Absorption. The aminoglycosides are highly polar cations and therefore are very poorly absorbed from the GI tract. Less than 1% of a dose is absorbed after either oral or rectal administration. The drugs are not inactivated in the intestine and are eliminated quantitatively in the feces. Long-term oral or rectal administration of aminoglycosides may result in accumulation to toxic concentrations in patients with renal impairment. Absorption of gentamicin from the GI tract may be increased by GI disease (e.g., ulcers or inflammatory bowel disease). Instillation of these drugs into body cavities with serosal surfaces also may result in rapid absorption and unexpected toxicity (i.e., neuromuscular blockade). Similarly, intoxication may occur when aminoglycosides are applied topically for long periods to large wounds, burns, or cutaneous ulcers, particularly if there is renal insufficiency.
All the aminoglycosides are absorbed rapidly from intramuscular sites of injection. Peak concentrations in plasma occur after 30-90 minutes and are similar to those observed 30 minutes after completion of an intravenous infusion of an equal dose over a 30-minute period. These concentrations typically range from 4-12 μg/mL following a 1.5-2 mg/kg dose of gentamicin, tobramycin, or netilmicin and from 20 to 35 μg/mL following a 7.5 mg/kg dose of amikacin or kanamycin. In critically ill patients, especially those in shock, absorption of drug may be reduced from intramuscular sites because of poor perfusion.
There is increasing use of aminoglycosides administered via inhalation, primarily for the management of patients with cystic fibrosis who have chronic Pseudomonas aeruginosa pulmonary infections. Amikacin and tobramycin solutions for injection have been used, as well as a commercial formulation of tobramycin designed for inhalation (TOBI, others). Studies of this formulation indicate that high sputum concentrations are obtained (mean of 1200 μg/g), but serum concentrations remain low (mean peak concentration of 0.95 μg/mL) (Geller et al., 2002).
Distribution. Because of their polar nature, the aminoglycosides do not penetrate into most cells, the CNS, or the eye. Except for streptomycin, there is negligible binding of aminoglycosides to plasma albumin. The apparent volume of distribution of these drugs is 25% of lean body weight and approximates the volume of extracellular fluid. The aminoglycosides distribute poorly into adipose tissue, which must be considered when using weight-based dosing regimens in obese patients. Approaches using ideal or adjusted body weight are recommended in conjunction with drug-level monitoring to avoid excessive serum concentrations.
Concentrations of aminoglycosides in secretions and tissues are low. High concentrations are found only in the renal cortex and the endolymph and perilymph of the inner ear; the high concentration in these sites likely contribute to the nephrotoxicity and ototoxicity caused by these drugs. As a result of active hepatic secretion, concentrations in bile approach 30% of those found in plasma, but this represents a very minor excretory route for the aminoglycosides. Penetration into respiratory secretions is poor (Panidis et al., 2005). Diffusion into pleural and synovial fluid is relatively slow, but concentrations that approximate those in the plasma may be achieved after repeated administration. Inflammation increases the penetration of aminoglycosides into peritoneal and pericardial cavities.
Concentrations of aminoglycosides achieved in CSF with parenteral administration usually are subtherapeutic. In patients, concentrations in CSF in the absence of inflammation are <10% of those in plasma; this value may approach 25% when there is meningitis (Kearney and Aweeka, 1999). Given the limit on dosage escalation due to the toxicity of aminoglycosides, treatment of meningitis with intravenous administration is generally suboptimal. Intrathecal or intraventricular administration of aminoglycosides has been used to achieve therapeutic levels, but the availability of third- and fourth-generation cephalosporins has made this unnecessary in most cases. Penetration of aminoglycosides into ocular fluids is so poor that effective therapy of bacterial endophthalmitis requires periocular and intraocular injections of the drugs.
Administration of aminoglycosides to women late in pregnancy may result in accumulation of drug in fetal plasma and amniotic fluid. Streptomycin and tobramycin can cause hearing loss in children born to women who receive the drug during pregnancy. Insufficient data are available regarding the other aminoglycosides; it is therefore recommended that they be used with caution during pregnancy and only for strong clinical indications in the absence of suitable alternatives.
Elimination. The aminoglycosides are excreted almost entirely by glomerular filtration, and urine concentrations of 50-200 μg/mL are achieved. A large fraction of a parenterally administered dose is excreted unchanged during the first 24 hours, with most of this appearing in the first 12 hours. The half-lives of the aminoglycosides in plasma are similar, 2-3 hours in patients with normal renal function. Renal clearance of aminoglycosides is approximately two-thirds of the simultaneous creatinine clearance; this observation suggests some tubular reabsorption of these drugs.
