Randomized comparison of serum teicoplanin concentrations following daily or alternate daily dosing in healthy adults

Trough serum teicoplanin concentrations were compared in healthy adults following intravenous administration of one of two regimens: (i) 12 mg/kg of body weight every 12 h for 3 doses and then 15 mg/kg every 48 h for 4 doses (n = 16 subjects) or (ii) 6 mg/kg every 12 h for 2 doses and then 6 mg/kg every 24 h for 9 doses (n = 8 subjects). The mean +/- standard deviation trough concentrations in serum on day 11 (24 and 48 h after administration of the last dose for the daily and alternate-day dosing schedules, respectively) were 16.0 +/- 2.1 and 17.9 +/- 3.5 mg/liter for subjects receiving the two regimens, respectively, by a fluorescence polarization immunoassay. The limits of the 95% confidence interval of the difference (-0.2, 3.6 mg/liter) determined by a nonparametric test were situated above the -1.3-mg/liter maximum set difference and indicated a noninferiority of the alternate-day dosing to the daily dosing. Throughout the study the individual trough concentrations in serum in the alternate-day dosing group constantly exceeded 10 mg/liter, the presently recommended target concentration for the treatment of severe infections. The trough concentrations in the sera of all subjects were bactericidal for six Staphylococcus aureus strains for which teicoplanin MICs are between 0.5 and 4 mg/liter. The bactericidal activity of serum was related to total teicoplanin (protein bound and unbound). In conclusion, an alternate-day dosing schedule (15 mg/kg on alternate days following administration of a 12-mg/kg loading dose three times every 12 h) could be considered for further efficacy and safety studies.     

Pharmacokinetic studies of linezolid and teicoplanin in the critically ill

OBJECTIVES: To determine the pharmacokinetic characteristics of linezolid and teicoplanin in critically ill patients. PATIENTS AND METHODS: Serum was collected frequently during day 0 and then pre- and 1 h post-dose on days 1, 2, 3, 5, 7 and every third day thereafter during treatment. Serum linezolid concentrations were analysed using HPLC. Serum teicoplanin levels were analysed by fluorescence polarization immunoassay. RESULTS: A two-compartment model was required to characterize linezolid pharmacokinetics (n=28) and account for the accumulation seen after multiple dosing. The estimated clearance was 0.049 +/-0.016 L/h/kg (+/-s.e.m. of estimate). At steady state (dosing interval 12 h), linezolid serum concentrations exceeded the breakpoint of 4 mg/L for 10.88 h (95% CI 10.09-11.66) after a 600 mg dose with an AUC/MIC of 92.4 (95% CI 57.2-127.7). Teicoplanin was best described by a two-compartment model (n=26). The clearance was 4.97+/-1.58 L/h. Serum levels exceeded the breakpoint of 4 mg/L for the entire dosing interval in all subjects (400 mg dose every 12 h) with an AUC/MIC of 399.3 (95% CI 329.6-469.0). However, only four of 14 exceeded trough serum concentrations of 10 mg/L. For both agents, trough levels were similar in those who survived and those who died. CONCLUSIONS: Linezolid dosage at 600 mg every 12 h was adequate in the critically ill without need for adjustment for renal function. For teicoplanin, further study is needed to confirm if a trough of 10 mg/L is associated with a higher rate of cure than 5 mg/L. If so, serum drug assays would be needed to ensure a therapeutic level.     

Human pharmacokinetics and distribution in various tissues of ceftriaxone

Multiple-dose pharmacokinetics of ceftriaxone were investigated in 7 patients with bronchopneumonia using an intramuscular regimen of 1 g given every 24 h for 7 days. Serum, sputum, and urine samples were collected serially following the first dose (day 1) and last dose (day 7). Mean peak serum concentrations of ceftriaxone occurred at 2 h on both days and were 67.8 and 75.1 micrograms/ml, respectively, on day 1 and day 7. Ceftriaxone had a half-life of 6.9 h on day 1 and 7.4 h on day 7. The half-life of ceftriaxone in sputum was 5.9 and 6.6 h, respectively, on days 1 and 7. Approximately 50% of the dose of ceftriaxone was recovered in the urine within 24 h on day 1, 60% on day 7. Tissue distribution of ceftriaxone was determined in 103 patients following intramuscular administration of a single 1-gram dose at different times up to 24 h prior to surgery. High concentrations of ceftriaxone were found in lung, tonsil, middle ear mucosa, and nasal mucosa, and therapeutic levels of ceftriaxone persisted for 24 h after administration.     

