Jürgen B Bulitta

Publications (18)73.38 Total impact

• Article: Quantifying subpopulation synergy for antibiotic combinations via mechanism-based modeling and a sequential dosing design.

  Cornelia B Landersdorfer, Neang S Ly, Hongmei Xu, Brian T Tsuji, Jürgen B Bulitta
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  ABSTRACT: Quantitative modeling of combination therapy can describe the effects of each antibiotic against multiple bacterial populations. Our aim was to develop an efficient experimental and modeling strategy that evaluates different synergy mechanisms using a rapidly killing peptide antibiotic (nisin) combined with amikacin or linezolid as probe drugs.Serial viable counts over 48h were obtained in time-kill experiments with all three antibiotics in monotherapy against a methicillin-resistant Staphylococcus aureus USA300 strain (inoculum: 108 CFU/mL). A sequential design (initial dosing of 8 or 32mg/L nisin, switched to amikacin or linezolid at 1.5h) assessed the rate of killing by amikacin and linezolid against nisin-intermediate and nisin-resistant populations. Simultaneous combinations were additionally studied and all viable count profiles co-modeled in S-ADAPT and NONMEM®.A mechanism-based model with six populations (three for nisin times two for amikacin) yielded unbiased and precise (r=0.99, slope=1.00, S-ADAPT) individual fits. The second-order killing rate constants for nisin against the three populations were 5.67, 0.0664, and 0.00691 L/(mg·h). For amikacin, the maximum killing rate constants were 10.1 h-1 against its susceptible and 0.771 h-1 against its less susceptible populations with 14.7 mg/L amikacin causing half-maximal killing. After incorporating the effects of nisin and amikacin against each population, no additional synergy function was needed. Linezolid inhibited successful bacterial replication but did not efficiently kill populations less susceptible to nisin.Nisin plus amikacin achieved subpopulation synergy. The proposed sequential and simultaneous dosing design offers an efficient approach to quantitatively characterize antibiotic synergy over time and prospectively evaluate antibiotic combination dosing strategies.
  Antimicrobial Agents and Chemotherapy 03/2013; · 4.84 Impact Factor
• Article: Evaluation of once-daily vancomycin against methicillin-resistant Staphylococcus aureus in a hollow-fiber infection model.

  Anthony M Nicasio, Jürgen B Bulitta, Thomas P Lodise, Rebecca E D'Hondt, Robert Kulawy, Arnold Louie, George L Drusano
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  ABSTRACT: For methicillin-resistant Staphylococcus aureus (MRSA) infections, data suggest that the clinical response is significantly better if the total vancomycin area under the concentration-time curve (AUC)/MIC ratio is ≥400. While the AUC/MIC ratio is the accepted pharmacokinetic/pharmacodynamic (PK/PD) index for vancomycin, this target has been achieved using multiple daily doses. We are unaware of a systematically designed dose fractionation study to compare the bactericidal activity of once-daily administration to that of traditional twice-daily administration. A dose fractionation study was performed with vancomycin in an in vitro hollow-fiber infection model against an MRSA USA300 strain (MIC of 0.75 μg/ml) using an inoculum of ∼10(6) CFU/ml. The three vancomycin regimens evaluated for 168 h were 2 g every 24 h (q24h) as a 1-h infusion, 1 g q12h as a 1-h infusion, and 2 g q24h as a continuous infusion. Free steady-state concentrations (assuming 45% binding) for a total daily AUC/MIC ratio of ≥400 were simulated for all regimens. A validated liquid chromatography-tandem mass spectrometry method was used to determine vancomycin concentrations. Although once-daily and twice-daily dosage regimens exhibited total trough concentrations of <15 μg/ml, all regimens achieved similar bactericidal activities between 24 and 168 h and suppressed the amplification of nonsusceptible subpopulations. No colonies were found on agar plates with 3× MIC for any of the treatment arms. Overall, the results suggest that once-daily vancomycin administration is feasible from a PK/PD perspective and merits further inquiry in the clinical arena.
  Antimicrobial Agents and Chemotherapy 11/2011; 56(2):682-6. · 4.84 Impact Factor
• Article: Relevance of pharmacokinetic and pharmacodynamic modeling to clinical care of critically ill patients.

