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Dosing and administration of parenteral aminoglycosides

Dosing and administration of parenteral aminoglycosides
Author:
Richard H Drew, PharmD, MS, FCCP, FIDP
Section Editor:
David C Hooper, MD
Deputy Editor:
Allyson Bloom, MD
Literature review current through: Aug 2021. | This topic last updated: Jan 02, 2020.

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 24-hour 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 that have gram-negative activity, 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 underweight, average weight, and obese patients. 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 obese patients, 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 takes into account the increase in creatinine production with increasing weight and the decline in creatinine production with age. (See "Assessment of kidney function", section on 'Estimation equations'.)

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 or preexisting auditory dysfunction, or for those receiving prolonged treatment (such as for mycobacterial infections).

TRADITIONAL VERSUS EXTENDED-INTERVAL DOSING — 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 higher doses administered at an extended interval.

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)

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'.)

In contrast to other aminoglycosides, plazomicin is routinely dosed every 24 hours for complicated urinary tract infections in patients without renal impairment. While both the dose and frequency of administration are adjusted in patients with moderate renal impairment below this level, 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 [4] and urinary tract infections [5]. (See 'Plazomicin' below.)

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 [6-14]. 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 [6]. Other meta-analyses in adults and children have demonstrated nonsignificant decreases in antibiotic failure with extended-interval versus traditional dosing [7,9,10,13,14].

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 [7]. 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 [15]. 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 [16]. (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 [6]

Risk ratio 0.74, 95% CI 0.54-1.00 [7]

Risk ratio 0.97, 95% CI 0.55-1.69 [10]

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 [6-9]:

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 [17]. 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 [18].

Data regarding the nephrotoxicity of plazomicin are limited [19]. 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 — The meta-analyses, the above trial, and other studies did not demonstrate a significant difference in ototoxicity with the two regimens [6-10,17,20]. In one meta-analysis, for example, the risk ratio for ototoxicity with extended-interval dosing was 0.67 (95% CI 0.35-1.28) [6]. Nevertheless, the presence or possibility of ototoxicity should be more closely monitored with extended-interval therapy because of the higher peak plasma concentrations. (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.

SELECTION OF DOSING STRATEGY — Because of comparable efficacy and safety with superior pharmacodynamic profiles and greater ease of administration, extended-interval (instead of traditional intermittent) aminoglycoside dosing is often preferred for patients with suspected or documented moderate to severe infections due to gram-negative aerobic bacteria and among whom this method has been clinically evaluated. These include [6-14,22]:

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

Urinary tract infections

Intraabdominal infections

Respiratory tract infections

Gynecologic infections (including pelvic inflammatory disease)

Soft-tissue infections

Bacteremia

Women with postpartum endometritis

Febrile neutropenia patients with malignancy (adults and children)

Extended-interval dosing strategies have also been evaluated in patients with cystic fibrosis and for synergistic therapy for patients with select serious gram-positive infections. However, typical doses used for these populations are considerably higher and lower (respectively) than those used for other indications. Aminoglycoside dosing for these circumstances are discussed in further detail elsewhere. (See 'Synergy for gram-positive infections' below.)

Use of extended-interval dosing of gentamicin (at 5 mg/kg in adults) is an alternative regimen for surgical prophylaxis in select procedures in patients with beta-lactam allergies [23].

In the setting of CNS or ophthalmologic infections, there are insufficient data to prefer one method of dosing over the other.

Certain patient groups may have altered aminoglycoside pharmacokinetics (independent of method of dosing) that render extended-interval dosing less useful. Additionally, certain patients may be more likely to have aminoglycoside toxicity when administered at high doses. There has also been a paucity of data among these groups, as they are generally not included in the dosing trials. Thus, we do not routinely use extended-interval dosing for the following:

Patients with burns (>20 percent total body surface area).

Patients with ascites.

Pregnant women (although some experts use extended-interval dosing for intra-amniotic infection). (See "Intraamniotic infection (clinical chorioamnionitis or triple I)", section on 'Antibiotic therapy'.)

