Population Pharmacokinetics of Intravenous and Intramuscular Streptomycin in Patients with Tuberculosis

Min Zhu, Ph.D., William J. Burman, M.D., George S. Jaresko, Pharm.D., Shaun E. Berning, Pharm.D., Roger W. Jelliffe, M.D.,and Charles A. Peloquin, Pharm.D.

Disclosures

Pharmacotherapy. 2001;21(9) 

In This Article

Discussion

The pharmacokinetics of streptomycin in patients with tuberculosis were evaluated in this study. No significant alterations were found for pharmacokinetic estimates after long-term dosing compared with values reported in the literature.[17] However, some patient demographic variables altered the kinetic behavior of streptomycin and contributed to variations of pharmacokinetic estimation.

Streptomycin Cmax after intramuscular doses increased with increasing mg/kg doses; however, linear relationship was not strong. This reflects variability among patients in rate of absorption from intramuscular injection sites and in volume of distribution. Data were insufficient to determine whether some degree of saturable absorption may occur when doses of 1000 mg or higher are used. Such analyses were further complicated by the fact that all 11 patients received smaller intramuscular doses earlier and larger doses later in treatment. Long-term intramuscular doses may induce changes in tissue at the injection site, and these changes also may have contributed to any perceived saturable absorption.

Although not statistically significant, both the median Kel and Cl/F in the intravenous group were 19% lower than that of the intramuscular group. This mainly reflected that the median Clcr of the intravenous group was 48% lower than that of the intramuscular group. Four patients from the intravenous group had considerably low Clcr (< 50 ml/min) and significantly prolonged drug elimination. In particular, one patient had a serum creatinine of 3.7 mg/ml and a Clcr of 25 ml/minute. After an 800-mg infusion, his streptomycin AUC was 979 µg

hour/ml, elimination half-life (Kel) 24 hours, and Cl/F 0.012 L/hour/kg, all quite different from population median values. Therefore, as with other aminoglycosides, streptomycin pharmacokinetic estimates correlated well with renal function.

Pharmacokinetic estimates of streptomycin were independent of route of administration. However, streptomycin intravenous infusions produced Cmax and AUC values 20% higher than those produced by the same dose given intramuscularly. Previous clinical studies have shown that streptomycin retains considerable activity, even at a constant dose, when the dosing interval was increased.[18] Based on a review of all available data, both the American Thoracic Society and the CDC advocate an increase in streptomycin dosage when the dosing interval is extended to 2-3 times/week. The dosage typically is increased from 15 mg/kg/day (intramuscular) to approximately 25 mg/kg 2-3 times/week.[1] Our data show that higher, less frequent streptomycin doses (twice/week or MWF) produced similar or higher Cmax:MIC, AUC:MIC, and AUC>MIC values compared with daily streptomycin doses. As an aminoglycoside, streptomycin has concentration-dependent bactericidal activity, which has been demonstrated clearly in vitro and in animal models.[10,19,20,21,22,23,24] Therefore, the higher-dose, intermittent regimens appear to maximize the antimycobacterial effect of streptomycin and may have relevance to treatment of tuberculosis in humans. In particular, this may hold true during the first 2 months of treatment, when many of the tubercle bacilli are freely multiplying in an extracellular environment. Further clinical comparisons are needed to prove this.

Estimates of bioavailability of intramuscular streptomycin were 0.84-0.88. These can be considered only estimates because different patients received intramuscular versus intravenous doses. A crossover study of intramuscular and intravenous doses was beyond the scope of this study. Consistent with previous reports, intravenous streptomycin was well tolerated and may be advantageous for certain patients with tuberculosis. Our experience suggests that intravenous dosing of streptomycin is comparable with that of other aminoglycosides. Rarely, we have had patients complain of circumoral numbness or tingling during streptomycin infusions. Typically, increasing the length of infusion from 30 to 60 minutes alleviates these symptoms.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....