Aminoglycosides

INTRODUCTION — The aminoglycoside class of antibiotics consists of many different agents. In the United States, gentamicin, tobramycin, amikacin, plazomicin, streptomycin, neomycin, and paromomycin are approved by the US Food and Drug Administration (FDA) and are available for clinical use. Of these, gentamicin, tobramycin, and amikacin are the most frequently prescribed by intramuscular or intravenous injection for systemic treatment.

The most common clinical application (either alone or as part of combination therapy) of the aminoglycosides is for the treatment of serious infections caused by aerobic gram-negative bacilli [1,2]. While less common, aminoglycosides (in combination with other agents) have also been used for the treatment of select gram-positive infections. In addition, certain aminoglycosides have demonstrated clinically relevant activity against protozoa (paromomycin), Neisseria gonorrhoeae (spectinomycin, not available in the United States), and mycobacterial infections (tobramycin, streptomycin, and [most commonly] amikacin).

This topic will review basic issues related to the clinical use of parenteral aminoglycosides, including mechanism of action, spectrum of activity, and adverse effects. Dosing and monitoring of aminoglycosides and administration in certain patient populations are discussed elsewhere. (See "Dosing and administration of parenteral aminoglycosides".)

The multiple clinical settings in which the aminoglycosides may be used are also discussed separately in the appropriate topic reviews. (See "Gram-negative bacillary bacteremia in adults", section on 'Indications and rationale for combination therapy' and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Intravenous antibiotics' and "Antimicrobial therapy of left-sided native valve endocarditis", section on 'Viridans streptococci and S. bovis/S. equinus complex'.)

MECHANISM OF ACTION — The aminoglycosides primarily act by binding to the aminoacyl site of 16S ribosomal RNA within the 30S ribosomal subunit, leading to misreading of the genetic code and inhibition of translocation [3,4]. The initial steps required for peptide synthesis, such as binding of mRNA and the association of the 50S ribosomal subunit, are uninterrupted, but elongation fails to occur due to disruption of the mechanisms for ensuring translational accuracy [4]. The ensuing antimicrobial activity is usually bactericidal against susceptible aerobic gram-negative bacilli.

Aminoglycosides initially penetrate the organism by disrupting the magnesium and calcium bridges between lipopolysaccharide moieties. They are transported across the cytoplasmic membrane in an energy-dependent manner. This step can be inhibited in vitro by divalent cations, increased osmolality, acidic pH, and an anaerobic environment [4].

The microbiologic activity of aminoglycosides is pH dependent. As a result, the antimicrobial effect may be reduced at the low pH found in lung and bronchial secretions. In an in vitro study, for example, the minimum inhibitory concentration (MIC) of aminoglycosides against five strains of Escherichia coli was increased almost five-fold at a pH <6.5 [5]. Activity may also be reduced in the presence of biofilms, such as those seen with mucoid-producing strains of Pseudomonas aeruginosa commonly isolated in cystic fibrosis patients. Studies have demonstrated reduced aminoglycoside (in particular amikacin) activity in conditions simulating epithelial lining fluid [6,7].

SPECTRUM OF ACTIVITY — In general, aminoglycosides are active across a broad spectrum of aerobic gram-negative and gram-positive organisms, including mycobacteria. Of note, anaerobic bacteria are intrinsically resistant to aminoglycosides.

Gram-negative organisms — Aminoglycosides exhibit potent in vitro activity against a wide range of aerobic gram-negative pathogens, including Enterobacteriaceae, Pseudomonas spp, Acinetobacter spp, and Haemophilus influenzae. However, in vitro activity against Burkholderia cepacia, Stenotrophomonas maltophilia, and anaerobic bacteria is usually poor or absent.

Differences may exist among the in vitro potencies of the various aminoglycosides. As an example, gentamicin usually demonstrates superior in vitro activity (one- to twofold dilutions) to tobramycin against Serratia spp, while tobramycin is usually more potent than gentamicin against P. aeruginosa [8]. Among the Enterobacteriaceae, plazomicin has the most potent activity in vitro, followed by amikacin and then gentamicin [9,10]. The magnitude of these differences can vary between different strains across different institutions. Plazomicin also retains activity against many Enterobacteriaceae resistant to other aminoglycosides. (See 'Gram-negative organisms' below.)

