UPLC/MS/MS assay for the simultaneous determination of seven antibiotics in human serum-Application to pediatric studies.

A rapid and highly sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay was developed for quantification of 7 antibiotics in low sample volumes (50 µL): amoxicillin, azithromycin, cefotaxime, ciprofloxacin, meropenem, metronidazole and piperacillin, for both routine monitoring and pharmacokinetic studies. After protein precipitation by acetonitrile, the antibiotics were separated on an Acquity UPLC HSS T3 column (run time, 4 min). The mobile phase consisted of a mixture of (A) ammonium acetate (pH 2.4; 5 mM) and (B) acetonitrile acidified with 0.1% formic acid, delivered at 500 µl/min in a gradient elution mode. Total time run was 2.75 min. Ions were detected in the turbo-ion-spray-positive and multiple-reaction-monitoring modes. The assay was accurate and reproductible for the quantification of the seven antibiotics in serum samples over large concentration ranges.

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.

Clinical on-site monitoring of ß-lactam antibiotics for a personalized antibiotherapy.

An appropriate antibiotherapy is crucial for the safety and recovery of patients. Depending on the clinical conditions of patients, the required dose to effectively eradicate an infection may vary. An inadequate dosing not only reduces the efficacy of the antibiotic, but also promotes the emergence of antimicrobial resistances. Therefore, a personalized therapy is of great interest for improved patients' outcome and will reduce in long-term the prevalence of multidrug-resistances. In this context, on-site monitoring of the antibiotic blood concentration is fundamental to facilitate an individual adjustment of the antibiotherapy. Herein, we present a bioinspired approach for the bedside monitoring of free accessible ß-lactam antibiotics, including penicillins (piperacillin) and cephalosporins (cefuroxime and cefazolin) in untreated plasma samples. The introduced system combines a disposable microfluidic chip with a naturally occurring penicillin-binding protein, resulting in a high-performance platform, capable of gauging very low antibiotic concentrations (less than 6 ng ml-1) from only 1 µl of serum. The system's applicability to a personalized antibiotherapy was successfully demonstrated by monitoring the pharmacokinetics of patients, treated with ß-lactam antibiotics, undergoing surgery.

Measurement of piperacillin plasma concentrations in cancer patients with suspected infection.

BACKGROUND: Piperacillin (PIP) in combination with tazobactam is commonly used for anti-infective treatment in cancer patients. PIP exerts a time-dependent killing. Thus, the maintenance of plasma concentrations above a pre-defined target concentration for a pre-defined time may be relevant for optimal efficacy. It is assumed that PIP-plasma concentrations above the clinical breakpoint of the target pathogen [Pseudomonas aeruginosa, clinical breakpoint at minimal inhibitory concentration (MIC) 16 mg/L] should be reached for 100% of the dosing interval or >4xMIC (64 mg/L) for 50% of the dosing interval. Whereas studies in the intensive-care setting have shown underdosing in patients with sepsis, little is known about PIP-plasma concentrations in cancer patients. METHODS: Data of 56 cancer patients who received piperacillin/tazobactam (PIP/TAZ, 4.5 g three times daily) as empiric therapy for suspected infection were analysed at baseline and 4 h after the infusion. RESULTS: Median trough concentrations in steady state [median 3 days (IQR 3-5) after start of PIP/TAZ] were 4.6 mg/L (95% CI 0.3-136.3) and median PIP-plasma concentrations 4 h after infusion were 46.2 mg/L (95% CI 10.1-285.6). A second evaluation 5 days (IQR 4-7) after start of PIP/TAZ confirmed these results: trough concentrations were 2.7 mg/L (95% CI 0.5-6.3), concentrations after 4 h 28.0 mg/L (95% CI 1.7-47.3). A good renal function was associated with lower plasma concentrations (r = -0.388, p < 0.003). Detailed pharmacokinetic measurements in six patients showed low maximum plasma concentration (median 165 mg/L) and a rapid decline of plasma concentrations (median plasma half time 1.38 h). CONCLUSION: In conclusion, piperacillin plasma concentrations in cancer patients are below target levels warranting prospective trials to investigate therapeutic drug monitoring.

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.

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.

