Aminoglycosides

Agents: gentamicin, tobramycin, amikacin,  streptomycin, spectinomycin

The aminoglycosides as a class dispel the notion that antibiotics are largely nontoxic. These drugs have a narrow therapeutic window, and improper dosing carries the risk of inflicting significant toxicity (primarily nephro- and ototoxicity) on your patients. Because of this, there has been a reduction in their use as primary therapy for most infections. That being said, they retain good activity against many problem pathogens (such as  Pseudomonas and Acinetobacter) that have developed resistance to the more benign drug classes. They are also excellent at synergizing with the beta-lactams and glycopeptides to improve the efficiency of bacterial killing. Gentamicin and tobramycin are the most widely used drugs, amikacin is generally reserved for pathogens resistant to the first two, and streptomycin (Enterococcus, tuberculosis [TB], and plague) and spectinomycin (gonorrhea) are niche drugs.

Spectrum: Gentamicin/tobramycin/amikacin

Good: Gram-negatives (E. coli,  Klebsiella,  Pseudomonas, Acinetobacter, most others)

Moderate: in combination with a beta-lactam or glycopeptide: staphylococci (including MRSA), viridans streptococci, enterococci

Poor : atypicals, anaerobes, Gram-positive organ-isms (as monotherapy)

Adverse Effects

Nephrotoxicity: Oliguric acute renal failure, preceded by a rising serum creatinine, is a dose-related adverse effect of aminoglycosides. Risk can be reduced by correct dosing (including the use of extended-interval dosing), as well as avoidance of co-administration of other nephrotoxins (cyclosporin, cisplatin, foscarnet, etc.).

Ototoxicity: Aminoglycosides cause dose-related cochlear and vestibular toxicity. For patients anticipated to receive long-term (<  2 weeks)  aminoglycosides, baseline and follow-up audiology are necessary. It is important to monitor patients closely for any hearing loss or balance problems, because these are not reversible and can significantly affect quality of life.

Neuromuscular blockade can occur when amino-glycosides are given, particularly in high doses in patients who are receiving therapeutic paralysis.

Important Facts

• Once-daily or extended-interval aminoglycoside dosing leverages the concentration-dependent killing of the drugs to create an equally effective, more convenient, and possibly safer dosing regimen. However, there are many populations in which once-daily dosing has had minimal study, including the pregnant, the critically ill, those with significant renal dysfunction, and the morbidly obese. Use this dosing method with caution, if at all, in these populations. Aminoglycosides are pregnancy category D and should be avoided if possible in pregnant women anyway.

• Aminoglycoside serum levels can help guide appropriate dosing and reduce the risk of toxicity,  but they must be drawn correctly to have meaningful interpretations. For traditional dosing methods, a peak level should be drawn half an hour after the end of the infusion, while trough levels should be drawn within 30 minutes of the  next dose. For once-daily dosing there are a number of potential monitoring points.

• Aminoglycosides have relatively poor distribution into many tissues, including the lungs.  They have minimal nervous system penetration. This makes them less than optimal as monotherapy for many severe infections. It also means that a dose should be based on the patient’s ideal or adjusted body weight, rather than his or her total body weight. Given the high prevalence of morbid obesity, serious over-dosing of patients can occur if the patient’s total body weight is used.

• Some older drug references and textbooks list streptomycin as a first-line treatment for tuberculosis. While it was the first anti-tuberculosis drug available, it has been supplanted by safer and more effective first-line drugs. It is still an alternative in resistant tuberculosis infections—these should be treated by an expert in their management.

What They’re Good For

In combination with a beta-lactam agent, treatment of serious infections with documented or suspected Gram-negative pathogens, including febrile neutropenia, sepsis, exacerbations of cystic fibrosis, and ventilator-associated pneumonia. Amino-glycosines are also used in combination with a beta-lactam or glycopeptide for treatment of serious Gram-positive infections, including endocarditis, osteomyelitis, and sepsis. In combination with other antimycobacterials, they are used for treatment of drug-resistant infections with M. tuberculosis or other mycobacteria (streptomycin and amikacin).

Don’t Forget!

Most aminoglycoside toxicity is dose related, so get the dose right from the start by adjusting for renal dysfunction and using ideal or adjusted body weight. Pharmacokinetic concentrations are useful for monitoring and dosing aminoglycosides if they are drawn correctly.

References

Gallagher ,J.C. and MacDougall ,c. (2012). Antibiotics Simplified. Second Edition. Jones & Bartlett Learning, LLC.