After a single dose of an aminoglycoside, disappearance from the plasma exceeds renal excretion by 10-20%; however, after 1-2 days of therapy, nearly 100% of subsequent doses eventually is recovered in the urine. This lag period probably represents saturation of binding sites in tissues. The rate of elimination of drug from these sites is considerably longer than from plasma; the t1/2 for tissue-bound aminoglycoside has been estimated to range from 30 to 700 hours. For this reason, small amounts of aminoglycosides can be detected in the urine for 10-20 days after drug administration is discontinued. Aminoglycoside bound to renal tissue exhibits antibacterial activity and protects experimental animals against bacterial infections of the kidney even when the drug no longer can be detected in serum (Bergeron et al., 1982).
The concentration of aminoglycoside in plasma produced by the initial dose depends only on the volume of distribution of the drug. Because the elimination of aminoglycosides depends almost entirely on the kidney, a linear relationship exists between the concentration of creatinine in plasma and the t1/2 of all aminoglycosides in patients with moderately compromised renal function. In anephric patients, the t1/2 varies from 20-40 times that is determined in normal individuals. Because the incidence of nephrotoxicity and ototoxicity is likely related to the overall drug exposure to aminoglycosides, it is critical to reduce the maintenance dosage of these drugs in patients with impaired renal function.
Aminoglycosides can be removed from the body by either hemodialysis or peritoneal dialysis. Approximately 50% of the administered dose is removed in 12 hours by hemodialysis, which has been used for the treatment of overdosage. As a general rule, a dose equal to half the loading dose administered after each hemodialysis should maintain the plasma concentration in the desired range; however, a number of variables make this a rough approximation at best. Continuous arteriovenous hemofiltration (CAVH) and continuous venovenous hemofiltration (CVVH) will result in aminoglycoside clearances approximately equivalent to 15 and 15-30 mL/min of creatinine clearance, respectively, depending on the flow rate. The amount of aminoglycoside removed can be replaced by administering ~15-30% of the maximum daily dose (Table 54–2) each day. Frequent monitoring of plasma drug concentrations is again crucial.
Peritoneal dialysis is less effective than hemodialysis in removing aminoglycosides. Clearance rates are ~5-10 mL/min for the various drugs but are highly variable. If a patient who requires dialysis has bacterial peritonitis, a therapeutic concentration of the aminoglycoside probably will not be achieved in the peritoneal fluid because the ratio of the concentration in plasma to that in peritoneal fluid may be 10:1 (Smithivas et al., 1971). Thus, it is recommended that antibiotic be added to the dialysate to achieve concentrations equal to those desired in plasma.
Aminoglycosides can be inactivated by various penicillins in vitro and thus should not be admixed in solution. Some reports indicate that this inactivation may occur in vivo in patients with end-stage renal failure (Blair et al., 1982), thus making monitoring of aminoglycoside plasma concentrations even more necessary in such patients. Amikacin appears to be the aminoglycoside least affected by this interaction, and penicillins with more nonrenal elimination (such as piperacillin) may be less prone to cause this interaction.
Although excretion of aminoglycosides is similar in adults and children >6 months of age, half-lives of the drugs may be prolonged significantly in the newborn: 8-11 hours in the first week of life in newborns weighing <2 kg and ~5 hours in those weighing >2 kg (Yow, 1977). Thus, it is critically important to monitor plasma concentrations of aminoglycosides during treatment of neonates (Philips et al., 1982). For unknown reasons, aminoglycoside clearances are increased and half-lives are reduced in patients with cystic fibrosis compared to subjects without cystic fibrosis, after controlling for age and weight (Mann et al., 1985). Larger doses of aminoglycosides may likewise be required in burn patients because of more rapid drug clearance, possibly because of drug loss through burn tissue.
Dosing. Recommended doses of individual aminoglycosides in the treatment of specific infections are given in later sections of this chapter. Historically, aminoglycosides have been administered as two or three equally divided doses, based on the short t1/2 of the drugs. However, studies of the pharmacokinetic/pharmacodynamic properties of aminoglycosides demonstrate that administering higher doses at extended intervals (typically once daily in patients with normal renal function) is likely to be at least equally efficacious and potentially less toxic than administration of divided doses. A comparison of this high-dose, extended-interval dosing method to traditional divided-dose methods is illustrated in Figure 54–3. Because of the post-antibiotic effect of aminoglycosides, good therapeutic response can be attained even when concentrations of aminoglycosides fall below inhibitory concentrations for a substantial fraction of the dosing interval. High-dose, extended-interval dosing schemes for aminoglycosides may also reduce the characteristic oto- and nephrotoxicity of these drugs. This diminished toxicity is probably due to a threshold effect from accumulation of drug in the inner ear or in the kidney. More drug accumulates with higher plasma concentrations, particularly at trough, and with prolonged periods of exposure. Net elimination of aminoglycoside from these organs occurs more slowly when plasma concentrations are relatively high. High-dose, extended-interval regimens, despite the higher peak concentration, provide a longer period when concentrations fall below the threshold for toxicity than does a multiple-dose regimen (12 hours versus <3 hours total in the example shown in Figure 54–3), potentially accounting for the lower toxicity of this approach.
