Advance Practice Nurse Pharmacology Credit – Aminoglycosides
In this educational program we will concentrate specifically on the aminoglycoside class of antibiotics which consists of many different agents including amikacin sulfate, gentamicin sulfate, neomycin sulfate, paromomycin, streptomycin and tobramycin sulfate. Of these, gentamicin, tobramycin and amikacin are the most frequently prescribed.
After completing this educational program, the learner will be able to meet the following 15 objectives:
- Describe the mechanism of action and spectrum of activity of the aminoglycosides.
- Relate the development of resistance demonstrated by the aminoglycosides.
- Compare and contrast the clinical indications of aminoglycosides in terms of monotherapy, combination antibacterial therapy and antimycobacterial therapy.
- Describe the specific patient parameters which should be assessed prior to the administration of any aminoglycoside.
- Differentiate between the traditional intermittent and extended-interval dosing strategies used when prescribing parenteral aminoglycosides and the pros and cons underlying each dosing strategy.
- Describe the general principles underlying the administration of parenteral aminoglycosides and the roles dosing weight and creatinine clearance play in aminoglycoside dosing.
- Describe the follow-up evaluation of patients taking aminoglycosides.
Mechanism of Action
Aminoglycosides are rapidly bactericidal. They act primarily by binding to the aminoacyl site of 16S ribosomal RNA within the 30S ribosomal subunit, leading to misreading of the genetic code and inhibition of translocation. Cell death ensues. Uptake into bacterial cells is facilitated by cell wall inhibitors such as Vancomycin and beta-lactams (Penicillins, Cephalosporins, Cephamycins, Carbapenems, Monobactams and Beta-lactamase inhibitors).
Spectrum of Activity
In general, the most common clinical applications of the aminoglycosides either alone or as part of combination therapy is in the treatment of serious infections caused by a broad spectrum of aerobic gram-negative bacilli. Less commonly, aminoglycosides in combination with other agents have also been used for the treatment of select gram-positive organisms, as well as, protozoa (paromomycin) and mycobacteria (tobramycin, streptomycin and amikacin). Anaerobic bacteria are intrinsically resistant to aminoglycosides.
- Aerobic gram-negative organisms:
- Acinetobacter spp
- Haemophilus influenza
- Pseudomonas aeruginosa
- Pseudomonas spp
- Serratia spp
- Gram-positive organisms:
- Staphylococcus aureus
- Pneumococci – Aminoglycoside activity is generally considered insufficient for clinical application against these organisms.
- Streptococci and Enterococci – Aminoglycosides are not active alone against these pathogens, although they may have additive or synergistic effects (i.e., antibiotic synergy occurs when multiple antibiotics are used to treat an infection and their response is stronger or faster than what use of a single antibiotic would be) when combined with other agents and in the absence of high-level resistance to these pathogens.
- Mycobacterium abscessus
- Mycobacterium chelonae
- Mycobacterium fortuitum
- Mycobacterium tuberculosis
The aminoglycosides have demonstrated relative stability against the development of resistance compared with other classes of antibiotics. However, both intrinsic and acquired mechanisms of resistance to aminoglycosides have occurred.
Aminoglycoside resistance among gram-negative organisms can occur through acquisition or upregulation of genes that encode inactivating enzymes or efflux systems. Emergence of resistance in gram-negative bacilli during treatment with aminoglycosides rarely occurs.
Enterococci have intrinsic resistance to low and moderate levels of aminoglycosides and can acquire resistance to high levels.
Cross resistance between the specific aminoglycoside agents does occur but it is often incomplete. Individual agents should be tested for susceptibility against the isolated pathogen whenever possible.
Although aminoglycosides exhibit a relatively broad spectrum of activity, their widespread clinical use is generally limited. Less toxic agents with comparable efficacy and without the need for serum drug concentration monitoring are available. Aminoglycosides remain important as a second agent in the treatment of serious infections due to aerobic gram-negative bacilli and certain gram-positive organisms and as part of a multi-drug regimen for certain mycobacterial infections. There are rare instances especially outside the urinary tract in which monotherapy with aminoglycosides is adequate treatment.
