In vitro and in vivo laboratory studies on three hydroxyiminophenylacetyl cephalosporins with particular reference to SK&F 80303, an unusually long-acting cephalosporin.

Three cephalosporins with 7-(2-hydroxyiminophenylacetamido) side chains (SK&F 79433, 80000 and 80303), differing in their 3-substituents, exhibited similar broad-spectrum antibacterial activity in vitro against strains of Staphylococcus aureus, Streptococcus faecalis and various Gram-negative bacilli. All three were active in vivo (s.c., mouse) against S. aureus, Escherichia coli or Klebsiella pneumoniae, but they differed significantly in serum pharmacokinetic profiles. SK&F 80303 produced high and extremely prolonged serum levels and protected mice when administered up to 24 hours prior to challenge with beta-lactamase-producing S. aureus or K. pneumoniae. It was resistant to hydrolysis by beta-lactamases from S. aureus, and variably so to beta-lactamases from E. coli strains. SK&F 80303 was bacteriolytic to logarithmically growing S. aureus, E. coli, Proteus mirabilis, K. pneumoniae and Enterobacter cloacae (partially). SK&F 80303 illustrates further the effect of the 3-sulfoalkyltetrazole substituent on the pharmacokinetic properties of cephalosporins. Its combined biological properties make it a possible candidate for therapeutic and long-term prophylactic use.

SK&F 75073, new parenteral broad-spectrum cephalosporin with high and prolonged serum levels.

SK&F 75073, a new parenteral cephalosporin, was found to have broad in vitro and in vivo antibacterial activity including isolates usually resistant to cephalothin and cefazolin. This activity included indole-positive Proteus and Enterobacter species and some Serratia isolates. Proteus mirabilis strains were particularly susceptible, as were Haemophilus influenzae and Neisseria species. The activity of SK&F 75073 against gram-positive bacteria was poorer than that of the control cephalosporins. This cephalosporin is highly bound to serum proteins, and a loss in in vitro activity was observed in the presence of serum. Parenteral administration of SK&F 75073 to experimental animals (mice, dogs, squirrel monkeys) resulted in high and prolonged serum levels when compared with cefazolin and other injectable cephalosporins. This favorable serum profile was reflected in the excellent protection observed in mice infected with pathogenic bacteria.

Biological and chemotherapeutic studies on three semisynthetic cephamycins.

Three semisynthetic cephamycin antibiotics (7alpha-methoxy-cephalosporins), SK&F 73678, SK&F 83088 (CS-1170) and cefoxitin, have been found to possess favorable biological and chemotherapeutic properties. All three cephamycins are active in vitro against strains of Staphylococcus aureus and a variety of gram-negative bacilli. Beta-lactamase producing organisms including indole-producing Proteus spp., Enterobacter spp. and Serratia strains as well as certain anaerobic bacteria were found to be susceptible to these antibiotics. SK&F 73768 showed somewhat better MIC values than cefoxitin against multiple strains of bacteria. Strains of Pseudomonas aeruginosa and group D streptococci are essentially insensitive to these compounds. Their binding to serum proteins is relatively low. In mice, cefoxitin showed the most favorable pharmacokinetics with respect to peak serum level, serum half-life and urinary recovery. These cephamycins protected mice experimentally infected with a variety of bacterial strains. All three compounds are rapidly bacteriolytic to the logarithmically growing Escherichia coli and belatedly so to Staphylococcus strains with complete sterilizing effect. SK&F 73678 and SK&F 83088 showed activity and potency comparable to or better than cefoxitin and thus can be considered candidates for clinical study.

Synthesis and biological activity of some broad-spectrum N-acylphenyglycine cephalosporins.

The synthesis and the in vitro and in vivo antibacterial activities of a series of N-acylated phenylglycine cephalosporins are described. These compounds exhibit activity against a broad spectrum of gram-positive and gram-negative bacteria including some strains of Pseudomonas aeruginosa, a bacterial species normally insensitive to the cephalosporin antibiotics. The cephalosporins were prepared by acylation of cephaloglycin or its 3-tetrazolylthiomethyl analogue. In several cases, the acylations produced mixtures of diastereomeric cephalosporins, the components of which, when separated, showed different levels of antibiotic activity. Optimum activity was obtained when the acyl moiety on the phenylglycine nitrogen contained an oxygen atom centrally located between the amide carbonyl and a carboxyl substituent, preferably in a three- or five-membered ring. Replacement of acetoxymethyl by (1-methyl-1H-tetrazol-5-yl)thiomethyl at the 3 position resulted in overall improvement in activity both in vitro and in vivo. Against a group of P. aeruginosa strains, the best compounds of this series showed activity on the order of carbenicillin.

In vitro studies with cefazaflur and other parenteral cephalosporins.

Cefazaflur has a broad-spectrum of in vitro antibacterial activity equal to or greater than that of the commercially-available cephalosporins. In addition, cefazaflur has activity against isolates of Enterobacter, Citrobacter and indole-positive Proteus; however, this activity decreased markedly when the MIC determinations were carried out with a large inoculum size. A similar inoculum effect was observed with cefamandole, however, cefoxitin's activity was relatively unchanged at increased inoculum sizes. Human serum had a relatively small effect on the in vitro activity of cefazaflur.

