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Aminoglycosides: A Practical Review

LUIS S. GONZALEZ III, PHARM.D., and JEANNE P. SPENCER, M.D.

Conemaugh Memorial Medical Center,

Johnstown, Pennsylvania

Aminoglycosides are potent bactericidal antibiotics that act by creating fissures in the outer membrane of the bacterial cell. They are particularly active against aerobic, gram-negative bacteria and act synergistically against certain gram-positive organisms. Gentamicin is the most commonly used aminoglycoside, but amikacin may be particularly effective against resistant organisms. Aminoglycosides are used in the treatment of severe infections of the abdomen and urinary tract, as well as bacteremia and endocarditis. They are also used for prophylaxis, especially against endocarditis. Resistance is rare but increasing in frequency. Avoiding prolonged use, volume depletion and concomitant administration of other potentially nephrotoxic agents decreases the risk of toxicity. Single daily dosing of aminoglycosides is possible because of their rapid concentration-dependent killing and post-antibiotic effect and has the potential for decreased toxicity. Single daily dosing of aminoglycosides appears to be safe, efficacious and cost effective. In certain clinical situations, such as patients with endocarditis or pediatric patients, traditional multiple dosing is still usually recommended.

The first aminoglycoside, streptomycin, was isolated from Streptomyces griseus in 1943. Neomycin, isolated from Streptomyces fradiae, had better activity than streptomycin against aerobic gram-negative bacilli but, because of its formidable toxicity, could not safely be used systemically. Gentamicin, isolated from Micromonospora in 1963, was a breakthrough in the treatment of gram-negative bacillary infections, including those caused by Pseudomonas aeruginosa. Other aminoglycosides were subsequently developed, including amikacin (Amikin), netilmicin (Netromycin) and tobramycin (Nebcin), which are all currently available for systemic use in the United States.¹

See editorial on page 1747.

The purpose of this article is to provide family physicians with a review of the aminoglycosides and their role in the treatment of infectious diseases. Despite the introduction of newer, less toxic antimicrobial agents, aminoglycosides continue to serve a useful role in the treatment of serious enterococcal and gram-negative bacillary infections.

Pharmacology

Tobramycin shows better activity against Pseudomonas aeruginosa and therefore may be the preferred treatment for infections caused by this organism.

Traditionally, the antibacterial properties of aminoglycosides were believed to result from inhibition of bacterial protein synthesis through irreversible binding to the 30S bacterial ribosome. This explanation, however, does not account for the potent bactericidal properties of these agents, since other antibiotics that inhibit the synthesis of proteins (such as tetracycline) are not bactericidal. Recent experimental studies show that the initial site of action is the outer bacterial membrane. The cationic antibiotic molecules create fissures in the outer cell membrane, resulting in leakage of intracellular contents and enhanced antibiotic uptake. This rapid action at the outer membrane probably accounts for most of the bactericidal activity.² Energy is needed for aminoglycoside uptake into the bacterial cell. Anaerobes have less energy available for this uptake, so aminoglycosides are less active against anaerobes.

Aminoglycosides are poorly absorbed from the gastrointestinal tract. After parenteral administration, aminoglycosides are primarily distributed within the extracellular fluid. Thus, the presence of disease states or iatrogenic situations that alter fluid balance may necessitate dosage modifications. When used parenterally, adequate drug concentrations are typically found in bone, synovial fluid and peritoneal fluid. Penetration of biologic membranes is poor because of the drug's polar structure, and intracellular concentrations are usually low, with the exception of the proximal renal tubule. Endotracheal administration results in higher bronchial levels compared with systemic administration, but differences in clinical outcome have not been consistent.

TABLE 1 Common Clinical Uses of Aminoglycosides* Serious, life-threatening gram-negative infection Complicated skin, bone or soft tissue infection Complicated urinary tract infection Septicemia Peritonitis and other severe intra-abdominal infections Severe pelvic inflammatory disease Endocarditis Mycobacterium infection Neonatal sepsis Ocular infections (topical) Otitis externa (topical) *--Often used in combination with other antibiotics for broad-spectrum coverage. Aminoglycosides are not necessarily first-line choices for all of these indications. Other antibiotic regimens may be more appropriate.

