Recommendations to achieve rapid therapeutic teicoplanin plasma concentrations in adult hospitalised patients treated for sepsis

The optimum teicoplanin loading dose and duration of therapy required for rapid attainment of a therapeutic trough plasma concentration (C(min)) (> or = 10mg/L for serious Gram-positive infections and > or = 20mg/L for deep-seated infections) are not known. In this open-label, multicentre, observational study, teicoplanin levels were determined following administration of loading doses of 6 mg/kg every 12h on Day 1 followed by 6 mg/kg once or twice daily to hospitalised patients with suspected or diagnosed Gram-positive infections. C(min) levels for the first 4 days of treatment were collected 15min prior to drug administration. Levels were determined with an Abbott TDx/FLx Analyzer and Seradyn Teicoplanin Innofluor Assay Kit. The two target trough values (> or = 10mg/L and > or = 20mg/L) were only achieved by Day 4 in the once-daily group (n=34; mean 9.55 mg/L, 95% confidence interval (CI) 8.17-10.94 mg/L) and in the twice-daily group (n=40; mean 21.8 mg/L, 95% CI 17.21-26.39 mg/L), respectively. However, the mean C(min) in the twice-daily group was > or = 10mg/L (11.03 mg/L) by Day 2. To achieve rapid therapeutic C(min) concentrations targeted for the majority of serious Gram-positive infections, we recommend teicoplanin loading doses of 6 mg/kg every 12h for 48h followed by once-daily for infections other than infective endocarditis, septic arthritis and osteomyelitis. Regarding the latter infections, higher loading doses might be warranted to reach rapid steady-state concentrations.     

Clinical pharmacokinetics of teicoplanin

The glycopeptide antibacterial teicoplanin has become increasingly popular in the last decade with the rise in infections related to methicillin-resistant Staphylococcus aureus. Teicoplanin has 6 major and 4 minor components. It is predominantly (90%) bound to plasma proteins. Of the several methods available to measure concentrations in serum, fluorescence polarisation immunoassay has high reliability and specificity. Teicoplanin is not absorbed orally, but intravenous and intramuscular administration are well tolerated. Teicoplanin is eliminated predominantly by the kidneys and only 2 to 3% of an intravenously administered dose is metabolised. Total clearance is 11 ml/h/kg. Steady state is reached only slowly, 93% after 14 days of repeated administration. Elimination is triexponential, with half-lives of 0.4 to 1.0, 9.7 to 15.4 and 83 to 168 hours. Volumes of distribution are 0.07 to 0.11 (initial phase), 1.3 to 1.5 (distribution phase) and 0.9 to 1.6 (steady state) L/kg. A standard dosage regimen of 6 mg/kg every 12 hours for 3 doses, then daily, will produce therapeutic serum concentrations of > or = 10 mg/L in most patients. Higher dosages may be required in certain patients, for example intravenous drug abusers or those with burns, because of unpredictable clearance. Concentrations in bone reach 7 mg/L at 12 hours after a dose of teicoplanin 6 mg/kg, but reach only 3.5 mg/L in the cartilage. Doses of 10 mg/kg are necessary to achieve adequate bone concentrations. There is little penetration into cerebrospinal fluid or the aqueous or vitreous humour. In fat, concentrations may be subtherapeutic (0.5 to 5 mg/L) after a dose of 400mg. A single prophylactic dose of 12 mg/kg is sufficient to maintain therapeutic concentrations during cardiopulmonary bypass or burns surgery. High loading doses reduce the delay to attaining therapeutic concentrations. Premature neonates require a loading dose of 15 mg/kg and a maintenance dosage of 8 mg/kg daily to ensure therapeutic serum concentrations. Children need loading with 10 mg/kg every 12 hours for 3 doses followed by maintenance with 10 mg/kg/day. Clearance is reduced predictably in renal failure, and dosage adjustments can be based on the ratio of impaired clearance to normal clearance. In patients on haemodialysis, 3 loading doses of 6 mg/kg at 12-hour intervals followed by maintenance doses every 72 hours produced trough plasma concentrations of 8 mg/L in most patients at 48 hours. The monitoring of serum concentrations is not necessary to avoid toxicity, but can be helpful in certain patient groups to ensure therapeutic concentrations are present, especially in those not responding to treatment.     