Patients with creatinine clearance less than 40 mL/min (including patients requiring dialysis) OR >120 mL/min. Some institutions permit extended-interval dosing for patients with a lower creatinine clearance (as low as 20 mL/min) but utilize a 48-hour interval for those who have a creatinine clearance <40 mL/min.

While patients receiving concomitant nephrotoxic or ototoxic agents and/or prolonged courses of therapy are at greater risk of aminoglycoside toxicity, it is unclear whether or not extended-interval dosing increases the risk of such toxicity (relative to that seen with traditional intermittent dosing). Therefore, while not specifically excluded for eligibility to receive extended-interval dosing, such patients should receive close monitoring.

Toxicity of and general precautions for aminoglycoside use are discussed elsewhere. (See "Aminoglycosides", section on 'Toxicity'.)

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

GENTAMICIN AND TOBRAMYCIN DOSING IN ADULTS

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 [24,25].

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 [26].

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.

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 dose of 7 mg/kg and determine the initial dosing interval based upon the estimated (or measured) creatinine clearance, as listed in the table (table 3). These dosing guidelines are consistent with the nomogram developed at Hartford Hospital, the most widely used nomogram in the United States (figure 1) [27]. While some institutions use lower initial doses (ie, 5 mg/kg) for either all or selected patients (such as pregnant women), these lower doses may be most appropriate for settings in which the pathogen is highly susceptible. Since our use of aminoglycosides is generally reserved for patients with serious, invasive illness in whom decreased susceptibility is more likely, we favor the higher initial dose for most patients.

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 'Individualized monitoring' below). The latter is generally employed when extended-interval dosing is used in special populations. (See 'Dosing for special circumstances' below.)

For extended-interval dosing, the serum drug concentration is usually measured at a pre-specified interval after the first dose. First or second doses are used for individualized drug concentration monitoring. These are discussed in detail elsewhere. (See 'Nomogram-based monitoring' below and 'Individualized monitoring' 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 [28]. 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 [27].

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.

Individualized 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).

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. The initial dosing interval is based upon the estimated (or measured) creatinine clearance, as listed in the table (table 3). Subsequent drug concentration monitoring and dosing interval determination are similar to those for gentamicin and tobramycin (figure 1). 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 'Individualized 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 [29].

Plazomicin — 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 [30].

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.

While not included in the nomogram's original development, 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 [4] and urinary tract infections [5].

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 [31], 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 [32]. 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 "Intraamniotic infection (clinical chorioamnionitis or triple I)", section on 'Antibiotic therapy'.)

Peritoneal dialysis — Gentamicin and tobramycin are frequently used for empiric treatment of continuous ambulatory peritoneal dialysis (CAPD) related peritonitis. The intraperitoneal concentrations of gentamicin or tobramycin most commonly targeted are 4 to 8 mg/L of dialysate. Patients with systemic illness may receive an intravenous loading dose. Intraperitoneal administration of higher doses to treat systemic illnesses has been reported, but is not routinely recommended. (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) [33,34]. 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 [35].

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. 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.

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 [33].

Septic patients — Septic patients undergoing aggressive fluid resuscitation in the setting of resolving or evolving acute renal failure often warrant especially close monitoring. Some suggest individualized monitoring for such patients [36] (see 'Individualized 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).

Elderly patients — Since many elderly 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 the elderly 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.

Morbid obesity — The impact of morbid 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.

Synergy for gram-positive infections — Lower concentrations of aminoglycosides are targeted when used in combination with other agents to treat serious gram-positive infections, whether traditional or extended-interval dosing intervals are used. Traditional intermittent dosing of gentamicin for synergy is discussed above (see 'Traditional dosing and monitoring' above) and is generally employed in settings of invasive enterococcal infections (such as endocarditis) in the absence of high-level aminoglycoside resistance. Extended-interval dosing of gentamicin (3mg/kg/day as a single daily dose) is effective in the treatment of native-valve endocarditis due to penicillin-sensitive Streptococcus viridans [37]. (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'.)

