The pharmacokinetics of etanercept in healthy volunteers

OBJECTIVE: To describe the pharmacokinetics of etanercept when administered by subcutaneous injection in single doses to healthy volunteers. METHODS: Twenty-six healthy volunteers between 19 and 50 years of age received single doses of etanercept 25 mg by subcutaneous injection into the abdomen. Serial serum samples were collected for 21 days. An enzyme-linked immunosorbent assay with a quantitation limit of 0.3 ng/mL was used to measure the drug concentrations. RESULTS: Etanercept was well tolerated by healthy volunteers. A one-compartment model was found to best describe the concentration-time data and was used to determine the pharmacokinetic parameters. Etanercept is slowly absorbed from the site of injection with a time of peak concentration (+/- SD) of 51 +/- 14 hours; peak concentration was 1.46 +/- 0.72 mg/L. The AUC was 235 +/-98 mg x h/L, apparent clearance was 132 +/- 85 mL/h, apparent volume of distribution was 12 +/- 6 L, and the half-life was 68 +/- 19 hours. CONCLUSIONS: Etanercept was slowly absorbed and slowly eliminated after subcutaneous administration. Dosing at the recommended rate of 25 mg twice weekly would be expected to result in concentrations of approximately 3 mg/L. Intersubject variability for apparent clearance in healthy volunteers was 64%.     

Surveillance of patients at high risk for colorectal cancer

Colorectal cancer (CRC) mortality may be greatly reduced by clinically feasible screening programs. The benefits of surveillance of high-risk programs are evident. Cancer mortality can be dramatically reduced by eradication of precursor lesions and by detection of cancer at an early and highly curable stage. Available screening methods, recommended intervals, and screening for other associated cancers are reviewed for specific high-risk groups.     

Multiple-dose pharmacokinetics of ceftibuten in healthy volunteers.

The pharmacokinetics of ceftibuten, a new cephalosporin antibiotic, and its conversion product, ceftibutentrans, were studied in healthy male volunteers following daily oral administration of a 400-mg capsule for 7 days. Mean concentrations of ceftibuten in plasma obtained on day 5 were similar to those obtained on day 7. Analysis of variance indicated that the concentrations in plasma on days 5 and 7 were at steady state. The mean accumulation factor was 1.14 for day 5 and 1.13 for day 7. The half-life (2.4 h) was independent of the duration of drug administration, and the mean maximum concentration of drug in plasma was 18 to 19 micrograms/ml. Urinary excretion was the major elimination route for ceftibuten, by which 57 to 59% of the drug was excreted unchanged over a 24-h period. The amounts of ceftibuten-trans in plasma and urine were low.     

Bioavailability and pharmacokinetics of ofloxacin in healthy volunteers.

The pharmacokinetics and bioavailability of ofloxacin in 20 healthy male volunteers were studied in an open-label, randomized, two-way crossover study. Ofloxacin (400 mg) was administered either as a 1-h infusion or as an oral tablet. The mean peak concentration after intravenous infusion was 4.30 +/- 0.69 microgram/ml, and that after oral administration was 3.14 +/- 0.53 microgram/ml, occurring 1.74 +/- 0.57 h after dosing. The bioavailability (F) of the oral dosage form of ofloxacin was virtually identical to that of the intravenous form (F = 105% +/- 7%). This complete bioavailability of ofloxacin is supportive of the use of the oral dosage form for the treatment of infections in hospitalized patients either as a replacement for intravenous ofloxacin therapy or in streamlining therapy from the intravenous to the oral route.     

Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers

OBJECTIVE: To investigate the effect of multiple-dose paroxetine intake on the stereoselective pharmacokinetics and the pharmacodynamics of metoprolol. METHODS: We conducted an open trial with two sessions in eight healthy male volunteers. Racemic metoprolol (100 mg single oral dose) was administered before and after paroxetine treatment (20 mg/day for 6 days). The (R)- and (S)-metoprolol pharmacokinetics, metoprolol metabolic ratio (MR), exercise heart rate and blood pressure were assessed for 12 (pharmacodynamic data) to 24 (pharmacokinetic data) hours after each metoprolol intake. RESULTS: Paroxetine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC) of (R)- and (S)-metoprolol significantly (169 to 1,340 ng x h/mL [P < .001] and 279 to 1,418 ng x h/mL [P < .001], respectively), with an approximately twofold increase in both maximum plasma concentration and terminal elimination half-life. Furthermore, the (S)/(R) AUC ratio was significantly decreased, from 1.72 to 1.07 (P < .001). The mean metoprolol MR was significantly increased, from 0.17 to 5.69 (P < .05). The AUC of the metoprolol-induced decrease in exercise heart rate versus time curve was increased, with 46% (P < .01) after multiple-dose paroxetine intake, reaching significance from 6 hours after metoprolol intake, illustrating a more sustained beta-blockade. Similar results were obtained for the effect on exercise systolic blood pressure. Multiple-dose metoprolol administration combined with paroxetine can lead to an accumulation of the beta-blocking (S)-enantiomer of metoprolol, possibly resulting in unacceptable bradycardia, loss of cardioselectivity, or both. CONCLUSION: Multiple-dose paroxetine intake affects both metoprolol pharmacokinetics and pharmacodynamics and suggests that when paroxetine is added to an ongoing metoprolol therapy, caution is warranted and a reduction of the metoprolol dose may be required to prevent undesired adverse effects.     

Multiple-dose pharmacokinetics of amdinocillin in healthy volunteers.

The pharmacokinetics of amdinocillin (mecillinam) after multiple intravenous doses to healthy subjects are described. Assay of plasma and urine samples was carried out with a sensitive and specific high-pressure liquid chromatographic technique. A dose of 10 mg/kg of body weight was administered every 4 h for six doses. No accumulation was noted. Mean peak plasma concentrations were approximately 50 micrograms/ml, and the plasma half-life was approximately 53 min. Total plasma clearance was 4.6 ml/min per kg after the first dose, which declined slightly to 4.1 ml/min per kg after the last dose. Renal clearance remained fairly constant at approximately 2.9 ml/min per kg, or twice the creatinine clearance. The fraction excreted unchanged totaled 63% during the 4-h interval after the first dose and was nearly 70% overall. The steady-state volume of distribution was calculated to be 0.26 liter/kg. Urinary concentrations of amdinocillin were far in excess of the usual inhibitory concentrations for susceptible pathogens and were as high as 3,000 micrograms/ml. Dose of amdinocillin every 4 h provide plasma and urine concentrations which should be effective for the treatment of infections.     

Comparable population pharmacokinetics and pharmacodynamic breakpoints of cefpirome in cystic fibrosis patients and healthy volunteers

Cystic fibrosis (CF) patients are often reported to have higher clearances and larger volumes of distribution per kilogram of total body weight (WT) for beta-lactams than healthy volunteers. As pharmacokinetic (PK) data on cefpirome from studies of CF patients are lacking, we systematically compared its population PK and pharmacodynamic breakpoints for CF patients and healthy volunteers of similar body size. Twelve adult CF patients (median lean body mass [LBM] = 45.7 kg) and 12 healthy volunteers (LBM = 50.0 kg) received a single 10-min intravenous infusion of 2 g cefpirome. Plasma and urine concentrations were determined by high-performance liquid chromatography (HPLC). Population PK and Monte Carlo simulations were performed using NONMEM and S-ADAPT and a duration of an unbound plasma concentration above the MIC ≥ 65% of the dosing interval as a pharmacodynamic target. Unscaled clearances for CF patients were similar to those seen with healthy volunteers, and the volume of distribution was 6% lower for CF patients. Linear scaling of total clearance by WT resulted in clearance that was 20% higher (P ≤ 0.001 [nonparametric bootstrap]) in CF patients. Allometric scaling by LBM explained the differences between the two subject groups with respect to average clearance and volume of distribution and reduced the unexplained between-subject variability of renal and nonrenal clearance by 10 to 14%. For the CF patients, robust (>90%) probabilities of target attainment (PTA) were achieved by the administration of a standard dose of 2 g/70 kg WT every 12 h (Q12h) given as 30-min infusions for MICs ≤ 1.5 mg/liter. As alternative dosage regimens, a 5-h infusion of 1.33 g/70 kg WT Q8h achieved robust PTAs for MICs ≤ 8 to 12 mg/liter and a continuous infusion of 4 g/day for MICs ≤ 12 mg/liter. Prolonged infusion of cefpirome is expected to be superior to short-term infusions for MICs between 2 and 12 mg/liter.     

