in the 7-acyl residue on antibacterial activity was examined. Against Gram-positive bacteria, cephems with hydrophilic functions in the R1 moiety such as hydroxyethyl, aminoethyl and carboxymethyl groups showed decrease of the activity, while cephems with lipophilic functions such as cyanomethyl, methylthiomethyl and halogenoethyl groups exhibited increase of the activity. However, influence of the substituents (R1) on activity against Gram-negative bacteria was observed to be relatively independent of the nature of their functional groups.     

Studies on anti-MRSA parenteral cephalosporins. III. Synthesis and antibacterial activity of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido-3

In the course of our exploration for a novel cephalosporin derivative having excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), we modified the C-3 linked spacers of cephem derivatives bearing a 1-methylimidazo[1,2-b]pyridazinium-6-yl group at the C-3' position and 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyloxy-iminoacetyl group at the C-7 position. The optimal spacers were the (E)-2-vinyl and (E)-2-thiovinyl groups seen in 19a and 29aa, respectively. Their anti-MRSA activity was 16 to 32 times as potent as that of cefozopran (CZOP). Focusing on the (E)-2-vinyl and (E)-2-thiovinyl spacers, we further modified the alkoxyimino groups in the C-7 acyl moiety and the 1-alkylimidazo[1,2-b]pyridazinium moieties at the C-3' position and investigated the structure-activity relationships (SAR) of the derivatives. Consequently, we selected 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetamido]-3-[(E)-2-(1-methylimidazo[1,2-b]pyridazinium-6-yl)thiovinyl]-3-cephem-4-carboxylate (29ca) as a new anti-MRSA parenteral cephalosporin candidate for further biological evaluation. The selected 29ca showed anti-MRSA activity comparable to that of vancomycin (VCM) both in vitro and in vivo, high affinity (IC50)=2.7 microg/ml) for penicillin binding protein 2' (PBP2') of MRSA and potent activity against Gram-negative bacteria as well.     

Pyridonecarboxylic acids as antibacterial agents. 9. Synthesis and antibacterial activity of 1-substituted 6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)-1,8-naphthyridine-3- carboxylic acids

The title compounds (7a-e) with ethyl, 2-fluoroethyl, 2-hydroxyethyl, vinyl, or cyclopropyl groups, respectively, at C-1 were prepared by the method involving the Balz-Schiemann reaction of 2-(4-pyridyl)pyridine- and 7-(4-pyridyl)-1,8-naphthyridinediazonium tetrafluoroborates (15 and 27). The 1-ethyl, 1-(2-fluoroethyl), and 1-vinyl derivatives showed in vitro activities as potent as the corresponding 7-(1-piperazinyl) analogues against Staphylococcus aureus 209P JC-1 and Escherichia coli NIHJ JC-2 but were less active against Pseudomonas aeruginosa 12. Among the 7-(4-pyridyl) derivatives having the different C-1 substituent, 1-cyclopropyl derivative 7e was found to be the most active. In vivo efficacy of 7e was superior to that of enoxacin against experimental infections due to S. aureus 50774. Some aspects of structure-activity relationships associated with the C-1, C-6, and C-7 substituents were discussed.     

Cephems: fifty years of continuous research

Since 1964, seven waves of parenteral cephems have been reported. All of them were designed to meet medical needs. The first (group I) and the third (group III) waves were very successful and drugs belonging to group III are widely used in the treatment of severe infections. A new series of compounds (group VII), with a new compound underdevelopment was designed for the treatment of Staphylococcus aureus strain resistant to methicillin but also to glyco- and lipoglycopeptides. By modifying the substituent at position 3 and 7 of the cephems rings optimal moieties have been fixed leading to potent anti-Gram-positive drugs. Alterations of substituents are still in progress to obtain optimal anti-Gram-positive (anti-MRSA) compounds. The first oral cephem cephalexin was introduced in clinical practice in 1967. Since this time, many esterified and non-esterified cephems have been synthesized and introduced in clinics. There are two groups of compounds, alpha-amino and non-alpha-amino cephems which are classified in six groups according to their chemical structure. The absorption route was explored and three transporting systems have been described according to the physico-chemical properties of these compounds, in addition prodrugs are passively absorbed.     

