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

Abstract and Introduction

Study Objectives. To determine population pharmacokinetic parameters of streptomycin after administration of multiple intramuscular and intravenous doses.

Design. Prospective, unblinded clinical study.
Setting. Two medical centers in Denver, Colorado.
Patients. Thirty patients with tuberculosis.
Intervention. Patients received multiple doses of streptomycin as part of their tuberculosis treatment. They received concurrent drugs based on in vitro susceptibility data.
Measurements and Main Results. Serum samples were collected over a 10-hour period and assayed by validated high-performance liquid chromatography. Concentration-time data were analyzed using population methods. Streptomycin concentrations increased linearly with increasing intravenous doses. The intramuscular doses did not produce as linear a relationship, presumably because of variability in rates of and, potentially, completeness of absorption. Streptomycin elimination decreased with declining renal function. Higher, intermittent doses were well tolerated and appeared to maximize the peak concentration:minimal inhibitory concentration ratio.
Conclusion. Overall, pharmacokinetic parameters of streptomycin were comparable with those previously published for streptomycin and other aminoglycosides. Higher, intermittent doses maximize pharmacodynamic parameter estimates and might have advantages for treatment of tuberculosis.

Streptomycin is an aminoglycoside antibiotic used to treat certain bacterial infections, including brucellosis, tularemia, plague, and certain cases of drug-resistant endocarditis. More commonly, streptomycin is used as a first-line agent for treatment of tuberculosis and is used with other antituberculosis drugs. To ensure adequate treatment of tuberculosis that is resistant to any single drug and to prevent emergence of multidrug-resistant tuberculosis, the American Thoracic Society and Centers for Disease Control and Prevention (CDC) recommend that most patients with tuberculosis begin therapy with an intensive four-drug regimen. This regimen includes streptomycin (or ethambutol) in addition to isoniazid, rifampin, and pyrazinamide until susceptibility data become available.[1]

The pharmacokinetic behavior of parenteral streptomycin was studied during the 1940s and has been explored occasionally since then.[2,3,4,5,6,7] Since streptomycin is poorly absorbed from the gastrointestinal tract, parenteral routes of administration are necessary. The drug usually is given by deep intramuscular injection, with alternating injection sites. With long-term use, some patients, especially those with limited muscle mass, become intolerant of injections due to pain at injection sites. Therefore, at some centers, intravenous infusion has become a frequent alternative route of administration.[8,9] Since the drug has a narrow therapeutic window and requires long-term use for tuberculosis treatment, population pharmacokinetic models should help in providing adequate dosages while potentially reducing the risk of toxicity. To our knowledge, population pharmacokinetic models of streptomycin using a sparse sampling strategy (< 3 data points) for either the intramuscular or the intravenous route of administration have not been established in patients with any type of infection.

In this study, the pharmacokinetics of intra-muscular and intravenous streptomycin were evaluated in patients with tuberculosis during routine treatment. Population models were established by using both rich and sparse data sets obtained from patients during their hospital stays or clinic visits. Correlations between the pharmacokinetic or pharmacodynamic parameter estimates and patient demographics were evaluated.

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