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Persons with CF (pwCF) present altered pharmacokinetics (PK) and are often infected with multidrug-resistant (MDR) bacteria. Herein, we describe the PK of cefiderocol, a siderophore cephalosporin with potent activity against MDR Gram-negative rods, in hospitalized adult pwCF with acute pulmonary exacerbation (APE). PwCF received ≥3 doses of 2 g cefiderocol (3 h infusion) with frequency determined according to their estimated glomerular filtration rate (eGFR). Blood sampling collected at steady state. Concentrations were fitted using the non-parametric adaptive grid algorithm in Pmetrics for R. Ten pwCF were enrolled; nine completed the study with six receiving 2 g q8 h and three 2 g q6 h. A two-compartment model best fitted the data. Mean (SD) PK parameters were clearance, 5.66 (1.28) L/h; volume of central compartment, 5.81 (3.52) L, and intercompartment transfer constants, k12, 4.29 (3.46) and k21, 2.25 (2.76) h -1 . Protein binding was 48% (35-57). The 2 g q8 h regimen achieved a mean free time above the MIC ( f T >MIC) of 99% (94-99), 90% (69-100), and 64% (41-81) at MICs of 4 (susceptible), 8 (intermediate), and 16 (resistant) mg/L, respectively, with AUC 24h of 1,191 (781-1,496) mg/L*h. In pwCF with eGFR >120 mL/min, 2 g q6 h attained 100% f T >MIC up to 8 mg/L and 87% (83-92) at 16 mg/L, with AUC 24h of 1,279 (1,054-1,590) mg/L*h. Among these nine pwCF with APE with normal or augmented renal clearance, cefiderocol using label prescribed dosing regimens according to eGFR was well tolerated and achieved optimal f T >MIC exposure for pathogens up to MICs of 8 mg/L and AUC 24h estimates similar to previously reported estimates in non-CF patients., Competing Interests: C.K. reports honoraria for speaking/advisory boards from Shionogi, Inc. R.K.S. reports receiving research funding and honoraria for advisory boards from Shionogi, Inc. D.P.N. reports receiving research funding and honoraria for speaking/advisory boards from Shionogi, Inc. J.L.K. reports receiving research funding and honoraria for speaking/advisory boards from Shionogi, Inc. The remaining authors have nothing to disclose.

Objective: To determine whether established ceftolozane/tazobactam (C/T) dosing is adequate for patients with augmented renal clearance (ARC) and bacterial infection., Methods: ARC (creatinine clearance [CrCl] ≥ 130 mL/min) was confirmed by directly measured CrCl in 11 critically ill patients in a phase 1 pharmacokinetics study. Patients received 3 g C/T (ceftolozane 2 g/tazobactam 1 g) as a 60-minute intravenous infusion. Pharmacokinetic sampling occurred at 0 (predose), 1, 2, 4, 6, and 8 hours after the start of the infusion. Noncompartmental analyses were conducted on concentration data. The following pharmacodynamic targets were evaluated: time that free (unbound) drug concentrations exceeded the minimum inhibitory concentration (fT>MIC) of 4 μg/mL for ceftolozane and time that the unbound concentration exceeded the 1 μg/mL target threshold (fT>threshold = 1 µg/mL) for > 20% of the dosing interval for tazobactam. Safety was evaluated., Results: Mean (SD) area under the plasma concentration-time curve from 0 to infinity, clearance and volume of distribution at steady state (V ss ) were 236 (118) h*µg/mL, 10.4 (4.5) L/h and 30.8 (10.8) L, respectively, for ceftolozane; and 35.5 (18.5) h*µg/mL, 35.3 (16.5) L/h and 54.8 (20.1) L, respectively, for tazobactam. Clearance and V ss were higher for both ceftolozane and tazobactam in patients with ARC compared with healthy individuals. The mean estimated ceftolozane fT>MIC at 4 µg/mL was 86.4%; the mean estimated tazobactam fT>threshold = 1 µg/mL was 54.9%. Treatment-emergent adverse events were mild to moderate., Conclusions: In patients with ARC, a 3 g C/T dose met respective pharmacodynamic targets for ceftolozane and tazobactam. CLINICALTRIALS., Gov Identifier: NCT02387372., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Describing the disposition of antimicrobial agents at the site of infection is crucial to guide optimal dosing for investigational agents. For antibiotics in development for the treatment of nosocomial pneumonia, concentrations in the epithelial lining fluid (ELF) of the lung are frequently determined from a bronchoscopy at a single time point. The influence of profiles constructed from a single ELF concentration point for each subject has never been reported. This study compares the pharmacokinetics of two β-lactams, ceftolozane and piperacillin, among different ELF sampling approaches using simulated human regimens in a swine pneumonia model. Plasma and ELF concentration-time profiles were characterized in two-compartment models by the use of robustly sampled ELF concentrations and by the random selection of one or two ELF concentrations from each swine. A 5,000-subject Monte Carlo simulation was performed for each model to define the ELF penetration, as described by the ratio of the area under the concentration curve (AUC) for ELF to the AUC for free drug in plasma (AUC ELF / f AUC plasma ) and the probability of target attainment (PTA). Given the intersubject variability of the ELF penetrations observed, differences between the models developed using robust numbers of ELF samples versus one or two ELF samples per swine were minimal for both drugs (maximum dispersion < 20%). Using a threshold exposure target of 60% of the time that the free drug concentration remains above the MIC target, the ceftolozane and piperacillin regimens achieved PTAs of ≥90% at MICs of up to 4 and 1 μg/ml, respectively, among the different ELF sampling strategies. These models suggest that the ELF models constructed with concentrations from sparse ELF sampling time points result in exposure estimates similar to those constructed from robustly sampled ELF profiles., (Copyright © 2019 American Society for Microbiology.)

