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.

In vitro assessment of the effect of clavulanic acid at concentrations achieved in human serum on the bactericidal activity of amoxicillin at physiological concentrations against Staphylococcus aureus: implications for dosage regimens.

The effects on Staphylococcus aureus viability and beta-lactamase activity of concentrations that simulated those in human serum after a combined dose of 875 mg of amoxicillin and 125 mg of clavulanic acid were studied in an in vitro pharmacodynamic model. Six hours of preexposure to concentrations of the amoxicillin-clavulanic acid combination that were higher than the amoxicillin-clavulanic acid MIC led to a reduction of the initial inoculum of >90% and to a significant decrease of beta-lactamase activity versus those of the control even from 6 h, when concentrations were subinhibitory. The postantibiotic effect and post-beta-lactamase inhibitor effect contributed to these results.

Comparative pharmacokinetics of amoxicillin/clavulanic acid combination after intravenous administration to sheep and goats.

The pharmacokinetic behaviour of an amoxicillin/clavulanic acid combination was studied after intravenous administration of single doses (20 mg/kg per kg body weight) to five sheep and six goats. The objective was to determine whether there are differences between sheep and goats in the disposition of amoxicillin and clavulanic acid. The plasma concentration-time data were analysed by compartmental pharmacokinetic and non-compartmental methods. The disposition curves for both drugs were best described by a biexponential equation (two-compartment open model) in sheep and goats. The elimination half-lives of amoxicillin were 1.43 +/- 0.16 h in sheep and 1.13 +/- 0.19 h in goats, and of clavulanic acid were 1.16 +/- 0.01 h and 0.85 +/- 0.09 h in sheep and goats respectively. The apparent volumes of distribution of amoxicillin and clavulanic acid were similar in the two species. Body clearances of amoxicillin were 0.09 +/- 0.01 L/h kg in sheep and 0.11 +/- 0.01 L/h kg in goats, and of clavulanic acid were 0.07 +/- 0.01 L/h kg and 0.12 +/- 0.01 L/h kg in sheep and goats respectively. The half-lives and body clearances of amoxicillin and clavulanic acid differed significantly between sheep and goats. It was concluded that the disposition of amoxicillin and clavulanic acid administered intravenously as an amoxicillin/clavulanic acid combination to sheep and goats differed between the two ruminant species. Even though the differences in disposition kinetics of both drugs were statistically significant, the same intravenous dosing rate of this antimicrobial combination can generally be used in sheep and goats.

Comparison of concentrations of two doses of clavulanic acid (200 and 400 milligrams) administered with amoxicillin (2,000 milligrams) in tissues of patients undergoing colorectal surgery.

The concentrations of clavulanic acid and amoxicillin were determined in sera and different abdominal tissues of 17 patients who underwent elective colorectal surgery. Patients were randomly allocated to two groups. At the time of induction of anesthesia, patients in group 1 were given 200 mg of clavulanic acid with 2,000 mg of amoxicillin and patients in group 2 received 400 mg of clavulanic acid with 2,000 mg of amoxicillin. In both groups, the initial dose was administered again after 2 h. Blood samples were collected to determine peak and trough antibiotic levels. Serial blood samples were also collected at predetermined periods (opening and closure of the abdominal cavity and surgical anastomosis). Abdominal wall fat, epiploic fat, and colonic wall tissue samples were collected simultaneously. Antibiotic concentrations were determined by high-performance liquid chromatography. Increasing the dose of clavulanic acid to 400 mg resulted in significantly higher peak and trough levels in serum (P < 0.03). Following the injection of 400 mg, mean concentrations of clavulanic acid in the fatty tissues were significantly increased at the time of opening (P < 0.02). The concentrations of clavulanic acid and amoxicillin in fatty tissues were 17 to 52% and 12 to 23% of the levels in sera, respectively. In the colonic wall, the concentrations of clavulanic acid and amoxicillin were 52 to 63% and 49 and 27% of the levels in sera, respectively. In sera, clavulanic acid given at a dose of 200 or 400 mg reached or exceeded the concentrations found to be effective in vitro to reduce the MICs of amoxicillin from the resistant to the susceptible category for 90% of the potential pathogens. In most of the tissues investigated, increased the dose of clavulanic acid to 400 mg resulted in a significantly higher number of samples with concentrations found to be effective in vitro (72 versus 11%; P < 0.05). In conclusion, increasing the dose of clavulanic acid to 400 mg resulted in higher levels in sera and improved penetration into the abdominal tissues in patients undergoing colorectal surgery.

