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Comparative antibacterial efficacies of erythromycin, clarithromycin, and azithromycin were examined against Streptococcus pneumoniae and Haemophilus influenzae, with amoxicillin-clavulanate used as the active control. In vitro, the macrolides at twice their MICs and at concentrations achieved in humans were bacteriostatic or reduced the numbers of viable S. pneumoniae slowly, whereas amoxicillin-clavulanate showed a rapid antibacterial effect. Against H. influenzae, erythromycin, clarithromycin, and clarithromycin plus 14-hydroxy clarithromycin at twice their MICs produced a slow reduction in bacterial numbers, whereas azithromycin was bactericidal. Azithromycin at the concentrations achieved in the serum of humans was bacteriostatic, whereas erythromycin and clarithromycin were ineffective. In experimental respiratory tract infections in rats, clarithromycin (equivalent to 250 mg twice daily [b.i.d.]) and amoxicillin-clavulanate (equivalent to 500 plus 125 mg b.i.d., respectively) were highly effective against S. pneumoniae, but azithromycin (equivalent to 500 and 250 mg once daily) was significantly less effective (P < 0.01). Against H. influenzae, clarithromycin treatment (equivalent to 250 or 500 mg b.i.d.) was similar to no treatment and was significantly less effective than amoxicillin-clavulanate treatment (P < 0.01). Azithromycin demonstrated significant in vivo activity (P < 0.05) but was significantly less effective than amoxicillin-clavulanate (P < 0.05). Overall, amoxicillin-clavulanate was effective in vitro and in vivo. Clarithromycin and erythromycin were ineffective in vitro and in vivo against H. influenzae, and azithromycin (at concentrations achieved in humans) showed unreliable activity against both pathogens. These results may have clinical implications for the utility of macrolides in the empiric therapy of respiratory tract infections.

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The beta-lactam susceptibilities of 65 strains of Streptococcus pneumoniae for which penicillin MICs covered a broad range were assessed. The order of potency was amoxicillin (AMX) = amoxicillin-clavulanate (AMC) > penicillin G > cefpodoxime (CPO) > cefuroxime (CXM) > cefprozil > cefaclor > loracarbef > cefixime. No decrease in susceptibility was seen following repeated subculture of two penicillin-susceptible strains of S. pneumoniae in AMX, AMC, cefaclor, or loracarbef, whereas repeated exposure to CPO and CXM resulted in 4- to 32-fold decreases in susceptibility for both strains. When one of these strains was exposed to concentrations of CPO, CXM, AMX, and AMC achieved in the serum of humans following the administration of an oral dose, all agents were rapidly bactericidal, with no decrease in susceptibility up to 72 h. This was consistent with antibiotic concentrations exceeding the MICs for 100% of the dosing interval. For a penicillin-resistant strain, MICs were exceeded for 29% of the 12-h dosing interval for 500 mg of AMX, 42% of the interval for AMC with 875 mg of AMX and 125 mg of clavulanate (875/125 mg of AMC) 21% of the interval for 500 mg of CXM, and 0% of the interval for 200 mg of CPO. Consequently, only 875/125 mg of AMC produced a sustained bactericidal effect. A four- to eightfold reduction in susceptibility to CPO and CXM and cross-resistance with cefotaxime, but not penicillin or AMC, were selected following exposure to simulated serum CPO and CXM concentrations. In addition, AMX and AMC were the only agents which consistently produced a >99% reduction in bacterial numbers in time-kill studies using concentrations of antibiotic achieved in middle ear fluid for all three strains of penicillin-resistant S. pneumoniae tested.

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The synthesis, antibacterial activity, and stability to human dehydropeptidase-1 (DHP-1) of a novel series of (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-heterocyclylcarbapen-2-em-3-carb oxylates are described. Of the compounds investigated 1,5-disubstituted pyrazol-3-yl and 3-substituted isoxazol-5-yl derivatives have the best combination of antibacterial activity and stability to DHP-1. They are particularly active against community-acquired respiratory tract pathogens and have stabilities to DHP-1 superior to that of meropenem.