Combination therapy is an attractive option for the treatment of multidrug-resistant (MDR) Pseudomonas aeruginosa infections; however, limited data are available on combinations with ceftolozane-tazobactam (C-T). The in vitro pharmacodynamic chemostat model was employed to compare human-simulated exposures of C-T at 3 g every 8 h alone or in combination with amikacin at 25 mg/kg of body weight daily or colistin at 360 mg daily against four MDR P. aeruginosa isolates. C-T alone resulted in 24-h changes in the number of CFU of -0.02 ± 0.21, -1.81 ± 0.55, -1.44 ± 0.40, and +0.62 ± 0.05 log 10 CFU/ml against isolates with C-T MICs of 4, 4, 8, and 16 μg/ml, respectively. Amikacin and colistin monotherapy displayed various results. The addition of amikacin to C-T resulted in -2.00 ± 0.23 ( P < 0.001, additive)-, -1.50 ± 0.83 ( P = 0.687, indifferent)-, -2.84 ± 0.08 ( P = 0.079, indifferent)-, and -2.67 ± 0.54 ( P < 0.001, synergy)-log 10 CFU/ml reductions, respectively. The addition of colistin to C-T resulted in -3.02 ± 0.22 ( P < 0.001, additive)-, -3.21 ± 0.24 ( P > 0.05, indifferent)-, -4.6 ± 0.11 ( P = 0.002, synergy)-, and -3.01 ± 0.28 ( P < 0.001, synergy)-log 10 CFU/ml reductions, respectively, against the MDR P. aeruginosa isolates with these MICs. Greater overall reductions in bacterial burden, including additive or synergistic interactions at 24 h, with C-T plus amikacin or colistin were observed against 3 out of 4 MDR P. aeruginosa strains tested, particularly those strains that were intermediate or resistant to C-T. Further studies assessing combination regimens containing C-T against MDR P. aeruginosa are warranted., (Copyright © 2018 American Society for Microbiology.)

Ceftolozane-tazobactam displays potent activity against Gram-negative bacteria that can cause diabetic foot infections (DFI), making it an attractive treatment option when few alternatives exist. The pharmacokinetics and tissue penetration of ceftolozane-tazobactam at 1.5 g every 8 h (q8h) in patients ( n = 10) with DFI were compared with those in healthy volunteers ( n = 6) using in vivo microdialysis. In the patient participants, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: maximum concentration ( C max ), 55.2 μg/ml (range, 40.9 to 169.3 μg/ml); half-life ( t 1/2 ), 3.5 h (range, 2.3 to 4.7 h); and area under the concentration-time curve (AUC) from time zero to 8 h (AUC 0-8 ), 191.6 μg · h/ml (range, 147.1 to 286.6 μg · h/ml). The median AUC for tissue (AUC tissue ; where AUC tissue was the AUC 0-8 for tissue for ceftolozane)/AUC for plasma for each antibiotic corrected by the fraction of free drug ( f AUC plasma ) was 0.75 (range, 0.35 to 1.00), resulting in a mean free time above 4 μg/ml (the Pseudomonas aeruginosa susceptibility breakpoint) in tissue of 99.8% (range, 87.5 to 100%). In the patient participants, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: C max , 14.2 μg/ml (range, 7.6 to 64.2 μg/ml); t 1/2 , 2.0 h (range, 0.7 to 2.4 h); and AUC 0-8 , 27.1 μg · h/ml (range, 15.0 to 70.0 μg · h/ml). The AUC tissue (where AUC tissue was the AUC from time zero to the time of the last measureable concentration in tissue for tazobactam)/ f AUC plasma for tazobactam was 1.18 (range, 0.54 to 1.44). In the healthy volunteers, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: C max , 91.5 μg/ml (range, 65.7 to 110.7 μg/ml); t 1/2 , 1.9 h (range, 1.6 to 2.1 h); and AUC 0-8 , 191.3 μg · h/ml (range, 118.1 to 274.3 μg · h/ml). The median AUC tissue / f AUC plasma was 0.87 (range, 0.54 to 2.20), resulting in a mean free time above 4 μg/ml in tissue of 93.8% (range, 87.5 to 100%). In the healthy volunteers, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: C max , 17.5 μg/ml (range, 15.4 to 27.3 μg/ml); t 1/2 , 0.7 h (range, 0.6 to 0.8 h); and AUC 0-8 , 22.2 μg · h/ml (range, 19.2 to 36.4 μg · h/ml). The AUC tissue / f AUC plasma for tazobactam was 0.85 (range, 0.63 to 2.10). Both ceftolozane and tazobactam penetrated into subcutaneous tissue with exposures similar to those of free drug in plasma in both patients with DFI and healthy volunteers. These data suggest that ceftolozane-tazobactam at 1.5 g q8h can achieve the optimal exposure with activity against susceptible Gram-negative pathogens in the tissue of patients with DFI. (This study has been registered at ClinicalTrials.gov under identifier NCT02620774.)., (Copyright © 2017 American Society for Microbiology.)