Clinical Pharmacology of Ceftriaxone in Patients with Neoplastic Disease

Pharmacological studies of ceftriaxone, a new semisynthetic cephalosporin, were conducted in 35 cancer patients. This antibiotic was administered in a variety of doses and schedules with no observed toxicity. Intramuscular administration of 500 mg of ceftriaxone to seven patients produced mean peak serum concentrations of 32.9 μg/ml 2.0 h after administration. The terminal serum half-life was 10.9 h. Intravenous infusion of 500 mg of ceftriaxone over 5 min to the same group of seven patients produced a mean peak concentration of the drug in serum of 83 μg/ml at the end of administration which decreased to 16.8 μg/ml at 8 h. A dose of 1 g of ceftriaxone given in identical fashion to the same group of seven patients produced mean peak concentrations in serum of 130 μg/ml at the end of administration and 17.3 μg/ml at 12 h. The mean percentages of drug recovered in urine 12 h after single intravenous doses of 500 mg and 1 g were 30 and 20%, respectively. A 1-g dose of ceftriaxone was administered every 8 h to 10 patients, and a 2-g dose was administered every 12 hours to 9 patients. Drug concentrations in serum were measured for each patient after drug administration on day 1, day 3 or 4, and day 7 or 8. The 1-g dose produced an observed mean peak concentration of 154 μg/ml and a mean terminal-phase half-life of 5.6 h on day 3 or 4. The 2-g dose produced a mean peak concentration in serum of 262 μg/ml and a terminal-phase serum half-life of 6.3 h on day 3 or 4. Continuous infusion studies were performed in nine neutropenic patients for up to 8 days by using a loading dose of 1 g over 30 min, followed by 2 g every 8 h. Mean concentrations in serum were maintained at about 135 μg/ml during the infusion period.     

Pharmacokinetics of teicoplanin upon multiple-dose intravenous administration of 3, 12, and 30 milligrams per kilogram of body weight to healthy male volunteers.

Teicoplanin pharmacokinetics were evaluated after multiple-dose intravenous administration to healthy male volunteers by using a randomized, double-blind, parallel design. Doses of 3, 12, or 30 mg of teicoplanin per kg of body weight were administered every 24 h for 14 days as 60-min constant-rate intravenous infusions. Blood and urine samples were collected over 21 days and analyzed by a microbiological assay. Twenty-three subjects were included in the pharmacokinetic analysis. The median pharmacokinetic parameters upon multiple-dose intravenous administration of 3, 12, and 30 mg/kg included steady-state volumes of distribution of 0.94, 0.77, and 0.68 liter/kg; total clearances of 11.9, 12.0, and 13.2 ml/h/kg; and terminal disposition half-lives of 143, 166, and 96 h, respectively. Renal clearance accounted for approximately 95% of total clearance. No dose-related differences existed for teicoplanin total or renal clearance. The steady-state volume of distribution decreased significantly with increasing doses. As a result of the decrease in the volume of distribution, the terminal disposition half-life at 30 mg/kg was significantly decreased. However, the decreases in the volume of distribution and terminal disposition half-life are of limited clinical importance, since steady-state trough concentrations in serum increase in proportion to dose. Combined results of all multiple-dose studies with similar durations of sample collection indicate no dose-related differences for any pharmacokinetic parameters from 3 to 12 mg/kg. As observed in the present study, no dose-related differences exist for teicoplanin total and renal clearances from 3 to 30 mg/kg. However, at 30 mg/kg, a significant decrease in the steady-state volume of distribution is observed. As a consequence of the reduction in the volume of distribution at 30 mg/kg with no change in clearance, the terminal disposition half-life is decreased.     