Following parenteral administration of an aminoglycoside, subtherapeutic concentrations are usually found in the cerebrospinal fluid, vitreous fluid, prostate and brain.^3,4 Aminoglycosides are rapidly excreted by glomerular filtration, resulting in a plasma half-life varying from two hours in a patient with "normal" renal function to 30 to 60 hours in patients who are functionally anephric.⁵ The half-life of aminoglycosides in the renal cortex is approximately 100 hours, so repetitive dosing may result in renal accumulation and toxicity.

Clinical Uses

Aminoglycosides display bactericidal, concentration-dependent killing action and are active against a wide range of aerobic gram-negative bacilli. They are also active against staphylococci and certain mycobacteria. Aminoglycosides are effective even when the bacterial inoculum is large, and resistance rarely develops during the course of treatment. These potent antimicrobials are used as prophylaxis and treatment in a variety of clinical situations⁵ (Table 1).

Gentamicin is the aminoglycoside used most often because of its low cost and reliable activity against gram-negative aerobes. However, local resistance patterns should influence the choice of therapy. In general, gentamicin, tobramycin and amikacin are used in similar circumstances, often interchangeably.⁴

Tobramycin may be the aminoglycoside of choice for use against P. aeruginosa because it has shown greater in vitro activity. Nevertheless, the clinical significance of this activity has been questioned.¹ Amikacin is particularly effective when used against bacteria that are resistant to other aminoglycosides, since its chemical structure makes it less susceptible to inactivating enzymes.⁴ Depending on local patterns of resistance, amikacin may be the preferred agent for serious nosocomial infections caused by gram-negative bacilli. Table 2 lists the cost of various antibiotics used to treat gram-negative infections.

TABLE 2 Cost Comparison of Antibiotics Used for Treatment of Gram-Negative Infections Drug Intravenous regimen Cost* Amikacin (Amikin) Aztreonam (Azactam) Ceftazidime (Fortaz) Ceftriaxone (Rocephin)† Cefotaxime (Claforan)† Ciprofloxacin (Cipro) Gentamicin Imipenem-cilastatin (Primaxin) Levofloxacin (Levoquin)‡ Piperacillin-tazobactam (Zosyn) Ticarcillin-clavulanate (Timentin) Tobramycin (Nebcin) Trimethoprim- sulfamethoxazole (Bactrim)‡ 1 g daily 1 g every 8 hours 2 g every 8 hours 1 g every 8 hours 2 g every 8 hours 2 g daily 1 g every 8 hours 400 mg every 12 hours 400 mg daily 500 mg every 6 hours 500 mg daily 3.375 g every 6 hours 3.1 g every 6 hours 400 mg daily 10 mL (160 mg/800 mg) every 12 hours $ 65.00 49.00 65.50 44.00 86.50 72.50 33.50 57.50 5.00 (per 80 mg) 109.00 39.50 61.00 58.00 7.00 (per 80-mg vial) 32.00 *--Estimated cost to the pharmacist based on average wholesale prices (rounded to the nearest half dollar) in Red book. Montvale, N.J.: Medical Economics Data, 1998. 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. †--Not effective against Pseudomonas. ‡--Not effective against Pseudomonas outside of the urinary tract.

Drug Resistance

Aminoglycosides enhance bactericidal activity of beta-lactam drugs, making a useful combination for the treatment of serious infections.

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.⁵

P. aeruginosa may show adaptive resistance to aminoglycosides. This occurs when formerly susceptible populations become less susceptible to the antibiotic as a result of decreased intracellular concentrations of the antibiotic. This decrease may result in colonization, slow clinical response or failure of the antibiotic despite sensitivity on in vitro testing.⁶

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.¹

Aminoglycosides have significant toxicity, most importantly nephrotoxicity and ototoxicity.

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.⁷

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.⁸ Nevertheless, resistance to aminoglycosides requires long periods of exposure or very large inocula of organisms and occurs less frequently than with other agents, such as third-generation cephalosporins, which are also effective against gram-negative organisms.¹

Drug Interactions and Adverse Effects

TABLE 3 Risk Factors Predisposing to Aminoglycoside Nephrotoxicity Potentially alterable factors Use of diuretics* Radiographic contrast exposure Effective circulating volume depletion Use of ACE inhibitors† Use of NSAIDs† Use of other nephrotoxic medications Concomitant use of amphotericin (Fungizone IV) Use of cisplatin (Platinol) Unalterable factors Age Pre-existing renal disease ACE=angiotensin converting enzyme; NSAIDs=nonsteroidal anti-inflammatory drugs. *--May cause effective circulating volume depletion. †--May cause prerenal acute renal failure in the setting of volume depletion. Information from references 10 and 11.