The quantitative impact of severity of illness on pharmacodynamic thresholds is poorly defined. We used a robust cefepime outcomes cohort and previously identified pharmacodynamic breakpoints of 68% [pharmacokinetic (PK) model 1] and 74% (PK model 2) to probe interactions and relationships with modified Acute Physiology and Chronic Health Evaluation (mAPACHE) II scores. When the time that serum concentration remains above the minimum inhibitory concentration during the dosing interval (fT >MIC ) was optimised, mortality was improved between mAPACHE II scores of 9-23 and 9-22 in models 1 and 2, respectively. No significant interactions were identified. These results suggest that mAPACHE II scores of 9-22 may fall within a 'Goldilocks' window in which hospital survival is improved among patients achieving goal fT >MIC thresholds., (Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Ceftolozane-tazobactam has potent activity against Pseudomonas aeruginosa, a pathogen associated with cystic fibrosis (CF) acute pulmonary exacerbations (APE). Due to the rapid elimination of many antibiotics, CF patients frequently have altered pharmacokinetics. In this multicenter, open-label study, we described the population pharmacokinetics and safety of ceftolozane-tazobactam at 3 g every 8 h (q8h) in 20 adult CF patients admitted with APE. Population pharmacokinetics were determined using the nonparametric adaptive grid program in Pmetrics for R. A 5,000-patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for the ceftolozane component at 1.5 g and 3 g of ceftolozane-tazobactam q8h across a range of MICs using a primary threshold exposure of 60% free time above the MIC (fT>MIC). In these 20 adult CF patients, ceftolozane and tazobactam concentration data were best described by 2-compartment models, and ceftolozane clearance (CL) was significantly correlated with creatinine clearance (r = 0.71, P < 0.001). These data suggest that ceftolozane and tazobactam clearance estimates in CF patients are similar to those in adults without CF (ceftolozane CF CL, 4.76 ± 1.13 liter/h; tazobactam CF CL, 20.51 ± 4.41 liter/h). However, estimates of the volume of the central compartment (V c ) were lower than those for adults without CF (ceftolozane CF V c , 7.51 ± 2.05 liters; tazobactam CF V c , 7.85 ± 2.66 liters). Using a threshold of 60% fT>MIC, ceftolozane-tazobactam regimens of 1.5 g and 3 g q8h should achieve PTAs of ≥90% at MICs up to 4 and 8 μg/ml, respectively. Ceftolozane-tazobactam at 3 g q8h was well tolerated. These observations support additional studies of ceftolozane-tazobactam for Pseudomonas aeruginosa APE in CF patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02421120.)., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Introduction: Cefepime trough concentrations >22 mg/L (T(>22)) have been associated with neurotoxicity in a single study., Patients and Methods: Neurotoxicity outcomes for 28 cefepime-treated adult patients with febrile neutropenia were abstracted from the literature. The precision of T(>22) to predict neurotoxicity was quantified using 95% confidence intervals. Thirty-two cefepime-treated patients contributed serum concentrations for a pharmacokinetic model, fit using the Nonparametric Adaptive Grid algorithm within the Pmetrics package for R. Concentration-time curves were simulated for common dosing schemes and 3 renal dispositions. Probabilities of neurotoxicity and numbers needed to harm were calculated from simulations according to the proposed pharmacokinetic/toxicodynamic threshold of T(>22). Bayesian modeling was utilized to explore other pharmacokinetic parameters relationships with neurotoxicity., Results: The mean probability of neurotoxicity at T(>22) was 51.4% (95% CI: 16.4-85.0%). Among the schemes and renal dispositions simulated, the combination of cefepime 2 g every 8 h and a creatinine clearance of 60 mL/min produced the greatest probability of neurotoxicity (48.3%). Estimated numbers needed to harm according to T(>22) ranged from 2.1 to 18.5 persons. Explorations of maximal serum concentration and area under the curve demonstrated high levels of collinearity, making it impossible to identify trough concentrations as the driver of