Antibiotic Dosing in Continuous Renal Replacement Therapy.

Appropriate antibiotic dosing is critical to improve outcomes in critically ill patients with sepsis. The addition of continuous renal replacement therapy makes achieving appropriate antibiotic dosing more difficult. The lack of continuous renal replacement therapy standardization results in treatment variability between patients and may influence whether appropriate antibiotic exposure is achieved. The aim of this study was to determine if continuous renal replacement therapy effluent flow rate impacts attaining appropriate antibiotic concentrations when conventional continuous renal replacement therapy antibiotic doses were used. This study used Monte Carlo simulations to evaluate the effect of effluent flow rate variance on pharmacodynamic target attainment for cefepime, ceftazidime, levofloxacin, meropenem, piperacillin, and tazobactam. Published demographic and pharmacokinetic parameters for each antibiotic were used to develop a pharmacokinetic model. Monte Carlo simulations of 5000 patients were evaluated for each antibiotic dosing regimen at the extremes of Kidney Disease: Improving Global Outcomes guidelines recommended effluent flow rates (20 and 35 mL/kg/h). The probability of target attainment was calculated using antibiotic-specific pharmacodynamic targets assessed over the first 72 hours of therapy. Most conventional published antibiotic dosing recommendations, except for levofloxacin, reach acceptable probability of target attainment rates when effluent rates of 20 or 35 mL/kg/h are used.

Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation.

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 (Vc) were lower than those for adults without CF (ceftolozane CF Vc, 7.51 ± 2.05 liters; tazobactam CF Vc, 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.).

Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for Susceptible-Dose-Dependent Organisms.

The Clinical and Laboratory Standards Institute (CLSI) revised cefepime (CFP) breakpoints forEnterobacteriaceaein 2014, and MICs of 4 and 8 µg/ml were reclassified as susceptible-dose dependent (SDD). Pediatric dosing to provide therapeutic concentrations against SDD organisms has not been defined. CFP pharmacokinetics (PK) data from published pediatric studies were analyzed. Population PK parameters were determined using NONMEM, and Monte Carlo simulation was performed to determine an appropriate CFP dosage regimen for SDD organisms in children. A total of 664 CFP plasma concentrations from 91 neonates, infants, and children were included in this analysis. The median patient age was 1.0 month (interquartile range [IQR], 0.2 to 11.2 months). Serum creatinine (SCR) and postmenstrual age (PMA) were covariates in the final PK model. Simulations indicated that CFP dosing at 50 mg/kg every 8 h (q8h) (as 0.5-h intravenous [i.v.] infusions) will maintain free-CFP concentrations in serum of >4 and 8 µg/ml for >60% of the dose interval in 87.1% and 68.6% of pediatric patients (age, ≥30 days), respectively, and extending the i.v. infusion duration to 3 h results in 92.3% of patients with free-CFP levels above 8 µg/ml for >60% of the dose interval. CFP clearance (CL) is significantly correlated with PMA and SCR. A dose of 50 mg/kg of CFP every 8 to 12 h does not achieve adequate serum exposure for older children with serious infections caused by Gram-negative bacilli with a MIC of 8 µg/ml. Prolonged i.v. infusions may be useful for this population.

Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia.

Ceftolozane/tazobactam is an antipseudomonal antibacterial approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) and in phase 3 clinical development for treatment of nosocomial pneumonia. A population pharmacokinetic (PK) model with the plasma-to-epithelial lining fluid (ELF) kinetics of ceftolozane/tazobactam was used to justify dosing regimens for patients with nosocomial pneumonia in phase 3 studies. Monte Carlo simulations were performed to determine ceftolozane/tazobactam dosing regimens with a > 90% probability of target attainment (PTA) for a range of pharmacokinetic/pharmacodynamic targets at relevant minimum inhibitory concentrations (MICs) for key pathogens in nosocomial pneumonia. With a plasma-to-ELF penetration ratio of approximately 50%, as observed from an ELF PK study, a doubling of the current dose regimens for different renal functions that are approved for cUTIs and cIAIs is needed to achieve > 90% PTA for nosocomial pneumonia. For example, a 3-g dose of ceftolozane/tazobactam for nosocomial pneumonia patients with normal renal function is needed to achieve a > 90% PTA (actual 98%) for the 1-log kill target against pathogens with an MIC of ≤ 8 mg/L in ELF, compared with the 1.5-g dose approved for cIAIs and cUTIs.