Few indications for monotherapy with systemic aminoglycosides exist. These include:
- Streptomycin and gentamicin are first-line agents.
- Other options may be used in less severe cases.
- Streptomycin and gentamicin are first-line agents.
- Other options may be used in patients who cannot tolerate aminoglycosides.
- Urinary tract infections due to multidrug resistant gram-negative organisms:
- Aminoglycosides achieve high levels of concentration in the urinary tract and in some cases, especially with amikacin, retain activity against gram-negative organisms resistant to most other classes of antibiotics.
- Susceptibility should be confirmed as aminoglycoside resistance is not uncommon among such organisms.
Aminoglycosides should not be relied upon as monotherapy in infections that involve the lungs, abscesses and the central nervous system because of poor activity and/or penetration into these sites.
Combination Antibacterial Therapy
The most frequent clinical use of aminoglycosides most commonly in combination with other antibacterial agents is empiric therapy of serious infections, such as:
- Anaerobic infections involving Bacteroides fragilis
- Aerobic gram-negative bacillary meningitis not susceptible to other antibiotics
- Complicated pulmonary infections
- Complicated urinary tract infections
- Complicated intraabdominal infections
- Initial empirical therapy in febrile, leukopenic patients
- Invasive enterococcal infections (ex. endocarditis)
- Nosocomial respiratory tract infections
- Osteomyelitis caused by aerobic gram-negative bacilli
- Serious staphylococcal, Pseudomonas aeruginosa and Klebsiella infections
- Skin, soft tissue, bone and joint infections
- Tuberculosis caused by Mycobacteria
Aminoglycosides are usually discontinued in favor of less toxic antibiotics to complete the treatment course once an organism has been identified and its susceptibilities to other agents determined.
Combination therapy with gentamicin is frequently used for the treatment of invasive enterococcal infections not exhibiting high-level aminoglycoside resistance (such as endocarditis) and sometimes for serious infections due to certain streptococci. However, even in some of these cases as with enterococcal endocarditis the toxicity of prolonged aminoglycosides has led to the preferred use of other combination regimens.
Aminoglycosides are also used for definitive combination treatment of severe infections due to organisms such as Brucella spp and Listeria monocytogenes.
Prophylactic use of aminoglycosides in combination with either clindamycin or vancomycin is usually restricted to select surgical procedures involving the gastrointestinal, urinary tract or female genital tract in patients with beta-lactam allergies.
Aminoglycosides are useful for the treatment of drug resistant tuberculosis and certain nontuberculous mycobacterial infections in combination with other antimycobacterial agents.
Other Clinical Indications
Other clinical indications and routes of administration of aminoglycosides include:
- External otitis media – topical
- Chronic pulmonary infections in cystic fibrosis – inhaled
- Gram-negative bacillary meningitis – intrathecal and intraventricular
- Continuous or intermittent peritoneal dialysis-associated peritonitis – intraperitoneal
- Prosthetic joint infections – impregnated cement formulations
Specific patient parameters should be assessed prior to the administration of any aminoglycoside. These include the patients:
- Past Medical History
- Infectious Diagnosis (specific site if appropriate)
- Current Antibiotic Therapy, as well as, other current medications
- Concurrent Disease States/Diagnoses that may impact therapy
- (e.g., cachexia, diabetes mellitus, bilateral AKA, etc.)
- Height, Weight, Ideal body weight (IBW)
- Renal and Hepatic Function
- Clinical Signs and Symptoms (Temp, RR, HR etc.)
- Laboratory Tests: gram stains, culture and sensitivity results, CBC with differential, BUN, WBC, I/O (past 24 hours)
- Determination of optimal blood levels based on diagnosis.
Aminoglycosides and Routes of Administration
Amikacin sulfate, gentamicin sulfate, neomycin sulfate, paromomycin, streptomycin and tobramycin sulfate may be prescribed via various routes of administration depending on the underlying pathogen(s) (Table 1).