SUMMARY AND RECOMMENDATIONS

Optimal dosing of aminoglycosides should lead to rapid attainment of therapeutic concentrations, which has been correlated with improved outcomes, while minimizing toxicity. The first steps in aminoglycoside administration include determination of the dosing weight and estimation of renal function. (See 'General principles' above.)

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 'Traditional versus extended-interval dosing' above.)

For most patients with suspected or documented moderate to severe infections due to gram-negative aerobic bacteria in whom an aminoglycoside is being used and who are expected to exhibit more predictable aminoglycoside pharmacokinetics, we suggest extended-interval rather than traditional intermittent dosing (Grade 2B). Certain patient groups may exhibit altered aminoglycoside pharmacokinetics that could render extended-interval dosing less useful or effective. (See 'Selection of dosing strategy' above.)

Specifically, we do not routinely use extended-interval dosing for the following patients:

Patients with burns (>20 percent total body surface area)

Patients with ascites

Pregnant women

Patients with creatinine clearance <40 mL/min (including patients requiring dialysis, although some institutions use a lower threshold) OR >120 mL/min

Traditional, intermittent dosing of gentamicin and tobramycin in adults 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.)

Extended-interval dosing of gentamicin and tobramycin in adults involves administration of a higher dose (we use 7 mg/kg) administered at an extended interval based upon the estimated (or measured) creatinine clearance (table 3). 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. (See 'Extended-interval dosing and monitoring' above.)

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. The initial dosing interval is based upon the estimated (or measured) creatinine clearance, as listed in the table (table 3). (See 'Amikacin' above.)

Specific or additional dosing adjustments are indicated in certain populations, including children, patients on dialysis, burn patients, the elderly, and those receiving aminoglycosides as synergistic therapy with beta-lactams for serious gram-positive infections. 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.)

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'.)

Discussion of aminoglycoside dosing in mycobacterial infections and for cystic fibrosis patients is discussed elsewhere.

