Relación estructura-fotoestabilidad u fototoxicidad de fluoroquinolonas / Structure-photostability and phototoxicity relationship in fluoroquinolones

Las quinolonas constituyen una familia de antibióticos de amplio uso en la actualidad, debido a su gran eficacia clínica en el tratamiento de infecciones del tracto respiratorio, urinario, tejidos blandos y enfermedades de transmisión sexual. De acuerdo a su estructura base se pueden clasificar en quinolonas naftiridínicas (enoxacino y ácido nalidíxico), quinolínicas (ciprofloxacino, norfloxacino, ácido oxolínico, rosoxacino) y pirimido-pirimidinicas (ácido pipemídico). Las quinolonas se caracterizan por presentar reacciones de fotosensibilidad y fotolabilidad. El ácido nalidíxico, quinolona de primera generación, presenta reacciones de fototoxicidad, evaluadas en el modelo del glóbulo rojo y en cultivos celulares. El ácido nalidíxico, exento del sustituyente piperazínico presenta una fotolabilidad disminuida. Las fluoroquinolonas, a diferencia del ácido nalidíxico, presentan un anillo piperazínico o metil piperazínico en posición 7, incorporado con el fin de mejorar las propiedades antibacterianas. En este trabajo se investiga la influencia del anillo piperazínico en posición 7 sobre la fotolabilidad y fototoxicidad, demostrándose que las fluoroquinolonas que poseen este sustituyente presentan una fotolabilidad aumentada y una fototoxicidad disminuída, en relación a quinolonas carentes de éste grupo. Es probable que la fotodegradación de quinolonas transcurra mediante un mecanismo radicalario, con la pérdida del grupo carboxílico

Quinolones constitute a large class of synthetic antimicrobial agents that are highly effective in the treatment of respiratory, urinary, sexually transmitted diseases and soft tissue infection. In agreement with his structure the quinolones can be classified into naftaridines (enoxacin and nalidixic acid), quinolines (ciprofloxacin, norfloxacin, oxolinic acid, roxosacin) and pyrid-pyrimidin (pipemidic acid). Some quinolones may undergo photodegradation reactions. On the other hand, quinolones can induce cutaneous photosensitivity reactions.and photolability as well. Nalidixic acid, a first quinolone generation, may undergo phototoxic effects on the red blood cells and in cell culture. Nalidixic acid, which has not the piperazine group in position 7, exhibit a moderated photolability. The fluoroquinolones as oppossed to nalidixic acid have a piperazine ring in position 7. We investigated the influence of the piperazine ring on the phototoxicity and photolability of several quinolones. We demonstrated that the fluoroquinolones with piperazinic group present higher photolability and less phototoxicity .It is possible that the photodegradation of quinolones takes place through a radical pathway, with the loss of a carboxylic acid group

Antibacterial activities of grepafloxacin, ciprofloxacin, ofloxacin and fleroxacin.

Grepafloxacin (OPC-17116) and three other fluoroquinolones were tested against 461 bacterial isolates representing 44 species. Grepafloxacin was superior to ciprofloxacin, ofloxacin and fleroxacin in its activity against the Gram-positive cocci, including staphylococci, pneumococci and hemolytic streptococci. Attempts to select grepafloxacin-resistant mutants from a methicillin-resistant Staphylococcus aureus strain were unsuccessful, although ciprofloxacin readily selected quinolone-resistant mutants of that strain. Among Gram-negative bacilli other than Escherichia coli, mutants were readily selected by in vitro exposure to either grepafloxacin or ciprofloxacin. All such mutants showed complete cross resistance to six other quinolones. The four study drugs were active against nalidixic acid-susceptible strains belonging to 13 species of the Enterobacteriaceae, but ciprofloxacin was the most potent drug studied. Against Acinetobacter spp. and Stenotrophomonas maltophilia, grepafloxacin was two- to four-times more active than ciprofloxacin. However, against Pseudomonas aeruginosa, ciprofloxacin was two- to four-times more potent than grepafloxacin. Grepafloxacin and ciprofloxacin were both found to be bactericidal agents.

Fleroxacin. A review of its pharmacology and therapeutic efficacy in various infections.

The fluoroquinolone antibacterial agent fleroxacin has a broad spectrum of in vitro activity which encompasses most Gram-negative species (particularly Enterobacteriaceae) and a number of Gram-positive organisms, including methicillin-sensitive staphylococci. It is available as oral and intravenous formulations. In clinical trials, fleroxacin has been evaluated in the treatment of uncomplicated urinary tract infections (single or multiple once-daily oral doses of 200 or 400mg), gonorrhoea and chancroid (single oral doses of 200 or 400mg), complicated urinary tract, nonpneumococcal lower respiratory tract and skin and soft tissue infections and typhoid fever (multiple once-daily oral or intravenous regimens, usually 400 mg/day), bacterial enteritis, and traveller's diarrhoea (single or multiple once-daily oral doses of 400mg). Bacteriological cure rates were generally around 90% or higher in complicated and uncomplicated urinary tract infections, uncomplicated gonorrhoea (approximately 100%), pyelonephritis, bacterial enteritis and typhoid fever, and exceeded 80% in lower respiratory tract, and skin and soft tissue infections and chancroid. These cure rates were similar to, or better than, those achieved with standard comparator antibacterial agents such as penicillins, cephalosporins, cotrimoxazole, or other quinolones. Fleroxacin 400mg once daily also achieved bacteriological cure in approximately 80% of patients with bone and joint infections in preliminary studies. In Japanese studies using a lower dosage of 200 or 300 mg/day, fleroxacin was reported to be bacteriologically effective in a range of infections, including urinary tract and upper and lower respiratory tract infections. Fleroxacin has a relatively long elimination half-life, which allows once-daily administration, and it appears to have less propensity for interactions with other medications in comparison to many other fluoroquinolones. Its tolerability profile is typical of this class of compound, with adverse events mostly relating to the gastrointestinal tract, CNS, and skin and appendages (including phototoxicity). Recent pooled tolerability data from worldwide clinical trials indicate that adverse events are reported by approximately 27% of patients receiving 200 mg/day orally or 400 mg/day orally or intravenously, and 17% of those receiving a single oral dose of 400mg. These exceed incidences reported for established fluoroquinolones, possibly indicating recent trends towards increased rates of reported adverse effects with these agents. However, in direct comparative studies with twice-daily fluoroquinolones, fleroxacin 400mg once daily produced a similar incidence of adverse effects to ofloxacin 800 mg/day and a slightly higher incidence than ciprofloxacin 1000 mg/day, while fleroxacin 200mg once daily produced a similar incidence to norfloxacin 800 mg/day.(ABSTRACT TRUNCATED AT 400 WORDS)

