Once-daily Administration Of Aminoglycosides Research Articles

Optimization of anti‐pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: V. Aminoglycosides

Intravenous (IV) anti-pseudomonal aminoglycosides (i.e., amikacin and tobramycin) have been shown to be tolerable and effective in the treatment of acute pulmonary exacerbations (APEs) in both pediatric and adult patients with cystic fibrosis. The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic, tolerability, and efficacy studies utilizing IV amikacin, gentamicin, and tobramycin in the treatment of APE and to highlight areas where further investigation is needed. The Cystic Fibrosis Foundation Pulmonary Guidelines recommend that once-daily administration of aminoglycosides is preferred over three times per day in the treatment of an APE. The literature supports dosing ranges for amikacin and tobramycin of 30-35 and 7-15 mg/kg/day, respectively, given once daily, with subsequent doses determined by therapeutic drug concentration monitoring. The literature does not support the routine use of gentamicin in the treatment of APE due to a lack of studies showing efficacy and evidence indicating an increased risk of nephrotoxicity. Further studies are needed to determine the optimal dosing strategy of amikacin in the treatment of an APE, and to further identify risk factors and determinants that influence the development of P. aeruginosa resistance with once-daily administration of tobramycin.

Prescriber adherence to pharmacokinetic monitoring service recommendations for aminoglycoside dosing and the risk of acute kidney injury

The importance of adherence to aminoglycoside dosing recommendations by a pharmacokinetic monitoring service for preventing acute kidney injury (AKI) is unknown. We aimed to examine the association between AKI and discordance in aminoglycoside dosing between physician orders and recommendations by a pharmacokinetic monitoring service. We utilized 2000 - 2003 data from a large quaternary care academic medical center, including: hand-written pharmacokinetic monitoring service recommendations; computerized physician order entry inpatient medication orders; and electronic inpatient laboratory orders and results. We conducted a case-control study, nested within users of intravenous aminoglycosides. Outcomes of interest were cases of AKI, as determined by changes in serum creatinine. Exposures of interest were discordances between pharmacokinetic monitoring service recommendations and physician orders in the past 2 days with regard to total daily aminoglycoside dose. Most patients received once-daily or less frequent aminoglycoside dosing. In 1,414 evaluable aminoglycoside courses, 220 patients developed AKI, for a cumulative incidence of 15.6%. We identified 690 controls, matched these to 220 cases, and found adjusted odds ratios of 0.72 (95% CI: 0.37 - 1.39) for overdose discordance and of 0.83 (0.51 - 1.34) for underdose discordance, suggesting that discordance in dosing is not associated with AKI. Non-adherence to dosing recommendations for aminoglycosides was not associated with risk of AKI in a setting primarily of once-daily aminoglycoside administration.

Aminoglucósidos y polimixinas

The emergence of multidrug-resistant strains of gram-negative bacilli during the last decade has generated renewed interest in older antimicrobials that had been relegated to a second line because of a poorer safety profile, but that are still active against these microorganisms. Once-daily administration of aminoglycosides has limited the toxicity of these agents and enabled their reintroduction into clinical practice. Recent studies have shown no additional benefits of concomitant administration of aminoglycosides with current ss-lactams, and the available evidence does not support the use of once-daily administration for all indications. The new formulations and dosages of polymyxins have also reduced the toxicity rates attributed to these agents in the past. Although more extensive studies are required to properly define their pharmacokinetics and effectiveness, the available data have shown favorable outcomes for patients with infection due to multiresistant gram-negative bacilli treated with colistin, either alone or combined with other antimicrobial agents.

Once-daily tobramycin in cystic fibrosis: better for clinical outcome than thrice-daily tobramycin but more resistance development?

