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Dosing and administration of parenteral aminoglycosides

Dosing and administration of parenteral aminoglycosides
Literature review current through: May 2024.
This topic last updated: Nov 02, 2023.

INTRODUCTION — The traditional approach to parenteral aminoglycoside dosing in adults involves the administration of a weight-based dose divided two to three times daily in patients with normal renal function. The dose is reduced and/or dosing interval extended in patients with decreased renal function or as indicated by measured serum drug concentration(s). Extended-interval aminoglycoside therapy (also known as once-daily aminoglycosides, single daily aminoglycoside dosing, consolidated or high-dose aminoglycoside therapy) utilizes a higher weight-based dose administered at an extended interval (every 24 hours for those with normal renal function and longer for those with renal dysfunction). Extended-interval aminoglycoside therapy (utilizing higher single doses) should not be confused with traditional, intermittent dosing with lower individual doses administered at extended intervals because of renal impairment.

This topic discusses the efficacy and safety, patient selection, and implementation of these two dosing strategies. Other (general) information about aminoglycosides is found elsewhere. (See "Aminoglycosides".)

This topic refers to dosing of aminoglycosides for the treatment of typical bacterial infections. While the pharmacokinetics of plazomicin are generally comparable to those of other aminoglycosides, published experience informing the optimal method of dosing (including the use of serum concentration monitoring to adjust therapy) is limited. Dosing of aminoglycosides in the treatment of mycobacterial infections, tularemia, plague, and brucella is discussed in the topics dedicated to those infections.

Of note, for most of these situations, with the exception of urinary tract infections, aminoglycosides are most commonly used in combination with other agents, regardless of dosing method. (See "Aminoglycosides", section on 'Clinical use'.)

GENERAL PRINCIPLES — The rapid attainment of therapeutic concentrations of aminoglycosides has been correlated with improved patient outcomes. Thus, dosing should be optimized to achieve this effect. Additionally, dosing should be tailored to minimize aminoglycoside toxicity. The following general principles apply to all patients, regardless of whether traditional intermittent versus extended-interval daily dosing strategies are used:

The initial dose and frequency of aminoglycosides is based upon the aminoglycoside chosen, method of administration (ie, traditional intermittent versus extended-interval daily dosing), indication, dosing weight, and renal function.

Dosing adjustments should be based upon the results of serum drug concentration monitoring. Targeted peak serum concentrations are intended to take advantage of the pharmacodynamic properties to optimize the potential for efficacy, while specific trough concentrations are targeted to avoid concentration-related toxicity (primarily nephrotoxicity). For plazomicin, dosing strategies based on the determination of the area under the time-concentration curve (AUC) have been proposed [1]. (See 'Plazomicin' below.)

Intravenous administration of aminoglycosides should occur over at least 30 minutes for traditional intermittent and at least 60 minutes for extended-interval dosing. Because beta-lactams inactivate aminoglycosides in vitro, they should not be mixed in the same solution [2]. However, the clinical significance of such interactions in vivo is not clear, since the interaction is time and concentration dependent.

Dosing weight — The first step in aminoglycoside administration, regardless of method of administration, is determination of the dosing weight.

Calculation of the dosing weight differs between patients who are underweight, are average weight, and have obesity. Underweight patients have a total body weight (TBW) less than the ideal body weight (IBW). For aminoglycoside dosing, obesity is defined as a TBW greater than 125 percent of the IBW. IBW can be estimated by the following formulas and calculator (calculator 1):

IBW, in kg (males) = 50 + (2.3 x inches above 60 inches)

IBW, in kg (females) = 45.5 + (2.3 x inches above 60 inches)

For underweight patients, use TBW to calculate dose.

For patients whose weight is 1 to 1.25 times their IBW, we typically use IBW to calculate dose.

For patients with obesity, whose weight is >1.25 times their IBW, use the adjusted body weight (AdjBW) as follows:

AdjBW, in kg = IBW + [0.4 x (TBW - IBW)]

Creatinine clearance estimation — Since aminoglycosides are eliminated primarily by glomerular filtration, renal function affects the rate of drug clearance, and thus affects the optimal dosing interval.

The creatinine clearance can be estimated from the serum creatinine concentration using the Cockcroft-Gault formula (calculator 2) [3]. This formula considers the increase in creatinine production with increasing weight and the decline in creatinine production with age. (See "Assessment of kidney function".)

Any formula estimating the creatinine clearance from the serum creatinine concentration presupposes that the serum creatinine is a stable value. In patients who develop acute renal failure, for example, the low glomerular filtration rate will cause creatinine to be retained and thus lead to an elevation in the serum creatinine concentration. However, until a stable value is reached, the above formula might overestimate the creatinine clearance. Similarly, during recovery from acute renal failure, the fall in serum creatinine concentration will lag behind the improvement in glomerular filtration rate due to the time required for excretion of the retained creatinine.

Additionally, certain disease states or other factors may alter the relationship between the serum creatinine concentration and creatinine clearance. In particular, creatinine production (and therefore the serum creatinine concentration) is reduced in severe liver disease, malnutrition and significant loss of muscle mass (such as quadriplegic, paraplegic, or amputees), possibly resulting in overestimation of the creatinine clearance with the above formula unless there has been an equivalent reduction in body weight.

