Aminoglycosides
- Usual intravenous (IV) adult dose for gram-negative infections: 5–7 mg/kg every 24 hours for gentamicin and tobramycin; 15 mg/kg for plazomicin; and 20–30 mg/kg every 24 hours for amikacin
- Usual dose for synergy against gram-positive infections: 3 mg/kg/day gentamicin every 8, 12, or 24 hours
- Dose reductions required in patients with chronic kidney disease and acute kidney injury (AKI) or dysfunction
- The plasma concentration–time curve to minimum inhibitory concentration (AUC/MIC) ratio is the pharmacokinetic/pharmacodynamic parameter most closely linked to bacterial killing and efficacy
- Therapeutic drug monitoring: not always necessary for brief administration (≤3 days); trough concentrations should be unmeasurable; typically, two serum concentrations in postdistribution phase (≥1 hour after administration, separated by ≥1.5 half-lives)
- Cerebrospinal fluid penetration: low
- Common adverse effects: AKI, ototoxicity
- Genotyping for the mitochondrial genome variant in MT-RNR1, m.1555A>G can help avoid use of aminoglycosides and prevent ototoxicity
- Drug-drug interactions: increased acute kidney risk with concomitant amphotericin B, cisplatin, cyclosporine, foscarnet, furosemide, IV radiocontrast agents, methoxyflurane, polymyxins, and vancomycin
- Indications: sepsis/septic shock; hospital-acquired/ventilator-associated pneumonia; complicated intraabdominal infections; urinary tract infections; neutropenic fever; acute exacerbation of pulmonary disease (cystic fibrosis patients only); bloodstream infections/IV catheter-related infections; infective endocarditis; multidrug-resistant tuberculosis; select nontuberculous mycobacterial infections; zoonotic infections (i.e., brucellosis, chronic forms of bartonellosis, tularemia, and yersiniosis); febrile neutropenia; surgical prophylaxis for patients undergoing genitourinary, gastrointestinal, or colorectal procedures; orthopedic surgery (antibiotic-impregnated cement); ocular infections (topical preparations); sexually transmitted infections; and select protozoal infections (e.g., amebiasis and cutaneous leishmaniasis)
Introduction and History
Aminoglycoside antibiotics have been used since the 1940s, when systematic screening of soil actinomycetes for the elaboration of antimicrobial substances yielded streptomycin. Produced by a species of Streptomyces (S. grisius), it was the first antibiotic in the aminoglycoside family (Table 1) to be derived, directly or indirectly, from Streptomyces spp. (aminoglycosides with names ending in -mycin) or from Micromonospora spp. (aminoglycosides with names ending in -micin). Neomycin, kanamycin, and gentamicin are fermentation products with two or three chemical constituents. Amikacin, netilmicin, and others are semisynthetic derivatives of the natural product. Plazomicin is a semisynthetic aminoglycoside derived from sisomicin (Wright, Berghuis, and Mobashery 1998). All aminoglycosides share similar physical, chemical, and pharmacologic properties. Four compounds—amikacin, gentamicin, tobramycin, and plazomicin—are currently approved by the US Food and Drug Administration (FDA) for the treatment of serious infections due to gram-negative or gram-positive bacteria (William A. Craig 2003; Edson and Terrell 1991).
Mechanism of Action
The advantages of the aminoglycoside class include rapid bactericidal activity, presence of a postantibiotic effect (PAE), synergy when combined with certain antibiotics, and well-defined pharmacokinetic (PK) profiles (Hancock 1981; Lortholary et al. 1995). As polycationic molecules, aminoglycosides bind to anionic compounds on the cell membrane, such as lipopolysaccharides (LPS), and displace outer membrane divalent cations, leading to increased permeability of the membrane and uptake of aminoglycosides (i.e., self-promoted uptake). Displacement of outer membrane divalent cations by aminoglycosides also compromises the integrity of the cell wall, and it is postulated that this contributes to the observed bactericidal action of aminoglycosides (Mingeot-Leclercq, Glupczynski, and Tulkens 1999; Krause et al. 2016).
