Microdialysis study of imipenem distribution in skeletal muscle and lung extracellular fluids of noninfected rats

The aim of this study was to investigate the imipenem distribution in muscle and lung interstitial fluids by microdialysis in rats and to compare the free concentrations in tissue with the free concentrations in blood. Microdialysis probes were inserted into the jugular vein, hind leg muscle, and lung. Imipenem recoveries in these three media were determined in each rat by retrodialysis by drug period before drug administration. Imipenem was infused intravenously at a dose of 120 mg . kg-1 over 30 min, and microdialysis samples were collected for 150 min. The whole study was conducted with nonhydrated rats (n=4) and hydrated rats (n=6) while the animals were under isoflurane anesthesia. The decay of free concentrations in blood, muscle, and lung with time were monoexponential; and the concentration profiles in these three media were virtually superimposed in both groups. Accordingly, the ratios of the area under the curve (AUC) for tissue (muscle or lung) to the AUC for blood were always virtually equal to 1. Compared to values previously determined with awake rats, clearance was reduced by 2 and 1.5 in nonhydrated and hydrated rats, respectively, but the volume of distribution was unchanged. By combining microdialysis in blood and tissues, it was possible to demonstrate that free imipenem concentrations were virtually identical in blood, muscle, and lung.     

Microdialysis study of imipenem distribution in the peritoneal fluid of rats with experimental acute pancreatitis

Imipenem distribution was characterized by microdialysis in the peritoneal fluid of rats with experimental pancreatitis. The ratios of peritoneal fluid to blood area under unbound concentration-versus-time curves were close to unity, suggesting that imipenem was not degraded in peritoneal fluid.     

Microdialysis study of imipenem distribution in skeletal muscle and lung extracellular fluids of Acinetobacter baumannii-infected rats

The aim of this study was to investigate imipenem distribution in muscle and lung interstitial fluids of rats with Acinetobacter baumannii pulmonary infection. By combining microdialysis in blood and tissues, it was possible to demonstrate that free imipenem concentrations were virtually identical in blood, muscle, and lung.     

Microdialysis study of imipenem distribution in the intraperitoneal fluid of rats with or without experimental peritonitis

The purpose of this study was to extend the use of microdialysis to the investigation of antibiotic distribution into the intraperitoneal fluid of rats with or without peritonitis. Microdialysis probes were inserted into the jugular vein and peritoneal cavity of control rats or rats with intra-abdominal sepsis (n = 8 in each group) induced by cecal ligation and punctures. Imipenem (IPM) probe recoveries were determined in each rat by retrodialysis by drug. IPM was infused intravenously at a dose of 30 mg · kg⁻¹ over 30 min, microdialysis samples were collected for 120 min, and IPM concentrations were determined by high-performance liquid chromatography. Intraperitoneal infection had no statistically significant effect on IPM clearance (11.9 ± 2.3 ml · min⁻¹ · kg⁻¹ in control rats versus 10.9 ± 2.1 ml · min⁻¹ · kg⁻¹ in rats with peritonitis) or the volume of distribution (296 ± 47 ml · kg⁻¹ in control rats versus 310 ± 49 ml · kg⁻¹ in rats with peritonitis). IPM concentration profiles in intraperitoneal fluid and blood were virtually superimposed in control rats, whereas in infected animals, the mean intraperitoneal IPM concentrations were apparently slightly lower than corresponding blood levels. However, the areas under the concentration-versus-time curve estimated in intraperitoneal fluid and blood were not significantly different in both groups, with the corresponding ratios close to unity (1.01± 0.19 and 0.89 ± 0.28 in control rats and rats with peritonitis, respectively). In conclusion, IPM distribution in intraperitoneal fluid is rapid and complete both in control rats and in rats with peritonitis.     