Photodynamic diagnosis using 5-aminolevulinic acid (5-ALA) for minimally-invasive treatment of cancer

Summary

Preclinical and clinical studies on 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PPIX) are currently being performed at various departments, following promising clinical results for the detection of bladder cancer in urology. This paper provides an overview on the progress of 5-ALA assisted fluorescence diagnosis in urology, pulmonology, neurosurgery, gynaecology and ENT, coordinated by the Laser Research Laboratory of the Ludwig-Maximilians-University in Munich. 5-ALA can be applied either topically or systemically to induce an intracellular accumulation of fluorescing PPIX. With appropriate dosage of 5-ALA, malignant tissue can be stained selectively, and irradiation with violet light excites a bright red fluorescence of the tumour, visible to the naked eye. Optical properties of the tissue tend to hamper the precise identification and demarcation of suspect areas in fluorescence images. Multicolour remission and fluorescence imaging, therefore, should improve tumour localisation in future.     

Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers

OBJECTIVE: To determine whether there are gender-specific differences in the pharmacokinetics and pharmacodynamics of metoprolol enantiomers. METHODS: Twenty normal volunteers (10 men and 10 women) received 100 mg oral metoprolol tartrate twice daily for a total of nine doses. Pharmacokinetics and pharmacodynamics were studied after the last dose. Subjects also completed a control pharmacodynamic study; the order of drug and control studies was randomized. Measurements of heart rate and systolic blood pressure were obtained during peak submaximal bicycle exercise testing. (R)-Metoprolol and (S)-metoprolol concentrations were determined by stereospecific HPLC. The percentage difference in exercise heart rate and systolic blood pressure (metoprolol versus control), and (R)- and (S)-metoprolol plasma concentrations were comodeled. RESULTS: Men and women showed stereoselective pharmacokinetics; (S)-metoprolol concentrations were significantly greater than those for (R)-metoprolol for both groups. Women had greater drug exposure than men (higher maximum concentration and area under the plasma concentration-time curve). No differences were observed between genders with respect to elimination half-life. Females had a greater reduction in exercise heart rate and systolic blood pressure; however, the area under the effect curve was significantly greater for heart rate only. Pharmacodynamic data were best fitted by the Hill equation with the effect site in the central compartment. The fitted maximum effect and the concentration at one-half of the maximum effect for heart rate and systolic blood pressure did not differ between men and women (P > .20). CONCLUSIONS: Gender-related differences exist in the pharmacokinetics of metoprolol enantiomers, resulting in greater drug exposure in female subjects. However, concentration-effect relationships did not differ between men and women. Therefore the observed differences in drug effects were the result of gender-specific differences in metoprolol pharmacokinetics.     

