Tobramycin

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Abstract
Synopsis: Tobramycin is a new aminoglycoside antibiotic with a broad antibacterial spectrum in vitro, and pharmacokinetic properties similar to those for gentamicin. Tobramycin is more active than gentamicin against Pseudomonas aeruginosa and active against many gentamicin resistant strains, but is not active against enterobacteriaceae resistant to gentamicin. Theoretically, tobramycin has an advantage over gentamicin against infections caused by P. aeruginosa, but any advantage in clinical practice has yet to be adequately demonstrated. Clinical experience with tobramycin is considerably less than with gentamicin. Whilst tobramycin appears to offer no clear advantages over gentamicin against sensitive organisms it is indicated in infection caused by strains of P. aeruginosa which are resistant to gentamicin, but sensitive to tobramycin. Like gentamicin, tobramycin acts synergistically with carbenicillin and the cephalosporins. The efficacy of the tobramycin-carbenicillin combination has been shown in endocarditis caused by P. aeruginosa which was unresponsive to gentamicin plus carbenicillin. Ototoxicity and nephrotoxicity similar to that seen with other aminoglycosides have been encountered in therapeutic trials with tobramycin and wider clinical experience is necessary to determine the relative incidence of these side-effects with gentamicin and tobramycin used under similar conditions. Antimicrobial activity: In comparative studies, in vitro, tobramycin is more active than gentamicin against clinical isolates of Pseudomonas aeruginosa. Similarly, the inhibitory index, which is the ratio between the serum concentration attained at usual therapeutic doses and the minimum inhibitory concentration, for Pseudomonas aeruginosa is higher for tobramycin than for gentamicin. Against Gram-negative bacteria other than Pseudomonas spp. the spectrum of activity of tobramycin is similar to that of gentamicin. For most species the activity of tobramycin is slightly less than that of gentamicin. Gentamicin is consistently more active than tobramycin against Serratia marcescens. Like other aminoglycoside antibiotics, tobramycin is active in vitro in low concentrations against Staphylococcus aureus. Tobramycin is essentially inactive against Streptococcus pyogenes, Streptococcus faecalis and Streptococcus pneumoniae (pneumococci). Many studies have reported the relative activity of tobramycin and other aminoglycosides and of other antibiotics against various bacteria in vitro, but comparisons between studies cannot always be interpreted literally because the activity of many antibiotics in vitro, including tobramycin, is influenced by the nature of the culture media and the presence of certain salts. The sensitivity of P. aeruginosa to tobramycin is influenced by the magnesium, and calcium content of the culture media whilst that of all species is reduced by sodium ions. Wide variations in the concentration of these ions may result in divergent MIC values and an inappropriate choice of antibacterial aeent to treat pseudomonas infection. In terms of the therapeutic ratio (LDS0/ED50) tobramycin is the most active of the aminoglycosides in promoting survival in mice infected experimentally with P. aeruginosa. Tobramycin is more effective than gentamicin in suppressing experimental pseudomonas keratitis in rabbits. An increase in the bactericidal activity of tobramycin against some strains of P. aeruginosa is elicited by the addition of therapeutic concentrations of carbenicillin. However, as synergy could not be predicted from the susceptibility to the individual antibiotics, there is a need to perform appropriate laboratory studies for each strain. The activity of tobramycin in vivo against experimental infection is enhanced by the addition carbenicillin or cephalothin. Such studies provide the basis of controlled therapeutic trials with such antibiotic combinations, but to date such studies have not been reported. Some cross-resistance exists between tobramycin and gentamicin for P. aeruginosa, but is not complete. Pharmacokinetics: The pharmacokinetic properties of tobramycin in persons with normal renal function closely resemble those of gentamicin. In cross-over studies comparing gentamicin and tobramycin in healthy volunteers or in cancer patients with normal renal and hepatic function, peak serum levels after therapeutic doses given by the same route have been similar. Serum levels after intravenous administration are related to the dose and the rapidity of the injection or infusion. Low concentrations of tobramycin are present in CSF after parenteral administration and intrathecal or intraventricular administration is required to achieve therapeutic concentrations. An apparent volume of distribution equivalent to about 30% of the total body weight has been reported by some investigators whilst others have recorded lower values. The serum half-life of tobramycin in several studies has been about 2 hours. There seems to be some uncertainty regarding the degree to which tobramycin is bound to serum