Monitoring for toxicity — The serum creatinine concentration should be monitored at baseline and repeated every one to three days, depending upon the individual circumstances. Monitoring for ototoxicity involves subjective patient assessment for the presence of auditory and vestibular dysfunction. The use of objective testing, such as audiometry or electronystagmography, is generally reserved for patients who have subjective symptoms of ototoxicity, pre-existing auditory dysfunction, or for those receiving prolonged treatment (such as for mycobacterial infections).

COMPARING EXTENDED-INTERVAL AND TRADITIONAL INTERMITTENT DOSING — Parenteral aminoglycosides can be administered using a traditional intermittent dosing strategy, which uses smaller doses given two to three times daily (in patients with normal renal function), or an extended-interval dosing strategy, which uses higher doses administered at an extended interval (between 24 and 48 hours).

Advantages of extended-interval dosing — Extended-interval aminoglycoside has efficacy comparable with traditional intermittent administration but offers three potential advantages:

Possibility of decreased nephrotoxicity (based on data from animal models) (see 'Nephrotoxicity' below)

Ease of administration and serum concentration monitoring

Reductions in administration and monitoring-related costs

Extended-interval dosing of aminoglycosides takes advantage of two pharmacodynamic properties: the post-antibiotic effect and concentration-dependent killing. The post-antibiotic effect refers to the persistent inhibitory effect against many gram-negative aerobic organisms that is seen after drug clearance, and concentration-dependent killing refers to the ability of escalating concentrations of aminoglycosides to induce more rapid killing of the pathogen. These properties are discussed in more detail elsewhere. (See "Aminoglycosides", section on 'Post-antibiotic effect' and "Aminoglycosides", section on 'Concentration-dependent killing'.)

Efficacy — Multiple trials in various adult and pediatric populations evaluating a wide spectrum of infections have demonstrated comparable efficacy of extended-interval dosing with traditional, intermittent dosing aminoglycoside therapy [4-12]. As an example, in one meta-analysis of 13 randomized controlled trials, extended-interval dosing of aminoglycosides resulted in bacteriologic cure (relative rate 1.02, 95% CI 0.99-1.05) and mortality rates (relative risk 0.91, 95% CI 0.63-1.31) that were comparable to those reported for traditional intermittent dosing [4]. Other meta-analyses in adults and children have demonstrated nonsignificant trends toward decreased antibiotic failure with extended-interval versus traditional dosing [5,7,8,11,12].

Specific patient populations in which extended-interval dosing (alone or as part of combination antibiotic therapy) has demonstrated favorable efficacy include the following [4-13]:

Immunocompetent, nonpregnant adults and children >3 months of age with:

Complicated urinary tract infections

Intra-abdominal infections

Respiratory tract infections

Gynecologic infections (including pelvic inflammatory disease)

Soft-tissue infections

Bacteremia

Females with postpartum endometritis

Febrile neutropenia patients with malignancy (adults and children)

There are minimal data evaluating extended-interval dosing for central nervous system, bone/joint infections, and ophthalmologic infections.

Toxicity

Nephrotoxicity — Protection against nephrotoxicity is supported primarily by studies in experimental animals, which suggest that the incidence of acute renal failure is diminished with extended-interval aminoglycoside administration [5]. This protective effect is thought to be associated with diminished aminoglycoside accumulation in the renal cortex, suggesting that drug uptake by the proximal tubule is most efficient at low doses [14]. The concept of saturable transport of gentamicin observed in rat models may explain how at higher doses, more of the drug is excreted without undergoing tubular reabsorption and therefore without accumulating in and injuring the tubular cells. Higher peaks for shorter periods and a prolonged period of very low exposure may allow for more efficient handling and excretion [15]. (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity".)

With respect to clinical data, three meta-analyses, the last in children, found the following risk ratios for nephrotoxicity with extended-interval dosing relative to conventional, intermittent dosing:

Risk ratio 0.87, 95% CI 0.60-1.26 [4]

Risk ratio 0.74, 95% CI 0.54-1.00 [5]

Risk ratio 0.97, 95% CI 0.55-1.69 [8]

Thus, in contrast to the animal data, there was no clear evidence of protection against nephrotoxicity with extended-interval dosing in humans. However, there are potentially important limitations to these meta-analyses in adults [4-7]:

The time period covered by the meta-analyses was similar, but the number of trials included for analysis ranged from 13 to 21, indicating differing methodologies.

The majority of trials focused on aminoglycosides other than gentamicin and tobramycin. Each meta-analysis included only two trials of gentamicin, the same two in two of the analyses and an additional one in the third. Only one meta-analysis included a study of tobramycin.

Other antibiotics were administered with aminoglycosides in the majority of trials, including at least one in which the known nephrotoxin amphotericin B was included.

Individual studies have attempted to address the nephrotoxic potential of extended-interval dosing. A prospective, randomized, double-blind trial performed after the meta-analyses included 74 patients, almost all of whom were treated with gentamicin or tobramycin [16]. Extended-interval dosing resulted in less nephrotoxicity than twice daily dosing in patients receiving aminoglycosides for at least 72 hours (0 versus 15 percent). In a multivariate logistic regression analysis, the daily area under plasma concentration-time curve (AUC) and concomitant use of vancomycin were significant factors in the development of nephrotoxicity. Experience in patients with cystic fibrosis has also suggested the potential for reduced nephrotoxicity compared with three times daily dosing [17].

Data regarding the nephrotoxicity of plazomicin are limited [18]. Based on data generated from studies in patients with either complicated urinary tract infection or infections caused by carbapenem-resistant Enterobacteriaceae, rates of plazomicin-associated nephrotoxicity (4.8 percent) were not statistically different from the comparator agent.