Comparison of the pharmacokinetics and pharmacodynamic profile of carumonam in cystic fibrosis patients and healthy volunteers

Our objectives were to compare the pharmacokinetics (PK) of carumonam, a monobactam, between cystic fibrosis (CF) patients and healthy volunteers and assess its pharmacodynamic profile. We studied 10 adult CF patients and 18 healthy volunteers of similar body size (dose: 2.166 g of carumonam as 15-min intravenous infusion). High performance liquid chromatography with ultraviolet detection (HPLC-UV) was used for drug analysis and NONMEM® (ICON, Ellicot City, MD) for population PK and Monte Carlo simulation with targets between ≥20% and 100% free time above MIC (fT > MIC). Unscaled renal clearance was 24% higher in CF patients. Lean body mass and creatinine clearance explained the difference in average clearance and volume of distribution between both subject groups. For a daily dose of 6 g per 70 kg of total body weight, 15-min infusions q8h achieved robust (>90%) probabilities of target attainment (PTAs) (target, 60% fT > MIC) for MICs ≤3 mg/L in CF patients and ≤6 mg/L in healthy volunteers. At the same dose, 4-h infusions q8h achieved robust PTAs up to markedly higher MICs ≤8 to 12 mg/L in CF patients and ≤16 mg/L in healthy volunteers.     

Comparative study of bioavailabilities and pharmacokinetics of clindamycin in healthy volunteers and patients with AIDS.

The absolute oral bioavailability and pharmacokinetics of clindamycin administered to 16 healthy volunteers and 16 patients with AIDS were compared. Clindamycin was given intravenously (i.v.) (Cleocin phosphate) at a dose of 600 mg as a 25-min infusion and orally (Cleocin hydrochloride) by use of a crossover design in both study groups. Plasma samples were analyzed by gas-liquid chromatography. Plasma drug clearance and volume of distribution at the steady state following the i.v. dose differed between study groups. The clearances were 0.27 +/- 0.06 liter/h/kg in healthy volunteers and 0.21 +/- 0.06 liter/h/kg in AIDS patients (P = 0.014; Mann-Whitney U test); the volumes of distribution at the steady state were 0.79 +/- 0.13 and 0.66 +/- 0.12 liter/kg in healthy volunteers and AIDS patients, respectively (P = 0.005). The elimination half-life did not differ between the two groups. The bioavailability of clindamycin capsules in AIDS patients was approximately 1.5 times that in healthy volunteers (0.53 +/- 0.14 versus 0.75 +/- 0.20; P = 0.002). Peak concentrations following the oral dose were higher in AIDS patients as well (7.7 +/- 2.5 versus 5.3 +/- 1.0 mg/liter; P = 0.0008). Three AIDS patients experienced severe diarrhea following the oral dose; four patients had mild diarrhea following the i.v. dose. No adverse effects were reported by the healthy volunteers. The pharmacokinetic parameters observed in this study for AIDS patients may be useful for the consideration of clindamycin dosage regimens in patients treated for toxoplasmic encephalitis. These findings suggest that the effect of AIDS on drug disposition deserves further investigation, particularly for orally administered drugs.     

汉防己甲素片在健康人体内的药代动力学研究

目的建立测定人血浆中汉防己甲素浓度的高效液相色谱法。方法色谱柱:Kromasil C18(250 mm×4.6 mm,5μ.m);流动相:甲醇-乙腈-水-冰醋酸(体积比为30:15:55:0.8)(pH 6.2);检测波长:282 nm;汉防己乙素作为内标,用HPLC法测定人血浆中汉防己甲素浓度。结果汉防己甲素线性范围为0.5～14.0μg/mL,回归方程Y=0.007 6X-0.01875(r=0.9998);回收率>80%,日内和日间RSD均<10%。结论本方法简便、快速、准确,适用于汉防己甲素药代动力学研究及血药浓度监测。     

Multiple-dose pharmacokinetics and safety of oral amifloxacin in healthy volunteers.

