In-vitro adsorption and sieving coefficient of ticarcillin-clavulanate during continuous haemofiltration.

There are very limited data on ticarcillin-clavulanate elimination by haemofiltration. We measured in vitro ticarcillin-clavulanate adsorption to polyacrylonitrile (PAN) filters and the sieving coefficient using a well-described bench model of haemofiltration. The dose of ticarcillin-clavulanate was 60/2 mg or 180/3 mg, and 0 or 12 g albumin was added to the 1 L of circulating blood-crystalloid mixture to produce four different experimental conditions. The experiment was repeated four times under each condition. Median (interquartile range [IQR] ) ticarcillin adsorption varied from 28 (27-30) mg to 85 (78-90) mg. Adsorption was increased when the dose of ticarcillin was higher (P<0.001), but was not affected by the addition of albumin. Median (IQR) adsorption of clavulanate ranged from 0.67 (0.55-0.75) mg to 1.8 (0.33-3.5) mg and was neither dose dependent (P = 0.505) nor significantly affected by the addition of albumin. Median (IQR) ticarcillin sieving coefficient ranged from 0.73 (0.67-0.75) to 0.99 (0.97-1.03). It was significantly higher with a higher dose of ticarcillin (P = 0.021) and without addition of albumin (P = 0.015). Median (IQR) clavulanate sieving coefficient ranged from 1.03 (1.00-2.24) to 2.0 (1.98-2.47). Clavulanate sieving coefficient was not significantly affected by dose or the addition of albumin. These data indicate that significant adsorption of both ticarcillin and clavulanate occurs in vitro; however, this requires confirmation by clinical pharmacokinetic studies. The sieving coefficient data may help guide appropriate dosing of critically ill patients receiving haemofiltration until more extensive clinical pharmacokinetic data are available.

Clinical pharmacology of timentin (ticarcillin and clavulanic acid).

Ticarcillin (4 gm) and clavulanic acid (0.1 gm) were simultaneously administered as timentin to patients with cancer as therapy for infections. The pharmacokinetics of both ticarcillin and clavulanic acid were studied in 15 patients after 30-minute and 2-hour intravenous infusions. The mean (+/- SD) ticarcillin plasma peak concentrations after the two infusions were 341 +/- 76 and 210 +/- 60 micrograms/ml. The plasma terminal t1/2 values of ticarcillin were 80 +/- 32 and 56 +/- 12 minutes. The AUCs were 631 +/- 189 and 601 +/- 230 mg/L X hr. The volumes of distribution of the area were 15 +/- 5 and 21 +/- 7 L and total clearances were 115 +/- 36 and 127 +/- 54 ml/min. The corresponding values for clavulanic acid after the infusions are as follows: mean peak concentrations, 5 +/- 1 and 4 +/- 1 micrograms/ml; plasma terminal t1/2 values, 84 +/- 24 and 74 +/- 36 minutes; AUCs, 11 +/- 3 and 11 +/- 6 mg/L X hr; volumes of distribution of the area, 22 +/- 3 and 32 +/- 6 L; and total clearances, 170 +/- 58 and 175 +/- 68 ml/min.

Comparison of ampicillin-sulbactam and ticarcillin-clavulanic acid in patients with chronic renal failure: effects of differential pharmacokinetics on serum bactericidal activity.

