Tobramycin Serum Concentrations After Aerosol and Oral Administration in Cystic Fibrosis

We sought to describe tobramycin absorption after aerosol administration to cystic fibrosis (CF) subjects. Serum tobramycin concentrations were determined by modification of the radioimmuno-assay (RIA) technique, lowering the limit of detection from 1.0 &mgr;g ml(minus sign1) to 0.05 &mgr;g ml(minus sign1). In 37 studies, after aerosol delivery of 666 plus minus 195 mg to the airway of 24 patients, in which 222 samples were assayed, only 1 serum sample contained tobramycin at a concentration greater than 1.0 &mgr;g ml(minus sign1). Twenty-six of the 37 studies permitted estimation of pharmacokinetic parameters of tobramycin. The serum clearance of tobramycin following aerosol adminstration is 39.13 plus minus 0.393 L h(minus sign1) (mean plus minus standard error of the mean), with an elimination half-life of 3.072 plus minus 0.194 h. The half-life was significantly longer than that found after intravenous adminstration. The elimination rate constant (K(e)) was calculated to be 0.234 plus minus 0.002 h(minus sign1). Estimated total-body clearance in which systemic absorption was determined from sputum and urinary recovery of tobramycin was 0.094 plus minus 0.002 1 hr(minus sign1) kg(minus sign1). We also studied tobramycin absorption in six CF subjects after ingestion of a 80-mg m(minus sign2) dose, to gain insight into the tobramycin levels observed after swallowing an aerosol. Four out of the six subjects had measurable serum tobramycin concentration after ingestion. The serum concentration-time curve mirrored what was seen after aerosol administration. We concluded that tobramycin has poor systemic absorption in CF subjects after aerosol administration. Tobramycin in serum after aerosol administration is in part due to the gastrointestinal absorption of swallowed drug, as well as absorption from lower respiratory tract.     

Antibacterial activity of ticarcillin, tobramycin and gentamicin alone and in combination against Pseudomonas aeruginosa in vitro.

Using the biophotometer with ticarcillin no persistent bactericidal effect was found against Pseudomonas aeruginosa NCTC 10490. After addition of 1.2 microgram/ml gentamicin an increase of multiplication of bacteria was observed, but not after 1.2 microgram/ml tobramycin. With 6.2 microgram/ml tobramycin bactericidal effects lasted more than 24 h. In tube dilution test with Isotonic Sensi-test Broth out of 109 examined strains 51% were resistant to gentamicin, 16% to tobramycin and 4.5% to ticarcillin. If MIC values of gentamicin and tobramycin were calculated for magnesium-free media the resistance rate would be 10% for gentamicin and 3% for tobramycin. Combining subinhibitory doses of gentamicin or tobramycin with ticarcillin, most of the strains resistant to gentamicin and tobramycin became susceptible. The rate of inactivation of tobramycin by ticarcillin depends on the fluid into which they are placed. In combination therapy both antibiotics should be applied separately and immediately one after the other.     

半自动和全自动透析器复用方式对透析器复用效果的影响

目的 探讨半自动和全自动透析器复用方式对透析器复用效果的影响.方法 将1728支可重复使用的透析器随机分为半自动复用组和全自动复用组各864支,观察2组透析器冲洗、检测时间、使用灭菌剂成本及热原反应、透析器破膜发生率、透析器重复检测数.结果 半自动复用组透析器冲洗、血室容积检测和压力测试时间分别为(26.443±3.237),(2.172±0.128),(2.157±0.090)min,灌注3.5%伦拿连灭菌剂成本为(1.698±0.107)元,支,共有499支和243支透析器需重复进行血室容积检测及压力检测,重复检测率达57.755%和28.125%;全自动复用组透析器冲洗、血室容积检测和压力测试时间为(5.793±0.193),(1.257±0.118),(1.110±0.076)min,透析器检测均能1次完成,灭菌剂成本(9.330±0.138)元/支,2组透析器用于血液透析均未见热原反应及透析器破膜发生.结论 半自动复用组在灌注过程中能有效节省灭菌剂成本.但透析器冲洗时间长、缺乏配套检测装置,检测费时、数据不易读取,透析器重复检测率高;而全自动复用组透析器冲洗、检测方便,但消耗灭菌剂成本高,设备投入昂贵,透析中心需配置合理数量才能满足临床需求.     