Pharmacokinetic-pharmacodynamic modelling of the electroencephalogram effect of imipenem in rats with experimental hypovolaemia or endotoxaemia

OBJECTIVES: The epileptogenic activity of imipenem in rats with experimentally induced hypovolaemia or endotoxaemia was investigated by pharmacokinetic-pharmacodynamic modelling of the electroencephalogram effect. METHODS: Hypovolaemia was induced by removal of 30% of the blood volume and endotoxaemia by intravenous lipopolysaccharide injection. RESULTS: Imipenem clearance and volume of distribution values of 16.4+/-1.1 mL/min per kg and 357+/-49 mL/kg (mean+/-S.E.M.) in healthy rats (n=5), were significantly reduced in hypovolaemic (n=6) and endotoxaemic (n=6) animals. A dose reduction from 250 mg/kg to 120 mg/kg was necessary in endotoxaemic rats. The pharmacokinetic-pharmacodynamic model with an effect compartment previously developed in healthy rats described the data adequately and pharmacodynamic parameters in hypovolaemic and endotoxaemic rats were not significantly different from corresponding values estimated in the control group. CONCLUSION: Hypovolaemia and endotoxaemia only had an effect on imipenem pharmacokinetics.     

Lack of in vitro inactivation of tobramycin by imipenem/cilastatin.

OBJECTIVE: Inactivation of aminoglycosides by beta-lactam antimicrobials both in vitro and in vivo has been documented. Such an interaction has not previously been documented between carbapenems and aminoglycosides. Examination of serum concentrations of tobramycin in a patient receiving both agents suggested that this interaction might exist. The purpose of this study was to look at this question in an in vitro model. METHODS: Low concentrations of tobramycin (10 micrograms/mL) were incubated with imipenem/cilastatin (concentrations of 10, 20, and 40 micrograms/mL) in human serum at 37 degrees C. Aliquots of these solutions were withdrawn at 0, 6, 24, 72, and 120 hours and assayed for tobramycin concentrations using a fluorescence polarization immunoassay. Aliquots of tobramycin 10 micrograms/mL and carbenicillin 200 micrograms/mL were analyzed in the same manner, as a positive control. High concentrations of tobramycin (800 micrograms/mL) and imipenem (5000 micrograms/mL)/cilastatin were incubated together at 21 degrees C and sampled at 0, 6, 24, and 72 hours for tobramycin concentrations. RESULTS: The degradation rates for low-concentration tobramycin and the various concentrations of imipenem/cilastatin were not statistically different from those of the controlled incubations. In contrast, carbenicillin significantly enhanced the degradation rate of tobramycin at this concentration (half-life 72 hours and a 34 percent loss at 24 hours, p = 0.0028). Higher in vitro concentrations of imipenem (5000 micrograms/mL)/cilastatin and tobramycin (800 micrograms/mL) resulted in significant, but moderate degradation over controlled incubations (half-life 80 hours and 10 percent loss at 12 hours, p = 0.0031). CONCLUSIONS: These results suggest that inactivation of tobramycin is not a problem at common clinically achievable imipenem serum concentrations in patients.     

Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effect of imipenem in healthy rats

A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was developed to investigate the epileptogenic activity of imipenem in rats. Initially, animals received an intravenous infusion of imipenem at a rate of 2.65 mg min(-1) for 30 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. A dramatic delay was observed between concentrations of imipenem in serum and the EEG effect; this effect was accompanied by tremors and partial seizures. Indirect-effect models failed to describe these data, which were successfully fitted using an effect compartment model. The relationship between effect and concentration at the effect site was best described by a spline function. The elimination rate constant from the effect compartment was severalfold lower than that from the central compartment. The robustness of the model was then confirmed after administering the imipenem dose over 60 and 90 min. In conclusion, the successful PK-PD modeling of the imipenem EEG effect in rats constitutes a major improvement for better prediction of the epileptogenic risk associated with this antibiotic.     

