Comparative therapeutic efficacy of clinafloxacin in a Pseudomonas aeruginosa mouse renal abscess model.

A deep-seated Pseudomonas aeruginosa mouse kidney abscess model was used to compare the therapeutic efficacy of clinafloxacin, a fluoroquinolone in clinical trials, with that of clinically relevant standard drugs. Following 50 mg/kg oral doses, twice daily for five consecutive days, clinafloxacin produced a 4 log decrease in mean bacterial count, the greatest decrease of all drugs tested. The same dosage regimen resulted in complete bacterial eradication in 88% of the kidneys.

Comparative therapeutic efficacy of clinafloxacin in leucopenic mice.

A cyclophosphamide-induced leucopenic mouse model was used to compare the therapeutic efficacy of clinafloxacin, a fluoroquinolone in clinical trials, with that of ciprofloxacin and imipenem/cilastatin, two clinically relevant standard drugs. Acute systemic infections induced by Escherichia coli, Pseudomonas aeruginosa, a penicillin-resistant Staphylococcus aureus and a methicillin-resistant S. aureus (MRSA) were used to evaluate drug efficacy.

A novel rapid throughput phototolerance screen in mice.

A relatively simple, rapid throughput phototolerance screen in small animals would be very useful in early drug development. It could prioritize or select potential lead compounds from among a number of analogs with similar biological activities. This study describes an in vivo mouse phototolerance screen established for that purpose.

The synthesis, structure-activity, and structure-side effect relationships of a series of 8-alkoxy- and 5-amino-8-alkoxyquinolone antibacterial agents.

A series of 1-cyclopropyl-6-fluoro-8-alkoxy (8-methyoxy and 8-ethoxy)-quionoline-3-carboxylic acids and 1-cyclopropyl-5-amino-6-fluoro-8-alkoxyquinoline-3-carboxylic acids has been prepared and evaluated for antibacterial activity. In addition, they were also compared to quinolones with classic substitution at C8 (H, F, Cl) and the naphthyridine nucleus in a phototoxicity and mammalian cell cytotoxicity assay. The series of 8-methoxyquinolones had antibacterial activity against Gram-positive, Gram-negative, and anaerobic bacteria equivalent to the most active 8-substituted compounds (8-F and 8-Cl).

In vivo therapeutic efficacies of PD 138312 and PD 140248, two novel fluoronaphthyridines with outstanding gram-positive potency.

PD 138312 and PD 140248 are novel broad-spectrum 7-pyrrolidinyl fluoronaphthyridines with a cyclopropyl or a difluorophenyl substitution at the 1 positions, respectively. They have been demonstrated to have excellent in vitro activity against gram-positive organisms. These compounds were evaluated for their in vivo potencies against acute systemic infections in mice and in a mouse pneumococcal pneumonia model.

Synthesis and antibacterial activity of new quinolones containing a 7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl] moiety. Gram-positive agents with excellent oral activity and low side-effect potential.

A series of the R and S isomers of 7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxoquinoline- and 1,8-naphthyridine-3-carboxylic acids was prepared to determine the effect on potency of the two methyl groups adjacent to the distal nitrogen in the pyrrolidinyl moiety. The antibacterial efficacy of these dimethylated derivatives was compared to the relevant 7-[3-(aminomethyl)-1-pyrrolidinyl] parent compounds and, to a lesser extent, the 7-[3-(1-aminoethyl)-1-pyrrolidinyl] analogues. The activity of the title and reference compounds was assayed in vitro using an array of Gram-negative and Gram-positive organisms and in vivo using a mouse infection model.

In vitro evaluation of cefdinir (FK482), a new oral cephalosporin with enhanced antistaphylococcal activity and beta-lactamase stability.

Cefdinir (FK482), a new oral cephalosporin with enhanced beta-lactamase stability, was tested by microbroth dilution against respiratory, urogenital, and skin and skin-structure bacterial pathogens. Included were beta-lactamase (beta LAC)-producing and -nonproducing isolates. Activity was compared with that of other orally administered beta-lactams.

Synthesis and antimicrobial evaluation of a series of 7-[3-amino (or aminomethyl)-4-aryl (or cyclopropyl)-1-pyrrolidinyl]-4-quinolone- and -1,8-naphthyridone-3-carboxylic acids.