neurotoxicity., Discussion: T(>22) had low precision as a predictive neurotoxic threshold. When a neurotoxic threshold of T(>22) was assumed, projected neurotoxicity rates and numbers needed to harm greatly exceeded observed neurotoxicity rates in the general population and in high risk subpopulations. Other drug exposure metrics should be explored., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The percentage of time that free drug concentrations remain above the MIC (fT>MIC) that is necessary to prevent mortality among cefepime-treated patients with Gram-negative bloodstream infections (GNBSI) is poorly defined. We conducted a retrospective study of adult patients with GNBSI. Eligible cases were frequency matched to ensure categorical representation from all MICs. Organism, MIC, infection source, gender, age, serum creatinine, weight, antibiotic history, and modified APACHE II score were collected from hospital records. Two population pharmacokinetic models (models 1 and 2) were used to impute exposures over the first 24 h in each patient from mean model parameters, covariates, and dosing history. From the imputed exposures, survival thresholds for fT>MIC were identified using classification and regression tree (CART) analysis and analyzed as nominal variables for univariate and multivariate regressions. A total of 180 patients were included in the analysis, of whom 13.9% died and 86.1% survived. Many patients (46.7% [n = 84/180]) received combination therapy with cefepime. Survivors had higher mean (standard deviation [SD]) fT>MIC than those who died (model 1, 74.2% [29.6%] versus 52.1% [33.8%], P < 0.001; model 2, 85.9% [24.0%] versus 64.4% [31.4%], P < 0.001). CART identified fT>MIC threshold values for greater survival according to models 1 and 2 at >68% and >74%, respectively. Survival was improved for those with fT>MIC of >68% (model 1 adjusted odds ratio [aOR], 7.12; 95% confidence interval [CI], 1.90 to 26.7; P = 0.004) and >74% (model 2 aOR, 6.48; 95% CI, 1.90 to 22.1) after controlling for clinical covariates. Similarly, each 1% increase in cefepime fT>MIC resulted in a 2% improvement in multivariate survival probability (P = 0.015). Achieving a cefepime fT>MIC of 68 to 74% was associated with a higher odds of survival for patients with GNBSI. Regimens targeting this exposure should be aggressively pursued., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Staphylococcus aureus, including methicillin-susceptible (MSSA) and -resistant (MRSA) strains, is an important pathogen of bacterial pneumonia. As antibiotic concentrations at the site of infection are responsible for killing, we investigated the activity of human-simulated epithelial lining fluid (ELF) exposures of three antibiotics (ceftaroline, ceftriaxone, and vancomycin) commonly used for treatment of S. aureus pneumonia. An in vitro pharmacodynamic model was used to simulate ELF exposures of vancomycin (1 g every 12 h [q12h]), ceftaroline (600 mg q12h and q8h), and ceftriaxone (2 g q24h and q12h). Four S. aureus isolates (2 MSSA and 2 MRSA) were evaluated over 72 h with a starting inoculum of ∼ 10(6) CFU/ml. Time-kill curves were constructed, and microbiological response (change in log10 CFU/ml from 0 h and the area under the bacterial killing and regrowth curve [AUBC]) was assessed in duplicate. The change in 72-h log10 CFU/ml was largest for ceftaroline q8h (reductions of >3 log10 CFU/ml against all strains). This regimen also achieved the lowest AUBC against all organisms (P < 0.05). Vancomycin produced reliable bacterial reductions of 0.9 to 3.3 log10 CFU/ml, while the activity of ceftaroline q12h was more variable (reductions of 0.2 to 2.3 log10 CFU/ml against 3 of 4 strains). Both regimens of ceftriaxone were poorly active against MSSA tested (0.1 reduction to a 1.8-log10 CFU/ml increase). Against these S. aureus isolates, ELF exposures of ceftaroline 600 mg q8h exhibited improved antibacterial activity compared with ceftaroline 600 mg q12h and vancomycin, and therefore, this q8h regimen deserves further evaluation for the treatment of bacterial pneumonia. These data also suggest that ceftriaxone should be avoided for S. aureus pneumonia., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