Pharmacokinetic Studies of Tobramycin and Gentamicin

Broth dilution susceptibility tests of 100 isolates of Pseudomonas aeruginosa and 101 isolates of Staphylococcus aureus against tobramycin (formerly nebramycin factor 6) and gentamicin showed that tobramycin was more effective against P. aeruginosa and less effective against S. aureus. The minimal inhibitory concentration of tobramycin against the Pseudomonas sp. isolates that required 5 mug of gentamicin per ml for inhibition ranged from 0.63 to 0.31 mug/ml. Peak concentrations in the blood of 10 healthy adults after intramuscular injection of 80 and 40 mg of tobramycin averaged 3.7 +/- 0.62 and 2.4 +/- 0.27 mug/ml, and declined to 0.56 +/- 0.05 and 0.26 +/- 0.02 mug/ml, respectively, after 6 h. The urine recovery averaged 60%. The half-life was 1.6 h. During continuous intravenous infusion of tobramycin and gentamicin (infusion rate 6.6 mg per h), blood levels at steady state were 0.94 +/- 0.10 and 1.04 +/- 0.06 mug/ml, respectively. For both antibiotics, the calculated distribution volume ranged from 15 to 17 liters. The renal clearance to tobramycin averaged 76% and that of gentamicin averaged 85% of the total clearance, indicating that the drugs are primarily eliminated by the kidneys. The present results suggest that tobramycin may be more successful in the treatment of Pseudomonas infections than gentamicin at the same dosage (80 mg intramuscularly three to four times daily).     

Feasibility of Administering Aminoglycoside Antibiotics by Continuous Intravenous Infusion

Eleven patients each received gentamicin sulfate, tobramycin, and sisomicin by continuous intravenous infusion after an initial loading dose. Subsequent doses of antibiotic were adjusted in an attempt to maintain constant serum concentrations. There was considerable variation in the serum concentration from patient to patient and in the same patient from day to day with each drug. Although the dosages of gentamicin sulfate and tobramycin were similar, the serum concentrations of the latter drug were consistently lower. Despite the daily administration of doses of at least 300 mg of gentamicin and tobramycin per m² and 160 mg of sisomicin per m², nephrotoxicity occurred in only three patients. This is a low frequency of nephrotoxicity, considering the dosages of drug administered. Although therapeutic efficacy was not an objective of this study, 8 of 11 documented infections were cured. This approach to the administration of aminoglycoside antibiotics deserves therapeutic trials.     

Assay of Gentamicin and Tobramycin in Sera of Patients by Gas-Liquid Chromatography

Therapeutic levels of gentamicin and tobramycin in the sera of patients were measured by gas-liquid chromatography. Concentration-response curves for both drugs were linear over an expected therapeutic range of 1.3 to 12.5 mug/ml (coefficient of determination was >0.97). Coefficients of variation for chromatographic response to gentamicin varied from 6.3 to 9.6%, and to tobramycin from 3.8 to 13.5%. Paired gas-liquid chromatography and microbiological assays for patient serum aminoglycoside levels were performed on 106 gentamicin and 40 tobramycin sera. At levels <2.0 mug/ml, the average difference of estimates between the two assay techniques for gentamicin and tobramycin were, respectively, 38 and 29%. At drug concentrations >2.0 mug/ml, the mean difference between paired estimates was near 20% for both aminoglycosides. The speed, precision, and accuracy of the gas-liquid chromatography assay indicate that it can be a useful alternative to the microbiological procedure for the determination of gentamicin and tobramycin levels in human serum.     

