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Aminoglycosides

1.5 Contact Hours including 1.5 Advanced Pharmacology Hours
This peer reviewed course is applicable for the following professions:
Advanced Registered Nurse Practitioner (ARNP), Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Midwife (MW), Nursing Student, Registered Nurse (RN)
This course will be updated or discontinued on or before Monday, July 25, 2022
Outcomes

≥ 90% of participants know basic pharmacology of aminoglycosides.

Objectives

After completing this educational program, the learner will be able to:

  1. Describe the mechanism of action and spectrum of activity of the aminoglycosides.
  2. Compare and contrast the clinical indications of aminoglycosides in terms of monotherapy, combination antibacterial therapy and antimycobacterial therapy.
  3. Describe the specific patient parameters which should be assessed prior to the administration of any aminoglycoside.
  4. Differentiate between the traditional intermittent and extended-interval dosing strategies used when prescribing parenteral aminoglycosides and the pros and cons underlying each dosing strategy.
  5. Describe the general principles underlying the administration of parenteral aminoglycosides and the roles dosing weight and creatinine clearance play in aminoglycoside dosing.
  6. Describe the follow-up evaluation of patients taking aminoglycosides.
CEUFast Inc. did not endorse any product, or receive any commercial support or sponsorship for this course. The Planning Committee and Authors do not have any conflict of interest.

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Author:    Pamela Downey (MSN, ARNP)

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 the 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).1

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.1 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.1

  • Aerobic gram-negative organisms:
    • Acinetobacter spp
    • Enterobacteriaceae
    • 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
  • Mycobacteria:
    • Mycobacterium abscessus
    • Mycobacterium chelonae
    • Mycobacterium fortuitum
    • Mycobacterium tuberculosis

Resistance

The aminoglycosides have demonstrated relative stability against the development of resistance compared with other classes of antibiotics.1 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.

Clinical Indications

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.1 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.

Monotherapy

Few indications for monotherapy with systemic aminoglycosides exist.1 These include:

  • Tularemia:
    • Streptomycin and gentamicin are first-line agents
    • Other options may be used in less severe cases
  • Plague:
    • 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, or the central nervous system because of poor activity 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 as1:

  • 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
  • Septicemia
  • 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.

Antimycobacterial Therapy

Aminoglycosides are useful for the treatment of drug resistant tuberculosis and certain nontuberculous mycobacterial infections in combination with other antimycobacterial agents.

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

Clinical Management

Specific patient parameters should be assessed prior to the administration of any aminoglycoside. These include the patients1:

  • Age
  • Sex
  • Past Medical History
  • Infectious Diagnosis (specific site if appropriate)
  • Allergies
  • 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

Routes of Administration

Aminoglycocides may be prescribed via various routes of administration depending on the underlying pathogen(s) (Table 1).

TABLE 1
Generic NameRoute Of Administration
Amikacin SulfateIM
IV infusion
Intrathecal/Intraventricular
Gentamycin SulfateOphthalmic Ointment/Solution
Topical Cream/Ointment
IM
IV infusion
Intrathecal
Via peritoneal dialysis fluid
Continuous renal replacement therapy
Neomycin SulfatePO Tablets/Solution
Topical Cream/Ointment
Ear Drops
Continuous irrigation of urinary bladder via indwelling catheter
Peritoneal installation
Do NOT use as surgical irrigation
Do NOT administer parenterally
ParomomycinPO capsule

Plazomicin

IV infusion

Streptomycin

IM

NOT recommended IV

Tobramycin Sulfate

Capsules for inhalation using Podhaler device

Nebulizer solution for inhalation

Ophthalmic Ointment/Solution
Intrathecal
Via peritoneal dialysis fluid
Continuous renal replacement therapy
IM
IV infusion

General Principles

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.

Dosing Weight

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).2

Table 2
Calculation of Dosing Weight2
(1) Calculate IBW = _____kg
    IBW (male) = 50 kg + 2.3 kg for each inch over 60"
    IBW (female) = 45.5 kg + 2.3 kg for each inch over 60"
    If average weight, use IBW. 
(2) Calculate Total Body Weight (TBW)
    TBW = ____kg

    For underweight patients, use TBW to calculate dose.