  Jurgen B Bulitta, Cornelia B Landersdorfer, Alan Forrest, Silvia V Brown, Michael N Neely, Brian T Tsuji, Arnold Louie
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  ABSTRACT: Efficacious therapy is of utmost importance to save lives and prevent bacterial resistance in critically ill patients. This review summarizes pharmacokinetic (PK) and pharmacodynamic (PD) modeling methods to optimize clinical care of critically ill patients in empiric and individualized therapy. While these methods apply to all therapeutic areas, we focus on antibiotics to highlight important applications, as emergence of resistance is a significant problem. Nonparametric and parametric population PK modeling, multiple-model dosage design, Monte Carlo simulations, and Bayesian adaptive feedback control are the methods of choice to optimize therapy. Population PK can estimate between patient variability and account for potentially increased clearances and large volumes of distribution in critically ill patients. Once patient- specific PK data become available, target concentration intervention and adaptive feedback control algorithms can most precisely achieve target goals such as clinical cure of an infection or resistance prevention in stable and unstable patients with rapidly changing PK parameters. Many bacterial resistance mechanisms cause PK/PD targets for resistance prevention to be usually several-fold higher than targets for near-maximal killing. In vitro infection models such as the hollow fiber and one-compartment infection models allow one to study antibiotic-induced bacterial killing and emergence of resistance of mono- and combination therapies over clinically relevant treatment durations. Mechanism-based (and empirical) PK/PD modeling can incorporate effects of the immune system and allow one to design innovative dosage regimens and prospective validation studies. Mechanism-based modeling holds great promise to optimize mono- and combination therapy of anti-infectives and drugs from other therapeutic areas for critically ill patients.
  Current pharmaceutical biotechnology 05/2011; 12(12):2044-61. · 3.40 Impact Factor
• Article: Effect of half-life on the pharmacodynamic index of zanamivir against influenza virus delineated by a mathematical model.

  Ashley N Brown, Jürgen B Bulitta, James J McSharry, Qingmei Weng, Jonathan R Adams, Robert Kulawy, George L Drusano
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  ABSTRACT: Intravenous zanamivir is recommended for the treatment of hospitalized patients with complicated oseltamivir-resistant influenza virus infections. In a companion paper, we show that the time above the 50% effective concentration (time>EC(50)) is the pharmacodynamic (PD) index predicting the inhibition of viral replication by intravenous zanamivir. However, for other neuraminidase inhibitors, the ratio of the area under the concentration-time curve to the EC(50) (AUC/EC(50)) is the most predictive index. Our objectives are (i) to explain the dynamically linked variable of intravenous zanamivir by using different half-lives and (ii) to develop a new, mechanism-based population pharmacokinetic (PK)/PD model for the time course of viral load. We conducted dose fractionation studies in the hollow-fiber infection model (HFIM) system with zanamivir against an oseltamivir-resistant influenza virus. A clinical 2.5-h half-life and an artificially prolonged 8-h half-life were simulated for zanamivir. The values for the AUC from 0 to 24 h (AUC(0-24)) of zanamivir were equivalent for the two half-lives. Viral loads and zanamivir pharmacokinetics were comodeled using data from the present study and a previous dose range experiment via population PK/PD modeling in S-ADAPT. Dosing every 8 h (Q8h) suppressed the viral load better than dosing Q12h or Q24h at the 2.5-h half-life, whereas all regimens suppressed viral growth similarly at the 8-h half-life. The model provided unbiased and precise individual (Bayesian) (r(2), >0.96) and population (pre-Bayesian) (r(2), >0.87) fits for log(10) viral load. Zanamivir inhibited viral release (50% inhibitory concentration [IC(50)], 0.0168 mg/liter; maximum extent of inhibition, 0.990). We identified AUC/EC(50) as the pharmacodynamic index for zanamivir at the 8-h half-life, whereas time>EC(50) best predicted viral suppression at the 2.5-h half-life, since the trough concentrations approached the IC(50) for the 2.5-h but not for the 8-h half-life. The model explained data at both half-lives and holds promise for optimizing clinical zanamivir dosage regimens.
  Antimicrobial Agents and Chemotherapy 01/2011; 55(4):1747-53. · 4.84 Impact Factor
• Article: Nonlinear pharmacokinetics of piperacillin in healthy volunteers--implications for optimal dosage regimens.