Evaluation of the pharmacokinetics and safety of single and multiple ceftaroline fosamil infusions in healthy Chinese and Western subjects.

OBJECTIVES: Two phase I studies in healthy Chinese (NCT01458743) and Western (NCT01612507) subjects evaluated the pharmacokinetics (PK) and safety of single and multiple ceftaroline fosamil 600 mg infusions administered every 8 or 12 hours (q8h or q12h). METHODS: Each study enrolled subjects sequentially into 1 of 2 cohorts (cohort 1: 60-minute infusions; cohort 2: 120-minute infusions). All subjects in the Chinese (n = 26) study received open label ceftaroline fosamil; in the Western study, subjects (n = 41) in each cohort were randomized 3 : 1 to ceftaroline fosamil or placebo infusions. Single infusions were administered on days 1 and 8. On days 2 - 7 (3 - 7 for Chinese study, cohort 1) subjects received q12h or q8h infusions. Plasma and urine were collected on days 1 and 8 for PK analysis. RESULTS: Ceftaroline PK was linear and time-independent following single and multiple doses of ceftaroline fosamil. The magnitude and timing of peak plasma concentrations of ceftaroline (active metabolite), ceftaroline fosamil (prodrug), and ceftaroline M-1 (inactive metabolite) varied according to the ceftaroline fosamil dosing schedule (q12h or q8h) and infusion duration (60 minutes or 120 minutes), but overall plasma ceftaroline exposures within the respective dosing intervals were broadly similar across cohorts. The most frequent adverse events were rash/drug eruption, most of which were of mild-moderate intensity and considered related to treatment. CONCLUSIONS: Ceftaroline PK was broadly similar in healthy Chinese and Western subjects receiving equivalent dose regimens. The tolerability profile of ceftaroline fosamil in Chinese and Western subjects was consistent with previous clinical trials.

Pharmacokinetic-pharmacodynamic target attainment analyses to evaluate in vitro susceptibility test interpretive criteria for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae.

To provide support for in vitro susceptibility test interpretive criteria decisions for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae, as well as dose adjustment recommendations for renal impairment, pharmacokinetic-pharmacodynamic (PK-PD) target attainment was evaluated for simulated patients administered intravenous (i.v.) ceftaroline fosamil at 600 mg twice daily (q12h) and simulated patients with renal impairment administered various dosing regimens. Using a previously developed population PK model, Monte Carlo simulation was used to generate ceftaroline plasma concentration profiles for simulated patients with normal renal function or mild, moderate, or severe renal impairment. Using these profiles, the percentage of time during the dosing interval that free-drug concentrations remained above the MIC (f%T>MIC) for ceftaroline at steady state was calculated. Percentages of simulated patients achieving f %T>MIC targets for S. aureus and S. pneumoniae based on murine infection models were calculated by MIC. At MICs of 2 mg/liter for S. aureus and 1 mg/liter for S. pneumoniae, the percentages of simulated patients with normal renal function and mild renal impairment following administration of ceftaroline fosamil at 600 mg q12h, moderate renal impairment following administration of ceftaroline fosamil at 400 mg q12h, and severe renal impairment following administration of ceftaroline fosamil at 300 mg q12h achieving f %T>MIC targets (≥26 for S. aureus and ≥44 for S. pneumoniae) exceeded 90%. The results of these analyses, which suggested that in vitro susceptibility test interpretive criteria defining susceptible could be as high as MICs of ≤2 and ≤1 mg/liter for ceftaroline against S. aureus and S. pneumoniae, respectively, provide support for current FDA and CLSI criteria, which define susceptible as MICs of 1 and 0.5 mg/liter, respectively. Recommendations for dose adjustments for patients with renal impairment were also supported by the results of these analyses.

Monte Carlo simulations based on phase 1 studies predict target attainment of ceftobiprole in nosocomial pneumonia patients: a validation study.