Basic and clinical studies on ceftriaxone in perinatal infections

Basic and clinical investigations were conducted on ceftriaxone (CTRX), a cephem antibiotic with a wide antibacterial spectrum and with especially high activity against Gram-negative bacteria. The results obtained are summarized as follows: 1. CTRX, following intravenous drip infusion of 1 g, had a serum half-life of 5.8 hours, which is longer than that of any other existing cephem antibiotics. 2. The level of CTRX in the umbilical cord serum 6 hours after intravenous drip infusion of 1 g was at a satisfactory level, 15 micrograms/ml. 3. The CTRX was remarkably effective or effective in 9 cases, and the activity was high even in cases where penicillin or other third-generation cephems were ineffective. These results seem to indicate that CTRX may be effective in perinatal and intrauterine fetal infections.     

Studies on FK482 (Cefdinir). IV. Synthesis and structure-activity relationships of 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]- 3-substituted cephalosporin derivatives

The synthesis of 7 beta-[(Z)-2-(aminothiazol-4-yl)-2-hydroxyiminoacetamido] cephalosporins (Ia-i) modified at the C-3 position of a cephem nucleus and the effect of the C-3 substituents on the antibacterial activity and oral absorbability are discussed. The cephems (Ie, h and i) having a C-3 substituent such as 1-propenyl, ethylthio and vinylthio group as well as FK482 (cefdinir) exhibited excellent antibacterial activities against both gram-positive and gram-negative bacteria. However, those compounds showed poor absorption rate after oral administration in rats. It is concluded that the vinyl moiety at the 3-position is necessary to display fairly oral absorptivity in a series of 7 beta-[(Z)-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]c eph ems.     

Synthesis and biological activity of a new cephalosporin, BMY-28232 and its prodrug-type esters for oral use

The synthesis and structure-activity relationships of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[( Z)-1- propenyl]-3-cephem-4-carboxylic acid (BMY-28232), its 3-alkenyl analogs (6 and 7) and O-substituted derivatives of the oxyimino moiety (10) are described, as well as the oral pharmacokinetics and in vivo activities of the 1-acetoxyethyl ester of BMY-28232 (BMY-28271) and its analogous esters (11). The 3-alkenyl groups were introduced by the Wittig reaction of the ylide (2) prepared from the 3-chloromethyl cephem (1) to afford the Z (main) and E (minor) isomers regarding the 3-side chain. The O-substituted derivatives (10) were prepared by 7-N-acylation of the 7-amino cephem (4a) with the corresponding O-substituted side chain acids (8). The prodrug esters (11) were prepared by esterification of BMY-28232 with an appropriate halide. BMY-28232 was the most active among the 3-alkenyl analogs tested against Gram-negative organisms and much more active than the O-substituted derivatives against Gram-positive bacteria. BMY-28271 showed good oral bioavailability (66%) and good in vivo efficacy in mice against infections of Staphylococcus aureus Smith (PD50, 0.68 mg/kg) and Escherichia coli Juhl (0.54 mg/kg).     

Orally active cephalosporins. I. Synthesis and structure-activity relationships of 7 beta-[2-(R)-amino-2-phenylacetamido]-3-(1H- 1,2,3-triazol-4-yl)alkylthiomethyl-3-cephem-4-carboxylic acid and related compounds]

The synthesis, antibacterial activity and oral absorbability of 7 beta-[2-(R)-amino-2-phenylacetamido]-3-(1H-1H-1,2,3-triazol- 4-yl)methylthiomethyl-3-cephem-4-carboxylic acid (1a) and related compounds (1b-p and 2) are described. The replacement of 1,2,3-triazole at the C-3 position of 1a with other heteroaromatics such as 1,2,4-triazole, imidazole and so on decreased its oral absorbability in mice (1b-j). The oral absorbability was also influenced by the spacer length between C-3 of cephem nucleus and C-4 of 1,2,3-triazole. The quantitative relationship between the bioavailability and the spacer length of cephalosporins (1a and 1k-p) is discussed. These results suggest that 1,2,3-triazole in the side chain at the C-3 position of cephems plays an important role in good oral absorption through its interaction with the transport system of small intestine.     