There are no comparative data evaluating outcomes of ertapenem treatment for infections with AmpC-producing Enterobacteriaceae. This retrospective matched case-control study was conducted between 2009 and 2012. Sixteen cases treated with ertapenem were matched 1:2 with 32 control cases treated with cefepime based on age, culture source, and hospital service. There were more cefepime-resistant organisms in the ertapenem group (cefepime resistance present in 44% of patients treated with ertapenem compared with 0% of control patients, p < 0.001). Ertapenem was used empirically in 25% of patients compared with 88% who received cefepime empirically (p < 0.001). Consequently, 56% of patients on ertapenem received inappropriate initial therapy compared with 9% of patients on cefepime (p < 0.001). No differences in clinical success were identified (69% for ertapenem vs 88% for cefepime, p = 0.138). Although a trend favoring cefepime could be suspected, it should be noted that no statistically significant difference in clinical success was detected despite the presence of more resistant organisms and delays in initiation of appropriate therapy among patients receiving ertapenem.

Advanced-generation cephalosporins are frequently used for empirical coverage of ventilator-associated pneumonia (VAP) due to their activity against a broad spectrum of Gram-positive and Gram-negative aerobic bacteria, including Pseudomonas aeruginosa and Enterobacteriaceae. Providing optimal antibiotic exposure is essential to achieving successful response in patients with VAP. We evaluated exposures of two antipseudomonal cephalosporins, ceftazidime and cefepime, in patients with VAP due to Gram-negative bacilli to identify the pharmacodynamic parameter predictive of microbiological success. Population pharmacokinetic models were used to estimate individual free drug exposures. Pharmacodynamic indices were determined for each patient using the baseline Gram-negative bacilli with the highest drug MIC. Classification and regression tree analysis was utilized to partition exposure breakpoints, and multivariate logistic regression was conducted to identify predictors of microbiological success. A total of 73 patients (18 receiving ceftazidime therapy and 55 receiving cefepime therapy) were included. MICs ranged widely from 0.047 to 96 μg/ml. The microbiological success rate was 58.9%. Predictive breakpoints were identified for all pharmacodynamic parameters, including a serum fT>MIC greater than 53% (P=0.02). When controlling for APACHE II (odds ratio [OR], 1.01; 95% confidence interval, 0.93 to 1.09; P=0.85) and combination therapy (OR, 0.74; 95% confidence interval, 0.25 to 2.19; P=0.59), achieving a greater than 53% fT>MIC remained a significant predictor of success (OR, 10.3; 95% confidence interval, 1.1 to 92.3; P=0.04). In patients with VAP due to Gram-negative bacilli, serum exposure of greater than 53% fT>MIC was found to be a significant predictor of favorable microbiological response for antipseudomonal cephalosporins. These data are useful when determining dosing regimens for cephalosporin agents under development for pneumonia.

The effects of prior vancomycin exposure on ceftaroline and daptomycin therapy against methicillin-resistant Staphylococcus aureus (MRSA) have not been widely studied. Humanized free-drug exposures of vancomycin at 1 g every 12 h (q12h), ceftaroline at 600 mg q12h, and daptomycin at 10 mg/kg of body weight q24h were simulated in a 96-h in vitro pharmacodynamic model against three MRSA isolates, including one heteroresistant vancomycin-intermediate S. aureus (hVISA) isolate and one VISA isolate. A total of five regimens were tested: vancomycin, ceftaroline, and daptomycin alone for the entire 96 h, and then sequential therapy with vancomycin for 48 h followed by ceftaroline or daptomycin for 48 h. Microbiological responses were measured by the changes in log10 CFU during 96 h from baseline. Control isolates grew to 9.16 ± 0.32, 9.13 ± 0.14, and 8.69 ± 0.28 log10 CFU for MRSA, hVISA, and VISA, respectively. Vancomycin initially achieved ≥3 log10 CFU reductions against the MRSA and hVISA isolates, followed by regrowth beginning at 48 h; minimal activity was observed against VISA. The change in 96-h log10 CFU was largest for sequential therapy with vancomycin followed by ceftaroline (-5.22 ± 1.2, P = 0.010 versus ceftaroline) and for sequential therapy with vancomycin followed by ceftaroline (-3.60 ± 0.6, P = 0.037 versus daptomycin), compared with daptomycin (-2.24 ± 1.0), vancomycin (-1.40 ± 1.8), and sequential therapy with vancomycin followed by daptomycin (-1.32 ± 1.0, P > 0.5 for the last three regimens). Prior exposure of vancomycin at 1 g q12h reduced the initial microbiological response of daptomycin, particularly for hVISA and VISA isolates, but did not affect the response of ceftaroline. In the scenario of poor vancomycin response for high-inoculum MRSA infection, a ceftaroline-containing regimen may be preferred.