REFERENCES

  1. Achaogen. Antimicrobial Drugs Advisory Committee Meeting Briefing Book: Plazomicin. May 2, 2018. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM606040.pdf (Accessed on July 18, 2018).
  2. Trissel LA. Handbook on Injectable Drugs, 14th Ed, American Society of Health-System Pharmacists, Bethesda 2007.
  3. Gault MH, Longerich LL, Harnett JD, Wesolowski C. Predicting glomerular function from adjusted serum creatinine. Nephron 1992; 62:249.
  4. Asempa TE, Kuti JL, Seroogy JD, et al. A Simulated Application of the Hartford Hospital Aminoglycoside Dosing Nomogram for Plazomicin Dosing Interval Selection in Patients With Serious Infections Caused by Carbapenem-Resistant Enterobacterales. Clin Ther 2019; 41:1453.
  5. Asempa TE, Kuti JL, Seroogy JD, et al. Application of the Hartford Hospital Nomogram for Plazomicin Dosing Interval Selection in Patients with Complicated Urinary Tract Infection. Antimicrob Agents Chemother 2019; 63.
  6. Hatala R, Dinh T, Cook DJ. Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis. Ann Intern Med 1996; 124:717.
  7. Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 1996; 312:338.
  8. Ferriols-Lisart R, Alós-Almiñana M. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health Syst Pharm 1996; 53:1141.
  9. Munckhof WJ, Grayson ML, Turnidge JD. A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses. J Antimicrob Chemother 1996; 37:645.
  10. Contopoulos-Ioannidis DG, Giotis ND, Baliatsa DV, Ioannidis JP. Extended-interval aminoglycoside administration for children: a meta-analysis. Pediatrics 2004; 114:e111.
  11. Rao SC, Ahmed M, Hagan R. One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates. Cochrane Database Syst Rev 2006; :CD005091.
  12. Smyth AR, Bhatt J. Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database Syst Rev 2012; :CD002009.
  13. French LM, Smaill FM. Antibiotic regimens for endometritis after delivery. Cochrane Database Syst Rev 2004; :CD001067.
  14. Mavros MN, Polyzos KA, Rafailidis PI, Falagas ME. Once versus multiple daily dosing of aminoglycosides for patients with febrile neutropenia: a systematic review and meta-analysis. J Antimicrob Chemother 2011; 66:251.
  15. Giuliano RA, Verpooten GA, De Broe ME. The effect of dosing strategy on kidney cortical accumulation of aminoglycosides in rats. Am J Kidney Dis 1986; 8:297.
  16. Giuliano RA, Verpooten GA, Verbist L, et al. In vivo uptake kinetics of aminoglycosides in the kidney cortex of rats. J Pharmacol Exp Ther 1986; 236:470.
  17. Rybak MJ, Abate BJ, Kang SL, et al. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother 1999; 43:1549.
  18. Smyth A, Tan KH, Hyman-Taylor P, et al. Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis--the TOPIC study: a randomised controlled trial. Lancet 2005; 365:573.
  19. Tang HJ, Lai CC. Plazomicin-associated Nephrotoxicity. Clin Infect Dis 2020; 71:1130.
  20. Mulheran M, Hyman-Taylor P, Tan KH, et al. Absence of cochleotoxicity measured by standard and high-frequency pure tone audiometry in a trial of once- versus three-times-daily tobramycin in cystic fibrosis patients. Antimicrob Agents Chemother 2006; 50:2293.
  21. Nicolau DP, Wu AH, Finocchiaro S, et al. Once-daily aminoglycoside dosing: impact on requests and costs for therapeutic drug monitoring. Ther Drug Monit 1996; 18:263.
  22. Gilbert DN, Lee BL, Dworkin RJ, et al. A randomized comparison of the safety and efficacy of once-daily gentamicin or thrice-daily gentamicin in combination with ticarcillin-clavulanate. Am J Med 1998; 105:182.
  23. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 2013; 70:195.
  24. Gentamicin (gentamicin sulfate). US FDA approved product information. National Library of Medicine. Available online at www.dailymed.nlm.nih.gov (Accessed on September 25, 2013).
  25. Tobramycin (tobramycin sulfate). US FDA approved product information. National Library of Medicine. Available online at www.dailymed.nlm.nih.gov (Accessed on September 25, 2013).
  26. Kashuba AD, Nafziger AN, Drusano GL, Bertino JS Jr. Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria. Antimicrob Agents Chemother 1999; 43:623.
  27. Nicolau DP, Freeman CD, Belliveau PP, et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995; 39:650.
  28. Karlowsky JA, Zhanel GG, Davidson RJ, Hoban DJ. Once-daily aminoglycoside dosing assessed by MIC reversion time with Pseudomonas aeruginosa. Antimicrob Agents Chemother 1994; 38:1165.
  29. Morris JT, Cooper RH. Intravenous streptomycin: a useful route of administration. Clin Infect Dis 1994; 19:1150.
  30. ZEMDRI (plazomicin). Package insert. Achaogen, Inc. June, 2018. https://www.zemdri.com/assets/pdf/Prescribing-Information.pdf (Accessed on July 18, 2018).
  31. Isemann BT, Kotagal UR, Mashni SM, et al. Optimal gentamicin therapy in preterm neonates includes loading doses and early monitoring. Ther Drug Monit 1996; 18:549.
  32. McDade EJ, Wagner JL, Moffett BS, Palazzi DL. Once-daily gentamicin dosing in pediatric patients without cystic fibrosis. Pharmacotherapy 2010; 30:248.
  33. Zaske DE. Aminoglycosides. In: Applied Pharmacokinetics, 3rd Ed, William EE, Schentag EJ, Jusko WJ (Eds), Applied Therapeutics Inc, Vancouver, WA 1994.
  34. Dager WE, King JH. Aminoglycosides in intermittent hemodialysis: pharmacokinetics with individual dosing. Ann Pharmacother 2006; 40:9.
  35. Roberts JA, Field J, Visser A, et al. Using population pharmacokinetics to determine gentamicin dosing during extended daily diafiltration in critically ill patients with acute kidney injury. Antimicrob Agents Chemother 2010; 54:3635.
  36. Buijk SE, Mouton JW, Gyssens IC, et al. Experience with a once-daily dosing program of aminoglycosides in critically ill patients. Intensive Care Med 2002; 28:936.
  37. Sexton DJ, Tenenbaum MJ, Wilson WR, et al. Ceftriaxone once daily for four weeks compared with ceftriaxone plus gentamicin once daily for two weeks for treatment of endocarditis due to penicillin-susceptible streptococci. Endocarditis Treatment Consortium Group. Clin Infect Dis 1998; 27:1470.
Topic 475 Version 26.0

