Pharmacodynamic profile of telithromycin against macrolide- and fluoroquinolone-resistant Streptococcus pneumoniae in a neutropenic mouse thigh model.

The new ketolide telithromycin has potent in vitro activity against Streptococcus pneumoniae, including strains resistant to penicillin, macrolides, and fluoroquinolones. The aim of the present study was to define the pharmacodynamic profile of telithromycin against S. pneumoniae strains with various resistance profiles in an in vivo system. Ten S. pneumoniae strains were studied; seven exhibited penicillin resistance, six demonstrated macrolide resistance, and two exhibited gatifloxacin resistance. The telithromycin MICs for all isolates were < or =0.5 microg/ml. Using the murine thigh infection model, CD-1/ICR mice were rendered neutropenic and were then inoculated with 10(5) to 10(6) CFU of S. pneumoniae per thigh. Telithromycin was administered orally at doses ranging from 25 to 800 mg/kg of body weight/day, with the doses administered one, two, three, or four times a day. The activity of telithromycin was assessed by determination of the change in the bacterial density in thigh tissue after 24 h of treatment for each treatment group and the untreated controls. Pharmacokinetic studies of telithromycin were conducted in infected, neutropenic animals. The levels of protein binding by telithromycin in mice ranged from 70 to 95% over the observed range of pharmacokinetic concentrations. By using either the total or the free concentrations of telithromycin, the area under the concentration-time curve (AUC)/MIC ratio was a strong determinant of the response against S. pneumoniae, regardless of the phenotypic resistance profile. The maximal efficacy (the 95% effective dose) against this cohort of S. pneumoniae strains and bacterial inhibition (stasis) of telithromycin were predicted by ratios of the AUC for the free drug concentration/MIC of approximately 1,000 and 200, respectively.

Optimizing antimicrobial pharmacodynamics: dosage strategies for meropenem.

INTRODUCTION: Carbapenems are broad-spectrum antibiotics that are often employed as the last line of therapy for patients with nonresponsive nosocomial infections. Consideration of pharmacodynamic principles in dosage regimens for these agents can maximize their antibacterial effectiveness and reduce the number of bacterial strains that survive to mutate or continue infection. OBJECTIVE: The objectives of this review were to highlight examples of the application of pharmacodynamics to the carbapenems (particularly meropenem) and to comment on clinical utility of these dosage regimens. METHODS: Relevant information was identified through a MEDLINE search of the literature (1980-present) using the terms carbapenem, pharmacodynamic, pharmacokinetic, pharmacoeconomic, meropenem, imipenem, ertapenem, biapenem, and panipenem. Additionally, meeting posters were identified from the International Conference of Antimicrobial Agents and Chemotherapy (years 2001-2003) and the International Conference of the American Thoracic Society (years 2002-2003). All studies demonstrating the pharmacodynamics of the carbapenems by incorporating changes in dosage strategies were included. RESULTS: Only relevant data for meropenem were identified in our literature search. The dosage scheme for meropenem may be modified to maximize the percentage of the dosage interval that drug concentrations remain above the minimum inhibitory concentration, an important parameter related to the bacterial kill rate. Only relevant data for meropenem were identified in our literature search. Human volunteer and Monte Carlo simulation studies suggested that in the treatment of susceptible pathogens, higher meropenem doses, increased frequency of administration, or prolonged duration of infusion resulted in improved pharmacodynamics. CONCLUSION: When proper pharmacodynamic principles are applied to dosage strategies for meropenem, clinical and microbiological outcomes can be optimized.

Steady-state intrapulmonary concentrations of moxifloxacin, levofloxacin, and azithromycin in older adults.

