Ticarcillin

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Abstract
Synopsis: Ticarcillin1 is a semisynthetic penicillin for parenteral administration. The antibacterial activity of ticarcillin is similar to that of carbenicillin except that it is two to four times more active in vitro against Pseudomonas aeruginosa, generally less active against Gram-positive cocci and more active against most Gram-negative bacilli. As the pharmacokinetics of ticarcillin and carbenicillin are also similar, ticarcillin should theoretically be clinically effective when administered at a lower dosage than carbenicillin. There is some evidence that ticarcillin is comparable in efficacy with carbenicillin when given in half to two-thirds the dosage, when the drugs are given in combination with an aminoglycoside and in clinical situations where these drugs are agents of choice. Ticarcillin has been used successfully in the treatment of complicated urinary tract infection, pulmonary infection in cystic fibrosis and bacteraemia and is effective when combined with an aminoglycoside in severe infections in patients with granulocytopenia. The efficacy in anaerobic infections is at present poorly documented, although preliminary results are promising. Tolerability has generally been good with hypokalaemia being the most frequently reported side effect. At the dosages used, bleeding and fluid overload have seldom occurred. Human Toxicology: Ticarcillin, which is related to carbenicillin, is a semisynthetic penicillin not absorbed orally. Like carbenicillin, ticarcillin produces dose-related platelet aggregation defects after repeated doses particularly in patients with impaired renal function, due to increased serum concentration. Bleeding times are lengthened to a varying degree between individuals, but the magnitude of the platelet defect with ticarcillin 300mg/kg daily is similar to that produced by the same dosage of carbenicillin. Platelet dysfunction induced by ticarcillin appears to last for the life span of the affected platelets. Antibacterial Activity: The antibacterial activity is similar to that of carbenicillin with the principal difference being that ticarcillin is consistently 2 to 4 times more active in vitro against Pseudomonas aeruginosa and more active in vivo against experimental Pseudomonas infection. At a concentration of 50μg/ml ticarcillin is active against about 75% of E. coli and Enterobacter species, 80% P. aeruginosa and 85% of P. mirabilis and indole-positive Proteus. It has little activity against K. pneumoniae, an organism which is often reported in nosocomial infections. Concentrations of about 16μg/ml are inhibitory to most Gram-positive species and for about 25 % of S. faecal is. Like other penicillins, ticarcillin is bactericidal against susceptible bacteria, the minimum bactericidal concentration generally being 2-fold greater than the inhibitory concentration. About 75% of strains of Bacteroides fragilis are inhibited in vitro by 32 to 64μg/ml of ticarcillin. Most other anaerobes are inhibited by lower concentrations of the drug. The influence of inoculum size on the susceptibility of bacteria to ticarcillin is similar to that with many other penicillins, although less than with some other antipseudomonal penicillins, and varies according to the bacterial species and strain. Ticarcillin is susceptible to β-lactamase produced by S. aureus and common Gram-negative organisms. In vitro and in vivo, ticarcillin combined with an aminoglycoside exhibits a synergistic effect against P. aeruginosa, E. coli, and enterococci. The response of P. aeruginosa to antibiotic combinations varies between strains and their response cannot be predicted from their behaviour to single antibiotics. The addition of clavulanic acid decreased the minimum inhibitory concentration of ticarcillin for resistant enterobacteriaceae, but had no appreciable effect on the susceptibility of ticarcillin-resistant P. aeruginosa. Pharmacokinetics: Ticarcillin is not absorbed to any appreciable extent when given orally and must be given by intravenous or intramuscular injection. Peak serum concentrations after intravenous injection vary with the rate of infusion and reach an average level of 260μg/ml after a rapid 3g dose, but decline quickly over the next 3 hours. An intramuscular injection of 1g ticarcillin produces peak serum concentrations of 22 to 33μg/ml 0.5 to 2 hours after administration, with concentrations declining to approximately 40% of these values at 4 hours. The apparent volume of distribution of ticarcillin in humans is 14 to 16L. After intravenous administration the maximum skin window fluid to serum concentration ratio is 0.24. In patients receiving treatment with ticarcillin for lower respiratory tract infection, concentration in sputum is 3 to 5 % of that in serum whilst pleural fluid concentrations reached 30 to 66 % of serum levels in patients with pneumonia. Cerebrospinal fluid levels are low when the meninges are not inflamed, but have been reported to be 39 to 63 % of corresponding serum concentrations in patients with meningitis. Ticarcillin is moderately bound to serum protein to the extent of 65%. There are no biologically active metabolites in the urine of subjects given ticarcillin either intravenously or intramuscularly. 