In vitro evaluation of E-4695, a new fluoro-naphthyridine.

Compound E-4695, a C-7 azetidinyl fluoro-naphthyridine, was compared to six structurally related quinolones and was generally two- to four-fold more active than ciprofloxacin. E-4695 was particularly active against Staphylococcus aureus (MIC90 0.06 mg/l), Staphylococcus haemolyticus (MIC90 0.5 mg/l), Klebsiella spp. (MIC90 less than or equal to 0.015 mg/l), Serratia marcescens (MIC90 0.06 mg/l), Acinetobacter spp. (MIC90 less than or equal to 0.015 mg/l), Pseudomonas aeruginosa (MIC90 0.5 mg/l), Xanthomonas maltophilia (MIC90 0.5 mg/l), and Neisseria gonorrhoeae (MIC90 less than or equal to 0.001 mg/l). This new quinolone-like drug requires further investigations to confirm these promising in vitro findings.

Enhanced repopulation of murine hematopoietic organs in sublethally irradiated mice after treatment with ciprofloxacin.

We analyzed the effect of ciprofloxacin, fleroxacin, and ceftazidime on production of colony-stimulating factors (CSF) by cultured murine spleen cells in the presence of pokeweed mitogen (PWM). Ciprofloxacin at concentrations of 5 to 10 micrograms/mL in concert with PWM stimulated CSF production by cultured spleen cells. A 3.5-fold increase in the number of CFU-C was observed in the presence of ciprofloxacin-PWM spleen conditioned medium (SCM) as compared with control cultures exposed to PWM-SCM only. Antimurine GM-CSF and antimurine interleukin-3 (IL-3) antibodies inhibited colony formation stimulated by PWM-SCM or ciprofloxacin-PWM-SCM. Fleroxacin and ceftazidime at concentrations of 1 to 100 micrograms/mL and ciprofloxacin at high concentration (greater than 10 micrograms/mL) either did not affect CSF production by spleen cells or had an inhibitory effect. In vivo treatment of sublethally irradiated (650 rad) mice with ciprofloxacin (15 mg/kg per dose three times daily for 5 days) resulted in an increased number of myeloid progenitors in the spleen and bone marrow (BM) of treated mice. In contrast, treatment with ceftazidime did not affect progenitor cell numbers. On days 4 and 8 postirradiation ciprofloxacin-treated mice had a 2.3- and 3.8-fold increase, respectively, in the number of CFU-C in the BM. The number of CFU-C in the spleen did not increase on day 4 postirradiation, but on day 8, the number increased 1.7-fold. On day 4 postirradiation, sublethally irradiated mice treated with ciprofloxacin had a higher WBC count, RBC count, and hemoglobin level as compared with ceftazidime- and saline-treated mice. Twenty-four days postirradiation, 45% of saline-treated mice (20 of 44), and 35% of ceftazidime-treated mice (8 of 23) died, as compared with 13% (5 of 38) of ciprofloxacin-treated mice (P less than .05). These studies indicate that ciprofloxacin may have an immune-enhancing effect on the hematopoietic system in neutropenic mice.

Antimicrobial activity evaluations of two new quinolones, PD127391 (CI-960 and AM-1091) and PD131628.

The in vitro activities of PD127391 and the new fluorinated-4-quinolone, PD131628, were compared with each other and with five similar fluoroquinolones (ciprofloxacin, enoxacin, fleroxacin, norfloxacin, and ofloxacin). A total of 844 isolates mainly from recent clinical bacteremias and additional stock strains with well-characterized resistance mechanisms were tested. PD127391 had slightly more activity than PD131628 (90% minimum inhibitory concentration (MIC90)] 0.008-0.12) against the Enterobacteriaceae, but both were two- to fourfold more potent than ciprofloxacin. PD131628 activity was equal to or greater than PD127391 when tested against Pseudomonas aeruginosa. PD127391 showed greatest activity against Bacteroides fragilis group strains (MIC90, 2 micrograms/ml) when compared with PD131628 (MIC90 greater than 8 micrograms/ml). Both PD127391 (MIC90s, 0.015-1.0 micrograms/ml) and PD131628 (MIC90s, 0.03 - greater than 8 micrograms/ml) were more active than ciprofloxacin against Gram-positive organisms. Altering the medium pH, adding divalent cations (magnesium), and increasing the inoculum concentration to 10(6) colony-forming units per spot adversely effected the activity of both PD127391 and PD131628. Resistance selection and mutational rates to resistance were identical to previously studied drugs in their class.