Welcome to Aminoglycoside Pharmacology
The aminoglycoside antibiotics -- amikacin, tobramycin, gentamicin, netilmicin and streptomycin are bactericidal drugs (MBC/MIC less than or equal to 4), used almost exclusively to treat infections caused by gram negative bacteria. The aminoglycosides are similar in pharmacokinetic, physical, chemical, pharmacologic, pharmacodynamic, and toxicologic properties.
Aminoglycosides are concentration dependent antibiotics, meaning that as aminoglycoside concentration increases, the rate and extent of bacterial killing increases. Presently, investigators suggest optimizing the aminoglycoside peak serum concentration to bacterial MIC ratio (Cp-max/MIC) to a value > 10:1. Likely, the antibacterial effect is optimized between a value of 10:1 and 20:1.
While the post antibiotics effect (PAE) is generally thought to increase with concentration dependent antibiotics, this may not be the case with aminoglycosides. Limited data suggest that the PAE in gram negative bacteria may wane over time with multiple doses of aminoglycoside.
Traditionally, tobramycin or gentamicin has been dosed 80mg every 8 hours or 1.5 mg/kg every 8 hours. Some clinicians have also attempted to individualize the aminoglycoside dose and dosage interval specific to individual patients using pharmacokinetic or Bayesian forecasting models. Single daily dosing (SDD) concepts have been advocated, which use daily doses ranging from 3 to 7 mg/kg/day. This approach is designed to produce higher peak concentrations than seen with conventional or individualized dosing strategies and thus increase the Cp-max/MIC ratio. The use of the 24 hour dosing interval is designed to create a period during the dosage interval where there will be essentially no aminoglycoside present. It is believed that the "aminoglycoside-free period" will reduce accumulation of aminoglycosides in tissues such as the inner ear and kidney and will thus reduce drug related toxicity. The "aminoglycoside-free interval" should also assist in overcoming adaptive resistance. The optimal timeframe for an "aminoglycoside-free interval" is presently unknown.
One large aminoglycoside dose given once daily rather than several divided doses given on multiple occasions through the day may result in less net transfer of aminoglycoside from the blood into the tissue. This is believed to be accomplished by saturating the rate by which aminoglycoside is moved into the tissue. Smaller but more frequent doses are not believed to saturate drug transport into the tissue and ultimately produce higher tissue concentrations than SDD. Thus, between saturation of the amount of aminoglycoside moving into the tissue and the use of an "aminoglycoside-free period," SDD strategies should be less toxic to the patient through a reduction in aminoglycoside tissue accumulation.
At this time, there appear to be at least three schools of thought regarding the appropriate dosing of aminoglycosides: traditional, individualized, and SDD.
Current Available Aminoglycosides:
Amikacin (Amikin©) IM, IV
Gentamicin (Garamycin©/generic) IM, IV
Netilmicin (Netromycin©) IM, IV
Streptomycin (generic) IM, IV
Tobramycin (Nebcin©, Tobi©) IM, IV, IH
The Mechanism of Action
Aminoglycosides interfere with protein synthesis in susceptible micro-organisms. It is thought that they are actively transported across the bacterial cell membrane, then bind to a specific receptor protein on the 30S subunit of bacterial ribosomes and interfere with an initiation complex between mRNA (messenger RNA) and the 30S subunit, inhibiting protein synthesis.
Bacterial killing is thought to occur in a biphasic fashion. Initially, bacteria are killed at an extremely rapid pace in a concentration-dependent fashion. After approximately two hours and a 3 log kill (99.99% killing), the rate of bacterial killing slows. This phenomenon is thought to be due to adaptive resistance or through a down regulation of aminoglycoside transport into the bacteria through energy dependent transport processes (EDP1 and EDP2).
The aminoglycoside antibiotics are less than 10 percent protein bound.
Aminoglycosides are primarily eliminated unchanged by the kidney through glomerular filtration. This route accounts for approximately 85 to 95 percent of the dose administered.
Spectrum of Antimicrobial Activity
Gram Negative Infections:
Aminoglycoside antibiotics are the most useful group of antimicrobials for gram negative infections. The primary pathogens they are used to treat include:
Serratia spp. (S. marcescens)
Tobramycin is more active by one or two MIC tube dilutions than gentamicin against Pseudomonas aeruginosa. Gentamicin is more active by one or two MIC tube dilutions against Serratia marcescens. Often amikacin is held in reserve to treat resistant pathogens that develop during therapy. Other aerobic gram-negative bacilli (Neisseria gonorrhoeae, Neisseria meningitidis, Haemophilus influenzae) are susceptible but are rarely treated with aminoglycosides.
Gram Positive Infections:
Aminoglycosides have activity against some gram positive isolates but are not considered primary agents. Enterococcal infections may be treated with a combination including penicillin, ampicillin, or vancomycin. Aminoglycosides may also be used as adjunctive therapy for Staphylococcal infections.
Enterococci are intrinsically resilient to aminoglycosides with MIC's > 500 mg/l. Here the primary problem is the ability of the aminoglycoside to get into the bacterial organism. Use of a cell wall active agent such as penicillin G, ampicillin, or if the patient is allergic to beta-lactams, vancomycin, in combination will break down the cell wall, allowing the aminoglycoside to enter the bacteria. Generally, the combination of a beta-lactam antibiotic or vancomycin with either gentamicin or streptomycin is considered to be synergistic in killing the bacterial organism. If aminoglycosides are to be used, current recommendations suggest peak gentamicin concentrations of 3 to 5 mg/L for gentamicin and 20 mg/L for streptomycin. Presently there is very little data to suggest a beneficial role for SDD in the management of enterococcal infections.