Once-daily administration of aminoglycosides in cystic fibrosis (CF) patients is considered equally efficacious and potentially less nephrotoxic than dosing three times a day. However, the choice of the most suitable PK/PD index (C(max)/MIC versus AUC(24)/MIC) to ensure optimum clinical outcome in this patient population is not clear. In a single-centre, open, randomized, controlled, non-blinded study 33 adult CF patients (20 females, 19-37 years) were treated with intravenous tobramycin (10 mg/kg/day) for 14 days given either as single dose once a day (Q24; 17 patients) or divided into three equal doses every 8 h (Q8; 16 patients). Tobramycin serum concentrations and MICs for Pseudomonas aeruginosa were determined on days 1 and 14. The clinical outcome parameter, correlated to PK/PD indices, was the percentage predicted forced expiratory volume in 1 s (FEV(1)% pred.). FEV(1)% pred. improved significantly for both treatments. There was a log-linear relationship between C(max)/MIC and FEV(1)% pred. and AUC/MIC and FEV(1)% pred. for both treatments. For equal values of AUC24/MIC, however, Q24 treatment provided better improvement in lung function than Q8 dosing, whereas C(max)/MIC did not show any dosing interval dependence. A statistically significant increase was observed for MIC (day 1) versus MIC (day 14) for Q24 treatment, however, no such difference was observed for Q8 treatment. The most important PK/PD parameter for clinical outcome in CF patients was C(max)/MIC. Outcome prediction of AUC(24)/MIC was dependent on the regimen. The increase of P. aeruginosa resistance after once-daily administration is linked to a long dosing interval. More and larger studies are needed to optimize the dosing regimen for maximum clinical outcome with minimum resistance development.

ONCE-DAILY DOSING OF AMINOGLYCOSIDE ANTIBIOTICS

Improved understanding of the pharmacodynamics and toxicity of aminoglycoside antibiotics has resulted in the study of once-daily dosing regimens. Although studies have suggested a therapeutic advantage and possibly a decrease in toxicity with once-daily administration, these effects have been modest. The cost savings associated with once-daily aminoglycoside administration, however, makes this approach appealing. Although a syndrome of fever, tachycardia, hypotension, and rigors has been associated with once-daily dosing of gentamicin, this appears to have been the result of impurities in the antibiotic from a single offshore supplier. This syndrome has not been associated with other aminoglycoside antibiotics, and the FDA has now withdrawn its recommendation that once-daily aminoglycoside use be avoided. As with any medical regimen, the decision to use once-daily dosing of aminoglycoside agents must take into account special patient characteristics and the disease state being treated. Although once-daily dosing appears effective in limited studies in children, in individuals with neutropenia, and in individuals with cystic fibrosis, its role in gram-positive coccal endocarditis and in individuals with altered volumes of distribution remains uncertain. Further data are needed to clarify the role of once-daily dosing in these situations.

Once-Daily Aminoglycosides: A Meta-Analysis of Nonneutropenic and Neutropenic Adults

Objective: To compare the efficacy, nephrotoxicity, and ototoxicity of once-daily dosing of aminoglycosides versus conventional dosing. Design: Meta-analysis of 14 randomized trials identified through a MEDLINE search (January 1965-May 1996). Patients: Neutropenic and nonneutropenic adults. Interventions: Patients were randomly selected to receive an aminoglycoside once daily or in multiple daily doses. Measurements and Main Outcomes: The outcomes considered were clinical cure, bacteriologic cure, nephrotoxicity, auditory toxicity, and vestibular toxicity. The data were analyzed in the following subgroups: (1) all trials, (2) nonneutropenic patients, (3) neutropenic patients, and (4) patients with undefined neutrophil status. For all trials the pooled risk ratio was 1.268 (95% CI 0.828 to 1.939) for clinical cure, and was 1.390 (95% CI 1.350 to 1.392) for bacteriologic cure. Nephrotoxicity had a pooled risk ratio of 0.765 (95% CI 0.468 to 1.252), that for auditory toxicity was 1.117 (95% CI 0.151 to 5.636), and that for vestibular toxicity was 1.155 (95% CI 0.221 to 6.039). Analysis of the subgroups, including a separate analysis of neutropenic patients, demonstrated similar results. Conclusions: When all trials were considered, once-daily administration of aminoglycosides had similar efficacy and no increase in nephrotoxicity or ototoxicity compared with conventional aminoglycoside dosing.

Evaluation of Nephrotoxicity Associated with Once-Daily Administration of Aminoglycoside

Objective: To determine the potential risk factors associated with nephrotoxicity in patients receiving once-daily aminoglycoside (ODA) therapy. Design: Case series. Setting: Large community teaching hospital. Patients: Twenty-five patients considered nephrotoxic during ODA therapy. Main Outcome Measures: This study is a retrospective chart review of patients in whom nephrotoxicity developed during ODA therapy. Nephrotoxicity was defined as a rise in serum creatinine (SCr) concentration of 0.5 mg/dL or more above the preaminoglycoside baseline value. Patients were identified from our institutional ODA database. Based on the previously identified risk factors for aminoglycoside-associated nephrotoxicity with conventional aminoglycoside therapy published by Bertino et al., a data collection tool was developed. Collected data included demographic information, concurrently administered drugs, diagnostic agents used, and potential comorbidity risk factors. Results: Similar to what has been found in patients receiving conventional aminoglycoside regimens, numerous risk factors, such as the concomitant use of cephalosporins, loop diuretics, intravenous contrast dye, angiotensin-converting enzyme inhibitors, and nonsteroidal antiinflammatory drugs, may have been responsible for the rise in SCr observed in our study population. In addition, common comorbidity risk factors in this population were pleural effusion, pneumonia, decrease in systolic blood pressure to less than 80 mm Hg, and preexisting renal disease. Conclusions: Nephrotoxicity is the result of multifactorial processes and is not solely due to the ODA administration technique.

