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Section 2 - Applied Pharmacokinetics

Aminoglycosides

Introduction


Antimicrobial spectrum

    Aminoglycosides have bactericidal activity against most gram-negative bacteria including Acinetobacter, Citrobacter, Enterobacter, E. Coli, Klebsiella, Proteus, Providencia, Pseudomanas, 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.


Pharmacokinetics

    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.

3 compartment plot
    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.

    However, it is important to keep the true picture in mind when evaluating serum level data.


Concentration-toxicity relationships

    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 (NSAIDs, loop diuretics, Vancomycin)and previous exposure to aminoglycosides.

    Aminoglycosides can cause permanent vestibular and auditory ototoxicity. Overt otoxicity generally occurs in 2% to 10% of patients treated with aminoglycosides. Factors associated with otoxicity include duration of therapy, elevated peak and trough levels, concurrent ototoxic drugs (loop diuretics), 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 ototoxicity due to a mutation found in mitochondrial DNA.

    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.

    For gentamicin, tobramycin and netilmicin risk of ototoxicity and nephrotoxicity is increased if trough levels consistently exceed 2 mcg/ml. For amikacin, trough levels consistently greater than 10 mcg/ml have been associated with a higher risk of ototoxicity and nephrotoxicity.


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 bactericide. 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


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 (or "once-daily") aminoglycoside dosing has gained popularity in recent years. The pharmacodynamic properties of AG's form the basis of EI dosing. The concentration dependent activity of AG's demonstrates that a large dose (5mg/kg) is needed to maximize killing. The persistent (post-antibiotic) effect of AG's allows a dosing interval of 24-36 hours. This extended interval provides a beneficial wash out period during the gamma (tissue-release) phase, thus decreasing the incidence of toxicity.

    This simplified dosing method is appropriate in young, otherwise healthy patients with sepsis. However, there are many patients who are not candidates for the Extended-interval dosing methodology, including those with the following conditions:

    • Elderly
    • Creatinine clearance less than 30
    • Dialysis
    • Pregnancy
    • Endocarditis
    • Cystic fibrosis
    • Ascites
    • Pediatrics
    • > 20% BSA burns
    • History of hearing loss or vestibular dysfunction
    • Gram positive infections (when aminoglycoside is used for synergy)
    • Mycobacterial infections


Population model parameters

    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. Also, ICU patients may have a Vd 25-50% above normal.

    Elimination rate
    AG elimination exhibits a close linear correlation with creatinine clearance, the average value for slope is between 0.0024 and 0.0029 and y-intercept of 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 hypermetabolic and therefore eliminate AG's more rapidly.

Clinical Pearl It is not possible to predict the exact effect a disease state will have on drug elimination, therefore, these special populations require intensive monitoring, usually on a daily basis.


Monitoring parameters
Careful observation for signs of drug toxicity is imperative.

  1. The following patient parameters should be monitored during aminoglycoside therapy:
    1. Aminoglycoside peak and trough levels
      Obtain levels 24 hours after initiating therapy, at steady state (approximately four half-lives), and every 2 to 3 days.
    2. BUN and serum creatinine
      Measure every two days, or every day in unstable renal function.
    3. Weight
      Weigh patient every two to seven days.
    4. Urine output
      Measure and monitor urine output daily
    5. Baseline and weekly audiograms, and check for tinnitus or vertigo daily.

  2. Therapeutic serum concentrations (mcg/ml)
    Below are some general guidelines, however, target serum concentrations should be individualized.
    1. Gentamicin, Tobramycin, Netilmicin
      Peak
        Serious infection: 6-8
        Life-Threatening infection: 8-10
      Trough
        Serious infection: 0.5-1.5
        Life-Threatening infection: 1- <2
    2. Amikacin, Kanamycin
      Peak
        Serious infection: 20-25
        Life-Threatening infection: 25-30
      Trough
        Serious infection: 1-4
        Life-Threatening infection: 4-8


Precautions

  1. Proper timing of serum sampling is critical.
    The trough sample should be obtained 30 minutes prior to the dose. Measure the peak level 15 to 30 minutes after completion of the IV infusion to avoid the distributive phase. Measure the peak level 90 minutes after an IM injection. Drawing the peak too soon will result in inaccurate analysis.

    Drawing at exactly the right time is not as important as having the lab note the exact times that the samples were drawn. Also, have the nurse note the exact times that the sample infusion was started and when it ended. Please be aware of the widespread policy of nursing personnel to record a dose as having been given exactly as ordered if it is given within 30 minutes of the recorded time. This will lead to significant errors in analysis, please ensure that all those involved record the exact times.

    This issue cannot be stressed enough. Inaccurate recording of drug administration times and lab draw times are the greatest source of calculation error, having a greater effect than pharmacy preparation error or lab assay error.

  2. Outliers
    In general the Bayesian approach to the determination of individual drug-dosage requirements performs better than other methods. However, outlying patients in a population (ie, those patients whose pharmacokinetic parameters lie outside of the 95th percentile of the population) may be put at risk. As is always the case, computerized algorithms can only assist in the decision-making process and should never become a substitute for informed clinical judgement.

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Section 2 - Applied Pharmacokinetics

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