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.

Piperacillin kinetics.

Piperacillin was administered to normal, healthy volunteers by an intravenous infusion over 30 min at dosage regimens of 12 gm daily (4 gm every 8 hr) and 24 gm daily (6 gm every 6 hr) for 5 consecutive days. Mean peak serum level after 12 gm daily was 244 +/- 24 (SE) microgram/ml and after 24 gm daily, 353 +/- 7 microgram/ml. After infusion the serum level declined monoexponentially in most subjects. On the 12-gm daily dosage mean values were 60 min for half-life (t1/2), 16 1 for volume of distribution, 188 ml/min for body clearance, and 139 ml/min for renal clearance. The same values on day 4 were 47 min, 12 1, 181 ml/min, and 125 ml/min; the volume of distribution was lower than on day 1. On the 24-gm daily dosage regimen, t1/2 was 60 min; volume of distribution, 16 1; body clearance, 183 ml/min; and renal clearance, 101 ml/min on day 1 compared to 68 min, 15 1, 148 ml/min, and 71 ml/min on day 4, the last 2 being significantly lower than on day 1. High renal clearance values were observed at low serum concentrations and vice versa, suggesting saturation of the tubular secretion process at high piperacillin concentrations in serum.

Pharmacokinetics of ticarcillin in patients with cystic fibrosis: a controlled prospective study.

We compared the pharmacokinetics of ticarcillin at a dose of 120 mg/kg in 11 patients with cystic fibrosis to 11 control subjects matched for age and sex. The mean elimination half-life of ticarcillin in serum was 70.8 minutes in the control subjects and 53.1 minutes in the patients with cystic fibrosis. The total body clearance of ticarcillin was significantly higher in cystic fibrosis patients (65.6 +/- 22.0 versus 46.2 +/- 10.9 ml/min/m2 in control subjects; p = 0.017). The nonrenal clearance of ticarcillin was also significantly higher in patients with cystic fibrosis (24.8 +/- 11.1 versus 13.3 +/- 6.0 ml/min/m2 for the control group; p = 0.006). There was no significant difference in volume of distribution between the two groups. We concluded that the shorter elimination half-life and the higher total body clearance of ticarcillin in patients with cystic fibrosis are a result of an increase in both renal and nonrenal elimination.

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.

Efficacy of single-agent therapy with azlocillin, ticarcillin, and amikacin and beta-lactam/amikacin combinations for treatment of Pseudomonas aeruginosa bacteremia in granulocytopenic rats.

The efficacy of azlocillin, ticarcillin, and amikacin as single agents and the penicillin/amikacin combinations for treatment of Pseudomonas aeruginosa bacteremia during cyclophosphamide-induced severe neutropenia in a rat model were assessed. Equivalent antibiotic dosing was based on the time rat serum antibiotic levels were above the minimal bactericidal concentration for the challenge organism. Antibiotic therapy was administered for 62 hours after bacterial challenge. Antimicrobial efficacy was based on the rate of bacteremia, the emergence of resistant organisms during therapy, life-table survival analysis, and rat survival seventy-two hours after bacterial challenge. For infection with a P. aeruginosa strain susceptible to all study antibiotics, therapy with azlocillin and ticarcillin (given so as to be equipotent) were equivalent, as judged by bacteremia rates or rat survival. However, combination therapy prevented the emergence of organisms resistant to azlocillin, but not to ticarcillin. Amikacin-containing combinations were more effective than single-agent regimens.

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.

Simultaneous determination of ticarcillin and clavulanate in rabbit serum and tissue cage fluid by liquid chromatography.

A gradient elution HPLC method with a wavelength switch technique was developed to simultaneously analyze the beta-lactam ticarcillin and the beta-lactamase inhibitor clavulanate in rabbit serum and tissue cage fluid (TCF). A C18 reversed-phase column with a programmable UV detector changing the wavelength from 218 to 254 nm at 9 min was used for chromatographic separation. The mobile phase consisted of acetonitrile, phosphate buffer and tetrabutylammonium hydrogen sulfate by following a gradient elution program at a flow-rate of 1 ml/min. Sample processing was carried out with liquid-liquid extraction. Good linearity, recoveries, precision and accuracy were obtained. The ranges of the standard curves were 1-100 microg/ml for ticarcillin, and 0.2-20 microg/ml for clavulanate. This assay has been successfully applied to analyze ticarcillin and clavulanate in rabbit serum and tissue cage fluid samples from a pharmacokinetic study.

High-pressure liquid chromatographic assays for ticarcillin in serum and urine.

