Activities of pefloxacin and ciprofloxacin in experimentally induced Pseudomonas pneumonia in neutropenic guinea pigs

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...

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

Kemmerich¹,

Small²,

Pennington³

1986

“…This can be concluded from in vitro models that simulate human pharmacokinetics to study the effects of changing the concentrations of fluoroquinolones on a number of pathogens (6,12,13,15,23,29,32). For fluoroquinolones, a 24-h AUC/MIC ratio of Ͼ125 is needed for rapid bacterial eradication, whereas a peak serum drug concentration/MIC ratio of Ͼ8 is needed to prevent the selection of resistant organisms.The effect of dose or dose interval on the therapeutic efficacy of fluoroquinolones has been evaluated in experimental infections such as pneumonia, sepsis, peritonitis, and thigh infection caused by gram-negative pathogens in mice, rats, guinea pigs, and rabbits (11,19,20,27,33,41). Dosage schedules resulting in high AUC/MIC ratios and high peak serum drug concentration/MIC ratios of 10 or 20 effected higher therapeutic efficacy than did regimens in which a more fractionated schedule was used at the same daily dose (24,28).…”

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confidence: 99%

“…The effect of dose or dose interval on the therapeutic efficacy of fluoroquinolones has been evaluated in experimental infections such as pneumonia, sepsis, peritonitis, and thigh infection caused by gram-negative pathogens in mice, rats, guinea pigs, and rabbits (11,19,20,27,33,41). Dosage schedules resulting in high AUC/MIC ratios and high peak serum drug concentration/MIC ratios of 10 or 20 effected higher therapeutic efficacy than did regimens in which a more fractionated schedule was used at the same daily dose (24,28).…”

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confidence: 99%

Improved Efficacy of Ciprofloxacin Administered in Polyethylene Glycol-Coated Liposomes for Treatment of Klebsiella pneumoniae Pneumonia in Rats

Bakker-Woudenberg

Kate

Guo³

et al. 2001

Animal and clinical data show that high ratios of the area under the concentration-time curve and the peak concentration in blood to the MIC of fluoroquinolones for a given pathogen are associated with a favorable outcome. The present study investigated whether improvement of the therapeutic potential of ciprofloxacin could be achieved by encapsulation in polyethylene glycol (PEG)-coated long-circulating sustained-release liposomes. In a rat model of unilateral Klebsiella pneumoniae pneumonia (MIC ‫؍‬ 0.1 g/ml), antibiotic was administered at 12-or 24-h intervals at twofold-increasing doses. A treatment period of 3 days was started 24 h after inoculation of the left lung, when the bacterial count had increased 1,000-fold and some rats had positive blood cultures. The infection was fatal within 5 days in untreated rats. Administration of ciprofloxacin in the liposomal form resulted in delayed ciprofloxacin clearance and increased and prolonged ciprofloxacin concentrations in blood and tissues. The ED 50 (dosage that results in 50% survival) of liposomal ciprofloxacin was 3.3 mg/kg of body weight/day given once daily, and that of free ciprofloxacin was 18.9 mg/kg/day once daily or 5.1 mg/kg/day twice daily. The ED 90 of liposomal ciprofloxacin was 15.0 mg/kg/day once daily compared with 36.0 mg/kg/day twice daily for free ciprofloxacin; 90% survival could not be achieved with free ciprofloxacin given once daily. In summary, the therapeutic efficacy of liposomal ciprofloxacin was superior to that of ciprofloxacin in the free form. PEG-coated liposomal ciprofloxacin was well tolerated in relatively high doses, permitting once daily administration with relatively low ciprofloxacin clearance and without compromising therapeutic efficacy.The pharmacodynamic and pharmacokinetic properties of antimicrobial agents have been intensively investigated in the recent past, years resulting in the optimization of dosage regimens. In vitro studies and dose-effect studies of experimental infections in animals have been performed with various classes of antibiotics to investigate which pharmacodynamic parameters determine therapeutic efficacy (9,24,26,28,42). Comparative studies of humans with different doses and dosage regimens have also been utilized to optimize antimicrobial treatment (9, 24).The fluoroquinolones are concentration dependent in their rates of bacterial killing. The area under the concentrationtime curve (AUC)/MIC ratio is the parameter that best correlates with the therapeutic efficacy of these agents. In addition, a sufficiently high peak concentration in serum/MIC ratio seems necessary to suppress the emergence of resistant mutants during treatment. This can be concluded from in vitro models that simulate human pharmacokinetics to study the effects of changing the concentrations of fluoroquinolones on a number of pathogens (6,12,13,15,23,29,32). For fluoroquinolones, a 24-h AUC/MIC ratio of Ͼ125 is needed for rapid bacterial eradication, whereas a peak serum drug concentration/MIC ratio of Ͼ8 is needed to preve...

“…It is of special interest that all of these antimicrobial agents are highly active against P. aeruginosa, including multiple-drug-resistant strains (2). Experimental models of P. aeruginosa pneumonia have previously demonstrated the efficacy of these fluorinated quinolones in normal as well as in neutropenic hosts (3,6).…”

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Should Pseudomonas aeruginosa isolates resistant to one of the fluorinated quinolones be tested for the others? Studies with an experimental model of pneumonia

Chidiac¹,

Roussel-Delvallez²,

Guery³

et al. 1995

A clinical isolate of Pseudomonas aeruginosa resistant to pefloxacin (Pef) but susceptible to ciprofloxacin (Cip) was studied to compare the in vitro and in vivo activities of Pef, ofloxacin (Ofl), and Cip. The time-kill curve method showed no bactericidal activity for Pef and Ofl, but a reduction of 4 log 10 CFU/ml was achieved with Cip at 1 h. A model of experimental P. aeruginosa pneumonia was used to evaluate in vivo the relevance of the difference in susceptibility observed in vitro. At 36 h, a 100% cumulative survival rate was observed in Cip-treated rats, which was far higher than the survival rate obtained with Pef (53%) or Ofl (46%) (P < 0.001). At 4 h, no bacteremia was observed in Cip-treated rats, whereas 93% of the Pef-treated rats and 80% of the Ofl-treated rats were bacteremic (P < 0.001). The best pulmonary bacterial clearance was observed with Cip. Interestingly, Pef and Ofl, to which the strain was resistant in vitro, showed a fairly good in vivo activity despite sub-MIC concentrations. Cip was more effective than Pef and Ofl in terms of pulmonary and systemic bactericidal activity and provided the best survival rate in animals. We conclude that differences between the different quinolones in terms of the organism's sensitivity assessed in vitro may be relevant and that it might be useful to reconsider the use of a quinolone to which P. aeruginosa shows resistance if the organism shows sensitivity to no other agent.