Parenteral aminoglycosides can be administered using the following two dosing strategies:
- The traditional intermittent dosing strategy 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.
- Extended-interval dosing strategy (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.
Improved patient outcomes have been correlated to the rapid attainment of therapeutic concentrations of aminoglycosides. Dosing of aminoglycosides 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 method of administration (i.e., traditional intermittent versus extended-interval daily dosing), the indication for usage, 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.
- Intravenous administration of aminoglycosides should occur over at least 30 minutes for the traditional intermittent dosing strategy and at least 60 minutes for the extended-interval dosing strategy.
The first step in aminoglycoside administration, regardless of dosing strategy, 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). Obesity is defined as a TBW greater than 125% of the IBW. IBW can be estimated by various formulas (Table 2).
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. This formula takes into account the increase in creatinine production with increasing weight and the decline in creatinine production with age.
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. 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 occurs in quadriplegia, paraplegia or amputees, possibly resulting in overestimation of the creatinine clearance.
Traditional Intermittent Versus Extended-Interval Dosing Strategies
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.
Extended-interval aminoglycoside dosing has efficacy comparable with traditional intermittent dosing but offers four potential advantages:
- Possibility of decreased nephrotoxicity based on data from animal models
- Ease of administration and reduced cost of serum concentration monitoring
- Reduced preparation and administration times
- Possibility of helping facilitate the transition from inpatient to outpatient care
Extended-interval dosing of aminoglycosides takes advantage of two pharmacodynamic properties:
- The post-antibiotic effect which refers to the persistent inhibitory effect against many gram-negative aerobic organisms that is seen after drug clearance.
- Concentration-dependent killing which refers to the ability of escalating concentrations of aminoglycosides to induce more rapid killing of the pathogen.
Multiple trials in various aged populations evaluating a wide spectrum of infections have demonstrated comparable efficacy of extended-interval dosing with traditional intermittent dosing aminoglycoside therapy.
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:
- Immunocompetent, nonpregnant adults and children older than 3 months of age with:
- Urinary tract infections
- Intraabdominal infections
- Respiratory tract infections
- Gynecologic infections (including pelvic inflammatory disease)
- Soft-tissue infections
- Women with postpartum endometritis
- Febrile, neutropenia patients with malignancy (adults and children)
Additionally, some institutions use extended-interval dosing in patients with lower creatinine clearances, with either 20 mL/min or 30 mL/min as the lower limit. In patients who have a creatinine clearance between this lower limit and 40 mL/min, the calculated aminoglycoside dose is administered at a 48 hour instead of 24 hour interval.
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.
Myasthenia gravis is an absolute contraindication to aminoglycoside use, regardless of dosing method used.
Extended-interval dosing strategies have also been evaluated in patients with cystic fibrosis and for synergistic therapy in 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.
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.
In the setting of central nervous system or ophthalmologic infections, there is 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 is little data among these groups, as these groups are generally not included in dosing trials. Thus, the use of extended-interval dosing is not recommended for:
- Patients with burns (greater than 20% total body surface area)
- Patients with ascites
- Pregnant women
- Patients with creatinine clearance less than 40 mL/min (including patients requiring dialysis) OR > 120 mL/min
However, there may be certain indications among such patients for which specific extended-interval dosing strategies have been studied and used. For example, some experts use extended-interval dosing in the treatment of chorioamnionitis.
Extended-interval aminoglycoside dosing represents a deviation from the U.S. 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, the use of extended-interval aminoglycoside dosing is compounded by the current “standard of practice” which suggests measuring and documenting serum concentrations within a defined therapeutic range. Peak serum concentrations will be considerably higher than those traditionally targeted by some laboratories and may trigger an alert.