Multiple-dose pharmacokinetics and toleration of intravenously administered cefoperazone and sulbactam when given as single agents or in combination.

The multiple-dose pharmacokinetics and toleration of cefoperazone (3 g every 12 h) and sulbactam (1.5 g every 12 h) were studied when these antimicrobial agents were administered continuously over 7 days as a 15-min infusion of individual agents and as a 3/1.5-g cefoperazone-sulbactam combination. Fourteen male volunteers participated in an open, three-way crossover study of Latin Square design with a 1-week washout period between phases. On days 1 and 7 of each phase, serial serum samples and urine were collected for drug assay over a 12-h period. Hematological and clinical chemistry determinations were made within 10 days before the first antibiotic dose and for each treatment phase just before the first dose, on day 4 of treatment, and within 24 h of the last dose. For cefoperazone as a single agent on days 1 and 7, the average maximal concentration in serum (Cmax) was approximately 430 micrograms/ml, the terminal elimination half-life (t1/2) was 1.8 h, and the average percentage of dose excreted unchanged in the urine (%Ur) was 30%. For sulbactam as a single agent, the Cmax was approximately 90 micrograms/ml, the t1/2 was 1 h, and the %Ur was 89% on days 1 and 7. When comparing individual versus simultaneous drug administration, the only pharmacokinetic alteration observed was a statistically significant but minor (about 10%) decrease in sulbactam renal clearance, on both days 1 and 7, resulting in a similar decrease in total body clearance (CL). The area under the curve, apparent volume of distribution by the area method (V), t1/2, and Cmax were not significantly altered. Although cefoperazone pharmacokinetic parameters were not significantly altered when comparing single-agent to combination drug administration, the area under the curve was slightly lower and CL, nonrenal clearance, and V were modestly higher from day 1 to day 7. Because Cmax and t1/2 were unaffected, these minor day effects would not be of clinical significance. Intravenous administration of cefoperazone and sulbactam given as individual agents compared with the combination did not show pharmacokinetic differences that are likely to produce clinically relevant effects. The combination of cefoperazone and sulbactam was well tolerated, and the safety profile of the combination was similar to that either drug given alone under the conditions of this study.     

Pharmacokinetics of teicoplanin in pediatric patients.

The pharmacokinetics of teicoplanin have been studied in 13 pediatric male patients from 2 to 12 years of age. Patients were given a single 3-mg/kg intravenous dose of teicoplanin for prophylaxis. Blood and urine samples were collected for 8 days after administration, and teicoplanin levels were determined by microbiological assay. Pharmacokinetic parameters were estimated from a three-compartment open pharmacokinetic model and from a noncompartmental analysis. Levels in plasma 1 h after the administration averaged 14.8 mg/liter. The half-lives of the two distribution phases were 1.3 and 9.7 h. The half-life of the terminal phase averaged 57.9 h, with similar estimates obtained from the noncompartmental analysis and from data from urine. The volume of distribution of the central compartment was 0.15 liter/kg, whereas the volume of distribution at steady state and during the elimination phase were 0.80 and 1.25 liters/kg. The total teicoplanin clearance averaged 14.8 ml/h per kg, with renal clearance accounting for about 60% of the total. The average cumulative recovery of teicoplanin in urine over 8 days was 59% of the dose, similar to the value obtained in adult volunteers. There was no significant linear correlation between elimination half-life and age. Preliminary data after repeated administration support the reliability of the model used and the validity of the mean estimated parameters. There were no local or systemic adverse reactions to teicoplanin.     