Simplified dosing regimens of teicoplanin for patient groups stratified by renal function and weight using Monte Carlo simulation

The purpose of this study was (i) to determine the optimal dosage of teicoplanin for each patient group stratified by renal function and weight based on a population pharmacokinetic model and observed distribution of patient characteristics and (ii) to develop new simplified dosing regimens designed to achieve 15-30μg/mL. Patient data were collected retrospectively from routine therapeutic drug monitoring files of adult patients who were given the standard loading dose regimen of teicoplanin (400mg twice on Day 1, followed by 400mg once daily for 2 days) and whose trough concentration was measured just before administration on Day 4. Monte Carlo simulation was conducted to estimate the trough concentration at 72h after the initial loading dose (C(min)(72h)) and at steady state (C(ss)(min)). The percentage of observed C(min)(72h) in patients who received the standard loading dose regimen outside the non-parametric 90% prediction interval (from 5th to 95th percentile) of the simulated C(min)(72h) was <10%. Simplified loading dose and maintenance dose regimens for each group stratified by renal function and weight were created to achieve C(min)(72h) and C(ss)(min) of 15μg/mL and 20-25μg/mL, respectively. The percentage of C(min)(72h) and C(ss)(min) in the range 15-30μg/mL was 43-65% and 61-82% across each renal function and weight strata, respectively. These new simplified dosing regimens of teicoplanin could be helpful in individual adjustment of the loading and maintenance doses to achieve 15-30μg/mL.     

Pharmacokinetic-pharmacodynamic aspects of antimicrobial prophylaxis with teicoplanin in patients undergoing major vascular surgery

A prospective, two-arm, open study assessing plasma exposure to teicoplanin with two different prophylactic regimens (Group A (n = 23), 800 mg pre-operatively versus Group B (n = 24), 400 mg pre-operatively plus two doses of 200 mg 24 h apart) was carried out in patients undergoing major vascular surgery. The intent was to define the feasibility and the possible advantages of the single pre-operative high dose in ensuring therapeutically effective plasma concentrations (>10 mg/L) of teicoplanin even during long-lasting operations. At the end of the intervention, mean teicoplanin concentrations (+/-S.D.) were 14.05 +/- 5.13 mg/L and 5.39 +/- 2.13 mg/L in Groups A and B, respectively. At 24 h, average teicoplanin levels were 5.10 +/- 1.25 mg/L and 2.08 +/- 0.73 mg/L in Groups A and B, respectively; at 48 h they declined to 2.86 +/- 0.70 mg/L in Group A, whereas they rose to 2.67 +/- 0.82 mg/L after administration of 2.63 +/- 0.51 mg/kg at 24 h in Group B. Single pre-operative high-dose teicoplanin may ensure effective plasma levels even in cases of very long-lasting operations (>8 h) with no need for intraoperative re-dosing and may enable more appropriate prophylactic exposure than that achievable with the same total dose given in three administrations 24 h apart.     

重症感染患者替考拉宁血药浓度影响因素探讨

摘要：目的 监测重症感染患者替考拉宁起始负荷剂量治疗第2天的血药谷浓度(Cmin)及目标浓度(Cmin≥10mg/L)达标情 况,探讨早期血药谷浓度的影响因素。方法 对2018年3月—2019年3月重症医学科38例使用替考拉宁治疗的重症感染患者进行 回顾性分析,根据起始负荷剂量分为高剂量组(≥10mg/kg)和低剂量组(＜10mg/kg),均间隔12h静脉注射3剂,于第3剂前30min 采集血样,应用高效液相色谱法(HPLC)测量Cmin。分析替考拉宁Cmin分布情况、目标浓度达标率及影响因素。结果 38例血样 Cmin为(11.06±3.88)mg/L,其中63.2%(24/38)达标,36.8%(14/38)未达标;高剂量组较低剂量组可明显提高目标Cmin达标率(82.4% vs 47.6%,P＜0.05),肾小球滤过率(GFR)≥60mL/min/1.73m2的患者达标率显著低于GFR＜60mL/min/1.73m2的患者(51.9% vs 90.9%,P＜0.05);Cmin未达标组的GFR明显高于Cmin达标组[(135.03±62.22)mL/min/1.73m2 vs (81.8±54.62)mL/min/1.73m2,P ＜0.05]。结论 重症感染患者使用≥10mg/kg的替考拉宁起始负荷剂量可较快达到有效血药谷浓度,高GFR是影响Cmin达标的重 要因素,有必要结合重症患者的药代动力学优化替考拉宁治疗剂量。     

