Pharmacokinetics-pharmacodynamics of tazobactam in combination with cefepime in an in vitro infection model

We previously demonstrated that for tazobactam administered in combination with ceftolozane, the pharmacokinetic-pharmacodynamic (PK-PD) index that best described tazobactam efficacy was the percentage of the dosing interval that tazobactam concentrations were above a threshold (%T>threshold). Using data from studies of Enterobacteriaceae-producing ESBL, a relationship between tazobactam %T>threshold and reduction in log10 CFU from baseline, for which tazobactam threshold concentration was the product of the isolate's ceftolozane-tazobactam MIC value and 0.5, was identified. However, since the kinetics of cephalosporin hydrolysis vary among ESBLs and compounds, it is likely that the translational relationship to derive the tazobactam threshold concentration varies among enzymes and compounds. Using a one-compartment in vitro infection model, the PK-PD of tazobactam administered in combination with cefepime was characterized and a translational relationship across ESBL-producing Enterobacteriaceae was developed. Four clinical isolates, two Escherichia coli and two Klebsiella pneumoniae, known to produce CTX-M-15 β-lactamase enzymes and displaying cefepime MIC values of 2 to 4 mg/L in the presence of 4 mg/L tazobactam, were evaluated. Tazobactam threshold concentrations from 0.0625-1 times the tazobactam-potentiated cefepime MIC value were considered. The threshold that best described the relationship between tazobactam %T>threshold and change in log10 CFU from baseline was the product of 0.125 and the cefepime-tazobactam MIC (R2=0.813). The magnitude of %T>threshold associated with net bacterial stasis and a 1-log10 CFU/mL reduction from baseline at 24 hours was 21.9 and 52.8%, respectively. These data will be useful to support the identification of tazobactam dosing regimens in combination with cefepime for evaluation in future clinical studies

Worldwide Antimicrobial Susceptibility Patterns and Pharmacodynamic Comparisons of Gatifloxacin and Levofloxacin against Streptococcus pneumoniae: Report from the Antimicrobial Resistance Rate Epidemiology Study Team

The use of fluoroquinolones for the treatment of community-acquired respiratory tract infection is increasing. Since for Streptococcus pneumoniae a ratio of the 24-h area under the concentration-time curve (AUC(24)) for the agent to the MIC (AUC(24)/MIC) greater than 30 for the fraction of unbound drug (f(u)) is the major pharmacokinetic-pharmacodynamic (PK-PD) parameter correlating with bacterial eradication by fluoroquinolones in nonclinical models of infection and in infected patients, the Antimicrobial Resistance Rate Epidemiology Study Team systematically compared the in vitro susceptibility patterns and estimated the probability of attainment of the PK-PD target ratios for gatifloxacin and levofloxacin against pneumococci worldwide. Monte Carlo simulation was used to estimate the probability that gatifloxacin or levofloxacin would achieve an f(u) AUC(24)/MIC ratio of 30 or greater. A total of 10,978 S. pneumoniae isolates collected from 1997 to 2000, each indexed by site of infection and geographic region (North America, Latin America, Europe, and Asia-Pacific), were used to estimate the probability mass functions of the microbiological activities for each region considered in the analysis. f(u) AUC(24) probability distribution functions were estimated by using data that were part of each product's submission accepted by the Food and Drug Administration. A 10,000-patient simulation was performed for each drug-organism-region combination. The percentages of strains susceptible to each drug by region were as follows: for gatifloxacin, North America, 99.6%; Latin America, 99.8%; Europe, 99.9%; and Asia-Pacific, 99.2%; for levofloxacin, North America, 99.6%; Latin America, 99.8%; Europe, 99.8%; and Asia-Pacific, 99.1%. The MIC at which 50% of isolates are inhibited (MIC(50)) and the MIC(90) of each drug by region were as follows: for gatifloxacin, North America, 0.25 and 0.5 mg/liter, respectively; Latin America, 0.25 and 0.5 mg/liter, respectively; Europe, 0.25 and 0.5 mg/liter, respectively; and Asia-Pacific, 0.25 and 0.5 mg/liter, respectively; for levofloxacin, North America, 1 and 2 mg/liter, respectively; Latin America, 1 and 2 mg/liter, respectively; Europe, 1 and 1 mg/liter, respectively; and Asia-Pacific, 1 and 1 mg/liter, respectively. The probabilities of attaining an f(u) AUC(24)/MIC ratio greater than 30 for each drug by region were as follows: for gatifloxacin, North America, 97.6%; Latin America, 98.3%; Europe, 99.1%; and Asia-Pacific, 98.8%; for levofloxacin, North America, 78.9%; Latin America, 84.1%; Europe, 87.1%; and Asia-Pacific, 86.5%. These results for a very large collection of recent clinical strains demonstrate that, globally, gatifloxacin is two- to fourfold more active than levofloxacin against S. pneumoniae and that gatifloxacin has an overall 14.3% higher probability of achieving clinically important PK-PD target ratios than levofloxacin

Antibacterial Drug Development: A New Approach Is Needed for the Field to Survive and Thrive