Enterococci are considered clinically resistant if their MIC's > 2000 mg/L. In this situation not only is there the problem of antibiotic penetration but also the enterococci have likely acquired (through a plasmid) the ability to enzymatically inactivate the aminoglycoside. There are approximately 5 aminoglycoside inactivating enzymes that are of clinical importance. Fortunately, when enterococci are gentamicin resistant, they are generally streptomycin susceptible and vice versa. This however is not the situation with tobramycin or amikacin which are not usually recommended as adjunct therapy for enterococcal infections.
We must also look at the susceptibility of the enterococci to beta-lactams and vancomycin. Most of the resistant strains of enterococci alter their penicillin binding proteins (PBP's) and become resistant to beta-lactam antibiotics. Less frequently, enterococci produce a beta-lactamase that will destroy beta-lactam antibiotics.
Vancomycin resistant enterococci (VRE) have been able to bypass the metabolic block caused by vancomycin in cell wall synthesis.
The value of aminoglycosides as adjunctive therapy for staphylococci has been extensively questioned in the literature. Data suggest that the addition of an aminoglycoside to nafcillin therapy shortens the duration of bacteremia by about one-half day. No beneficial effect has been shown for a reduction in mortality. Despite these data, aminoglycosides will still be used by many clinicians in this situation. If an aminoglycoside is to be used, the clinician should recognize that extending aminoglycoside therapy beyond five days may place the patient at risk of aminoglycoside toxicity. Thus far peak gentamicin concentrations of 3 to 5 mg/L seem adequate for adjunctive therapy. Very little data is available to suggest a meaningful role for SDD in staphylococcal infections being primarily managed with either vancomycin or a beta-lactam antibiotic.
Anaerobic bacteria are uniformly resistant to all of the aminoglycosides.
Aminoglycosides effectively treat infections caused by gram negative organisms in:
- Lower respiratory infections (only 30-50% penetration)
- Urinary tract (Aminoglycosides concentrate in urine and kidney)
- Skin and soft tissue infections
Aminoglycosides penetrate most fluid spaces at levels similar to serum concentrations. Therapeutic concentrations are achieved in synovial, pericardial, peritoneal, pleural and amniotic fluids, and bile.
Aminoglycosides DO NOT penetrate well into the cerebrospinal fluid (CSF) or into the aqueous humor of the eye. Treatment of gram negative meningitis or ventriculitis involves administration of the aminoglycoside intrathecally or intraventricularly. A preservative-free form of aminoglycoside should be used.
Several beta-lactam antibiotics are synergistic with aminoglycosides. Meaning the combined effect of both antibiotics is better than either alone. For example, the action of piperacillin or a "piperacillin-like penicillin" with an aminoglycoside against Pseudomonas, or, as discussed, the action of penicillin, ampicillin, or vancomycin combined with a gentamicin or tobramycin against Enterococcus.
Inhibitory Concentrations (MIC's)
Most gram negative bacteria have MIC's of < 0.5 to 2 mg/L to gentamicin, tobramycin or netilmicin. Higher MICs are seen with amikacin.
Antibiotic activity of aminoglycosides is heavily dependent on pH. Aminoglycosides are much more active at an alkaline pH. The antibacterial action of the aminoglycoside at standard concentrations can be entirely eliminated as the pH reaches 5 to 5.5.
Small changes in the pH of the medium will affect the ratio of ionized and un-ionized aminoglycoside. This is significant since only the un-ionized drug is active. pH is particularly important in treating urinary tract infections. Alkalinizing the urine with bicarbonate or carbonic anhydrase inhibitors (e.g., acetazolamide) may dramatically increase the antimicrobial effect on bacterial pathogens.
Protein Synthesis Inhibitors
Antibiotics that inhibit protein synthesis, such as chloramphenicol or clindamycin, may have an antagonistic effect with aminoglycoside antibiotics since aminoglycosides interfere with protein synthesis.
Drugs that form chemical complexes with glycoproteins, such as heparin, penicillins, and cephalosporins, must be administered separately to prevent in-vivo inactivation. Aminoglycoside levels drawn on patients receiving concomitant beta-lactam antibiotics with an aminoglycoside should be rapidly processed by the laboratory to prevent drug inactivation.
Aminoglycoside inactivation is dependent on time, temperature, and concentration. Gentamicin is more vulnerable to this chemical reaction than other aminoglycosides. In patients with severe renal impairment, this chemical inactivation may occur in vivo.
Cations, such as calcium or magnesium, inhibit the activity of aminoglycosides and decrease their antimicrobial effect.
Serious toxicity has limited the use of aminoglycosides. The two most concerning problems are ototoxicity and nephrotoxicity; both reportedly occur in approximately < 2 to 10% of patients. Ototoxicity can be broken down into auditory and vestibular toxicity. Auditory toxicity is generally a high frequency loss that generally will not greatly affect most patient's lifestyle but will likely be with the patient for the rest of their life. Vestibular toxicity on the other hand is perhaps the most severe form of aminoglycoside toxicity in that it permanently affects the patient's ability to balance.
Other less frequent problems attributed to aminoglycoside therapy include neuromuscular blockade, hypersensitivity reactions, and gastrointestinal, hematologic, and central nervous system effects.
Hypersensitivity is rare with aminoglycosides, thus other drugs should be considered to be the cause.
Aminoglycosides cross the placental barrier. Prolonged use may cause otologic damage to the fetus.
No problems are documented. However, the risk/benefit should be considered.