Teicoplanin pharmacokinetics in patients with chronic renal failure

The pharmacokinetic profile of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, was studied in 5 healthy male volunteers and 29 adult patients with various degrees of renal impairment, given a single 3 mg/kg intravenous dose. Teicoplanin was assayed in plasma and urine specimens by a microbiological method. Pharmacokinetic parameters for teicoplanin were estimated both by a 3-compartment open pharmacokinetic model and by non-compartmental analysis. Elimination half-life increased with the decrease in creatinine clearance and mean values ranged from 41 hours in volunteers to 163 hours in anuric patients. Renal failure did not affect either the volume of distribution of the central compartment (mean approximately 0.09 L/kg) or the steady-state volume of distribution (mean approximately 0.9 L/kg). Both total and renal clearance decreased with severity of disease, particularly the latter, while non-renal clearance was unaffected by renal failure. Average values were from 19 to 6 ml/min for total clearance and from 12 to 0.4 ml/min for renal clearance. There was a linear correlation between the total clearance of teicoplanin and creatinine clearance, as well as between renal clearance and creatinine clearance. The total urinary excretion of active teicoplanin averaged 65% of the administered dose in normal subjects, but was significantly reduced in the presence of renal insufficiency. Guidelines for administration of teicoplanin in patients with renal failure are given.     

Loading dose required to achieve rapid therapeutic teicoplanin trough plasma concentration in patients with multidrug-resistant gram-positive infections

Teicoplanin is an antibiotic drug prescribed for the treatment of multidrug‐resistant Gram‐positive infections. However, there is currently no consensus as to the optimal teicoplanin loading dose. The objective of this study was to compare plasma concentrations of teicoplanin in patients with multidrug‐resistant Gram‐positive infections after the administration of two different loading doses. Two groups of patients were infused intravenously with four loading doses of 6 mg/kg body‐weight (group A, n = 12) or 12 mg/kg body‐weight (group B, n = 11). The first three loading doses were administered at 12‐hr intervals, and the fourth was given 24 hr after the third dose. Maintenance doses of 6 mg/kg were administered every day, every other day or every third day depending on the individual's creatinine clearance, and teicoplanin trough plasma concentrations were monitored. Only samples obtained on the same day for both groups were compared statistically. A higher percentage of group B patients achieved the desired therapeutic concentration of teicoplanin (C_min. ≥ 10 mg/L) on days 2 and 3 (90.0% and 100%, respectively) compared with patients in group A (18.2% and 16.7%, respectively) (p < 0.001). In addition, more patients in group B achieved therapeutic concentrations from days 2 through 12. In conclusion, despite limitations in drawing definitive conclusions because of a relatively small sample size and variability in renal impairment among patients, our findings suggest that a teicoplanin loading dose of 12 mg/kg body‐weight results in a safe and rapid attainment of therapeutic trough plasma concentrations. This regimen may enhance treatment efficacy.     

Aminoglycoside dosages and nephrotoxicity: quantitative relationships

OBJECTIVE: To develop a model that relates the probability of occurrence of nephrotoxicity to the cumulative area under the curve (AUC) of amikacin serum concentration. DESIGN AND PATIENTS: This was a retrospective study of two groups of patients in whom nephrotoxicity was observed after administration of amikacin. The first group consisted of patients treated with once-daily administration (ODA) [n = 13]. The second group consisted of patients treated with twice-daily administration (TDA) [n = 22]. MAIN OUTCOME MEASURES: The probability of nephrotoxicity occurrence. RESULTS: The model is a powerful tool to represent and describe the influence of the dosage regimen on aminoglycoside nephrotoxicity. The onset of nephrotoxicity is delayed in the ODA group (p = 0.01) for the same total daily dose among the two groups. The cumulative serum AUC values at onset of nephrotoxicity were greater for the ODA group (p = 0.029). In addition, for the same probability of nephrotoxicity occurrence (50%), the cumulative AUC for the ODA dosage regimen is 2 613 mg. h/L versus only 1 521 mg. h/L for the TDA dosage regimen. The difference in nephrotoxicity between ODA and TDA is greatest for a cumulative AUC of 2 495 mg. h/L, which corresponds to standard therapy with amikacin 900 mg/day during a 7-day period, i.e. 15 mg/kg/day for a 60kg patient with normal renal function (initial creatinine clearance >80 mL/min). For an AUC above 2 495 mg. h/L, the difference in nephrotoxicity decreases slowly to zero. This result means that ODA is especially justified when the treatment is administered over a short duration, i.e. less than 7 days. CONCLUSIONS: The utility of selecting ODA in order to obtain less nephrotoxicity in comparison with TDA is therefore not established when the treatment is prolonged. In clinical use, the choice of the dosage regimen is not clear-cut, and both expected efficacy and expected toxicity must be taken into account in order to obtain an overall optimisation of each patient's therapy.     