Lack of effect of ofloxacin on theophylline pharmacokinetics in rats

Effect of ofloxacin, a new quinolone antibacterial agent, on the pharmacokinetics of theophylline was studied in rats in comparison with that of enoxacin and cimetidine. Ofloxacin by pretreatment with five oral doses of 50 mg/kg did not increase serum concentrations of theophylline (5 mg/kg, i.v. single) and showed no significant effect on total body clearance, serum half-life (T1/2) and AUC of theophylline, while enoxacin by the same pretreatment increased significantly serum theophylline concentrations and resulted in significant effect on all the pharmacokinetic parameters. Coadministration of ofloxacin (80 mg/kg, p.o. twice) did not induce a significant effect on the pharmacokinetic parameters of theophylline at repeated doses (50 mg/kg, i.v., twice daily for 3 days). On the contrary, coadministration of enoxacin and cimetidine at the same dose as ofloxacin remarkably increased serum concentrations of theophylline at the same repeated doses, and caused a significant decrease in clearance and an increase in T1/2 and AUC. The three drugs had no influence on rat serum protein binding of theophylline. Ofloxacin exhibited a weak inhibitory effect on rat hepatic microsomal cytochrome P-450-dependent monooxygenases, whereas enoxacin and cimetidine induced a significant inhibition of the enzymes. Thus, it is concluded that ofloxacin has no significant effect on the pharmacokinetics of theophylline in rats, and that enoxacin raises serum theophylline concentrations and results in a significant effect on the theophylline pharmacokinetics by inhibition of the hepatic microsomal monooxygenases in rats.     

Interaction of imipenem with erythromycin and tetracycline assessed by microdilution checkerboard techniques.

Microdilution methodology was used to study the interaction of imipenem with erythromycin and tetracycline, a combination therapy that might be used for the treatment of serious pelvic inflammatory disease. The combination of imipenem and erythromycin showed no antagonism for Escherichia coli and Haemophilus influenzae but was antagonistic for Staphylococcus aureus, Enterococcus faecalis, and group B streptococci; the combination of imipenem and tetracycline was antagonistic for all strains except H. influenzae. Correlation between the results of kill curves and the measurement of fractional bactericidal concentration (FBC) indices was good, although FBC indices showed less antagonism than kill curves. Fractional inhibitory concentration indices showed poor correlation, rarely showing antagonism, and indeed showed synergy in three cases. If erythromycin or tetracycline is considered necessary in addition to imipenem in the treatment of pelvic inflammatory disease, it is probably more effective when given after the course of imipenem has been completed.     

运动对制动大鼠骨骼肌中雄激素受体的影响

目的探讨在废用性肌肉萎缩和康复过程中骨骼肌雄激素受体(androgenreceptor,AR)的变化,以及不同的康复锻炼方式对肌萎缩恢复的作用.方法将30只雄性SD大鼠随机分为5组A组,正常对照组;B组,外固定3周后即刻宰杀组;C组,外固定3周后自然恢复3周组;D组,外固定3周后跑台训练3周组;E组,外固定3周后游泳训练3周组.以葡聚糖包裹活性炭吸附法测定AR结合容量.结果外固定3周后,大鼠股四头肌组织的AR结合容量(7.99±2.19fmol/mg)较正常对照组(11.61±2.96fmol/mg)显著下降;自然康复组的AR结合容量(10.41±3.90fmol/mg)无明显变化.运动组的AR结合容量较对照组及自然康复组均有显著增高,以跑台组(25.70±7.53fmol/mg)增高的幅度更大.结论外固定造成萎缩肌组织的AR结合容量显著下降;适宜的运动训练可以通过提高局部肌肉组织的AR结合容量加速肌萎缩的康复进程;雄激素对骨骼肌AR的正相调节作用是运动后AR水平增高的原因之一.     