     For obese patients whose weight is 1 to 1.25 times their IBW, calculate the dosing weight, 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. 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.

Efficacy

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
    • Bacteremia
  • 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.

Traditional Intermittent 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 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

Precautions

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.

Drug Specific Dosing

Aminoglycoside dosing for pediatrics, renal disease, and indicator specific conditions are drug specific. Refer to the manufacturer’s recommendations for guidance on these dosing situations.

Amikacin Dosing in Adults

Individualization of the dosage is critical because of the low therapeutic index.2 In underweight and nonobese patients, use of total body weight (TBW) instead of ideal body weight for determining the initial mg/kg/dose is widely accepted. Ideal body weight (IBW) also may be used to determine doses for patients who are neither underweight nor obese.

Initial and periodic peak and trough plasma drug levels should be determined, particularly in critically ill patients with serious infections or in disease states known to significantly alter aminoglycoside pharmacokinetics (e.g., cystic fibrosis, burns, or major surgery). Manufacturer recommends a maximum daily dose of 15 mg/kg/day (or 1.5 g/day in heavier patients).2 Higher doses may be warranted based on therapeutic drug monitoring or susceptibility information.

Usual dosage range: IM, IV: 5 to 7.5 mg/kg/dose every 8 hours.2 Some clinicians suggest a daily dose of 15 to 20 mg/kg/day for all patients with normal renal function. This dose is at least as efficacious with similar, if not less, toxicity than conventional dosing.

See manufacturer recommendations for indication specific dosing for the following conditions:

  • Cerebrospinal fluid (CSF) shunt infection (susceptible gram-negative organisms)
  • Intraventricular/intrathecal (adjunct to systemic therapy; use a preservative-free preparation)
  • Cystic fibrosis exacerbation (off-label use/route)
  • Meningitis, bacterial (susceptible gram-negative organisms)
  • Mycobacterium avium complex (MAC) (off-label use)
  • Mycobacterium fortuitum, M. chelonae, or M. abscessus
  • Pneumonia, hospital-acquired (HAP) or ventilator-associated (VAP) (alternative therapy) (off-label dose)

Gentamicin Dosing in Adults

For underweight patients (i.e., total body weight [TBW] < ideal body weight [IBW]), calculate the dose based on TBW. For nonobese patients (i.e., TBW 1 to 1.25 × IBW), calculate the dose based on TBW or IBW. TBW may be preferred in nonobese patients who may have increased volume of distribution (e.g., critically ill).2 For obese patients (i.e., TBW >1.25 × IBW), calculate the dose based on 40% adjusted body weight (IBW + [0.4 × (TBW-IBW)]).

Therapeutic drug monitoring: Monitoring of serum concentrations is recommended to ensure efficacy and avoid toxicity, particularly in critically ill patients with serious infections or in disease states known to significantly alter aminoglycoside pharmacokinetics (e.g., cystic fibrosis, burns, major surgery). Timing and frequency of concentration monitoring is individualized based on dosing and monitoring strategy.

Usual Dosage Range

Gram-negative infections: Conventional/traditional dosing: IV, IM: 3 to 5 mg/kg/day in divided doses every 8 hours. Some experts favor an initial loading dose of 2.5 to 3 mg/kg.2

Target peak concentration depends on indication and site of infection; in general, adjust dose to achieve peak of 4 to 6 mcg/mL for urinary tract infections and 7 to 10 mcg/mL for serious infections (including life-threatening infections).2 Target trough concentrations should be <2 mcg/mL; ideal target <1 mcg/mL.

High-dose extended-interval dosing (once-daily dosing)2: IV: 5 to 7 mg/kg once daily; method is generally not recommended in patients with ascites, burns covering >20% of the total body surface area, end-stage renal disease (e.g., requiring hemodialysis), or pregnancy (except for intrapartum therapy for intra-amniotic infection) due to altered pharmacokinetics. Use with caution in patients with CrCl <40 mL/minute. Adjust gentamicin dose and interval to achieve an extrapolated peak concentration of ~15 to 20 mcg/mL and trough concentration ≤1 mcg/mL; ideal target <0.5 mcg/mL.