Monte Carlo simulation (MCS) of antimicrobial dosage regimens during drug development to derive predicted target attainment values is frequently used to choose the optimal dose for the treatment of patients in phase 2 and 3 studies. A criticism is that pharmacokinetic (PK) parameter estimates and variability in healthy volunteers are smaller than those in patients. In this study, the initial estimates of exposure from MCS were compared with actual exposure data in patients treated with ceftobiprole in a phase 3 nosocomial-pneumonia (NP) study (NTC00210964). Results of MCS using population PK data from ceftobiprole derived from 12 healthy volunteers were used (J. W. Mouton, A. Schmitt-Hoffmann, S. Shapiro, N. Nashed, N. C. Punt, Antimicrob. Agents Chemother. 48:1713-1718, 2004). Actual individual exposures in patients were derived after building a population pharmacokinetic model and were used to calculate the individual exposure to ceftobiprole (the percentage of time the unbound concentration exceeds the MIC [percent fT > MIC]) for a range of MIC values. For the ranges of percent fT > MIC used to determine the dosage schedule in the phase 3 NP study, the MCS using data from a single phase 1 study in healthy volunteers accurately predicted the actual clinical exposure to ceftobiprole. The difference at 50% fT > MIC at an MIC of 4 mg/liter was 3.5% for PK-sampled patients. For higher values of percent fT > MIC and MICs, the MCS slightly underestimated the target attainment, probably due to extreme values in the PK profile distribution used in the simulations. The probability of target attainment based on MCS in healthy volunteers adequately predicted the actual exposures in a patient population, including severely ill patients.

[Assessment of efficacies of imipenem, cefoperazone-sulbactam and cefepime in rats with experimental thigh abscess model with multidrug resistant and susceptible Acinetobacter baumannii strains]. / Sefoperazon-sulbaktam, imipenem ve sefepimin antibiyoterapi etkinliklerinin çogul dirençli ve duyarli acinetobacter baumannii ile olusturulan deneysel ikili apse modelinde karsilastirilmasi.

Imipenem, cefaperazon-sulbactam and cefepime are the antibiotics of choice for the treatment of soft tissue infections due to Acinetobacter baumannii. In this study, it was aimed to determine the invivo and invitro efficacy of, these antibiotics against drug susceptible and multidrug resistant A.baumannii in an experimental abscess model. Abscess models were established in Wistar-Albino type female rats. Susceptibility tests were performed by E-test. Rats were divided randomly into four groups with eight rats in one group. Standard absorbent paper discs containing 6 log10 CFU microorganisms were used to form an abscess model. The first group was regarded as the control group and the other three groups were the study group each treated with one of the test antibiotics. Cardiac blood samples for serum antibiotic efficacy test, were obtained on the fourth day of treatment and 30 minutes after the last dose. The number of live bacteria at the area of infection was determined by colony count method. All of the three antibiotics reached sufficient concentration in sera of rats and there were no statistically important difference between the efficacies of these antibiotics (p= 0.778). In all of the antibiotic-treated groups, the weight of the abscess material were less, macroscopic views were smaller and the colony counts per gram of abscess tissue were less than the control group (p< 0.001). All antibiotics were effective against susceptible and resistant strains in vitro. No resistance was detected against imipenem, cefaperazon-sulbactam and cefepime in the course of therapy. Cefaperazone-sulbactam and cefepime were as effective as imipenem against susceptible and multi-drug resistant A.baumannii both in vivo and in vitro. Since irrational use of extended spectrum cephalosporins are frequently associated with the emergence of carbapenem resistant strains, the use of relatively narrow spectrum antibiotics should better be considered in the empirical treatment of A.baumannii infections.

Development and validation of a high-performance liquid chromatography method for determination of cefquinome concentrations in sheep plasma and its application to pharmacokinetic studies.