Tissue distribution of imipenem in critically ill patients

BACKGROUND AND METHODS: Imipenem is a broad-spectrum antibiotic used mainly for serious infections in critically ill patients. Because the infection originates mostly from a certain tissue, we assessed tissue concentrations of imipenem using microdialysis in patients in intensive care with serious infections compared with healthy volunteers. Most patients were >60 years old and had renal failure; most patients also had impaired liver, heart, or lung function. RESULTS: Muscle and subcutaneous tissue concentrations in patients (maximum of 2.3 +/- 1.5 microg/mL for both muscle and subcutaneous tissue) were significantly lower than those in healthy subjects (maximum of 12.8 +/- 1.6 and 10.7 +/- 1.0 microg/mL for muscle and subcutaneous tissue). The tissue distribution rate constants for muscle and subcutaneous tissue were also significantly lower in patients (1.95 +/- 0.6 and 1.1 +/- 0.2 h(-l), respectively) than in healthy subjects (5.2 +/- 1.0 and 6.6 +/- 1.7 h(-1), respectively), meaning that tissue distribution in patients was reduced and retarded. Values for area under the plasma concentration-time curve did not significantly differ between patients and healthy subjects (37.4 +/- 5.9 microg. h/mL and 46.0 +/- 4.4 microg. h/mL, respectively,) although the elimination of imipenem in patients was prolonged (clearance, 6.3 +/- 0.8 L/h and 13.2 +/- 1.4 L/h in patients and healthy subjects, respectively). CONCLUSIONS: Our data suggest that the amount and velocity of imipenem tissue distribution in seriously ill patients is reduced compared with those values in healthy volunteers. Dose adjustments that are exclusively based on plasma concentration data may therefore be misleading and may result in potential underdosing.     

The effect of ultrasound on experimental oedema in rats

The effect of ultrasound at a space-averaged intensity of 0.5 W/cm²:administered for 2–5 min at frequencies of 2.9, 1.5 and 0.79 MHz and mark-space ratios of 1:4(2 ms:8 ms) and 1:1(2 ms:2 ms) was investigated on the acute oedema response of rats to intracutaneous injection of silver nitrate. Rats. anaesthetized with ether were given Evans blue intravenously and two intracutaneous injections of silver nitrate (2 × 10^?6 mol) into the abdominal skin. Insonation of one skin site and mock-insonation of the other was performed immediately after the injections. Rats were killed 30 min after the injections and oedema response measured by the amount of dye leakage expressed as absorbance. Significant reduction of dye leakage occurred with treatment of injection sites with ultrasound at 0.79 MHz frequency and durations of application of 2 and 4 min for both mark-space ratios,but not with the other frequencies and durations tested. Further studies are necessary to determine the relevance of this finding to the clinical efficacy of ultrasound in certain inflammatory conditions     

Postantibiotic effect of imipenem on Pseudomonas aeruginosa.

Imipenem (formerly N-formimidoyl thienamycin) and ceftazidime were investigated for their postantibiotic effect on Pseudomonas aeruginosa. Four strains of P. aeruginosa in the logarithmic phase of growth were exposed for 1 and 2 h to concentrations of antibiotics achievable in human serum. Recovery periods of test cultures were evaluated after dilution or addition of beta-lactamase. A consistent postantibiotic effect against all strains was obtained with imipenem but not with ceftazidime. Although ceftazidime did not have a postantibiotic effect, it did suppress the growth of the organisms at concentrations equivalent to one-third of the MIC. The clinical implications of these effects need further evaluation.     

Lack of extracellular slime effect on treatment outcome of Staphylococcus epidermidis experimental endocarditis

We studied the response of two slime negative Staphylococcus epidermidis strains (NS1 and NS2) and one slime producing strain (S1) to treatment with vancomycin in the rabbit catheter-induced endocarditis model. All micro-organisms had vancomycin minimal inhibitory concentration and minimal bactericidal concentration of 4 mg/l. Three days after infection, treatment with vancomycin 25 mg/kg every 12 h was begun and continued for 4 days. Cardiac valve vegetations were harvested 12 h after the last dose of vancomycin and cultured quantitatively. In treated animals the mean +/- S.D. log10 colony forming units per g of cardiac valve vegetation were 1.6 +/- 0.1 for NS1, 4.4 +/- 1.9 for NS2, and 2.3 +/- 1.2 for S1. Slime production did not influence the results of vancomycin therapy of S. epidermidis experimental endocarditis. Other factors may cause strain-dependent variability in response to antimicrobial treatment in this model.     

Pharmacokinetics and distribution over the blood brain barrier of two acyclic guanosine analogs in rats, studied by microdialysis.

The free extracellular concentrations of acyclovir and (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G) in the blood and in brain tissue of rats were measured in microdialysis samples by high-pressure liquid chromatography with UV detection. The half-life of acyclovir in blood was 2 h, while that of H2G was 28 min. The concentration attained in the brain compared with the concentration in blood was slightly lower for H2G than for acyclovir. The results show that the pharmacokinetic profiles of acyclic nucleosides may vary as a consequence of the structure of the acyclic chain corresponding to the sugar moiety.     