In vivo uptake kinetics of aminoglycosides in the kidney cortex of rats

The renal cortical uptake kinetics of four aminoglycosides were studied in vivo. Gentamicin, netilmicin, tobramycin or amikacin were administered to rats by continuous infusion over 6 hr achieving constant serum levels ranging from 0.2 to 100 micrograms/ml. Renal cortical concentrations at the end of the infusion were plotted against the steady-state serum levels. Steady-state elevations of serum gentamicin and netilmicin were associated with nonlinear increases in cortical levels, suggesting saturable uptake. Analysis of the data using Michaelis-Menten kinetics indicates that the apparent Km for gentamicin and netilmicin were 15.01 and 23.84 micrograms/ml and Vmax 149.83 and 178.36 micrograms/g of cortex per hr, respectively. The "initial" rate of uptake (at serum levels below 15 micrograms/ml) was highest for gentamicin. The cortical uptake of tobramycin was linearly related to elevations in serum levels [cortex concentration (conc) = 9.24 + 1.40 serum conc]. The initial rate of tobramycin uptake was considerably lower than that for gentamicin and netilmicin. For amikacin, the initial rate of uptake followed Michaelis Menten kinetics and the second phase of the titration curve was linear. The equation for total amikacin uptake was: cortex conc = 12.98 + 1.71 serum conc. Aminoglycosides exhibit differing kinetics for renal cortical uptake in the rat during constant infusions. These results indicate that more than one mechanism probably mediates the uptake of each aminoglycoside. Depending on which mechanism predominates, the kinetic pattern may be saturable, linear or mixed.     

Antibacterial activity of tobramycin against gram-negative bacteria and the combination of ampicillin/tobramycin against E. coli.

The antibacterial activity of tobramycin, gentamicin, erythromycin, cloxacillin, kanamycin, cephalexin, penicillin, carbenicillin and polymyxin were compared against 303 clinical bacterial isolates from a pediatric hospital patient population. Standard disk diffusion and agar-dilution methods were employed. Significant activity was demonstrated for tobramycin against pseudomonas, Klebsiella, Escherichia coli and both Staphylococcus aureus and albus; Tobramycin was significantly more active against Pseudomonas than gentamicin or the other antibiotics testedmcomparable activity to gentamicin was present for the other types of bacteria; Cross-resistance was not encountered between tobramycin and gentamicin. 30 isolates of E. coli were tested against the combination of tobramycin and ampicillin by the growth-curve method. Synergism was demonstrated in 4 isolates, antagonism in 1 and an additive effect in 25. A bactericidal effect was present at 24h against 17 isolates with tobramycin alone and against 25 isolates when combined with ampicillin. These results provide in vitro rationale for the consideration of tobramycin for clinical use in patients with Psuedomonas infections for the combination of ampicillin and tobramycin for the treatment of selected E.coli infections.     

Activity of Netilmicin Compared with Those of Gentamicin and Tobramycin Against Enterobacteria and Pseudomonas aeruginosa

The inhibitory activity of netilmicin against 500 isolates of gram-negative bacteria was compared with those of gentamicin and tobramycin. Netilmicin was considerably less active than tobramycin and slightly less inhibitory than gentamicin for Pseudomonas aeruginosa but was at least as active against Escherichia coli and Klebsiella pneumoniae as were the other two antibiotics. A few Klebsiella and Serratia isolates resistant to gentamicin and tobramycin were inhibited by netilmicin. All three antibiotics were strongly bactericidal for E. coli, K. pneumoniae and P. aeruginosa but had less lethal activity against the otherwise susceptible Serratia isolates tested. Some necessary precautions in reading minimal inhibitory concentrations on agar media are stressed, and some possible advantages of a 4-h bactericidal test, using a constant antibiotic concentration, are defined.     

血液透析机表面污染境况调查

目的调查现行感染控制管理制度下,血液透析机治疗前后表面污染情况及进行消毒擦拭前后的差别。方法在严格按照《北京市血液透析质量控制管理规范》实施感染控制管理的前提下,进行日常2个班次的透析治疗。依据《医院消毒卫生标准》GB15982-1995要求,对上、下午透析前后33台血液透析机的台面及面板取样进行细菌培养,并依据《医院消毒卫生标准》GB15982-1995标准评价其检测结果。结果所有样本总合格率96.2%,其中上、下午透析前合格率均为100%,上、下午透析后未擦拭前合格率分别为93.9%和90.9%。各班次透析前、后菌落计数对比差异有统计学意义(P<0.05);2班次之间进行消毒擦拭前后菌落计数对比差异无统计学意义(Z=-1.61,P>0.05),但是擦拭后的合格率达100%。结论《北京市血液透析质量控制管理规范》规定的透析治疗各班次之间擦拭消毒血液透析机是必要而且有效的。     

Pseudomonas aeruginosa bacteremia: susceptibility of 100 blood culture isolates to seven antimicrobial agents and its clinical significance.