  Jürgen B Bulitta, Martina Kinzig, Verena Jakob, Ulrike Holzgrabe, Fritz Sörgel, Nicholas H G Holford
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  ABSTRACT: (i) To describe the first-order and mixed-order elimination pathways of piperacillin, (ii) to determine the between occasion variability (BOV) of pharmacokinetic parameters and (iii) to propose optimized dosage regimens. We performed a five-period replicate dose study in four healthy volunteers. Each subject received 4g piperacillin as a single 5min intravenous infusion in each study period. Drug analysis was performed by HPLC. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and Monte Carlo simulation to predict the probability of target attainment (PTA) with a target time of non-protein bound concentration above MIC >50% of the dosing interval. A model with first-order nonrenal elimination and parallel first-order and mixed-order renal elimination had the best predictive performance. For a 70kg subject we estimated 4.40lh(-1) for nonrenal clearance, 5.70lh(-1) for first-order renal clearance, 170mgh(-1) for V(max) , and 49.7mgl(-1) for K(m) for the mixed-order renal elimination. The BOV was 39% for V(max) , 117% for K(m) , and 8.5% for total clearance. A 30min infusion of 4g every 6h achieved robust (≥90%) PTAs for MICs ≤12mgl(-1) . As an alternative mode of administration, a 5h infusion of 6g every 8h achieved robust PTAs for MICs ≤48mgl(-1) . Part of the renal elimination of piperacillin is saturable at clinically used doses. The BOV of total clearance and volume of distribution were low. Prolonged infusions achieved better PTAs compared with shorter infusions at similar daily doses. This benefit was most pronounced for MICs between 12 and 48mgl(-1) .
  British Journal of Clinical Pharmacology 11/2010; 70(5):682-93. · 2.96 Impact Factor
• Article: Attenuation of colistin bactericidal activity by high inoculum of Pseudomonas aeruginosa characterized by a new mechanism-based population pharmacodynamic model.

  Jürgen B Bulitta, Jenny C Yang, Liliana Yohonn, Neang S Ly, Silvia V Brown, Rebecca E D'Hondt, William J Jusko, Alan Forrest, Brian T Tsuji
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  ABSTRACT: Colistin is increasingly being utilized against Gram-negative pathogens, including Pseudomonas aeruginosa, resistant to all other antibiotics. Since limited data exist regarding killing by colistin at different initial inocula (CFUo), we evaluated killing of Pseudomonas aeruginosa by colistin at several CFUo and developed a mechanism-based mathematical model accommodating a range of CFUo. In vitro time-kill experiments were performed using >or=8 concentrations up to 64 x the MIC of colistin against P. aeruginosa PAO1 and two clinical P. aeruginosa isolates at CFUo of 10(6), 10(8), and 10(9) CFU/ml. Serial samples up to 24 h were simultaneously modeled in the NONMEM VI (results shown) and S-ADAPT software programs. The mathematical model was prospectively "validated" by additional time-kill studies assessing the effect of Ca(2+) and Mg(2+) on killing of PAO1 by colistin. Against PAO1, killing of the susceptible population was 23-fold slower at the 10(9) CFUo and 6-fold slower at the 10(8) CFUo than at the 10(6) CFUo. The model comprised three populations with different second-order killing rate constants (5.72, 0.369, and 0.00210 liters/h/mg). Bacteria were assumed to release signal molecules stimulating a phenotypic change that inhibits killing. The proposed mechanism-based model had a good predictive performance, could describe killing by colistin for all three studied strains and for two literature studies, and performed well in a prospective validation with various concentrations of Ca(2+) and Mg(2+). The extent and rate of killing of P. aeruginosa by colistin were markedly decreased at high CFUo compared to those at low CFUo. This was well described by a mechanism-based mathematical model, which should be further validated using dynamic in vitro models.
  Antimicrobial Agents and Chemotherapy 03/2010; 54(5):2051-62. · 4.84 Impact Factor
• Article: Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid.

  Cornelia B Landersdorfer, Carl M J Kirkpatrick, Martina Kinzig, Jürgen B Bulitta, Ulrike Holzgrabe, Ulrich Jaehde, Andreas Reiter, Kurt G Naber, Michael Rodamer, Fritz Sörgel
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  ABSTRACT: Probenecid influences transport processes of drugs at several sites in the body and decreases elimination of several quinolones. We sought to explore extent, time course, and mechanism of the interaction between ciprofloxacin and probenecid at renal and nonrenal sites. A randomized, two-way crossover study was conducted in 12 healthy volunteers (in part previously published Clin Pharmacol Ther 1995; 58: 532-41). Subjects received 200 mg ciprofloxacin as 30-min intravenous infusion without and with 3 g probenecid divided into five oral doses. Drug concentrations were analysed by liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography. Ciprofloxacin and its 2-aminoethylamino-metabolite (M1) in plasma and urine with and without probenecid were modelled simultaneously with WinNonlin. Data are ratio of geometric means (90% confidence intervals). Addition of probenecid reduced the median renal clearance from 23.8 to 8.25 l h(-1)[65% reduction (59, 71), P < 0.01] for ciprofloxacin and from 20.5 to 8.26 l h(-1) (66% reduction (57, 73), P < 0.01] for M1 (estimated by modelling). Probenecid reduced ciprofloxacin nonrenal clearance by 8% (1, 14) (P < 0.08). Pharmacokinetic modelling indicated competitive inhibition of the renal tubular secretion of ciprofloxacin and M1 by probenecid. The affinity for the renal transporter was 4.4 times higher for ciprofloxacin and 3.6 times higher for M1 than for probenecid, based on the molar ratio. Probenecid did not affect volume of distribution of ciprofloxacin or M1, nonrenal clearance or intercompartmental clearance of ciprofloxacin. Probenecid inhibited the renal tubular secretion of ciprofloxacin and M1, probably by a competitive mechanism and due to reaching >100-fold higher plasma concentrations. Formation of M1, nonrenal clearance and distribution of ciprofloxacin were not affected.
  British Journal of Clinical Pharmacology 02/2010; 69(2):167-78. · 2.96 Impact Factor
• Article: Comparison of the pharmacokinetics and pharmacodynamic profile of carumonam in cystic fibrosis patients and healthy volunteers.

