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PubMed1985

Pharmacokinetics and serum bactericidal activity of ticarcillin and clavulanic acid.

The pharmacokinetics of ticarcillin 5.0 g and clavulanic acid 0.2 g were examined both alone and combined (3.0 or 5.0 g ticarcillin + 0.2 g clavulanic acid as 3.2 or 5.2 g timentin) after a 15 min infusion in ten healthy volunteers. At the same time, the serum bactericidal activity of 5.0 g ticarcillin alone and 5.2 g Timentin was determined against two ticarcillin resistant strains each of Klebsiella oxytoca and Pseudomonas aeruginosa in the first and sixth hour after administration. The serum kinetics of both ticarcillin and clavulanic acid could best be described by an open 2-compartment model. Both substances showed similar kinetic behaviour in serum with a T 1/2 beta of 74.8 +/- 11.5 min for ticarcillin and 76.6 +/- 4.6 min for clavulanic acid. The total clearance of clavulanic acid was 158 +/- 23 ml/min and thus clearly exceeded that of ticarcillin (112 +/- 9 ml/min). The recovery rate in the 24 h urine was 41.3% for clavulanic acid as compared to 79.4% for ticarcillin. Concomitant administration of both substances led to a limited change in the kinetics of both ticarcillin and clavulanic acid. A significant enhancement of the serum bactericidal action of ticarcillin and clavulanic acid was only detected for both Klebsiella species and not for the Ps. aeruginosa species, and only in the first hour.

Adult↗
PubMed1986

Comparative activities of the beta-lactamase inhibitors YTR 830, clavulanate and sulbactam combined with extended-spectrum penicillins against ticarcillin-resistant Enterobacteriaceae and pseudomonads.

The in-vitro synergistic activity of YTR 830, a new beta-lactamase inhibitor, combined with four extended-spectrum penicillins (ticarcillin, piperacillin, mezlocillin and apalcillin) against ticarcillin-resistant clinical isolates of Gram-negative enteric bacilli was compared with that of clavulanate and sulbactam. Synergy testing was performed with fixed concentrations of beta-lactamase inhibitors (8 mg/l) combined with doubling dilutions of beta-lactams in microdilution trays. Synergy was defined as a four-fold or greater decrease of beta-lactam MIC in the combination compared with the beta-lactam alone. For 79 ticarcillin-resistant Enterobacteriaceae, ticarcillin-YTR 830 and ticarcillin-clavulanate were synergistic against 90% of strains; for ticarcillin-sulbactam, 70% showed synergy. The synergistic activity of all three inhibitors was similar against strains resistant only to ticarcillin; for strains resistant to all four extended-spectrum penicillins, the activity of ticarcillin with YTR 830 and clavulanate was similar (synergy against 79% of strains) and superior to ticarcillin-sulbactam (synergy against 39% of strains). YTR 830 was more active than clavulanate against Serratia, Citrobacter, Proteus and Providencia spp. Piperacillin, mezlocillin and apalcillin susceptible strains, with MICs of 8-16 mg/l, showed synergy with inhibitors against 37-87% of strains. Amongst pseudomonads, no synergy was demonstrated against Pseudomonas aeruginosa; ticarcillin produced synergy with the inhibitors against Ps. maltophilia, while piperacillin-YTR 830 and apalcillin-YTR 830 were synergistic against Ps. cepacia. YTR 830 appears to have comparable in-vitro activity to that of clavulanate, and further development of this compound is warranted.

Ampicillin↗
PubMed1975

Comparative in vitro activity and clinical pharmacology of ticarcillin and carbenicillin.

The in vitro activity and human pharmacology of ticarcillin, a semisynthetic penicillin more active than carbenicillin against Pseudomonas, were compared. There has been no increase in resistance to ticarcillin of Pseudomonas strains over the past 5 years, but resistance of indole-positive Proteus and Serratia strains has been documented. After intramuscular (i.m.) injection of 1 g of ticarcillin, mean peak levels occurred at 1 h (26.9 mug/ml) with a decline over 6 h (6.8 mug/ml). Serum half-life was 84 min. Dilution of ticarcillin lidocaine reduced pain on i.m. injection but did not alter serum levels. Blood levels after 1 g i.m. are adequate to treat infections produced by Escherichia coli, Proteus mirabilis, and some Enterobacter, but not Pseudomonas. After rapid intravenous infusion of 3 and 5 g, mean peak serum levels of ticarcillin were slightly lower for 1 h than those achieved with carbenicillin. Probenecid administered before infusion produced increases in blood levels, half-lives, and volume of distribution. The biological half-life of ticarcillin was 72 min compared to 66 min with carbenicillin. There was a larger volume of distribution for ticarcillin than carbenicillin (15 liters versus 14 liters). The ticarcillin half-life when administered with probenecid was 108 min. Urinary recovery of ticarcillin was 77% against 95% of carbenicillin. However, approximately 10% of ticarcillin is recovered as penicilloic acid so that 95% of an intravenously administered dose is recovered.

