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.

Tobramycin: A Review of its Antibacterial and Pharmacokinetic Properties and Therapeutic Use

Data from 42 patients were analyzed to determine the predictability of the peak serum level and the t1 of gentamicin on the bases of age, sex, body weight, serum concentration of creatinine, and blood hematocrit. Renal function was normal in 21 patients and impaired in 21. The most striking finding was the relatively poor predictability of tV2 of gentamicin from serum concentration of creatinine. The overall correlation coefficient was 0.749 (P 0.9 reported by others. There was a significant correlation of the t1 of gentamicin with the reciprocal of hematocrit (r = 0.647, P < 0.001). Linear regression equations taking account of sex, serum creatinine concentration, and reciprocal of hematocrit provided a somewhat higher correlation coefficient (0.821) with the t1 of gentamicin than did the equation including serum creatinine concentration alone but were still not fully satisfactory. Thus the pharmacokinetics of gentamicin may not be adequately predictable from standardized equations or nomograms. A major problem in the use of gentamicin arises because of the narrow range between effective and toxic concentrations in serum. Although efficacy and toxicity appear to be influenced by factors other than serum concentration of the antibiotic, there is evidence that levels below 4 gg/ml are frequently insufficient for the treatment of serious infections due to Pseudomonas [1-4], while those in the range of 12-15 I g/ml may be associated with an increased risk of ototoxicity, especially in the presence of renal failure [3, 5, 6]. Gentamicin is eliminated from the body largely by renal glomerular filtration [7-9]. A small component of tubular secretion has also been postulated [10] but has not been substantiated [8]. The direct dependence of the excretion of gentamicin on renal function has led to the development of nomograms for determination of dosage for patients with renal insufficiency. These nomograms have been based on endogenous creatinine clearance [11-13] or serum creatinine concentration [14, 15] and have been reported to be highly predictive of the rate of clearance of the antibiotic. During the past year we have had occasion to measure the serum levels of gentamicin in 42 patients at frequent intervals after the first dose of the drug. In this report we present our findings

Predictability of Blood Levels of Gentamicin in Man

One hundred fifty-two bacterial strains that possess resistance to kanamycin A, gentamicin, or tobramycin, or to more than one of these antibiotics, were collected from various sources in Canada, Europe, Japan, and the United States. This collection was composed of Staphylococcus aureus and Pseudomonas aeruginosa and members of the Enterobacteriaceae family. Their susceptibility to BB-K8 (amikacin), a new broad-spectrum semisynthetic derivative of kanamycin A, and to the other agents, was determined on Mueller-Hinton Medium by the twofold agar dilution method. Test results revealed that 60.5% of the isolates were resistant to 8 mug of tobramycin per ml, 67.1% to 8 mug of gentamicin per ml, 86.2% to 20 mug of kanamycin A per ml, and only 8.6% to 20 mug of amikacin per ml. Of interest is the fact that the amikacin-resistant strains were generally resistant to all of the other aminoglycosides. The broad spectrum of amikacin was not totally unexpected, because the compound has been shown to be a poor substrate for most enzymes that inactivate other aminoglycosides through O-phosphorylation, O-adenylylation, or N-acetylation. A number of susceptibility profiles were obtained when the organisms were tested against a series of nine aminoglycosides. The majority of these profiles resembled those found for organisms that possess known mechanisms of enzymatic inactivation.

Activity of BB-K8 (Amikacin) Against Clinical Isolates Resistant to One or More Aminoglycoside Antibiotics

Five tables are presented that provide guidelines for drug usage in patients with renal insufficiency. The data are derived from the current medical literature. If specific information about a drug is unavailable, emphasis is given to normal pharmacokinetic variables in arriving at recommendations for therapy. Nephrotoxicity of adverse effects in patients with renal disease are noted and adjustments for dialysis suggested.

Guidelines for Drug Therapy in Renal Failure

The pharmacokinetics of widely used and of investigated aminoglycosides, namely kanamycin, gentamicin, tobramycin, amikacin, sisomicin and netilmicin, in normal volunteers and in patients with physiological states and disturbances known to alter their disposition are critically examined in view of recent developments. Analytical methods for the assay of aminoglycosides in biological fluids are briefly but critically described. Emphasis is placed on multicompartmental characterisation of aminoglycoside kinetics, especially as it relates to certain heretofore unexplained observations such as tissue accumulation and delayed elimination. Other components of the kinetic profile of aminoglycosides are reviewed. For practical purposes, aminoglycosides are neither protein bound nor biotransformed. The major route of elimination is glomerular filtration, and aminoglycosides undergo some tubular reabsorption. Relevant pharmacokinetic parameters from significant studies have been tabulated. Some practical aspects of distribution kinetics are then presented. All aspects considered, and even though therapeutic concentrations can be obtained in some patients, the penetration of aminoglycoside into the cerebrospinal fluid, bronchial secretions and biliary tract remains somewhat unpredictable, depending in particular on the underlying diseases. When feasible, local treatment such as aerosols, intrathecal or intraventricular supplementation of parenteral administration are to be recommended. Due to the almost exclusive excretion from the body by glomerular filtration, the elimination rate of aminoglycoside antibiotics is greatly affected by impairment of renal function. The mathematical relationships between pharmacokinetic parameters and renal function indicators are tabulated and discussed. The predictive potential of nomograms can be greatly improved by taking into consideration some physiological parameters such as sex, age, lean body mass, haematocrit and characterisation of disposition kinetics by multicompartmental models. However, actual serial monitoring of aminoglycoside concentrations in serum appears to be the most reliable method for therapeutic monitoring. Half-lives in patients with minimal renal function during haemodialysis, during peritoneal dialysis and during interdlalysis periods are tabulated and the practical implications of these data discussed. In the neonatal period, the absorption rate after intramuscular injection appears to be faster than reported in adults and the volume of distribution is significantly larger. The major pharmacokinetic difference between neonates, infants and adults is the slower elimination: for instance, half-lives which average around 2 hours in adults with normal renal function can reach and sometimes exceed 5 to 6 hours during the very first days of life. The volume of distribution per kilogram of body weight is relatively smaller in obese subjects and in dehydrated patients than in normal subjects and can lead to overdosing when dosages are calculated on a body weight basis. Anaemia, fever, hypoxaemia and major burns are other pathological states which significantly influence pharmacokinetics of aminoglycosides. Inactivation by heparin, carbenicillin and ticarcillin is reviewed. The methods of administration currently favoured are briefly examined and a procedure which may be more applicable to the kinetics of aminoglycosides is suggested so that further comparative clinical trials may be undertaken of the assessment of the relative merits of different modes of administration.

Clinical pharmacokinetics of aminoglycoside antibiotics.

The serum half-life of tobramycin was found to be the same as that of gentamicin in patients with similar renal function. The values ranged from 2 hr in normal volunteers to 53.4 hr in anephric patients. Both drugs were readily removed from the serum by the Kiil artificial kidney, with a 70% reduction in serum concentrations during a 12-hr dialysis period.

Tobramycin and Gentamicin Concentrations in the Serum of Normal and Anephric Patients

Theserum half-life oftobramycin was found tobethesame as thatofgentamicin inpatients withsimilar renal function. Thevalues ranged from2hrin normal volunteers to53.4hrinanephric patients. Bothdrugs were readily removedfromtheserum' bytheKiilartificial kidney, witha 70%reduction in serum concentrations during a12-hr dialysis period.

W. R. Lockwood

Papers

Tobramycin and Gentamicin Concentrations in the Serum of Normal and Anephric Patients

Tobramycin andGentamicin Concentrations intheSerumofNormalandAnephric Patients