Because the body does not metabolize aminoglycosides, aminoglycoside activity is unchanged by induction or inhibition of metabolic enzymes, such as those in the cytochrome P450 system. Certain medications may increase the risk of renal toxicity with aminoglycoside use (Table 3).

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 30- to 60-minute infusions of aminoglycosides.⁹

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.¹⁰ Although serum creatinine levels are frequently monitored during aminoglycoside use, an elevation of serum creatinine is more likely to reflect glomerular damage rather than tubular damage. In most clinical trials of aminoglycosides, however, nephrotoxicity has been defined by an elevation of serum creatinine.⁵ Periodic monitoring of serum creatinine concentrations may alert the clinician to renal toxicity.

In order to minimize toxicity, family physicians should remember a few key considerations. (1) Aminoglycosides should be used only when their unique antibiotic potency is needed, such as treatment of infection in critically ill patients, and in nosocomial infections or infections with organisms resistant to less toxic therapies. (2) The clinician should change to a potentially less toxic antibiotic as soon as the infecting organism and its antibiotic sensitivities have been determined. (3) Potential risk factors that predispose to nephrotoxicity should be identified and, when possible, corrected (Table 3).

TABLE 4 Meta-Analyses Comparing Multiple Daily Dosing vs. Single Daily Dosing Regimens of Aminoglycosides Study Studies reviewed Studies included Clinical response Nephrotoxicity Ototoxicity Galloe, et al.17 Unknown 16 ND ND ND Hatala, et al.18 6 4 ND Trend favoring SDD Trend favoring SDD Ali, et al.19 40 26 SDD better ND ND Bailey, et al.20 Unknown 20 SDD better ND ND Hatala, et al.21 42 17 * Trend favoring SDD Trend favoring SDD Freeman, et al.22 35 15 † SDD better Not studied Ferriols-Lisart, et al.23 67 18 SDD better SDD better ND ND=no difference; SDD=single daily dosing. *--Significant heterogeneity prevents determination. †--SDD better or ND, depending on the method of data analysis. Information from references 17 through 23.

Single vs. Multiple Daily Doses

Aminoglycoside antibiotics exhibit rapid concentration-dependent killing action.^5,11 Increasing concentrations with higher dosages increases both the rate and the extent of bacterial cell death. In addition, aminoglycosides have demonstrated persistent suppression of bacterial growth after short exposure, a response referred to as the post- antibiotic effect.^5,12 The post-antibiotic effect is defined as the time required for an organism to demonstrate viable regrowth following the removal of an antibiotic.

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.¹³

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.¹⁴

TABLE 5 Single Daily Dosing of Aminoglycosides in Adults with Dosing Interval Adjusted for Creatinine Clearance* Drug Dosage (mg per kg)† CrCl: >60 mL per minute CrCl: 40 to 59 mL per minute CrCl: 20 to 39 mL per minute CrCl: <20 mL per minute Amikacin (Amikin) 15 Every 24 hours Every 36 hours Every 48 hours NR Gentamicin 5 to 7 Every 24 hours Every 36 hours Every 48 hours NR Netilmicin (Netromycin) 5 to 7 Every 24 hours Every 36 hours Every 48 hours NR Tobramycin (Nebcin) 5 to 7 Every 24 hours Every 36 hours Every 48 hours NR CrCl=creatinine clearance; NR=not recommended, use traditional dosing. *--Estimate creatinine clearance as follows: Men: CrCl=140 ­ age/serum creatinine Women: CrCl=140 ­ age/serum creatinine 3 0.85 ALTERNATE FORMULA Men: [weight (kg) 3 (140 ­ age)] / 72 3 serum creatinine (mg per dL) Women: 0.85 3 calculation for men †--Adjust dosage for obese patients (>30% ideal body weight [IBW]) as follows: Women: IBW=45 kg + 2.3 kg for every inch above 5 feet Men: IBW=50 kg + 2.3 kg for every inch above 5 feet Dosing weight=IBW + (total body weight ­ IBW) 0.4 ALTERNATE FORMULA Women: 100 lb + 5 lb for every inch above 5 feet Men: 110 lb + 5 lb for every inch above 5 feet NOTE: Single daily dosing is currently not recommended for pediatric patients, burn patients, or patients with cystic fibrosis, enterococcal infections or bacterial endocarditis. Information from references 1, 3, 5, 23-25.