10 to 14% of the total dose recovered in the urine over 12 hours is in the form of penicilloic acid and the remainder is unchanged drug. Urinary concentrations reach 12,000μg/ml after a 3g intravenous dose and 2000 to 3000μg/ml after an intramuscular dose of 1g. The serum half-life is 72 minutes in patients with normal renal function. The clearance of ticarcillin from the plasma decreases as renal function decreases and the elimination half-life reaches 15 to 16 hours when creatinine clearance is less than 10ml/minute. Half-life increases further when liver function is also impaired. Dosage adjustment is therefore essential in moderate to marked renal impairment to prevent cumulation. Ticarcillin is readily removed from the body by haemodialysis and to a lesser extent by peritoneal dialysis. Infants in the first week of life have higher peak serum concentrations and delayed elimination compared with older babies. Plasma clearance increases with increasing age and body weight within the first few weeks of age. Therapeutic Trials: Ticarcillin has been successfully used to treat complicated urinary tract infection caused mostly by Pseudomonas aeruginosa. In studies that have allowed an adequate follow-up period, sterile urine has persisted in about three-quarters of patients. Pseudomonas aeruginosa has been eliminated in about 90 % of instances at the end of treatment. Superinfection with penicillinase-producing bacteria occurred in 10 to 20% of patients and was due most frequently to Klebsiel la or Enterobacter species or E. coli. Ticarcillin 1g 8-hourly was at least as effective as gentamicin 80mg 8-hourly in male patients with infection due to urinary tract obstruction. As with other antibacterial agents, relapse or reinfection has been frequent in patients with renal stones or an indwelling catheter. In open and comparative studies, ticarcillin has been shown to be clinically effective in severe Pseudomonas infections of the lower respiratory tract. Ticarcillin alone 300mg/kg daily appeared to be as clinically effective as the same dose combined with gentamicin 3 to 7mg/kg daily in cystic fibrosis patients with Pseudomonas pulmonary infections. Response was not related to eradication of P. aeruginosa from the sputum, but rather to the severity of the underlying disease and the susceptibility of the infecting organism. Ticarcillin 1g 6-hourly was clinically effective in 83% of acute exacerbations of chronic bronchitis unresponsive to other antibacterial agents. Ticarcillin has been combined with cephalothin or aminoglycosides in the empirical treatment of microbiologically documented and suspected infections in patients with granulocytopenia. The response rate was similar when ticarcillin was combined with either gentamicin or cephalothin or with amikacin, or netilmicin. Similarly, the response rate to ticarcillin 12g/m2 or carbenicillin 24g/m2 daily was comparable. Response to treatment was influenced by the change in granulocyte count and the severity and site of the infection. Although there was little to choose between the various drug regimens with respect to the overall clinical response the ticarcillin-aminoglycoside regimen appeared to be more effective than the cephalosporin-aminoglycoside combination in infections caused by P. aeruginosa. Treatment with two drugs appears better than one with regard to susceptibility patterns when the initial granulocyte count is less than 100/pi and does not increase during the course of the infection. The combination of cephalothin and an aminoglycoside caused azotaemia more frequently than the other drug combinations. Ticarcillin has also been used successfully in the treatment of bacteraemia, burns infections and anaerobic infections caused principally by Bacteroides fragilis and other Bacteroides species. Side Effects: Ticarcillin has been well tolerated by the majority of patients, the most frequently reported adverse effects being skin rash, hypokalaemia, eosinophilia and pain after intramuscular or phlebitis with intravenous injection. Although dosages of ticarcillin required to treat serious infection may cause platelet dysfunction, there have been few reports of bleeding. Although ticarcillin injection contains 5mEq of sodium per gram, fluid overload has seldom been noted and ototoxicity and nephrotoxicity have seldom occurred, and then only when ticarcillin was given in combination with an aminoglycoside. There is no evidence that ticarcillin contributes to the nephrotoxicity or ototoxicity reported with combination regimens. Drug Interactions: Like carbenicillin, ticarcillin inactivates gentamicin in vitro and in vivo, particularly in patients with renal failure. Dosage: In serious systemic infections the usual dosage is 300mg/kg daily intravenously given in divided doses every 3, 4 or 8 hours. Dosage must be adjusted according to creatinine clearance in patients with impaired renal function.

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