Montvale, N. Cost to the patient will be greater, depending on prescription filling fee. Costs listed in this table are for brand names and for one day's therapy. Most resistance to aminoglycosides is caused by bacterial inactivation by intracellular enzymes. Because of structural differences, amikacin is not inactivated by the common enzymes that inactivate gentamicin and tobramycin.
Therefore, a large proportion of the gram-negative aerobes that are resistant to gentamicin and tobramycin are sensitive to amikacin. In addition, with increased use of amikacin, a lower incidence of resistance has been observed compared with increased use of gentamicin and tobramycin. This occurs when formerly susceptible populations become less susceptible to the antibiotic as a result of decreased intra-cellular concentrations of the antibiotic.
This decrease may result in colonization, slow clinical response or failure of the antibiotic despite sensitivity on in vitro testing. Aminoglycosides are often combined with a beta-lactam drug in the treatment of Staphylococcus aureus infection. This combination enhances bactericidal activity, whereas aminoglycoside monotherapy may allow resistant staphylococci to persist during therapy and cause a clinical relapse once the antibiotic is discontinued.
Infective endocarditis that is due to enterococci with high levels of resistance to aminoglycosides is becoming increasingly common. All enterococci have low-level resistance to aminoglycosides because of their anaerobic metabolism. In the treatment of bacterial endocarditis, a beta-lactam drug is also used synergistically to facilitate aminoglycoside penetration into the cell. When high-level resistance occurs, it is typically due to the production of inactivating enzymes by the bacteria.
Because of the increasing frequency of this resistance, all enterococci should be tested for antibiotic susceptibility. As with all antibiotics, resistance to aminoglycosides is becoming increasingly prevalent. Repeated use of aminoglycosides, especially when only one type is employed, leads to an increased incidence of resistance. Because the body does not metabolize aminoglycosides, aminoglycoside activity is unchanged by induction or inhibition of metabolic enzymes, such as those in the cytochrome P system.
Certain medications may increase the risk of renal toxicity with aminoglycoside use Table 3. Information from references 10 and The toxicities of aminoglycosides include nephrotoxicity, ototoxicity vestibular and auditory and, rarely, neuromuscular blockade and hypersensitivity reactions. Nephrotoxicity receives the most attention, perhaps because of easier documentation of reduced renal function, but it is usually reversible. Ototoxicity is usually irreversible.
Originally, ototoxicity was believed to result from transiently high peak serum concentrations, resulting in a high concentration of drug in the inner ear. Recent studies in animal models have indicated that aminoglycoside accumulation in the ear is dose-dependent but saturable.
Once a threshold concentration of the antibiotic has been reached, increasing the drug concentration results in no further uptake. Experimental studies have shown increased drug accumulation by the cochlear organ of Corti with continuous infusion versus intermittent to minute infusions of aminoglycosides. Nephrotoxicity results from renal cortical accumulation resulting in tubular cell degeneration and sloughing.
Examination of urine sediment may reveal dark-brown, fine or granulated casts consistent with acute tubular necrosis but not specific for aminoglycoside renal toxicity. In most clinical trials of aminoglycosides, however, nephrotoxicity has been defined by an elevation of serum creatinine.
In order to minimize toxicity, family physicians should remember a few key considerations. Aminoglycoside antibiotics exhibit rapid concentration-dependent killing action. In addition, aminoglycosides have demonstrated persistent suppression of bacterial growth after short exposure, a response referred to as the post-antibiotic effect. The higher the aminoglycoside dosage, the greater the post-antibiotic effect, up to a certain maximal response.
In vivo, the post-antibiotic effect for aminoglycosides is prolonged by the synergistic effect of host leukocyte activity.
It is believed that leukocytes have enhanced phagocytosis and killing activity after exposure to aminoglycosides.
The previously mentioned principles and the distinct differences in antimicrobial activity between aminoglycosides and other anti-infectives provide support for the development of novel dosing schemes.
A number of neutropenic and nonneutropenic animal models of infection have been used to evaluate once-daily dosing of aminoglycosides. Demonstrated antibacterial efficacy and the potential for reduced toxicity prompted investigators to recommend the study of single daily dosing of aminoglycosides in the treatment of human infections.
Another area of interest related to single daily dosing of aminoglycosides is circadian variation in glomerular filtration. Glomerular filtration rates are lower in humans during the rest period midnight to a. A report from a recently published nonrandomized, unblinded study showed a higher incidence of nephrotoxicity when aminoglycosides were administered during the rest period. Currently, human trial designs have included pharmacokinetic assessments, non-comparative trials involving single daily dosing regimens and comparative clinical trials to support the concept of single daily dosing.