TABLE 6 Values for Monitoring Aminoglycoside Serum Concentration Levels When Using the Single Daily Dosing Method of Administration* Drug Serum concentration level for dosing every 24 hours (µg per mL) Serum concentration level for dosing every 36 hours (µg per mL) Serum concentration level for dosing every 48 hours (µg per mL) Traditional method preferred (µg per mL) Expected trough, before next dose (µg per mL) Amikacin (Amikin) <8 9 to 15 16 to 26 >26 <5.0 Gentamicin† <3 3 to 5 5 to 7 >7 <0.5 to 1.0 Netilmicin (Netromycin)† <3 3 to 5 5 to 7 >7 <0.5 to 1.0 Tobramycin (Nebcin)† <3 3 to 5 5 to 7 >7 <0.5 to 1.0 *--Check the patient's aminoglycoside serum concentration level (µg per mL) 12 hours after the start of the 60-minute transfusion. 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. †--A once-daily nomogram may also be used if serum concentration is measured at time other than 12 hours.23 Information from references 1, 3, 5, 23 and 24.

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 7:30 a.m.). A report from a recently published nonrandomized, unblinded study showed a higher incidence of nephrotoxicity when aminoglycosides were administered during the rest period.¹⁵ Thus, the effect of varying time of aminoglycoside administration also requires further study.

Currently, human trial designs have included pharmacokinetic assessments, noncomparative trials involving single daily dosing regimens and comparative clinical trials to support the concept of single daily dosing.¹⁶ Unfortunately, the question of clinical superiority of single daily dosing versus multiple daily dosing remains unanswered because of a lack of sufficient statistical power in the studies published to date. To address these shortcomings, seven meta-analyses comparing single daily with multiple daily regimens have been published (Table 4).^17-23

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.

TABLE 7 Traditional Multiple Daily Dosing of Aminoglycosides in Adults* Drug: route Loading dose† (mg per kg) Maintenance dose† (mg per kg) Age: <60 and CrCl: >90 mL per minute Age: >60 or CrCl: 50 to 90 mL per minute CrCl: 10 to 50 mL per minute Amikacin (Amikin): IV/IM 7.5 7.5 Every 12 hours Every 24 hours Every 48 hours Gentamicin: IV/IM 2 to 3 1.7 Every 8 hours Every 12 hours Every 24 to 48 hours Netilmicin (Netromycin): IV/IM 2 to 3 1.7 Every 8 hours Every 12 hours Every 24 to 48 hours Tobramycin (Nebcin): IV/IM 2 to 3 1.7 Every 8 hours Every 12 hours Every 24 to 48 hours Streptomycin: IM 7.5 7.5 Every 12 hours Every 24 hours Every 48 hours CrCl=creatinine clearance; IV=intravenously; IM=intramuscularly. *--Dosing interval based on estimated creatinine clearance (mg per mL) and/or age (years). Estimation of creatinine clearance as follows: Men: CrCl=140 ­ age/serum creatinine Women: CrCl=140 ­ age/serum creatinine 3 0.85 ALTERNATE FORMULA: Men: [weight (kg) 3 (140 ­ age)] / 72 3 serum creatinine (mg per dL) Women: 0.85 3 calculation for men †--Adjust dosage for obese patients (>30% ideal body weight [IBW]) as follows: Women: IBW=45 kg + 2.3 kg for every inch above 5 feet Men: IBW=50 kg + 2.3 kg for every inch above 5 feet Dosing weight=IBW + (total body weight ­ IBW) 0.4 ALTERNATE FORMULA: Women: 100 lb + 5 lb for every inch above 5 feet Men: 110 lb + 5 lb for every inch above 5 feet Information from references 1, 3, 5 and 23 through 25.