Pharmacokinetics of ponsinomycine with repeated ingestion in healthy volunteers

Ponsinomycin or miocamycin (MOM) is a new macrolide which is totally metabolized in vivo. The disposition of its 3 major metabolites (Mb12, Mb6 and Mb9a), was investigated following multiple dosing with ponsinomycin at a dose of 800 mg every 12 h, for 8 days, in healthy volunteers. Drug measurements were conducted by high performance liquid chromatography. In agreement with the low values of their apparent elimination half-lives, respectively less than 1.5 h and 3.0 h, metabolites Mb12 and Mb9a did not accumulate with time. Their pharmacokinetics was apparently stable with time. Conversely Mb6 did accumulate, by approximatively a factor 2, although its apparent elimination half-life was only close to 2 h. This value must therefore be considered with caution. A dose dependency effect was previously observed, Mb6 pharmacokinetics could be non linear with time as well. The relative importance of this metabolite is therefore greater at steady-state, following multiple administration than after single dosing with ponsinomycin.     

Recommended initial loading dose of teicoplanin, established by therapeutic drug monitoring, and outcome in terms of optimal trough level

Teicoplanin has a long serum half-life, and therefore it takes time to reach a steady-state concentration. An initial loading procedure has been recommended for teicoplanin to enable prompt reaching of the optimal serum trough level (10–15 μg/ml). However, the dose of teicoplanin that should be administered to patients with varying renal function levels remains inconclusive. In this study, we monitored the serum concentrations of teicoplanin in patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia and compared different teicoplanin serum concentrations and their clinical efficacy, investigating the significance of the mean dose administered during the initial 3 days. The study included 48 patients with MRSA pneumonia. The peak and trough concentrations of teicoplanin were determined utilizing a fluorescence polarization immunoassay and a two-compartment Bayesian population model. Teicoplanin was given at a loading dose of 400 or 800 mg on the first day, followed by maintenance doses of 200 or 400 mg. The mean initial dose (MID) over the first 3 days was calculated as: (loading dose + dose on 2nd day + dose on 3rd day)/3. Patients with an MID of 266.7 mg or less (400 mg for loading, 200 mg over the 2nd and 3rd days) did not have a trough level that exceeded 10 μg/ml at the point before the injection on the 4th day. Even in patients with hemodialysis (HD), an MID of 266.7 mg was not enough to provide a trough level of 10 μg/ml. Patients with an MID than 533.3 mg had significantly elevated trough levels, showing better outcomes. A multiple regression formula for predicting trough level before the fourth day of administration is given as: 0.034 + 0.030 × (MID; mg) − 0.057 × creatinine clearance (Ccr; ml/min). These findings suggest that 800 mg as an initial dose, followed by 400 mg maintenance doses over the following 2 days, makes it possible to safely attain an optimal trough level, even in the patients with HD.     

Changes in the pharmacokinetics of ciprofloxacin and fecal flora during administration of a 7-day course to human volunteers.

Twelve male subjects, aged 19 to 40 years, shown to be healthy by examination and laboratory tests, took 500 mg of ciprofloxacin every 12 h for 7 days. After the first and the last dose, blood and urine samples were taken and drug concentrations were determined by bioassay. There was a significant buildup in mean concentrations in serum from day 1 to day 7; mean peak levels (attained after 1 to 2 h) were 1.9 and 2.8 micrograms/ml, respectively. The terminal half-life was 3.5 to 4 h. About 40% of the drug was excreted into the urine during the 12-h period after dosing; minimum mean concentrations in urine were 105 micrograms/ml on day 1 and 174 micrograms/ml on day 7. Considerable amounts of ciprofloxacin were found in the feces on day 7 (185 to 2,220 micrograms/g). Marked changes in the aerobic part of the fecal flora were observed as a result of taking ciprofloxacin: coliforms were absent on day 7, and concentrations of streptococci and staphylococci were significantly reduced. There was no overgrowth by yeasts. One week later the fecal flora had returned to a state similar to that found before treatment. Anaerobes were little affected quantitatively but acquired resistance to ciprofloxacin. Side effects were mild and transient.     

Multiple-dose pharmacokinetics of ceftazidime in cancer patients.