Rapid and sensitive high-pressure liquid chromatographic (HPLC) assays for ticarcillin in serum and urine have been developed. Sample pretreatment and optimized chromatographic conditions are presented for a C-18-bonded reversed-phase column used in an internal standard assay method. Ticarcillin has a retention time of or approximately 5.3 min at a flow rate of 1.5 ml/min for a mobile phase of acetonitrile-aqueous 0.06 M sodium biphosphate, pH 2.05, (50.5:100). In a two-step extraction procedure, the ticarcillin extraction efficiencies from serum and urine were 76.1 +/- 4.7 and 80.9 +/- 3.2% respectively. The assay sensitivity limit for ticarcillin in these fluids is approximately 1.0 microgram/ml. A comparison is made of the HPLC and microbiological assay results for ticarcillin in 20 different but equally divided serum samples obtained from two volunteers.

Determination of ticarcillin in human plasma and in urine by reversed-phase LC.

A liquid chromatographic assay for ticarcillin (ticar.) in plasma and urine is described. For analysis, the internal standard cefoperazone (cfp) is dissolved in acetonitrile, which is used for precipitating the protein. The supernatant is evaporated, reconstituted in running mobile phase and injected directly onto the reversed-phase C18 column, with detection at 205 nm. The mobile phase is composed of water-acetonitrile-o-phosphoric acid-tetramethylammonium chloride (TMA). Coefficients of variation for reproducibility were in the range of 2.2-15.5% for extra-low, low, medium and high controls. Limits of detection were 0.5 microgram ml-1 for plasma and 1 microgram ml-1 for urine. No interference from other cephalosporins or other antibiotics was noted. This liquid chromatographic assay is simple, accurate, requires no extraction and overcomes previous problems related to the drug's peak splitting due to isomerization.

Ticarcillin: pharmacokinetics in man according to different administration schedules.

The pharmacokinetic characteristics of ticarcillin, a semisynthetic penicillin more active than carbenicillin against Pseudomonas, were studied. Following a rapid intravenous infusion of 1 g, 2 g, 5 g and 10 g ticarcillin respectively the serum half-life was 72-4 minutes independent of the dosage administered. If ticarcillin is administered under steady-state conditions, e.g. continuous infusion of either 2g/hr or 1g/hr following a loading dose of 1g (total dose 5 g) the average steady-state serum concentrations are 125 microgram/ml and 105 microgram/ml respectively.

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.

Pharmacokinetics of ticarcillin in the horse after intravenous and intramuscular administration.

Serum and peritoneal fluid concentrations of ticarcillin were measured in 10 healthy adult horses from 0.5 to 8 hours after IV or IM administration of 44 mg/kg of body weight. After IV injection, the serum concentration at 30 minutes was 104.3 +/- 6.1 mg/L and the mean peak peritoneal fluid concentration (61.4 +/- 29.0 mg/L) occurred 2 hours after injection. The peak serum (28.3 +/- 5.5 mg/L) and the peak peritoneal fluid concentrations (19.2 +/- 6.0 mg/L) occurred 2 hours after the IM injection. Ticarcillin (greater than or equal to 2 mg/L) persisted in serum and peritoneal fluid for 6 hours after IV injection and 8 hours after IM injection. The half-life of ticarcillin was 0.94 hour after IV injection and the bioavailability of ticarcillin administered IM was 64.9%.

Pharmacokinetics of ticarcillin in the dog.

Five healthy adult dogs were given a single IV dose (40 mg/kg of body weight) of ticarcillin disodium. Serum concentrations were measured serially over a period of 12 hours. Five days later, the drug was administered IM to the dogs at the same dose rate, and serum concentrations were measured serially for 12 hours. The mean peak serum concentration after IM administration was 120.5 micrograms/ml at 1.5 hours. Pharmacokinetic values following IV administration were (i) elimination rate constant = 0.8/hour-1, (ii) half-life = 0.8 hour, (iii) serum clearance = 292 ml/hr/kg, and (iv) apparent volume of distribution = 347 ml/kg. Estimated values after IM administration were (i) elimination rate constant = 0.6/hour, (ii) half-life = 1.1 hours, (iii) serum clearance = 218 ml/hr/kg, and (iv) apparent volume of distribution = 345 ml/kg; only the elimination rate constants were significantly different between the 2 routes of administration.

Effect of mucin on the pharmacokinetics of antibiotics in the rat.

The intramuscular pharmacokinetics of ticarcillin and amikacin in rats receiving 1 ml of 5% mucin suspension (equivalent to 250 mg/kg) administered intraperitoneally were not altered compared with the control animals. However, it is important to investigate the effect of mucin on the pharmacokinetics of antimicrobial agents in animals which are used to evaluate the efficacy of the agents.

[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.