  Jürgen B Bulitta, Stephen B Duffull, Cornelia B Landersdorfer, Martina Kinzig, Ulrike Holzgrabe, Ulrich Stephan, George L Drusano, Fritz Sörgel
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  ABSTRACT: Our objectives were to compare the pharmacokinetics (PK) of carumonam, a monobactam, between cystic fibrosis (CF) patients and healthy volunteers and assess its pharmacodynamic profile. We studied 10 adult CF patients and 18 healthy volunteers of similar body size (dose: 2.166 g of carumonam as 15-min intravenous infusion). High performance liquid chromatography with ultraviolet detection (HPLC-UV) was used for drug analysis and NONMEM (ICON, Ellicot City, MD) for population PK and Monte Carlo simulation with targets between > or =20% and 100% free time above MIC (fT > MIC). Unscaled renal clearance was 24% higher in CF patients. Lean body mass and creatinine clearance explained the difference in average clearance and volume of distribution between both subject groups. For a daily dose of 6 g per 70 kg of total body weight, 15-min infusions q8h achieved robust (>90%) probabilities of target attainment (PTAs) (target, 60% fT > MIC) for MICs < or =3 mg/L in CF patients and < or =6 mg/L in healthy volunteers. At the same dose, 4-h infusions q8h achieved robust PTAs up to markedly higher MICs < or =8 to 12 mg/L in CF patients and < or =16 mg/L in healthy volunteers.
  Diagnostic microbiology and infectious disease 10/2009; 65(2):130-41. · 2.45 Impact Factor
• Article: Pharmacodynamics of vancomycin at simulated epithelial lining fluid concentrations against methicillin-resistant Staphylococcus aureus (MRSA): implications for dosing in MRSA pneumonia.

  Yoriko Harigaya, Jürgen B Bulitta, Alan Forrest, George Sakoulas, Alan J Lesse, Joseph M Mylotte, Brian T Tsuji
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  ABSTRACT: Little is known regarding killing activity of vancomycin against methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) in pneumonia since the extent of vancomycin penetration into epithelial lining fluid (ELF) has not been definitively established. We evaluated the impact of the extent of ELF penetration on bacterial killing and resistance by simulating a range of vancomycin exposures (24-h free drug area under the concentration-time curve [fAUC24]/MIC) using an in vitro pharmacodynamic model and population-based mathematical modeling. A high-dose, 1.5-g-every-12-h vancomycin regimen according to American Thoracic Society/Infectious Diseases Society of America guidelines (trough concentration, 15 mg/liter) with simulated ELF/plasma penetration of 0, 20, 40, 60, 80, or 100% (fAUC24/MIC of 0, 70, 140, 210, 280, or 350) was evaluated against two agr-functional, group II MRSA clinical isolates obtained from patients with a bloodstream infection (MIC = 1.0 mg/liter) at a high inoculum of 10(8) CFU/ml. Despite high vancomycin exposures and 100% penetration, all regimens up to a fAUC24/MIC of 350 did not achieve bactericidal activity. At regimens of < or = 60% penetration (fAUC24/MIC < or = 210), stasis and regrowth occurred, amplifying the development of intermediately resistant subpopulations. Regimens simulating > or = 80% penetration (fAUC24/MIC > or = 280) suppressed development of resistance. Resistant mutants amplified by suboptimal vancomycin exposure displayed reduced rates of autolysis (Triton X-100) at 72 h. Bacterial growth and death were well characterized by a Hill-type model (r2 > or = 0.984) and a population pharmacodynamic model with a resistant and susceptible subpopulation (r2 > or = 0.965). Due to the emergence of vancomycin-intermediate resistance at a fAUC24/MIC of < or = 210, exceeding this exposure breakpoint in ELF may help to guide optimal dosage regimens in the treatment of MRSA pneumonia.
  Antimicrobial Agents and Chemotherapy 07/2009; 53(9):3894-901. · 4.84 Impact Factor
• Article: Competitive inhibition of renal tubular secretion of gemifloxacin by probenecid.

