Review articlePharmacodynamics and dosing of aminoglycosides
Section snippets
Pharmacokinetic properties
Aminoglycosides are very poorly absorbed when administered orally, and must be given parenterally for the treatment of systemic infections. The agents demonstrate remarkably similar kinetics, with similar elimination half-lives of generally 2 to 3 hours in normal subjects, and similar volumes of distribution (Table 1). When given by intravenous injection they demonstrate three-compartment first-order elimination, although two- and one-compartment models fit the time-concentration profiles
Pharmacodynamics
Pharmacodynamics refers to the dynamics of drug action (ie, inhibition and killing). More precisely it is the relationship between the fluctuating concentrations seen with dosing and the killing of bacteria. It is often referred to as “pharmacokinetics-pharmacodynamics.” In this article it is referred to as “pharmacodynamics.” Readers are directed to some more detailed reviews for further elaboration of aminoglycoside PD concepts and findings [7], [8].
Nephrotoxicity
Aminoglycosides are obligate nephrotoxins, and renal impairment is eventually detected in all patients if treated for long enough [21]. The toxicity occurs because of the accumulation of aminoglycosides within the proximal tubular epithelial cell in lysosomal phospholipid complexes, which eventually rupture and initiate cell death [22]. As a consequence, the local renin-angiotensin system is activated, leading to local vasoconstriction and a decrease in the glomerular filtration rate, so-called
The move to once-daily (extended-interval) dosing
Once-daily dosing of aminoglycosides was initially introduced for the treatment of urinary tract infection [42], [43], [44], [45]. The high and prolonged urinary levels justified this move. It was less obvious initially that this approach might be useful for the treatment of systemic infection, and there was considerable concern that giving the total daily dose as a single dose once-daily increases toxicity because of the high peaks. Nevertheless, the cumulative in vitro and animal data noted
Dosing by age
Because renal function varies with age, recommendations for starting doses should vary with age if the AUC24:MIC ratio is the PD target. Although once-daily dosing is now used widely for standard therapeutic situations, there is no consensus on doses. Doses used in prospective once-daily comparative studies outside the urinary tract have ranged from 3 to 5 mg/kg daily for gentamicin, 4 mg/kg for tobramycin, 3.8 to 6.6 mg/kg for netilmicin, and 11 to 20 mg/kg for amikacin. Only one of these
Dosing in special situations
In certain clinical situations the kinetics of aminoglycosides may differ from those seen in children and adults, the doses may be different or there may be special toxicity issues. These clinical situations are discussed later, with an emphasis on selection of starting doses. It is recommended that doses thereafter be based on monitoring, using one of the methods described later.
Renal impairment
The introduction of third- and fourth-generation cephalosporins, carbapenems, and monobactams has significantly reduced reliance on aminoglycosides in patients with significant renal impairment. Nevertheless, there are circumstances in these types of patients when aminoglycosides are considered a necessary part of the treatment, and hence it is important to have a safe approach to their use. Choices of approach are influenced in part by the need or otherwise to preserve residual renal function.
Monitoring
Conventionally, aminoglycosides have been monitored during therapy to reduce the likelihood of toxicity. The collection of peak and trough levels with 8-hourly dosing became standard practice worldwide, and laboratory assays became universally available and inexpensive as a result. This method of monitoring has a number of problems. It focuses on somewhat arbitrary targets for peak and trough based on values seen in adults with normal renal function and there is no real accounting for the
References (147)
- et al.
Pharmacokinetics of once-daily dosing of gentamicin in neonates
Pediatrics
(1997) - et al.
Extended interval aminoglycoside dosing: from concept to clinic
Int J Antimicrob Agents
(2002) - et al.
Once-daily dosage regimen for aminoglycoside plus β-lactam combination therapy of serious bacterial infections: comparative trial with netilmicin and ceftriaxone
Am J Med
(1990) - et al.
A randomised, prospective study comparing once-daily versus thrice-daily gentamicin in the treatment of puerperal infection
Am J Obstet Gynecol
(1997) - et al.
A prospective, randomized, double-blind study of single high dose versus multiple standard dose gentamicin both in combination with metronidazole for colorectal surgical prophylaxis
J Hosp Infect
(2000) - et al.
A randomised comparison of the safety and efficacy of once-daily gentamicin or thrice-daily gentamicin in combination with ticarcillin-clavulanate
Am J Med
(1998) - et al.