Carbenicillin↗
PubMed1983

Susceptibility of gram-negative bacteria and Staphylococcus aureus to combinations of ticarcillin and clavulanic acid.

Four hundred and fifty-nine blood culture isolates were tested for susceptibility to ticarcillin alone and ticarcillin plus clavulanic acid, a potent beta-lactamase inhibitor. The susceptibilities of the Staphylococcus aureus strains to cloxacillin, methicillin, vancomycin, rifampicin, cefoperazone, ceftriaxone and moxalactam and of the gram-negative strains to Augmentin, azlocillin, mezlocillin, piperacillin, cefoperazone, ceftriaxone, cefotaxime, cefsulodin and tobramycin were also measured. Seventy-one percent of staphylococcal strains were beta-lactamase positive. In the presence of clavulanic acid the ticarcillin spectrum was extended to include beta-lactamase producing Staphylococcus aureus, Serratia marcescens and Klebsiella. All the ticarcillin-resistant Enterobacteriaceae were rendered ticarcillin-sensitive by clavulanic acid. The anti-Pseudomonas activity of ticarcillin plus clavulanic acid differed little from that of azlocillin and piperacillin and was comparable to that of the third generation cephalosporins. The combination of ticarcillin with clavulanic acid should be tested in the treatment of patients with infections caused by ticarcillin-sensitive and ticarcillin-resistant bacteria.

Clavulanic Acid↗
PubMed1986

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.

Adult↗
PubMed1991

Pharmacokinetics and bioavailability of ticarcillin and clavulanate in foals after intravenous and intramuscular administration.

The pharmacokinetics and bioavailability of ticarcillin and clavulanate were determined after intravenous (i.v.) or intramuscular (i.m.) administration of ticarcillin disodium (50 mg/kg) combined with clavulanate potassium (1.67 mg/kg) to groups of healthy foals at 3 days and 28 days of age. After i.v. administration of the combination to five foals, the disposition kinetics of ticarcillin and clavulanate were best described using a two-compartment open model. Mean plasma elimination-rate constant (beta) and clearance (ClB) for ticarcillin were significantly less (P less than 0.01), and volume of distribution at steady state (Vd(ss)) was significantly larger (P less than 0.05), in the foals at 3 days compared with 28 days of age. This indicated that renal excretion mechanisms were immature and ticarcillin was more widely distributed in 3-day-old foals. The mean elimination rate constant for clavulanate was significantly less (P less than 0.01) at 3 days than at 28 days of age. Values of the major kinetic terms describing the disposition of ticarcillin after i.m. administration to five 3-day-old foals were not significantly different from values of these parameters in the same foals at 28 days of age. After i.m. administration of the drug combination, plasma clavulanate concentrations peaked significantly later (P less than 0.01), and the elimination-rate constant (kd) for clavulanate was significantly less (P less than 0.01), in 3-day-old foals than in 28-day-old foals. The bioavailabilities of ticarcillin and clavulanate after i.m. administration in 3-day-old foals were 100% and 88.3%, respectively, and in 28-day-old foals were 100% and 27.4%, respectively. Mean plasma ticarcillin concentrations exceeded 16 micrograms/ml for a longer period after i.m. administration of the drug combination than after i.v. administration to foals of both age groups. By virtue of the frequency of administration required and the painful response elicited by i.m. injection, it is recommended that when the combination of ticarcillin disodium (50 mg/kg) and clavulanate potassium (1.67 mg/kg) is used in foals to treat infections caused by susceptible organisms (MIC less than or equal to 16 micrograms/ml), it should be administered i.v. four times daily.

Age Factors↗
PubMed1986

Bactericidal effects of ticarcillin-clavulanic acid against beta-lactamase-producing bacteria in vivo.