STUDY OBJECTIVES: To evaluate the pharmacodynamic antibacterial activity of ticarcillin-clavulanic acid (T-C) and ampicillin-sulbactam (A-S) combinations against reference bacterial strains in patients with end-stage renal disease maintained on long-term hemodialysis. DESIGN: Randomized, crossover, controlled study. SETTING: National Institutes of Health-funded general clinical research unit in a Veterans Administration Medical Center. PATIENTS: Nine adult men with end-stage renal disease maintained on long-term hemodialysis. Two subjects did not complete the study due to problems of vascular access, and another withdrew for personal reasons. INTERVENTIONS: On a nondialysis day, each subject was randomly administered either T-C 3.1 g or A-S 3 g as a slow intravenous infusion over 30 minutes. Serial blood samples were collected for measurement of antibiotic serum concentrations and determination of serum bactericidal titers. Following a washout period, the study was repeated with the alternative antibiotic combination. MEASUREMENTS AND MAIN RESULTS: The mean observed apparent beta-half-life of clavulanic acid was substantially shorter than that for the other three drugs. The bactericidal activity of both A-S and T-C against non-beta-lactamase-producing (N beta-LP) strains of S. aureus and E. coli was consistently high, as indicated by geometric mean SBTs of at least 1:5 at 24 hours. Against beta-lactamase-producing (beta-LP) S. aureus, the geometric mean SBTs for A-S were at least 1:25 throughout the study period, while the geometric mean SBTs for T-C decreased over 24 hours from 1:29 to 1:6. Against beta-LP E. coli, the bactericidal activities for both A-S and T-C were poor, with geometric mean peak SBTs of only 1:6 and 1:3, respectively. The geometric mean SBT for T-C against this E. coli strain had declined to 1:1 at 6 hrs. CONCLUSION: Increasing the dosing interval for T-C in patients with end-stage renal disease may lead to periods of insufficient clavulanic acid to protect ticarcillin from beta-lactamase degradation.

Stopped-flow photometric determination of clavulanic acid in pharmaceutical and serum samples.

The stopped-flow mixing technique was used to develop a simple, fast kinetic method for the determination of clavulanic acid by reaction with imidazole. Whereas the conventional method requires about 12-15 min for equilibrium to be reached, kinetic measurements can be made within a few seconds. The calibration graph was linear over the range 1-40 microgram ml-1 of clavulanic acid and the detection limit achieved was 0.3 microgram ml-1. The precision and selectivity of the method are reported. The results obtained by applying the proposed method to the analysis of pharmaceutical and serum samples show how easily it can be adapted for routine analyses.

A sensitive assay for clavulanic acid and sulbactam in biological fluids by high-performance liquid chromatography and precolumn derivatization.

Precolumn derivatization procedures using 1,2,4-triazole for the detection and quantitation of sulbactam and clavulanic acid spiked into urine and blood serum at trace levels have been developed. Sulbactam and clavulanic acid produced derivatives which absorbed maximally at 325 and 315 nm, respectively. The methods allow the detection of clavulanic acid and sulbactam down to 0.05 micrograms ml-1 in serum and 0.5 micrograms ml-1 in urine. The relative standard deviation for five replicate analyses of sulbactam and clavulanic acid at a concentration of 20 micrograms ml-1 in serum and urine ranged from 2-6%. In further HPLC experiments with sulbactam in phosphate buffer solution, ampicillin was found as a contaminant (0.5% by mass) in the sulbactam sample provided. The significance of this finding is discussed.

Pharmacokinetics of intravenously and intramuscularly administered ticarcillin and clavulanic acid in foals.

Serum concentrations of ticarcillin and clavulanic acid were measured in healthy foals (2 to 6 months old) given the drugs in combination by intravenous and intramuscular routes of administration. Five foals were administered 50 mg of ticarcillin/kg of body weight and 1.67 mg of clavulanic acid/kg, IV. Five foals were administered 100 mg of ticarcillin/kg and 3.33 mg of clavulanic acid/kg, IV, and 4 of those 5 were given the same combined dose IM. The elimination half-life of ticarcillin for intravenous administration was 0.83 hour for the low dosage and 0.96 hour for the high dosage. After intramuscular administration, the half-life of elimination was 2.9 hours, with bioavailability of 54.6%. For IV administered clavulanic acid, the elimination half-life was 0.65 hour for the low dosage and 0.74 hour for the high dosage. After intramuscular administration, the elimination half-life was 0.92 hour, and bioavailability was 68.1%. A combined dosage, 50 mg of ticarcillin/kg and 1.67 mg of clavulanic acid/kg, given every 6 hours is recommended.

An investigation into the effect of traumatically produced cerebrospinal fluid fistulae on the passage of Augmentin across the blood-brain barrier.