A series of 6-fluoroquinolone- and 6-fluoro-1,8-naphthyridone-3-carboxylic acids possessing a [3-amino (or aminomethyl)-4-aryl (or cyclopropyl)-1-pyrrolidinyl] group at C-7 were synthesized and evaluated for their antimicrobial activity. The effect of the relative stereochemistry of the pyrrolidinyl substituents, as well as the presence of different functional groups on the 4-aryl (or cyclopropyl) moiety, was investigated in conjunction with their attachment to several quinolone or naphthyridone nuclei. In general, the incorporation of substituents on the aryl (or cyclopropyl) ring decreased in vitro and in vivo activity, regardless of the nature and relative position of the substituent.

Quinolone antibacterials containing the new 7-[3-(1-aminoethyl)-1- pyrrolidinyl] side chain: the effects of the 1-aminoethyl moiety and its stereochemical configurations on potency and in vivo efficacy.

A series of stereochemically pure 7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1, 4-dihydro-4-oxoquinoline and 1,8-naphthyridine-3-carboxylic acids, with varied substituents at the 1-, 5-, and 8-positions, were synthesized to study the effects of the 7-[3-(1-aminoethyl)-1- pyrrolidinyl] moiety on potency and in vivo efficacy relative to the known 7-[3-(aminomethyl)-1- pyrrolidinyl] derivatives. The antibacterial efficacies of the target compounds and their relevant reference agents were determined in vitro using an assortment of Gram-negative and Gram-positive organisms and in vivo using Escherichia coli and Streptococcus pyogenes mouse infection models. The effects of the 7-[3-(1-aminoethyl)-1-pyrrolidinyl] moiety were also examined at the level of the target enzyme by employing a DNA-gyrase supercoiling inhibition assay.

Quinolone antibacterial agents. Synthesis and structure-activity relationships of a series of amino acid prodrugs of racemic and chiral 7-(3-amino-1-pyrrolidinyl)quinolones. Highly soluble quinolone prodrugs with in vivo pseudomonas activity.

A series of amino acid prodrugs of racemic and chiral 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1,8-naphthyridine-3-carboxylic acids, 1-cyclopropyl-6,8-difluoro-3-quinolinecarboxylic acids, 1-cyclopropyl-6-fluoro-3-quinolinecarboxylic acids, and 5-amino-1-cyclopropyl-6,8-difluoro-3-quinolinecarboxylic acids have been prepared and evaluated for comparative antibacterial activity. Compounds were prepared by acylation of the 3-amino group of the pyrrolidine with common amino acids using standard peptide chemistry. This series has been compared with the parent compounds for antibacterial activity in vitro and in vivo as well as for comparative solubility.

Interpretive criteria and quality control limits for testing susceptibility of Neisseria gonorrhoeae to enoxacin.

For testing the susceptibility of Neisseria gonorrhoeae to enoxacin, a proposed susceptibility category includes strains for which MICs are less than or equal to 0.5 micrograms/ml and zones of inhibition are greater than or equal to 32 mm in diameter. Because of the sparcity of resistant gonococci, a resistance category was not defined, but laboratory-selected resistant mutants were appropriately categorized by the proposed criteria.

New 8-(trifluoromethyl)-substituted quinolones. The benefits of the 8-fluoro group with reduced phototoxic risk.

A series of 8-(trifluoromethyl)-substituted quinolones has been prepared and evaluated for in vitro and in vivo antibacterial activity, and phototolerance in a mouse phototolerance assay. These analogues were compared to the corresponding series of 6,8-difluoro- and 6-fluoro-8H-quinolones (ciprofloxacin type). Although their in vitro antibacterial activities are less than the 6,8-difluoro analogues, the 8-(trifluoromethyl)quinolones are generally equivalent to their 8H analogues.

Synthesis and biological activity of 5-amino- and 5-hydroxyquinolones, and the overwhelming influence of the remote N1-substituent in determining the structure-activity relationship.

A series of 5-amino- and 5-hydroxyquinolone antibacterials substituted at C7 with a select group of common piperazinyl and 3-aminopyrrolidinyl side chains was prepared. These 5-substituted derivatives were compared to the analogous 5-hydrogen compounds for antiinfective activity by using DNA gyrase inhibition, minimum inhibitory concentrations against a variety of bacteria, and in vivo efficacy in the mouse infection model. The influence on the structure-activity relationships of varied substituents at C8 (H, F, Cl) and N1 (ethyl, cyclopropyl, difluorophenyl) was also studied.

Quinolone antibacterials: preparation and activity of bridged bicyclic analogues of the C7-piperazine.