Gentamicin And Tobramycin Dosing In Adults
Traditional intermittent dosing involves administration of a loading dose then a maintenance dose at a specific interval depending on renal function and subsequent monitoring of serum drug concentrations of gentamicin or tobramycin to guide dose adjustments. Below is a step-by-step method used for dosing gentamicin and tobramycin in adults.
- Determination of dosing weight and estimation of creatinine clearance, both of which are important for dose and dosing interval determination. Dosing for children, burn patients, patients on dialysis and other specific populations is discussed later under dosing for special circumstances.
- The initial loading dose (Table 3) is determined by type or site of infection for which different peak serum gentamicin or tobramycin concentrations are desired. 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 compared with uncomplicated urinary tract infections because of the lower serum gentamicin or tobramycin concentrations required to successfully treat uncomplicated urinary tract infections. In the setting of synergy for gram-positive infections, loading doses are not generally employed.
- For maintenance dosing (Table 4), a specific percentage of the loading dose is given at a specific dosing interval both of which depend on the creatinine clearance which is an estimate of glomerular filtration rate. In those patients in whom a loading dose was not given, the maintenance dose is still determined by the estimated loading dose. For adults with normal renal function who have serious but not life-threatening 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 serum gentamicin or tobramycin concentration monitoring.
**The loading dose is not adjusted for renal impairment.
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.
Serum concentrations should be determined when the patient has received therapy for three to five half-lives of the drug which is typically around two to three maintenance doses or after adjustment of the dose. Two or more serum 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 of 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 the interpretation of the results. Sample times should be documented on the laboratory requisition. Drug administration records should be checked to verify that doses have been administered as scheduled.
Desired peak concentrations for gentamicin and tobramycin are dependent upon the indication for usage and the site of infection.
The peak levels of gentamicin should be 3 to 4 mcg/mL when the drug is being given for synergy such as in the treatment of gram-positive infections. Target peak concentrations for gentamicin and tobramycin in the treatment of serious, invasive infections are 6 to 8 mcg/mL. For patients with gram-negative pneumonia or who are critically ill due to a life-threatening gram-negative infection, peak concentrations of 7 to 9 mcg/mL should be targeted. Higher peak serum concentrations up to 12 mcg/mL, depending on susceptibility of the organism have been targeted in patients with cystic fibrosis.
Trough concentrations for gentamicin and tobramycin should be below 2 mcg/mL. Many pharmacists will target a trough concentration of less than 1 mcg/mL when estimating dose and frequency to avoid excessive trough concentrations in settings where population kinetic parameters are less predictable.
In general, changes in the dose will result in proportional changes in both peak and trough concentration values. For example, a 25% dosage increase will result in a 25% 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. 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 of Gentamicin and Tobramycin in Adults
Administration of a higher dose of gentamicin or tobramycin at an extended-interval is dependent on renal function and subsequent monitoring of serum gentamicin or tobramycin concentrations. Calculation of dosing weight and creatinine clearance, both of which are important for dose and dosing interval determination, need to be frequently monitored.
Initial Dose and Dosing Interval
A loading dose is not needed in the setting of extended-interval gentamicin or tobramycin administration (Table 5).
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 intermittent dosing. Concentrations can be targeted either by using a published nomogram that extrapolates the desired dosing interval based on a single drug concentration or by analysis of two or more serum concentrations checked during the dosing cycle. The latter is generally employed when extended-interval dosing is used in special populations.
For either dosing method, indications to repeat the measurement of drug concentrations are changing renal function and duration of therapy beyond 7 to 10 days.
Regardless of the method used to determine patient dosing needs, sampling times must be documented by the phlebotomist for accurate interpretation of results. Requests for laboratory determinations of serum levels should include a provision to indicate that extended-interval dosing is being used. Since serum levels obtained, especially the peak levels, 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.
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 minimum inhibitory concentration (MIC) of the pathogen. Trough serum concentrations should be less than 1 mcg/mL which are most often undetectable because of the long dosing interval. The estimated drug-free interval (i.e., concentration = 0) is less than 8 hours.