  Cornelia B Landersdorfer, Carl M J Kirkpatrick, Martina Kinzig, Jürgen B Bulitta, Ulrike Holzgrabe, George L Drusano, Fritz Sörgel
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  ABSTRACT: Probenecid interacts with transport processes of drugs at several sites in the body. For most quinolones, renal clearance is reduced by concomitant administration of probenecid. The interaction between gemifloxacin and probenecid has not yet been studied. We studied the extent, time course, site(s), and mechanism of this interaction. Seventeen healthy volunteers participated in a randomized, two-way crossover study. Subjects received 320 mg gemifloxacin as an oral tablet without and with 4.5 g probenecid divided in eight oral doses. Drug concentrations in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry. WinNonlin was used for noncompartmental analysis, compartmental modeling, and statistics, and NONMEM was used for visual predictive checks. Concomitant administration of probenecid increased plasma gemifloxacin concentrations and amounts excreted in urine compared to baseline amounts. Data are average estimates (percent coefficients of variation). Modeling showed a competitive inhibition of the renal tubular secretion of gemifloxacin by probenecid as the most likely mechanism of the interaction. The estimated K(m) and Vmax for the saturable part of renal elimination were 9.16 mg/liter (20%) and 113 mg/h (21%), respectively. Based on the molar ratio, the affinity for the renal transporter was 10-fold higher for gemifloxacin than for probenecid. Since probenecid reached an approximately 200-times-higher area under the molar concentration-time curve from 0 to 24 h than gemifloxacin, probenecid inhibited the active tubular secretion of gemifloxacin. Probenecid also reduced the nonrenal clearance of gemifloxacin from 25.2 (26%) to 21.0 (23%) liters/h. Probenecid inhibited the renal tubular secretion of gemifloxacin, most likely by a competitive mechanism, and slightly decreased nonrenal clearance of gemifloxacin.
  Antimicrobial Agents and Chemotherapy 07/2009; 53(9):3902-7. · 4.84 Impact Factor
• Article: Bone penetration of amoxicillin and clavulanic acid evaluated by population pharmacokinetics and Monte Carlo simulation.

  Cornelia B Landersdorfer, Martina Kinzig, Jürgen B Bulitta, Friedrich F Hennig, Ulrike Holzgrabe, Fritz Sörgel, Johannes Gusinde
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  ABSTRACT: Amoxicillin (amoxicilline)-clavulanic acid has promising activity against pathogens that cause bone infections. We present the first evaluation of the bone penetration of a beta-lactam by population pharmacokinetics and pharmacodynamic profiling via Monte Carlo simulations. Twenty uninfected patients undergoing total hip replacement received a single intravenous infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid before surgery. Blood and bone specimens were collected. Bone samples were pulverized under liquid nitrogen with a cryogenic mill, including an internal standard. The drug concentrations in serum and total bone were analyzed by liquid chromatography-tandem mass spectrometry. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and a target time of the non-protein-bound drug concentration above the MIC for > or = 50% of the dosing interval for near-maximal bactericidal activity in serum. The median of the ratio of the area under the curve (AUC) for bone/AUC for serum was 20% (10th to 90th percentile for between-subject variability [variability], 16 to 25%) in cortical bone and 18% (variability, 11 to 29%) in cancellous bone for amoxicillin and 15% (variability, 11 to 21%) in cortical bone and 10% (variability, 5.1 to 21%) in cancellous bone for clavulanic acid. Analysis in S-ADAPT yielded similar results. The equilibration half-lives between serum and bone were 12 min for amoxicillin and 14 min for clavulanic acid. For a 30-min infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid every 4 h, amoxicillin achieved robust (> or = 90%) probabilities of target attainment (PTAs) for MICs of < or = 12 mg/liter in serum and 2 to 3 mg/liter in bone and population PTAs above 95% against methicillin-susceptible Staphylococcus aureus in bone and serum. The AUC of amoxicillin-clavulanic acid was 5 to 10 times lower in bone than in serum, and amoxicillin-clavulanic acid achieved a rapid equilibrium and favorable population PTAs against pathogens commonly encountered in bone infections.
  Antimicrobial Agents and Chemotherapy 04/2009; 53(6):2569-78. · 4.84 Impact Factor
• Article: Penetration of moxifloxacin into bone evaluated by Monte Carlo simulation.

