Pharmacokinetic dosing of aminoglycosides: a controlled trial

doi:10.1016/S0002-9343(02)01476-6

The American Journal of Medicine

Volume 114, Issue 3, 15 February 2003, Pages 194-198

https://doi.org/10.1016/S0002-9343(02)01476-6 Get rights and content

Abstract

Purpose

To evaluate whether individualized pharmacokinetic dosing of aminoglycosides can reduce nephrotoxicity and improve the outcome of patients with gram-negative sepsis.

Methods

We conducted a prospective controlled trial at a tertiary care university hospital. Eighty-one patients with suspected or documented gram-negative infections were enrolled. All were treated with either gentamicin or amikacin, according to clinical judgement. Patients were allocated to one of two groups based on the last digit (odd/even) of their identification number. In the study group (pharmacokinetic dosing) of 43 patients, plasma aminoglycoside levels were determined 1 hour after initiation of drug infusion and 8 to 16 hours later to estimate the elimination half-life and volume of distribution, from which the subsequent dosage schedule was calculated. Target peak plasma levels were 20 μg/mL for gentamicin and 60 μg/mL for amikacin. Target trough levels were <1 μg/mL for both drugs. The control group (fixed once-daily dosing) consisted of 38 patients who were prescribed single daily doses of gentamicin or amikacin. The primary endpoints were renal toxicity (≥25% increase in serum creatinine level or a serum creatinine level ≥1.4 mg/dL) and 28-day mortality.

Results

The two study groups were similar in age, sex, indications for therapy, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and clinical assessment at baseline. Although the pharmacokinetic group received significantly greater doses of aminoglycosides than did the once-daily group, the incidence of nephrotoxicity was significantly lower in the pharmacokinetic group (5% [2/43] vs. 21% [8/38], P = 0.03). There was no statistically significant difference in 28-day mortality (27% [12/43] vs. 22% [8/38], P = 0.3).

Conclusion

These results suggest that individualized pharmacokinetic dosing of aminoglycosides reduces the incidence of nephrotoxicity and allows the use of greater doses of aminoglycosides.

Section snippets

Patients

Nonsurgical patients aged ≥18 years who were hospitalized at the Soroka University Medical Center with suspected or documented gram-negative sepsis were included if the house staff decided to prescribe gentamicin (Garamycin; Teva, Jerusalem, Israel) or amikacin (Amikin; Bristol-Myers Squibb, Anagni, Italy). A diagnosis of suspected gram-negative sepsis was made on the basis of conventional sepsis criteria and a clinical picture of infection (23). We excluded patients with allergy or

Results

Eighty-one patients were enrolled between November 1999 and May 2000. Two patients declined to participate. There were 38 patients in the fixed once-daily dose group and 43 in the pharmacokinetic group. The baseline characteristics of the patients in the two groups were generally similar (Table 1). Fifty-one patients (63%) were treated with gentamicin, and 30 patients (37%) were treated with amikacin. The most common indication for treatment was continued fever despite treatment with another

Discussion

Pharmacokinetic dosing of aminoglycosides is based on sound microbiologic and pharmacologic rationale. Our results indicate that it is also a safe regimen, leading to a significantly reduced incidence of nephrotoxicity of only 5%. A similar reduction in nephrotoxicity to 5% was also observed in a study of pharmacokinetic monitoring in patients in a surgical intensive care unit (13).

Several studies have shown the utility of monitoring peak and trough aminoglycoside levels in enhancing efficacy

References (24)

J.M. Prins et al.
Once versus thrice daily gentamicin in patients with serious infections
Lancet
(1993)
T. Dorman et al.
Impact of altered aminoglycoside volume of distribution on the adequacy of three milligram per kilogram loading dose. Critical Care Research Group
Surgery
(1998)
A.M. MacConnachie
Gentamicin once a day
Intens Crit Care Nurs
(1996)
S.L. Barriere
Bacterial resistance to beta-lactams, and its prevention with combination therapy
Pharmacotherapy
(1992)
C.I. Miyagawa
Aminoglycosides in the intensive care unit: an old drug in a dynamic environment
New Horizons
(1993)
G.H. Hottendorf et al.
Aminoglycoside nephrotoxicity
Toxicol Pathol
(1986)
C.D. Freeman et al.
Once-daily dosing of aminoglycosidesreview and recommendations for clinical practice
J Antimicrob Chemother
(1997)
W.R. Summer et al.
Initial aminoglycoside levels in the critically ill
Crit Care Med
(1983)
R.D. Moore et al.
Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration
J Infect Dis
(1987)
G.G. Jackson et al.
The inducive role of ionic binding in the bactericidal and postexposure effects of aminoglycoside antibiotics with implications for dosing
J Infect Dis
(1990)

G.L. Daikos et al.

First exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal use

Antimicrob Agents Chemother

(1991)

M. Averbuch et al.

Gentamicin once-daily levels: ordered too soon and too often

Hosp Formul

(1989)

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Cmin levels of Amikacin are indicators of toxicity. Exact safe Cmin level may vary from patient to patient, Cmin of <2 mcg/mL are generally considered to be safe and levels above 5 mcg/mL are known to herald toxicity.9,18 A recent meta-analysis demonstrated that Amikacin trough levels <10 mcg/mL may reduce the risk of nephrotoxicity.24
Amikacin, an aminoglycoside, is a widely used parenteral antibiotic. Therapeutic drug monitoring (TDM) is recommended for aminoglycosides to avoid toxicity. However, the lack of infrastructure at most places precludes it. This pilot and novel study attempt to estimate the real-world serum levels of Amikacin in hospitalised patients.
Thirty admitted patients, given Amikacin injections, were included in the study. In addition, 15 clinical specimens isolated with gram-negative bacteria were tested for minimum inhibitory concentration (MIC) value of Amikacin. Trough and peak serum levels of Amikacin were estimated by high-pressure liquid chromatography (HPLC).
The average MIC value of Amikacin estimated in our laboratory was 3.92 mcg/mL. Peak and trough serum levels of Amikacin ranged from 12.1 to 66.4 mcg/ml and 1.1 to 20.7 mcg/ml, respectively. More than 83% of our patients achieved peak Amikacin levels of 15 mcg/mL, and 37% had trough levels above 5 mcg/mL. These levels are desirable watersheds as per available literature.
Trough levels of Amikacin in all cases and a review of dosing according to MIC values are recommended to achieve drug safety and therapeutic efficacy.
Bayesian prediction-based individualized dosing of anti-methicillin-resistant Staphylococcus aureus treatment: Recent advancements and prospects in therapeutic drug monitoring
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As one of the efficient techniques for TDM, the population pharmacokinetic (popPK) model approach for dose individualization has been developed due to the rapidly growing innovative progress in computer technology and has recently been considered as a part of model-informed precision dosing (MIPD). Initial dose individualization and measurement followed by maximum a posteriori (MAP)-Bayesian prediction using a popPK model are the most classical and widely used approach among a class of MIPD strategies. MAP-Bayesian prediction offers the possibility of dose optimization based on measurement even before reaching a pharmacokinetically steady state, such as in an emergency, especially for infectious diseases requiring urgent antimicrobial treatment. As the pharmacokinetic processes in critically ill patients are affected and highly variable due to pathophysiological disturbances, the advantages offered by the popPK model approach make it highly recommended and required for effective and appropriate antimicrobial treatment.
In this review, we focus on novel insights and beneficial aspects of the popPK model approach, especially in the treatment of infectious diseases with anti-methicillin-resistant Staphylococcus aureus agents represented by vancomycin, and discuss the recent advancements and prospects in TDM practice.
Interest of therapeutic drug monitoring of aminoglycosides administered by a monodose regimen
2019, Nephrologie et Therapeutique
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Interestingly, we showed, based on ROC analysis, that patients with a CLcr ≤ 41.66 mL/min have a 11.29-folder risk to have a toxic Cmin than patients having a Clcr > 41.66 mL/min. This finding is consistent with previous reports, which demonstrated that high Cmin values were closely related to a decrease in creatinine clearance rate [19–22]. For example, Plager et al. reported that gentamicin target Cmin was achieved in 0%, 15%, 61% and 97%, in patients having a Clcr < 20 mL/min, between 20–39 mL/min, between 40–59 mL/min, and > 60 mL/min, respectively [20].
Although the once-daily regimen of aminoglycosides (AG) is considered as predominantly used by many centers, the level of evidence of Therapeutic Drug Monitoring (TDM) of AG in cases of once-daily has not been clearly defined. The objective of this study is to evaluate the impact of TDM in achievement or maintaining target serum concentrations in patients receiving once-daily administration of AG.
We performed a retrospective analysis of data from patients having received a once daily amikacin or gentamicin and underwent routine TDM. A longitudinal follow up was performed. Data were analyzed according to the adhesion or not to recommendations. A logistic regression was performed in order to evaluate the effect of covariates (age, gender, weight, creatinine clearance [CLcr], TDM-based dose adjustment, weighted dose of AG) on the achievement of non-toxic Cmin.