Application of the published nomogram requires that a single serum concentration be obtained 6 to 14 hours after the first dose. Results from this measurement are then used to determine the necessary dosing interval.
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.
An alternative to the use of the nomogram is to obtain a peak serum aminoglycoside concentration 60 minutes post-infusion and a second level 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 (e.g., 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.
Gentamicin and Tobramycin General Guidelines for Renal Impaired Patients
- Dosing interval may be extended (e.g., every 48 hours) in patients with moderate renal impairment (CrCl 30 to 59 mL/minute) and/or adjusted based on serum level determinations.
Intermittent Hemodialysis (IHD):
- Administer after hemodialysis on dialysis days since both gentamicin and tobramycin are dialyzed off. The amount of drug dialyzed off (~50% for gentamycin; 25% to 70% for tobramycin) is variable depending on the type of filter used, duration of IHD and the type of IHD.
- Administer a loading dose of 2 to 3 mg/kg followed by:
- Mild UTI or synergy: IV 1 mg/kg every 48 – 72 hours. Consider redosing for pre-IHD or post-IHD concentrations < 1 mg/L.
- Moderate-to-severe UTI: IV 1 to 1.5 mg/kg every 48 – 72 hours. Consider redosing for pre-IHD concentrations < 1.5 to 2 mg/L or post-IHD concentrations < 1 mg/L.
- Systemic gram-negative rod infection: IV 1.5 to 2 mg/kg every 48 – 72 hours. Consider redosing for pre-IHD concentrations < 3 to 5 mg/L or post-IHD concentrations < 2 mg/L.
- Dosing dependent on the assumption of 3 times/week, complete IHD sessions.
Peritoneal Dialysis (PD):
- Administration via PD fluid:
- Gram-positive infection (e.g., synergy): 3 to 4 mg/L (3 to 4 mcg/mL) of PD fluid.
- Gram-negative infection: 4 to 8 mg/L (4 to 8 mcg/mL) of PD fluid.
- Administration via IV or IM route during PD: Dose as for CrCl < 10 mL/minute and follow serum levels.
Continuous Renal Replacement Therapy (CRRT):
- Drug clearance is highly dependent on the method of renal replacement, filter type and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as, drug concentrations in relation to target trough (if appropriate). The following are general recommendations only based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function and should not supersede clinical judgment:
- Loading dose of 2 to 3 mg/kg followed by:
- Mild UTI or synergy: IV 1 mg/kg every 24 – 36 hours. Redose when concentration < 1 mg/L.
- Moderate-to-severe UTI: IV 1 to 1.5 mg/kg every 24 – 36 hours. Redose when concentration < 1.5 to 2 mg/L.
- Systemic gram-negative infection: IV 1.5 to 2.5 mg/kg every 24 – 48 hours. Redose when concentration < 3 to 5 mg/L.
Gentamicin and tobramycin may also be administered IM into a large muscle mass (Table 6).
Amikacin Dosing In Adults
Target serum concentration for traditional intermittent 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 up to 40 to 50 mcg/mL are generally achieved with extended-interval dosing.
For patients receiving traditional intermittent 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 – 12 hours for patients with normal renal function (Table 7). Similar to gentamicin and tobramycin, adjustments in the frequency of administration should be made for reductions in renal function.
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 (Table 8). Subsequent drug concentration monitoring and dosing interval determination are similar to those for gentamicin and tobramycin.
Amikacin may also be administered IM into a large muscle mass (Table 9).
Amikacin General Guidelines for Renal Impaired Patients
For patients with renal impairment here are some general guidelines for amikacin administration:
Intermittent Hemodialysis (IHD):
- Administer amikacin after hemodialysis on dialysis days since amikacin is dialyzed off. The amount of amikacin dialyzed off is variable depending on the type of filter used, duration of IHD and the type of IHD.
- Recommended dose: 5 to 7.5 mg/kg every 48 – 72 hours. Monitor serum amikacin levels.
- May need to redose when pre-IHD concentration < 10 mg/L and redose when post-IHD concentration < 6 – 8 mg/L.