After entering the cell, aminoglycosides bind to the 30S component of the prokaryotic ribosome (Fourmy et al. 1996). Affinity for the ribosomal target contributes to the rapid bactericidal action of aminoglycosides (Fourmy et al. 1996; Moore, Lietman, and Smith 1987). Aminoglycoside activity is pH-dependent and is inhibited in acidic environments (Hancock 1981). In vitro studies have shown that aminoglycosides have a prolonged PAE, during which bacterial growth is suppressed for a further 3 to 8 hours after drug concentrations fall below the minimum inhibitory concentration (MIC) (Hancock 1981; Zhanel, Hoban, and Harding 1991; Lortholary et al. 1995; Zhanel and Craig 1992).
Aminoglycosides are highly synergic with cell wall–active drugs (i.e., β-lactams or glycopeptides) in vitro. In preclinical pharmacokinetic/pharmacodynamic (PK/PD) infection models, concomitant use of an aminoglycoside with a β-lactam often enhances bacterial killing and prevents regrowth and resistance emergence to both the aminoglycoside and companion β-lactam (Bliziotis et al. 2005; Davis 1999).
PK/PD Parameters
The ratio of the maximum plasma drug concentration to the MIC (Cmax/MIC) ratio has long been considered the PK/PD driver for aminoglycosides, but more recent evidence suggest the area under the plasma concentration–time curve to MIC (AUC/MIC) ratio is the PK/PD parameter most closely linked to bacterial killing and efficacy (Deziel-Evans, Murphy, and Job 2006; Drusano 2007; Kashuba et al. 1999; Nicolau 2006; Ambrose et al. 2007; W. A. Craig 2003).
Spectrum of Activity
Aminoglycosides are active in vitro against both gram-positive and gram-negative pathogens, but they are primarily recommended for use in combination therapy for most infections (Moellering 1983; Gilbert 2009). Three legacy aminoglycosides—amikacin, gentamicin, and tobramycin—are broadly active against Staphylococcus spp. (primarily gentamicin) and gram-negative bacteria including Pseudomonas spp. (primarily amikacin and tobramycin), Citrobacter spp., Enterobacter spp., Escherichia coli, Klebsiella spp., Proteus spp., and Serratia spp. (William A. Craig 2003; Edson and Terrell 1991).
Plazomicin, a newly approved aminoglycoside, is highly active in vitro against Staphylococcus aureus, including methicillin-resistant (MRSA) strains, and most Enterobacterales, including carbapenem-resistant Enterobacterales (CRE) and strains resistant to ≥1 aminoglycosides (Edson and Terrell 1991; Castanheira et al. 2018; Clark and Burgess 2019). Some aminoglycosides have useful activity against mycobacteria, paromomycin has activity against selected colonic protozoan pathogens, and spectinomycin, a related antibiotic, has activity against Neisseria gonorrhoeae (Sharma and Mohan 2011; Sundar and Chakravarty 2007; Stamm 1983; White 2015).
Family of Aminoglycosides in Clinical Use
| Generic Name | Proprietary Name | Source | Year Reported | Chemistry |
|---|---|---|---|---|
| Streptomycin | None | Streptomyces griseus | 1944 | Unique central aminocyclitol ring |
| Neomycin | Mycifradin, Neobiotic | Streptomyces fradiae | 1949 | Roughly equal proportions of neomycin B and C |
| Kanamycin | Kantrex | Streptomyces kanamyceticus | 1957 | Mixture of 95% kanamycin A and 5% kanamycin B |
| Paromomycin | Humatin | S. fradiae | 1959 | Part of neomycin family |
| Spectinomycin | Trobicin | Streptomyces spectabilis | 1961 | Chemically distinct but closely related to aminoglycosides |
| Gentamicin | Garamycin | Micromonospora purpurea and Micromonospora echinospora | 1963 | Roughly equal proportions of gentamicin C1, C1a, and enantiomers C2 and C2a |
| Tobramycin | Nebcin | Streptomyces tenebrarius | 1967 | Natural 3′-deoxy derivative of kanamycin B |
| Sisomicina | Siseptin | Micromonospora inyoensis | 1970 | Dehydro analogue of gentamicin C1a |
| Dibekacina,b | — | S. kanamyceticus | 1971 | Dideoxy derivative of kanamycin B |
| Amikacinb | Amikin | S. kanamyceticus | 1972 | Semisynthetic derivative of kanamycin A |
| Netilmicinb | Netromycin | M. inyoensis | 1975 | N-Ethyl derivative of sisomicin |
| Isepamicina,b | — | M. purpurea | 1978 | 1-N-S-α-Hydroxy B amino propionyl derivative of gentamicin B |
| Plazomicin | Zemdri | M. inyoensis | 2018 | Semisynthetic derivative of sisomicin |
a Approved for human use in countries other than the United States. b Semisynthetic aminoglycosides.