We evaluated cefepime exposures in patients infected with Pseudomonas aeruginosa to identify the pharmacodynamic relationship predictive of microbiological response. Patients with non-urinary tract P. aeruginosa infections and treated with cefepime were included. Free cefepime exposures were estimated by using a validated population pharmacokinetic model. P. aeruginosa MICs were determined by Etest and pharmacodynamic indices (the percentage of the dosing interval that the free drug concentration remains above the MIC of the infecting organism [fT > MIC], the ratio of the minimum concentration of free drug to the MIC [fC(min)/MIC], and the ratio of the area under the concentration-time curve for free drug to the MIC [fAUC/MIC]) were calculated for each patient. Classification and regression tree analysis was used to partition the pharmacodynamic parameters for prediction of the microbiological response. Monte Carlo simulation was utilized to determine the optimal dosing regimens needed to achieve the pharmacodynamic target. Fifty-six patients with pneumonia (66.1%), skin and skin structure infections (SSSIs) (25%), and bacteremia (8.9%) were included. Twenty-four (42.9%) patients failed cefepime therapy. The MICs ranged from 0.75 to 96 microg/ml, resulting in median fT > MIC, fC(m)(in)/MIC, and fAUC/MIC exposures of 100% (range, 0.8 to 100%), 4.3 (range, 0.1 to 27.3), and 206.2 (range, 4.2 to 1,028.7), respectively. Microbiological failure was associated with an fT > MIC of < or =60% (77.8% failed cefepime therapy when fT > MIC was < or =60%, whereas 36.2% failed cefepime therapy when fT > MIC was >60%; P = 0.013). A similar fT > MIC target of < or =63.9% (P = 0.009) was identified when skin and skin structure infections were excluded. While controlling for the SSSI source (odds ratio [OR], 0.18 [95% confidence interval, 0.03 to 1.19]; P = 0.07) and combination therapy (OR, 2.15 [95% confidence interval, 0.59 to 7.88]; P = 0.25), patients with fT > MIC values of < or =60% were 8.1 times (95% confidence interval, 1.2 to 55.6 times) more likely to experience a poor microbiological response. Cefepime doses of at least 2 g every 8 h are required to achieve this target against CLSI-defined susceptible P. aeruginosa organisms in patients with normal renal function. In patients with non-urinary tract infections caused by P. aeruginosa, achievement of cefepime exposures of >60% fT > MIC will minimize the possibility of a poor microbiological response.

Background: Because of the high frequency of multidrug resistant bacteria in our intensive care units (ICUs), we implemented a ventilator-associated pneumonia (VAP) clinical pathway based on unit-specific minimum inhibitory concentration (MIC) distributions and pharmacodynamic modeling in 3 of our ICUs., Methods: This was a prospective, observational evaluation with a historical control group in adult patients (n = 168) who met clinical and radiologic criteria for VAP. Monte Carlo simulation was used to determine antibiotic regimens having the greatest likelihood of achieving bactericidal exposures against Pseudomonas aeruginosa. Antibiotic regimens were incorporated into an ICU-specific computerized clinical pathway as empiric agents of choice., Results: Pharmacodynamic modeling found 3-hour infusions of cefepime 2 g every 8 hours or meropenem 2 g every 8 hours plus tobramycin and vancomycin would provide the greatest probability of empirically treating VAP in these ICUs. Infection-related mortality was reduced by 69% (8.5% vs 21.6%; P = .029), infection-related length of stay was shorter (11.7 +/- 8.1 vs 26.1 +/- 18.5; P < .001), and fewer superinfections were observed in patients treated on the pathway. A number of patients with nonsusceptible P aeruginosa were successfully treated with high-dose, 3-hour infusion regimens., Conclusions: In our ICUs where multidrug resistant bacteria are common, an approach considering ICU-specific antibiotic MICs coupled with pharmacodynamic dosing strategies resulted in improved outcomes and shorter duration of treatments., (Copyright 2010 Elsevier Inc. All rights reserved.)

A population pharmacokinetic model of cefepime was constructed from data from adult critical care patients with ventilator-associated pneumonia (VAP). A total of 32 patients treated with high-dose cefepime, 2 g every 8 h (3-h infusion) or a renal function-adjusted equivalent dose, were randomized into two groups--26 for the initial model and 6 for model validation. Serum samples of cefepime were collected at steady state. Nonparametric adaptive grid population modeling was employed using a two-compartment K(slope) pharmacokinetic model relating the elimination rate constant (K(10)) to renal function, as defined by creatinine clearance (CL(CR)), and central distribution volume (V(1)) to total body weight (TBW). The final model was described by the following equations: K(10) = 0.0027 x CL(CR) + 0.071 h(-1) and V(1) = TBW x 0.21 liter/kg. The median intercompartmental transfer constants K(12) and K(21) were 0.780 h(-1) and 0.472 h(-1), respectively. Using these median parameter estimates, the bias, precision, and coefficient of determination for the initial model were 11.3 microg/ml, 24.0 microg/ml, and 26%, respectively. The independent validation group displayed a bias, precision, and coefficient of determination of -1.64 microg/ml, 17.1 microg/ml, and 62%, respectively. Time-concentration profiles were assessed for various dosing regimens, using 5,000-patient Monte Carlo simulations. Among the regimens, the likelihoods of 2 g every 8 h (3-h infusion) achieving free drug concentrations above the MIC for 50% of the dosing interval were 91.8%, 78.1%, and 50.3% for MICs of 8, 16, and 32 microg/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.