Ototoxicity — Meta-analyses and most studies have not demonstrated a clear difference in ototoxicity with the two regimens [4-8,16,19]. In one meta-analysis, for example, the risk ratio for ototoxicity with extended-interval dosing compared with traditional-intermittent dosing was 0.67 (95% CI 0.35-1.28) [4]. In contrast, some observational data have suggested that extended-interval dosing was associated with vestibular toxicity at lower cumulative doses and shorter durations of therapy [20]. Differences in study design (eg, lack of randomization, variable endpoint definitions or detection measurements) and patient populations may account for some of the differences observed. Nevertheless, the presence or possibility of ototoxicity should be more closely monitored with extended-interval therapy because of the higher peak plasma concentrations. In addition, extended-interval dosing is commonly used in patients receiving extended durations of therapy, which may increase the risk. (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity", section on 'Ototoxicity'.)

Convenience and cost — As noted above, other potential advantages of extended-interval aminoglycoside therapy relative to traditional intermittent dosing include ease of administration and reduced preparation and administration times. Published reports have confirmed the ability of extended-interval dosing to reduce the costs associated with therapeutic drug monitoring if the monitoring approach suggested below is followed [21]. (See 'Extended-interval dosing and monitoring' below.)

Furthermore, an extended dosing interval may also help facilitate the transition from inpatient to outpatient care.

Precautions with extended-interval dosing — Extended-interval aminoglycoside dosing represents a deviation from the US Food and Drug Administration (FDA)-approved manufacturer's package insert. Prescribing outside the recommendations of the package insert is not uncommon for aminoglycosides or many other drugs. However, use of extended-interval aminoglycoside therapy also deviates from the "standard of practice" of measuring and documenting serum concentrations within a defined therapeutic range. Peak serum concentrations with extended-interval dosing are considerably higher than those traditionally targeted by some laboratories and may trigger an alert.

SELECTION OF DOSING STRATEGY

Patients with normal renal function

For gram-negative bacterial infection — For most patients receiving aminoglycosides for suspected or documented infection due to gram-negative aerobic bacteria, we suggest extended-interval dosing rather than traditional intermittent dosing. Extended-interval dosing has comparable efficacy and safety with superior pharmacodynamic profiles and greater ease of administration (see 'Comparing extended-interval and traditional intermittent dosing' above). This approach is consistent with recommendations from the Infectious Diseases Society of America (IDSA) guidelines on the treatment of multidrug-resistant gram-negative infections [22].

It is unknown whether extended-interval aminoglycoside dosing is associated with a greater risk of oto- or nephrotoxicity in settings such as the use of concomitant nephrotoxic or ototoxic agents, prolonged courses of therapy, and pre-existing vestibular or hearing loss. Although we do not exclude such patients from receiving extended-interval dosing, we monitor them closely for toxicity during therapy.

For gram-positive bacterial infections — Aminoglycosides may be used in combination with other agents to treat specific serious gram-positive bacterial infections (ie, for synergy). In such settings, lower concentrations of aminoglycosides are targeted, whether traditional or extended-interval dosing intervals are used. Selection of dosing regimen depends on the pathogen being treated:

For invasive enterococcal infections (such as endocarditis), traditional intermittent dosing of gentamicin is preferred when the agent is used for synergy because of insufficient data informing clinical outcomes with extended-interval dosing [23].

For prosthetic valve endocarditis due to Staphylococcus species, traditional intermittent dosing of gentamicin is preferred when the agent is used for synergy because of insufficient data informing clinical outcomes with extended-interval dosing [23].

For endocarditis due to Streptococcus species, extended-interval dosing of gentamicin (3 mg/kg/day as a single daily dose) is preferred when the agent is used for synergy [23,24]. (See "Antimicrobial therapy of left-sided native valve endocarditis", section on 'Viridans streptococci and S. bovis/S. equinus complex' and "Antimicrobial therapy of left-sided native valve endocarditis", section on 'Enterococci'.)

Patients with renal impairment — Patients with renal impairment may be more likely to have aminoglycoside toxicity when administered at a high dose, and there has been a paucity of data in this population. Therefore, when aminoglycosides are used in patients with renal impairment (creatinine clearance is less than 40 mL/min), requiring renal replacement therapy, or unstable renal function, we suggest traditional intermittent dosing rather than extended-interval dosing.

Although some institutions permit extended-interval dosing for patients with a creatinine clearance as low as 30 mL/min (with the interval extended to 48 hours), we generally advise against this practice.

Patients with augmented renal aminoglycoside clearance

Identifying patients with augmented renal clearance – Augmented renal clearance (ARC) is often defined as a calculated creatinine clearance >130 mL/min using an 8- to 24-hour urine creatinine collection [25]. ARC of aminoglycosides can occur in patients with sepsis, burn injury, trauma, traumatic brain injury, and cystic fibrosis. Associated clinical features may also include age <40 years, higher lean body mass, increased urine output, and normal or low serum creatinine concentration. In addition to these clinical features, one of the best methods for recognizing ARC is identifying those with subtherapeutic serum aminoglycoside concentrations despite adequate dosing.

Identification of patients with ARC based on urine creatine collection is often impractical given the urgent need to initiate treatment in many cases [26]. Common equations used to estimate creatinine clearance (such as the Cockcroft-Gault [CG] equation) may underestimate actual clearance if the estimate is >120 mL/min [27-29]. Alternate methods (including measurement of cystatin C) have been investigated, but most lack the necessary sensitivity and specificity to be clinically useful [26].