Modified from Wright GD, Berghuis AM, Mobashery S. Aminoglycoside antibiotics: structures, functions, and resistance. In: Rosen BP, Mobashery S, eds. Resolving the Antibiotic Paradox: Progress in Understanding Drug Resistance and Development of New Antibiotics. New York: Plenum; 1998.
Adverse Effects
Although aminoglycosides are effective at bacterial cell killing and have a low potential for allergic reactions, their mechanism of action can also increase the potential for certain toxicities (Selimoglu 2007; Mingeot-Leclercq, Glupczynski, and Tulkens 1999; Wargo and Edwards 2006; Rybak et al. 2008).
Nephrotoxicity
The affinity of aminoglycosides for receptors on the proximal renal tubular epithelial cells can lead to acute kidney injury (AKI) (Lortholary et al. 1995).
Ototoxicity
Ototoxicity (cochlear and vestibular) and, rarely, neuromuscular blockade are potential aminoglycoside-related side effects (Fourmy et al. 1996; Moore, Lietman, and Smith 1987; Munckhof, Grayson, and Turnidge 1996).
Since the mid-1990s, clinicians have generally adopted weight-based, extended-interval short-course dosing strategies for aminoglycosides, which have been shown to reduce nephrotoxicity while maintaining efficacy and not increasing the occurrence of ototoxicity (Hancock 1981; Moore, Lietman, and Smith 1987; Ali and Goetz 1997; Rybak et al. 2008).
Genetic Risk for Ototoxicity
Point-of-care genotyping technology has recently been tested in neonates as a potential screening tool to avoid ototoxicity associated with a mitochondrial genome variant in MT-RNR1, m.1555A>G (Bitner-Glindzicz et al. 2009; Prezant et al. 1993).
Current Clinical Use
Amid concerns about toxicity (particularly irreversible vestibular injury), the use of aminoglycosides began to decline in the 1980s in favor of newer antibiotic classes such as fluoroquinolones, which were perceived to be less toxic (Fourmy et al. 1996). The 2021 National Safety Network Antimicrobial Use Option Report indicates that amikacin, tobramycin, and gentamicin account for 1% to 2% and 2% to 10% of adult and pediatric antibiotic prescriptions in the inpatient setting, respectively (National Healthcare Safety Network 2021).
However, the increasing prevalence of multidrug-resistant (MDR) gram-negative pathogens, including CRE, Pseudomonas aeruginosa, and Acinetobacter spp., and nontuberculous mycobacteria—for which therapeutic options are limited—has led to renewed interest in aminoglycosides for use as monotherapy or in combination with other antibacterials (Hancock 1981; Stamm 1983; Standiford et al. 1973; Rybak et al. 2008; Tamma et al. 2022).
Although most studies have failed to demonstrate improved outcomes in patients treated with antibiotic combinations with an aminoglycoside relative to monotherapy (Bliziotis et al. 2005; Paul et al. 2006), patients with septic shock receiving combinations including aminoglycosides in hospital settings where aminoglycoside resistance rates are low have had improved outcomes (Bowers, Lichtenberger, and Gentry 2010; Kumar et al. 2010; Paul et al. 2010).
Inhaled Aminoglycosides
Cystic Fibrosis
The Cochrane Library Review analyzed outcomes between inhaled aminoglycosides and placebo with regards to treatment-related adverse events of interest (i.e., auditory impairment, pneumothorax, and hemoptysis). However, tinnitus and voice alteration were significantly more common in individuals who received inhaled aminoglycosides (Langton Hewer and Smyth 2018).