Objective: This study was designed to compare cefepime exposures with microbiological outcomes in ESBL and non-ESBL infections and determine the pharmacodynamic profiles associated with successful outcome., Methods: Cefepime pharmacodynamic exposures of unbound drug [time above MIC (fT>MIC), minimal concentration over MIC (fC(min)/MIC), and area under the curve over MIC (fAUC/MIC)] for 18 patients with ESBL and non-ESBL infections were determined by using a published population pharmacokinetic model. Classification and regression tree analysis was used to identify pharmacodynamic breakpoints that predicted eradication. A 5000-patient Monte Carlo Simulation was conducted to estimate the probability of target attainment for the goal pharmacodynamic exposures., Results: Eradication was 80% when fT>MIC was 50% compared with 0% when T>MIC was less than 50% (p<0.05). The median fC(min)/MIC ratio for ESBL group was statistically lower than that for the non-ESBL group (1.54 versus 138, p<0.001). Regardless of ESBL production, all pathogens were eradicated when fC(min)/MIC>7.6 and only 33.3% were eradicated when fC(min)/MIC< or =7.6 (p<0.05). Pharmacodynamic exposures of 50% fT>MIC and fAUC/MIC>1654 were also predictive of eradication. While conventional dosage regimens of 2g q 12h and q 8h failed to achieve adequate target attainment, 4 g continuous infusion and 2g q 6-8h prolonged infusion could attain more than 90% of target attainment at the MIC of 2 microg/ml for the breakpoint of fCmin/MIC=7.6., Conclusion: Microbiological eradication in patients receiving cefepime was best predicted by fCmin/MIC ratio greater than 7.6 regardless of the presence of an ESBL. Continuous or prolonged infusion regimens provided the greatest probability of attaining this exposure.

Objective: To determine the affect of ESBL production among Klebsiella species and Escherichia coli on cefepime effectiveness., Methods: This was a retrospective, case-controlled study comparing the clinical and microbiologic responses of patients receiving cefepime for ESBL producing Klebsiella species or E. coli from a non-urine source with matched controls receiving cefepime for non-ESBL strains. Cases with ESBLs were included if they received monotherapy and were clinically evaluable. Non-ESBL controls were matched in a 2:1 ratio based on age, infection site, intensive care unit (ICU) stay, pathogen species and date of hospitalization., Results: Ten patients receiving cefepime for ESBLs were matched to 20 controls. Most patients received cefepime 1g q12h. Patients receiving cefepime for an ESBL infection were 9.7 (95% CI: 1.4-68.8) and 28.5 (95% CI: 2.6-306.6) times as likely to have an unsuccessful clinical and microbiological response compared with those with a non-ESBL infection. The presence of an ESBL did not have a statistically significant effect on all cause or infection-related mortality., Conclusion: These data indicate that ESBL production among non-urinary Klebsiella species and E. coli negatively affected cefepime effectiveness. Further studies are required to evaluate if higher doses of cefepime may improve responses in ESBLs that are initially susceptible.

Objectives: Ceftolozane/tazobactam is approved for hospital-acquired/ventilator-associated bacterial pneumonia at double the dose (i.e. 2 g/1 g) recommended for other indications. We evaluated the bronchopulmonary pharmacokinetic/pharmacodynamic profile of this 3 g ceftolozane/tazobactam regimen in ventilated pneumonia patients.Methods: This was an open-label, multicentre, Phase 1 trial (clinicaltrials.gov: NCT02387372). Mechanically ventilated patients with proven/suspected pneumonia received four to six doses of 3 g of ceftolozane/tazobactam (adjusted for renal function) q8h. Serial plasma samples were collected after the first and last doses. One bronchoalveolar lavage sample per patient was collected at 1, 2, 4, 6 or 8 h after the last dose and epithelial lining fluid (ELF) drug concentrations were determined. Pharmacokinetic parameters were estimated by non-compartmental analysis and pharmacodynamic analyses were conducted to graphically evaluate achievement of target exposures (plasma and ELF ceftolozane concentrations >4 mg/L and tazobactam concentrations >1 mg/L; target in plasma: ≥30% and ≥20% of the dosing interval, respectively).Results: Twenty-six patients received four to six doses of study drug; 22 were included in the ELF analyses. Ceftolozane and tazobactam Tmax (6 and 2 h, respectively) were delayed in ELF compared with plasma (1 h). Lung penetration, expressed as the ratio of mean drug exposure (AUC) in ELF to plasma, was 50% (ceftolozane) and 62% (tazobactam). Mean ceftolozane and tazobactam ELF concentrations remained >4 mg/L and >1 mg/L, respectively, for 100% of the dosing interval. There were no deaths or adverse event-related study discontinuations.Conclusions: In ventilated pneumonia patients, 3 g of ceftolozane/tazobactam q8h yielded ELF exposures considered adequate to cover ceftolozane/tazobactam-susceptible respiratory pathogens. [ABSTRACT FROM AUTHOR]