TABLE 8 Desired Peak and Trough Concentrations and Intervals for Creatinine Monitoring of Selected Aminoglycosides in Traditional Multiple Daily Dosing Drug Peak concentration (µg per mL)* Trough concentration (µg per mL)† Serum creatinine Amikacin (Amikin) 15 to 30 5 to 10 Every 3 days Gentamicin 4 to 10 <2 Every 3 days Netilmicin (Netromycin) 4 to 10 <2 Every 3 days Tobramycin (Nebcin) 4 to 10 <2 Every 3 days Streptomycin 15 to 30 5 to 10 Every 3 days NOTE: Peak and trough concentrations should be measured after the first or second maintenance dose is administered. *--Concentration obtained one hour after the start of a 30-minute infusion or one hour after intramuscular administration. †--Concentration obtained within 30 minutes of the next scheduled maintenance dose. Information from references 1, 3, 5, 23 and 24.

Tables 5 through 8 outline the dosing and monitoring of single and multiple daily dosing aminoglycoside regimens.^24-27 It is important to note that single daily dosing is not currently recommended for use in pediatric patients or patients with cystic fibrosis, burns, enterococcal infection or bacterial endocarditis. Table 9²⁷ 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.¹

TABLE 9 Aminoglycoside Regimens for Treatment of Endocarditis in Adults* Regimen Trough concentration (µg per mL) Streptococcal and enterococcal endocarditis Gentamicin, 1 mg per kg (up to 80 mg) IV/IM every 8 hours Streptomycin, 7.5 mg per kg (up to 500 mg) IM every 12 hours Staphylococcal endocarditis Gentamicin, 1 mg per kg (up to 80 mg) IV/IM every 8 hours <2 <5 <2 IV=intravenously; IM=intramuscularly. *--Regimens listed are for adult patients with normal renal function. Dosages should be modified for patients with renal dysfunction. Information from Bansal RC. Infective endocarditis. Med Clin North Am 1995;79:1205-40.

TABLE 10 Aminoglycoside Dosing in Infants and Children* Age Drug: route Zero to 7 days Infants Children Amikacin (Amikin): IV 7.5 to 10 mg per kg every 12 hours 10 to 15 mg per kg every 12 hours 7.5 mg per kg every 12 hours Gentamicin: IV 2.5 mg per kg every 12 hours 2.5 mg per kg every 8 hours 2.5 mg per kg every 8 hours Netilmicin (Netromycin): IV 2.5 mg per kg every 12 hours 2.5 mg per kg every 8 hours 2.5 mg per kg every 8 hours Tobramycin (Nebcin): IV 2.5 mg per kg every 12 hours 2.5 mg per kg every 8 hours 2.5 mg per kg every 8 hours IV=intravenously. *--Single daily dosing currently is not recommended in pediatric patients. Information from Gilbert DN. Aminoglycosides. In: Mandell GL, Bennett JE, Dolin R, eds. Douglas and Bennett's Principles and practice of infectious diseases. New York: Churchill Livingston, 1995:279-301.

Cost

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.²⁸ Since single daily dosing is often at least equally effective (and may be less toxic and more cost effective), it may be the preferred method of administration in many clinical situations.

Richard W. Sloan, M.D., R.PH., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.

The authors thank Linda Adamczyk and Evelyn Everhart-Yost for assistance in the preparation of the manuscript.

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The Authors

LUIS S. GONZALEZ III, PHARM.D.,
is clinical pharmacy coordinator and adjunct faculty member of the departments of family medicine, internal medicine and surgery at Conemaugh Memorial Medical Center in Johnstown, Pa. 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.

JEANNE P. SPENCER, M.D.,
is assistant director of the family practice residency program at Conemaugh Memorial Medical Center and clinical assistant professor of family and community medicine at Pennsylvania State University College of Medicine, Hershey. Dr. Spencer is a graduate of the University of Rochester (N.Y.) School of Medicine and Dentistry, and completed a residency in family practice at Conemaugh Memorial Hospital.

Address correspondence to Jeanne P. Spencer, M.D., 1086 Franklin St., Johnstown, PA 15905. Reprints are not available from the authors.

REFERENCES

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