Validated HPLC-UV detection method for the simultaneous determination of ceftolozane and tazobactam in human plasma.

AIM: A simple, rapid, economical and sensitive HPLC-UV method was developed for the simultaneous quantification of ceftolozane and tazobactam in plasma samples. METHODOLOGY: After deproteinization followed by a liquid-liquid back-extraction, the compounds were separated on a C18 column (150 mm × 4.6 mm, 5 µm) with UV-visible detection at 220 nm. The mobile phase consisted of acetonitrile and potassium dihydrogenphosphate buffer at pH 3.0 (8:92, v/v), delivered isocratically at a flow rate of 1.0 ml/min and at a column oven temperature of 30°C. Cefepime was used as an internal standard. RESULTS: Linearity was achieved in the concentration range of 0.50-100.00 µg/ml for ceftolozane and 0.25-50.00 µg/ml for tazobactam. The intra- and interday precision showed good reproducibility with coefficients of variation of less than 9.26% for ceftolozane and 9.62% for tazobactam. CONCLUSION: The sample preparation procedure avoids expensive or time-consuming steps used by other previously published methods. The methodology was validated according to standard guidelines and was used for quantification of ceftolozane and tazobactam in plasma samples from critically ill patients.

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.

Standard dosing of piperacillin and meropenem fail to achieve adequate plasma concentrations in ICU patients.

BACKGROUND: Controversies remain regarding optimal dosing and the need for plasma concentration measurements when treating intensive care patients with beta-lactam antibiotics. METHODS: We studied ICU patients treated with either antibiotic, excluding patients on renal replacement therapy. Antibiotic concentrations were measured at the mid and end of the dosing interval, and repeated after 2-3 days when feasible. Glomerular filtration rate (GFR) was estimated from plasma creatinine and cystatin C, GFR calculated from cystatin C (eGFR) and measured creatinine clearance (CrCl). Measured concentrations were compared to the clinical susceptible breakpoints for Pseudomonas aeruginosa, 16 and 2 mg/l for piperacillin and meropenem respectively. RESULTS: We analysed 33 and 31 paired samples from 20 and 19 patients treated with piperacillin-tazobactam and meropenem respectively. Antibiotic concentrations at the mid and end of the dosing interval were for piperacillin, 27.0 (14.7-52.9) and 8.6 (2.7-30.3); and for meropenem, 7.5 (4.7-10.2) and 2.4 (1.0-3.5). All values median (interquartile range) and concentrations in mg/l. The percentage of measured concentrations below the breakpoint at the mid and end of the dosing interval were for piperacillin, 27% and 61%; and for meropenem, 6% and 48%. Lower estimates of GFR were associated with higher concentrations but concentrations varied greatly between patients with similar GFR. The correlation with terminal concentration half-life was similar for eGFR and CrCl. CONCLUSIONS: With standard doses of meropenem and piperacillin-tazobactam, plasma concentrations in ICU patients vary > 10-fold and are suboptimal in a significant percentage of patients. The variation is large also between patients with similar renal function.

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.).

High-risk febrile neutropenia and its management in children with solid tumors and lymphoma.

BACKGROUND/AIM: The clinical characteristics and treatment results of febrile neutropenia attacks that occurred in patients with lymphoma and solid tumors were analyzed. MATERIALS AND METHODS: A total of 50 patients with 94 high-risk attacks were evaluated for malignant diseases in this study. RESULTS: The fever etiology was determined as clinical (50%), microbiological (5.31%), clinical-microbiological (5.31%), or unknown (39.3%). A few of the attacks (21.3%) were observed in lymphoma cases and 77.7% were observed in patients with solid tumors. Patients who were in remission had 59.6% of the attacks, and 39.4% occurred in patients not in remission. Among the groups tested, 73% (the imipenem/amikacin group) and 47.9% (the piperacillin-tazobactam/amikacin group) of patients were in remission. Glycopeptide addition rates in these groups were 22.2% and 40.8% and antifungal addition rates were 8.8% and 18.3%, respectively. CONCLUSION: Clinical progress was more problematic in patients who were not in remission during the attacks. This was due to the fact that some patients had other factors that placed them in the high-risk group, as well as increased C reactive protein and procalcitonin values on the first day. Therefore, it may not be accurate to associate the success achieved in the different treatment regimens with antibiotics alone.

Penetration of piperacillin-tazobactam into human prostate tissue and dosing considerations for prostatitis based on site-specific pharmacokinetics and pharmacodynamics.