Standard gentamicin dosage regimen in neonates.

A standard gentamicin dosage regimen intended to result in fewer trough concentrations of >2 microg/mL was studied. At a neonatal intensive care unit, gentamicin dosage guidelines of 2.5 mg/kg (as the sulfate) administered i.v. over 30 minutes every 12, 18, or 24 hours to neonates with a gestational age (GA) of > or =30 weeks were resulting in some relatively high trough serum concentrations (>2 microg/mL). Pharmacokinetic values derived for this baseline group were used to predict the gentamicin concentrations that would result from a standard regimen of gentamicin 3.5 mg/kg i.v. over 30 minutes every 24 hours. No patient in the baseline group was predicted to have a trough of >2 microg/mL with the new regimen, which was then approved for routine use. The new regimen was used for every neonate with a GA of > or =30 weeks who was admitted and treated with gentamicin (the protocol group). One set of concentrations was collected for each infant. Compared with the baseline group, the protocol group had significantly lower trough and significantly higher peak gentamicin concentrations. The total frequency of high troughs in the baseline group (23 [33%] of 69 patients) differed significantly from that in the protocol group (3 [4%] of 74 patients). No patient had or developed renal impairment. A gentamicin dosage protocol of 3.5 mg/kg every 24 hours for neonates with a GA of > or =30 weeks resulted in higher gentamicin peaks, lower troughs, and a lower frequency of troughs of >2 microg/mL, compared with previous dosage practice.     

Rufinamide for pediatric patients with Lennox-Gastaut syndrome: a comprehensive overview

Rufinamide is a triazole derivative with broad-spectrum antiepileptic effects that is unrelated to any antiepileptic drug currently on the market. The European Commission and the US FDA approved rufinamide in 2007 and 2008, respectively, for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children 4 years of age or older and adults. The mechanism of action of rufinamide is not completely understood but it is believed to prolong the inactive state of sodium channels, therefore limiting excessive firing of sodium-dependent action potentials. Rufinamide is well absorbed when taken with food, with an absolute bioavailability between 70% and 85%. The elimination half-life of the drug is around 6-10 hours, with a time to maximum plasma concentration (C(max)) of approximately 4-6 hours. The C(max) at a dosage of 10?mg/kg/day and 30?mg/kg/day is 4.01?μg/mL and 8.68?μg/mL, respectively, and the area under the plasma concentration-time curve from time 0 to 12 hours was 37.8?±?47?μg?·?h/mL and 89.3?±?58?μg?·?h/mL, respectively. Rufinamide exerts non-linear pharmacokinetics with increasing doses. The volume of distribution in children is similar to that in adults (0.8-1.2?L/kg) and the drug binds rather poorly to plasma protein (26.2-34.8%). Rufinamide is mainly metabolized by carboxylesterases to an inactive metabolite (CGP 47292), and the majority of the metabolites are excreted in the urine (91%). No dosage adjustment is required in patients with renal dysfunction. Rufinamide does not affect the plasma concentration of other antiepileptics, but phenytoin, phenobarbital, valproate, and primidone affect the clearance of rufinamide. In a clinical study of 138 patients averaging 12 years of age, rufinamide used as an adjunctive therapy (with an initial dosage of 10?mg/kg/day up to a target dosage of 45?mg/kg/day) in patients with Lennox-Gastaut syndrome reduced the median total seizure frequency by 32.7% versus 11.7% in the placebo group (p?=?0.0015). Similar reduction in total seizure frequency was maintained in the extension phase of this study. In other studies, rufinamide also seemed to provide improvement in both partial seizures and refractory epilepsy, but further studies need to validate this observation and to identify its clinical significance. Rufinamide is usually started orally at 10?mg/kg/day, titrating up by 10?mg/kg/day every 2 days to a target dosage of 45?mg/kg/day divided twice daily (maximum dosage of 3200?mg/day). Dosing of rufinamide has not been established in patients <4 years of age. Rufinamide is available as 100, 200, and 400?mg tablets in Europe, and 200 and 400?mg tablets in the US; a suspension of 40?mg/mL can be prepared extemporaneously. Rufinamide is well tolerated, with the most common adverse effects being dizziness, fatigue, nausea, vomiting, diplopia, and somnolence. From the current data, rufinamide serves as an adjunctive therapy in the management of Lennox-Gastaut syndrome. Further studies need to evaluate its efficacy as a first-line agent in the management of this neurologic disorder.     