Purpose. Selected i.v. antimicrobials were evaluated against Pseudomonas aeruginosa isolates collected from U.S. hospitals to predict the likelihood of achieving maximal bactericidal activity. Methods. The pharmacodynamic profiles of ceftazidime, doripenem, imipenem-cilastatin, levofloxacin, meropenem, and piperacillin.tazobactam were simulated for 5000 adult patients using pharmacokinetic data from infected patients with the minimum inhibitory concentrations of 6142 P. aeruginosa isolates in U.S. hospitals collected during 2009. The probability of achieving bactericidal activity in this population, referred to as the cumulative fraction of response (CFR), was calculated for each antimicrobial. An optimal regimen was defined as achieving a CFR of .90%. Results. The majority of isolates were collected from male inpatients who were not in an intensive care unit (ICU) and were over age 65 years. Standard dosing for all antimicrobials failed to achieve optimal CFRs, regardless of hospital location. While high-dose prolonged infusions improved the CFRs for the β-lactams, optimal exposures were only attained by doripenem (2 g every 8 hours infused over 1 hour; 0.5-2 g every 8 hours infused over 4 hours) and meropenem (2 g every 8 hours infused over 0.5 and 3 hours) for all isolates. Non-ICU isolates had approximately 5-10% higher CFRs compared with those collected in the ICU. Lower-respiratory-tract isolates had a lower predicted CFR than did isolates from the blood and skin or wounds. Conclusion. Simulated pharmacodynamic profiles of i.v. antimicrobials commonly used to treat P. aeruginosa indicated that higher dosages and prolonged infusion times are needed to achieve optimal exposure for bactericidal activity. [ABSTRACT FROM AUTHOR]

Resistant Gram-positive infections present serious challenges to patients and providers who care for them. Ceftaroline is a novel advanced-generation cephalosporin with a broad spectrum of activity against many pathogens. Recently, ceftaroline was approved by FDA for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP). Like other cephalosporins, ceftaroline has predictable pharmacokinetics and is primarily renally excreted, increasing the ease of dosing. Ceftaroline has demonstrated activity against methicillin-resistant Staphylococcus aureus and multidrug-resistant Streptococcus pneumoniae as well as common respiratory Gram-negatives including Haemophilus, Moraxella, and Klebsiella species. During clinical trials, ceftaroline demonstrated noninferiority to vancomycin plus aztreonam for the treatment of complicated skin and skin structure infections (now called ABSSSIs) and ceftriaxone for the treatment of CABP. Ceftaroline was well tolerated in clinical trials with gastrointestinal side effects being the most common adverse event. Ceftaroline's unique spectrum of activity and ease of dosing based on renal function make it a unique addition to the clinician's armamentarium. [ABSTRACT FROM AUTHOR]

Focuses on cefditoren pivoxil, a broad-spectrum oral cephalosporin. Chemistry; Pharmacokinetics; Microbiology; Pharmacodynamics.

Purpose. The physical compatibility of isavuconazonium sulfate with 95 i.v. drugs during simulated Y-site administration was studied. Methods. Isavuconazonium sulfate for injection and all other drugs were reconstituted according to the manufacturer's recommendation and further diluted with 0.9% sodium chloride injection or 5% dextrose injection to a final concentration (1.5 mg/mL for isavuconazonium sulfate and standard concentrations used clinically for other drugs). A Y site was simulated in glass culture tubes by mixing 5 mL of the tested drug and isavuconazonium sulfate solutions in each diluent. Incompatibility was defined as changes in visual characteristics or increases in turbidity by greater than 0.5 nephelometric turbidity units over the 120-minute experiment. Results. Of the 95 drugs tested, isavuconazonium sulfate was physically compatible with 66 drugs in 0.9% sodium chloride injection and 60 drugs in 5% dextrose injection. Incompatibility was observed with albumin, am-photericin B deoxycholate, amphotericin B lipid complex, amphotericin B liposome, ampicillin-sulbactam, cefazolin, cefepime, ceftaroline fosamil, ceftazidime, ceftriaxone, cefuroxime, colistimethate sodium, cyclosporine, ertapenem, esomeprazole, filgrastim, fosphenytoin, furosemide, hepa-rin, meropenem, methylprednisolone, micafungin, phenytoin, potassium phosphate, propofol, sodium bicarbonate, sodium phosphate, and tediz-olid. Azithromycin, bumetanide, penicillin G potassium, and piperacillin-tazobactam were incompatible with isavuconazonium sulfate in 5% dextrose injection only. Conclusion. Of the 95 drugs tested, isavuconazonium sulfate 1.5 mg/mL was physically compatible with 66 drugs in 0.9% sodium chloride injection and 60 drugs in 5% dextrose injection. Incompatibility was observed with 18 antimicrobials, including most cephalosporins tested, and 14 other i.v. drugs in at least 1 of the 2 tested diluents. [ABSTRACT FROM AUTHOR]