In the management of cerebrospinal fluid (csf) fistulae, associated with head and facial injury, prophylactic antimicrobial drugs are employed commonly to prevent the occurrence of bacterial meningitis. Under normal circumstances, penicillins achieve a low csf/plasma concentration ratio, but trauma may reduce the efficacy of the blood-brain barrier and permit increased amounts of penicillins to enter the csf. To test this hypothesis, with respect to Augmentin (amoxycillin and clavulanic acid), an animal study was undertaken. Under general anaesthesia, the brains and meninges of a group of 10 rabbits were traumatised to produce csf fistulae. Following the administration of an intravenous bolus of Augmentin, the blood and csf concentrations of Augmentin were measured over a period of 6 h and compared with those measurements from an untraumatised control group of 10 rabbits. No difference in the csf/plasma ratio was apparent between the two groups. The results of this study, therefore, suggest that trauma to the brain and meninges does not increase the permeability of the blood-brain barrier to Augmentin.

[Penetration of potassium clavulanate/ticarcillin sodium into cerebrospinal fluid in neurosurgical patients].

Concentrations of potassium clavulanate (CVA) and ticarcillin sodium (TIPC) in the plasma and cerebrospinal fluid (CSF) of patients after neurosurgical intervention were determined at various times after a 1-hour drip infusion (3.2-g dose). Patients whose blood-brain barriers were supposed to be maintained in almost a normal condition were selected. CSF was obtained through a catheter placed in the anterior horn of the lateral ventricle in all the patients. Maximum plasma levels (micrograms/ml) of 57.6 to 384.0 with an average of 169.7 (TIPC) and 0.41 to 26.2 with an average of 6.1 (CVA) were achieved at the termination of infusion. The maximum CSF levels (micrograms/ml) were 0.61 to 18.8 (TIPC) and 0.1 to 6.81 (CVA) with mean values of 4.5 and 1.2, respectively. Plasma half lives (T1/2) (minute) were 24 to 93 (TIPC) and 32 to 227 with mean values of 58 and 127, respectively. The mean values of the CSF half lives (minute) were 237 (TIPC) and 113 (CVA). The ratios (%) of CSF levels to plasma levels in maximum concentration (Cmax), AUC (area under concentration curve) and half life (T1/2) were calculated. Cmax ratios were 0.2 to 29.2 (TIPC) and 1.4 to 69.8 (CVA) with mean values of 4.4 and 22.8, respectively. AUC ratios were 0.3 to 23.5 (TIPC) and 1.1 to 70.2 (CVA) with mean values of 4.3 and 22.4, respectively. T1/2 ratios were 1.3 to 18 (TIPC) and 1.1 to 4.3 (CVA) with mean values of 5.5 and 2.3, respectively. These values indicate that CVA/TIPC may be classified into a group of antibiotics with good penetration into the CSF.

[Experimental and clinical studies of BRL 25000 (clavulanic acid-amoxicillin) granules in the field of pediatrics].

BRL 25000 granules, a formulation consisting of amoxicillin (AMPC) and clavulanic acid (CVA), was evaluated in the field of pediatrics. In a pharmacokinetic study, serum concentrations were determined in a patient after oral administration of BRL 25000 granules in the non-fasting state at a dose of 11.76 mg/kg. The serum levels of amoxicillin (AMPC) and clavulanic acid (CVA) 1 hour after administration were 7.76 micrograms/ml and 6.64 micrograms/ml, with biological half-lives of 0.86 hour and 0.88 hour respectively. The serum concentration profile at a dose of 31.58 mg/kg showed almost the same tendency as at 11.76 mg/kg, although the peak level and biological half-life of the serum concentrations were not obtained. These serum levels and their peak levels were considered reasonable compared with those obtained in adults at similar dose levels. In clinical studies, 34 patients were evaluated including 8 patients with acute pharyngitis or acute tonsillitis, 1 patient with acute bronchitis, 1 patient with bronchopneumonia, 23 patients with scarlet fever and 1 patient with pertussis. BRL 25000 granules were administered orally 3-4 times per day for 4-8 days to 2 patients at doses of 20 approximately less than 30 mg/kg/day, to 18 patients at doses of 30 approximately less than 40 mg/kg/day, to 11 patients at doses of 40 less than approximately 50 mg/kg/day, and to 3 patients at doses of 50-60 mg/kg/day. The clinical response was assessed excellent in 13 cases and good in 21 cases giving an overall clinical efficacy rate of 100% (34/34). The causative organisms were isolated in 17 cases and included 12 strains of Streptococcus group A, 2 S. pneumoniae, 3 H. influenzae and 1 H. parainfluenzae.(ABSTRACT TRUNCATED AT 250 WORDS)