Cefquinome has a broad spectrum of antibacterial activity and was developed especially for use in animals. A simple and sensitive high-performance liquid chromatography (HPLC) method with UV-visible detection for quantification of cefquinome concentrations in sheep plasma was developed and validated. Separation of cefquinome from plasma components was achieved on a Phenomenex Gemini C(18) column (250 mm by 4.6 mm; internal diameter [i.d.], 5 µm). The mobile phase consisted of acetonitrile and 0.1% trifluoroacetic acid in water and was delivered at a rate of 0.9 ml/min. A simple and rapid sample preparation involved the addition of methanol to 200 µl of plasma to precipitate plasma proteins followed by direct injection of 50 µl of supernatant into the high-performance liquid chromatography system. The linearity range of the proposed method was 0.02 to 12 µg/ml. The intraday and interday coefficients of variation obtained from cefquinome were less than 5%, and biases ranged from -3.76% to 1.24%. Mean recovery based on low-, medium-, and high-quality control standards ranged between 92.0 and 93.9%. Plasma samples were found to be stable in various storage conditions (freeze-thaw, postpreparative, short-term, and long-term stability). The method described was found to be readily available, practicable, cheap, rapid, sensitive, precise, and accurate. It was successfully applied to the study of the pharmacokinetics of cefquinome in sheep. This method can be very useful and an alternate to performing pharmacokinetic studies in the determination of cefquinome for clinical use.

Identifying exposure targets for treatment of staphylococcal pneumonia with ceftobiprole.

Ceftobiprole is a cephalosporin with potent activity against methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). In order to treat patients with severe staphylococcal pneumonia, it is important to understand the drug exposure required to mediate the killing of multiple log(10) cells in a preclinical-infection model. We measured drug exposure in terms of the percentage of penetration of the drug into epithelial lining fluid (ELF) and in terms of the time for which the drug concentration was above the MIC (time>MIC) in plasma and ELF. In a murine model of staphylococcal pneumonia, we demonstrated that ceftobiprole penetrated into ELF from the plasma at a median level of nearly 69% (25th to 75th percentile range, 25 to 187%), as indexed to the ratio of values for the area under the concentration-time curve in ELF and plasma. The total-drug times>MIC in ELF that were required to kill 1 log(10) and 2 log(10) CFU/g of lung tissue were 15% and 25% of the dosing interval. We also examined the penetration of ELF by ceftobiprole in volunteers, demonstrating mean and median penetration percentages of 25.5% and 15.3%, respectively (25th to 75th percentile range, 8 to 30%). Attainment rates were calculated for kill targets of 1 log(10) and 2 log(10) CFU/g, taken from the murine model, but using the volunteer ceftobiprole ELF penetration data. The standard dose for ceftobiprole is 0.5 g every 8 h as a 2-h infusion. The attainment rates remained above 90% for 1-log(10) and 2-log(10) CFU/g kill targets at MICs of 1 and 0.5 mg/liter, respectively. Taking the expectation over the distribution of ceftobiprole MICs for 4,958 MRSA isolates showed an overall target attainment of 85.6% for a 1-log(10) CFU/g kill and 79.7% for a 2-log(10) CFU/g kill. It is important to derive exposure targets in preclinical-infection models of the infection site so that these targets can be explored in clinical trials in order to optimize the probability of a good clinical outcome.

Peritoneal pharmacokinetics of cefepime in laparotomy patients with inflammatory bowel disease, and dosage considerations for surgical intra-abdominal infections based on pharmacodynamic assessment.

This study aimed to examine the peritoneal pharmacokinetics of cefepime and to assess its pharmacodynamic exposure in peritoneal fluid (PF). Cefepime (1 g) was administered to eight patients with inflammatory bowel disease before abdominal surgery. Venous blood and PF samples were obtained at the end of the 0.5-h infusion and at 1, 2, 3, 4, 5, and 6 h thereafter. Drug concentrations in plasma and PF were determined, analyzed pharmacokinetically, and used for a Monte Carlo simulation with minimum inhibitory concentration (MIC) data. Cefepime penetrated well into PF, with a maximum drug concentration in a PF/plasma ratio of 0.59 +/- 0.15 (mean +/- SD, n = 8), and an area under the concentration-time curve ratio of 0.90 +/- 0.10. The probabilities of attaining the bacteriostatic and bactericidal targets (40% and 70% of the time above the MIC, respectively) in PF were > or =85% against Escherichia coli, Klebsiella species, and Enterobacter cloacae with 0.5 g every 12 h, 1 g every 12 h, 1 g every 8 h, and 2 g every 12 h. However, 1 g every 8 h or 2 g every 12 h was required for bacteriostatic and bactericidal probabilities > or =85% against Pseudomonas aeruginosa. These conventional regimens did not achieve a high probability against Bacteroides species. These results should help to give us a better understanding of the peritoneal pharmacokinetics of cefepime while also helping to choose the appropriate dosage to prevent surgical intra-abdominal infections on the basis of the pharmacodynamic assessment.

