Comparative efficacies of levofloxacin and ciprofloxacin against Streptococcus pneumoniae in a mouse model of experimental septicaemia

Onyeji, Cyprian O.; Bui, Khanh Q.; Owens, Robert C.; Nicolau, David P.; Quintiliani, Richard; Nightingale, Charles H.

doi:10.1016/s0924-8579(98)00087-9

Cited by 37 publications

(32 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…on days Ϫ4 (150 mg/kg of body weight) and Ϫ1 (100 mg/kg) before treatment began. This regimen has been shown to induce neutropenia in the animals for 5 days (1,5,12). In addition, renal impairment was produced by a single i.p.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacodynamic Assessment of Gatifloxacin against Streptococcus pneumoniae

Mattoes¹,

Banevicius²,

Li³

et al. 2001

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The pharmacodynamic parameters of peak serum drug concentration/MIC (peak/MIC) ratio and the area under the curve (AUC)/MIC ratio have been used to characterize in vivo drug exposure and its relationship to bacterial killing for the fluoroquinolones. Our study objectives were to describe the pharmacodynamic relationship between gatifloxacin exposure and outcome as assessed by bacterial density and survival in an immunocompromised murine thigh model of pneumococcal infection and to assess the relationship between drug exposure and these outcomes in an immunocompetent host. ICR mice were rendered neutropenic, and thigh infection was induced by intramuscular administration of 0.1 ml of 10 5 to 10 7 CFU of Streptococcus pneumoniae/ml. Mice received 1 to 5 mg of uranyl nitrate/kg of body weight at day ؊3 and were randomized to receive 10 to 80 mg of gatifloxacin/kg every 6 to 24 h orally, starting at 2 h postinoculation. Bacterial density studies were completed 24 h after initiation of therapy, and survival was assessed after 4 days of treatment. MICs for clinical isolates (n ‫؍‬ 8) ranged from 0.25 to 1.0 g/ml. Correlations were assessed between the change in bacterial density, as well as survival, and the AUC/MIC ratio, peak/MIC ratio, and the duration of time that serum drug concentration remained above the MIC. The best predictor of bacterial response was the AUC/MIC ratio for both outcome measures. There was greater efficacy, as measured by a decrease in log change in CFU as well as by survival data, in the immunocompetent mice compared to the immunocompromised mice. These data demonstrate (i) the appropriateness of the AUC/MIC ratio as a dynamic predictor of response to pneumococcal infection for the fluoroquinolones, (ii) that gatifloxacin AUC/MIC ratios of 30 to 40 appear to optimize bactericidal activity and survival in this model, and (iii) that immunocompetency of the host plays a role in efficacy.Considerable controversy exists regarding the most appropriate way to administer antibiotics to maximize bacterial killing and minimize toxicity. In the case of the fluoroquinolones, debate exists as to not only the best pharmacodynamic parameter (i.e., peak serum drug concentration/MIC [peak/MIC] ratio or area under the curve [AUC]/MIC ratio) to characterize bactericidal activity but also the magnitude of the required interaction to optimize therapeutic outcome (10, 13).The current study was undertaken to investigate the pharmacodynamic relationship between gatifloxacin exposure and outcome as assessed by bacterial density and survival in a murine thigh model of pneumococcal infection. Additionally, the influence of the host on these outcomes was assessed in an immunocompetent model. MATERIALS AND METHODSAntimicrobial test agents. Gatifloxacin analytical grade standard was obtained for in vitro testing from Bristol-Myers Squibb, Princeton, N.J. For all in vivo studies, laboratory standard grade gatifloxacin (lot no. 9D07329; expiration date, Sept. 2000) was obtained from the manufacturer, reconstituted based on ...

show abstract

Section: Methodsmentioning

confidence: 99%

“…In addition, renal impairment was produced by a single i.p. injection of uranyl nitrate on day Ϫ3 prior to the initiation of antimicrobial therapy (1,12).…”

Section: Methodsmentioning

confidence: 99%

Pharmacodynamic Assessment of Gatifloxacin against Streptococcus pneumoniae

Mattoes¹,

Banevicius²,

Li³

et al. 2001

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…During the last decade, pharmacokinetic and pharmacodynamic analyses of dose-response relationships have resulted in a wealth of information. With regard to the quinolones, various studies have shown that the area under the curve (AUC)/MIC ratio and in some cases the peak concentration/MIC (peak/MIC) ratio are predictive of efficacy in studies with in vitro pharmacokinetic models (18,20,21,24) and animals (2,4,5,10,12,28,29) and in clinical studies (1,13,14,17,30).Several controversies remain, however, and these are best exemplified by the recent discussion between Drusano et al (11) and Schentag et al (32,33). While the latter group of investigators maintain the view that the AUC/MIC ratio is the best predictor of quinolone efficacy, the former group of investigators take a more conservative approach.…”

mentioning

confidence: 99%

Pharmacodynamics of Levofloxacin and Ciprofloxacin in a Murine Pneumonia Model: Peak Concentration/MIC versus Area under the Curve/MIC Ratios