[Direct determination of clavulanic acid in biological fluids using HPLC]. / Détermination directe de l'acide clavulanique dans les liquides biologiques par HPLC.

The so far described HPLC methods for clavulanic acid (CA) monitoring needed post-column derivatization with imidazole, resulting in poorly practicable methods. We propose here a direct determination of CA in human biological fluids with a ion-pairing technology using the bathochromic shift of tetrabutylammonium bromide (TBAB). The separation is performed on a reversed phase analytical column (250 X 4.6 mm) with the following mobile phase: 10% acetonitrile in 1 mM TAB and 20 mM ammonium acetate (pH = 5). The U.V. detection is at 214 nm. Serum and bile are prepared with acetonitrile and methylene chloride, and urines are diluted 1/10 prior the analysis. Retention time of CA is 8.4 min. Detection limit for bile and serum is 0.1 mg/l and 5 mg/l for urines. Within and between-day reproducibility is respectively 5.4% and 7.2% for serum and bile, and 4.7% and 6.8% for urine. This method may be suitable for clinical routine analysis and pharmacokinetic studies.

Pharmacokinetic studies on clavulanate potentiated ticarcillin in normal subjects and patients with renal insufficiency.

Pharmacokinetics of the novel combination of ticarcillin with the beta-lactamase inhibitor clavulanic acid (BRL 28500, Timentin, Betabactyl) was investigated in order to calculate the dose reduction factor (DRF) and elaborate dosage recommendations for patients with varying degrees of renal impairment. Serum and urine levels of ticarcillin and clavulanic acid have been determined following the i.v. application of 3.2 g and 5.2 g BRL 28500 consisting of 3.0 g and 5.0 g ticarcillin, respectively, and 0.2 g of clavulanic acid each. 10 healthy volunteers and 9 patients received the 5.2 g formulation, and 6 normal subjects and 9 patients the 3.2 g formulation. The pharmacokinetics of both components of BRL 28500 behave fairly similarly and provides the combination with a logic basis. The dose reduction factor, being 1 by definition in normal renal function, rises in final renal failure to 2-3 for clavulanic acid and to 4-5 for ticarcillin. A dosis reduction to 1/2-1/4 will roughly produce the same AUC in a patient with terminal renal insufficiency as the normal dosage in a healthy subject. The distribution volume of ticarcillin and clavulanic acid was found to be enlarged probably due to overhydration in this group of patients. The recovery of both BRL 28500 components decreased with impaired renal function. The recovery 6 h after administration of 0.2 g clavulanic acid in the 5.2 g (3.2 g) BRL 28500 formulation fell from 58 +/- 12% (52 +/- 6) in healthy subjects to 25 +/- 14% (25 +/- 13) in patients with renal insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

The disposition of clavulanic acid in man.

Following oral administration of potassium 14C-clavulanate to four human subjects, at least 73% of the radioactive dose was absorbed. The mean absolute bioavailability was 64%. Absorption was rapid with peak plasma concentrations of radioactivity and clavulanic acid (2-6 micrograms/ml) occurring between 45 min and three hours after dosing. Values for the volume of distribution at steady-state and terminal half-life of clavulanic acid in the plasma were 12.01 and 0.8 h respectively. Following intravenous administration of clavulanic acid to the same subjects, the clearance, and volume of distribution at steady-state were 0.21 l/min, and 12.01, respectively. Clavulanic acid was the major radioactive component present in 0-24 h urine following oral dosing (23% of the dose). The two major metabolites were 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid (15% of the dose) and 1-amino-4-hydroxybutan-2-one (8.8% of the dose). Clavulanic acid and 1-amino-4-hydroxybutan-2-one were the major components in plasma following oral administration (52 and 21% of plasma radioactivity respectively at two hours after dosing). The major route of excretion of radioactivity following oral administration was via the urine (73% of the dose). Most of this radioactivity was excreted in the first 24 h after dosing (68% of the dose). The renal clearance of clavulanic acid was 0.1 l/min. Elimination of radioactivity also occurred via the expired air (17% of the dose) and the faeces (8% of the dose).