The susceptibility of 100 blood culture isolates of Pseudomonas aeruginosa observed during 4 1/2 years was tested for tobramycin, netilimicin, gentamicin, amikacin, pirbenicillin, ticarcillin and carbenicillin, singly and in combination. For aminoglycosides, the agar MICs were twofold to threefold greater than tube dilution MICs but for the penicillins they were similar. For aminoglycosides and ticarcillin, the MBCs were twofold greater than the tube dilution MICs. The MBCs were not achieved at concentrations as high as 512 micrograms/ml for 40% of the isolates for pirbenicillin and for 10% for carbenicillin. Tobramycin and pirbenicillin had the lowest MICs for the aminoglycosides and penicillins, respectively. Synergism was tested and observed between tobramycin + ticarcillin and amikacin + ticarcillin. No overall increase in resistance to gentamicin or carbenicillin was seen from 1974 to 1977. However, patients given repeated courses of gentamicin had more resistant strains. Following the administration of 1.5 mg/kg/dose of gentamicin, peak serum concentrations failed to achieve the MIC for the microorganism in 22% of the patients. The MIC was achieved in all patients receiving the same dose of tobramycin. The overall fatality rate was 67% with one third of the patients dying within 36 hr. There was no relationship of patient fatality rate and MIC for the microorganism. Although in the rapidly fatal group of all patients receiving inappropriate therapy died, the fatality rates of appropriately or inappropriately treated patients in the ultimately fatal and nonfatal groups were similar. Underlying host disease was the major determining factor in patient survival.     

Comparative nephrotoxicity of gentamicin and tobramycin: pharmacokinetic and clinical studies in 201 patients.

A total of 201 critically ill patients were studied during 267 courses of gentamicin or tobramycin treatment (139 gentamicin courses and 128 tobramycin courses). Of these 267 courses, pharmacokinetic and clinical data were obtained for 240 (120 gentamicin and 120 tobramycin). The data collected for pharmacokinetic analysis included measurements of serial blood and urine levels, urinary excretion of beta 2-microglobulin, protein levels, and granular casts. A two-compartment model was used to assess tissue accumulation, and in 89 courses the predicted accumulation was confirmed by cumulative urine collection or postmortem tissue analysis. As groups, the patients given gentamicin and tobramycin did not differ in age, weight, creatine clearance, total dose given, duration of treatment, initial aminoglycoside through serum levels, number of dosage adjustments, concurrent use of furosemide, or concurrent cephalosporins. Previous aminoglycoside treatment (usually gentamicin) had occurred more frequently in the tobramycin treated patients (P less than 0.01), and more males than females received tobramycin (P less than 0.05). Pharmacokinetic assessments of renal damage were based on both changes in glomerular filtration rate (serum creatinine levels, creatinine clearance) and renal tubular damage (beta 2-microglobin, casts), but only patients with elevated aminoglycoside tissue levels leading to renal tubular damage and subsequent creatinine clearance decreases were considered to have experienced aminoglycoside nephrotoxicity. In the pharmacokinetic analysis of nephrotoxicity, 29 gentamicin courses (24%) and 12 tobramycin courses (10%) were complicated by nephrotoxicity (P less than 0.01). The 201 study patients were also evaluated independently for clinical nephrotoxicity (defined as a serum creatinine level increase of 0.5 mg/dl or more). Clinical nephrotoxicity occurred at rates of 37% in the gentamicin-treated group and 22% in the tobramycin-treated group (P less than 0.02). In these similar groups of critically ill patients, tobramycin was less nephrotic than gentamicin.     

Tandem plasmapheresis and hemodialysis.

Many patients requiring plasmapheresis (PE) have renal failure and also need hemodialysis. If done separately almost 6-7 h is required. Hence, we decided to perform the procedures simultaneously in those patients requiring both PE and hemodialysis. The plasmafilter was inserted into the extracorporeal circuit after the hemodialyzer. A total of 8 such sessions of tandem PE and hemodialysis were performed in 2 patients. This is called tandem PE/hemodialysis. The total procedure was completed in the same time as is required for routine hemodialysis. The total amount of priming fluid is also less when PE and hemodialysis are performed separately. Thus, it is economically beneficial to the hospital and also convenient to the patient. Apart from transient episodes of hypotension, which were corrected by saline infusion, no other complications were noted.     