STUDY OBJECTIVE: To determine the steady-state, extracellular, and intracellular pulmonary disposition of moxifloxacin (MXF), levofloxacin (LEVO), and azithromycin (AZI) relative to that of the plasma over a 24-h dosing interval. DESIGN: Randomized, multicenter, open-label investigation. PATIENTS: Forty-seven older adults (mean [+/- SD] age, 62 +/- 13 years) undergoing diagnostic bronchoscopy. INTERVENTIONS: Oral administration of MXF, 400 mg, LEVO, 500 mg daily for five doses, or AZI, 500 mg for one dose, then 250 mg daily for four doses. BAL and venipuncture were completed at 4, 8, 12, or 24 h following the administration of the last dose. MEASUREMENTS AND RESULTS: Steady-state MXF, LEVO, and AZI concentrations were determined in the plasma, epithelial lining fluid (ELF), and alveolar macrophages (AMs). The concentrations of all three agents were greatest in the AMs followed by the ELF compared to the plasma. Plasma concentrations were similar to those previously reported with these agents. The mean ELF concentrations at 4, 8, 12, and 24 h were as follows: MXF, 11.7 +/- 11.9, 7.8 +/- 5.1, 10.5 +/- 3.7, and 5.7 +/- 6.3 micro g/mL, respectively; LEVO, 15.2 +/- 4.5, 10.2 +/- 6.7, 6.9 +/- 4.4, and 2.9 +/- 1.7 micro g/mL, respectively; and AZI, 0.6 +/- 0.4, 0.7 +/- 0.4, 0.9 +/- 0.5, and 0.9 +/- 0.7 micro g/mL, respectively. The AM concentrations at 4, 8, 12, and 24 h were as follows: MXF, 47.7 +/- 47.6, 123.3 +/- 126.4, 26.2 +/- 19.4, and 32.8 +/- 16.5 micro g/mL, respectively; LEVO, 28.5 +/- 30.2, 26.1 +/- 15.7, 28.3 +/- 12.6, and 8.2 +/- 6.1 micro g/mL, respectively; and AZI, 71.8 +/- 50.1, 73.8 +/- 75.3, 155.9 +/- 81.3, and 205.2 +/- 256.3 micro g/mL, respectively. CONCLUSIONS: The intrapulmonary concentrations of MXF, LEV, and AZI were superior to those obtained in the plasma. The AM concentrations of all agents studied were more than adequate relative to the minimum concentration required to inhibit 90% of the organism population (MIC(90)) of the common intracellular pathogens (< 1 micro g/mL). These data indicate that attainable extracellular concentrations of AZI are insufficient to reliably eradicate Streptococcus pneumoniae, based on the agent's current minimum inhibitory concentration profile, whereas the mean concentrations of MXF and LEVO in the ELF exceed the MIC(90) of the S pneumoniae population. Moreover, MXF concentrations exceeded the S pneumoniae susceptibility breakpoint (1.0 micro g/mL) at all time points, while 2 of 15 concentrations (13%) failed to maintain LEVO concentrations above the breakpoint (2.0 micro g/mL) throughout the dosing interval.

Pharmacodynamics of a novel des-F(6)-quinolone, BMS-284756, against Streptococcus pneumoniae in the thigh infection model.

BMS-284756 is a novel quinolone that lacks the six-position fluorine typical of existing compounds. Despite this structural change, BMS-284756 maintains potent antibacterial activity against gram-negative and gram-positive aerobic and anaerobic pathogens. The objective of this study was to define the pharmacodynamic profile of BMS-284756 against Streptococcus pneumoniae. Protein binding in mice was assessed by the ultrafiltration method. For pharmacodynamic studies, neutropenic ICR mice were used, as well as an immunocompetent mouse species, CBA/J, in order to evaluate the impact of white blood cells on infection outcome. Mice were infected with 10(5) to 10(6) CFU per thigh, and therapy was initiated after 2 h. Animals received BMS-284756 orally over a range of 1.25 to 100 mg/kg/day divided into one to four doses. At 0 and 24 h postinfection, thighs were harvested for bacterial density measurement. Survival was assessed during 96 h of therapy and again at 3 days after therapy. Pharmacokinetic studies were also conducted with infected mice. Protein binding was determined to be 80%. The MICs for clinical isolates (n = 8) ranged from 0.03 to 2 micro g/ml. The change in bacterial density and survival was correlated with the pharmacodynamic parameters percentage of time that the drug concentration in serum remains above the MIC, AUC (area under the concentration-time curve)/MIC ratio, and peak/MIC ratio, and the best predictor of response was the AUC/MIC ratio for both outcome measures. Total AUC/MIC ratios of 100 to 200 appear to result in maximal bactericidal effects. While a total AUC/MIC ratio exposure value of 100 (free AUC/MIC ratio, approximately 20) resulted in nearly 100% survival at the conclusion of therapy, a total AUC/MIC ratio of 200 (free AUC/MIC ratio, approximately 40) was required to ensure survival at 3 days posttherapy. These data demonstrate (i) the in vivo bactericidal activity of BMS-284756 against S. pneumoniae, (ii) that protein binding has a profound impact on the in vivo pharmacodynamic assessment of BMS-284756, and (iii) that an AUC/MIC ratio of 200 (free AUC/MIC ratio, approximately 40) appears to best characterize the required dynamic exposure for optimization of bactericidal activity and maximal survival.