References

1 : Achaogen. Antimicrobial Drugs Advisory Committee Meeting Briefing Book: Plazomicin. May 2, 2018. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM606040.pdf (Accessed on July 18, 2018).

2 : Trissel LA. Handbook on Injectable Drugs, 14th Ed, American Society of Health-System Pharmacists, Bethesda 2007.

3 : Predicting glomerular function from adjusted serum creatinine.

4 : A Simulated Application of the Hartford Hospital Aminoglycoside Dosing Nomogram for Plazomicin Dosing Interval Selection in Patients With Serious Infections Caused by Carbapenem-Resistant Enterobacterales.

5 : Application of the Hartford Hospital Nomogram for Plazomicin Dosing Interval Selection in Patients with Complicated Urinary Tract Infection.

6 : Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis.

7 : Single or multiple daily doses of aminoglycosides: a meta-analysis.

8 : Effectiveness and safety of once-daily aminoglycosides: a meta-analysis.

9 : A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses.

10 : Extended-interval aminoglycoside administration for children: a meta-analysis.

11 : One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates.

12 : Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis.

13 : Antibiotic regimens for endometritis after delivery.

14 : Once versus multiple daily dosing of aminoglycosides for patients with febrile neutropenia: a systematic review and meta-analysis.

15 : The effect of dosing strategy on kidney cortical accumulation of aminoglycosides in rats.

16 : In vivo uptake kinetics of aminoglycosides in the kidney cortex of rats.

17 : Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity.

18 : Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis--the TOPIC study: a randomised controlled trial.

19 : Plazomicin-associated Nephrotoxicity.

20 : Absence of cochleotoxicity measured by standard and high-frequency pure tone audiometry in a trial of once- versus three-times-daily tobramycin in cystic fibrosis patients.

21 : Once-daily aminoglycoside dosing: impact on requests and costs for therapeutic drug monitoring.

22 : A randomized comparison of the safety and efficacy of once-daily gentamicin or thrice-daily gentamicin in combination with ticarcillin-clavulanate.

23 : Clinical practice guidelines for antimicrobial prophylaxis in surgery.

24 : Clinical practice guidelines for antimicrobial prophylaxis in surgery.

25 : Clinical practice guidelines for antimicrobial prophylaxis in surgery.

26 : Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria.

27 : Experience with a once-daily aminoglycoside program administered to 2,184 adult patients.

28 : Once-daily aminoglycoside dosing assessed by MIC reversion time with Pseudomonas aeruginosa.

29 : Intravenous streptomycin: a useful route of administration.

30 : Intravenous streptomycin: a useful route of administration.

31 : Optimal gentamicin therapy in preterm neonates includes loading doses and early monitoring.

32 : Once-daily gentamicin dosing in pediatric patients without cystic fibrosis.

33 : Once-daily gentamicin dosing in pediatric patients without cystic fibrosis.

34 : Aminoglycosides in intermittent hemodialysis: pharmacokinetics with individual dosing.

35 : Using population pharmacokinetics to determine gentamicin dosing during extended daily diafiltration in critically ill patients with acute kidney injury.

36 : Experience with a once-daily dosing program of aminoglycosides in critically ill patients.

37 : Ceftriaxone once daily for four weeks compared with ceftriaxone plus gentamicin once daily for two weeks for treatment of endocarditis due to penicillin-susceptible streptococci. Endocarditis Treatment Consortium Group.