维持血液透析患者血清钙、磷、甲状旁腺激素水平及高通量滤器干预观察

目的 改善慢性肾衰竭尿毒症维持血液透析患者钙、磷、甲状旁腺代谢紊乱.方法 对解放军第451医院原有82例患者改用高通量滤器透析治疗3个月后,对照钙、磷、甲状旁腺素（iPTH）水平.所有患者B超检测甲状旁腺,并进一步分为增生、非增生2组对比此效果.结果 高通量滤器透析患者血钙升高（t=-4.786,P＜0.05）,血磷、甲状旁腺素水平降低（t=2.341,P＜0.05,iPTH=2.937,P＜0.05）,甲状旁腺增生组效果更为明显（Ca∶ t=-3.583/-3.207,P=0.001/0.003;P：t=1.74/1.619,P=0.089/0.113,iPTH∶ t=2.408/1.830,P=0.001/0.074）. 结论 高通量滤器透析改善了尿毒症维持血液透析患者钙、磷、甲状旁腺代谢紊乱.     

Aminoglycoside resistance and aminoglycoside usage: ten years of experience in one hospital.

For 10 years the 700-bed Minneapolis Veterans Affairs Medical Center has conducted a policy of carefully controlled aminoglycoside usage and monitoring of resistance of over 25,000 aerobic and facultative gram-negative bacillary isolates to the aminoglycosides. On two occasions during the 1980s, our experience of introducing amikacin at a high level of usage was associated with a significant reduction in resistance to gentamicin and tobramycin among gram-negative bacilli. Rapid reintroduction of gentamicin usage in 1982 after the first amikacin period was associated with a significant and rapid increase in gentamicin and tobramycin resistance. However, in 1986, gentamicin was again reintroduced to this institution at an initially modest level, and the percentage of usage of gentamicin was gradually increased over a 15-month period without a significant change in resistance to gentamicin, tobramycin, or amikacin while maintaining an overall 68% gentamicin usage and 30% amikacin usage. Aminoglycoside usage (measured as patient days) rose steadily from under 2,000 patient days per quarter in 1980 and 1981 to over 3,000 days per quarter in 1985. Since 1985, usage has declined to under 2,500 patient days per quarter in 1990. This usage rise and fall occurred during a steadily declining daily patient census that was 590 in 1980 and 465 in 1989. A move to a new hospital building in June 1988 was associated with an additional significant decline in resistance to all aminoglycosides (P less than 0.05), continuing a trend that was evident for the year preceding the move. Resistance to aminoglycoside antibiotics is now at the lowest level in 10 years at this institution, with only one gram-negative organism, Pseudomonas aeruginosa, that exhibits more than 5% resistance to gentamicin and no gram-negative species that are more than 5% resistant to amikacin and tobramycin.     

Pharmacokinetics of aerosolized tobramycin in adult patients with cystic fibrosis.

This study was performed to determine the clinical pharmacokinetics of tobramycin in six patients with cystic fibrosis (CF) after inhalation of 600 mg. Tobramycin was administered with an ultrasonic nebulizer (WISTO SENIOR). Blood and urine were sampled until 24 h after inhalation. Maximum tobramycin levels in serum varied from 0.19 to 2.57 mg/liter (mean 1.27 mg/liter; standard deviation, 1.07 mg/liter). Systemic availability (calculated from urinary output) ranged from 6.0 to 27.4% (mean, 17.5%; standard deviation, 8.8%). The results illustrate that, provided that the systemic availability of tobramycin is a reflection of pulmonary deposition, inhalation studies with CF patients should have a concentration-controlled design. Furthermore, reliance on dose recommendations from the literature for a new patient starting on this treatment is not justified, but it is mandatory that deposition kinetics be studied for each patient and for each nebulizer. It may well be that, with higher levels of deposition, dosages lower than those recommended in the literature will suffice to obtain the desired clinical effect. In addition, the reverse may also be the case.     