The effect of multifactorial, multidisciplinary educational interventions on appropriate use of teicoplanin

The aim of this study was to determine the effect of multifactorial, multidisciplinary educational interventions over a 3-year period on the appropriate use of teicoplanin. Teicoplanin was considered a valid surrogate marker of good antibiotic use in clinical practice owing to its peculiar pharmacokinetics (i.e. necessity for an initial loading dose regardless of the patient's renal function for early achievement of optimal exposure, namely C(min) > or = 10 mg/L) and to the opportunity of comparing current routine therapeutic drug monitoring (TDM) results with those of a historical retrospective study. A significantly higher proportion of patients received appropriate loading doses of teicoplanin in the present prospective study than in the retrospective study, both when considered as a whole (66.6% versus 38.6%, respectively; P<0.001) or when stratified according to the degree of estimated renal function (78.4% versus 60.4% for creatinine clearance (CL(Cr)) > 50 mL/min; 59.8% versus 26.8% for CL(Cr) 20-50 mL/min; and 27.7% versus 5.5% for CL(Cr) <20 mL/min). The highest adherence was observed in haematological wards (97.7%). The percentages of patients with teicoplanin C(min) > or = 10 mg/L during the treatment period in the present and retrospective study, respectively, were: 61.4% versus 3.2% on Day 2; 88% versus 35% on Day 4; 94% versus 70% on Day 7; and 99% versus 90% on Day 11. Our findings suggest that continuous application of a multifactorial educational programme including active TDM may be efficacious in improving and maintaining over time the appropriate use in a hospital setting of a theoretically difficult-to-use drug such as teicoplanin.     

A critical review of the dosage of teicoplanin in Europe and the USA

The glycopeptide antibiotic, teicoplanin, is increasingly used in Europe in the treatment of Gram-positive infection. It is administered as a bolus once daily, it has little potential for nephrotoxicity, and serum monitoring is usually unnecessary. However, poor results were reported in early trials at a daily dose of 200 mg and, more recently, at 400 mg/day in monotherapy of staphylococcal endocarditis. While 400 mg (6 mg/kg day(-1)) is now standard, US trials have tried very high doses in an attempt to improve its efficacy in monotherapy of deep-seated staphylococcal sepsis. European centres continue to use 6 mg/kg day(-1) as the usual maintenance dose and 6-12 mg/kg as the loading dose. For the more difficult cases, teicoplanin is used in combination with other agents. All available published and unpublished literature was reviewed to try to solve these problems. With the exception of endocarditis, failure rates in the 84 European open studies varied more between trials than between the dosages used. In 32 European and eight US randomized trials, a dose of 6 mg/kg day(-1) of teicoplanin was effective, except in staphylococcal endocarditis if teicoplanin was used as monotherapy. In that case, 12 mg/kg day(-1) or more was needed to achieve a cure rate similar to that of vancomycin. Treatment was most successful with trough levels over 20 mg/l. However, lower doses were effective in combination with aminoglycosides, as is common in clinical practice. An open trial suggested that 12 mg/kg day(-1) was needed for treatment of septic arthritis. It is suggested that 6 mg/kg day(-1) of teicoplanin be used for all indications except staphylococcal endocarditis and septic arthritis when it should be given in a dose of 12 mg/kg day(-1) or in combination with other agents.     

Aminoglycoside dosage in hemodialysis patients

Regulating aminoglycoside dosage in patients undergoing hemodialysis is difficult because its elimination depends entirely on renal function and because the therapeutic margin is narrow. Guidelines for aminoglycoside dosage were derived from published population-based kinetics and investigated in a prospective clinical study over a 12-month period in 50 consecutive patients undergoing hemodialysis with acute (70%) or chronic (30%) renal failure. Based on body weight, each patient received one loading dose (1.5 mg/kg) and a daily maintenance dose (0.5 mg/kg) of netilmicin. The dosage interval was 24 hours. On each hemodialysis day, the dose of netilmicin was given immediately after hemodialysis. Each posthemodialysis dose (1.3 mg/kg) was the sum of the daily maintenance dose plus a supplementary dose to replace the amount of the drug removed during hemodialysis. A blood sample was taken at the start and the end of each hemodialysis and one hour after the start of the posthemodialysis dosage. Netilmicin plasma concentrations were determined by substrate-labeled fluorescence immunoassay. The mean (+/- standard deviation) peak plasma concentration of the pooled data for all patients was 7.5 +/- 2.7 mg/L, and the mean trough level was 3.6 +/- 1.3 mg/L. The theoretically postulated range of therapeutic peak levels (5-10 mg/L) was the same as in patients with normal renal function, whereas the theoretically postulated range of therapeutic trough levels (2.2-5.0 mg/L) was considerably higher than in healthy persons. Peak and trough levels within the postulated range were achieved in 81% of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic intravenous toxicity of the new antibiotic cefpirome in monkeys