Use of population pharmacokinetic modeling and Monte Carlo simulation to describe the pharmacodynamic profile of cefditoren in plasma and epithelial lining fluid.

Cefditoren is a broad-spectrum, oral cephalosporin that is highly active against clinically relevant respiratory tract pathogens, including multidrug-resistant Streptococcus pneumoniae. This study described its pharmacodynamic profile in plasma and epithelial lining fluid (ELF). Plasma and ELF pharmacokinetic data were obtained from 24 patients under fasting conditions. Cefditoren and urea concentrations were determined in plasma and bronchoalveolar lavage fluid by liquid chromatography-tandem mass spectrometry. Concentration-time profiles in plasma and ELF were modeled using a model with three disposition compartments and first-order absorption, elimination, and transfer. Pharmacokinetic parameters were identified in a population pharmacokinetic analysis (big nonparametric adaptive grid with adaptive gamma). Monte Carlo simulation (9,999 subjects) was performed with the ADAPT II program to estimate the probability of target attainment at which the free-cefditoren plasma concentrations (88%) protein binding and total ELF concentrations exceeded the MIC for 33% of the dosing interval for 400 mg cefditoren given orally every 12 h. After the Bayesian step, the overall fits of the model to the data were good, and plots of predicted versus observed concentrations for plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. In the plasma probability of target attainment analysis, the probability of achieving a time for which free, or unbound, plasma concentration exceeds the MIC of the organism for 33% of the dosing interval was <80% for a MIC of >0.06 mg/liter. Similar to plasma, the probability of achieving a time above the MIC of 33% was <80% for MIC of >0.06 mg/liter in ELF. Cefditoren was found to have a low probability of achieving a bacteriostatic effect against MICs of >0.06 mg/liter, which includes most S. pneumoniae isolates with intermediate susceptibility to penicillin, when given in the fasting state in both plasma and ELF.

Pharmacokinetic and pharmacodynamic profiling of cefepime in plasma and peritoneal fluid of abdominal surgery patients.

This study was conducted to characterise the pharmacokinetics and pharmacodynamics of cefepime in plasma and peritoneal fluid (PF). One gram of cefepime was administered to eight laparotomy patients and plasma and PF samples were collected at the end of 0.5 h infusion and every hour for 6 h. Drug concentrations were determined, analysed by population pharmacokinetic modelling and used for a Monte Carlo simulation with minimum inhibitory concentration (MIC) data. The maximum concentration in PF was two-thirds of the value in plasma; however, the concentrations were higher in PF than in plasma at 0.68 h post dose. The probabilities of attaining the pharmacodynamic target (65% of the time above the MIC) were 92-99% in plasma (90% fraction unbound) and 93-100% in PF against Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae with a regimen of 1 g every 12 h. However, 1 g every 8 h or 2 g every 12 h was required for values of 94-95% in plasma and 95-96% in PF against Pseudomonas aeruginosa. These results demonstrate that the pharmacodynamic exposures in PF were almost identical to those estimated from plasma data and provided a pharmacokinetic/pharmacodynamic rationale for the dosing regimen for surgical intra-abdominal infections.

Comparison of the probability of target attainment between ceftriaxone and cefepime in the cerebrospinal fluid and serum against Streptococcus pneumoniae.