Selection of dosing strategy with ARC – Published data are limited to determine the optimal method of initial aminoglycoside dosing in the setting of ARC, particularly in adults. As a result, clinical practice varies between traditional intermittent dosing, and extended-interval dosing. Regardless of dosing method used, we recommend early and frequent monitoring of drug concentrations with pharmacist assistance to inform dosing adjustments. We recommend against nomogram-based dosing in patients with ARC.

As in other populations, a potential benefit of extended-interval dosing is that it takes advantage of the pharmacokinetics/pharmacodynamics to optimize the ratio of the peak concentration or the area under the curve to the minimum inhibitory concentration (Cmax/MIC or AUC/MIC) by using higher doses less frequently. This may also minimize toxicity with increased drug-free time compared with traditional intermittent dosing. The potential risks of undertreatment with excess drug-free time are generally mitigated by the other antibiotics used in combination with aminoglycosides.

For pathogens that have a MIC of ≥2 to gentamicin and tobramycin (as seen in many multidrug-resistant gram-negative bacteria), an optimal Cmax/MIC or AUC/MIC may not be achievable, even with an extended-interval dosing approach [30-32]. In such cases, antibiotics other than aminoglycosides should be used.

Approach to extended-interval dosing with ARC – When treating invasive gram-negative bacterial infections in patients with ARC, aminoglycoside dosing should also consider the high volumes of distribution often observed in patients with critical illness. A reasonable modification to an extended-interval dosing approach in the setting of ARC is to:

Use an initial dose of at least 7 mg/kg for gentamicin and tobramycin or 15 to 20 mg/kg for amikacin.

These doses generally achieve pharmacodynamic targets for aminoglycosides for susceptible pathogens (MIC <0.5 mcg/mL) in critically ill patients [30]. Some sources recommend higher initial dosing (eg, 8 to 10 mg/kg for gentamicin or tobramycin and 20 mg/kg for amikacin) to increase the probability of achieving pharmacodynamic targets for pathogens with higher MICs (but still <1 mcg/mL) and/or for patient populations with higher volumes of distribution [30]. However, routine use of higher initial doses is generally reserved for populations for whom increased clearance is most predictable (such as in patients with cystic fibrosis). (See 'Cystic fibrosis' below.)

Obtain two serum aminoglycoside concentrations:

-The first concentration should be obtained approximately one to two hours after the initial dose (to allow for drug distribution). This concentration should be used to extrapolate a true peak concentration (Cmax).

-The second concentration should optimally be obtained at least one half-life following the initial measurement but still allow sufficient time to determine dose requirements prior to the next scheduled dose. This is usually within 12 to 18 hours after administration.

Based on serum concentration results and pharmacokinetic calculations, adjust the adjusted dose and dosing interval to target:

-A goal peak concentration of 15 to 20 mcg/mL for gentamicin and tobramycin or 35 to 50 mcg/mL for amikacin.

-A goal trough concentration of <0.25 mcg/mL (below the limit of detection) for gentamicin and tobramycin or <4 mcg/mL for amikacin for >4 hours prior to redosing.

Reassess the aminoglycoside concentrations early and frequently. Given the significant variation in the duration of ARC [29], this is important to optimize both efficacy and safety. In patients with stable renal function and dosing, monitoring should be repeated at least weekly if therapy will be prolonged beyond 7 to 10 days.

Approach to traditional intermittent dosing with ARC – The approach is the same as that used in patients without ARC and is discussed elsewhere. (See 'Traditional dosing and monitoring' below.)

GENTAMICIN AND TOBRAMYCIN DOSING IN ADULTS

Extended-interval dosing and monitoring — Administration of a higher dose of gentamicin or tobramycin at an extended interval is dependent on renal function and subsequent monitoring of serum drug concentrations. Below is the method we use in adults.

Calculation of dosing weight and creatinine clearance, both of which are important for dose and dosing interval determination, are discussed above. (See 'Dosing weight' above and 'Creatinine clearance estimation' above.)

Dosing for children and other specific populations are discussed elsewhere. (See 'Dosing for special circumstances' below.)

Initial dose and dosing interval — A loading dose is not needed in the setting of extended-interval aminoglycoside administration. At our institution, we use an initial gentamicin or tobramycin dose of 7 mg/kg and determine the interval based on serum concentration plotted on a nomogram. We use the nomogram developed at Hartford Hospital, the most widely used nomogram in the United States (figure 1) [33]. An alternative is to use more intensive monitoring to determine the appropriate dosing interval based on target concentrations. (See 'Intensive monitoring' below and 'Target concentrations' below.)

While some institutions use lower initial doses (ie, gentamicin 5 mg/kg) for either all or selected patients (such as postpartum individuals with endometritis), these lower doses may be most appropriate for settings in which the pathogen is highly susceptible. Use of nomograms to adjust doses may also be unreliable with such doses. Since our use of aminoglycosides is generally reserved for patients with serious, invasive illness in whom decreased susceptibility is more likely, with the exception of postpartum endometritis, we favor 7 mg/kg dose for most patients.

The 5 mg/kg dose of gentamicin and tobramycin is also used for selected cases of urinary tract infection; this is discussed in detail elsewhere. [34]. (See "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents", section on 'Outpatients'.)

