Aminoglycosides

In general, the most common clinical application of the aminoglycosides either alone or as part of combination therapy is the treatment of serious infections caused by a broad spectrum of aerobic gram-negative bacilli (Drew, 2018). Less commonly, aminoglycosides in combination with other agents have also been used to treat select gram-positive organisms, as well as protozoa (paromomycin) and mycobacteria (tobramycin, streptomycin, and amikacin). Anaerobic bacteria are intrinsically resistant to aminoglycosides (Drew, 2018).

• 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. However, they may have additive or synergistic effects (i.e., antibiotic synergy occurs when multiple antibiotics are used to treat 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

The aminoglycosides have demonstrated relative stability against resistance development compared with other antibiotic classes (Drew, 2018). However, both intrinsic and acquired mechanisms of resistance to aminoglycosides have occurred.

Aminoglycoside resistance among gram-negative organisms can occur through acquiring or upregulation of genes that encode inactivating enzymes or efflux systems. The emergence of resistance in gram-negative bacilli during treatment with aminoglycosides rarely occurs.

Enterococci have intrinsic resistance to low and moderate 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.

Few indications for monotherapy with systemic aminoglycosides exist (Drew, 2018). 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. 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.

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
• 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 to treat 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 the 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 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

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

Improved patient outcomes have been correlated to the rapid attainment of therapeutic concentrations of aminoglycosides. The 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 are 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 on 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. In contrast, 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 determining 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 ideal (IBW). Obesity is defined as a TBW greater than 125% of the IBW. IBW can be estimated by various formulas (Table 2) (Drew, 2020).

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 considers 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. For example, in patients who develop acute renal failure, 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 serum creatinine concentration are reduced in severe liver disease, malnutrition, and significant loss of muscle mass, such as in quadriplegia, paraplegia, or amputees, possibly resulting in an overestimation of the creatinine clearance.

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.

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 with a creatinine clearance between this lower limit and 40 mL/min, the calculated aminoglycoside dose is administered at 48 hours instead of a 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 the dosing method.

Extended-interval dosing strategies have also been evaluated in patients with cystic fibrosis and synergistic therapy in patients with select serious gram-positive infections. However, typical doses used for these populations are considerably higher and lower than those used for other indications.

The 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 central nervous system setting 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 the dosing method that renders 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 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.

Parenteral aminoglycosides can be administered using a traditional intermittent dosing strategy that uses smaller doses given several times each day or an extended-interval dosing strategy that 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 refers to the persistent inhibitory effect against many gram-negative aerobic organisms seen after drug clearance.
• Concentration-dependent killing refers to the ability to escalate concentrations of aminoglycosides to induce more rapid killing of the pathogen.

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.

Individualization of the dosage is critical because of the low therapeutic index (Drew, 2020). In underweight and nonobese patients, the 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). The manufacturer recommends a maximum daily dose of 15 mg/kg/day (or 1.5 g/day in heavier patients) (Drew, 2020). 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 (Drew, 2020). 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)

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 with increased distribution volume (e.g., critically ill) (Drew, 2020). 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.

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 nonobese patients. Patients with TBW greater than ideal body weight (IBW) by ≥25%. See manufacturer's recommendations for dosing in obesity.

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 (Drew, 2020).

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

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

In underweight and nonobese patients, the 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 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).

Concentration-dependent killing refers to 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, predisposing to nephrotoxicity. Relative to traditional intermittent dosing methods, the consolidated dosing approach is more likely to achieve optimal peak concentrations that result in the concentration-dependent killing.

A synergistic effect has been demonstrated in vitro for selected organisms when aminoglycosides are combined with other antibiotics, most often with cell wall-active agents, e.g., beta-lactam antibiotics.

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 (Drew, 2020). 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.

Nephrotoxicity (Molitoris, 2019).

• A 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 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 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.