Although the disposition of ceftriaxone and cefepime in the cerebrospinal fluid (CSF) has been described, the ability of these agents to achieve critical pharmacodynamic targets against Streptococcus pneumoniae in CSF has not been reported. Plasma and CSF pharmacokinetic data were obtained from hospital patients with external ventricular drains and receiving ceftriaxone or cefepime. Concentration-time profiles in plasma and CSF were modeled using a 3-compartment model with 0-order infusion and 1st-order elimination and transfer. The model parameters were identified with population pharmacokinetic analysis (Big Non-Parametric Adaptive Grid with adaptive gamma). A Monte Carlo Simulation (9999 subjects) estimated the probability of target attainment (PTA) for total drug CSF concentrations at 50% and 100% T>MIC for ceftriaxone 2G IV Q12H and cefepime 2G IV Q8H. The S. pneumoniae bloodstream infection isolates from the SENTRY Antimicrobial Surveillance Program (USA) provided the distribution of contemporary (2003-2004) MICs. Post-Bayesian measures of bias and precision, observed-predicted plots, and R2 values were highly acceptable for both drugs. The probabilities of achieving 50% and 100% T>MIC in the CSF for ceftriaxone were 76% and 65%, respectively. For cefepime, the PTA at 50% and 100% T>MIC in the CSF were 91.8% and 82%, respectively. The CSF pharmacodynamics against S. pneumoniae for cefepime were superior to that of ceftriaxone. The implications of these findings need to be reexamined in the clinical setting.

Population pharmacokinetics and pharmacodynamics of cefpirome in critically ill patients against Gram-negative bacteria.

OBJECTIVES: To develop a population pharmacokinetics model for cefpirome in ICU patients, to assess pharmacokinetic-pharmacodynamic profiles vs. MIC distribution of likely ICU pathogens, and to assess their expected cumulative fraction of response (CFR). DESIGN AND SETTING: Prospective observational study in a multidisciplinary ICU. MEASUREMENTS AND RESULTS: Twelve patients received 2g cefpirome intravenously over 12h. Thirteen blood samples were taken on two occasions. Demographic and creatinine clearance data were collected. Based on the final covariate model obtained using NONMEM, Monte Carlo simulations were undertaken to simulate free-drug concentrations for two administration methods: intermittent bolus administration (IBA) and continuous infusion (CI) with a loading dose of 0.5 g. Concentration-time profiles were evaluated by the probability of achieving free-drug concentrations above the MIC for more than 65% of dosing interval. Using MIC distributions from the EUCAST programme the CFR for each method was evaluated. A three-compartment model with zero-order input best described the concentration-time data. The CFR for Escherichia coli and Klebsiella spp. was greater than 97% in all IBA and CI doses but for Pseudomonas aeruginosa, and Acinetobacter spp. achieved target concentrations of 56% and 46%, respectively. High-dose CI cefpirome (6g/day) for P. aeruginosa and Acinetobacter spp. was required to achieve CFR of 89%. CONCLUSION: Measured creatinine clearance appears to be a good marker of cefpirome clearance and potentially could be used to individualise cefpirome therapy. When given as IBA or CI for E. coli and Klebsiella spp., cefpirome should be successful. Cefpirome fails to achieve the bactericidal target even when administered at high-doses such as 6g/day for P. aeruginosa and Acinetobacter spp. Prospective clinical studies are needed to conclusively validate these findings.

Pharmacodynamic profiling of cefepime in plasma and cerebrospinal fluid of hospitalized patients with external ventriculostomies.

Population pharmacokinetic (PK) modeling and Monte Carlo simulation (MCS) were used to describe the pharmacodynamic profile of cefepime in the both plasma and cerebrospinal fluid (CSF). Plasma and CSF cefepime data were obtained from a PK study of 7 hospitalized patients with external ventricular drains. Concentration-time profiles in plasma and CSF were modeled using a 3-compartment model with zero-order infusion and first-order elimination and transfer. Estimates of the PK parameters were identified in the Big Non Parametric Adaptive Grid with adaptive gamma (BigNPAG) program of Leary, Jelliffe, Schumitzky, and Van Guilder. MCS (10,000 subjects) was performed to estimate the probability of attaining the targets of free plasma concentration (20% protein binding) and total drug CSF concentration of 50-100% T>minimal inhibitory concentration (MIC) for MICs 0.06-8 mg/L for cefepime 2 g, iv, every 8 h (0.5-h infusion); cefepime 2 g, iv, every 12 h (0.5-h infusion); and cefepime 2 g (0.5-h infusion) once and 250 mg/h continuous infusion. After the Bayesian step, the observed-predicted regression and r(2) for plasma and CNS were as follows: plasma, observed=0.984 x predicted+2.570, r(2)=0.944; CSF, observed=0.785 x predicted+0.868, r(2)=0.821. The median penetration of cefepime as measured by AUC(CSF)/AUC(plasma) was 7.8%. In the MCS, the target attainment rates in plasma for 60-70% fT>MIC were high at each MIC value between 0.03 and 8 microg/mL for each regimen examined. In CSF, none of the regimens achieved 50-100% T>MIC for>80% of patients for MICs>0.5 mg/L.