Numerous studies and meta-analyses demonstrate that administration of the total dose once daily is associated with less nephrotoxicity and is just as effective as multiple-dose regimens (Bailey et al., 1997; Buijk et al., 2002). Extended-interval dosing also costs less and is administered more easily. For these reasons, high-dose, extended-interval administration of aminoglycosides is the preferred means of administering aminoglycosides for most indications and patient populations. Although the use of extended-interval dosing has been controversial in pregnancy, neonatal, and pediatric infections (Knoderer et al., 2003; Rastogi et al., 2002), data from meta-analyses now support this mode of administration in appropriately selected patients from these populations (Contopoulos-Ioannidis et al., 2004; Nestaas et al., 2005; Ward and Theiler, 2008). One key exception to the use of extended-interval dosing is for aminoglycoside use as combination therapy with a cell wall–active agent in the treatment of gram-positive infections, such as endocarditis. In these infections, administration of multiple daily doses (with a lower total daily dose) is preferred because data documenting equivalent safety and efficacy of extended-interval dosing are inadequate. Although schemes exist for adjusting dosages of aminoglycosides dosed by extended-interval methods in patients with significant renal dysfunction (i.e., creatinine clearance <25 mL/minute), some clinicians prefer to use the traditional multiple-dose regimen in such patients.
Nomograms may be helpful in selecting initial doses, but variability in aminoglycoside clearance among patients is too great for these to be relied on for more than a few days (Bartal et al., 2003). If it is anticipated that the patient will be treated with an aminoglycoside for >3-4 days, then plasma concentrations should be monitored to avoid drug accumulation. Whether extended-interval or multiple-daily dosing is chosen, the dose must be adjusted for patients with creatinine clearances of <80-100 mL/minute (Table 54–2), and plasma concentrations must be monitored. Determination of the concentration of drug in plasma is an essential guide to the proper administration of aminoglycosides. In patients with life-threatening systemic infections, aminoglycoside concentrations should be determined several times per week (more frequently if renal function is changing) and should be determined within 24-48 hours of a change in dosage. The size of the individual dose, the interval between doses, or both can be altered based on the results of monitoring of drug levels in plasma. Methods for calculation of dosage are described in Appendix II. There are obvious difficulties in using any of these approaches for ill patients with rapidly changing renal function. In addition, even when known factors are taken into consideration, concentrations of aminoglycosides achieved in plasma after a given dose vary widely among patients. If the extracellular volume is expanded, the volume of distribution is increased, and concentrations will be reduced.
For twice- or thrice-daily dosing regimens, both peak and trough plasma concentrations are determined. The trough sample is obtained just before a dose, and the peak sample is obtained 60 minutes after intramuscular injection or 30 minutes after an intravenous infusion given over 30 minutes. The peak concentration documents that the dose produces therapeutic concentrations, generally accepted to be 4-10 μg/mL for gentamicin, netilmicin, and tobramycin and 15-30 μg/mL for amikacin and streptomycin. The trough concentration is used to avoid toxicity by monitoring for accumulation of drug. Trough concentrations should be <1-2 μg/mL for gentamicin, netilmicin, and tobramycin and <10 μg/mL for amikacin and streptomycin.
Monitoring of aminoglycoside plasma concentrations also is important when using an extended-interval dosing regimen, although peak concentrations are not determined routinely (these will be three to four times higher than the peak achieved with a multiple-daily-dosing regimen). Several approaches may be used to determine that drug is being cleared and not accumulating.
The most accurate method for monitoring plasma levels for dose adjustment is to measure the concentration in two plasma samples drawn several hours apart (e.g., at 2 and 12 hours after a dose). The clearance then can be calculated and the dose adjusted to achieve the desired target range.
Another approach relies on nomograms to target a range of concentrations in a sample obtained earlier in the dosing interval. For example, if the plasma concentration from a sample obtained 8 hours after a dose of gentamicin is between 1.5 and 6 μg/mL, then the concentration at 18 hours will be <1 μg/mL (Chambers et al., 1998). Target ranges of 1-1.5 μg/mL for gentamicin at 18 hours for patients with creatinine clearances >50 mL/min and 1-2.5 μg/mL for those with clearances <50 mL/min also have been used. This method also tends to be inaccurate, particularly when conditions that alter aminoglycoside clearance are present (Bartal et al., 2003; Toschlog et al., 2003).
The simplest method is to obtain a trough sample 24 hours after dosing and adjust the dose to achieve the recommended plasma concentration, (e.g., <1-2 μg/mL in the case of gentamicin or tobramycin). This approach probably is the least desirable. An undetectable trough concentration could reflect grossly inadequate dosing in patients who clear the drug rapidly with prolonged periods (perhaps well over half the dosing interval) during which concentrations are subtherapeutic. In contrast, a 24-hour trough concentration target of 1-2 μg/mL actually would increase aminoglycoside exposure compared with a multiple-daily-dosing regimen (Barclay et al., 1999), which defeats the goal of providing a washout with concentrations of 0-1 μg/mL between 18 and 24 hours after a dose.