The multiple-dose pharmacokinetics and safety of amifloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy male volunteers. Amifloxacin was administered orally at 200, 400, or 600 mg every 12 h (q12h) and 400, 600, or 800 mg every 8 h (q8h) for 10 days. An additional dose was administered on day 11. Concentrations of amifloxacin in plasma and urine were measured on days 1, 5, and 11 by high-performance liquid chromatography. Steady-state amifloxacin concentrations were reached by day 5. Mean +/- standard deviation maximum observed amifloxacin concentrations in plasma were 2.52 +/- 1.12, 4.98 +/- 1.44, 5.40 +/- 2.02, 4.59 +/- 2.17, 6.53 +/- 2.44, and 8.01 +/- 3.00 micrograms/ml after the initial dose and 2.30 +/- 0.98, 5.41 +/- 0.74, 8.05 +/- 1.68, 6.87 +/- 2.81, 9.53 +/- 0.50, and 11.9 +/- 1.92 micrograms/ml on day 11 of the study for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. Amifloxacin was rapidly absorbed, as evidenced by the mean time to the maximum observed amifloxacin concentration of 0.98 h. Mean values for the terminal amifloxacin half-life in plasma ranged from 3.58 to 5.78 h. Mean amifloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 micrograms/ml for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. The mean amount of the dose excreted in the urine as amifloxacin was 53.9%. Amifloxacin was generally well tolerated, although there was a tendency for the subjects who received amifloxacin to experience more gastrointestinal, central nervous system, and cutaneous complaints than did those who received placebo. Clinically significant adverse reactions, including pruritus and transaminase elevations, occurred only at doses of 1,200 mg/day or above. Clinical and pharmacokinetic data suggest that orally administered amifloxacin may have utility in the treatment of urinary tract infections.     

癌症志愿者参与晚期癌症患者安宁疗护的效果研究

目的 组织康复期癌症志愿者参加晚期癌症患者安宁疗护,改善入住安宁疗护示范病房的晚期癌症患者的优质死亡结局。方法 采用随机数字表法将入住安宁疗护示范病房的69例晚期癌症患者随机分成试验组和对照组,康复期癌症志愿者参与试验组的安宁疗护活动,活动内容包括读国学经典、满足1个心愿、心灵的声音主题活动、节日家文化等。两组都由医务工作者组成的安宁疗护小组给予病情评估、安宁疗护计划、中医症状管理、灵性照护之关爱时间等干预措施。采用肿瘤患者生活质量综合评价量表、灵性安适量表和综合性医院焦虑抑郁量表评价两组的生活质量、灵性安适程度和焦虑抑郁情绪。结果 试验组在生活质量的社会/家庭状况维度、灵性安适程度和焦虑抑郁情绪方面都优于对照组,差异均有统计学意义（均P<0.05）;而试验组生活质量的身体状况、情感状况、功能状况3个维度和生活质量总分与对照组比较,差异无统计学意义（均P>0.05）。与干预前比较,干预后两组生活质量、灵性安适程度、焦虑抑郁情绪差异均有统计学意义（均P<0.05）。结论 相比于完全由医务工作者组成的安宁疗护小组,有康复期癌症志愿者参与的安宁疗护活动,能更好地改善晚期癌症患者的优质死亡结局。     

5-氨基酮戊酸光动力疗法治疗痤疮的护理

痤疮是皮肤科就诊率较高的疾病之一,大约80％～909／6的青少年患过痤疮,而痤疮是一种常见的多发于青春期的慢性毛囊及皮脂腺炎症,临床上主要是以粉刺、丘疹、脓疱、结节、囊肿、瘢痕等形态表现。此病由多种因素造成,如痤疮丙酸杆菌过度增殖,皮脂分泌过多,毛囊上皮角化改变等。轻度痤疮患者皮损较易治疗,顽固性的中、     

Clinical pharmacokinetics of aztreonam in cancer patients.

The pharmacokinetics of aztreonam were studied in 25 adult patients with hematological malignancies. Two groups of nine patients each received aztreonam (1 or 2 g every 8 h) prophylactically, and seven infected patients received a therapeutic regimen of aztreonam (1.5 g every 4 h). The mean peak serum concentration after a 1-g dose of aztreonam (given over 0.5 h on day 1) was 75.5 micrograms/ml; after a 2-g dose it was 177.2 micrograms/ml. The mean peak serum concentration after a 1.5-g dose of aztreonam (given over 2 h on day 1) was 68.5 micrograms/ml. The serum half-life ranged between 1.7 and 2.0 h for all regimens studied. The urinary concentration of the metabolite of aztreonam, SQ 26,992, increased during 1 week of administration of the drug; however, serum levels of the metabolite were barely detectable.     