Serum antimicrobial concentrations for surgical antimicrobial prophylaxis in radical nephrectomy and radical prostatectomy.

To evaluate the current methods of surgical antimicrobial prophylaxis from the viewpoint of pharmacokinetics for patients undergo urologic surgery, this study was designed to measure the serum concentrations of two different prophylactic antimicrobial agents in different types of urologic surgery. This prospective study included 39 patients with prostate cancer, renal pelvic cancer, ureteral cancer or renal cancer treated by radical surgery from August 2005 to March 2006. Blood samples were taken intraoperatively at 30 min and 180 min after the beginning of the first administration. The half-life of the beta phase of cefazolin is 2.46 h and that of piperacillin is 0.7 h according to their manufacturers. The average serum concentration of cefazolin at 30 min was 144 µg/mL in the prostatectomy group and 175 µg/mL in the nephrectomy group. At 180 min, the average concentration of cefazolin was 37 µg/mL in prostatectomy group and 59 µg/mL in the nephrectomy group. The average concentration of piperacillin at 30 min was 134 µg/mL in the prostatectomy group and 137 µg/mL in the nephrectomy group. At 180 min, the average concentration of piperacillin was 10 µg/mL in the prostatectomy group and 22 µg/mL in the nephrectomy group. Thus, the concentration at 180 min after the beginning of infusion was different according to the half-life of each antimicrobial agent. Therefore, up-to-date guidelines for surgical antimicrobial prophylaxis that deal with additional types of intraoperative prophylaxis should be consulted if the operation exceeds two half-lives of the prophylactic antimicrobial agents used in real-life clinical practice.

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.

Mass spectrometric characterization of circulating and functional antigens derived from piperacillin in patients with cystic fibrosis.

A mechanistic understanding of the relationship between the chemistry of drug Ag formation and immune function is lacking. Thus, mass spectrometric methods were employed to detect and fully characterize circulating Ags derived from piperacillin in patients undergoing therapy and the nature of the drug-derived epitopes on protein that can function as an Ag to stimulate T cells. Albumin modification with piperacillin in vitro resulted in the formation of two distinct haptens, one formed directly from piperacillin and a second in which the dioxopiperazine ring had undergone hydrolysis. Modification was time and concentration dependent, with selective modification of Lys(541) observed at low concentrations, whereas at higher concentrations, up to 13 out of 59 lysine residues were modified, four of which (Lys(190), Lys(195), Lys(432), and Lys(541)) were detected in patients' plasma. Piperacillin-specific T lymphocyte responses (proliferation, cytokines, and granzyme B release) were detected ex vivo with cells from hypersensitive patients, and analysis of incubation medium showed that modification of the same lysine residues in albumin occurred in situ. The antigenicity of piperacillin-modified albumin was confirmed by stimulation of T cells with characterized synthetic conjugates. Analysis of minimally modified T cell-stimulatory albumin conjugates revealed peptide sequences incorporating Lys(190), Lys(432), and Lys(541) as principal functional epitopes for T cells. This study has characterized the multiple haptenic structures on albumin in patients and showed that they constitute functional antigenic determinants for T cells.

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.

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.

Systematic comparison of the population pharmacokinetics and pharmacodynamics of piperacillin in cystic fibrosis patients and healthy volunteers.

Respiratory tract infections cause 90% of premature mortality in patients with cystic fibrosis (CF). Treatment of Pseudomonas aeruginosa infection is often very problematic. Piperacillin-tazobactam has good activity against P. aeruginosa, but its pharmacokinetics (PK) in CF patients has not been compared to the PK in healthy volunteers in a controlled clinical study. Therefore, we compared the population PK and pharmacodynamics (PD) of piperacillin between CF patients and healthy volunteers. We studied 8 adult (median age, 20 years) CF patients (average total body weight [WT], 43.1 +/- 7.8 kg) and 26 healthy volunteers (WT, 71.1 +/- 11.8 kg) who each received 4 g piperacillin as a 5-min intravenous infusion. We determined piperacillin levels by high-performance liquid chromatography, and we used NONMEM for population PK and Monte Carlo simulation. We used a target time of nonprotein-bound concentration above the MIC of 50%, which represents near-maximal bacterial killing. Unscaled total clearance was 25% lower, and the volume of distribution was 31% lower in CF patients. Allometric scaling by lean body mass reduced the unexplained (random) between-subject variability in clearance by 26% compared to the variability of linear scaling by WT. A standard dosage regimen of 3 g/70 kg body WT every 4 h as a 30-min infusion (daily dose, 18 g) achieved a robust (> or =90%) probability-of-target attainment (PTA) for MICs of < or =12 mg/liter in CF patients and < or =16 mg/liter in healthy volunteers. Alternative modes of administration allowed a marked dose reduction to 9 g daily. Prolonged (4-h) infusions of 3 g/70 kg WT every 8 h and continuous infusion (daily dose, 9 g), achieved a robust PTA for MICs of < or =16 mg/liter in both groups. Piperacillin achieved PTA expectation values of 64% and 89% against P. aeruginosa infection in CF patients, based on susceptibility data from two German CF clinics.