Chronic intravenous toxicity studies in monkeys were carried out with 3-[(2,3-cyclopenteno-1-pyridinium)-methyl]-7-[2-syn-methoximino - 2-(2-aminothiazol-4-yl)-acetamido]-ceph-3-em-4-carboxylate (cefpirome, HR 810; CAS 84957-29-9) a new cephalosporin derivative. In a 90-day study in rhesus monkeys (4 males/4 females per group) dosages of 0, 50, 160 and 500 mg/kg/day were administered. In a 6-month study 5 groups of 6 male and 6 female cynomolgus monkeys received NaCl-solution (0.9%), the vehicle, and 50, 200 or 800/400 mg/kg/d (the highest dosage had to be lowered after the first week due to acute drug intolerance). For clarification of the dose relationship to the findings in the 800/400 mg/kg group, a supplementary 6-month study with 500 mg/kg cefpirome including a vehicle control was also performed. 50 mg cefpirome/kg/d was well tolerated; so too were 160 and 200 mg/kg apart from a slight beta 2-microglobulinuria and/or enzymuria. Almost exclusively at the high dosages retching and vomiting, and exclusively at the high dosages diarrhea, inappetence and physical weakness were sporadically seen in the first phase of the studies. 500 and 400 mg/kg led to increasing signs of discrete renal tubular changes (enzymuria, beta 2-microglobulinuria, cylindruria and minimal histological changes in 2 animals of the 400 mg/kg group). In one rhesus monkey (500 mg/kg) and two cynomolgus monkeys (800 mg/kg) severe kidney damage had developed within the first week. In all dosage groups of the 90-day study special histological methods revealed a dose-dependent increase and enlargement of lysosomes in the epithelia of the proximal renal tubules. Increased cytolysis was, however, not observed. In all the studies there was a dose-dependent increase in the kidney weights of the intermediate and highest dosage groups. The females of the 400 mg/kg group showed slight anemia accompanied by a slight increase in the reticulocyte count. One animal of this group died prematurely probably due to pulmonary embolism. The signs of slight renal impairment including lysosome enlargement, and the slight anemia proved to be reversible.     

替考拉宁血药浓度监测对肺炎患者用药方案的指导意义探讨

目的：探讨替考拉宁血药浓度监测（TDM）对肺炎患者用药负荷剂量、临床疗效和不良反应的指导意义。方法：对95例肺炎患者的临床资料进行回顾性分析,按替考拉宁负荷给药方式和剂量不同,分为3组,A组：负荷量400 mg q 12 h,静注3次,持续400 mg qd;B组：负荷量400 mg q 12 h,静注2次,持续400 mg qd;C组：负荷量400 mg,q 12 h,静注2次,持续200 mg qd。采用高效液相色谱（HPLC）法检测血清谷浓度（C_min）。血常规、CRP、PCT、胸部CT、细菌学情况、ALT、AST、CLcr、BUN、PLT和ALP分别在治疗前、治疗7 d进行检测。结果：A（14.74±5.25）、B（13.14±4.71）和C（15.36±7.08）3组间C_min比较,无显著差异（P=0.409）,但A组和C组平均值总体比B组略高。3组患者首次C_min达到10~30 mg·L^-1的比率分别78.85%,68.18%,86.67%（P=0.392）,但C组满足治疗范围的比例明显高于A组和B组。第4天根据C_min值调整剂量后,复测C_min,3组患者均能达到10~30 mg·L^-1。A、B和C 3组间总有效率无显著差异（P=0.848）,并极少有不良反应发生。结论：使用替考拉宁时,要规范给予负荷剂量,且有必要进行TDM监测,根据结果调整给药剂量,避免替考拉宁疗效不佳或不良反应发生。     