Gram-positive organisms — Aminoglycosides also demonstrate activity in vitro against gram-positive organisms, such as Staphylococcus aureus. However, most authorities believe these drugs are not adequate therapy as monotherapy for serious infections caused by S. aureus. Aminoglycoside activity against pneumococci is generally considered insufficient for clinical application against these organisms. Aminoglycosides are not active alone against streptococci and enterococci, although may have additive or synergistic effects against these pathogens when combined with other agents and in the absence of high-level resistance. (See 'Combination antibacterial therapy' below.)

Mycobacteria — Streptomycin, tobramycin, and amikacin demonstrate favorable activity in vitro against mycobacteria [11,12]. Specifically, streptomycin is particularly active against Mycobacterium tuberculosis, and amikacin is generally the most active aminoglycoside in vitro against Mycobacterium fortuitum, Mycobacterium abscessus, and Mycobacterium chelonae.

RESISTANCE — Compared with other classes of antibiotics, the aminoglycosides have demonstrated relative stability against the development of resistance during treatment. Both intrinsic and acquired mechanisms of resistance to aminoglycosides have been described.

While cross resistance between the specific aminoglycoside agents does occur, it may be incomplete. Therefore, individual agents should be tested for in vitro susceptibility against the isolated pathogen whenever possible.

Gram-negative organisms — Resistance of gram-negative organisms to aminoglycosides occurs by two major mechanisms [4]:

●Bacterial production of inactivating enzymes – The most common mechanism has been inactivation of the drug by phosphorylation (mediated by aminoglycoside kinases), adenylation, or acetylation (mediated by transferases) [4,13-15]. Inactivating enzymes can be encoded by plasmids or associated with transposable elements [4,16]. Plasmid exchange and dissemination of transposons facilitate the acquisition of drug resistance.

Another mechanism of inactivation is methylation of 16S ribosomal RNA. This effect is mediated by an enzyme encoded by the rmtA gene and has been associated with high-level resistance to all parenteral aminoglycosides in current use [16,17]. Binding to the aminoacyl site on 16S ribosomal RNA is the mechanism by which aminoglycosides normally interfere with protein synthesis [3,4].

●Decreased permeability and reduced intracellular accumulation of the drug — Aminoglycoside resistance independent of inactivating enzymes has been known for some time in P. aeruginosa [18]. This resistance is characterized by resistance to all aminoglycosides and may be due to either to an efflux system or decreased drug permeability that results in reduced levels of aminoglycoside accumulation [19].

Multidrug-resistant organisms resistant to other antimicrobials (such as those producing extended-spectrum beta-lactamases [ESBLs] or carbapenemases) are often also resistant to most aminoglycosides due to aminoglycoside-modifying enzymes [20]. In contrast, certain aminoglycoside agents may retain activity despite resistance to other drugs in the class, depending on the mechanisms of resistance. Plazomicin often retains activity against Klebsiella pneumoniae carbapenemase (KPC)- or ESBL-producing Enterobacteriaceae despite the presence of aminoglycoside-modifying enzymes that inactivate other aminoglycosides [21,22]. However, in vitro evidence suggests poor activity against multidrug-resistant gram-negative Pseudomonas or Acinetobacter spp [22]. Amikacin has also been effective in some institutions against selected organisms with high rates of in vitro microbial resistance to gentamicin and tobramycin. Rates of susceptibility to gentamicin and tobramycin have also been observed to improve after amikacin was introduced [23,24].

Enterococci — Enterococci are intrinsically resistant to aminoglycosides and can acquire resistance to high concentrations. However, the potential for synergy exists when enterococci are exposed to a combination of the aminoglycoside with a cell wall-active agent (such as penicillin or vancomycin) in the absence of high-level resistance (reported as “SYN-S”). (See 'Combination antibacterial therapy' below.)

The presence of high-level enterococcal resistance to aminoglycosides (MIC ≥500 mcg/mL of gentamicin or ≥2000 mcg/mL of streptomycin, reported as “SYN-R”) eliminates the synergism expected between an aminoglycoside and a cell wall active agent. Different genetic mutations are responsible for high-level resistance to different aminoglycosides. (See "Mechanisms of antibiotic resistance in enterococci", section on 'Aminoglycoside resistance'.)

A naturally occurring characteristic of Enterococcus faecium is moderate-level resistance to tobramycin (MICs 64 to 1000 mcg/mL) and resistance to synergism. This is due to the presence of an aminoglycoside modifying enzyme that modifies tobramycin but not gentamicin [25]. This enzyme also eliminates synergy between cell wall-active agents and tobramycin, kanamycin, and netilmicin. (See "Mechanisms of antibiotic resistance in enterococci".)