This study aimed to investigate the penetration of PIPC-TAZ into human prostate, and to assess effectiveness of PIPC-TAZ against prostatitis by evaluating site-specific PK-PD. Patients with prostatic hypertrophy (n = 47) prophylactically received a 0.5 h infusion of PIPC-TAZ (8:1.2-0.25 g or 4-0.5 g) before transurethral resection of the prostate. PIPC-TAZ concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were analyzed with a three-compartment PK model. The estimated model parameters were, then used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria (T > MIC, the PD indicator for antibacterial effects) in prostate tissue for six PIPC-TAZ regimens (2.25 or 4.5 g; once, twice, three times or four times daily; 0.5 h infusions). Prostate tissue/plasma ratio of PIPC was about 36% both for the maximum drug concentration (Cmax) and the area under the drug concentration-time curve (AUC). Against MIC distributions for isolates of Escherichia coli, Klebsiella species and Proteus species, regimens of 4.5 g twice daily and 2.25 g three times daily achieved a >90% probability of attaining the bacteriostatic target for PIPC (30% T > MIC) in prostate tissue; regimens of 4.5 g three times daily and 2.25 g four times daily achieved a >90% probability of attaining the bactericidal target for PIPC (50% T > MIC) in prostate tissue. However, against Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability. PIPC-TAZ is appropriate for the treatment of prostatitis from the site-specific PK-PD perspective.

Pharmacokinetics of piperacillin/tazobactam in cancer patients with hematological malignancies and febrile neutropenia after chemotherapy.

INTRODUCTION: Patients with febrile neutropenia (FN) exhibit changes in extracellular fluid that may alter the plasma concentrations of beta-lactams and result in therapeutic failure or toxicity. We evaluated the pharmacokinetics of piperacillin/tazobactam in patients with hematological malignancies and FN after receiving chemotherapy at a primary public cancer center. METHODS: This was an open, nonrandomized, observational, descriptive, and prospective study. Samples from 15 patients with hematological malignancies and FN were evaluated after the administration of chemotherapy. Five blood samples were taken from each patient when the antibiotic level was at steady-state 10, 60, 120, 180, and 350 min after each dose. Antibiotic concentrations were measured using gel diffusion with Bacillus subtilis. All study participants provided written informed consent. RESULTS: We investigated the pharmacokinetics of piperacillin in 14 patients between the ages of 18 years and 59 years and with a mean absolute neutrophil count of 208 cells per mm³ (standard deviation (SD) ± 603.2). The following pharmacokinetic measurements were obtained: maximum concentration, 94.1-1133 mg/L; minimum concentration, 0.47-37.65 mg/L; volume of distribution, 0.08-0.65 L/kg (mean, 0.34 L/kg); drug clearance (CL), 4.42-27.25 L/h (mean, 9.93 L/h); half-life (t(1/2)), 0.55-2.65 h (mean, 1.38 h); and area under the curve, 115.12-827.16 mg · h/L. CONCLUSION: Patients with FN after receiving chemotherapy exhibited significant variations in the pharmacokinetic parameters of piperacillin compared with healthy individuals; specifically, FN patients demonstrated an increase in t1(/2) and decreased CL.

Piperacillin-tazobactam penetration into human pancreatic juice.

Piperacillin-tazobactam was administered as a single dose (4.5 g intravenous) to five patients with stabilized external pancreatic fistula. The penetration into pancreatic juice was prompt, and inhibitory concentrations were achieved and maintained for different periods (0.5 to 6 h) according to bacterial susceptibility and patients' characteristics. Piperacillin and tazobactam showed superimposable pharmacokinetics in both serum and pancreatic juice.

Concentrations of piperacillin-tazobactam in human jaw and hip bone.

OBJECTIVES: It is unclear to what extent pharmacokinetic data from bone outside the facial area can be transferred to the maxillofacial area. The aim of this study was to evaluate the penetration characteristics of piperacillin-tazobactam into human jaw and hip bone as a model for different bone characteristics. MATERIALS AND METHODS: The drug was administered at the start of surgery in a single 15-min intravenous infusion dose (4g piperacillin & 0.5g tazobactam i.v.). Plasma and bone samples of ten patients were analyzed. RESULTS: Mean concentration of piperacillin in plasma was 309microg/ml at 0.5h declining at 4h to 14microg/ml. The respective values for tazobactam were 34microg/ml declining to 2.8microg/ml. The piperacillin-tazobactam ratio dropped during the study interval from 0.5h: 9.2%+/-0.8 to 2h: 7.2%+/-1.1 and 4h: 4.9%+/-0.7. Mean bone concentrations of piperacillin and tazobactam were 9.0+/-11.6microg/g and 1.2+/-1.3microg/g, respectively. Mean penetration ratios for all bone samples were 15% (+/-17) for piperacillin and 13% (+/-14) for tazobactam without a difference between bone of different origin. DISCUSSION: Piperacillin-tazobactam levels in jaw bone tissue after a single dose are sufficient to assure antibacterial activity of the combination and are above the minimal inhibitory concentrations of the most relevant pathogens in head and neck surgery. Our data suggests the use of piperacillin-tazobactam as an alternative for the therapy of severe infections of the head and neck.

Steady-state plasma and intrapulmonary concentrations of piperacillin/tazobactam 4 g/0.5 g administered to critically ill patients with severe nosocomial pneumonia.