Drug concentration monitoring — When an extended-interval daily dosing strategy is employed, the timing and frequency of serum drug concentration monitoring differ from those used in traditional dosing. Concentrations can be targeted either by using a published nomogram that extrapolates desired dosing interval based on a single drug concentration (see 'Nomogram-based monitoring' below) or by analysis of two or more serum concentrations checked during the dosing cycle (see 'Intensive monitoring' below). The latter (intensive monitoring) is generally employed when extended-interval dosing is used in special populations that may have unpredictable pharmacokinetics, such as patients with burns, ascites, and critical illness. (See 'Dosing for special circumstances' below.)

When the course of extended-interval aminoglycosides is not expected to exceed three daily doses (eg, for most cases of postpartum endometritis), serum drug concentration monitoring is likely unnecessary in patients with normal renal function. Even in such cases, monitoring of renal function is still warranted in order to reflect potential drug-related nephrotoxicity and to signal a change in drug elimination. Drug concentration measurements should be repeated with a change in renal function and when duration of therapy exceeds 7 to 10 days. Although most manufacturers recommend measuring aminoglycoside concentrations throughout the course of therapy, such recommendations are based upon traditional intermittent dosing strategies and may not apply to extended-interval dosing.

Regardless of the method used to determine patient dosing needs, sampling times must be documented by the phlebotomist for accurate interpretation of results. In addition, requests for laboratory determinations of serum concentrations should include a provision to indicate that extended-interval dosing is being utilized. Since serum concentrations obtained (especially the peak concentrations) will be substantially different from those obtained with traditional intermittent dosing, clinicians, pharmacists, and laboratory personnel need to know the dosing method for appropriate interpretation.

Target concentrations — Although peak and trough concentrations are not directly measured for extended-interval dosing, serum concentrations obtained within specified intervals during the dosing cycle are used to extrapolate and adjust dosing to achieve intended targets. Extended-interval aminoglycoside dosing targets a peak serum concentration of approximately 15 to 20 mcg/mL for gentamicin and tobramycin in order to target approximately 10 times the MIC of the pathogen [35]. Trough serum concentrations should be less than 1 mcg/mL (are most often undetectable) because of the extended dosing interval. The estimated drug-free interval (ie, concentration is undetectable) is less than eight hours.

Nomogram-based monitoring — Application of the published nomogram requires that a single serum concentration be obtained 6 to 14 hours after the first dose (figure 1) [21]. Results from this measurement are then used to determine the necessary dosing interval. Successful application of this approach has been documented [33].

Although unlikely to result in peak serum concentrations below the desired target value when doses of 7 mg/kg are employed, single-concentration serum monitoring requires assumptions that individual patients exhibit kinetic parameters comparable to other patients. Patients not conforming to usual population kinetic parameters may have suboptimal serum aminoglycoside concentrations if doses are calculated from the standard nomogram. Appropriate patient selection should significantly reduce the risk of such variability.

Intensive monitoring — An alternative to the use of the nomogram is to obtain a peak serum aminoglycoside concentration (60 minutes post-infusion) and a second concentration approximately 6 to 12 hours after the first or second dose. Dosing adjustment based on these concentrations is generally performed with the assistance of a clinical pharmacist based on individualized patient pharmacokinetic parameters.

Additional samples may be obtained during the course of therapy (eg, sample 6 to 12 hours post-infusion after the same dose) to verify that concentrations have not changed significantly. The disadvantage to this method is the requirement of more sophisticated analyses (usually performed by pharmacists).

Traditional dosing and monitoring — Traditional, intermittent dosing involves administration of a loading dose, administration of a maintenance dose at a specific interval (depending on renal function), and subsequent monitoring of serum concentrations of gentamicin or tobramycin to guide dose adjustments. Below is a step-by-step method used for dosing gentamicin and tobramycin in adults. This differs slightly from manufacturer recommendations, since dosing according to the package insert consistently resulted in suboptimal peak serum concentrations at our institution. Recommendations from the manufacturer can be obtained by reviewing the package insert [36,37].

Determination of dosing weight and estimation of creatinine clearance, both of which are important for dose and dosing interval determination, are discussed above. (See 'Dosing weight' above and 'Creatinine clearance estimation' above.)

Dosing for children, burn patients, patients on dialysis, and other specific populations are discussed elsewhere. (See 'Dosing for special circumstances' below.)

Loading dose — The initial loading dose is determined by type or site of infection, for which different peak serum gentamicin or tobramycin concentrations are desired (table 1). In general, loading doses for gram-negative infections are generally 2.5 to 3 mg/kg dosing weight. Higher loading doses are used for pneumonia or acute life-threatening gram-negative infections than for acute simple cystitis (eg, uncomplicated lower urinary tract infections) because of the lower serum drug concentrations required to successfully treat cystitis. In the setting of synergy for gram-positive infections, loading doses are not employed.

Initial maintenance dose and dosing interval — For maintenance dosing, a specific percentage of the loading dose is given at a specific dosing interval, both of which depend on the creatinine clearance, an estimate of glomerular filtration rate (table 2). In those patients in whom a loading dose was not given, the maintenance dose is still determined by the estimated loading dose (table 1) for the indication. For adults with normal renal function who have serious gram-negative infections, the maintenance dose of gentamicin or tobramycin is generally 2 mg/kg every eight hours.

In order to meet the desired target concentrations, both the maintenance dose and the dosing interval may need to be adjusted based on the results of drug concentration monitoring, as below.