Semisynthetic cephalosporins. Synthesis and structure-activity relationships of analogues with 7-acyl groups derived from 2-(cyanomethylthio)acetic acid or 2-[(2,2,2-trifluoroethyl)thio]acetic acid and their sulfoxides and sulfones.

The synthesis and in vitro and in vivo activities of a series of cephalosporins having side chains derived from 2-[(2,2,2-trifluoroethyl)thio]acetic acid or 2-(cyanomethylthio)acetic acid and with acetoxymethyl or 3-heterocyclic thiomethyl substituents at the 3 position are described. In both series, increasing the oxidation state of the side-chain sulfur atom from sulfide to sulfoxide/sulfone decreased the in vitro gram-positive activity, but the effect on gram-negative activity was variable and less pronounced. The protective effectiveness in mice infected with Escherichia coli increased as the oxidation level of the side-chain sulfur was raised from sulfied to sulfoxide/sulfone. Replacement of the 3-acetoxymethyl by a 3-heterocyclic thiomethyl group resulted in overall improvement of activity both in vitro and in vivo for all oxidation states.

Semisynthetic cephalosporins. Synthesis and structure-activity relationships of 7-sulfonylacetamido-3-cephem-4-carboxylic acids.

The synthesis and in vitro and in vivo activities of a series of 7-sulfonylacetamido-3-cephem-4-carboxylic acids with acetoxymethyl or heterocyclic thiomethyl substituents at the 3 position are described. Lengthening the alkyl chain attached to the sulfonyl group increased gram-positive activity but the effect on gram-negative activity was variable. Other structural changes on the 7-acyl side chain resulted in only minor changes in vitro activity. the protective effectiveness in infected mice generally paralleled the in vitro activity, except that the butylsulfonyl derivatives were less protective than predicted by in vitro activity. replacement of the 3-acetoxymethyl by a 3-heterocyclic thiomethyl group resulted in an overall improvement of activity both in vitro and in vivo.

Relationships between in vitro susceptibility and efficacy in experimental mouse infection-protection assay of cefazolin and cephalothin using Escherichia coli strains.

The disc sensitivity and minimal inhibitory concentrations (MIC) of cefazolin and cephalothin were compared against a series of Escherichia coli isolates. These data were correlated with the mouse protective doses of the 2 cephalosporins in animals infected with E. coli strains selected according to their various degrees of in vitro sensitivity to the 2 cephalosporins. The overwhelming majority of E. coli strains showed a significantly higher degree of susceptibility and lower MIC values for cefazolin than for cephalothin. There has been found a good correlation between the inhibition zones and especially the MIC values and the ED50 results for both cephalosporins. Using E. coli clinical isolates, cefazolin was found to be superior to cephalothin not only in vitro experiments but also more potent in protecting the experimentally infected mice.

Laboratory studies with cefatrizine (SK + F 60771), a new broad-spectrum orally-active cephalosporin.

Cefatrizine (SK&F 60771), a new orally-active semisynthetic cephalosporin antibiotic with broad-spectrum antibacterial activity, was compared with cephalexin and cefazolin for in vitro and in vivo antibacterial activity and pharmacokinetic behavior in laboratory animals. The average MIC values obtained with cefatrizine against gram-positive and gram-negative bacteria were superior to those obtained with cephalexin and somewhat poorer than those of cefazolin. In addition, a large percentage of the enterobacter and enterococcus isolates were found to be susceptible. Cefatrizine had a longer biological half-life and a higher peak serum level than either cefazolin or cephalexin when administered parenterally or orally to mice at 20 mg/kg. It had striking in vivo protective activity in mice infected with Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Hemophilus influenzae, Proteus morganii or Staphylococcus aureus reflecting its superior pharmacokinetic profile in this animal species. A variable pharmacokinetic response between animal species was observed when cefatrizine was administered either orally or parenterally to dogs, squirrel monkeys or rabbits.

A new parenteral cephalosporin. SK&F 59962: in vitro and in vivo antibacterial activity and serum levels in experimental animals.

SK&F 59962, a new parenteral cephalosporin was found to have a high order of in vitro and in vivo antibacterial activity against a broad-spectrum of clinical isolates. When tested in vitro against gram-negative organisms, SK&F 59962 was consistently more active than cefazolin and far superior to cephalothin. This new antibiotic had activity equal to that of cephalothin against gram-positive bacteria. Enterobacter species were found to be susceptible to SK&F 59962. In mouse infection studies using bacterial pathogens, SK&F 59962 had protective activity of the order of that of cefazolin and superior to that of cephalothin. Following parenteral administration the serum profile of SK&F 59962 in the mouse, dog and squirrel monkey was similar to that of cephalothin. SK&F 59962 and cephalothin had lower peak serum concentrations and shorter biologic half-lives than those of cefazolin.