  Cornelia B Landersdorfer, Martina Kinzig, Friedrich F Hennig, Jürgen B Bulitta, Ulrike Holzgrabe, George L Drusano, Fritz Sörgel, Johannes Gusinde
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  ABSTRACT: Moxifloxacin is a fluoroquinolone with a broad spectrum of activity and good penetration into many tissues, including bone. Penetration of moxifloxacin into bone has not yet been studied using compartmental modeling techniques. Therefore, we determined the rate and extent of bone penetration by moxifloxacin and evaluated its pharmacodynamic profile in bone via Monte Carlo simulation. Twenty-four patients (10 males, 14 females) undergoing total hip replacement received 400 mg moxifloxacin orally 2 to 7 h prior to surgery. Blood and bone specimens were collected. Bone samples were pulverized under liquid nitrogen by a cryogenic mill, including an internal standard. Drug concentrations were analyzed by high-performance liquid chromatography. We used ADAPT II (results reported), NONMEM, and WinBUGS for pharmacokinetic analysis. Monte Carlo simulation was performed to reverse engineer the necessary area under the free concentration-time curve fAUC(SERUM)/MIC in serum and total AUC(BONE)/MIC in bone for a successful clinical or microbiological outcome. The median (10% to 90% percentile for between-subject variability) of the AUC in bone divided by the AUC in serum (AUC(BONE)/AUC(SERUM)) was 80% (51 to 126%) for cortical bone and 78% (42 to 144%) for cancellous bone. Equilibration between serum and bone was rapid. Moxifloxacin achieved robust (> or = 90%) probabilities of target attainment (PTAs) in serum, cortical bone, and cancellous bone up to MICs of < or = 0.375 mg/liter based on the targets fAUC(SERUM)/MIC > or = 40 and AUC(BONE)/MIC > or = 33. Moxifloxacin showed high bone concentrations and a rapid equilibrium between bone and serum. The favorable PTAs compared to the 90%-inhibitory MIC of Staphylococcus aureus warrant future clinical trials on the effectiveness of moxifloxacin in the treatment of bone infections.
  Antimicrobial Agents and Chemotherapy 02/2009; 53(5):2074-81. · 4.84 Impact Factor
• Article: Penetration of antibacterials into bone: pharmacokinetic, pharmacodynamic and bioanalytical considerations.

  Cornelia B Landersdorfer, Jürgen B Bulitta, Martina Kinzig, Ulrike Holzgrabe, Fritz Sörgel
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  ABSTRACT: Antibacterials play a key role in the treatment of bone infections and appropriate surgical prophylaxis. The rate and extent of penetration of antimicrobials into bone has been assessed and shown to be important for successful treatment in numerous studies. However, no recent review or critical evaluation of the analytical techniques is available. This review compares established and new sample preparation and analytical methods to measure bone concentrations. We performed a systematic literature search in MEDLINE, EMBASE, conference abstracts and references from published articles on bone penetration of antibacterials. This article focuses on the standardization of drug analysis in bone, the extent and rate of bone penetration of antibacterials, and the design, evaluation and reporting techniques of pharmacokinetic studies of bone penetration. The focus is on studies conducted between 1998 and 2007, since a previous review was published in 1999. WinNonlin Professional version 5.0.1 software was used for statistics. Very different methods for sample preparation, drug analysis, data handling and reporting have been employed in bone penetration studies. There is substantial variability in the reported mean bone penetration between drugs and between different studies of the same drug. Quinolones, macrolides and linezolid have mean bone : serum concentration ratios that are commonly between 0.3 and 1.2, and higher ratios have been found for azithromycin (bone concentration in mg/kg of total bone). The ratios are usually between 0.15 and 0.3 for cephalosporins and glycopeptides, and between 0.1 and 0.3 for penicillins. Cephalosporins and penicillins have shown significantly lower (p < 0.05) concentration ratios than linezolid. For 20 of 25 different drugs, the ratios were higher for cancellous bone than for cortical bone. The available data show a larger extent of bone penetration for quinolones, macrolides and linezolid than for beta-lactams. The bone penetration of penicillins and cephalosporins was significantly lower than that of linezolid. Guidelines on sample preparation, drug analysis, study design and pharmacokinetic evaluation of bone penetration studies are vitally needed.
  Clinical Pharmacokinetics 01/2009; 48(2):89-124. · 5.40 Impact Factor
• Article: Inhibition of flucloxacillin tubular renal secretion by piperacillin.

