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Aminoglycosides

 

Introduction

The aminoglycosides are the mainstay in the treatment of serious gram-negative systemic infections.  A disadvantage of the aminoglycosides is their association with nephrotoxicity and ototoxicity, both of which are associated with elevated trough levels and sustained elevated peak levels.

 

1.   Antimicrobial spectrum

Aminoglycosides have bactericidal activity against most gram-negative bacteria including Acinetobacter, Citrobacter, Enterobacter, E. Coli, Klebsiella, Proteus, Providencia, Pseudomonas, Salmonella, Serratia and Shigella. The MIC's of gram negative bacteria are usually less than 2 mcg/ml for gentamicin and tobramycin and 8 mcg/ml for amikacin.

 

Aminoglycosides are active against most strains of Staphylococcus aureus and S. epidermidis. Most strains of enterococcus are resistant to aminoglycosides alone, however when used in combination with penicillins they are often effective in enterococcal endocarditis due to synergistic antimicrobial mechanisms. Anaerobic bacteria are universally resistant because aminoglycoside transport into cells is oxygen-dependent.

 

2.        Toxicity

Aminoglycoside nephrotoxicity manifests clinically as nonoliguric renal failure, with a slow rise in serum creatinine and a hypoosmolar urinary output developing after several days of therapy. The reported incidence of nephrotoxicity varies substantially between studies, averaging 6% to 10%. Nephrotoxicity rates do not vary significantly among the different aminoglycosides. Factors associated with nephrotoxicity include duration of treatment, increasing age, compromised renal function, volume depletion, elevated peak and trough levels, concurrent nephrotoxic drugs (i.e., vancomycin) and previous exposure to aminoglycosides.

 

Aminoglycosides can cause permanent vestibular and/or auditory ototoxicity. Overt otoxicity occurs in 2% to 10% of patients treated with aminoglycosides. Factors associated with otoxicity include increasing age, duration of therapy, elevated peak and trough levels, concurrent loop diuretics or vancomycin, underlying disease states and previous exposure to aminoglycosides.

 

Vestibulotoxicity is difficult to diagnose and there is no reliable monitoring process. Recent studies indicate a genetic predisposition to aminoglycoside auditory ototoxicity due to a mutation of mitochondrial DNA. However, this genetic component does not appear to influence aminoglycoside vestibular ototoxicity. Gentamicin toxicity is the most common single known cause of bilateral vestibulopathy, accounting for 15-50% of all cases. A web site, Wobblers Anonymous presents personal testimony from patients who have suffered from this disabling ADE.

 

3.   Concentration-toxicity relationships

For gentamicin, tobramycin and netilmicin risk of ototoxicity and nephrotoxicity is increased if peak levels are consistently maintained above 12 to 14 mcg/ml or trough levels consistently exceed 2 mcg/ml. For amikacin, peak levels consistently above 32 to 34 mcg/ml or trough levels greater than 10 mcg/ml have been associated with a higher risk of ototoxicity and nephrotoxicity.

         

4.   Concentration-efficacy relationships

The pharmacodynamic properties of aminoglycosides are:

Concentration-dependent killing
Significant post-antibiotic effect

 

Aminoglycosides eliminate bacteria quickest when their concentration is appreciably above the MIC for an organism, this is referred to as concentration dependent activity. The aminoglycosides also exhibit a significant post-antibiotic effect (PAE). PAE is the persistent suppression of bacterial growth following antibiotic exposure. Practically speaking this means that trough levels can drop below the MIC of targeted bacteria for a sustained period without decreasing efficacy.

 

For AG's the ideal dosing regimen would maximize concentration, because the higher the concentration, the more extensive and the faster is the degree of bacteriocide. Therefore, the Peak/MIC ratio is an important predictor of efficacy. It has been shown that aminoglycosides eradicate bacteria best when they achieve a Peak/MIC ratio of at least 8-10. Therefore it is important to give a large enough dose to produce a peak level 8 to 10 times greater than the MIC.