- Dosing dependent on the assumption of 3 times/week, complete IHD sessions.
Peritoneal Dialysis (PD):
- Dose as CrCl < 20 mL/minute. Monitor serum amikacin levels.
Continuous Renal Replacement Therapy (CRRT):
- Drug clearance is highly dependent on the method of renal replacement, filter type and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as, drug concentrations in relation to target trough (if appropriate). The following are general recommendations only based on dialysate flow/ultrafiltration rates of 1 – 2 L/hour and minimal residual renal function and should not supersede clinical judgment:
- CVVH/CVVHD/CVVHDF: Loading dose of 10 mg/kg followed by maintenance dose of 7.5 mg/kg every 24 – 48 hours.
- For severe gram-negative rod infections, target peak concentration of 15 to 30 mg/L and redose when concentration < 10 mg/L.
Streptomycin Dosing In Adults
The dosing of streptomycin is based on the indications for its use which include:
- Tuberculosis (second-line antituberculosis therapy)
- Native valve endocarditis (antimicrobial therapy)
- Nontuberculous mycobacterial infections of the lung in HIV-negative patients
- Plague (Yersinia pestis infection)
Streptomycin General Guidelines for Renal Impaired Patients
For patients with renal impairment here are some general guidelines for streptomycin administration:
End-Stage Renal Disease (ESRD):
- Intermittent Hemodialysis (IHD):
- One-half the recommended dose administered after hemodialysis on dialysis days.
- Dosing dependent on the assumption of 3 times weekly complete IHD sessions.
- Peritoneal Dialysis (PD):
- Administration via PD fluid: 20 to 40 mg/L (20 to 40 mcg/mL) of PD fluid.
- Continuous Renal Replacement Therapy (CRRT):
- Administer every 24 to 72 hours.
- Monitor serum streptomycin levels.
- Drug clearance is highly dependent on the method of renal replacement, filter type and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as, drug concentrations in relation to target trough (if appropriate).
Dosing For Special Circumstances
Dose adjustments need to be made in a variety of special populations. These include:
- Neonates and children: Not discussed in this article.
- 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.
- Intermittent Hemodialysis: Intermittent hemodialysis can decrease pre-dialysis concentrations by 50%. 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. 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 (e.g., flow rate and membrane type). Assessment of post-dialysis concentrations should allow for redistribution of the 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.
- 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 traditional 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.
- 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 gentamicin and tobramycin concentrations. Serum concentration monitoring and individualized dosing correlates with survival in this patient population.
- 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. 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% over baseline requires careful evaluation of urine output and urinalysis for evidence of drug-induced nephrotoxicity.
- 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 intermittent or extended-interval dosing intervals are used. Traditional intermittent dosing of gentamicin for synergy 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 (3 mg/kg/day as a single daily dose) is effective in the treatment of native-valve endocarditis due to penicillin-sensitive Streptococcus viridans.
Pharmacodynamics and Kinetics
Certain pharmacodynamic and kinetic properties of the aminoglycosides are important for their clinical application.
- The post antibiotic effect (PAE) and concentration-dependent killing characteristics of aminoglycosides allow for efficacy when dosed at an extended-interval for certain infections and the synergistic effect with cell wall-active agents has led to the frequent use of aminoglycosides in combination with these agents for serious infections. Limitations in the distribution of aminoglycosides restrict their use for infections at certain anatomical sites such as the cerebral spinal fluid, biliary tree and bronchial secretions.
- The post antibiotic effect (PAE) refers to the persistent suppression of bacterial growth that occurs after the drug has been removed in vitro or cleared by drug metabolism and excretion in vivo. Initially described for gram-negative bacilli, aminoglycosides also exhibit PAE against Staphylococcus aureus but not against other gram-positive cocci. The duration of the PAE (approximately 3 hours [range 1 to 7.5 hours]) depends upon the method of evaluation and the organism studied. In general, the PAE is longer for gram-negative organisms than gram-positive organisms. The duration of the PAE is reduced in the absence of polymorphonuclear leukocytes (PMNs).