It is often said that the marketplace for new antibiotics is broken. This notion is supported by the observation that many recently-approved antibiotics to treat drug-resistant bacteria have failed commercially in a spectacular fashion. Today, companies with peak market-cap values in excess of USD 500 million to 1 billion prior to product launch regularly sell for pennies on the dollar a few years after market introduction. It is possible, however, that the market is not as broken as we perceive. That is, in the collective mind of the clinician, recently-approved antibiotics may be too-poorly differentiated to justify their broad use and inordinate cost relative to those already existing. Perhaps we in the antibacterial drug development field must change our way of thinking if we are to survive and thrive. Rather than reflexively developing new β-lactam-β-lactamase inhibitor combinations for every new enzyme that evades our current inhibitors, we should focus discovery and development efforts on agents that revolutionize how we potentiate antibiotics. To this end, there has been renewed interest in phage therapies, virulence inhibitors, bacterial growth rate modulators, monoclonal antibodies, and other approaches to augment antibiotic effects. Herein, we suggest that the unmet medical need is less about adding poorly-differentiated antibiotics to our armamentarium and more about the need for innovation in how we augment antibiotic regimen effects

Comparison of Censored Regression and Standard Regression Analyses for Modeling Relationships between Antimicrobial Susceptibility and Patient- and Institution-Specific Variables

In order to identify patients likely to be infected with resistant bacterial pathogens, analytic methods such as standard regression (SR) may be applied to surveillance data to determine patient- and institution-specific factors predictive of an increased MIC. However, the censored nature of MIC data (e.g., MIC ≤ 0.5 mg/liter or MIC > 8 mg/liter) imposes certain limitations on the use of SR. In order to investigate the nature of these limitations, simulations were performed to compare a regression tailored for censored data (censored regression [CR]) and one tailored for an SR. By using a model relating piperacillin-tazobactam MICs against Enterobacter spp. to patient age and hospital bed capacity, 200 simulations of 500 isolates were performed. Various MIC censoring patterns were imposed by using 26 left- or right-censored (L,R) pairs (i.e., MICs ≤ 2 mg/liter(L) [2(L)] or MICs > 2 mg/liter(R) [2(R)], respectively). Data were fit by CR and SR for which censored MICs were either (i) excluded, (ii) replaced by 2(L) or 2(R), or (iii) replaced by 2(L − 1) or 2(R + 1). Total censoring for the 26 pairs ranged from 7 to 86%. By CR, deviations of average parameter estimates from the true parameter values were <0.10 log(2) (mg/liter) for all parameters for each of the 26 pairs. By SR, these deviations were >0.10 log(2) (mg/liter) for at least 18 of the 26 pairs for all but one parameter. Two-standard-error confidence intervals for individual parameters contained as little as 0% of cases for all SR approaches but ≥91.5% of cases for the CR approach. When censored MIC data are modeled, CR may reduce or eliminate biased parameter estimates obtained by SR

Association of Fluconazole Pharmacodynamics with Mortality in Patients with Candidemia▿

Recent studies of nonneutropenic patients with candidemia or candidiasis suggest that fluconazole pharmacodynamic parameters correlate with clinical outcomes; however, additional data of correlation to mortality in patients with candidemia would be valuable. We assessed the impact of MICs for Candida, fluconazole pharmacodynamics, and patient characteristics on all-cause mortality with use of a prospective cohort of 96 hospitalized patients with candidemia. Among 84 patients for whom Candida isolates were available for testing, the most frequent Candida species isolated were Candida albicans (44%), followed by Candida parapsilosis (20.2%), and Candida glabrata (20.2%). Fluconazole resistance (MIC of ≥64 μg/ml) was present in 7 (8.3%) to 10 (11.9%) of 84 isolates, depending on the MIC endpoint determination method (50% or 80% inhibition read at 24 or 48 h). Overall mortality occurred in 27 (28.1%) of 96 patients, and nonsurvivors were more likely to have fluconazole-resistant isolates (25% versus 6.7%; P = 0.02). Multivariable analysis demonstrated an association between fluconazole resistance and mortality, but it did not reach statistical significance (odds ratio, 5.3; 95% confidence interval, 0.8 to 33.4; P = 0.08). By pharmacodynamic analysis, a fluconazole area under the concentration-time curve/MIC of <11.5 or MIC of ≥64 was associated with increased patient mortality (P ≤ 0.09). These data support previous findings of an antifungal exposure-response relationship to mortality in patients with candidemia. In addition, similar MICs were obtained using a 24- or 48-h MIC endpoint determination, thus providing the opportunity to assess earlier the impact of isolate susceptibility on therapy

Use of Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Phase 2 and 3 Dosing Strategies for Doripenem

A doripenem population pharmacokinetic model and Monte Carlo simulations were utilized for dose regimen decision support for future clinical development. Simulation results predict that 500 mg of doripenem administered over 1 h every 8 h would be effective against bacterial strains with MICs less than 2 μg/ml and that less susceptible strains could be treated with prolonged infusions