Synergy dosing for non-CNS gram-positive infections2: IV, IM: 3 mg/kg/day in 1 to 3 divided doses in combination with a gram-positive active agent. When divided doses are used, adjust gentamicin dose to achieve peak concentration of 3 to 4 mcg/mL and trough concentration <1 mcg/mL.

See manufacturer recommendations for indication specific dosing for the following conditions:

  • Bartonella spp. infections (off-label use)
  • Cat scratch disease, disseminated (e.g., hepatosplenic, prolonged systemic febrile illness) (alternative agent)
  • Bloodstream infection
  • Antibiotic lock technique (catheter-salvage strategy) (off-label use)
  • Intracatheter
  • Brucellosis (alternative agent) (off-label use)
  • CNS infection, health care-associated (e.g., cerebrospinal fluid [CSF] shunt infection) (adjunct to systemic therapy)
  • Intraventricular (use a preservative-free preparation)
  • Endocarditis, treatment
  • Enterococcus spp.(native or prosthetic valve, without high-level gentamicin resistance)
  • Staphylococcus spp.(prosthetic valve) (off-label use)
  • Viridans group streptococci and Streptococcus bovis (off-label use)
  • Native valve
  • Native valve Relatively penicillin-resistant (MIC >0.12 and <0.5 mcg/mL
  • Native valve Penicillin-resistant (MIC ≥0.5 mcg/mL)
  • Prosthetic valve: Highly penicillin-susceptible (MIC ≤0.12 mcg/mL)
  • Prosthetic valve: Relatively penicillin-resistant (MIC >0.12 and <0.5 mcg/mL) or fully penicillin-resistant (MIC ≥0.5 mcg/mL)
  • Meningitis, bacterial
  • Enterococcus spp
  • Listeria monocytogenes
  • Pelvic infections (off-label use)
  • Intra-amniotic infection (chorioamnionitis)
  • Postpartum endometritis
  • Sepsis or septic shock, adjunctive empiric gram-negative coverage (e.g., in the setting of intra-abdominal infection, pneumonia, gram-negative bacteremia, or severe burn)
  • Sexually transmitted infections
  • Pelvic inflammatory disease (including tubo-ovarian abscess) (off-label use)
  • Surgical prophylaxis (alternative agent for select GI tract, GU tract, or gynecologic/obstetric procedures) (off-label use)
  • Tularemia (off-label use)
  • Urinary tract infection, complicated (pyelonephritis or cystitis symptoms with signs/symptoms of systemic infection) (alternative agent)

Neomycin Dosing in Adults

Surgical (perioperative) prophylaxis: Oral: 1 g at 1 PM, 2 PM, and 11 PM on the day preceding 8 AM surgery as an adjunct to mechanical cleansing of the intestine in combination with oral erythromycin (manufacturer’s labeling) or in combination with erythromycin or metronidazole, and IV antibiotics on the day of surgery.

Hepatic encephalopathy: Oral: 4 to 12 g daily divided every 4 to 6 hours for 5 to 6 days.

Chronic hepatic insufficiency: Oral: 4 g daily for an indefinite period.

See manufacturer recommendations for indication specific dosing for the following conditions:

  • Hepatic coma
  • Intestinal amebiasis
  • Cryptosporidiosis-associated diarrhea in HIV-infected patients (off-label use)
  • Dientamoeba fragilis (off-label use)

Paromomycin Dosing in Adults

Hepatic coma: Oral: 4 g daily in divided doses (at regular intervals) for 5 to 6 days.

Intestinal amebiasis: Oral: 25 to 35 mg/kg/day in 3 divided doses for 5 to 10 days.

Cryptosporidiosis-associated diarrhea in HIV-infected patients (off-label use): Oral: 500 mg 4 times daily for 14 to 21 days (must be used in conjunction with optimized ART, electrolyte replacement, and symptomatic treatment and rehydration).

Dientamoeba fragilis (off-label use): Oral: 25 to 35 mg/kg/day in 3 divided doses for 7 days.