The pharmacokinetic parameters of ceftazidime were determined in 25 patients with neoplastic diseases. A group of 13 patients each received 1 g of ceftazidime over 15 min as a single intravenous dose. The mean peak drug concentration in serum was 77.4 micrograms/ml, and the serum half-life was 144 min. Urinary excretion at 12 h was 64.5%. These 13 patients also received 2 g of ceftazidime over 15 min at 8-h intervals for 7 or 8 days. The mean peak drug concentrations in serum were 103.6 micrograms/ml on day 1 and 87 micrograms/ml on day 7 or 8. A second group of 12 patients received 1 g of ceftazidime over 30 min, followed by 1 g over 2 h and every 4 h thereafter. The mean peak drug concentration in serum at 30 min was 57.5 micrograms/ml. Average peak and trough levels obtained on day 2 or 3 were 65 and 34.8 micrograms/ml, respectively, and remained in this range thereafter. The above-mentioned dose schedules produced high and adequate ceftazidime concentrations in serum.     

Pharmacokinetics and tissue penetration of fleroxacin after single and multiple 400- and 800-mg-dosage regimens.

The pharmacokinetics and suction-induced blister fluid penetration of fleroxacin following single and multiple (every 24 h for 5 days) oral administration of 400- and 800-mg-dosage regimens were studied in 12 young male volunteers. Plasma and urine samples up to 72 h were assayed by high-pressure liquid chromatography. The peak levels of fleroxacin in plasma were significantly higher after multiple dosing of 800 mg (14.3 versus 8.2 micrograms/ml; P less than 0.01) but not after the last 400-mg dose (6.7 versus 5.0 micrograms/ml). Increased elimination half-life occurred after multiple dosing of 800 mg, from 13.45 +/- 2.94 to 15.60 +/- 3.16 h (P less than 0.05). Mean peak concentrations in blister fluid were significantly different when the first (3.7 +/- 0.8 and 7.7 +/- 1.8 micrograms/ml for 400 and 800 mg, respectively) and last (5.7 +/- 0.9 and 12.3 +/- 2.1 micrograms/ml for 400 and 800 mg, respectively) doses were compared (P less than 0.01). The percentage of blister fluid (BF) penetration (AUCBF/AUCplasma, where AUC is area under the concentration-time curve) yielded values greater than 100% (range, 113.7 to 132.6%). After multiple administration of 800 mg, fleroxacin was cleared from the body more slowly: from 98.80 ml/min after a single dose to 77.72 ml/min following 800 mg every 24 h (P less than 0.01). Saturation of apparent nonrenal clearance is suggested to explain this difference. Fleroxacin was well tolerated by the volunteers.     

The pharmacokinetics and extravascular diffusion of teicoplanin in rabbits and comparative efficacy with vancomycin in an experimental endocarditis model

The serum protein binding, extravascular diffusion and urinary excretion of teicoplanin were studied in rabbits. Extravascular diffusion was studied after a 20 min iv infusion, and after one or five im injections (7.5 mg/kg), and was compared with the results obtained after im administration of vancomycin (7.5 and 15 mg/kg). In an experimental model of Staphylococcus aureus endocarditis, the efficacy of both antibiotics was also investigated. We observed teicoplanin serum protein binding of 87 +/- 4%. The serum concentrations of teicoplanin showed a three-phase exponential decline: T1/2 alpha, 0.11 +/- 0.01 h; T1/2 beta, 1.4 +/- 0.4 h; T1/2 gamma, 8.3 +/- 2.2 h. Teicoplanin appeared to be slightly secreted by renal tubules. The extravascular diffusion and the therapeutic efficacy of both drugs were studied with intervals between two injections based on the same multiple of beta half-life. Teicoplanin, like vancomycin, appeared slowly in extravascular fluid and the diffusibility of both drugs was similar. Peak extravascular concentrations of teicoplanin after 5 im injections were greater when the compound was administered every 16 h, rather than every 24 h and, for this drug, iv administration induced higher peak extravascular concentrations (P less than 0.01) than im injection. In the experimental model of S. aureus endocarditis, vancomycin 9 mg/kg/12 h and teicoplanin 4.5 mg/kg/16 h were similarly active and more effective than teicoplanin 4.5 mg/kg/24 h.     