No clinically meaningful differences in outcomes, resistance emergence, and safety were observed in studies that compared the long-term use of different inhalational formulations of aminoglycosides (i.e., tobramycin inhalation powder, tobramycin for inhalation solution [TOBI], inhaled tobramycin [intravenous preparation], and amikacin liposome inhalation suspension) in individuals with cystic fibrosis (Langton Hewer and Smyth 2018).
Hospital-Acquired/Ventilator-Associated Pneumonia
Aerosolized aminoglycosides have shown promise in chronic bronchiectatic infections but none are presently approved by the FDA for this indication (MacLean et al. 2011; Niederman et al. 2020; Kollef, Ricard, and Roux 2012; Palmer 2011). Aerosolized aminoglycosides also are regularly used in patients with VAP but none is approved for use for this indication. Despite the lack of FDA approval, the HAP/VAP expert guidelines recommend use of aerosolized aminoglycosides or colistin, in combination with systemic agents, for patients with HAP/VAP caused by gram-negative organisms only susceptible to aminoglycosides or polymyxins (Moellering 1983).
A meta-analysis presented in the IDSA/ATS guidelines identified a significant improvement in clinical cure rate with the addition of inhaled antibiotics for the treatment of MDR pathogens, though no differences in mortality were identified. In contrast, the IDSA Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections panel does not suggest the use of nebulized antibiotics for the treatment of respiratory infections caused by resistant gram-negative pathogens due to the lack of benefit observed in clinical trials, concerns regarding unequal distribution in infected lungs (Bassetti, Vena, and Russo 2019), and concerns for respiratory complications such as bronchoconstriction in patients receiving aerosolized antibiotics (Tamma et al. 2022; Burgess et al. 2022).
NTM Pulmonary Disease
There are mounting data with inhaled amikacin (parenteral formulation or liposome inhalation suspension) for multidrug regimen for NTM pulmonary disease. However, inhaled amikacin is currently not recommended for inclusion in the initial regimen at this time, and its use should be reserved to patients with MAC pulmonary disease who have failed therapy after at least 6 months of guideline-based therapy (Sharma and Mohan 2011).
Prophylaxis
Clinical practice guidelines for antimicrobial prophylaxis in surgery suggest gentamicin or tobramycin, 5 mg/kg IV, as an alternative in patients with β-lactam allergy undergoing genitourinary and gastrointestinal procedures (Bratzler et al. 2013). For patients undergoing cardiac or vascular surgeries or those with valvular heart disease, prophylaxis with an aminoglycoside is no longer recommended. For patients undergoing colorectal procedures, a mechanical bowel preparation combined with oral neomycin sulfate plus oral erythromycin base or with oral neomycin sulfate plus oral metronidazole is often used with IV prophylaxis (Bratzler et al. 2013).
The risk of infection after elective colorectal procedures was significantly reduced by mechanical cleansing of the bowel plus oral administration of neomycin and erythromycin or metronidazole in addition to standard intravenous antibiotic prophylaxis in controlled trials (Cannon et al. 2012; Morris et al. 2015).
A controlled trial demonstrated that an oral selective digestive decontamination containing gentamicin effectively eradicated carbapenem-resistant K. pneumoniae gastrointestinal carriage (Stoma, Karpov, et al. 2018) and may be used in nosocomial outbreaks (Tacconelli et al. 2019).
The safety and efficacy of topical gentamicin in cardiac surgery have not been clearly established (American Society of Health-System Pharmacists 2013). Multiple tunneled-catheter antibiotic lock studies including a prospective randomized trial (Drosu et al. 2013) have demonstrated reduced catheter-related infections, but emergence of resistant pathogens remains a concern (Drosu et al. 2014).
Aminoglycosides in Orthopedic Surgery
Antibiotic-impregnated cement is used with increasing frequency in primary hip and knee arthroplasties and revision procedures of infected total joint arthroplasties, for which the FDA has approved premixed aminoglycoside in bone cement products (McConoughey et al. 2014). Incorporation of larger amounts of antibiotic, usually gentamicin or tobramycin, allows release of higher drug concentrations but may adversely affect mechanical properties. Concentrations and properties vary among producers (Anagnostakos 2020; Buchholz and Engelbrecht 1984; Hendriks et al. 2004; Neut et al. 2001; Penner, Duncan, and Masri 1996).