  Cornelia B Landersdorfer, Carl M J Kirkpatrick, Martina Kinzig, Jürgen B Bulitta, Ulrike Holzgrabe, Fritz Sörgel
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  ABSTRACT: To explore the extent, time course, site(s), mechanism and possible clinical relevance of the pharmacokinetic (PK) interaction between piperacillin and flucloxacillin. A single-dose, randomized, six-way crossover study in 10 healthy volunteers where all subjects received all of the following as 5-min intravenous infusions: (i) 1.5 g piperacillin, (ii) 0.5 g flucloxacillin, (iii) 1.5 g piperacillin + 0.5 g flucloxacillin, (iv) 3 g piperacillin, (v) 1 g flucloxacillin, and (vi) 3 g piperacillin + 1 g flucloxacillin. Drug concentrations in plasma and urine were determined by high-performance liquid chromatography. WinNonlin was used for PK modelling and statistics. Piperacillin significantly decreased the renal clearance of flucloxacillin from 5.44 to 2.29 l h(-1) (medians, P < 0.01) and the nonrenal clearance of flucloxacillin from 2.67 to 1.80 l h(-1) (P < 0.01). The renal clearance of flucloxacillin was reduced to 45% (point estimate, 90% confidence interval 40 to 50%) and the nonrenal clearance to 66% (59, 73). The extent of interaction was larger at the higher doses. Competitive inhibition of tubular secretion by piperacillin was identified as the most likely mechanism for the decreased renal clearance of flucloxacillin. Piperacillin had a 15-times higher affinity for the renal transporter than flucloxacillin based on the molar ratio. Piperacillin PK was only slightly affected by flucloxacillin. Piperacillin inhibits renal and nonrenal elimination of flucloxacillin. This interaction seems clinically significant, as total clearance was reduced by a factor of 1.5 for the lower and 2.1 for the higher doses. PK interactions, especially with piperacillin, are likely to occur also with other beta-lactam combinations and might be useful to improve the effectiveness of antibacterial treatment.
  British Journal of Clinical Pharmacology 12/2008; 66(5):648-59. · 2.96 Impact Factor
• Article: Development and qualification of a pharmacodynamic model for the pronounced inoculum effect of ceftazidime against Pseudomonas aeruginosa.

  Jürgen B Bulitta, Neang S Ly, Jenny C Yang, Alan Forrest, William J Jusko, Brian T Tsuji
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  ABSTRACT: Evidence is mounting in support of the inoculum effect (i.e., slow killing at large initial inocula [CFUo]) for numerous antimicrobials against a variety of pathogens. Our objectives were to (i) determine the impact of the CFUo of Pseudomonas aeruginosa on ceftazidime activity and (ii) to develop and validate a pharmacokinetic/pharmacodynamic (PKPD) mathematical model accommodating a range of CFUo. Time-kill experiments using ceftazidime at seven concentrations up to 128 mg/liter (MIC, 2 mg/liter) were performed in duplicate against P. aeruginosa PAO1 at five CFUo from 10(5) to 10(9) CFU/ml. Samples were collected over 24 h and fit by candidate models in NONMEM VI and S-ADAPT 1.55 (all data were comodeled). External model qualification integrated data from eight previously published studies. Ceftazidime displayed approximately 3 to 4 log(10) CFU/ml net killing at 10(6.2) CFUo and concentrations of 4 mg/liter (or higher), less than 1.6 log(10) CFU/ml killing at 10(7.3) CFUo, and no killing at 10(8.0) CFUo for concentrations up to 128 mg/liter. The proposed mechanism-based model successfully described the inoculum effect and the concentration-independent lag time of killing. The mean generation time was 28.3 min. The effect of an autolysin was assumed to inhibit successful replication. Ceftazidime concentrations of 0.294 mg/liter stimulated the autolysin effect by 50%. The model was predictive in the internal cross-validation and had excellent in silico predictive performance for published studies of P. aeruginosa ATCC 27853 for various CFUo. The proposed PKPD model successfully described and predicted the pronounced inoculum effect of ceftazidime in vitro and integrated data from eight literature studies to support translation from time-kill experiments to in vitro infection models.
  Antimicrobial Agents and Chemotherapy 11/2008; 53(1):46-56. · 4.84 Impact Factor
• Chapter: Non‐Compartmental Analysis

  Jürgen B. Bulitta, Nicholas H. G. Holford
  06/2008; , ISBN: 9780471462422
• Article: Population pharmacokinetics and pharmacodynamics of continuous versus short-term infusion of imipenem-cilastatin in critically ill patients in a randomized, controlled trial.