The comparative efficacies of ticarcillin and ticarcillin plus clavulanic acid have been determined in the mouse against experimental infections caused by ticarcillin-resistant bacteria. The infections studied comprised an intraperitoneal infection, local tissue infections, pyelonephritis, and pneumonia. Both ticarcillin and clavulanic acid penetrated readily to the sites of infection studied and at the doses employed were present at concentrations of the same order as those obtained in humans after the administration of ticarcillin-clavulanic acid formulations (Timentin; Beecham). At these concentrations, the ticarcillin-clavulanic acid combination caused significant bactericidal effects at the sites of infection against the ticarcillin-resistant strains of Bacteroides fragilis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus investigated. The efficacy of ticarcillin plus clavulanic acid against the infections resistant to therapy with ticarcillin demonstrated the beta-lactamase-inhibitory activity of clavulanic acid in vivo.

Animals↗
PubMed1989

Simulation of human serum pharmacokinetics of ticarcillin-clavulanic acid and ceftazidime in rabbits, and efficacy against experimental Klebsiella pneumoniae meningitis.

The penetration into cerebrospinal fluid (CSF) and efficacy of ticarcillin-clavulanic acid, ticarcillin alone, and ceftazidime were compared in rabbits with experimentally induced Klebsiella pneumoniae meningitis. The compounds were administered to simulate in rabbit plasma the concentration-versus-time curves observed in humans after 30-min infusions of Timentin (3 g of ticarcillin plus 100 mg of clavulanic acid), ticarcillin (3 g), and ceftazidime (2 g). Single- and multiple-dosing schedules were used. The penetrations of clavulanic acid into CSF (expressed as [area under the concentration-time curve for CSF/area under the curve for plasma] x 100) after the two dosing schedules were 28 and 24.5%, similar to that for ceftazidime (21%; multiple-dosing only) and greater than those for ticarcillin (8.4 and 9.3%). Ticarcillin was ineffective in reducing viable counts in CSF but, in the presence of clavulanic acid, reduced bacterial numbers by approximately 99% at 4 h after a single dose and by 99.99% at 12 h after three doses given at 4-h intervals. Two doses of ceftazidime given 8 h apart were more effective than the three doses of ticarcillin-clavulanic acid, in keeping with the in vitro activities of these compounds against the infecting organism. These results illustrate the ability of clavulanic acid to penetrate the blood-CSF barrier such that concentrations of the inhibitor in CSF potentiate the activity of ticarcillin against the ticarcillin-resistant, beta-lactamase-producing strain of K. pneumoniae.

Animals↗
PubMed1986

[In vitro activity of the combination ticarcillin-clavulanic acid on bacterial isolates in surgery].

The in vitro activity of ticarcillin in combination with clavulanic acid was tested, by disc diffusion, against 1,380 clinical bacterial isolates and was compared with that of ticarcillin alone. 83.8% of the isolates were susceptible to ticarcillin + clavulanic acid, whereas 56.6% were susceptible to ticarcillin alone. Minimal inhibitory concentrations (MIC) of ticarcillin in the presence of 4 micrograms/ml of clavulanic acid were determined against 157 ticarcillin resistant (MIC greater than 128 micrograms/ml) but ticarcillin + clavulanic acid susceptible strains of Gram negative bacilli and against 20 strains of beta-lactamase producing Staphylococcus aureus. With the addition of clavulanic acid, MICs of ticarcillin were respectively less than or equal to 16 micrograms/ml and less than or equal to 64 micrograms/ml for 50 and 90% of the Gram negative bacilli. All the Staphylococcus aureus were inhibited by concentrations of ticarcillin less than or equal to 1 microgram/ml.

Bacteria↗
PubMed1985

Ticarcillin plus clavulanic acid in the treatment of patients with cancer.