Comparative pharmacokinetic and pharmacodynamic profile of piperacillin/tazobactam 3.375G Q4H and 4.5G Q6H.

When piperacillin/tazobactam has been used to treat hospitalized patients with serious infections, including nosocomial pneumonia caused by Pseudomonas aeruginosa, it has usually been dosed at 3.375 g q4h to provide serum concentrations above commonly encountered organisms' MICs (T > MIC) for at least 40-50% of the dosing interval. Pharmacodynamic principles suggest that a similar efficacy can be realized with extended dosing intervals when a larger dose (e.g. 4.5 g q6h) is administered, which was the objective of this study. Twelve healthy volunteers, 29.4 +/- 8.9 years of age, were enrolled in this multiple-dose, open-labeled, randomized, two-period crossover study. Blood samples were collected after the third dose and concentrations of piperacillin/tazobactam were determined with a validated HPLC method. Pharmacokinetic profiles were determined by noncompartment analysis. T > MIC of piperacillin was calculated for a range of MIC values. Piperacillin/tazobactam was well tolerated in 11 subjects who completed both regimens. The C(max), T(1/2), K, and AUC of P were significantly different according to a paired t test (p < 0.05) between two study regimens. Significant differences (p < 0.05) in tazobactam regimens were noted for C(max), and AUC. The piperacillin/tazobactam regimen of 4.5 g q6h achieved a 44% T > MIC for MIC values of < or = 16 microg/ml, while the 3.375-gram q4h regimen achieved 42% T > MIC, for MIC values of < or = 32 microg/ml. Dosage regimens for treating serious infections can be extended safely and effectively to 4.5 g q6h and obtain at least 40-50% T > MIC in the coverage of pathogens implicated with serious infections, including P. aeruginosa.

Pharmacokinetic and pharmacodynamic evaluation of two dosing regimens for piperacillin-tazobactam.

STUDY OBJECTIVE: To compare the pharmacokinetic and pharmacodynamic profiles of two dosing regimens for piperacillin-tazobactam against commonly encountered pathogens. The regimens compared were piperacillin 4.0 g-tazobactam 0.5 g administered every 8 hours, and piperacillin 3.0 g-tazobactam 0.375 g administered every 6 hours. DESIGN: Multiple-dose, open-label, randomized, crossover study. SETTING: Clinical research center at Hartford Hospital. SUBJECTS: Twelve healthy volunteers. INTERVENTION: The two dosing regimens for piperacillin-tazobactam were administered intravenously in crossover design. Blood was sampled after the third dose. MEASUREMENTS AND MAIN RESULTS: Drug concentrations were determined by a validated high-performance liquid chromatography assay. The percentage of time above minimum inhibitory concentration (%T>MIC) for piperacillin was calculated for a range of MIC values. The maximum concentration (Cmax), area under the concentration-time curve (AUC0-tau), and total clearance of piperacillin differed significantly between the two study regimens, as did the Cmax, AUC0-tau, volume of distribution, and total clearance of tazobactam (p<0.05). The piperacillin 4.0 g-tazobactam 0.5 g regimen provided 40-50% T>MIC for MIC values 8-16 microg/ml; a similar value for the piperacillin 3.0 g-tazobactam 0.375 g regimen was 16-32 microg/ml. CONCLUSION: Although statistically significant differences in the pharmacodynamic profile were noted for the regimens, both provide adequate T>MIC against commonly encountered pathogens considered susceptible to piperacillin-tazobactam. However, for treatment of Pseudomonas aeruginosa infection, combination therapy or higher-dosage regimens (e.g., piperacillin 3.0 g-tazobactam 0.375 g every 4 hours, piperacillin 4.0 g-tazobactam 0.5 g every 6 hours, or continuous-infusion piperacillin 12 g-tazobactam 1.5 g/day) may be a prudent option when full MIC data are unavailable.