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Streptomycin
Indications
Streptomycin is an aminoglycoside antibiotic originally isolated from the bacteria Streptomyces griseus. It is the first discovered aminoglycoside antibiotic. Its use is primarily treating aerobic gram-negative bacterial infections, such as brucellosis, tularemia, plague (Y. pestis), tuberculosis (in combination with isoniazid, pyrazinamide, and rifampin), and certain cases of endocarditis when combined with beta-lactam antibiotics. In contrast to other aminoglycoside antibiotics, namely gentamycin and tobramycin, it lacks reliable activity against Pseudomonas aeruginosa. The originally wide spectrum of activity against gram-negative and gram-positive bacteria has diminished largely due to developing antibiotic resistance. The mechanism of resistance appears to be associated with the inhibition of its active transport into the bacterial cell. Commonly resistant bacteria include Enterobacteriaceae and most Streptococci species.[1][2][3][4]
Although streptomycin was historically one of the first and most effective treatments for pulmonary tuberculosis, it is now largely an alternative therapy, second to the current standard of "RIPE" (rifampin, isoniazid, pyrazinamide, and ethambutol) therapy. That said, it remains a potentially effective treatment and is important to keep in mind in cases where RIPE therapy may not be tolerated or is otherwise unavailable. The use of streptomycin becomes particularly applicable in the emerging discussion of how to treat an infection with drug-resistant Mycobacterium tuberculosis in which the standard combination therapy of rifampin, isoniazid, pyrazinamide, and ethambutol is not effective. In these cases, streptomycin is considered an acceptable alternative therapy among other choice antibiotics with activity against M. tuberculosis such as rifapentine, rifabutin, linezolid, and certain fluoroquinolone antibiotics such as levofloxacin, gatifloxacin, and moxifloxacin.[5]
Mechanism of Action
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Mechanism of Action
As with all aminoglycosides, streptomycin is bactericidal and provides interference with ribosomal peptide/protein synthesis. It binds to a side of 16S rRNA located on the smaller 30S component of the bacterial ribosome, inhibiting its functionality and halting further protein synthesis through inhibition of peptide bond formation. Aminoglycosides are hydrophilic, meaning they are not able to penetrate the hydrophobic bacterial cell membrane. An electron transport system used during the cell’s respiratory cycle is needed to accomplish this, hence why aminoglycosides are only active against aerobic bacteria.[3][6][7]
Administration
Streptomycin is poorly absorbed within the gastrointestinal tract and is typically administered parenterally via deep intramuscular injection. Alternatively, patients requiring multiple doses or who have less than adequate muscle mass may become intolerant of injections due to pain. In these cases, intravenous administration can be an alternative administration method. The serum half-life of streptomycin is approximately 2.5 hours, with serum drug levels peaking at the level of around 50mg/ml. The distribution of aminoglycosides is mainly in lean tissue. Therefore, dosing in obese patients should be based upon ideal body weight instead of total body weight.[1][7] With IM and IV administration, young adults are typically treated with 1g per day, either as a single dose or divided into two separate doses. However, in adults over age 40, a modified dose of 0.75g/day is used. The typical dosage in children is 20 mg/kg daily and never exceeding 40 mg/kg.[3]
Adverse Effects
Hypersensitivity reactions are not uncommon with streptomycin use, often manifesting as a rash or mild fever. Other potential adverse effects include hypomagnesemia with long-term treatment, seizures, and encephalopathy in extreme cases.[7] Streptomycin has loose associations with immuno-allergic hemolytic anemia.[8] Additionally, streptomycin correlates with a myriad of more severe side effects related to its toxicity, which this article will discuss in more detail in the toxicity section.