To address these shortcomings, seven meta-analyses comparing single daily with multiple daily regimens have been published Table 4. Galloe, et al. Hatala, et al. Bailey, et al. Freeman, et al. Ferriols-Lisart, et al. Information from references 17 through Combining data from studies using meta-analytical techniques assumes that the differences among studies are due to chance. In addition, the choice of meta-analytic method and selection of data can lead to differing conclusions regarding the safety and efficacy of aminoglycosides.
Nevertheless, our goal is to present a review of both multiple and single daily dosing in various patient populations. Despite methodologic flaws in the available literature, current evidence would suggest that when single and multiple daily dosing regimens are compared there is no difference in efficacy, and there is a trend toward reduced toxicity with the single regimens. Tables 5 through 8 outline the dosing and monitoring of single and multiple daily dosing aminoglycoside regimens.
Table 9 27 outlines aminoglycoside dosing regimens for endocarditis, and Table 10 gives pediatric dosing regimens. Dosing for premature infants differs from that of other pediatric patients and is reviewed elsewhere.
Information from references 1 , 3 , 5 , 23 — Adjust the dosing interval according to the results of the serum concentration level. Example: if level is 4 for gentamicin, change dosing to every 36 hours; if level is 2, keep dosing at every 24 hours; if level is 8, switch to traditional dosing method.
Information from references 1 , 3 , 5 , 23 and Estimation of creatinine clearance as follows :. Information from references 1 , 3 , 5 and 23 through Dosages should be modified for patients with renal dysfunction. Information from Bansal RC. Infective endocarditis. Med Clin North Am ;— Information from Gilbert DN. Douglas and Bennett's Principles and practice of infectious diseases.
New York: Churchill Livingston, — A comparison of the costs of single daily dosing and traditional multiple dosing should include not only the cost of the antibiotic but also the costs of labor, laboratory monitoring and drug toxicity.
A pharmacoeconomic comparison of single daily dosing versus traditional dosing of gentamicin found a 54 percent reduction in drug supply and labor costs with single daily dosing. The same study showed a 62 percent reduction in monitoring costs with single daily dosing. Already a member or subscriber? Log in. Interested in AAFP membership? Learn more.
LUIS S. He is also clinical assistant professor of pharmacy practice at the Duquesne and University of Pittsburgh Schools of Pharmacy. He received his pharmacy degree from the University of Illinois at Chicago. Spencer is a graduate of the University of Rochester N. School of Medicine and Dentistry, and completed a residency in family practice at Conemaugh Memorial Hospital.
Address correspondence to Jeanne P. Spencer, M. Reprints are not available from the authors. The authors thank Linda Adamczyk and Evelyn Everhart-Yost for assistance in the preparation of the manuscript. Gilbert DN. Montie T, Patamasucon P. Aminoglycosides: the complex problem of antibiotic mechanisms and clinical applications [Editorial].
The aminoglycosides. Mayo Clin Proc. Goodman and Gilman's The pharmacological basis of therapeutics. New York: McGraw-Hill, ;— Med Clin North Am. Aminoglycoside adaptive resistance. Neu HC. The crisis in antibiotic resistance. Swartz MN.
Use of antimicrobial agents and drug resistance. N Engl J Med. Aminoglycoside ototoxicity: influence of dosage regimen on drug uptake and correlation between membrane binding and some clinical features. Acta Otolaryngol [Stockh]. Choudhury D, Ahmed Z. Drug-induced nephrotoxicity. Hock R, Anderson RJ.
Prevention of drug-induced nephrotoxicity in the intensive care unit. J Crit Care. Vogelman B, Craig WA. Kinetics of antimicrobial activity. J Pediatr. Craig WA, Gundmundson S. Postantibiotic effect. In: Lorian V, ed. Antibiotics in laboratory medicine. Baltimore: Williams and Wilkins — Once-daily aminoglycoside therapy.
Antimicrob Agents Chemother. Circadian variations in serum levels and the renal toxicity of aminoglycosides in patients. Clin Pharmacol Ther. Aminoglycoside administration as a single daily dose. Preexisting renal, vestibular, or auditory impairment; Patients with depressed neuromuscular transmission eg, myasthenia gravis ; Risk factors for the development of aminoglycoside toxicity include the following: concomitant administration potentially neurotoxic or nephrotoxic drugs, age, and dehydration; Concomitant use with potent diuretics eg, ethacrynic acid or furosemide ; Local irrigation or application may lead to significant absorption.
Cyclosporine: Nephrotoxicity decreased renal function, decreased fractional sodium excretion, and a decline in diuresis. Peak serum levels of gentamicin in traditional dosing are:. Pretreatment audiograms should be undertaken and repeated throughout therapy if the drug is administered for periods greater than 5 days. Particularly in patients with renal dysfunction.
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