proteins. Whilst in one study a value of up to 70% was obtained with therapeutic concentrations, other workers consider that there is little or no serum binding. The latter view is probably correct. After intravenous or intramuscular injection tobramycin is rapidly excreted as the unchanged drug largely in the urine. It appears that the renal excretion of tobramycin, like that of gentamicin, is almost entirely by glomerular filtration. Renal clearance rates in different studies have varied from 76 to 92% of the total clearance. The urinary recovery has varied between 74 and 93% of a 100mg intravenous or intramuscular dose, most of which is recovered during the first 6 hours. The concentration of tobramycin in the urine is highest during the first 2 to 3 hours after a dose and averages about 150μg/ml after a 100mg dose. In patients with reduced renal function serum levels of tobramycin tend to be generally higher than in subjects with normal renal function given an equal dose. As the rate of elimination of tobramycin is related to creatinine clearance and to serum creatinine, the serum half-life is greatly increased in renal failure. Tobramycin is removed from the body relatively slowly by peritoneal dialysis, but is readily removed from the blood by haemodialysis. The cumulative excretion of tobramycin in the urine is reduced in patients with impaired renal function, but urinary concentrations may still be adequate to effectively treat urinary tract infections caused by susceptible organisms. The apparent volume of distribution in renal failure appears to be similar to that in normal renal function. In the newborn, serum levels of tobramycin after an intramuscular dose of 2mg/kg tobramycin vary according to the birth weight and are higher during the first days of life than a week later. The serum half-life is longer in low birth weight infants than in those of higher birth weight. The low urine recovery and increased serum half-life in low birth weight infants may reflect the greater renal immaturity in these infants. In animal studies, tobramycin appeared to be less ototoxic and less nephrotoxic than an equal dose of gentamicin, but the relevance of these studies to humans is not clear at present. Therapeutic trials: In limited therapeutic trials conducted mainly in North America, Europe and the United Kingdom tobramycin has been successfully used to treat infections in the urinary and respiratory tracts, septicaemia, meningitis and infections of the eye, ear, nose and throat and of skin and soft tissue caused principally by Gram-negative bacteria. Comparative trials to date have involved only small numbers of patients. Although the efficacy of tobramycin and gentamicin against infections caused by P. aeruginosa appears to be similar, further suitably designed trials in adequate numbers of patients are needed to determine the relative efficacy of tobramycin and gentamicin against serious infections caused by this species. Results obtained with tobramycin in urinary tract infections have generally been more impressive than those in infections of the lower respiratory tract or of skin and soft tissue. In children with lower respiratory tract infections associated with cystic fibrosis, best results were obtained with tobramycin 10mg/kg daily plus inhalation of 200mg daily. However, administration of a dose in the vicinity of 10mg/kg daily should not be undertaken unless the serum concentration of the drug can be monitored. Septicaemia caused by E. coli or Klebsiella spp. responded better to tobramycin at usual dosages than septicaemia caused by P. aeruginosa. There have been only a few cases of Gram-negative meningitis treated with tobramycin reported in the published literature. Results have been fair or poor when tobramycin has been given parenterally with or without concomitant intrathecal injection. It appears that optimum therapy in meningitis is likely to be associated with parenteral plus intraventricular injection particularly in moribund patients who have failed to respond to previous therapy with parenteral plus intrathecal aminoglycosides. Side-effects: The most frequently reported adverse effects thought to be associated with the use of tobramycin have been a reduction in renal function, hearing disturbances and clinical evidence of ototoxicity and alterations in liver function test values. Dosage: The dosage of tobramycin is determined by the body weight of the patient and this must be obtained for calculation of correct dosage. The usual dose in adults and beyond the neonatal period is 1.0 to 1.5mg/kg 8-hourly (3 to 4.5mg/kg daily) in serious infections and 5 to 6mg/kg daily in life-threatening infections. Larger doses may be needed in some life-threatening infections. In neonates the dosage is 2mg/kg 12-hourly (4mg/kg daily) intramuscularly or as a 2-hour intravenous infusion. In patients with impaired renal function serum levels of tobramycin should be monitored whenever possible. Following a loading dose of lmg/kg, subsequent dosage should be adjusted either by giving reduced doses at 8-hourly intervals or normal doses at increased intervals.