Pharmacodynamic Assessment of Cefprozil against
            <i>Streptococcus pneumoniae</i>
            : Implications for Breakpoint Determinations

Nicolau, David P.; Onyeji, Cyprian O.; Zhong, Mingkang; Tessier, Pamela R.; Banevicius, Mary Anné; Nightingale, Charles H.

doi:10.1128/aac.44.5.1291-1295.2000

Cited by 38 publications

(23 citation statements)

References 15 publications

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“…Numerous studies have demonstrated that this index value is independent of the dosing interval, animal species, site of infection, or the cephalosporin used as long as free drug levels are considered (1,2,5,11,17,18). In these studies as well, the %TϾMIC associated with efficacy was similar in the thigh and lung infection models.…”

Section: Discussionsupporting

confidence: 51%

“…A variety of in vitro and in vivo studies have demonstrated that the killing activity of beta-lactam antibiotics is not enhanced by exposure to drug concentrations far exceeding the MIC (1,4,11,13,14,17,18). Furthermore, PAE studies have demonstrated minimal persistent effects with drugs from the beta-lactam class with most bacteria.…”

Section: Discussionmentioning

confidence: 99%

“…The efficacy of antibiotics characterized by this pattern of activity is optimized by prolonging the time that serum levels exceed the MIC of the infecting bacteria. Several animal infection models have identified the %TϾMIC as the principal PK-PD index predictive of efficacy (1,3,5,(17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

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Pharmacodynamics of a New Cephalosporin, PPI-0903 (TAK-599), Active against Methicillin-Resistant Staphylococcus aureus in Murine Thigh and Lung Infection Models: Identification of an In Vivo Pharmacokinetic-Pharmacodynamic Target

Andes

Craig

2006

Antimicrob Agents Chemother

131

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PPI-0903 is a new cephalosporin with broad-spectrum activity, including beta-lactam-resistant Streptococcus pneumoniae and Staphylococcus aureus. We used the neutropenic murine thigh and lung infection models to examine the pharmacodynamic characteristics of PPI-0903. Serum drug levels following four fourfold-escalating single doses of PPI-0903 were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were determined after doses of 1.56, 6.25, 25, and 100 mg/kg of body weight in mice infected with S. pneumoniae ATCC 10813, S. aureus ATCC 29213, or Escherichia coli ATCC 25922. Dose fractionation studies over a 24-h dose range of 0.39 to 1,600 mg/kg were administered every 3, 6, 12, or 24 hours. Nonlinear regression analysis was used to determine which pharmacokinetic-pharmacodynamic (PK-PD) index (total and free 65% drug) best correlated with CFU/thigh at 24 h. Similar to other beta-lactam antibiotics, PPI-0903 produced short to modest in vivo PAEs with either S. pneumoniae or E. coli. The percent time that serum concentrations were above the MIC (%T>MIC) was the PK-PD index that best correlated with efficacy (R 2 ‫؍‬ 84 to 88% for the three organisms, compared with 9 to 41% for peak/MIC and 30 to 82% for the area under the concentration-time curve/MIC). In subsequent studies we used the neutropenic murine thigh infection model to determine if the magnitude of the free-drug %T>MIC needed for efficacy of PPI-0903 varied among pathogens (including resistant strains). Mice infected with one of five isolates of S. pneumoniae, four isolates of S. aureus, or four gram-negative bacilli were treated for 24 h with 0.10 to 400 mg/kg of PPI-0903 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h and to produce a reduction in the burden of organisms from the start of therapy by 1 and 2 log 10 CFU/thigh. MICs ranged from 0.008 to 1 g/ml. Mean free-drug %T>MICs ؎ the standard deviation associated with the static effect endpoint for S. pneumoniae, S. aureus, and gram-negative isolates were 39 ؎ 9, 26 ؎ 8, and 32 ؎ 6, respectively. Methicillin and penicillin resistance did not alter the magnitude of free-drug %T>MIC required for efficacy. The free-drug %T>MIC necessary for efficacy was slightly reduced in animals with normal neutrophil counts. Treatment effect was similar in both the thigh and lung infection models. The pharmacodynamic characteristics of PPI-0903 are similar to those of other compounds within the cephalosporin class.PPI-0903 is a new cephalosporin with broad-spectrum antimicrobial activity and is in early clinical development. PPI-0903 has enhanced potency against gram-positive cocci, including multiply drug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (10).The goals of our experiments were to characterize the in vivo time course antimicrobial activity of PPI-0903 and determine the pharmacokinetic-pharmacodynamic (PK-PD) index and index magnitude predictive of effica...