Contraindications
Streptomycin is contraindicated in patients with known renal impairment, which directly links to their inability to excrete streptomycin at the same rate as individuals with normal renal function. Contraindications to streptomycin also include pregnancy due to its ability to cross the placenta in combination with its known ototoxic effects. Thus, streptomycin is considered to be teratogenic. Aminoglycoside antibiotics are also contraindicated in patients with myasthenia gravis due to inhibition of neuromuscular transmission, leading to a lower threshold for neuromuscular blockade.[9][7]
Monitoring
Monitoring is based on the limited therapeutic index of aminoglycosides and known toxicities, particularly nephrotoxicity and ototoxicity. In general, clinicians should avoid concomitant the use of additional medications with possible ototoxic or nephrotoxic effects. In courses that extend beyond 2 to 3 days, serum concentration requires monitoring to ensure efficacy as well as avoid excessive trough concentrations. Renal function should be monitored both before and during the use of streptomycin.[7]
Toxicity
Monitoring for streptomycin toxicity is especially important in the young and patients with renal impairment, as streptomycin occurs via glomerular filtration. Renal impairment can prolong the drug's half-life by 50 to 100 hours. Ototoxicity and vestibular impairment are often thought to be the hallmark of streptomycin toxicity. In extreme cases, deafness may occur due to ototoxicity; thus, caution must be exercised when combining streptomycin with other potentially ototoxic drugs. Vestibular impairment usually manifests during the course of treatment and is typically permanent. Streptomycin is also a potentially nephrotoxic agent. This will manifest as mild proteinuria, excess cellular excretion, and mild elevations in blood urea. Unlike ototoxic effects, nephrotoxicity is usually only transient. There are also reports of neuromuscular blockade with streptomycin use in association with installation into body cavities, use during anesthesia involving the use of neuromuscular blocking agents, and overdose in children. Neurotoxic effects can lead to optic nerve dysfunction, peripheral neuritis, and encephalopathy. Intrathecal use, while rarely used, has been associated with arachnoiditis. In the event of drug toxicity, dialysis can lower serum streptomycin concentration.[3][6][7]
Enhancing Healthcare Team Outcomes
Streptomycin is an important antibiotic therapy primarily used to treat the infection from M. tuberculosis and other aerobic gram-negative bacteria. The MRC randomized trial of streptomycin established streptomycin as an effective therapy for pulmonary tuberculosis. However, it also highlighted the susceptibility of developing resistance with streptomycin use. Hence, using streptomycin as monotherapy is generally discouraged, and its use as a treatment for tuberculosis is always in combination with isoniazid, rifampin, and pyrazinamide. Streptomycin is an important antibiotic therapy primarily used to treat the infection from M. tuberculosis and other aerobic gram-negative bacteria. Although efficacious in this role, it is important for all interprofessional healthcare team members that utilize this medication to monitor serum levels throughout the course of treatment and be aware of developing signs of ototoxicity and/or nephrotoxicity. The patient's renal function requires assessment both before and during therapy with streptomycin. Healthcare workers should be aware of co-administering streptomycin with other potentially ototoxic or nephrotoxic agents due to the risk of synergistic toxicity.[10][1][11] That is why all interprofessional team members, including clinicians, specialists, nurses, and pharmacists, must take an active role in selecting streptomycin, dosing, monitoring, and checking therapeutic progress. This interprofessional approach will yield improved patient results with fewer adverse effects. [Level 5]
References
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Daniel TM. Selman Abraham Waksman and the discovery of streptomycin. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2005 Feb:9(2):120-2 [PubMed PMID: 15732728]
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Mitnick CD, McGee B, Peloquin CA. Tuberculosis pharmacotherapy: strategies to optimize patient care. Expert opinion on pharmacotherapy. 2009 Feb:10(3):381-401. doi: 10.1517/14656560802694564. Epub [PubMed PMID: 19191677]
Level 3 (low-level) evidenceVianna JF, S Bezerra K, I N Oliveira J, Albuquerque EL, Fulco UL. Binding energies of the drugs capreomycin and streptomycin in complex with tuberculosis bacterial ribosome subunits. Physical chemistry chemical physics : PCCP. 2019 Sep 21:21(35):19192-19200. doi: 10.1039/c9cp03631h. Epub 2019 Aug 22 [PubMed PMID: 31436279]
Germovsek E, Barker CI, Sharland M. What do I need to know about aminoglycoside antibiotics? Archives of disease in childhood. Education and practice edition. 2017 Apr:102(2):89-93. doi: 10.1136/archdischild-2015-309069. Epub 2016 Aug 9 [PubMed PMID: 27506599]
Pla RP,Martin C,Odriozola J,Armengol R,Triginer J, [Immuno-allergic hemolytic anemia connected with streptomycin]. Revue francaise de transfusion et immuno-hematologie. 1976 Jun; [PubMed PMID: 981877]
Level 3 (low-level) evidenceSnider DE Jr, Layde PM, Johnson MW, Lyle MA. Treatment of tuberculosis during pregnancy. The American review of respiratory disease. 1980 Jul:122(1):65-79 [PubMed PMID: 6996549]
Crofton J. The MRC randomized trial of streptomycin and its legacy: a view from the clinical front line. Journal of the Royal Society of Medicine. 2006 Oct:99(10):531-4 [PubMed PMID: 17021304]
Level 1 (high-level) evidenceNewcombe HB, Hawirko R. SPONTANEOUS MUTATION TO STREPTOMYCIN RESISTANCE AND DEPENDENCE IN ESCHERICHIA COLI. Journal of bacteriology. 1949 May:57(5):565-72 [PubMed PMID: 16561734]