CLINICAL USE — Despite the relatively broad spectrum of activity of aminoglycosides, their widespread clinical use is limited because of the availability of alternative, less toxic agents with comparable efficacy and without the need for serum drug concentration monitoring. In the United States, there are differences in the Food and Drug Administration-approved indications among the different aminoglycosides.

Aminoglycosides remain important as a second agent in treatment of serious infections due to aerobic gram-negative bacilli and certain gram-positive organisms and as part of a multidrug regimen for certain mycobacterial infections. There are rare instances (especially outside the urinary tract) in which monotherapy with aminoglycosides is adequate treatment.

Combination antibacterial therapy — The most frequent clinical use of aminoglycosides (most commonly in combination with other antibacterial agents) is empiric therapy of serious infections, such as septicemia, nosocomial respiratory tract infections, complicated urinary tract infections, complicated intra-abdominal infections, and osteomyelitis caused by aerobic gram-negative bacilli. The intent of such therapy is to increase the chances that the pathogen is susceptible to at least one agent in the initial empiric combination. This strategy appears less relevant in settings where the incidence of antibiotic resistance is low (particularly given the risks of aminoglycoside-related adverse effects) or in patients at increased risk of aminoglycoside-induced toxicity [26,27].

Once an organism has been identified and its susceptibilities determined to alternate agents, aminoglycosides are usually discontinued in favor of less toxic antibiotics to complete a treatment course. Combination therapy against gram-negative organisms is discussed in detail elsewhere. (See "Gram-negative bacillary bacteremia in adults", section on 'Indications and rationale for combination therapy' and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Role of combination antimicrobial therapy'.)

Combination therapy with gentamicin is also used for the treatment of invasive enterococcal infections (such as endocarditis) not exhibiting high-level aminoglycoside resistance and (less often) 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 preferred use of other combination regimens. These uses are discussed in detail elsewhere. (See "Antimicrobial therapy of left-sided native valve endocarditis", section on 'Viridans streptococci and S. bovis/S. equinus complex' and "Antimicrobial therapy of left-sided native valve endocarditis", section on 'Enterococci' and "Treatment of enterococcal infections", section on 'Clinical approach' and "Antimicrobial therapy of left-sided native valve endocarditis", section on 'Streptococcal groups A, B, C, F, and G'.)

Aminoglycosides are also used for definitive combination treatment of severe, invasive infections due to organisms such as Brucella spp and Listeria monocytogenes. (See "Brucellosis: Treatment and prevention", section on 'Nonpregnant adults' and "Treatment and prevention of Listeria monocytogenes infection", section on 'Antibiotic therapy'.)

Prophylactic use of aminoglycosides (in combination with either clindamycin or vancomycin) is usually restricted to select surgical procedures involving the gastrointestinal tract, urinary tract, or female genital tract in patients with allergies that preclude beta-lactam use [28]. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures" and "Antibiotic prophylaxis for gastrointestinal endoscopic procedures".)

Antimycobacterial therapy — Select aminoglycosides are useful for the treatment of drug resistant tuberculosis and certain nontuberculous mycobacterial infections (in combination with other antimycobacterial agents). These indications are discussed in detail elsewhere. (See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum", section on 'Treatment' and "Treatment of Mycobacterium avium complex pulmonary infection in adults", section on 'Regimen selection' and "Antituberculous drugs: An overview", section on 'Injectable-only agents'.)

Monotherapy — There are few indications for monotherapy with systemic aminoglycosides:

●Tularemia – Streptomycin and gentamicin are first-line agents, although other options may be used in less severe cases. (See "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention", section on 'Treatment'.)

●Plague – Streptomycin and gentamicin are first-line agents, although other options may be used in patients who cannot tolerate aminoglycosides. (See "Clinical manifestations, diagnosis, and treatment of plague (Yersinia pestis infection)", section on 'Alternative options'.)

●Urinary tract infections due to multidrug-resistant (MDR) gram-negative organisms – Aminoglycosides can be an option for select patients with MDR gram-negative infections when the organism is susceptible in vitro and other antibiotics are either impractical or contraindicated. Aminoglycosides achieve high concentration in the urinary tract, and in some cases (particularly with plazomicin as well as amikacin), retain activity against some gram-negative organisms resistant to many other classes of antibiotics. (See "Carbapenem-resistant E. coli, K. pneumoniae, and other Enterobacterales (CRE)", section on 'Isolates susceptible to standard-spectrum antibiotics'.)