OBJECTIVE: To determine the steady-state plasma and epithelial lining fluid (ELF) concentrations of piperacillin/tazobactam (P/T) administered to critically ill patients with severe bacterial pneumonia. DESIGN: Prospective, open-label study. SETTING: An intensive care unit and research ward in a university hospital. PATIENTS: Ten adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation. INTERVENTIONS: All subjects received a 30-min intravenous infusion of P/T 4 g/0.5 g every 8 h. The steady-state plasma and ELF concentrations of P/T were determined by high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: The mean+/-SD steady-state plasma trough, peak, and intermediate concentrations were 8.5+/-4.6 microg/ml, 55.9+/-21.6 microg/ml, and 24.0+/-13.8 microg/ml for piperacillin, and 2.1+/-1.0 microg/ml, 4.8+/-2.1 microg/ml, and 2.4+/-1.2 microg/ml for tazobactam, respectively. The mean+/-SD steady-state intermediate ELF concentrations were 13.6+/-9.4 microg/ml for piperacillin and 2.1+/-1.1 microg/ml for tazobactam, respectively, showing a mean percentage penetration of piperacillin and tazobactam into ELF of 56.8% and 91.3 %, respectively, with a P/T ratio of 6.5:1. CONCLUSION: Our results show that during the treatment of severe nosocomial pneumonia, a regimen of P/T 4 g/0.5 g every 8 h might provide insufficient concentrations into lung tissue to exceed the MIC of many causative pathogens. This suggests that higher doses of P/T should be administered in order to maximize the antibiotic concentration at the site of infection, or that a second antimicrobial agent should be used in association.

Sultamicillin--a new antibiotic in the treatment of persistent lower respiratory tract infections caused by Haemophilus influenzae.

Haemophilus influenzae is a frequent cause of recurrent or chronic lower respiratory tract infections in patients suffering from cystic fibrosis (CF) and other chronic obstructive pulmonary disease (COPD). Ampicillin and its derivatives are routinely used in treatment, but resistant strains producing beta-lactamase frequently necessitate the use of other antibiotics. Sultamicillin is a compound agent for oral use in which ampicillin and the beta-lactamase inhibitor sulbactam are linked as a double ester. This combination is active in vitro against many beta-lactamase producing bacteria including ampicillin-resistant H. influenzae. Eight CF children and ten children with other COPD suffering from chronic or recurrent H. influenzae infection of the lower respiratory tract were treated with sultamicillin orally, 25 mg/kg, 12-hourly, for two weeks. Nine infections were caused by ampicillin-resistant strains. At the end of the treatment 65% of the patients were free of H. influenzae. The only adverse reaction was diarrhoea which occurred in 14 patients, and necessitated withdrawal of one patient from the study.

Concentrations of ampicillin plus sulbactam in serum and intestinal mucosa and effects on the colonic microflora in patients undergoing colorectal surgery.

Ampicillin and sulbactam were administered intravenously in 2 g and 1 g doses respectively every 8 h for two days to ten patients undergoing colorectal surgery. Drug concentrations were determined in serum, intestinal mucosa and faeces. The first dose was given at induction of anesthesia. The serum half-life was 2.1 h for ampicillin and 2.0 h for sulbactam on the first day. The concentrations in intestinal mucosa were in most cases 50% or more of the serum concentrations and there was no statistical difference between the two drugs. Faecal concentrations of both drugs were found in eight patients: a mean of 10.5 micrograms/g for ampicillin and a mean of 7.5 micrograms/g for sulbactam. Faecal samples were also collected during the investigation period for culture of aerobic and anaerobic bacteria. Among the aerobic bacteria enterococci, streptococci and enterobacteria decreased markedly during the prophylaxis period. Anaerobic bacteria were also suppressed significantly during the same period. The changes in colonic microflora were related to the concentrations of ampicillin and sulbactam in the intestinal mucosa and faeces. Overgrowth of yeasts was observed in six patients and overgrowth of Pseudomonas fluorescens in two others. These strains were resistant to the combination ampicillin and sulbactam. The microflora normalized in all patients after two weeks. No postoperative infections occurred.

Human pharmacology of 6-[D-alpha-(3-guanylureido)-phenylacetamido]-penicillanic acid (BL-P1654).

BL-P1654 is a new alpha-substituted ureido penicillin which has broad-spectrum activity. Doses of 0.5 and 1.0 g administered by rapid intravenous injection produce mean peak serum concentrations of 40.7 and 80.8 mug/ml, respectively. The same doses administered by 1-h intravenous infusions produce mean peak serum concentrations of 22.6 and 47 mug/ml, respectively. The mean serum concentrations from 1 to 6 h after onset of administration of the drug are the same for both schedules. The mean serum concentration at 6 h after the rapid intravenous injection of 0.5- and 1.0-g doses of BL-P1654 are 3.4 and 5.4 mug/ml, respectively. A dose of 1.0 g every 4 h maintains a serum concentration of about 15 mug/ml. About 50 to 65% of the BL-P1654 is excreted in the urine during the first 6 h.