  Samir G Sakka, Anna K Glauner, Jürgen B Bulitta, Martina Kinzig-Schippers, Wolfgang Pfister, George L Drusano, Fritz Sörgel
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  ABSTRACT: Beta-lactams are regularly administered in intermittent short-term infusions. The percentage of the dosing interval during which free drug concentrations exceed the MIC (fT(>MIC)) is the measure of drug exposure that best correlates with clinical outcome for beta-lactams. Therefore, administration by continuous infusion has gained increasing interest recently. We studied 20 critically ill patients with nosocomial pneumonia and investigated whether continuous infusion with a reduced total dose, compared to the standard regimen of intermittent short-term infusion, results in a superior probability of target attainment as assessed by the fT(>MIC) value of imipenem. In this prospective, randomized, controlled clinical study, patients received either a loading dose of 1 g/1 g imipenem and cilastatin (as a short-term infusion) at time zero, followed by 2 g/2 g imipenem-cilastatin per 24 h as a continuous infusion for 3 days (n = 10), or 1 g/1 g imipenem-cilastatin three times per day as a short-term infusion for 3 days (total daily dose, 3 g/3 g; n = 10). Imipenem concentrations in plasma were determined by using a validated liquid chromatography-tandem mass spectrometry assay. A two-compartment open model was employed for population pharmacokinetic modeling. We simulated 10,000 intensive-care-unit patients via Monte Carlo simulations for pharmacodynamic evaluation using the target 40% fT(>MIC). The probability of target attainment by MIC for intermittent infusion was robust (>90%) up to MICs of 1 to 2 mg/liter. The corresponding value for continuous infusion was 2 to 4 mg/liter. Although all 20 patients had an fT(>MIC) of 100%, 3 patients died. Patient survival was best described by employing a sepsis-related organ failure assessment score as a covariate in a logistic regression analysis. Larger clinical trials are warranted for evaluation of continuous infusions at a reduced dose of imipenem for critically ill patients.
  Antimicrobial Agents and Chemotherapy 10/2007; 51(9):3304-10. · 4.84 Impact Factor
• Article: Population pharmacokinetics at two dose levels and pharmacodynamic profiling of flucloxacillin.

  Cornelia B Landersdorfer, Carl M J Kirkpatrick, Martina Kinzig-Schippers, Jürgen B Bulitta, Ulrike Holzgrabe, George L Drusano, Fritz Sörgel
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  ABSTRACT: Flucloxacillin is often used for the treatment of serious infections due to sensitive staphylococci. The pharmacokinetic (PK)-pharmacodynamic (PD) breakpoint of flucloxacillin has not been determined by the use of population PK. Targets based on the duration of non-protein-bound concentrations above the MIC (fT(>MIC)) best correlate with clinical cure rates for beta-lactams. We compared the breakpoints for flucloxacillin between several dosage regimens. In a randomized, two-way crossover study, 10 healthy volunteers received 500 mg and 1,000 mg flucloxacillin as 5-min intravenous infusions. Drug concentrations were determined by high-pressure liquid chromatography. We used the programs WinNonlin for noncompartmental analysis and statistics and NONMEM for population PK and Monte Carlo simulation. We compared the probability of target attainment (PTA) for intermittent- and continuous-dosage regimens based on the targets of fT(>MIC)s of > or =50% and > or =30% of the dosing interval. The clearance and the volume of distribution were very similar after the administration of 500 mg and 1,000 mg flucloxacillin. We estimated renal and nonrenal clearances of 5.37 liters/h (coefficient of variation, 19%) and 2.73 liters/h (33%). For near maximal killing (target, fT(>MIC) of > or =50%) flucloxacillin showed a robust (> or =90%) PTA up to MICs of 0.75 to 1 mg/liter (PTA of 86% at 1 mg/liter) for a continuous or a prolonged infusion of 6 g/day. Short-term infusions of 6 g/day had a lower breakpoint of 0.25 to 0.375 mg/liter. The flucloxacillin PK was linear for doses of 500 mg and 1,000 mg. Prolonged and continuous infusion at a 66% lower daily dose achieved the same PK-PD breakpoints as short-term infusions. Prolonged infusion and continuous infusion are appealing options for the treatment of serious infections caused by sensitive staphylococci.
  Antimicrobial Agents and Chemotherapy 10/2007; 51(9):3290-7. · 4.84 Impact Factor