The penetration of amoxycillin/clavulanic acid into peritoneal fluid.

Thirty patients undergoing elective abdominal surgery were given 1 g amoxycillin plus 0 . 2 g clavulanic acid as a single intravenous injection at varying times prior to the operation. Sterile assay discs were placed on the peritoneal surface in order to measure peritoneal fluid levels of each agent. Simultaneous serum levels were also measured. A total of 44 simultaneous serum and peritoneal samples were analysed. There was rapid penetration of both agents into peritoneal fluid. The mean peritoneal fluid levels of amoxycillin were 84% (S.D. 34) of the serum level and 66% 42) for clavulanic acid. The peritoneal levels of both agents declined in parallel to the serum levels (the half-lives all being about 1 h) and the ratio of amoxycillin: clavulanic acid in serum and peritoneal fluid was similar to that as administered.

High-performance liquid chromatographic assay of clavulanate in human plasma and urine by fluorimetric detection.

A high-performance liquid chromatographic method with fluorimetric detection has been developed for the determination of clavulanate in human urine and plasma. Clavulanate in plasma samples was ultrafiltered using YMT membrane and reacted with benzaldehyde in phosphate buffer solution (pH 3.8) at 100 degrees C for 20 min. Clavulanate in urine samples was filtered with a polyacrylate membrane after ten-fold dilution, and reacted under the same conditions as those for plasma samples. The fluorescent product thus formed from clavulanate was separated from ordinary components of plasma and urine on a reversed-phase C18 column followed by fluorimetric detection (lambda ex = 386 nm, lambda em = 460 nm). The within- and between-run precisions were of the order of 4.02% (n = 10) and 6.23% (n = 5) for plasma samples at a level of 0.67 microgram/ml. The detection limit was as low as 10 ng/ml in plasma samples with a 50-microliter injection. Coexisting ticarcillin, amoxicillin or 1-amino-4-hydroxybutan-2-one (which is a metabolite of clavulanate in rat and dog) did not interfere in the clavulanate assay.

The pharmacokinetics of ticarcillin/clavulanate acid in neonates.

The pharmacokinetics of a 25:1 combination of ticarcillin and clavulanate were studied in nine pre-term and seven full-term neonates. Pre-term neonates with a gestational age ranging from 30 to 36 weeks received 83.3 mg of ticarcillin and 3.3 mg of clavulanate per kg bw and full-term neonates with a gestational age from 39 to 43 weeks received 100 mg of ticarcillin and 4 mg of clavulanate per kg bw 8-hourly, each by a slow infusion over 10 min. Serum was sampled 15, 30, 60, 120, 240 and 480 min after the first dose and trough samples were additionally obtained on the fourth day of treatment. The patients were allocated to Groups 1-3 on the basis of the pharmacokinetic characteristics obtained. Group 1 comprised seven full-term babies. Group 2 contained seven pre-term neonates with a birth weight between 1915 and 2650 g and Group 3 consisted of two pre-term neonates of low birth weight (1400 g and 1640 g). Mean (+/- S.E.) pharmacokinetic characteristics of Group 1 patients for ticarcillin were: Cmax = 404.9 mg/l (36.0); T = 2.68 h (0.23); AUC = 1287 h.mg/l (69); Vd = 266 ml/kg (28) and for clavulanate: Cmax = 15.0 mg/l (1.2); T = 1.39 h (0.12); AUC = 30.1 h.mg/l (1.7); Vd = 263 ml/kg (22). Corresponding parameters for Group 2 patients for ticarcillin were: Cmax 278.7 mg/l (30.4); T = 4.20 h (0.49); AUC = 1107 h.mg/l (57); Vd = 338 ml/kg (35) and for clavulanate: Cmax = 8.4 mg/l (0.56); T = 2.56 h (0.18); AUC = 27.1 h.mg/l (2.0); Vd = 414 ml/kg (29). Drug accumulation was not observed in patients of Groups 1 and 2. Each of the two patients of Group 3 presented a pharmacokinetic profile which was considerably different from those observed in Groups 1 and 2. While in patients of the latter group the peak serum concentrations were achieved at 15-30 min after the end of infusion, these concentrations occurred between 120 and 240 min in one of the Group 3 patients. In the other Group 3 patient a remarkable drug accumulation was noted but was not associated with clinical or laboratory evidence of toxicity. These data show that ticarcillin and clavulanic acid in these dose ranges achieved adequate peak and trough concentrations in pre-term and full-term neonates.