Urinary tract infection (UTI), complicated: IV2: 15 mg/kg once daily for 4 to 7 days; may follow with appropriate oral therapy to complete a total of 7 to 10 days of therapy (IV plus oral). Note: Use total body weight (TBW) to calculate dose in non-obese patients. For patients with TBW greater than ideal body weight (IBW) by ≥25%. See manufacturers recommendations for dosing in obesity.

Streptomycin Dosing in Adults

Manufacturer’s labeling states for IM administration only, however, IV administration (off-label route) has been described. Usual dosage range: IM: 15 to 30 mg/kg/day or 1 to 2 g daily.2

See manufacturer recommendations for indication specific dosing for the following conditions:

  • Brucellosis
  • Endocarditis
    • Enterococcal
    • Streptococcal
  • Mycobacterium avium complex (MAC) (off-label use)
  • Mycobacterium avium complex (MAC) disease, disseminated in HIV-infected patients (off-label use)
  • Mycobacterium kansasii disease (rifampin-resistant) (off-label use)
  • Mycobacterium ulcerans (Buruli ulcers) (off-label use)
  • Plague
  • Tuberculosis
  • Tularemia

Tobramycin Dosing in Adults

Individualization of the dose is critical because of the narrow therapeutic index.

In underweight and nonobese patients, use of total body weight (TBW) instead of ideal body weight for determining the initial mg/kg/dose is widely accepted.7 Ideal body weight (IBW) also may be used to determine doses for patients who are neither underweight nor obese.

Initial and periodic plasma drug levels (e.g., peak and trough with conventional dosing, post dose level at a prespecified time with extended-interval dosing) should be determined, particularly in critically-ill patients with serious infections or in disease states known to significantly alter aminoglycoside pharmacokinetics (e.g., cystic fibrosis, burns, or major surgery).

Severe Life-threatening Infections

Conventional2: 1 to 2.5 mg/kg/dose every 8 to 12 hours; to ensure adequate peak concentrations early in therapy, higher initial dosage may be considered in selected patients when extracellular water is increased (edema, septic shock, postsurgical, and/or trauma).

Once-daily2: 4 to 7 mg/kg/dose once daily; some clinicians recommend this approach for all patients with normal renal function; this dose is at least as efficacious with similar, if not less, toxicity than conventional dosing.

See manufacturer recommendations for indication specific dosing for the following conditions:

  • Brucellosis
  • Cerebrospinal fluid (CSF) shunt infection (adjunct to systemic therapy
  • Cholangitis
  • Diverticulitis, complicated
  • Meningitis, bacterial due to Pseudomonas aeruginosa
  • Pelvic inflammatory disease
  • Plague (Yersinia pestis)
  • Pneumonia, hospital-acquired or ventilator-associated
  • Prophylaxis against endocarditis (dental, oral, upper respiratory procedures, GI/GU procedures)
  • Tularemia
  • Urinary tract infection, complicated (including pyelonephritis) (alternative agent)

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

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.

Synergistic Effect

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.

Distribution

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.

Elimination

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.

Toxicity

The primary toxicities of aminoglycosides are nephrotoxicity and ototoxicity. Rarely, neuromuscular blockade can occur. 

Nephrotoxicity

Nephrotoxicity3:

  • Reasonable estimate of occurrence may be 10 to 20%
  • In most cases, aminoglycoside toxicity is reversible
  • Risk factors for nephrotoxicity include:
    • Age
    • 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.

Ototoxicity3

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

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.

Drug Interactions

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.

Follow-up Evaluation

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
  • 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
    • Surgery
    • Other nephrotoxic drugs: amphotericin, cisplatin, etc
    • Acute cardiovascular dysfunction
  • 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
  • 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?

Summary

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 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.

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References

  1. Drew R (2018) Aminoglycosides. Updated June 11, 2020. Accessed May 24, 2020. Visit Source.
  2. Drew R. (2020) Dosing and administration of parenteral aminoglycosides. Updated January 02, 2020. Accessed May 24, 2020. Visit Source.
  3. Molitoris B. Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicy. Updated August 19, 2019. Accessed May 24, 2020. Visit Source.