Pharmacokinetic modelling of a once-daily dosing regimen for intravenous tobramycin in paediatric cystic fibrosis patients

OBJECTIVES: This study was designed to determine an optimal dose range for the once-daily dosing (ODD) of tobramycin in the treatment of an acute pulmonary exacerbation in paediatric cystic fibrosis (CF) patients. In addition, we aimed to assess whether certain patient characteristics affect tobramycin pharmacokinetics and, therefore, dosing. METHODS: Patient characteristics and pharmacokinetic parameters of patients receiving tobramycin three times daily from 1 January 1992 to 31 October 2005 were analysed using univariate analysis and multiple linear regression to determine statistically significant relationships and to derive dosing models. The binary partitioning method was used to derive critical values to determine stratification within the chosen dosing model. RESULTS: Using multiple linear regression, age and sex were significantly associated with the volume of distribution divided by the body weight (V/kg). By the binary partitioning method, the critical value for age was 13.75 years. CONCLUSIONS: Age and sex were used to derive an ODD regimen for tobramycin in paediatric CF. Using a target peak concentration range of 25-35 mg/L, the initial dose for female CF patients at least 14 years of age was calculated to be 7 mg/kg/day given intravenously as a single daily dose. All other CF patients would receive an initial dose of 9 mg/kg/day given intravenously as a single daily dose. These dosing guidelines will require prospective evaluation for safety and efficacy.     

Renal toxicity during therapy with gentamicin or tobramycin

Twenty-seven patients who had normal pretherapy renal clearance by the [125I]iothalamate test were randomly assigned either gentamicin or tobramycin for therapy of infections due to susceptible bacteria. No patients were critically ill or had evidence of bacteremia. Mean age and duration of therapy were 51 years and 14 days, respectively, for 15 patients treated with gentamicin, and 45 years and 13 days for 12 patients treated with tobramycin. At the completion of therapy, six (40%) gentamicin and seven (58%) tobramycin patients had a decrease in renal clearance of at least 14% below baseline. The mean decrease was 26% in the gentamicin group and 23% in the tobramycin group. Simultaneous increases in serum creatinine concentrations (greater than or equal to 0.2 mg/dl) occurred in only 4 (31%) of the 13 patients. Of four patients who had renal clearance studies repeated 3 weeks to 6 months after therapy, two had stable function, but at 16 to 19% below baseline. Mean urinary concentration of N-acetyl glucosaminidase and alanine aminopeptidase increased faster and to higher levels with gentamicin than with tobramycin. However, on an individual patient basis, they were not predictive of a decrease in renal clearance in either therapy group.     

Comparative Activity of Tobramycin, Amikacin, and Gentamicin Alone and with Carbenicillin Against Pseudomonas aeruginosa

The effect of gentamicin against 130 clinical isolates of Pseudomonas aeruginosa was compared with that of two investigational aminoglycoside antibiotics, tobramycin and amikacin. Minimal inhibitory concentration data indicated that, on a weight basis, tobramycin was two to four times as active as gentamicin against most isolates. However, 14 of 18 organisms highly resistant to gentamicin (>/=80 mug/ml) were also highly resistant to tobramycin. Amikacin was the least active aminoglycoside on a weight basis, but none of the isolates were highly resistant to this antibiotic. When therapeutically achievable concentrations were used, adding carbenicillin to gentamicin or to tobramycin enhanced inhibitory activity against those isolates susceptible (相似文献   

In Vitro Activity of Tobramycin and Gentamicin

The in vitro antimicrobial activity of tobramycin and gentamicin was compared against 362 bacterial isolates. The minimal inhibitory concentration (MIC) of tobramycin was fourfold less than the MIC of gentamicin against most of 119 Pseudomonas organisms. Gentamicin and tobramycin had similar in vitro activity against Enterobacteriaceae and Staphylococcus aureus. Proteus rettgeri were commonly resistant to both tobramycin and gentamicin. The 10-mug tobramycin disc separated resistant (MIC >/=5 mug/ml) and susceptible (MIC <5 mug/ml) organisms in 359 of 362 tested. In disc diffusion testing, the tobramycin and gentamicin zone diameters were found to vary significantly with concentrations of magnesium ions in the media employed. The MIC of tobramycin varied with the size of the inoculum, and tobramycin was most effective at a neutral pH.