A series of quinolone and naphthyridine antibacterial agents possessing as the C7-heterocycle bicyclic 2,5-diazabicyclo[n.2.m]alkanes, where n = 2, 3 and m = 1, 2, and a series including 4-aminopiperidine and 3-amino-8-azabicyclo[3.

Quinolone antibacterial agents substituted at the 7-position with spiroamines. Synthesis and structure-activity relationships.

A series of fluoroquinolone antibacterials having the 7-position (10-position of pyridobenzoxazines) substituted with 2,7-diazaspiro[4.4]nonane (4b), 1,7-diazaspiro[4.4]nonane (5a), or 2,8-diazaspiro[5.

Comparative chemotherapeutic activity of new fluorinated 4-quinolones and standard agents against a variety of bacteria in a mouse infection model.

The new fluorinated 4-quinolones appear to represent orally effective alternatives to parenteral and oral agents currently in use. A number of new fluorinated 4-quinolones were compared in acute systemic mouse-infection models with various Gram-positive cocci (streptococci and staphylococci), Enterobacteriaceae and Pseudomonas aeruginosa. Also included were standard oral and parenteral antimicrobial agents.

New "ofloxacin" type antibacterial agents. Incorporation of the spiro cyclopropyl group at N-1.

The first example incorporating a spiro cyclopropyl group into an "ofloxacin" type of quinolone antibacterial agent has been prepared by potassium fluoride mediated ring closure of the hydroxymethyl cyclopropyl intermediate to give 9'-fluoro-7'-oxo-10'-(1-piperazinyl)spiro[cyclopropane-1,3'(2'H)-[7H] pyrido[1,2,3-de][1,4]benzoxazine]-6'-carboxylic acid. Analogues were made by substitution at C-7 by various complex amines. Evaluation of these compounds for antibacterial activity was carried out.

Enoxacin: in-vitro and animal evaluation as a parenteral and oral agent against hospital bacterial isolates.

Enoxacin was evaluated in in-vitro tests and in studies of effectiveness and blood concentrations in the mouse. Enoxacin was active against both susceptible and multiresistant hospital isolates of Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Neisseria gonorrhoeae and staphylococci. Less susceptible were streptococci and anaerobes.

5-Amino-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid (PD 124,816). Synthesis and biological evaluation of a new class of quinolone antibacterials.

A series of 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acids with piperazinyl or pyrrolidinyl side-chains appended at C7 were prepared to test the effect of the 5-amino group on the biological and physicochemical properties of these quinolones. The target compounds were synthesized from 2-nitro-3,4,5,6-tetrafluorobenzoic acid and were tested against a variety of Gram-negative and Gram-positive bacteria and the bacterial enzyme DNA gyrase, using standard microtitration techniques. The results are compared to reference quinolones such as ciprofloxacin.

Comparative in-vitro activity of enoxacin against penicillinase- and non-penicillinase-producing Neisseria gonorrhoeae.

The in-vitro antigonococcal activity of enoxacin was measured by a broth microdilution method. Comparisons were made with five clinically relevant marketed drugs against 23 clinical isolates of Neisseria gonorrhoeae, including several penicillinase producers as well as multiply resistant strains. Results showed that enoxacin possessed potent activity against all organisms tested, with MIC values ranging from less than or equal to 0.

Comparison of microdilution and agar dilution procedures for testing antibiotic susceptibility of Neisseria gonorrhoeae.

Studies were run in parallel to compare the broth microdilution method and the chocolate agar dilution method for testing antibiotic susceptibility of Neisseria gonorrhoeae. Six clinically relevant drugs were tested against 23 clinical isolates of N. gonorrhoeae, including several penicillinase-producing, as well as multiply resistant, strains.

"5-Amino-5"-deoxybutirosin, a semisynthetic analogue of butirosin A: antibacterial activity in vitro and in mice.

Aminodeoxybutirosin (AD-BTN), the 5''-amino-5''-deoxy derivative of butirosin (BTN), was synthesized to improve on the antibacterial activity of BTN by preventing bacterial enzymatic phosphorylation at the 5'' position. AD-BTN possesses the spectrum characteristic of BTN and gentamicin (GTM) and was active at low levels in vitro against a wide variety of gram-negative species including Pseudomonas aeruginosa, indole-positive Proteus and Serratia marcescens; its action was bactericidal against both light and heavy inocula, and it was not antagonized by human serum. AD-BTN was as active as GTM against GTM-sensitive P.