PK-PD Target Research Articles

Assessment of pharmacokinetic–pharmacodynamic target attainment of gemifloxacin against Streptococcus pneumoniae

The treatment of community-acquired respiratory tract infections has been complicated by the emergence of multidrug-resistant Streptococcus pneumoniae. Although traditionally rare, a growing concern for fluoroquinolone-resistant pneumococci has surfaced. More pharmacodynamically potent antimicrobial agents are clearly needed, as the use of such agents may further optimize clinical and microbiological outcomes for patients and slow the emergence of fluoroquinolone resistance. For fluoroquinolones, the ratio of the 24-h area under the concentration–time curve of the agent to the minimum inhibitory concentration of the agent against the pathogen for the fraction of unbound drug is the major pharmacokinetic–pharmacodynamic (PK–PD) measure correlating with efficacy in nonclinical models and infected patients. A 2500-patient Monte Carlo simulation, utilizing a patient–population pharmacokinetic model derived from phase 3 registration trials and the minimum inhibitory concentration distribution for gemifloxacin against 3117 clinical strains of S. pneumoniae, was carried out to estimate the probability of gemifloxacin attaining exposures associated with efficacy. The overall probability PK–PD target attainment for gemifloxacin was greater than 0.99. Gemifloxacin is among the most pharmacodynamically potent fluoroquinolones and is more potent than ciprofloxacin, ofloxacin, and levofloxacin. Preferential use of pharmacodynamically potent agents over other alternatives may lead to improved clinical outcomes and decreased selection of fluoroquinolone-resistant pneumococci.

Pharmacokinetics-pharmacodynamics of cefepime and piperacillin-tazobactam against Escherichia coli and Klebsiella pneumoniae strains producing extended-spectrum beta-lactamases: report from the ARREST program.

The frequency of resistance to beta-lactams among nosocomial isolates has been increasing due to extended-spectrum beta-lactamase (ESBL)-producing enteric bacilli. Although clinical outcome data are desirable, assessment of clinical efficacy has been limited due to the lack of a statistically meaningful number of well-documented cases. Since time above the MIC (T>MIC) is the pharmacokinetic-pharmacodynamic (PK-PD) measure that best correlates with in vivo activity of beta-lactams, a stochastic model was used to predict the probability of PK-PD target attainment ranging from 30 (P30) to 70% (P70) T>MIC, for standard dosing regimens of both piperacillin-tazobactam and cefepime against Escherichia coli and Klebsiella pneumoniae ESBL phenotypes. The P70/30 T>MIC for cefepime at 2 g every 12 h against E. coli and K. pneumoniae was 0.99/1.0 and 0.96/1.0 and for a regimen of 1 g every 12 h was 0.96/1.0 and 0.93/0.99, respectively. For piperacillin-tazobactam at 3.375 g every 4 h against E. coli and K. pneumoniae, the P70/30 T>MIC was 0.77/0.96 and 0.48/0.77 and for a regimen of 3.375 g every 6 h was 0.28/0.91 and 0.16/0.69, respectively. These data suggest that the probability of achieving T>MIC target attainment rates is generally higher with cefepime than with piperacillin-tazobactam for present-day ESBL-producing strains when one uses contemporary dosing regimens.

Sphingolipid activator proteins

The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400 mg/kg/d divided every 6 hours, (maximum 24 g/d). This dosing strategy is higher than the Food and Drug Administration (FDA)–approved package labeling. We evaluated the microbiologic efficacy of this dosing regimen.The primary study objective was to predict the pharmacokinetic (PK) and pharmacodynamic (PD) MIC breakpoints (the highest MIC with a probability of target attainment [PTA] of at least 90%) for the bacteriostatic and bactericidal targets of ticarcillin activity against Pseudomonas aeruginosa using the study dosing regimen. A secondary objective was to evaluate the tolerability profile of the higher ticarcillin-clavulanate dosing regimen in children with cystic fibrosis (CF).This was a population-based PK-PD modeling study of pediatric CF patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7 days. Population PK and PD models were used to estimate PK and PD parameters for 127 clinically evaluable patients. A 10,000-patient Monte Carlo simulation was performed to estimate the target time in which free drug concentrations exceeded the MIC of the infecting organism. The 2 PK-PD targets of microbiologic efficacy included ≥30% for bacteriostasis and ≥50% for bactericidal effects of ticarcillin-clavulanate at higher than FDA-approved doses.A total of 127 patients (age, 0–19 years) met inclusion criteria. Serum concentration levels were modeled in this patient population using published PK parameters with intermittent ticarcillin peak concentrations reaching 288 (93.4) mg/L. The model predicted the PTA of the MICs for P. aeruginosa with a near-maximal bactericidal PK-PD MIC breakpoint of 16 μg/mL and a bacteriostasis PK-PD MIC breakpoint of 32 μg/mL.The results of our simulation suggest that in this select pediatric population, higher than FDA-approved doses of ticarcillin-clavulanate were effective in achieving bactericidal effects among pseudomonal isolates with MICs <16 μg/mL. Bacteriostatic and bactericidal effects were not frequently achieved among P. aeruginosa isolates with MICs >32 μg/mL. Additional studies are warranted to determine the clinical effectiveness of this dosing regimen.

Treatment of neutropenic children with cancer

The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400 mg/kg/d divided every 6 hours, (maximum 24 g/d). This dosing strategy is higher than the Food and Drug Administration (FDA)–approved package labeling. We evaluated the microbiologic efficacy of this dosing regimen.The primary study objective was to predict the pharmacokinetic (PK) and pharmacodynamic (PD) MIC breakpoints (the highest MIC with a probability of target attainment [PTA] of at least 90%) for the bacteriostatic and bactericidal targets of ticarcillin activity against Pseudomonas aeruginosa using the study dosing regimen. A secondary objective was to evaluate the tolerability profile of the higher ticarcillin-clavulanate dosing regimen in children with cystic fibrosis (CF).This was a population-based PK-PD modeling study of pediatric CF patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7 days. Population PK and PD models were used to estimate PK and PD parameters for 127 clinically evaluable patients. A 10,000-patient Monte Carlo simulation was performed to estimate the target time in which free drug concentrations exceeded the MIC of the infecting organism. The 2 PK-PD targets of microbiologic efficacy included ≥30% for bacteriostasis and ≥50% for bactericidal effects of ticarcillin-clavulanate at higher than FDA-approved doses.A total of 127 patients (age, 0–19 years) met inclusion criteria. Serum concentration levels were modeled in this patient population using published PK parameters with intermittent ticarcillin peak concentrations reaching 288 (93.4) mg/L. The model predicted the PTA of the MICs for P. aeruginosa with a near-maximal bactericidal PK-PD MIC breakpoint of 16 μg/mL and a bacteriostasis PK-PD MIC breakpoint of 32 μg/mL.The results of our simulation suggest that in this select pediatric population, higher than FDA-approved doses of ticarcillin-clavulanate were effective in achieving bactericidal effects among pseudomonal isolates with MICs <16 μg/mL. Bacteriostatic and bactericidal effects were not frequently achieved among P. aeruginosa isolates with MICs >32 μg/mL. Additional studies are warranted to determine the clinical effectiveness of this dosing regimen.