Since the combination of ticarcillin with clavulanic acid is active against many otherwise resistant organisms that commonly affect patients with cancer, a therapeutic trial with ticarcillin disodium plus clavulanate potassium for treating infections in cancer patients was conducted. A total of 127 evaluable patients were treated with this antibiotic. Of these, 63 percent were women with breast carcinoma, 28 percent were patients with leukemia, and the remainder were patients with sarcomas and lung cancer. The median duration of therapy was 7.7 days. There were 63 documented infections, with bacteriologic documentation in 39 episodes. Because of the high incidence of gram-positive infections and after the failure of ticarcillin plus clavulanate potassium in two of these episodes, vancomycin was added to the regimen. The overall response rate was 75 percent. In microbiologically proved infections, the response rate was 79 percent. Thirteen of 17 gram-negative infections responded (76 percent), including four of four episodes caused by Pseudomonas aeruginosa. The only failures in this group were two episodes with Klebsiella species, one episode with Escherichia coli, and one episode with Enterobacter species. Of the gram-positive infections treated without vancomycin, five of eight (63 percent) responded and only two episodes due to Staphylococcus aureus and one due to JK diphtheroid bacteria failed. All episodes treated with the combination of ticarcillin plus clavulanate potassium and vancomycin responded. Seven of eight (88 percent) polymicrobial infections and 73 percent of those infections without identified organisms responded as well. The overall response rates for septicemia, pneumonia, soft tissue infections, and urinary tract infections were 71, 50, 71, and 83 percent, respectively. Of five microbiologically proved superinfections, three were fungal, and one each was due to Klebsiella species and S. aureus. No toxicity was observed. For 12 organisms, the minimal inhibitory concentration was lower for ticarcillin plus clavulanate potassium than for ticarcillin alone; in six it was identical. Five organisms were resistant to both, and three that were resistant to ticarcillin were sensitive to ticarcillin plus clavulanate potassium. Ticarcillin plus clavulanate potassium is a safe drug with an expanded spectrum of activity. More therapeutic trials need to be conducted to better define its role in the therapy of serious infections in cancer patients.

Adolescent↗
PubMed1986

The pharmacokinetics of ticarcillin, clavulanic acid and their combination.

The pharmacokinetics of ticarcillin and clavulanic acid were examined both alone and combined (3.0 and 5.0 g ticarcillin + 0.2 g clavulanic acid as 3.2 or 5.2 g Timentin) after a 15-min infusion in ten healthy volunteers. The serum kinetics of both ticarcillin and clavulanic acid were described by an open two-compartment model. After the end of the infusion, the serum concentrations of ticarcillin (clavulanic acid) ranged between 576.2 +/- 98.7 mg/l (26.1 +/- 2.6 mg/l) after separate and 621.8 +/- 62.6 mg/l (22.9 +/- 4.6 mg/l) after combined administration. Both substances showed similar kinetic behaviour in serum with a T1/2 beta of 74.8 +/- 11.5 min for ticarcillin and 76.6 +/- 4.6 min for clavulanic acid. The total clearance of clavulanic acid was 158 +/- 23 ml/min and thus clearly exceeded that of ticarcillin (112 +/- 9 ml/min). The recovery rate in the 24 h urine was 41.3% for clavulanic acid as compared to 79.4% for ticarcillin. Concomitant administration of both substances had little effect on the kinetics of either agent alone. With increasing doses of ticarcillin, a decrease of the non-renal clearance of clavulanic acid was observed. The ratio of the two compounds in serum varied from 25:1 (for 5.2 g Timentin, 15:1 for 3.2 g Timentin) at the time of administration to 59:1 (34:1, respectively) 4 h after infusion.

Adult↗
PubMed1987

Pseudomonas peritonitis in neutropenic rats treated with amikacin, ceftazidime and ticarcillin, alone and in combination.

Peritonitis in neutropenic rats, caused by a strain of Pseudomonas aeruginosa resistant to amikacin and ticarcillin alone but susceptible to ceftazidime and combinations of amikacin with ticarcillin, amikacin with ceftazidime and ticarcillin with ceftazidime, was investigated. Four hours after a bacterial challenge with a LD70 intraperitoneal dose of P. aeruginosa (1.5 X 10(8) cfu/ml), either amikacin, ticarcillin, ceftazidime, amikacin-ticarcillin, amikacin-ceftazidime, or ticarcillin-ceftazidime was administered at dosing intervals that mimicked the serum concentrations of the drugs found in humans after therapeutic doses. When the serum concentrations did not exceed the MIC, as occurred with amikacin, no difference in survival was observed compared with controls. All other regimens resulted in animal survival during the treatment. When therapy was stopped only those regimens resulting in serum concentrations above the MBC were effective (amikacin-ticarcillin, amikacin-ceftazidime, ticarcillin-ceftazidime). The recovery of viable bacteria from the peritoneum agreed well with mortality.

Agranulocytosis↗
PubMed1988

Induction of chromosomal beta-lactamases by different concentrations of clavulanic acid in combination with ticarcillin.