Studies on beta-lactam antibiotics. X. Synthesis and structure-activity relationships of 7 beta-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino)acetamido] cephalosporin derivatives

The synthesis of 7 beta-([Z) -2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino) acetamido]-cephalosporins (2a-h) modified at the C-3 position of a cephem nucleus and the effect of the C-3 substituents on the antibacterial activity, oral absorptivity and therapeutic activity are discussed. The cephems (2a and 2b) having a C-3 substituent such as hydrogen or vinyl were more potent than other cephalosporins against Gram-negative bacteria. However, the cephalosporin (2f) having methylthio group at the 3-position showed the highest absorption rate in rats. These three cephalosporins (2a, b and f) exhibited equally good protective activities in mice infected. Furthermore, the serum levels of these cephalosporins (2a, b and f) were examined in dogs, and 2b and 2f showed outstanding high and prolonged serum levels.     

Studies on orally active cephalosporin esters

The synthesis and the biological properties of orally active cephalosporin esters are described. 3-Methoxymethyl cephem derivatives having a 2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamide function at C-7 (1) showed good activity against a wide variety of bacteria including some beta-lactamase producing species. The prodrug type esters of 1 exhibited a good urinary recovery after oral administration to mice and 1-(isopropoxycarbonyloxy)ethyl ester (2a, CS-807) has been pre-clinically tested as an orally active cephem prodrug.     

Antibiotic sensitivity of Branhamella catarrhalis isolated from respiratory tract infections

The efficacy of antibiotics including some newly developed penicillins and cephems on clinically isolated Branhamella catarrhalis was evaluated in vitro. Among 44 strains of B. catarrhalis which were isolated from expectorated sputum of patients with respiratory tract infections 36 strains were proved to produce beta-lactamase. MICs of penicillins for beta-lactamase positive strains ranged from less than or equal to 0.05 to 3.13 micrograms/ml, while those for beta-lactamase negative strains were all less than 0.05 microgram/ml. MICs of cephems, on the other hand, ranged more variably, especially among beta-lactamase positive strains. The most effective cephem we tested was LMOX which could inhibit all the strains of B. catarrhalis at the concentration of 0.05 microgram/ml or less. Aminoglycosides as well as macrolides also showed sufficiently low MIC values. We therefore concluded that the confirmation of beta-lactamase production by B. catarrhalis seems to be indispensable for the determination of an antibacterial activity of beta-lactam antibiotics.     

High performance liquid chromatography of natural products. I. Separation of cephalosporin C derivatives and cephalosporin antibiotics;isolation of cephalosporin C from fermentation broth.

Microbonded propylamine silica with a solvent system containing acetic acid, methanol, acetonitrile and water (2:4:7.5:86.5) is suitable for an efficient separation of mixtures containing several closely related cephem derivatives. The same system with preparative columns was used for the isolation of cephalosporin C directly from the filtered broth of C. acremonium fermentation.     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from urinary tract infections (1987). III. Secular changes in susceptibility

Sensitivity spectra of major species of bacteria (namely Escherichia coli, Klebsiella spp., Proteus spp., Citrobacter spp., Enterobacter spp., Serratia marcescens and Pseudomonas aeruginosa) which were among the clinical isolates mentioned in the first and second reports to various antibacterial and antibiotic agents and time courses of the spectra are reported below. 1. E. coli was sensitive to cefmenoxime (CMX), latamoxef (LMOX), ceftazidime (CAZ), cefzonam (CZON) and flomoxef (FMOX) which are third generation cephems, carumonam (CRMN) which is a monobactam, imipenem (IPM) which is a carbapenem, ofloxacin (OFLX) and ciprofloxacin (CPFX) which are new quinolones. Compared to the preceding 5-year period, sensitivities to most drugs have increased. 2. Klebsiella spp. were sensitive to CMX, CZON and FMOX which are third generation cephem antibiotics, CRMN which is a monobactam and gentamicin (GM) and arbekacin (HBK) which are aminoglycosides. Compared to the preceding 5-year period, the sensitivity on the whole has increased slightly. 3. Proteus spp. were sensitive to CMX, LMOX, CAZ and CZON which are third generation cephems, CRMN, a monobactam and OFLX and CPFX which are new quinolones. Compared to the preceding 5-year period, increased sensitivities, particularly to parenteral cephems, were found. 4. Citrobacter spp. were sensitive to CPFX which is a new quinolone antibiotic and CRMN, a monobactam. Compared to the preceding 5-year period, the sensitivity as a whole increased but there were still strains against which cefotiam, cefmetazole and, cefoperazone (CPZ) showed high MIC values. 5. Enterobacter spp. were sensitive to OFLX and CPFX, which are new quinolones, IPM, a carbapenem, and GM and HBK which are aminoglycosides. Compared to other bacteria, bacteria of this group were less sensitive to CPZ, CAZ, CZON, and FMOX which are third generation cephems. Compared to the preceding 5-year period, slight increases in sensitivity were found in cases of simple urinary tract infections. 6. S. marcescens as a whole was not very sensitive to antibiotics tested. Compared to the preceding 5-year period, sensitivities to CRMN and minocycline improved slightly. 7. P. aeruginosa was not very sensitive to any drug, as other bacteria were. Compared to the preceding 5-year period, sensitivities to new quinolones OFLX and CPFX and carbapenem IPM decreased slightly.     