A total 437 blood samples issued from 324 patients were analyzed. The cut-off value of Clcr associated with a risk of toxic Cmin was ≤ 41.66 mL/min (OR: 11.29; 95%CI: 7.21–17.61; P < 0.0001). Eighty-eight patients (27.1%) have at least two sampling points. The univariate analysis showed that the age, weight, CLcr and TDM-based dose adjustment were found to be significant factors in the achievement of non-toxic Cmin. In multivariate analysis, only TDM-based dose adjustment remains a significant factor in the achievement of non-toxic Cmin (OR: 6.66; 95%CI: 2.26–19.63; P = 0.0006).
Our study demonstrates the usefulness of TDM-based dosing adjustment of AG antibiotics in achieving nontoxic trough concentrations, particularly in critically ill patients, as they are prone to a renal impairment.
Aminoglycoside-Induced Nephrotoxicity
2018, Comprehensive Toxicology: Third Edition
Aminoglycosides remain critical antibiotics in the armamentarium for serious Gram-negative bacterial infections despite their well-known risk for nephrotoxicity and ototoxicity. Aminoglycosides manifest their bactericidal activity by binding to the 30S ribosomal subunit which interferes with the initiation of protein synthesis. They are most commonly administered intravenously with peak serum concentrations occurring in 30 min. Aminoglycosides are excreted unchanged in the urine by glomerular filtration with an elimination half-life of 2–3 h in patients with normal renal function. The incidence of aminoglycoside nephrotoxicity is 5%–10%. Patient risk factors for aminoglycoside nephrotoxicity include advanced age, male gender, ascites, hypoalbuminemia, and leukemia. Medications such as clindamycin, vancomycin, piperacillin, cephalosporins, and angiotensin-converting enzyme inhibitors also increase the risk of nephrotoxicity when administered with aminoglycosides. Morphological changes seen in animals during aminoglycoside nephrotoxicity consist of epithelial cell damage confined to the S1 and S2 segments of the proximal tubule. The biochemical alterations that occur with aminoglycoside nephrotoxicity include decrements in the transport of organic base, ions, glucose, and low-molecular-weight proteins. The initial renal cortical binding sites for aminoglycosides are the acidic, anionic phospholipids found in the plasma membranes of the apical and basolateral surfaces of the proximal tubule cells. Once binding has occurred, aminoglycosides are transported across the apical or basolateral plasma membrane by receptor-mediated endocytosis via megalin. After endocytosis, the endosomes containing the aminoglycosides fuse with lysosomes. Once-daily aminoglycoside dosing in which a large loading dose of an aminoglycoside is given every 24–48 h has been shown to maintain clinical efficacy and reduce the incidence of nephrotoxicity. Various interventions to prevent aminoglycoside nephrotoxicity have been proposed such as polyaspartic acid, superoxide dismutase, N-acetylcysteine, and melatonin. A congener of gentamicin has also been isolated that retains clinical efficacy, but does not cause nephrotoxicity. Until these interventions become adopted in clinical practice, however, clinicians must utilize established strategies to reduce the incidence of aminoglycoside-induced nephrotoxicity. These include selection of the least nephrotoxic aminoglycoside, correcting hypokalemia and hypomagnesemia, minimizing concomitant nephrotoxic medications, limiting the duration of therapy to 7–10 days, adjusting the dose of aminoglycoside for the level of renal function, and utilizing once-daily dosing of aminoglycoside when clinically appropriate.
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Regular articlePharmacokinetic dosing of aminoglycosides: a controlled trial

Abstract

Purpose

Methods

Results

Conclusion

Section snippets

Patients

Results

Discussion

Lancet

Surgery

Intens Crit Care Nurs

Bacterial resistance to beta-lactams, and its prevention with combination therapy

Pharmacotherapy

Aminoglycosides in the intensive care unit: an old drug in a dynamic environment

New Horizons

Aminoglycoside nephrotoxicity

Toxicol Pathol

Once-daily dosing of aminoglycosidesreview and recommendations for clinical practice

J Antimicrob Chemother

Initial aminoglycoside levels in the critically ill

Crit Care Med

Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration

J Infect Dis

The inducive role of ionic binding in the bactericidal and postexposure effects of aminoglycoside antibiotics with implications for dosing

J Infect Dis

First exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal use

Antimicrob Agents Chemother

Gentamicin once-daily levels: ordered too soon and too often

Hosp Formul

Regular article
Pharmacokinetic dosing of aminoglycosides: a controlled trial