Concentration-dependent killing refers to the ability of higher concentrations of aminoglycosides to induce more rapid and complete killing of the pathogen. Achieving optimal peak concentrations of aminoglycosides with standard dosing regimens can be difficult since efforts must be made to avoid sustained elevated trough concentrations which can predispose to nephrotoxicity. Relative to traditional intermittent dosing methods, the consolidated dosing approach is more likely to achieve optimal peak concentrations that result in concentration-dependent killing.
A synergistic effect has been demonstrated in vitro for selected organisms when aminoglycosides are used in combination with other antibiotics, most often with cell wall-active agents e.g., beta-lactam antibiotics.
Absorption and Time to Peak Levels
Peak serum aminoglycoside concentrations are measured approximately 30 to 60 minutes after termination of an intravenous infusion or 30 to 90 minutes after an intramuscular injection. The aminoglycosides are not absorbed after oral administration. However, local instillation into the pleural space or peritoneal cavity can result in significant serum concentrations.
The volume of distribution in adults ranges from 0.2 to 0.4 L/kg and is increased in patients with ascites, burns, pregnancy and other conditions such as cystic fibrosis. Aminoglycosides reach concentrations in the urine 25 to 100 fold that of serum. In contrast, they show poor penetration into the CSF, biliary tree and bronchial secretions.
Approximately 99% of the administered dose is eliminated unchanged in the urine primarily by glomerular filtration. The terminal half-life ranges from 1.5 to 3.5 hours in adults with normal renal function. The half-life is prolonged in neonates, infants and patients with decreased renal function.
Aminoglycosides are effectively removed by hemodialysis both continuous and intermittent and peritoneal dialysis. As a result, supplemental doses after hemodialysis are generally required.
The primary toxicities of aminoglycosides are nephrotoxicity and ototoxicity. Rarely, neuromuscular blockade can occur.
- Reasonable estimate of occurrence may be 10 to 20%.
- In most cases, aminoglycoside toxicity is reversible.
- Risk factors for nephrotoxicity include:
- Renal insufficiency
- Elevated trough concentrations
- Total daily dose
- Cumulative dose
- Concurrent nephrotoxic drugs
- Prior aminoglycoside exposure
- Duration of treatment
- The process of nephrotoxicity (uptake by cells) is saturable and the number of insults determines toxicity. It is imperative to minimize the number of insults and allow the tubular cells a relatively drug free period in which to regenerate cells.
- Serum creatinine and BUN determinations 2 – 3 times/week should monitor renal toxicity. More frequent determinations are advised for patients with changing renal function. Creatinine clearance, I/O’s, urinalysis, when available, will help to identify patients with possible 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. 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.
- Aminoglycoside-induced ototoxicity may result in either vestibular or cochlear damage. Symptoms of vestibular toxicity include vertigo, disequilibrium, lightheadedness, nausea, vomiting and ataxia. The usual symptoms of cochlear toxicity are tinnitus and hearing loss. In many cases, ototoxicity is irreversible.
- 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.
- If prolonged courses of aminoglycosides are anticipated, baseline and periodic assessment of hearing with audiometry are recommended.
- Neuromuscular blockade is a rare but serious adverse effect induced by aminoglycoside therapy. Most patients experiencing such reactions have disease states and/or concomitant drug therapy that interfere with neuromuscular transmission.
- Neuromuscular toxicity is most likely seen in patients with preexisting neuromuscular disease or patients with hypocalcemia.
- Myasthenia gravis is an absolute contraindication to aminoglycoside use.
The aminoglycosides can interact with a variety of other drugs causing increased toxicity and/or decreased efficacy. Prior to the administration of any aminoglycoside be sure to check with a pharmacist to prevent any potential drug reactions.
The following questions should be posed when evaluating the effectiveness of aminoglycosides:
- Is the drug working?