Pharmacokinetics of cefepime in patients with thermal burn injury

The pharmacokinetics of cefepime following administration of a single 2-g dose were evaluated for 12 adult patients with thermal burn injury and suspected or documented infection. Serial blood and urine samples for cefepime concentration determination were obtained for 24 h following drug administration. Serum and urine cefepime concentrations were determined by high-performance liquid chromatography and serum concentrations were fit to a two-compartment pharmacokinetic model. Mean (standard deviation [SD]) age, actual body weight (ABW), percent total body surface area burned, and days postburn at the time of study were 41 (13) years, 84 (22) kg, 36 (17)%, and 9 (3) days, respectively. Mean (SD) measured creatinine clearance (CL(CR)), total clearance (CL(T)), renal clearance (CL(R)), alpha phase half-life, beta phase half-life, and volume of distribution at steady state (V(SS)) were 135 (31) ml/min, 8.8 (2.4) liters/h, 8.1 (2.0) liters/h, 0.33 (0.14) h, 2.8 (0.6) h, and 0.43 (0.10) liters/kg ABW, respectively. Cefepime CL(T) and CL(R) in burn patients were similar to previously reported values for healthy volunteers when normalized by CL(CR). Stepwise multiple regression was used to associate CL(T) with CL(CR) and days postburn (r(2) = 0.861), CL(R) with CL(CR) and days postburn (r(2) = 0.773), nonrenal clearance with percent third-degree (% 3 degrees ) burn and albumin concentration (r(2) = 0.550), and V(SS) only with % 3 degrees burn (r(2) = 0.624). Simulated steady-state serum concentrations obtained by using the patients' pharmacokinetic parameters exceeded the susceptibility interpretive standard (breakpoint) of cefepime for at least 60% of the dosing interval with dosing regimens of 1 g every 8 h (q8h), 2 g q8h, and 2 g q12h. Despite differences in pharmacokinetic parameters between our patients and healthy volunteers, it appears that these dosing regimens may be adequate in similar burn patients.     

Pharmacokinetics of cefepime after single and multiple intravenous administrations in healthy subjects.

The pharmacokinetics of cefepime in 31 young, healthy volunteers were assessed after the administration of single and multiple 250-, 500-, 1,000-, or 2,000-mg intravenous doses. Each subject received a single dose of cefepime via a 30-min intravenous infusion on day 1 of the study. Starting from day 2, subjects received multiple doses of cefepime every 8 h for 9 days, and on the morning of day 11, they received the last dose. Serial blood and urine samples were collected after administration of the first dose and on days 1, 6, and 11. Cefepime concentrations in plasma and urine were assayed by using reverse-phase high-performance liquid chromatography with UV detection. Data were evaluated by noncompartmental methods to determine pharmacokinetic parameters. The mean half-life of cefepime was approximately 2 h and did not vary with the dose or duration of dosing. The regression analyses of peak levels (Cmax) in plasma at the end of the 30-min intravenous infusion and the area under the plasma concentration-versus-time curve (AUCo-infinity) showed a dose-proportional response. The steady-state volume of distribution (Vss) was approximately 18 liters and was independent of the administered dose. The multiple-dose pharmacokinetic data are suggestive of a lack of accumulation or change in clearance of cefepime on repeated dosing. Cefepime was excreted primarily unchanged in urine. The recovery of intact cefepime in urine was invariant with respect to the dose and accounted for over 80% of the dose. The values for renal clearance ranged from 99 to 132 ml/min and were suggestive of glomerular filtration as the primary excretion mechanism. It is concluded that cefepime linear pharmacokinetics in healthy subjects.     