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

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Pharmacodynamics of a New Cephalosporin, PPI-0903 (TAK-599), Active against Methicillin-Resistant Staphylococcus aureus in Murine Thigh and Lung Infection Models: Identification of an In Vivo Pharmacokinetic-Pharmacodynamic Target

Andes

Craig

2006

Antimicrob Agents Chemother

131

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“…As demonstrated in Fig. 1, differences in the growth control are inherent in in vivo studies, due to natural variations between isolates, and similar growth differences have been published previously (11). Results obtained through analyses of these current gatifloxacin data reveal that all the pharmacodynamic parameters were correlated; however, the AUC/MIC ratio was the best predictor of success for both outcome parameters studied.…”

Section: Discussionmentioning

confidence: 71%

Pharmacodynamic Assessment of Gatifloxacin against Streptococcus pneumoniae

Mattoes¹,

Banevicius²,

Li³

et al. 2001

Antimicrob Agents Chemother

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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 ...

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“…Also, the size of rabbit used (4.75¡0.5 kg) permitted the use of equipment, instruments and techniques intended for clinical paediatric practice, and the rabbits tolerated the daily BAL and blood sampling well. In contrast to previous reports [27,28], the present study used immunocompetent animals, which made pneumonia development more natural. The strain of S. pneumoniae used in the present study was a clinical isolate with a common serotype, and inoculated rabbits were observed over a comparatively long period of time (up to 96 h after inoculation).…”

Section: Discussionmentioning

confidence: 77%

Relationship between the inoculum dose of Streptococcus pneumoniae and pneumonia onset in a rabbit model

Yershov

Jordan²,

Guymon³

et al. 2005

European Respiratory Journal

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It is generally assumed that the development of bacterial pneumonia becomes possible when the dose of inhaled or aspirated pathogens overwhelms the respiratory tract host defence system, but this hypothesis has not yet been tested either clinically or experimentally.This study evaluated inoculum dose in relation to onset of experimental pneumococcal pneumonia, and estimated the median effective dose resulting in pneumonia in healthy New Zealand White rabbits (mean¡SD 4.75¡0.25 kg (n527)). Rabbits were endobronchially inoculated with increasing doses of Streptococcus pneumoniae and pneumonia onset was observed over the following 96 h. The diagnostic approach was based on the Clinical Pulmonary Infection Score, modified for use in rabbits.Inoculation of S. pneumoniae at doses of .4.60 log 10 cfu made the development of pneumonia in rabbits more predictable (up to 90%). Lower doses of bacteria failed to cause pneumonia in 80% of inoculated animals. The median effective dose was estimated by means of logistical regression, probit analyses and the Reed-Muench method, and corresponded to 4.32, 4.38 and 4.67 log 10 cfu, respectively.It is speculated that development of pneumococcal pneumonia becomes more likely when the inoculum dose exceeds a threshold of antibacterial protection, making inoculum dose a risk factor for disease onset.

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Pharmacodynamic Assessment of Cefprozil against Streptococcus pneumoniae : Implications for Breakpoint Determinations

Cited by 38 publications

References 15 publications

Pharmacodynamics of a New Cephalosporin, PPI-0903 (TAK-599), Active against Methicillin-Resistant Staphylococcus aureus in Murine Thigh and Lung Infection Models: Identification of an In Vivo Pharmacokinetic-Pharmacodynamic Target

Pharmacodynamics of a New Cephalosporin, PPI-0903 (TAK-599), Active against Methicillin-Resistant Staphylococcus aureus in Murine Thigh and Lung Infection Models: Identification of an In Vivo Pharmacokinetic-Pharmacodynamic Target

Pharmacodynamic Assessment of Gatifloxacin against Streptococcus pneumoniae

Relationship between the inoculum dose of Streptococcus pneumoniae and pneumonia onset in a rabbit model

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