Drug concentration monitoring — Monitoring of serum aminoglycoside concentrations is essential to ensure efficacy and to avoid toxicity. Routine measurement of serum aminoglycoside concentrations is not necessary with prophylactic therapy given for less than 24 hours.

Timing — Serum concentrations should be determined when the patient has received therapy for three to five half-lives of the drug (typically around two to three maintenance doses or after adjustment of the dose). Two or more concentrations measured after the first dose may be useful for patients who are unlikely to exhibit predictable kinetics (such as those with unstable renal function or extremes of age or weight) or in whom routine monitoring would otherwise be significantly delayed due to a prolonged half-life from renal dysfunction.

Trough concentrations are measured within 30 minutes prior to the next dose and peak concentrations 30 to 45 minutes after the end of an intravenous infusion or approximately 60 minutes after an intramuscular injection. An accurate record of aminoglycoside administration times and the time the samples are obtained is essential in interpreting the results. Thus, sample times should be documented on the laboratory requisition. Drug administration records should be checked to verify that doses have been administered as scheduled.

"Target" concentrations — Desired peak concentrations for gentamicin and tobramycin are dependent upon the indication and site of infection (table 1):

When gentamicin is given for synergy of infections outside the central nervous system (eg, for certain gram-positive infections), the target peak concentration is 3 to 4 mcg/mL. Higher target peak concentrations are sometimes used for certain gram-positive central nervous system infections in an attempt to achieve concentrations at the site of infection that are adequate for synergy, but the optimal serum peak concentrations for this are uncertain. Tobramycin is not administered for synergy.

When gentamicin or tobramycin is given for the treatment of serious, invasive infections (including gram-negative pneumonia or critical illness due to gram-negative infection), target peak concentrations are 7 to 10 mcg/mL. Higher peak serum concentrations (up to 12 mcg/mL, depending on susceptibility of the organism) have been targeted for treatment of pulmonary infections in patients with cystic fibrosis. A maximum concentration (Cmax)/minimum inhibitory concentration (MIC) ratio of at least 4.5 may correspond to a better clinical outcome [38].

Trough concentrations for gentamicin and tobramycin should be below 2 mcg/mL. Many pharmacists will target a trough concentration of <1 mcg/mL when estimating dose and frequency to avoid excessive trough concentrations in settings where population kinetic parameters are less predictable.

Dosing adjustments — In general, changes in the dose (while keeping the frequency fixed) will result in proportional changes in both peak and trough concentration values. As an example, a 25 percent dosage increase will result in a 25 percent increase in both peak and trough steady-state serum concentrations.

Changes in the dosing interval while keeping the dose constant will also result in similar directional changes to both peak and trough, although such changes are not proportional. Therefore, calculation of patient-specific pharmacokinetic parameters (most frequently performed by institution-based pharmacists) is the optimal method to determine needed dose and frequency modification based on serum concentration values.

Frequency of monitoring — Once the desired peak and trough serum concentrations are achieved, serum aminoglycoside concentrations should be re-evaluated throughout therapy when there are any changes in renal function. The need for repeated serum concentration monitoring once desired concentrations are achieved in patients with stable renal function is less clear. However, monitoring should be repeated at least weekly if therapy will be prolonged beyond 7 to 10 days.

DOSING OF OTHER AMINOGLYCOSIDES IN ADULTS

Amikacin — Target serum concentration for traditional dosing of amikacin are a peak of 20 to 30 mcg/mL and a trough of <8 mcg/mL (often targeted at 1 to 4 mcg/mL). Higher peak concentrations (up to 40 mcg/mL) are often recommended for serious, life-threatening infections such as nosocomial pneumonia. Higher peaks (40 to 50 mcg/mL) are generally achieved with extended-interval dosing.

For patients receiving traditional dosing of amikacin, the usual loading dose is 7.5 mg/kg, with a subsequent maintenance dose of 15 mg/kg per day. The maintenance dose is typically given in divided doses every 8 to 12 hours for patients with normal renal function. Similar to gentamicin and tobramycin, adjustments in the frequency of administration should be made for reductions in renal function (table 2).

For patients receiving extended-interval dosing of amikacin, a 15 mg/kg dose is administered. Subsequent drug concentration monitoring and dosing interval determination are similar to those for gentamicin and tobramycin (ie, making dose and interval adjustments using a nomogram (figure 1) or more intensive monitoring to target concentrations). However, since the Hartford nomogram was not designed for amikacin, the random serum amikacin concentration should be divided by two if using the nomogram to determine the dosing frequency. (See 'Nomogram-based monitoring' above and 'Intensive monitoring' above.)

Streptomycin — The dosing of streptomycin is based on the indications for its use and is discussed elsewhere:

(See "Antimicrobial therapy of left-sided native valve endocarditis", section on 'Enterococci'.)

(See "Treatment of Mycobacterium avium complex pulmonary infection in adults", section on 'Regimen selection'.)

(See "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention", section on 'Treatment'.)

(See "Clinical manifestations, diagnosis, and treatment of plague (Yersinia pestis infection)", section on 'Treatment'.)

The drug is approved for intramuscular administration. Intravenous use is not recommended but has been described in the medical literature [39].

Plazomicin — For complicated urinary tract infection, plazomicin is administered as a 15 mg/kg intravenous dose every 24 hours in adult patients with a creatinine clearance ≥60 mL/min. For patients with a creatinine clearance <60 and ≥30 mL/min, the dose is 10 mg/kg every 24 hours, and for patients with a creatinine clearance <30 and ≥15 mL/min, the dose is 10 mg/kg every 48 hours [40].