Multiple intravenous dose pharmacokinetic study of carumonam in healthy subjects

Steady-state pharmacokinetics of carumonam were investigated in twelve healthy adult male volunteers after 20 min intravenous infusions of three consecutive carumonam dosage regimens: 1 g every 8 h (3 g/day) from 0-72 h, 2 g every 8 h (6 g/day) from 88-120 h and 2 g every 6 h (8 g/day) from 132-216 h. Serial plasma samples were collected after the first dose of the first regimen and the last dose of all three regimens and were analysed for carumonam by a specific HPLC method. The overall mean maximal plasma concentrations were 108 and 211 mg/l at the end of infusion of 1 and 2 g, respectively. The steady-state pharmacokinetic parameters and plasma concentration-time profiles of carumonam when adjusted for dose were similar for the three regimens. The overall terminal elimination half-life was 1.4 h (range 1.1-1.8 h), the apparent volume of distribution at steady state reached 11.5 l (range 8.7-15.5 l) and the total systemic clearance amounted to 118 ml/min (range 83-158 ml/min). Considering the frequency of dosing relative to the elimination half-life, accumulation of the drug in plasma was not expected and none was found from any of the three regimens. Carumonam was well tolerated up to 8 g/day and exhibited dose-independent pharmacokinetics which were not altered upon multiple dosing.     

Teicoplanin pharmacokinetics in critically ill paediatric patients.

Twenty-one critically ill children aged between 7 days and 12 years were treated with teicoplanin (three loading dosages of 10 mg/kg at 12 h intervals, followed by a maintenance dosage of 10 mg/kg/day). Serum teicoplanin concentrations were monitored by HPLC. Mean concentrations in plasma 30 min after drug administration were 20 +/- 16.1 mg/L. The volume of distribution was 0.30 L/kg and the terminal half-life was 17.41 h. Only 11% of trough values were >10 mg/L (established as desirable values). In critically ill children a dosage of 10 mg/kg/day does not assure serum trough values >10 mg/L.     

Pharmacokinetics and safety of oral levofloxacin in human immunodeficiency virus-infected individuals receiving concomitant zidovudine.

This phase I, double-blind, randomized, placebo-controlled, parallel-design study was conducted to evaluate the safety and pharmacokinetics of levofloxacin in human immunodeficiency virus (HIV)-infected subjects concomitantly receiving a stable regimen of zidovudine (AZT). Sixteen HIV-infected males with CD4-cell counts ranging from 100 to 550 and not experiencing significant AZT intolerance were enrolled. Subjects received levofloxacin (350 mg of levofloxacin hemihydrate) or a placebo (eight subjects per treatment group) as a single oral dose on day 1, multiple doses every 8 h from days 3 to 9, and a single dose on day 10. On days 1 and 10, an AZT dose (100 mg) was administered concurrently with the study drug. In between these doses, AZT was administered according to the regimen used by the subject prior to entering the study up to a maximum of 500 mg/day. Plasma levofloxacin concentrations were monitored for 36 h after levofloxacin dosing on day 1, immediately prior to the morning doses on days 3 to 9, and for 72 h after dosing on day 10. Plasma AZT concentrations were monitored on day 0 for baseline (for 6 h after the AZT dose) and for 4 h after the AZT doses on days 1 and 10. Levofloxacin was rapidly absorbed (time to maximum plasma concentration, approximately 1.0 h) and extensively distributed in the body with an apparent volume of distribution of approximately 104 liters (approximately 1.34 liters/kg). Steady-state conditions on day 10 were confirmed. Pharmacokinetic profiles of levofloxacin from single doses and multiple (three-times-daily) doses were similar, with a moderate accumulation (observed day 10-to-day 1 ratio of the maximum plasma concentration, approximately 185% versus expected 169%; for the corresponding ratio of the area under the concentration-time curve from 0 to 8 h [AUC(0-8)], the values were observed 217% versus expected 169%) at steady state. Mean average steady-state peak plasma concentration, plasma levofloxacin concentration at the end of the dosing interval, AUC(0-8), terminal half-life, and total body clearance were 7.06 microg/ml, 3.62 microg/ml, 37.4 microg x h/ml, 7.2 h, and 9.4 liters/h (0.12 liters/h/kg), respectively. Pharmacokinetic profiles of levofloxacin in HIV-infected patients did not appear to be affected by the concomitant administration of AZT; nor were AZT pharmacokinetics altered by levofloxacin. Oral administration of 350 mg of levofloxacin hemihydrate every 8 h appeared to be well tolerated by the subjects. There were no apparent differences in adverse events between the two treatment groups. There were no clinically significant changes from baseline in any laboratory parameter or vital sign following treatments observed in this study. The study results suggest that there is no need for levofloxacin dosage adjustment in HIV-seropositive subjects who concomitantly receive AZT.     