Modifications de la cinétique des aminosides chez les sujets de réanimation : conséquences thérapeutiques

Aminoglycosides pharmacokinetics are modified in ICU patients compared to healthy subjects. A number of studies have shown that the volume of distribution was increased (resulting in lower peak serum levels), the elimination clearance was decreased (resulting in higher trough serum levels), which in turn yield a longer elimination half-life and a higher-than-expected accumulation. Patients undergoing continuous hemofiltration or hemodialysis require specific dosing adjustements. The interindividual variability in aminoglycosides pharmacokinetics is large in ICU patients. A standard dosing regimen results in a large dispersion of serum concentrations. Pharmacokinetic parameters are more or less correlated to body weight, creatinine clearance, illness severity scores, and presence of a mechanical ventilation. These correlations can be used to define the initial dose on an individual basis. Intraindividual variability in aminoglycosides pharmacokinetics is also large and requires frequent drug serum level monitoring. Once-daily administration of aminoglycosides represents a possibly more effective and less toxic therapeutic alternative which ensures an adequate peak aminoglycoside concentration after the first dose, especially when a loading dose is given. La cinétique des aminosides est modifiée de manière importante chez les patients de réanimation par rapport aux sujets sains. D'une manière générale, de nombreuses études ont montré une augmentation du volume de distribution (qui se traduit par des pics plus bas), une diminution de la clairance d'élimination (qui se traduit par des concentrations résiduelles plus élevées) et en conséquence un allongement de la demivie, qui peut entraîner une accumulation plus importante que prévue. Les patients de réanimation peuvent être soumis à des techniques d'épuration extrarénale continue, qui réclament des adaptations posologiques particulières. La variabilité interindividuelle de la cinétique est très importante chez les patients de réanimation, et se traduit par une grande dispersion des concentrations obtenues après administration d'une dose standard. Il existe une corrélation entre les paramètres cinétiques des aminosides et certaines covariables comme les scores de gravité, la clairance de la créatinine, le poids et la présence d'une ventilation mécanique. Ces corrélations permettent de mieux définir les schémas posologiques des aminosides. La variabilité intraindividuelle est également importante, et explique la nécessité de réaliser un suivi thérapeutique répété chez les patients de réanimation. L'administration des aminosides en dose unique journalière représente une possibilité thérapeutique efficace et bien tolérée sur le plan rénal, et qui assure une concentration au pic généralement adéquate dès la première dose, surtout si l'on recourt à une dose de charge.

The economic impact of once-daily versus conventional administration of gentamicin and tobramycin.

This retrospective, observational study was designed to compare once-daily with conventional aminoglycoside administration for costs while determining equivalency in efficacy and toxicity. 100 consecutive patients who had been treated with once-daily aminoglycosides after 1st August 1993, were evaluated via retrospective chart review. For comparison, 100 consecutive patients who were treated with conventional regimens of aminoglycosides, over the same calender period 1 year earlier (beginning on 1st August 1992), were evaluated in a similar manner. Aminoglycoside antibacterials, excluding amikacin, were administered as a single daily dose of 6 mg/kg. 89 patients were cured or improved with once-daily administration versus 90 patients with conventional administration. One patient in each group developed definite aminoglycoside-induced renal toxicity. The total cost [in 1993 Canadian dollars ($Can)] per patient for once-daily and conventionally administered aminoglycosides was $Can97.62 and $ Can199.43, respectively. Thus, once-daily administration of aminoglycosides is as effective and well tolerated, while considerably less expensive than, aminoglycoside treatment utilising conventional regimens.

Once-daily aminoglycoside administration: can it be done?

Once-daily aminoglycoside administration: can it be done?