Pharmacokinetics and pharmacodynamics of cefepime in patients with various degrees of renal function.

This study evaluated the pharmacokinetics of cefepime in 36 patients with different levels of renal function. Pharmacokinetic and pharmacodynamic parameters were calculated using samples obtained at steady state. Patients with creatinine clearance (CL(CR)) of >100 ml/min had more rapid clearance (CL) and a lower minimum concentration in serum (C(min)). C(min) in this group was found to be 3.3 +/- 3.6 mg/liter (mean and standard deviation), compared to 19.5 +/- 21.5 mg/liter in patients with a CL(CR) of between 60 and 100 ml/min (P = 0.025) and 14.0 +/- 11.5 mg/liter in patients with a CL(CR) of <60 ml/min (P = 0.009). Patient data were also analyzed by the nonparametric expectation maximization method and Bayesian forecasting. The median volume of distribution in the central compartment was 27.08 liters. CL and CL(CR) were highly correlated (P = 0.00033) according to the equation CL= 0.324 liters/h + (0.0551 x CL(CR)). The median rate constants from the central compartment to the peripheral compartment and from the peripheral compartment to the central compartment were 12.58 and 41.09 h(-1), respectively. The time-concentration profiles for 1,000 patients (CL(CR)s, 120, 60, and 30 ml/min) each receiving various dosing regimens were simulated by using Monte Carlo simulations. Standard dosing resulted in a C(min) that was greater than or equal to the MIC in more than 80% of the simulated profiles with MICs < or = 2 mg/liter. Current dosing recommendations may be suboptimal for monotherapy of infections due to less susceptible pathogens (e.g., those for which MICs are > or = 4 mg/liter), particularly when CL(CR) exceeds 120 ml/min.

Serum concentrations of cefuroxime after continuous infusion in coronary bypass graft patients.

OBJECTIVE: To describe the serum concentrations of continuous infusion of cefuroxime for postsurgical prophylaxis of sternal wound infection in patients undergoing coronary artery bypass graft (CABG), and to assess the incidence of sternal wound infection in this population. METHODS: This was a prospective, noncomparative trial involving 54 patients undergoing elective CABG surgery. All patients enrolled in the study received cefuroxime 1.5 g as a single intravenous dose 30 minutes preoperatively, followed by a continuous infusion of 3 g every 24 hours until removal of all central venous catheters. RESULTS: Of the 53 evaluable patients, the mean steady-state cefuroxime serum concentration was 21.6 +/- 14.2 microg/mL (range 6.56-59.5). No patient developed a sternal wound infection. The mean treatment duration was 2.58 +/- 2.13 days (range 1-13). The median hospital and intensive care unit lengths of stay were six days and 46 hours, respectively. The average antibiotic cost per day was $32.76. CONCLUSIONS: These preliminary results of continuous infusion of cefuroxime 3 g/d for prophylaxis of sternal wound infections in CABG patients indicate that serum concentrations are highly variable, but reliably above the minimum inhibitory concentration for the common anticipated pathogens in this setting. Further comparative trials in a larger number of patients are necessary before this mode of administration can be routinely advocated for prophylaxis.

Antimicrobials and therapeutic decision making: an historical perspective.

In an effort to remedy inappropriate and excessive use of antimicrobials and to control costs, most hospitals have developed some type of antimicrobial management program. At Hartford Hospital, our most effective approaches have been those that reduce the chances for physician error, decrease the burden on ancillary services, and encourage short hospital stays. These include automatic correction of dose and dosing intervals of antimicrobials and, if possible, their conversion by pharmacy to cost-effective alternative agents; daily review of patients who are taking the drugs by an antimicrobial team; and replacement of parenteral with oral agents as soon as possible. Physician acceptance of these approaches will require significant changes in traditional prescribing styles and willingness to allow pharmacists to implement the recommendations of therapeutic and medical staff committees.