3-Sulfonyl-1-carba-1-dethiacephems

The stability of the 1-carba-1-dethiacephalosporin framework has allowed the synthesis of a range of 3-sulfonyl-1-carba-1-dethiacephems unavailable for a variety of reasons in the cephem arena. The known p-nitrobenzyl 7 beta-(phenoxyacetamido)-3-[[(trifluoromethyl)sulfonyl]oxy]-1-carba -1- dethia-3-cephem-4-carboxylate served as a precursor to this series of compounds. Displacement of the enol triflate with various sulfinates in acetonitrile or DMF and deprotection of the intermediates led to 7 beta-[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]- 3-[alkyl(aryl)sulfonyl]-1-carba-1-dethia-3-cephem-4-carboxyl ic acids. The 3-sulfonyl-1-carba-1-dethiacephems display potent activity against both Gram-positive and Gram-negative bacteria. The following MIC's (microgram/mL) for the 3-cyclopropyl sulfone are representative: Staphylococcus aureus = 4, Streptococcus pyogenes = 1, Haemophilus influenzae = 0.25, Escherichia coli = 0.03, Enterobacter cloacae = 0.25, Proteus rettgeri = 0.25. The excellent in vitro antibacterial activity of this series indicates the potential of the carbacephalosporin framework for exploring substituents which are unknown or which produce unstable cephems.     

New chiral and isomeric cyclopropyl ketoxime propanolamine derivatives with potent beta-adrenergic blocking properties

The synthesis of R-(+) and S-(-) isomers of O-[3-tert-butylamino)-2-hydroxypropyl] cyclopropyl methyl ketone oxime (falintolol) is described. The syn and anti isomers of falintolol were obtained in two different ways from cyclopropyl methyl ketoxime or from falintolol. For comparison purposes, the enantiomers of the dicyclopropyl ketone oxime derivatives were also prepared. Structure-activity relationships are described.     

Synthesis and biological activity of 3-vinylthio- and 3-vinylthiomethylcephem derivatives

The synthesis and biological properties of some 3-vinylthio- and 3-vinylthiomethylcephem derivatives are described. Both series possess potent antibacterial activity. Among them, 3-[(Z)-2-cyanovinylthiomethyl]cephem derivative was found to have an expanded antibacterial spectrum.     

Antibacterial activity of panipenem against clinical isolates in 2000 and 2001

As the post-marketing surveillance of panipenem/betamipron (Carbenin), MICs of panipenem (PAPM) against 1355 clinical isolates of 28 species from 15 medical institutions all over Japan from June 2000 to March 2001 were measured using the broth microdilution method approved by the Japanese Society of Chemotherapy and compared with those of parenteral carbapenem antibacterials, imipenem (IPM) and meropenem (MEPM), and parenteral cephem antibacterials, cefozopran, cefepime, and sulbactam/cefoperazone. The activity of PAPM was comparable to that of IPM against almost all species tested. Compared with MEPM, PAPM was more active against Gram-positive bacteria and Bacteroides spp., and less active against Gram-negative bacteria. Compared with the parenteral cephems, PAPM was more active against most of species tested and its MIC ranges were narrower than those of the cephems as were those of other carbapenems. In this surveillance study, the incidence of resistance in various species were as follows: 39.3% for methicillin-resistant Staphylococcus aureus, 47.3% for penicillin-intermediate Streptococcus pneumoniae (PISP), 15.1% for penicillin-resistant S. pneumoniae (PRSP), 0.9% for extended-spectrum beta-lactamase (ESBL) producing Escherichia coli, 3.4% for ESBL producing Klebsiella pneumoniae, 19.2% for beta-lactamase producing Haemophilus influenzae, 24.0% for beta-lactamase-negative ampicillin-resistant (BLNAR) H. influenzae, and 1.0% for metallo-beta-lactamase producing Pseudomonas aeruginosa. Against these resistant strains, carbapenems including PAPM showed generally more potent activity than cephems. It was noted that PAPM showed the most potent activity against PISP and PRSP, which showed high incidence of 62.4% totally, among tested drugs. Metallo-beta-lactamase producing P. aeruginosa exhibited high resistance and BLNAR H. influenzae also exhibited low susceptibility against all tested drugs. But no remarkable change in the activity of PAPM against other species was observed in this study compared with that in the studies before the marketing of Carbenin. Furthermore, it is necessary to pay much attention to the trend of resistant strains such as PRSP, metallo-beta-lactamase producing bacteria, and BLNAR H. influenzae.     