Pharmacokinetic issues in the critically ill patient

The critically ill patient is often characterized by unique pharmacokinetic findings because of the dynamic nature of their illness and the common presence of multiple organ system dysfunction. Pharmacokinetics in the ICU patient are affected by altered volumes of distribution, altered protein binding, changes in liver and renal blood flow, hypoxia, and cytokines. Once-daily administration of aminoglycosides has been an area of interest within the past few years. Once-daily administration appears to be at least as effective and no more toxic than traditional dosing regimens. The enthusiasm of therapeutic drug monitoring in vancomycin dosing has diminished recently because of a lack of correlation between serum concentration and efficacy or toxicity. Well-designed outcome studies addressing therapeutic drug monitoring of a wide variety of drugs are lacking. Evidence does suggest that therapeutic drug monitoring decreases toxicity, but evidence regarding efficacy is more difficult to locate. Several studies have shown therapeutic drug monitoring to be cost-effective. Further research is needed to evaluate the effects of therapeutic drug monitoring on clinical outcomes in ICU patients.

Experience of once-daily aminoglycoside dosing using a target area under the concentration-time curve.

Many centres are changing to once-daily aminoglycoside administration. However, proposed methods for this practice often have theoretical and practical difficulties. We have developed a method in which a target area under the concentration-time curve (AUC) is used instead of traditional peak and trough serum concentrations. To analyse our experience with the target AUC method in the first 100 courses of once-daily aminoglycoside administration in the Christchurch, New Zealand hospitals. Following a starting dose of 5-7 mg/kg, administered by 30-minute infusion, the AUC was calculated using two serum aminoglycoside concentrations taken at one and six-14 hours after the start of the infusion. Dose adjustment was made to correct for any difference between the calculated AUC and a target AUC (72-101 mg.1(-1).h). The method was assessed for practicality and precision in 100 courses of treatment. The incidence of aminoglycoside toxicity was documented. The mean final dose of 6.68 mg/kg, and AUC of 92.8 mg.1(-1).h, were significantly different from the mean starting dose and AUC of 5.67 mg/kg and 74.0 mg.1(-1).h, respectively. The method appeared to be more precise than empirical dosing at achieving the target AUC even though the final recommended dose had more variability than the starting dose. Although the study was uncontrolled, observed nephrotoxicity (2%) and ototoxicity (up to 6.9%) were no greater than expected from the results of other studies. There were no deaths related to antibiotic failure. The AUC method was practical, and more appropriate for once-daily dosing than the conventional method of aiming for target peak and trough concentrations. Dose adjustment can be made before the next dose.

Extended dosage intervals for aminoglycosides

The rationale for and effectiveness of extended dosage intervals for aminoglycosides are discussed. Aminoglycosides can be given once daily despite an elimination half-life of two to three hours because of the postantibiotic effect (PAE) of these agents. Aminoglycosides have a prolonged PAE against a variety of common gram-negative and gram-positive organisms. Higher serum aminoglycoside concentrations are associated with longer PAEs and increased bactericidal activity. Once-daily administration may reduce the potential for adaptive postexposure resistance by allowing less contact time between organism and drug. A major concern with aminoglycosides is the risk of nephrotoxicity and ototoxicity. The uptake of specific aminoglycosides by renal cortical cells is saturable; a longer dosage interval may decrease the risk of nephrotoxicity because higher transient serum aminoglycoside levels appear to be less nephrotoxic than lower but more persistent serum concentrations. Once-daily administration may reduce the risk of ototoxicity through a similar mechanism. An increasing number of clinical trials suggest tht once-daily administration of aminoglycosides and regimens involving shorter dosage intervals are equally effective in patients with normal renal function and gram-negative infections and that once-daily administration may reduce the frequency of toxicity or delay it. Patients with renal dysfunction or neutropenia may also benefit from once-daily administration. Most trials have been small, and in some of them other antimicrobials were given concurrently. Although more study is needed, the evidence to date suggests that once-daily administration of aminoglycosides is as effective as traditional regimens entailing shorter dosage intervals and may reduce the potential for toxicity.

What is the evidence for once-daily aminoglycoside therapy?