- Is the patient experiencing any adverse effects from the drug?
- Is the treatment failing?
- Indications of treatment failure include:
- Increasing temperature
- Increasing WBC
- Worsening symptoms
- Worsening vital signs
- Is the treatment failing?
- Are other causes of acute renal failure occurring?
- In hospitalized patients, other causes of acute renal failure may include:
- Severe or prolonged hypotension causing decreased renal perfusion
- Other nephrotoxic drugs: amphotericin, cisplatin, etc.
- Acute cardiovascular dysfunction
- In hospitalized patients, other causes of acute renal failure may include:
- Is the patient responding to treatment?
- Indications of treatment response may include:
- Reversal of initial signs and symptoms
- Decrease in the patient’s temperature
- Negative culture results
- Return to baseline of patient’s heart rate and respiratory rate
- Decrease in WBC
- Normalization of blood gases
- Indications of treatment response may include:
- Is the current regimen appropriate?
- Is the patient’s renal function stable?
- Are current serum levels (peak and trough) appropriate?
- Is the drug still required?
Aminoglycosides bind to the aminoacyl site of 16S ribosomal RNA and disrupt bacterial peptide elongation which is usually bactericidal against susceptible aerobic gram-negative bacilli. Microbiologic activity is pH-dependent and acidic environments like those found in the lung and bronchial secretions may decrease the antimicrobial effect.
Emergence of aminoglycoside resistance during treatment of gram-negative infections is infrequent but can occur through bacterial production of enzymes that inactivate the drug or methylate the target 16S ribosomal RNA and through an efflux system that decreases aminoglycoside accumulation.
Aminoglycosides are most frequently used in combination with another antibacterial agent for empiric therapy of septicemia, nosocomial respiratory tract infections, complicated urinary tract infections, complicated intraabdominal infections and osteomyelitis caused by aerobic gram-negative bacilli. They are often discontinued in favor of less toxic antibiotics once organism identity and susceptibility has been confirmed.
Combination therapy with gentamicin is frequently used for the treatment of invasive infections caused by enterococci in the absence of high-level resistance.
Parenteral aminoglycosides are also used as part of a regimen for mycobacterial infections and, as a single agent, for the treatment of tularemia, plague and uncomplicated urinary tract infections caused by drug-resistant gram-negative organisms.
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.
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 time 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.
For most patients with suspected or documented moderate to severe infections due to gram-negative aerobic bacteria in whom an aminoglycoside is being administered and who are expected to exhibit more predictable aminoglycoside pharmacokinetics, extended-interval rather than traditional intermittent dosing is preferred. Certain patient groups may exhibit altered aminoglycoside pharmacokinetics that could render extended-interval dosing less useful or effective.
Traditional intermittent dosing of gentamicin and tobramycin in adults involves administration of a loading dose based on indication, administration of a maintenance dose at a specific interval several times daily depending on renal function and subsequent monitoring of serum concentrations to guide dose adjustments.
Extended-interval dosing of gentamicin and tobramycin in adults involves administration of a higher dose administered at an extended interval based upon the estimated or measured creatinine clearance. 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 or through individualized monitoring with the assistance of a pharmacist.
Target serum concentrations 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 intermittent 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.
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.
For serious infections due to typical gram-negative bacteria, with the exception of uncomplicated lower urinary tract infections, aminoglycosides are generally used in combination with other agents that have gram-negative activity regardless of dosing method.
Aminoglycosides demonstrate both post-antibiotic effect and concentration-dependent killing. Aminoglycosides reach concentrations in the urine 25 to 100 fold that of serum but have poor penetration into the CSF, biliary tree and bronchial secretions. They are effectively removed by both hemodialysis and peritoneal dialysis.
The primary toxicities of aminoglycosides are nephrotoxicity which is generally reversible and ototoxicity, both vestibular and cochlear. Neuromuscular blockade is a rare but serious adverse effect and myasthenia gravis is an absolute contraindication to aminoglycoside use.