Persistence of bacterial growth as adherent biofilms remains a potential problem (Lewis 2019; Anagnostakos 2020; Seldes et al. 2005), and AKI has been reported (Winkler, Janata, and Gattringer 2000; Curtis, Sternhagen, and Batts 2005). To date, one multicenter evaluation failed to show reduction in the risk of infection (Parvizi et al. 2008). Additionally, a review of 20 mostly uncontrolled reports of antibiotic-containing spacers did not allow evaluation of whether such adjunctive therapy provided additional benefits to systemic antibiotic therapy (Barth et al. 2010). Prospective trials in aminoglycoside-containing beads for established osteomyelitis and prosthetic joint–associated infections are needed (Gogia et al. 2009).
Other Clinical Uses
Aminoglycosides are commercially available as topical ophthalmic preparations (e.g., ointments or suspensions) and are frequently used, alone and in combination, to treat patients with ocular infections (Perez et al. 2015). Oral paromomycin has been employed as an alternative therapy for infection caused by Entamoeba histolytica and ulcerative Leishmania major (Gilles et al. 1971; Chunge et al. 1985; Alvar, Croft, and Olliaro 2006; El-On, Jacobs, and Weinrauch 1986).
Intravesicular gentamicin has been investigated, with anecdotal success, for recurrent UTIs in intermittently catheterized patients (Hachen 1983). Spectinomycin was an alternative agent used intramuscularly in the treatment of N. gonorrhoeae (Moran and Levine 1995), but it is no longer distributed in the United States. It was previously recommended for pregnant women, patients in areas with a high prevalence of fluoroquinolone resistance, and men who have sex with men. It showed 98% efficacy in uncomplicated urogenital and anogenital gonococcal infections but only 52% efficacy in gonococcal infections involving the pharynx, where it does not reach therapeutic concentrations (Moran 1995). Spectinomycin is also not effective in the treatment of infections with Treponema pallidum or Chlamydia trachomatis. Currently, spectinomycin is an alternative therapy for patients who are allergic to β-lactams and for patients who are infected with resistant strains of gonococci. Alternatively, gentamicin has been used to treat urogenital gonococcal infection (Centers for Disease Control and Prevention 2021).
Individualized Aminoglycoside Dosing
Aminoglycosides have traditionally been dosed on weight (mg/kg) and an estimate of the kidney function (eCrCL or eGFR) (Deziel-Evans, Murphy, and Job 2006). Suggested initial dosing regimens for typical aminoglycosides in clinical use are listed in Table 24.5. Higher initial doses of amikacin (20–30 mg/kg) have been suggested with further dose adjustment after therapeutic drug monitoring (TDM), but consensus is needed (Drusano et al. 2019). Given the age and generic status of this drug class, high-quality clinical studies are unfortunately unlikely to be performed to validate these doses apart from plazomicin, which is the most contemporary addition to the armamentarium (Pai 2019).
However, the lack of alternate therapeutic agents for MDR gram-negative pathogens has led individual institutions to adopt these higher doses (Roberts and Lipman 2014; Cotta, Roberts, and Lipman 2015).
Dosing in Obesity
One out of two adults in the United States will be obese by 2030, which impacts aminoglycoside dosing considerations (Finkelstein et al. 2012). Use of actual weight in obese patients can lead to overexposure (Bauer, Black, and Lill 2012). To prevent this, the most common approach is to use adjusted body weight, which is ideal body weight plus 40% of the difference between actual and ideal body weight in obese patients (Bauer, Black, and Lill 2012). The typical definition of obesity for this use of adjusted body weight is when actual weight exceeds ideal body weight by 25% to 30% or if the body mass index ≥30 kg/m2 (Pai and Bearden 2012).
More recent work indicates that lean body weight permits simplified aminoglycoside dosing across all weight strata, with clearance best predicted by the Chronic Kidney Disease Epidemiology Collaboration equation (Pai 2017; Inker et al. 2012; Smit et al. 2018). However, most institutions rely on the Cockcroft-Gault equation to estimate clearance and to decide whether once-daily dosing is justifiable (Deziel-Evans, Murphy, and Job 2006). Use of TDM after the first dose permits individualization of the aminoglycoside dose (Deziel-Evans, Murphy, and Job 2006).