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.

Double beta-lactam regimen compared to an aminoglycoside/beta-lactam regimen as empiric antibiotic therapy for febrile granulocytopenic cancer patients.

In a prospective, randomized trial, 205 febrile episodes in granulocytopenic cancer patients were treated with ceftazidime with or without tobramycin (C +/- T), both agents being administered only if the initial granulocyte count was below 200/microliters, or ceftazidime plus piperacillin (C + P). The overall response rate was 71% (39 of 60 for C +/- T and 45 of 58 for C + P). Logistic regression analyses documented no evidence of a significant difference between the two regimens in overall treatment effect after accounting for the linear effects of potentially important variables, such as infection type and granulocyte count. Although the response rates for the subgroup of patients with bacteremias was better with the C + P regimen (P = 0.06), there was no difference in response for patients with bacteremia and profound (< 100/microliters) sustained granulocytopenia. The double beta-lactam combination demonstrated in vitro synergism in 73%; antagonism was not seen. Both regimens produced excellent serum bactericidal levels (C +/- T geometric mean peak 1:170; C + P peak 1:137) against gram-negative but not gram-positive pathogens (1:4; 1:7 respectively) that had caused bacteremia. Emergence of resistance and significant coagulopathy and/or bleeding did not occur during therapy. Antibiotic-related nephrotoxicity was noted in 7 of 95 trials in the C + P and in 6 of 89 trials in the C +/- T group (P = 0.19). The incidence of secondary infections in patients with profound (< 100/microliters) sustained granulocytopenia was lower in the C +/- T group (P = 0.04). Alimentary canal anaerobic flora preservation with C +/- T, and suppression with C + P, was demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

[Diffusion of piperacillin in the eye]. / Diffusion de la pipéracilline dans l'ceil.

Intraocular diffusion of piperacillin was studied in 42 patients scheduled for cataract surgery (n = 35) or vitrectomy (n = 7). Piperacillin was administered intravenously (4 g/injection). Thirty-four patients were given a single dose and 8 were given two doses 12 hours apart. Peak piperacillin levels in the aqueous (7.3 mg/l) occurred one hour after the injection; levels in the vitreous were low (less than 0.6 mg/l). Intraocular diffusion of piperacillin was also studied in rabbits with an experimental Staphylococcus epidermidis infection of one eye; the other eye served as the control. In pigmented rabbits (6 Fauve de Bourgogne animals), increased diffusion and decreased elimination of piperacillin were seen in the aqueous, iris and cornea of the infected eyes, as compared with uninfected control eyes. In albino rabbits (6 New Zealand animals), results were less conclusive, with a difference between the infected and healthy eyes appearing only during the second hour following the injection. The good diffusion of piperacillin in the aqueous, especially in infected eyes (at least in rabbits), suggests that this drug may be useful for the treatment of ocular infections provided it is initiated early and given in combination with another antimicrobial exhibiting good intraocular diffusion.

Antibiotic prophylaxis for biliary tract surgery: selection of patient and agent.