Serum levels of gentamicin and tobramycin after slow intravenous bolus injection
Lancet
(1974) - et al.
The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children and adolescents
Pediatr Clin North Am
(1987) Aminoglycosides
- et al.
Pharmacokinetics of gentamicin at traditional versus high doses: implications for once-daily aminoglycoside dosing
Antimicrob Agents Chemother
(1997)
Experience with a once-daily dosing program of aminoglycosides in critically ill patients
Intensive Care Med
Population pharmacokinetic study of amikacin administered once or twice daily to febrile, neutropenic patients
Antimicrob Agents Chemother
Isepamicin disposition in subjects with various degrees of renal function
Antimicrob Agents Chemother
The pharmacodynamics of aminoglycosides
Clin Infect Dis
Killing and regrowth of bacteria in vitro: a review
Scand J Infect Dis Suppl
Postantibiotic effect
In vivo postantibiotic effect in a thigh infection in neutropenic mice
J Infect Dis
The postantibiotic effect: a review of in vitro and in vivo data
Ann Pharmacother
Aminoglycoside adaptive resistance: importance for effective dosage regimens
Drugs
Selection of aminoglycoside-resistant variants of Pseudomonas aeruginosa in an in vivo model
J Infect Dis
Physiology and antibiotic susceptibility of Staphylococcus aureus small-colony variants
Microb Drug Resist
Once-daily dosing of aminoglycosides
Eur J Clin Microbiol Infect Dis
Population pharmacokinetics of gentamicin in preterm neonates: evaluation of a once-daily dosage regimen
Ther Drug Monit
Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimum inhibitory concentration
J Infect Dis
Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria
Antimicrob Agents Chemother
Experience with a once-daily aminoglycoside program administered to 2,184 adult patients
Antimicrob Agents Chemother
A model for predicting nephrotoxicity in patients treated with aminoglycosides
J Infect Dis
Aminoglycoside: nephrotoxicity
Antimicrob Agents Chemother
Determinants of efficacy and toxicity of aminoglycosides
J Antimicrob Chemother
Once-daily aminoglycoside therapy
Antimicrob Agents Chemother
Once-daily dosing decreases renal accumulation of gentamicin and netilmicin
Clin Pharmacol Ther
Empiric therapy for infections in patients with granulocytopenia: continuous versus interrupted infusion of tobramycin plus cefamandole
Arch Intern Med
A comparative trial of Sisomicin therapy by intermittent versus continuous infusion
J Med Sci
Clinical and pharmacokinetic characteristics of aminoglycoside nephrotoxicity in 201 critically ill patients
Antimicrob Agents Chemother
Aminoglycoside nephrotoxicity: modeling, simulation and control
Antimicrob Agents Chemother
Aminoglycoside-associated nephrotoxicity in the elderly
Ann Pharmacother
Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity
Antimicrob Agents Chemother
Aminoglycoside nephrotoxicity: do time and frequency of administration matter?
Curr Opin Crit Care
Aminoglycoside commentary
Nephrotoxicity associated with combined gentamicin-amphotericin B therapy
Nephron
Aminoglycoside–induced hearing loss in humans
Antimicrob Agents Chemother
Vestibular and cochlear toxicity of aminoglycosides–a review
Acta Otolaryngol
Antibiotic prophylaxis in vascular reconstructive surgery: a double-blind placebo-controlled study
J Antimicrob Chemother
Evidence that amikacin ototoxicity is related to total perilymph area under the concentration-time curve regardless of concentration
Antimicrob Agents Chemother
A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses
J Antimicrob Chemother
Genetic factors in aminoglycoside toxicity
Ann N Y Acad Sci
The single daily dose of gentamicin in the treatment of urinary tract infections
MMW Munch Med Wochenschr
Single dose daily gentamicin therapy in urinary tract infection
Antimicrob Agents Chemother
Single daily doses of tobramycin in therapy of urinary tract infections
J Infect Dis
Treatment of urinary tract infections in children with a single daily dose of gentamicin
Helv Pediatr Acta
Cited by (154)
Aminoglycoside Antibiotics
2022, Comprehensive PharmacologyImproved characterization of aminoglycoside penetration into human lung epithelial lining fluid via population pharmacokinetics
2024, Antimicrobial Agents and ChemotherapyTime-dependent pharmacodynamics of amikacin on Mycobacterium abscessus growth and resistance emergence
2024, Microbiology Spectrum