Ticarcillin-clavulanic acid pharmacokinetics in preterm neonates with presumed sepsis.

The objective of the reported study was to characterize the pharmacokinetics of ticarcillin and clavulanic acid in premature low-birth-weight (less than 2,200 g) neonates with presumed sepsis. Eleven infants received 12 courses of ticarcillin-clavulanic acid at 75 mg/kg of body weight intravenously every 12 h. Blood samples were collected at 0.5, 1.5, 4, and 8 h following the infusion of the initial dose. The concentrations of ticarcillin and clavulanic acid were determined by a microbiologic assay. Median (interpatient coefficients of variation) values for the volume of the central compartment, total steady-state volume, distributional clearance, total clearance, and terminal elimination half-life for ticarcillin were 0.030 liter/kg (21%), 0.26 liter/kg (48%), 0.41 liter/h/kg (47%), 0.047 liter/h/kg (47%), and 4.2 h (45%), respectively. For clavulanic acid the parameters were 0.28 liter/kg (32%), 0.36 liter/kg (34%), 11 liters/h/kg (36%), 0.12 liters/h/kg (72%), and 1.95 h (40%), respectively. Our results suggest that the current dosing recommendations of 75 mg/kg every 12 h risk subtherapeutic clavulanic acid concentrations and that 50 mg/kg every 6 h is a more rational dosing strategy.

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.

[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.

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.

[Tissue diffusion of amoxicillin-clavulanic acid for antibiotic prophylaxis in colorectal surgery]. / Diffusion tissulaire de l'amoxicilline-acide clavulanique pour une antibioprophylaxie en chirurgie colorectale.

Tissue penetration of amoxicillin and clavulanic acid given for antibiotic prophylaxis was studied in 15 patients. On induction of anesthesia patients were given 2 g amoxicillin and 200 mg clavulanic acid. The same dose was given two hours later. At time of surgical incision amoxicillin and clavulanate levels were 15.9 +/- 7.7 micrograms/g and 2.23 +/- 2.69 micrograms/g in abdominal wall fat and 16.6 +/- 10.5 and 1.72 +/- 1.35 micrograms/g in epiploic fat, respectively. Similar levels were measured at time of closure of the abdomen. In colonic wall, amoxicillin et clavulanate levels were 22.7 +/- 13.4 micrograms/g and 2.65 +/- 2.35 micrograms/g. By comparison with blood levels, tissue penetration of both drugs was 20 to 30 p. cent into fatty tissues and 60 to 70 p. cent into colonic wall.

Antibiotic-primed fibrin gel improves outcome in contaminated splenic injury.

Fibrin gel (FG) has recently been shown to be bactericidal in the management of contaminated hepatic injury; antibiotic loading of fibrin gel (AFG) may augment this effect. We evaluated the antimicrobial properties of FG and AFG in a rat model of contaminated splenic injury. Fibrin gel was made from centrifuged plasma of separate donor rats and bovine thrombin. Antibiotic fibrin gel was similarly produced following intravenous injection of 70 mg/kg ticarcillin. Male Holtzman rats (250-300 g) were anesthetized and a laparotomy done. The abdomen was contaminated with 1 x 10(7) Bacteroides fragilis and the spleen transected in the midportion. Treatment consisted of splenorrhaphy (S) (n = 7), FG application (n = 7), or AFG (n = 7). The animals were autopsied at 1 week to evaluate abscess formation and abdominal adhesions (grade I = none, grade II = mild, grade III = severe). Antibiotic/fibrin gel significantly decreased abscess formation following splenic injury when compared with S (2 of 7 vs. 7 of 7; p less than 0.05 by ANOVA) without an increase in adhesions. Fibrin gel also decreased abscess formation but not significantly (4 of 7 vs. 7 of 7). Histologic analysis confirmed the beneficial effect of FG and AFG on wound healing. The bactericidal effect of FG is improved by antibiotic loading in contaminated intraabdominal injury.