Dosing in Renal Impairment
In resource-poor settings where TDM may be unavailable or delayed, an estimate of kidney function will be more informative than weight to define the daily dose (Pai and Bearden 2012). As noted, aminoglycoside clearance is a close surrogate of the measured glomerular filtration rate. Creatinine clearance overestimates GFR by 10% to 15% as it includes tubular secretion (an elimination process not applicable to aminoglycosides). In contrast, use of the most contemporary GFR equations based on serum creatinine (or cystatin C when available) can be translated to an estimate of aminoglycoside clearance (CL) (Inker et al. 2012).
An AUC target exposure multiplied by this CL estimate approximates the daily dose that is necessary in the individual patient (Pai and Bearden 2012). Although this bedside approach is a “best guess,” in the absence of resources to measure aminoglycoside concentrations, use of estimated kidney function is much better than body weight to estimate the daily dose.
Dosing in Dialysis
In patients with kidney failure who require kidney replacement therapies such as dialysis, the dosing of aminoglycosides will depend on the characteristics of the dialysis membrane, duration of dialysis, the patient’s blood pressure during dialysis, and other variables (Heintz, Matzke, and Dager 2009; Sowinski et al. 1993; Matzke, Lucarotti, and Shapiro 1984). Patients in sepsis who may be receiving continuous hemofiltration or dialysis the clearance of aminoglycosides is 80% to 90% of the effluent rate or equivalent to a CrCl of 10 to 50 mL/minute (Sowinski et al. 1993; Pinder, Bellomo, and Lipman 2002).
For patients on hemodialysis, a traditional dose is given every 48 to 72 hours, and on the day of hemodialysis an additional one-half of the full dose is given (if the traditional dose was administered before dialysis) after dialysis to replace drug that was removed by the dialysis or simply dosed after dialysis. Because of individual variability, serum levels should be measured (Ariano et al. 1997; Santre et al. 1995).
Administration of high doses of aminoglycosides may be necessary for less susceptible gram-negative bacteria but theoretically increases the risk of ototoxicity and nephrotoxicity in patients with residual renal function. Administration of the dose during dialysis can allow for administration of higher doses (5 mg/kg) and improve the exposure profile compared with the traditional approach of postdialysis dosing (Ariano et al. 1997; Teigen et al. 2006).
For patients undergoing continuous ambulatory peritoneal dialysis who have a systemic infection and are receiving an intravenous dose of aminoglycoside every 2 to 3 days, it is necessary to give small daily intravenous supplements to replace the drug lost in the dialysate or dosed based on serum concentrations. However, intermittent daily dosing (i.e., amikacin 2 mg/kg daily, gentamicin/netilmicin/tobramycin 0.6 mg/kg daily) of intraperitoneal aminoglycosides (1 exchange daily for at least 6 hours) is now favored over administration of intravenous administration as a measure to minimize toxicity and adaptive resistance while maintaining drug efficacy (Warady et al. 2012).
Therapeutic Drug Monitoring Approach
If therapy is expected to continue for ≥3 days and TDM is available, multiple possible approaches exist with varying levels of precision and complexity as ranked below (highest to lowest precision) that are resource dependent:
- Measurement of two concentrations and use of Bayesian software (software using two concentrations to gauge)
- Measurement of two concentrations and use of PK equations (linear, so calculate)
- Measurement of one concentration and use of Bayesian software
- Measurement of one concentration (random) and use of a dosing nomogram
- Measurement of two concentrations and interpretation using concentration thresholds (trough and peak)
- Measurement of one concentration (peak or trough) and interpretation using concentration thresholds
It is unclear whether every patient administered an aminoglycoside requires an individual PK evaluation (Bailey et al. 2013), but some patient populations may benefit more from TDM than others.
Trough concentrations should be unmeasurable (<1 mg/L for gentamicin/tobramycin; <5 mg/L for amikacin). When measuring two concentrations, they should be in the postdistribution phase (≥1 hour after administration) and separated by ≥1.5 half-lives for accurate parameter estimation.