 

Aminoglycoside Pharmacodynamics in Vivo

Initial serum peak level

Died

Survived

< 5mcg/ml

21%

79%

>= 5mcg/ml

2%

98%

Moore et al, J Infect Dis 149: 443, 1984

 

5.   Dosing methods

When given by IV infusion over 30 minutes, aminoglycosides follow a 3-compartment pharmacokinetic model; alpha (distribution), ß (elimination), and gamma (tissue release). When infused over one hour, the distribution phase is usually not observed. The gamma phase begins approximately sixteen hours post infusion, drug that was tissue bound to various organs is released. The amount released from tissue is very small, but does accumulate over time, contributing to AG toxicity.

 

Although this model accurately represents the time course of AG serum levels, it cannot be used clinically because of its complexity. Therefore, the simpler one compartment model is widely used, and does, in fact, accurately predict serum AG levels.

 

Volume of distribution

The average Vd of AG's in otherwise healthy adults is 0.26 L/kg (range: 0.2-0.3). Although AG's do not distribute into adipose tissue, they do enter the extracellular fluid contained therein. Therefore, obese patients require a correction in the weight used for Vd calculation: LBW + 40% of weight above LBW. Patients with cystic fibrosis have a markedly increased Vd of 0.35 L/kg due to increases in extracellular fluid brought about by the disease process. Patients with ascites have additional extracellular fluid because of accumulation of ascitic fluid, which increases the Vd to approximately 0.32 L/kg. ICU patients may have a Vd 25-50% above normal.

 

Elimination rate

AG elimination is closely correlated with creatinine clearance, the average value for the slope is between 0.0024 and 0.0029 and the y-intercept is typically 0.01 to 0.015. Cystic fibrosis patients show a 50% increase in elimination rate. A major body burn increases the basal metabolic rate resulting in a marked increase in AG elimination. ICU patients are often hyper metabolic and therefore eliminate AG's more rapidly.

 

6.   Dosing methods

Achieving therapeutic serum levels of aminoglycosides early in the course of treatment is critical to therapeutic success.  Dosing error on the high side is preferable to the risks of under-treatment.  An adequate loading dose is critical for rapid attainment of therapeutic peak levels.

 

The method of Sarrubi and Hull utilizes serum creatinine, lean body weight, age, and sex to estimate creatinine clearance.  This method considers more patient variables, which may improve the estimation of aminoglycoside elimination.  Lesar et al found that the Sarubbi and Hull nomogram achieved therapeutic concentrations in 78% of patients.  Tsubaki and Chandler evaluated 5 methods for determining initial dosing requirements for gentamicin.  They concluded that the Sarubbi and Hull method was the most accurate.  However, dosing nomograms are initial guidelines only.  They can produce substantial variations in serum concentrations and should be subsequently adjusted based on serum level determinations and clinical response.

 

Dosage regimens necessary to achieve therapeutic aminoglycoside serum concentrations can be quantitatively determined by using simple pharmacokinetic principles.  Individualized  pharmacokinetic parameters are determined from the patient's serum concentration versus time data.  Sawchuk and Zaske have described a method for establishing multiple infusion  regimens based  on individually calculated pharmacokinetic parameters.  Lesar, et al found that this individualized method achieved therapeutic concentrations in 90% of patients.

 

For evaluation of serum level data, methods incorporating Bayesian principles appear to give the best overall predictive performance compared with traditional methods of vancomycin dosage adjustment. The Bayesian approach combines both population and patient-specific information (i.e., serum level data) in predicting dosage requirements.

 

Extended-interval aminoglycoside dosing has gained popularity in recent years. This simplified dosing method is appropriate in young, otherwise healthy patients with sepsis. However, there are many patient groups who are not candidates for this dosing methodology: the elderly, CrCl less than 30, dialysis, pregnancy, endocarditis, cystic fibrosis, ascites, neutropenia, infants, 20% or greater BSA burns, history of hearing loss or vestibular dysfunction, gram positive infections (when aminoglycoside is used for synergy), or mycobacterial infections.

 

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