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Several classes of antibiotics were assessed for activity against non-growing Escherichia coli and cells grown as a biofilm. Antibiotics which had activity against non-growing cells also showed some activity against biofilms. Cephamycins were more active than other cephalosporins, but the most effective antibiotics were imipenem and ciprofloxacin, which were also active against steady state biofilms. However, none of the antibiotics studied was capable of completely eradicating a biofilm. These results suggest that growth rate plays a role in mediating resistance of biofilms to antibiotics.

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The synthesis and antibacterial activity of a series of beta-lactamase stable, broad spectrum 7-[2-(2-amino-thiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-cephalo sporins, characterised by a C-3-[N-(substituted-amino)pyridinium-4-thiomethyl] group, is described. Gram-positive and Gram-negative bacteria including extended spectrum beta-lactamase-producing strains were most susceptible to the N-amino- and N-methylamino derivatives (3a) and (3b); with the exception of Pseudomonas aeruginosa, (3b) was more active in vitro and in vivo than cefpirome or ceftazidime.

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beta-Lactam antibiotics containing a catechol moiety show potent activity against Gram-negative bacteria, particularly organisms grown under iron-limited conditions, suggesting that the iron-regulated outer membrane proteins (IROMPs) play a role in antibiotic uptake. A catecholic C(7) alpha-formamido-substituted cephalosporin showed increased penetration into Escherichia coli cells grown in an iron-deficient medium compared with cells grown in a medium supplemented with iron. In contrast, penetration of the corresponding monohydroxyphenyl analogue was not influenced by iron concentration. Susceptibility studies with mutants of E. coli lacking one or more IROMPs suggested that the catecholic analogue was able to utilize the Fiu (83 kDa) and Cir (74 kDa) proteins, but not the enterobactin receptor FepA (81 kDa). Mutants lacking both Fiu and Cir showed a specific decreased susceptibility for catechol-containing cephalosporins. Radio-ligand binding studies with a Fe-catecholic cephalosporin confirmed an association with these proteins.

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The structure-activity relationships within a series of penicillins and cephalosporins containing an N(4)-substituted piperazine-2,3-dione moiety in the C(6)/C(7)-beta-side chain are discussed.

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The synthesis and antibacterial activity of a series of penicillins and 6 alpha-formamidopenicillins containing a C(5) or C(6)-substituted piperazine-2,3-dione moiety in the C(6)-beta-sidechain is described.

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The synthesis and antibacterial activity of 7 beta-[D-2-(aryl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl) carbonylamino] acetamido]-7 alpha-formamidocephalosporins with various substituents at the C-3 position of the cephalosporin nucleus is described. Inhibition of Gram-positive and Gram-negative bacteria including beta-lactamase producing strains was observed with phenyl as the aryl residue. The 3,4-dihydroxyphenyl group further enhanced the activity against Gram-negative organisms; in this series, the 3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl] and 3-[(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl] analogues (2 and 12b) exhibited exceptional activity against Gram-negative bacteria, including Pseudomonas aeruginosa.

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BRL 36650 is a new type of penicillin in which a formamido group has been introduced into the 6 alpha-position of the nucleus. The compound is highly active against aerobic gram-negative bacteria and is stable to a wide range of beta-lactamases produced by these organisms. Against members of the family Enterobacteriaceae, BRL 36650 was considerably more active than piperacillin, particularly against beta-lactamase-producing strains, and showed a similar level of activity to moxalactam, aztreonam, and the third-generation cephalosporins cefotaxime and ceftazidime. Against Pseudomonas aeruginosa and other Pseudomonas species, BRL 36650 was more active than piperacillin, cefoperazone, and aztreonam and compared favorably with ceftazidime. BRL 36650 was highly active against Haemophilus influenzae and Neisseria gonorrhoeae, including beta-lactamase-producing strains, and against Acinetobacter calcoaceticus. Clinical isolates of Enterobacter species and P. aeruginosa which showed markedly reduced susceptibility to cefotaxime, ceftazidime, and aztreonam were only slightly less susceptible to BRL 36650. Against Bacteroides fragilis and most gram-positive bacteria, BRL 36650 showed only a low level of activity. BRL 36650 was found to be only 35% bound to human serum protein, and the antibacterial activity was little affected by the presence of serum. In contrast, the composition of the test medium influenced the activity of BRL 36650 slightly, and an antagonistic effect could be demonstrated between the compound and a component of certain Mueller-Hinton media.

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