Retrospective review of serum teicoplanin concentrations in clinical trials and their relationship to clinical outcome

Twenty-five published clinical studies were reviewed in which teicoplanin serum concentrations were determined. A variety of assay methods were used, including bioassay, solid phase enzyme receptor assay, HPLC and immunoassay, and in some studies, more than 1 methodology was used. Fourteen studies gave sufficient data on the method of assay, timing of assays relative to dosage or during therapy, and route of administration of teicoplanin to be included in a detailed pharmacokinetic analysis. Since a wide range of dosing regimens were employed, the studies were grouped in order to facilitate analysis according to the teicoplanin maintenance dose, either 200 mg, 400 mg or 6 mg/kg/day. Six studies used a dose of 200 mg/day and although the mean trough concentrations varied by as much as 3-fold, they did not exceed 10 mg/L in the first 7 days of therapy. Six studies used a 400 mg/day maintenance dose and the mean trough concentrations varied from 4 to 11 mg/L on days 1–2, to 9 to 17 mg/L on days 6–7 of therapy. In 5 of these studies, the mean trough concentration was less than 10 mg/L for the first 48 hours of treatment. In 2 studies where a dose of 6 mg/kg/day was used, the mean concentrations did not exceed 10 mg/L until day 7, while in the other study they were greater than 10 mg/L beginning on day 1. A retrospective analysis of 58 clinical cases reported in the literature, 42 of whom had staphylococcal infections, indicated that serum concentrations and teicoplanin concentration/MIC ratios were related to clinical cure particularly for patients with staphylococcal infections. Trough concentrations of greater than 10 mg/L were related to favorable outcomes when all 58 patients were analyzed and trough concentrations of greater than 20 mg/L were related to cure for those who had staphylococcal infections. While retrospective in nature, this review indicates that there is considerable variation in teicoplanin pharmacokinetics in the different patient groups, only some of which is related to differences in dosing, timing of blood collection for assay or assay methodology. In addition, these data suggest that pharmacokinetic parameters such as trough and postdose teicoplanin concentrations, and phamracodynamic factors such as serum concentration MIC ratios may be related to clinical outcome with teicoplanin therapy.     

Impact of ciprofloxacin on theophylline clearance and steady-state concentrations in serum.

The effect of a multiple-dose regimen of oral ciprofloxacin (750 mg every 12 h for 11 doses) on the clearance and steady-state concentrations of theophylline in trough (predose) serum was evaluated in nine healthy male subjects, each serving as his own control. Theophylline was taken as a sustained release tablet per os in a dose of 200 mg every 12 h for 19 doses. Theophylline concentrations in serum were measured immediately before each theophylline dose. Ciprofloxacin was administered on study day 4 through the first dose of study day 8. Theophylline concentrations in serum were also measured on study days 3, 6, 8, and 10 at the following times after the first dose of each day: 0, 0.25, 0.50, 1, 2, 4, 6, 8, 10, and 12 h. Steady-state theophylline concentrations in trough serum were significantly higher during ciprofloxacin treatment (day 8) than before (day 3) or after (day 10) ciprofloxacin administration (P less than 0.01). Likewise, theophylline clearance was significantly slower (P less than 0.01) during ciprofloxacin treatment (day 8) than before it (day 3) or after it (day 10). The magnitude of ciprofloxacin-induced changes was approximately 30%. These results suggest that a multidose regimen of ciprofloxacin significantly slows the clearance of theophylline and elevates theophylline concentrations in serum.