Dose-dependent pharmacokinetics of delavirdine in combination with amprenavir in healthy volunteers

OBJECTIVES: To investigate different dose combinations of amprenavir and delavirdine in order to assess an optimal dose suitable for clinical use. METHODS: This was a prospective, open-label, controlled, three-period, multiple-dose study with nine healthy volunteers. The volunteers received three different dose combinations of amprenavir and delavirdine twice a day for 10 days with a subsequent 12 h pharmacokinetic evaluation. Combination 1: amprenavir 600 mg and delavirdine 600 mg; combination 2: amprenavir 600 mg and delavirdine 800 mg; combination 3: amprenavir 450 mg and delavirdine 1000 mg. The combinations were taken at least 2 weeks apart. RESULTS: Differences in median delavirdine Cmax, C12 and AUC0-12 were seen when comparing the three combinations (3 > 2>1) (P<0.04). A considerable and clinically important higher median C12 was seen with combination 3 when compared to combination 1 (835 to 3944 ng/mL) (P=0.0039). Only small differences in the amprenavir pharmacokinetic parameters were seen between the three dose combinations, with a median C12 of 412, 434 and 536 ng/mL, respectively. CONCLUSIONS: In this study, an increase of 472% in median delavirdine C12 was seen with a delavirdine dose increase of only 67% (600 to 1000 mg). Saturation of the CYP3A4 enzymes and/or possibly also P-glycoprotein could be involved. Combination 3 was considered most suitable for clinical use, but because of the large inter-individual variation in steady-state concentrations, the use of the combination should be supported by therapeutic drug monitoring and restricted to certain patients.     

Single- and multiple-dose pharmacokinetics of linezolid and co-amoxiclav in healthy human volunteers

In an open, randomized, two-period crossover study the pharmacokinetics of linezolid and co-amoxiclav were investigated after single- and multiple-dose administration in 12 healthy volunteers (six females and six males). Linezolid was given in tablets of 600 mg twice a day for 7 days and co-amoxiclav in tablets of 1000 mg (875 + 125 mg) once a day for 7 days. The wash-out period was 4 weeks between the administration of the two antibacterial agents. Blood and urine samples were collected on days 1 and 7 before and at different time points up to 24 h after medication. The concentrations of the antibiotics in serum and urine were measured by validated high-performance liquid chromatography methods. Linezolid exhibited a mean C(max) of 14.5 +/- 4.6 mg/L after T(max) of 47.5 +/- 20.1 min on day 1, with a significant increase to 24.0 +/- 6.9 mg/L on day 7 (P < 0.01). The AUD(tot) (total area under the data) revealed a significant increase from 140.5 +/- 28.3 mg.h/L on day 1 to 220.2 +/- 42.6 mg.h/L on day 7 (P < 0.01). There were no significant differences in terminal elimination half-life between days 1 and 7 (9.53 +/- 2.87 versus 7.97 +/- 3.08 h) or in total clearance (71.6 +/- 17.6 versus 81.5 +/- 14.7 ml/min.1.73 m(2)). Results are in agreement with the assumption of a limited accumulation of linezolid under the dosage regimen given. Serum linezolid concentrations in females were always higher than those in males. The volume of distribution V(ss)/f differed significantly between females and males (41.6 +/- 4.2 versus 52.2 +/- 3.3 L/70 kg; P < 0.01). Pharmacokinetic parameters of amoxicillin and clavulanic acid found in this study were similar to previously published data. No accumulation was found with co-amoxiclav. No serious adverse event was observed with the study drugs.     

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.