Nephrotoxicity of teicoplanin in rats

Teicoplanin, a glycopeptide antibiotic, is marketed in a number of European countries and has recently been put on the market in Japan. The spectrum of antibacterial activity of teicoplanin is equivalent or superior to that of vancomycin. The aim of the present study is to examine the nephrotoxicity of teicoplanin compared with vancomycin in rats. Wistar male rats, housed in a light-controlled room at room temperature for 1 week, were used. They were injected with either 15 or 50 mg/kg/day of teicoplanin or 50 or 200 mg/kg/day of vancomycin at 13:00 daily for 14 days. The rats were randomly assigned to groups of five rats each and were housed individually in metabolic cages to collect urine. Urine samples were collected 24 hours prior to the drug treatment and every 24 hours thereafter for 14 days. N-Acetyl-beta-D-glucosaminidase (NAG) activity was determined in the supernatant and expressed in international units per total urine collected for 24 hours. The group which was given vancomycin 200 mg/kg/day had significantly elevated urinary NAG levels compared with the other groups (p < 0.05). No significant differences were observed in the NAG levels in urine among the remaining three groups. These results suggest that the nephrotoxicity of teicoplanin may be only one-fourth that of vancomycin in rats. It appears that by extrapolating the dose amount required for the treatment in humans to rats, the high dose of teicoplanin was set at 50 mg/kg/day and that of vancomycin, 200 mg/kg/day. The recommended dose for teicoplanin will probably be 200 mg/day compared to 2 g/day of vancomycin. If the teicoplanin dose is only one-tenth that of the vancomycin dose, then teicoplanin should be better tolerated than vancomycin in terms of nephrotoxicity.     

Atypical pharmacokinetics and metabolism of mycophenolic acid in a young kidney transplant recipient with impaired renal function

A juvenile, female renal transplant recipient suffered two acute rejection episodes: the first on posttransplant day 31 while taking cyclosporine, prednisone, and mycophenolate mofetil (MMF); and the second on posttransplant day 67, when she was taking tacrolimus, prednisone, and MMF. Dosage of MMF was initially started at 2 g/d (corresponding to 600 mg MMF/m(2) twice daily.), but was reduced to 250 mg/d to 500 mg/d after severe diarrhea and a paralytic ileus on posttransplant day 16. During therapy with tacrolimus, prednisone, and MMF, predose plasma mycophenolic acid (MPA) concentrations varied from 1.1 mg/L to 8.2 mg/L (median 3.0 mg/L). On posttransplant day 91, a 12-hour pharmacokinetic profile was obtained. The concentrations of MPA and its metabolites were determined with a validated high-performance liquid chromatography (HPLC) procedure. After oral MMF (250 mg) administration, the MPA concentration showed an atypical decline from a predose concentration of 6.0 mg/L to a value of 3.8 mg/L at 75 minutes postdose, and 3.4 mg/L at 6 hours postdose, before returning to 6.0 mg/L after 12 hours. The 12-hour area under the concentration-time curve (AUC) values for MPA and its major metabolite the phenolic glucuronide MPAG were 55.1 mg.h/L and 800 mg.h/L, respectively. An unusually high concentration (12-h AUC, 165 mg.h/L) of the phenolic glucose conjugate of MPA was found. The apparent renal clearance of MPAG was only 2.2 mL/min. Her creatinine clearance was 30 mL/min. MPAG clearances have been reported to range from approximately. 5.5 mL/min to 35 mL/min at a creatinine clearance of approximately 30 mL/min in renal transplant recipients. The authors' findings suggest that conjugation and clearance of MPA through the kidney is strongly impaired in this patient. The relatively high predose MPA concentrations could result from an enhanced enterohepatic circulation of MPA and its metabolites.     

A simple method to calculate cyclosporine dosage to obtain a target C2 drug level

C(2) Cyclosporine (CsA) level, as a surrogate of area under the time-concentration curve (AUC) 0-4 hours, is a good predictor of drug absorption and clinical outcome after kidney transplantation. It has been difficult to define the optimal C(2) level in the individual case and given the broad range of C(2) due to interindividual absorption variability it has been troublesome to determine the drug dose needed to obtain an expected C(2)-CsA concentration. In this study data of 16 stable renal and renal/pancreas recipients treated with prednisone, azathioprine, and CsA (Neoral) managed by C(0) level was examined. CsA concentrations at time 0 (basal), 2, 6, and 12 hours post CsA (Neoral) intake were determined the day of the study. A significant linear regression level was established between C(2) (but not C(0), C(6) and C(12)) and the dosage expressed as mg/kg/d (P = 0.0113, correlation coefficient r = 0.573018). Subsequently, another 27 renal transplant recipients were studied retrospectively and divided into three groups according to posttransplant period: 1 to 6, 7 to 12, and beyond 12 months after transplant. Equations derived from the relationship between C(2) and dose (mg/kg/d) were similar between the three groups and when compared with the first study. A formula obtained from the 27 patients in the whole posttransplant period (mg/kg/d = C(2) x 0.0010208 + 1.86125) was applied to patients of the first study obtaining a regression coefficient between actual and calculated CsA dose of 0.6145 (P = 0.01). A more accurate equation (P = 0.0001, r = 0.5925) was obtained by analyzing 145 C(2) determinations covering a period from 1 month to 8 years following transplant which gave a linear regression line defined by the equation C(2) x 0.001473 + 1.6673. This equation would permit the calculation mg/kg/d of CsA (Neoral) dose to obtain an expected C(2) level. The derived equation shown in this paper has a predictive value of 50% to 60% only, but can help to find adequate dosage in the presence of an inappropriate C(2) level.     

