Comparative evaluation of ciprofloxacin, enoxacin, and ofloxacin in experimental Pseudomonas aeruginosa pneumonia

Abstract

The therapeutic activity of ciprofloxacin, enoxacin, and ofloxacin was evaluated in guinea pigs with acute and chronic experimental Pseudomonas aeruginosa pneumonia. Ciprofloxacin, enoxacin, and ofloxacin are three newly developed quinoline carboxylic acid derivatives with excellent in vitro activity against Pseudomonas aeruginosa (1,2,4,7,9,15,16,29,33). These compounds also offer interesting therapeutic alternatives for the treatment of P. aeruginosa infections because of their prolonged half-life and high tissue penetration (5,6,10,14,17,28,34,35). The high rate of absorption after oral administration (6, 14, 17, 34) might be particularly useful in the treatment of chronic P. aeruginosa bronchopulmonary infections, such as those seen in patients with cystic fibrosis.Ciprofloxacin was shown recently to be as active as tobramycin and superior to ticarcillin in experimental P. aeruginosa pneumonia in guinea pigs (31). No such information is available for enoxacin and ofloxacin. Also, information about the oral treatment of experimental lung infections and about combination therapy of quinolones with ,-lactams or aminoglycosides for respiratory infection is not available. The objectives of the present study were (i) to investigate the comparative efficacy of ciprofloxacin, enoxacin, and ofloxacin in acute and chronic P. aeruginosa pneumonia, (ii) to provide an in vivo evaluation of monotherapy with ciprofloxacin versus combination with a Pseudomonasactive 1-lactam or an aminoglycoside, and (iii) to compare oral and parenteral administration of ciprofloxacin in chronic P. aeruginosa bronchopneumonia.MATERIALS AND METHODS Animals. Disease-free Hartley strain guinea pigs weighing 350 to 400 g each were obtained from the Charles River Breeding Laboratories, Inc., Wilmington, Mass. The animals were housed in standard cages and fed guinea pig chow (Ralston-Purina, St. Louis, Mo.) and water.Antibiotics. Antibiotics used in this study were ciproflox- Ciprofloxacin, azlocillin, and ceftazidime were supplied as a powder and reconstituted in water to a final concentration of 20, 250, and 250 mg/ml, respectively. Powdered ofloxacin was dissolved in 0.1 N NaOH to a concentration of 10 mg/ml and thereafter titrated with concentrated HCl to a neutral pH. Enoxacin, supplied as a solution of 200 mg/ml, was diluted in water to a concentration of 40 mg/ml, and tobramycin was diluted with isotonic saline to a final concentration of 4 mg/ml. Bacteria. Three clinical isolates of P. aeruginosa were used for infections. Strains 220 and A-5 were used in the acute pneumonia experiments, and the mucoid strain 2192M was used in the chronic model. The origins and characteristics of these strains were described previously (21,22,31). Maintenance and preparation of the bacteria for experimental infections were done as reported elsewhere (24). The MICs and MBCs of the antibiotics used in this study against the three challenge strains were determined by a microdilution method in Mueller-Hinton broth supplemented with calcium (50 ,ug/ml) and magn...

Combination Therapy with Ciprofloxacin plus Azlocillin against Pseudomonas aeruginosa: Effect of Simultaneous versus Staggered Administration in an In Vitro Model of Infection

“…The benefit of adding azlocillin to ciprofloxacin therapy was particularly evident in studies using doses of ciprofloxacin that resulted in low ratios of the peak drug concentration to the MIC [23][24][25][26]; addition of azlocillin was associated with improved bacterial killing [23,24] or survival [25,26] or suppression of bacterial resistance to ciprofloxacin [23]. In contrast, other investigators concluded that adding an antipseudomonal penicillin to ciprofloxacin was not advantageous [27][28][29]. The discrepancies in outcome between different studies as well as those obtained in our model may stem from differences in initial bacterial inoculums used (critical to include drug-resistant subpopulations) [6,27], assessment only of early bactericidal effects [29], or dosage regimens that produced higher ciprofloxacin [28] or lower JS-lactam concentrations [27] in animals than those obtained in humans with usual doses.…”

“…Reduction in cfu/rnilliliter over 24 h was significantly greater for combination therapy using any dosing schedule against the two azlocillin-susceptible and the doubly resistant strains than that observed for single-drug therapies (P < .05); there were no differences between simultaneous and staggered regimens against the three strains (P > .05). For the strain with the highest MIC to ciprofloxacin (i.e., CRAs), simultaneous and staggered administration with azlocillin given first (i.e., C-O/ apy with a fluoroquinolone plus a JS-lactam [23][24][25][26][27][28][29]. The benefit of adding azlocillin to ciprofloxacin therapy was particularly evident in studies using doses of ciprofloxacin that resulted in low ratios of the peak drug concentration to the MIC [23][24][25][26]; addition of azlocillin was associated with improved bacterial killing [23,24] or survival [25,26] or suppression of bacterial resistance to ciprofloxacin [23].…”

Pharmacokinetics of ofloxacin after parenteral and oral administration

“…The amount of known metabolites (demethyl and N-oxide compounds) excreted in urine reached only 4.3% (intravenously) and 4.0% (orally). Transient headaches in some volunteers were the only side effects registered.6-Fluoro-7-piperazino-4-quinolones are noteworthy both for the wide range and intensity of activities against gramnegative bacilli and cocci in vitro and the capacity to control experimentally induced systemic infections with selected bacteria when administered orally in well-tolerated doses (9,15,27).Ofloxacin {HOE 280, DL 8280; (±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl) -7-oxo-7H-pyrido[1,2,3-de] [1,4]benzoxacine-6-carboxylic acid} is a new quinolone carboxylic acid derivative showing a broad antimicrobial spectrum against gram-positive and gram-negative bacteria (1,11,17,22,27). This substance was found to be more active than norfloxacin and pipemidic acid (22), its in vitro antibacterial activity being almost comparable to those of gentamicin, tobramycin, and newer cephalosporins (9,11,27).…”

“…6-Fluoro-7-piperazino-4-quinolones are noteworthy both for the wide range and intensity of activities against gramnegative bacilli and cocci in vitro and the capacity to control experimentally induced systemic infections with selected bacteria when administered orally in well-tolerated doses (9,15,27).…”

Effects of the combination of lipopolysaccharide-specific monoclonal antibodies and sparfloxacin against Pseudomonas aeruginosa pneumonia in neutropenic mice

“…It has been demonstrated that several quinolone derivatives are useful in the treatment of P. aeruginosa pneumonia in normal and neutropenic guinea pigs (4,9,27). Sparfloxacin (AT-4140) is a newly developed quinolone for oral use that has broad and potent antibacterial activity (14).…”