For all patients with moderate to severe renal impairment (ie, a creatinine clearance <90 and ≥15 mL/min) expected to receive therapy beyond five days, measurement of a plazomicin trough concentration within 30 minutes prior to the second or third dose is recommended. The dosing interval should be extended when the trough concentration exceeds 3 mcg/mL.

Data are lacking to determine optimal plazomicin dosing for infections outside the urinary tract.

While both the dose and frequency of plazomicin administration are adjusted in patients with renal impairment, such administration is not considered part of the extended-interval dosing strategy. However, application of the Hartford Hospital Aminoglycoside Dosing nomogram has been proposed as a method to dose plazomicin in the setting of invasive gram-negative infections [41] and urinary tract infections [42].

DOSING FOR SPECIAL CIRCUMSTANCES — Dose adjustments need to be made in a variety of special populations.

Neonates and children — The initial dosing and administration of aminoglycosides for neonates and children vary from that in adults and should be based upon age.

For traditional intermittent dosing strategies, target drug concentrations are the same as those for adults. Studies in neonates suggest that a loading dose of 2.5 mg/kg of gentamicin may not be sufficient to obtain therapeutic peak concentrations [43], and loading doses of 4 to 5 mg/kg may thus be required. Subsequently, neonates should receive 3.5 to 4 mg/kg per day of gentamicin or tobramycin depending on gestation age, day of life, and renal function. Infants and children older than three months should receive 5 to 7.5 mg/kg per day in divided doses.

Studies regarding the use of extended-interval dosing of aminoglycosides in children are somewhat limited. Use of extended-interval dosing is generally not recommended in children younger than three months of age because of decreases in drug clearance at this age. For children older than three months, extended-interval dosing requirements may be age-dependent. In one report of non-critical care, non-cystic fibrosis patients, the following age-related recommendations were made for the initial maintenance dose of gentamicin given once daily: 9.5 mg/kg for those three months to less than two years old, 8.5 mg/kg for those two years to less than eight years old, and 7 mg/kg for those 8 to 18 years old [44]. Most information of pediatric use of extended-interval aminoglycoside dosing is from cystic fibrosis patients; however, further increased doses may be required in this patient population given increases in volume of distribution and elimination.

In all cases, appropriate serum concentration monitoring should be performed.

Pregnant women — Aminoglycosides are not commonly used in pregnant women because of concerns for fetal safety and altered pharmacokinetics (primarily enhanced drug clearance). The majority of published data in this population is with "traditional" (ie intermittent) dosing. The primary use of aminoglycosides during pregnancy is during the intrapartum period in the setting of intra-amniotic infection. Dosing for this indication is discussed elsewhere. (See "Clinical chorioamnionitis", section on 'Antibiotic therapy'.)

Renal replacement therapy

Peritoneal dialysis — Aminoglycosides are sometimes administered intraperitoneally to treat peritonitis related to peritoneal dialysis. The use and dosing of aminoglycosides in this setting are discussed in detail elsewhere. (See "Microbiology and therapy of peritonitis in peritoneal dialysis".)

Intermittent hemodialysis — Intermittent hemodialysis can decrease pre-dialysis concentrations by 50 percent. Therefore, patients undergoing intermittent hemodialysis generally require supplemental doses of gentamicin or tobramycin of 1 to 2 mg/kg after each dialysis (depending on the time lapsed after the first dose and characteristics of the dialysis delivered) [45,46]. The post-dialysis dose may best be predicted based on pre-dialysis concentrations. Large variability of kinetic parameters within this population generally necessitates more intensive serum concentration monitoring to achieve target concentrations. This is particularly true when comparing patients with acute versus chronic renal failure and can be dependent on the properties of the hemodialysis sessions (eg, flow rate and membrane type). Assessment of post-dialysis concentrations should allow for redistribution of drug back into the blood and therefore ideally be delayed until up to four hours post-dialysis.

Continuous AV hemofiltration — Similar to that observed in patients with intermittent hemodialysis, significant inter-patient variability exists among patients undergoing continuous arteriovenous (AV) hemofiltration. Empiric initial daily gentamicin or tobramycin doses of 2.5 mg/kg administered once daily should be followed by serum concentration monitoring to assure adequate peak and trough concentrations. Alternate dosing regimens at higher dose 6 mg/kg every other day have been explored for sustained low-efficiency dialysis with careful patient monitoring [47].

Cystic fibrosis — Both the volume of distribution and clearance of aminoglycosides are greatly increased in patients with cystic fibrosis, necessitating higher starting doses (with both intermittent and extended-interval dosing) to achieve target serum concentrations. Initial doses for extended-interval dosing are 10 mg/kg for gentamicin or tobramycin and 25 mg/kg for amikacin; these doses are generally limited to patients with creatinine clearance >70 mL/min.

In addition, since renal clearance may be more challenging to estimate in this patient population, early determination of drug elimination (through use of repeated serum concentration monitoring following the initial dose for patients receiving extended-interval dosing) is advised in patients for whom prior dosing requirements have not been determined. Aminoglycoside dosing in cystic fibrosis patients is discussed in detail elsewhere. (See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations", section on 'Aminoglycosides'.)

Burn patients — Patients with significant burns may exhibit larger volumes of distribution when compared with most patient populations. As a result, maintenance doses of gentamicin and tobramycin of up to 7 to 8 mg/kg per day (in divided doses) may be needed to attain therapeutic serum aminoglycoside concentrations. Serum concentration monitoring and individualized dosing correlates with survival in this patient population [45].