Synthesis and beta-adrenergic blocking activity of new aliphatic and alicyclic oxime ethers

We describe the synthesis and pharmacological properties of two new series of aliphatic and alicyclic beta-adrenergic blockers, most of them containing a cyclopropyl ring. They belong either to 2-hydroxy-3-(tert-butylamino)propyl ether A or 2-hydroxy-3-tert-(butylamino)propyl ketoxime ether B derivatives. The O-[2-hydroxy-3-(tert-butylamino)propyl] dicyclopropyl ketoxime 5 exhibited a beta-adrenergic antagonist activity comparable to that of propranolol. It was found that ketoxime ethers B generally showed higher potency than the corresponding ethers A. We confirm that the presence of an aromatic nucleus is not crucial for the beta-adrenergic activity. Structure-activity relationships among these series are discussed.     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from urinary tract infections (1987). I. Susceptibility distribution

Since 1979, Ikemoto et al. have been retrospectively surveying the sensitivity of major species of bacteria isolated from patients with urinary tract infections to various antibacterial agents and antibiotics. Their findings for the past year are reported below. A total of 825 clinical strains of bacteria was investigated. Of this total, Gram-positive bacteria accounted for 28.0% (231 strains) and Gram-negative bacteria for 72.0% (594 strains). Taxonomically, Escherichia coli accounted for 34.7% (286 strains), Enterococcus faecalis for 14.3% (118), Pseudomonas aeruginosa for 11.0% (91), Klebsiella pneumoniae for 7.8% (64), and coagulase-negative staphylococci for 7.3% (60). Sensitivity spectra of these major bacteria to various drugs were as follows. 1. E. faecalis was sensitive to parenteral imipenem (IPM) and ampicillin and oral vancomycin. It was also sensitive to ofloxacin (OFLX) and ciprofloxacin (CPFX), which are new quinolones. Some strains were only slightly sensitive to second and third generation cephems cefmenoxime (CMX) and cefuzonam (CZON) aminoglycosides amikacin (AMK) and arbekacin (HBK), and erythromycin which is a macrolide. 2. Staphylococcus aureus was sensitive to dicloxacillin (MDIPC) which is a penicillin drug, cefotiam (CTM) which is a cephem, IPM, minocycline (MINO), and HBK. A fairly large number of strains were only slightly sensitive to cefazolin (CEZ), OFLX and CPFX. 3. Coagulase-negative staphylococci were sensitive to MDIPC which is a penicillin derivative, cephems CTM and CZON, IPM, HBK, clindamycin (CLDM) and MINO. Some strains, however, were only slightly sensitive to a majority of these drugs. 4. E. coli was sensitive to CTM, CMX, latamoxef (LMOX), ceftazidime (CAZ), CZON, and flomoxef (FMOX), all of which are second or third generation cephems. It was also sensitive to IPM, a carbapenem, carumonam (CRMN), a monobactam, and new quinolones, OFLX and CPFX. 5. K. pneumoniae was sensitive to cephems, viz. CTM, CAZ, CZON, FMOX and cefixime, CRMN which is a monobactam, IPM, a carbapenem and new quinolones, OFLX and CPFX. Some strains were only slightly sensitive to CTM, cefmetazole cefoperazone (CPZ), and FMOX. 6. Citrobacter freundii was sensitive to CRMN which is a monobactam, and new quinolones, OFLX and CPFX. Many strains were only slightly sensitive to cephems, viz. CEZ, CTM, CPZ and CAZ. 7. Enterobacter cloacae was sensitive to gentamicin and AMK which are aminoglycosides, but showed a bimodal pattern of sensitivity to CPZ, CAZ and CZON, all of which are cephems, and to quinolones, OFLX and CPFX.(ABSTRACT TRUNCATED AT 400 WORDS)