The effect of different concentrations of clavulanic acid (CA) in combination with ticarcillin on beta-lactamase production and ticarcillin MIC was studied in four clinical isolates of Pseudomonas aeruginosa, Enterobacter cloacae, Serratia marcescens, Citrobacter freundii and indole positive Proteus strains. Ticarcillin alone showed a low inducing effect for all species tested, Ser. marcescens excepted. The increase in beta-lactamase activity after addition of CA (2-10 mg/l) was strain and species dependent. No synergy or antagonism was observed on the ticarcillin MIC for the micro-organisms producing only a chromosomally mediated beta-lactamase, though the susceptibility to ticarcillin strongly increased if the strains also produced a plasmid-mediated beta-lactamase. Addition of 50 or 100 mg/l CA resulted in all strains. C. freundii excepted, in a strong increase in beta-lactamase activity and in a strong synergistic effect on the ticarcillin MIC. However, these concentrations are unlikely to be achieved at clinical doses. Thus, irrespective of the inducing effect of ticarcillin and CA (2-10 mg/l) combinations, induction of the chromosomal beta-lactamase did not result in a decrease in ticarcillin susceptibility.

Bacteria↗
PubMed1976

Comparative activity in vitro of ticarcillin, BL-P1654, and carbenicillin.

The activity of ticarcillin, BL-P1654, and carbenicillin was compared in vitro using a microtiter tube dilution test in Mueller-Hinton broth against 50 recent clinical isolates each of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella species, Enterobacter species, Proteus species, and Pseudomonas aeruginosa. Bactericidal end points were determined using a modified Steers replicator. Ticarcillin was generally two to four times more active against all organisms tested except S. epidermidis against which BL-P1654 was most active. Median minimum inhibitory concentrations in micrograms per milliliter were for S. aureus: ticarcillin (6.2), carbenicillin (12.5), BL-P1654 (25); for S. epidermidis: BL-P1654 (1.6), ticarcillin (3.2), carbenicillin (3.2); for E. coli: ticarcillin (3.2), BL-P1654 (6.2), carbenicillin (6.2); for Klebsiella sp.: >100 for all three drugs; for Enterobacter sp.: ticarcillin (3.2), carbenicillin (6.2), BL-P1654 (12.5); for Proteus sp.: ticarcillin (1.6), carbenicillin (1.6), BL-P1654 (3.2); for P. aeruginosa: ticarcillin (31), BL-P1654 (62), carbenicillin (125). Bactericidal end points were dependent on both the drug and the species but were in general no more than twofold more than the minimum inhibitory concentration with the exception of BL-P1654 against P. aeruginosa. BL-P1654 was bactericidal for only 60% of the strains tested at a concentration of 500 mug/ml.

Bacteria↗
PubMed1979

Effect of time and concentration upon interaction between gentamicin, tobramycin, Netilmicin, or amikacin and carbenicillin or ticarcillin.

An aminoglycoside antibiotic and carbenicillin or ticarcillin are widely used in the treatment of patients with gram-negative bacillus infections. This study evaluated the effect of time upon in vitro interaction between mixtures of four aminoglycosides at two concentrations with carbenicillin or ticarcillin at four concentrations. By linear regression analysis, the inactivation of each aminoglycoside was shown to be directly proportional to the concentration of carbenicillin (P < 0.001). Inactivation was significantly (P < 0.01) greater for gentamicin and tobramycin than for amikacin or netilmicin at all carbenicillin concentrations. At carbenicillin concentrations of 300 and 600 mug/ml, significantly (P < 0.005) less inactivation of amikacin occurred when compared to netilmicin. Ticarcillin produced a significant (P < 0.025) inactivation of gentamicin and tobramycin, with inactivation being directly proportional to ticarcillin concentration. No inactivation of amikacin or netilmicin activity occurred unless the ticarcillin concentration was 600 mug/ml. No significant change in aminoglycoside activity occurred when stored with ticarcillin or carbenicillin at concentrations ranging from 100 to 600 mug/ml at -70 degrees C for 56 days. When an aminoglycoside and carbenicillin or ticarcillin are indicated in patients with renal failure, this study supports the use of ticarcillin with either amikacin or netilmicin.

Amikacin↗
PubMed1987

Pharmacokinetics and distribution of ticarcillin-clavulanic acid (Timentin) in experimental animals.