[Bactericidal effect of cefadroxil, amoxicillin alone or in combination with clavulanic acid in sera of healthy volunteers]. / Etude de l'activité bactéricide du céfadroxil, de l'amoxicilline seule ou associée à l'acide clavulanique, à partir de sérums de volontaires sains.

Determination of minimal inhibitory concentrations (MICs) provides data on the susceptibility or resistance of a bacteria; however, in susceptible bacteria this parameter is not predictive of effectiveness of the antimicrobial agent. Bactericidal activities of cefadroxil, of amoxicillin, and of the amoxicillin-clavulanic acid combination on bacteria commonly found in ENT and lower respiratory tract disease were studied comparatively. The antibiotics were given by the oral route to six healthy volunteers. With beta-lactamase-producing and non-beta-lactamase-producing strains of Escherichia coli, amoxicillin produced MICs consistent with susceptibility but failed to exhibit a bactericidal effect, whereas cefadroxil was bactericidal. Combination of amoxicillin with an inhibitor did not modify this activity on E. coli and failed to produce a bactericidal effect on Klebsiella pneumoniae similar to that seen with cefadroxil. Amoxicillin with and without clavulanic acid exhibited comparable effectiveness on Streptococcus pyogenes and S. Pneumoniae. The bactericidal effect of cefadroxil on S. pneumoniae was of similar magnitude but shorter duration than that of amoxicillin. Cefadroxil and the amoxicillin-clavulanic acid combination had similar bactericidal effects against Staphylococcus aureus. These antibiotics exhibited a time-dependent effect on Gram positive microorganisms. These pharmacodynamic data, together with measures of bactericidal activity, may be very helpful for selecting the appropriate antibiotic and dosage.

Efficacy of amoxycillin/clavulanic acid in experimental Staphylococcus aureus endocarditis in the rat.

The efficacy of amoxycillin/clavulanic acid was compared with that of flucloxacillin, vancomycin and amoxycillin in an experimental model of Staphylococcus aureus endocarditis. Doses of the antibiotics were selected to produce peak concentrations in rat serum similar to those achievable in man after administration of parenteral therapeutic doses. Amoxycillin clavulanic acid was more effective than amoxycillin alone against endocarditis caused by beta-lactamase producing strains of Staph. aureus, illustrating the beta-lactamase inhibitory activity of clavulanic acid in vivo. Amoxycillin/clavulanic acid was as effective as flucloxacillin in these infections whereas vancomycin was generally less active. These results illustrate the clinical potential of amoxycillin/clavulanic acid in the prophylaxis, or in the therapy of severe staphylococcal infections.

Penetration of amoxycillin, ticarcillin and clavulanic acid into lymph after intravenous infusion in rabbits to simulate human serum pharmacokinetics.

The distribution of amoxycillin, ticarcillin and clavulanic acid into lymph collected from the right lymphatic duct of rabbits was examined after intravenous administration. The compounds were administered to simulate, in the plasma of rabbits, the concentrations of amoxycillin, ticarcillin and clavulanic acid measured in human serum after the administration of either an iv bolus dose of amoxycillin 1.0 g plus clavulanic acid 200 mg, ticarcillin 3.0 g plus clavulanic acid 200 mg, or an iv infusion of amoxycillin 2.0 g plus clavulanic acid 200 mg or ticarcillin 3.0 g plus clavulanic acid 200 mg given over 30 min. Lymph concentrations of the compounds reached a peak rapidly after the simulation of a bolus dose (0-1 h) and the concentration-versus-time profiles in plasma and lymph were generally similar after 45 min. Following simulation of an iv infusion, peak concentrations of amoxycillin and clavulanic acid in lymph were reached at approximately the same time as for the bolus simulation, but that of ticarcillin occurred slightly later. The elimination half-lives of the compounds were similar in plasma and lymph. The percentage penetration values were high (greater than 80%) irrespective of the concentration-versus-time curve simulated. The penetration of clavulanic acid was compatible with that of the coadministered penicillin agent and was similar when given with either amoxycillin or ticarcillin.

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.

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.

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.