Posaconazole pharmacokinetics, safety, and tolerability in subjects with varying degrees of chronic renal disease

Posaconazole is a triazole antifungal in development for the treatment of invasive fungal infections. The authors evaluated the pharmacokinetics and safety of posaconazole in healthy subjects and in those with mild (CL(CR) = 50-80 mL/min), moderate (CL(CR) = 20-49 mL/min), and severe chronic renal disease (CL(CR) <20 mL/min; receiving outpatient hemodialysis) (n = 6/group). Subjects received one 400-mg dose of posaconazole oral suspension with a standardized high-fat breakfast. For hemodialysis-dependent subjects, this dose was given on a nonhemodialysis day, and a second 400-mg dose was given 6 hours before hemodialysis. Blood samples were collected before dose and up to 120 hours postdose. For hemodialysis-dependent subjects following the second dose, additional samples (predialyzed and postdialyzed) were collected before, during, and after dialysis. There was no correlation between posaconazole pharmacokinetics and mild to moderate renal disease; the slopes of the linear regressions for creatinine clearance versus posaconazole AUC, C(max), CL/F, and t1/2 values were not significantly different from zero (P > .130). Mean CL/F values before and during hemodialysis were comparable. Furthermore, the difference in the predialyzed and postdialyzed posaconazole concentrations was only approximately 3%, supporting that posaconazole was not removed by hemodialysis. Protein binding was similar in all groups (approximately 98%) and was unaffected by hemodialysis. Posaconazole was generally well tolerated. One patient had elevated liver function test results that were not present at baseline and were thought to be possibly related to posaconazole. Results of this single-dose study indicate that dosage adjustments for patients with varying degrees of renal disease are not required.     

Clinical pharmacokinetics of candesartan

Candesartan cilexetil is the prodrug of candesartan, an angiotensin II type 1 (AT1) receptor antagonist. Absorbed candesartan cilexetil is completely metabolised to candesartan. Oral bioavailability is low (about 40%) because of incomplete absorption. Plasma protein binding in humans is more than 99%. The volume of distribution in healthy individuals is 0.13 L/kg. CV-15959 is the inactive metabolite of candesartan. Candesartan that reaches the systemic circulation is mainly cleared by the kidneys, and to a smaller extent by the biliary or intestinal route. The apparent oral clearance of candesartan is 0.25 L/h/kg after a single dose in healthy individuals. Oral clearance (3.4 to 28.4 L/h) is highly variable among patients. No relevant pharmacokinetic drug-food or drug-drug interactions are known. The terminal elimination half-life remains unclear, but appears to be longer than the currently used range of 4 to 9 hours. Non-compartmental models do not appear to be appropriate for the analysis of candesartan pharmacokinetic data. A 2-compartment analysis revealed a much longer half-life of 29 hours using data from patients with hypertension. However, a further indepth analysis has never been performed. The concentration-effect relationship is unaffected by age. No gender or race differences have been shown in the effect or pharmacokinetics of candesartan. Renal function affects the pharmacokinetic profile of candesartan. For patients with creatinine clearances of >60 ml/min x 1.73m(2), 30 to 60 ml/min x 1.73m(2) and 15 to 30 ml/min x 1.73m(2), the elimination half-life is 7.1, 10.0 and 15.7 hours, respectively, at a dose of 8 mg/day. However, at 12 mg/day an accumulation factor of 1.71 was found. Thus, a maximum daily dose of up to 8mg appears suitable in patients with severe renal dysfunction. No significant elimination of candesartan occurs with haemodialysis. In patients with mild to moderate hepatic impairment, no relevant pharmacokinetic alterations have been observed. Dosages of up to 12 mg/day do not require precautions in patients with mild to moderate liver disease. Clinically effective dosages range between 8 and 32 mg/day. The response rate of monotherapy with candesartan in patients with hypertension increases with dosage, but never exceeds 60% at a daily dosage of 16mg of candesartan. Dosages up to 32 mg/day do not increase this response rate.