Scaglione

Mouton

Mattina

et al. 2003

Antimicrob Agents Chemother

View full text Add to dashboard Cite

During the last decade some studies have shown that the area under the curve (AUC)/MIC ratio is the pharmacodynamic index that best predicts the efficacies of quinolones, while other studies suggest that the predictive value of the peak concentration/MIC (peak/MIC) ratio is superior to the AUC/MIC ratio in explaining clinical and microbiological outcomes. In classical fractionated dose-response studies with animals, it is difficult to differentiate between the AUC/MIC ratio and the peak/MIC ratio because of colinearity. Three different levofloxacin and ciprofloxacin dosing regimens were studied in a neutropenic mouse pneumonia model. The different regimens were used with the aim of increasing the AUC/MIC ratio without changing the peak/MIC ratio and vice versa. The first regimen (RC) consisted of daily doses of 5 up to 160 mg/kg of body weight divided into one, two, or four doses. In the second regimen (R0), mice were given 1.25 mg/kg every hour from 1 to 23 h, while the dose given at 0 h was 2.5, 5, 10, 20, 40, or 80 mg/kg. In the third regimen (R11), mice also received 1.25 mg/kg every hour from 0 to 23 h; but in addition, they also received 2.5, 5, 10, 20, 40, or 80 mg/kg at 11 h. The level of protein binding was also evaluated. The results indicate that the unbound fraction (f u ) was concentration dependent for both levofloxacin and ciprofloxacin and ranged from approximately 0.67 to 0.88 for both drugs between concentrations of 0.5 and 80 mg/liter. The relationships between the AUC/MIC ratio and the number of CFU were slightly better than those between the peak/MIC ratio and the number of CFU. There was no clear relationship between the amount of time that the concentration remained above the MIC and effect (R 2 < 0.1). For both drugs, the peak/MIC ratio that resulted in a 50% effective concentration was lower for the R0 and R11 dosing regimens, indicating the importance of the AUC/MIC ratio. The same was true for the static doses. Survival studies showed that for mice treated with the low doses the rate of survival was comparable to that for the controls, but with the higher doses the rate of survival was better for mice receiving the R0 regimen. We conclude that for quinolones the AUC/MIC ratio best correlates with efficacy against pneumococci and that the effect of the peak/MIC ratio found in some studies could be partly explained by concentration-dependent protein binding.When anti-infective agents are investigated, a measure of the potency of the drug toward the infecting pathogen is required, in addition to a measure of drug exposure. During the last decade, pharmacokinetic and pharmacodynamic analyses of dose-response relationships have resulted in a wealth of information. With regard to the quinolones, various studies have shown that the area under the curve (AUC)/MIC ratio and in some cases the peak concentration/MIC (peak/MIC) ratio are predictive of efficacy in studies with in vitro pharmacokinetic models (18,20,21,24) and animals (2,4,5,10,12,28,29) and in clinical studies (1,13,14,17,30).Sever...

show abstract

“…1 ml subcutaneous injection, twice daily. Onyeji et al (1999) determined that administration of a single subcutaneous dose of 14 . 25 mg CIP kg À1 in mice with renal impairment induced with 10 mg uranyl nitrate kg À1 was required to achieve a value similar to humans for 24 h area under the curve (AUC) on the concentration-versus-time graph (12-19 h mg l À1 ).…”

Section: Methodsmentioning

confidence: 99%

Comparison of clarithromycin and ciprofloxacin therapy for Bacillus anthracis Sterne infection in mice with or without 60Co gamma-photon irradiation

Brook

Giraldo

Germanà

et al. 2005

Journal of Medical Microbiology

Self Cite

View full text Add to dashboard Cite

Biological agents and ionizing radiation lead to more severe clinical outcomes than either insult alone. This study investigated the survival of non-irradiated and 60 Co-gamma-irradiated mice given therapy for inhalation anthrax with ciprofloxacin (CIP) or a clinically relevant mixture of clarithromycin (CLR) and its major human microbiologically important metabolite 14-hydroxy clarithromycin (14-OH CLR). All B6D2F1/J 10-week-old female mice were inoculated intratracheally with 3 3 10 8 c.f.u. of Bacillus anthracis Sterne spores 4 days after the non-lethal 7 Gy dose of 60 Co gamma radiation. Twenty-one days of treatment with CLR/14-OH CLR, 150 mg kg À1 twice daily, or CIP, 16 . 5 mg kg À1 twice daily, began 24 h after inoculation. Pharmacokinetics indicate that the area under the curve (AUC) for 14-OH CLR on the concentration-versus-time graph was slightly higher in gamma-irradiated than non-irradiated animals. Neither drug was able to increase survival in gammairradiated animals. CIP and CLR/14-OH CLR therapies in non-irradiated animals increased survival from 49 % (17/35 mice) in buffer-treated animals to 94 % (33/35) and 100 %, respectively (P , 0 . 001). B. anthracis Sterne only was isolated from 25-50 % of treated mice with or without irradiation. Mixed infections with B. anthracis Sterne were present in 50-71 % of gamma-irradiated mice but only in 5-10 % of mice without irradiation.

show abstract

Comparative efficacies of levofloxacin and ciprofloxacin against Streptococcus pneumoniae in a mouse model of experimental septicaemia

Cited by 37 publications

References 36 publications

Pharmacodynamic Assessment of Gatifloxacin against Streptococcus pneumoniae

Pharmacodynamic Assessment of Gatifloxacin against Streptococcus pneumoniae

Pharmacodynamics of Levofloxacin and Ciprofloxacin in a Murine Pneumonia Model: Peak Concentration/MIC versus Area under the Curve/MIC Ratios

Comparison of clarithromycin and ciprofloxacin therapy for Bacillus anthracis Sterne infection in mice with or without 60Co gamma-photon irradiation

Contact Info

Product

Resources

About