The pharmacokinetics and distribution of ticarcillin and clavulanic acid were studied in rats and rabbits after intravenous coadministration of the compounds. The elimination half-lives for ticarcillin and clavulanic acid were similar in both rats (ticarcillin, 0.22 h; clavulanic acid, 0.24 h) and rabbits (ticarcillin, 0.38 h; clavulanic acid, 0.31 h). Both compounds distributed widely throughout rat tissues, and the patterns of distribution were similar to those observed for other beta-lactams. Values for penetration into rat pleural, peritoneal, and subcutaneous fluids calculated from the equation (AUCfluid/AUCserum) X 100, where AUC is the area under the concentration-time curve, were between 83 and 93% for ticarcillin and 86 and 103% for clavulanic acid. Values for penetration into tissue cages in rabbits were 139% +/- 45% for ticarcillin and 109% +/- 22% for clavulanic acid. The penetration of clavulanic acid into rabbit cerebrospinal fluid was higher (P less than 0.05) (4.0% +/- 0.61%) than that of ticarcillin (1.3% +/- 0.53%). Overall, the results show that ticarcillin and clavulanic acid distribute readily throughout body tissues and fluids and predict that the penicillin and beta-lactamase inhibitor would be present together at sites of infection.

Animals↗
PubMed1987

Pharmacokinetics and bacteriological efficacy of ticarcillin-clavulanic acid (timentin) in experimental Escherichia coli K-1 and Haemophilus influenzae type b meningitis.

The pharmacokinetics and bacteriological efficacy of ticarcillin and clavulanic acid administered individually or in combination were assessed in rabbits with experimental Escherichia coli K-1 and Haemophilus influenzae type b meningitis. The mean penetrations into the cerebrospinal fluid (CSF) of infected animals after a single dose of ticarcillin-clavulanic acid were approximately 11 and 28% for ticarcillin and clavulanic acid, respectively. In continuous-infusion experiments, the mean penetrations into CSF were 14.6 and 35% for ticarcillin and clavulanic acid, respectively, in rabbits with E. coli meningitis and 6.1 and 24%, respectively, in rabbits with H. influenzae meningitis. In animals that received a continuous infusion of the two drugs alone or in combination, the median CSF bactericidal titers for E. coli were less than 1:2, less than 1:2, and 1:2 for ticarcillin, clavulanic acid, and ticarcillin-clavulanic acid, respectively, and for H. influenzae the titers were less than 1:2, less than 1:2, and 1:4, respectively. The addition of clavulanic acid potentiated significantly the bacteriological efficacy of ticarcillin in reducing the number of bacteria in CSF of infected rabbits. Additional studies in animals and humans are required before recommendations can be made regarding the use of ticarcillin-clavulanic acid for treatment of meningitis.

Animals↗
PubMed1999

Clavulanate induces expression of the Pseudomonas aeruginosa AmpC cephalosporinase at physiologically relevant concentrations and antagonizes the antibacterial activity of ticarcillin.

Although previous studies have indicated that clavulanate may induce AmpC expression in isolates of Pseudomonas aeruginosa, the impact of this inducer activity on the antibacterial activity of ticarcillin at clinically relevant concentrations has not been investigated. Therefore, a study was designed to determine if the inducer activity of clavulanate was associated with in vitro antagonism of ticarcillin at pharmacokinetically relevant concentrations. By the disk approximation methodology, clavulanate induction of AmpC expression was observed with 8 of 10 clinical isolates of P. aeruginosa. Quantitative studies demonstrated a significant induction of AmpC when clavulanate-inducible strains were exposed to the peak concentrations of clavulanate achieved in human serum with the 3.2- and 3.1-g doses of ticarcillin-clavulanate. In studies with three clavulanate-inducible strains in an in vitro pharmacodynamic model, antagonism of the bactericidal effect of ticarcillin was observed in some tests with regimens simulating a 3.1-g dose of ticarcillin-clavulanate and in all tests with regimens simulating a 3.2-g dose of ticarcillin-clavulanate. No antagonism was observed in studies with two clavulanate-noninducible strains. In contrast to clavulanate. No antagonism was observed in studies with two clavulanate-noninducible strains. In contrast to clavulanate, tazobactam failed to induce AmpC expression in any strains, and the pharmacodynamics of piperacillin-tazobactam were somewhat enhanced over those of piperacillin alone against all strains studied. Overall, the data collected from the pharmacodynamic model suggested that induction per se was not always associated with reduced killing but that a certain minimal level of induction by clavulanate was required before antagonism of the antibacterial activity of its companion drug occurred. Nevertheless, since clinically relevant concentrations of clavulanate can antagonize the bactericidal activity of ticarcillin, the combination of ticarcillin-clavulanate should be avoided when selecting an antipseudomonal beta-lactam for the treatment of P. aeruginosa infections, particularly in immunocompromised patients. For piperacillin-tazobactam, induction is not an issue in the context of treating this pathogen.

Anti-Bacterial Agents↗