One hundred and three patients undergoing biliary surgery have been entered in a randomized prospective trial for antibiotic prophylaxis. Fifty six received piperacillin (2 gr) and 47 tobramycin (100 mg). Cultures were taken from bile at operation and a clinical and microbiological assessment for infection was carried out postoperatively. Overall infection rate was significantly lower in the piperacillin group (P less than 0.05). The positive bile culture and wound infection rates were also lower in the piperacillin group, though this did not reach statistical significance. Anaerobic bacteria (three patients) and Streptococcus faecalis (one patient) were isolated in the tobramycin group. Overall postoperative infection rate was similar in patients with risk factors for infection and in those without. In conclusion, piperacillin did not significantly improve bile and wound infection rates compared to tobramycin. However piperacillin showed a more appropriate spectrum of activity. Antibiotic prophylaxis is suggested for all patients undergoing biliary surgery.

A prospective evaluation of optimal sampling theory in the determination of the steady-state pharmacokinetics of piperacillin in febrile neutropenic cancer patients.

We examined the use of optimal sampling theory in the determination of the pharmacokinetics of piperacillin in febrile, neutropenic cancer patients. Patients were studied prospectively as part of a randomized, double-blind clinical trial of piperacillin and amikacin versus imipenem and placebo. The results from the analysis of 5 optimal samples were compared with those derived from 15 concentration determinations (10 samples, with the 5 optimal samples assayed in duplicate). The use of a standard least-squares estimator as opposed to a bayesian estimator, with normal prior distributions placed on beta and serum clearance, was also examined. Finally, the use of duplicate determinations in improving the precision of parameter estimation was studied. Plasma concentrations obtained at time points determined by optimal sampling theory, when analyzed with a bayesian estimator, produced estimates of pharmacokinetic parameter values that were in good agreement with those derived from the 15-determination set. Duplicate assay did not improve the precision of parameter estimation. Estimation of plasma clearance was quite robust, irrespective of the estimator used, probably because this evaluation was performed at steady state. Optimal sampling theory is a promising technique that can be employed to determine patient-specific estimates of pharmacokinetic parameter values in target populations.

Penetration of clindamycin, cefoxitin, and piperacillin into pancreatic juice in man.

In our segmental pancreatic transplantation technique the pancreatic juice is temporarily diverted to the exterior via a pancreatic duct catheter. This permits studies on pure pancreatic juice to be carried out. In 11 such patients we studied the penetration of clindamycin, cefoxitin, and piperacillin into pancreatic juice. These three antibiotics all have good effect against the bacteria commonly isolated during pancreatic infections. Simultaneous blood and pancreatic juice samples were collected immediately before drug administration and at 30, 60, 90, and 120 minutes and 3, 4, 5, 6, and 8 hours after administration. The concentration of clindamycin in pancreatic juice was 34% of that in serum and exceeded the minimum inhibitory concentration for most bacteria associated with pancreatic infections. In spite of adequate serum concentrations of cefoxitin and piperacillin, the concentrations in pancreatic juice were only 8% and 5%, respectively, and did not exceed the minimum inhibitory concentration for the relevant bacteria. In view of these findings, clindamycin seems to be preferable in the treatment of pancreatic infections.

Comparison of piperacillin vs. ticarcillin plus tobramycin in the treatment of acute pulmonary exacerbations of cystic fibrosis.

During a 22-month period 35 children with cystic fibrosis received 52 courses of antibiotic therapy for acute pulmonary exacerbations, including 26 cases of therapy with piperacillin and 26 courses with ticarcillin plus tobramycin. Groups were similar in age (5 vs. 5.4 years), disease severity based on Schwachman scores and presenting symptoms. Pseudomonas aeruginosa was the most common organism isolated in 90% of sputum cultures. Mean minimal inhibitory concentrations for piperacillin, ticarcillin and tobramycin were 8, 64 and 1 microgram/ml, respectively. Piperacillin pharmacokinetic data revealed an average half-life in serum of 36 minutes. Peak serum concentrations averaged 144 micrograms/ml, and after 4 hours serum concentrations continued to exceed the P. aeruginosa 90% minimal inhibitory concentration in 50% of children. The dosage requirement for tobramycin was quite variable, necessitated monitoring of aminoglycoside serum concentrations and in most cases resulted in at least one dosage adjustment. Emergence of resistant bacteria was not seen in 26 courses of piperacillin therapy. Both regimens were effective and well-tolerated. Single agent therapy has the advantage of providing reliable serum concentrations and, in contrast to the standard therapy, does not necessitate monitoring of serum drug concentrations.