Aminoglycosides are important antibacterial agents for the treatment of serious infection. Evidence suggests that high peak plasma concentrations must be achieved early in the course of treatment if these agents are to be effective, but prolonged high concentrations may cause ototoxicity and nephrotoxicity. Peak plasma concentrations of 6 to 10 mg/L and trough concentrations of less than 2 mg/L for gentamicin and tobramycin have been traditional goals of therapy. Extensive recent evidence from in vitro, animal and human studies suggests that these target concentrations need revision. Aminoglycosides display concentration-dependent bacterial killing, have a long postantibiotic effect, and induce adaptive resistance in Gram-negative bacteria. All of these factors support the use of larger doses of aminoglycosides that are given less frequently than conventional therapy. Studies in vitro support this approach, showing greater activity when aminoglycosides are given less frequently. Animal studies comparing different dosage intervals have shown varying results, with only a slight bias favouring the longer dosage interval. However, the short elimination half-lives for the drugs in animals limit the applicability of these models to humans. Importantly, there is convincing evidence in animal studies that nephrotoxicity and ototoxicity are both reduced when the same total daily dose is administered in less frequent doses. There have been at least 29 clinical trials comparing once-daily administration of aminoglycosides with conventional administration 2 to 4 times daily. In general, efficacy has not been shown to be different between regimens, although one trial showed an advantage for once-daily administration compared with administration 3 times daily. A small number of trials have shown less nephrotoxicity and ototoxicity with once-daily administration, leading several authors to suggest that there is sufficient evidence to warrant a change to once-daily administration of aminoglycosides. However, once-daily administration has not been well studied in the paediatric population, or in patients with renal failure or endocarditis, and cannot be recommended in these patients as yet. The choice of a 24-hour dosage interval is somewhat arbitrary, and the optimal interval may not necessarily be 24 hours. No studies have included dosage adjustment based on pharmacokinetic modelling methods, and the effect of this on treatment outcome needs to be assessed. The best method of administering aminoglycosides once daily is yet to be determined.

Prevention and attenuation of acute renal failure.

Recent progress in our understanding of the pathogenetic processes involved in ischemic acute renal failure is considerable. Blockade of the production of endothelium-derived relaxing factor may markedly improve survival in patients with septic shock. Atrial natriuretic peptide and growth factors enhance renal recovery in animal models of acute renal failure, even when administered well after the ischemic insult. Aminoglycosides and radiocontrast agents are the most common causes of drug-induced acute renal failure. Once-daily administration of aminoglycosides is an effective treatment modality that may limit the occurrence of nephrotoxicity. Awareness of the patient's volume status has decreased the incidence of radiocontrast-induced acute renal failure. The new, expensive, nonionic, low-osmolar radiocontrast agents do not offer apparent benefits in patients with normal or slightly decreased renal function. However, use of such agents may decrease the incidence of radiocontrast-induced renal failure in diabetic patients with severe renal failure. The prognosis for patients with renal vasculitis has improved greatly in the past decade. The discovery of antibodies directed against antigenic targets in the cytoplasm of neutrophils has facilitated the diagnosis of renal vasculitides, has improved our knowledge of the pathogenesis of these diseases, and may guide rational treatment.

Once-daily aminoglycoside therapy

The once-daily administration of aminoglycosides is an attractive concept. In animal experiments and clinical trials, there is either a reduction in or no influence on the risk of toxicity. Less frequent dosing reduces the contact time between host tissue binding sites and drug. Thanks to the PAE and perhaps other as-yet-unrecognized factors, the fall in the level in serum below the MIC does not appear to impair antibacterial efficacy; in fact, the higher peak level in serum may enhance drug efficacy early in a dosage interval. In neutropenic patients, the in vivo PAE may be lost or small-colony variants with a shorter PAE may be selected unless a concomitant beta-lactam is administered. Because it will be some time before data from clinical trials in the United States are available, because the results from the international trials are encouraging, and because there is potential benefit to patients, it seems reasonable for infectious diseases consultants to cautiously initiate the educational process necessary to implement once-daily aminoglycoside therapy in their institutions.

Once-daily aminoglycoside administration: New strategies for an old drug

Considerable in vitro and clinical research has been conducted concerning once-daily administration of aminoglycosides. Inherent to such regimens are elevated peak concentrations and prolonged periods during which concentrations are below the MIC for the pathogen. High peak concentration to MIC ratios may maximize bactericidal rates but the problem of toxicity remains. Although sustained exposure to sublethal concentrations could undermine efficacy, antimicrobial activity may be prolonged by the post-antibiotic effect. A wide variety of animal toxicity and efficacy models has been investigated. Findings suggest that less frequent administration is associated with less toxicity while efficacy remains unaltered. Elevated doses appeared to be well tolerated in studies in volunteers and patients, however relatively few critically ill patients have been assessed. Efficacy in the treatment of urinary tract, respiratory and other infections appears unaffected by administration frequency. In an attempt to standardize dosage regimens to allow comparisons among diverse patient groups in clinical trials, guidelines for dosage adjustment based on renal function are outlined.