Lack of effect of indomethacin on systemic and splanchnic haemodynamics in portal hypertensive rats

Portal hypertension was produced experimentally in rats by partial constriction of the portal vein. Twelve rats were injected daily with indomethacin, 4 mg/kg body weight, and 12 with the vehicle (80% ethanol, 0.5 ml/day). There were no differences in portal-systemic shunts nor systemic or splanchnic haemodynamics between indomethacin-treated and untreated rats. These results suggest that cyclo-oxygenase products do not play a significative role in haemodynamic alterations shown by portal-ligated rats.     

Analysis of ceftriaxone and ceftazidime distribution in cerebrospinal fluid of and cerebral extracellular space in awake rats by in vivo microdialysis.

In vivo microdialysis was used to estimate the extracellular concentrations of ceftazidime and ceftriaxone, two expanded-spectrum cephalosporins commonly used in the treatment of bacterial meningitis, in two brain regions (the right corpus striatum and the left lateral ventricle_ of awake, freely moving rats. Antibiotics were administered by constant intravenous infusion at 18 mg/h until steady-state levels were reached. Ceftriaxone levels measured at the steady state in the extracellular space of the corpus striatum (0.80 +/- 0.17 micrograms/ml) were statistically equivalent to those obtained in the cerebrospinal fluid of the lateral ventricle (0.71 +/- 0.15 micrograms/ml). The ratios of these levels in the brain to the steady-state levels in plasma were 0.5 +/- 0.1% for both regions. The postinfusion concentrations of ceftriaxone in the brain declined monoexponentially, with an elimination half-life similar to that obtained in plasma. However, the mean antibiotic concentration of ceftazidime in the striatum (2.2 +/- 0.4 micrograms/ml) was lower (P < 0.001) than that in the lateral ventricle (3.8 +/- 0.5% and 4.0 +/- 1.8%, respectively) were higher than those obtained with ceftriaxone. Moreover, the half-life of ceftazidime elimination from plasma was lower than that obtained in the two brain regions. It was concluded that the in vivo microdialysis technique yields useful data on antibiotic distribution in the extracellular space of the brain, that the distribution may not be homogeneous, and that the decay of postinfusion concentrations in the brain may be different from the decay of postinfusion concentrations in plasma.     

Noradrenaline release in skeletal muscle and in adipose tissue studied by microdialysis.

1. In adipose tissue and in skeletal muscle the extracellular noradrenaline levels were studied by microdialysis in the conscious dog and compared with the noradrenaline concentration in arterial plasma. 2. The experiments were performed with and without tyramine added to the perfusion medium, and noradrenaline was measured by a sensitive radioenzymic assay. 3. In the absence of tyramine, the interstitial noradrenaline levels in adipose tissue and skeletal muscles were similar to arterial blood concentrations, provided that the former were corrected for recovery. The recovery estimated from experiments in vitro averaged 16% at room temperature. 4. With tyramine added to the perfusates, noradrenaline levels increased 10-fold. Arterial noradrenaline concentrations did not change, indicating that noradrenaline was released only locally in the tissue. 5. Our results indicate that the microdialysis technique combined with a sensitive assay for measuring noradrenaline may be applicable to the assessment of local noradrenaline release in adipose tissue and in skeletal muscle. This may be of interest, especially in adipose tissue during physiological stimulation in which sympathetic activity is difficult to evaluate by other techniques.     

Penetration of ertapenem into muscle measured by in vivo microdialysis in mechanically ventilated patients

Ertapenem at 1 g once daily has been suggested to be underdosed in intensive care unit (ICU) patients to attain optimal concentrations in target tissues. Therefore, our study aimed to assess the kinetics of ertapenem in plasma and skeletal muscle in ICU patients using microdialysis. Average muscle free-ertapenem concentrations were above the MIC values of targeted pathogens. In a few patients, the concentrations were below the MIC values. The clinical efficiency of ertapenem at 1 g once daily should be evaluated in a large population of ICU patients.