Critical illness (including sepsis) — Septic patients undergoing aggressive fluid resuscitation in the setting of resolving or evolving acute renal failure often warrant especially close monitoring. Critically ill patients may need higher doses to obtain targeted concentrations [48]. Some suggest individualized, intensive monitoring for such patients [49] (see 'Intensive monitoring' above). Peak concentrations of aminoglycosides may be affected by high volumes of intravenous fluids or extravascular fluid shifts, requiring adjustments in determination of pharmacokinetic parameters (such as volume of distribution).

Older adult patients — Since many older adult patients have reduced renal function and/or are receiving concomitant nephrotoxic agents, caution should be used in prescribing aminoglycosides in this patient population. Reduced muscle mass and the resulting reductions in serum creatinine concentration in older adults may result in overestimation of renal function when formulas such as the Cockcroft-Gault equation are utilized. Therefore, a relatively normal serum creatinine may be associated with a substantial loss of renal function in this patient population. A creatinine increase greater than 50 percent over baseline requires careful evaluation of urine output and urinalysis for evidence of drug-induced nephrotoxicity.

Class 2 or greater obesity — The impact of obesity on estimations of renal function is discussed elsewhere (see "Calculation of the creatinine clearance"). In addition, determination of an adjusted body weight, as discussed above (see 'Dosing weight' above), is necessary to recognize the partial distribution of aminoglycosides into adipose tissue.

SUMMARY AND RECOMMENDATIONS

Dosing weight and renal function The first steps in aminoglycoside administration include determination of the dosing weight and estimation of renal function. Calculation of the dosing weight differs between patients who are underweight, average weight, and with obesity. (See 'General principles' above.)

Dosing options – Parenteral aminoglycosides can be administered using a traditional intermittent dosing strategy, which uses smaller doses given several times each day, or an extended-interval dosing strategy, which uses high doses administered at an extended interval. These two strategies have comparable efficacy and safety. High dose extended-interval administration takes advantage of the pharmacodynamic properties of aminoglycosides and offers greater ease of preparation, administration, and monitoring. (See 'Comparing extended-interval and traditional intermittent dosing' above.)

Preference for extended-interval dosing – For most patients receiving an aminoglycoside for suspected or documented gram-negative aerobic bacterial infection, we suggest extended-interval rather than traditional intermittent dosing (Grade 2B). We avoid extended-interval dosing in patients with creatinine clearance <30 mL/min (including patients requiring dialysis) because of the potentially greater risk of toxicity with higher doses. (See 'Selection of dosing strategy' above.)

Patients who have augmented renal clearance (eg, some patients with burns, critical illness, trauma) have altered aminoglycoside pharmacokinetics that could render extended-interval dosing less reliable. If extended-interval dosing is used for such patients, individualized monitoring with pharmacist assistance should be used to determine dose adjustments rather than nomogram-based monitoring. (See 'Patients with augmented renal aminoglycoside clearance' above.)

Dosing of gentamicin or tobramycin

Extended-interval dosing – This involves administration of a higher dose (we use 7 mg/kg) administered at an extended interval. Extended-interval dosing targets a peak serum concentration of 15 to 20 mcg/mL and trough concentrations less than 1 mcg/mL. Dose adjustments can be made using a published nomogram (figure 1) or through individualized monitoring with the assistance of a pharmacist. For serious, invasive infections (including gram-negative pneumonia or critical illness due to gram-negative infection), target peak concentrations are 7 to 10 mcg/mL; target trough concentrations are at least <2 mcg/mL (many target a trough <1 mcg/mL). (See 'Extended-interval dosing and monitoring' above.)

Traditional, intermittent dosing – This involves administration of a loading dose based on indication (table 1), administration of a maintenance dose at a specific interval several times daily (depending on renal function) (table 2), and subsequent monitoring of serum concentrations to guide dose adjustments. Our approach to traditional, intermittent dosing differs slightly from manufacturer recommendations, since dosing according to the package insert consistently resulted in suboptimal peak serum concentrations at our institution. (See 'Traditional dosing and monitoring' above.)

Amikacin dosing – Target serum concentration for amikacin are a peak of 20 to 30 mcg/mL and a trough of at least <8 mcg/mL (often targeted at 1 to 4 mcg/mL). Higher peak concentrations (up to 40 mcg/mL) are often recommended for serious, life-threatening infections. For patients receiving traditional dosing of amikacin, the usual loading dose is 7.5 mg/kg, with a subsequent maintenance dose of 15 mg/kg per day in two or three divided doses. For patients receiving extended-interval dosing of amikacin, a 15 mg/kg dose is administered, with subsequent dosing determined by a nomogram (figure 1) or more intensive monitoring to target concentrations. (See 'Amikacin' above.)

Special circumstances warranting dosing adjustments – Dosing adjustments are indicated in certain populations, including children, patients on dialysis, burn patients, and older adults. Septic patients undergoing aggressive fluid resuscitation in the setting of resolving or evolving acute renal failure often warrant especially close monitoring. (See 'Dosing for special circumstances' above.)

Aminoglycosides generally used in combination – For serious infections due to typical gram-negative bacteria, with the exception of urinary tract infections, aminoglycosides are generally used in combination with other agents that have gram-negative activity, regardless of dosing method. (See "Aminoglycosides", section on 'Clinical use'.)

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References

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