Penetration to peripheral human lymph of clavulanic acid and ticarcillin.

An intravenous dose of 3.0 g ticarcillin and 0.2 g clavulanic acid was given to 11 healthy human volunteers in whom peripheral lymph, serum and urine were monitored for 8 h. The concentrations were assayed microbiologically. The mean levels in lymph collected during the period 0-1 h was 39.3 mg/l of ticarcillin and 2.93 mg/l of clavulanic acid. The mean peak concentration in lymph (appearing between 1.25 and 2.25 h) was 66.3 mg/l for ticarcillin and 4.1 mg/l for clavulanic acid. Elimination was slightly slower from lymph than from serum, the half-life being only 1.04 times longer from lymph than from serum for ticarcillin, but 1.22 times longer for clavulanic acid. The total areas under the concentration curves in lymph was 58% of the serum value of ticarcillin and 81.0% of clavulanic acid. This reflects the ability of the substances to penetrate to lymph. The mean 8-h urinary recovery was 63.7% of the dose of ticarcillin and 43.8% of clavulanic acid. The total body clearances were 14.61/h for ticarcillin and 7.91/h for clavulanic acid and the corresponding d beta distribution volumes 12.21 and 19.11. The ratio of the concentrations of ticarcillin to clavulanic acid in all body fluids increased with time. Pharmacokinetically, clavulanic acid is well suited to be given together with ticarcillin.

Pharmacokinetics of ticarcillin and clavulanic acid given in combination to adult horses by intravenous and intramuscular routes.

The pharmacokinetics of ticarcillin and clavulanic acid following administration by the intravenous (i.v.) and intramuscular (i.m.) routes were investigated in six normal adult horses. Following i.v. administration, the ticarcillin disposition data conformed to a two-compartment model with an elimination half-life of 1.0 h. The disposition of clavulanic acid was described by a one-compartment model with an elimination half-life of 0.40 h. Following i.m. administration, the half-lives of both drugs were prolonged (ticarcillin 1.8 h, clavulanic acid 1.2 h). The bioavailability of ticarcillin was 84.4% and clavulanic acid 94.3%.

Pharmacokinetics of clavulanic acid, given in combination with amoxycillin, in volunteers.

To study the absorption and disposition of clavulanic acid, ten healthy men received one intravenous and one oral dose of 125 mg clavulanic acid in combination with amoxycillin. Serum and urine concentrations were measured with high-performance liquid chromatography. The mean terminal half-lives in serum were 0.97 and 0.94 h, respectively. Total serum clearance was 248 +/- 55 ml/min X 1.73 m2. Renal clearance was 108 +/- 20 and 115 +/- 18 ml/min X 1.73 m2 after intravenous and peroral administration. Urinary recovery over 12 h was 49.4 +/- 8.7% of the intravenous and 35.7 +/- 13.0% of the oral dose. The bioavailability of the oral dose averaged 60.0 +/- 23.1% but varied considerably (range 31.4-98.8%), indicating very variable absorption from the gastrointestinal tract.