Given their lack of predictable activity against MDR gram-negative organisms, susceptibility should be confirmed. Furthermore, the appropriateness of aminoglycoside use for invasive infections caused by carbapenem-resistant Enterobacteriaceae (CRE) is questionable (even in the setting of susceptibility in vitro), given the difficulty attaining pharmacodynamics targets in such settings with standard and high-dose regimens [29].

●N. gonorrhoeae – Spectinomycin is an alternate therapy for non-pharyngeal gonococcal infections in patients who have severe penicillin allergy. However, it is not available in the United States. The combination of gentamicin and azithromycin is also an alternative therapy for selected gonococcal infections for those who cannot use other regimens. (See "Treatment of uncomplicated gonorrhea (Neisseria gonorrhoeae infection) in adults and adolescents", section on 'Alternate regimens'.)

Because of poor activity and/or penetration into lungs, abscesses, and the central nervous system, intravenous aminoglycosides should not be relied upon as monotherapy in infections that involve these sites.

Other aminoglycoside formulations — Paromomycin is an oral, poorly absorbed aminoglycoside that is mainly used as treatment for intraintestinal amebic infection. (See "Intestinal Entamoeba histolytica amebiasis", section on 'Symptomatic infection'.)

Aminoglycosides are also available in topical, inhaled, intraventricular, intraperitoneal, and impregnated cement formulations for specific indications. (See "Nosocomial infections in the intensive care unit: Epidemiology and prevention", section on 'Digestive and oropharyngeal decontamination' and "Prosthetic joint infection: Treatment", section on 'Resection arthroplasty with reimplantation' and "External otitis: Treatment", section on 'Antibiotics' and "Microbiology and therapy of peritonitis in peritoneal dialysis", section on 'Route of administration' and "Health care-associated meningitis and ventriculitis in adults: Treatment and prognosis", section on 'Intrathecal and intraventricular therapy'.)

DOSING AND MONITORING — The initial dose and frequency of aminoglycosides are based upon method of administration, indication, dosing weight, and renal function. Dosing adjustments should be based upon the results of serum drug concentration monitoring. Certain populations have significant variability in dosing requirements, including (but not limited to) neonates and patients with burns, critical illness, renal impairment, and cystic fibrosis [30,31]. Dosing and monitoring of parenteral aminoglycosides are discussed in detail elsewhere. (See "Dosing and administration of parenteral aminoglycosides".)

PHARMACODYNAMICS AND KINETICS — Certain pharmacodynamic and kinetic properties of the aminoglycoside are important for their clinical application. The postantibiotic effect (PAE) and concentration-dependent killing characteristics of aminoglycosides allow dosing at an extended interval for certain infections, and the synergistic effect with cell wall-active agents has led to the 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.

Post-antibiotic effect — 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 S. 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 [32]. 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) [33].

Concentration-dependent killing — Concentration-dependent killing refers to the ability of higher concentrations of aminoglycosides (relative to the organism's MIC) to induce more rapid, and complete, killing of the pathogen [34]. Aminoglycosides exhibit concentration-dependent microbiologic activity in both in vivo and in vitro models. 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 dosing methods, the consolidated dosing approach is more likely to achieve optimal peak concentrations that result in concentration-dependent killing [35]. (See "Dosing and administration of parenteral aminoglycosides".)

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 (eg, beta-lactam antibiotics) [36].

Absorption and time to peak concentrations — Peak serum aminoglycoside concentrations are observed 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 of gentamicin, tobramycin, and amikacin in adults ranges from 0.2 to 0.4 L/kg and is increased in patients with ascites, burns, pregnancy, critical illness, and other conditions (such as cystic fibrosis). For plazomicin, the volume of distribution was dependent on population, ranging from 13.3 to 18.5 L in healthy adult subjects to as much as 52.9 L in adult patients with bloodstream infections and hospital-acquired pneumonia [37].

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 percent 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 both hemodialysis (continuous and intermittent) and peritoneal dialysis. As a result, supplemental doses after hemodialysis are generally required. (See "Dosing and administration of parenteral aminoglycosides", section on 'Intermittent hemodialysis'.)

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

Nephrotoxicity — The reported incidence of nephrotoxicity varies widely due to variations in study design, toxicity definitions, patient population, and concomitant risk factors. A reasonable estimate (depending on definition) may be 10 to 20 percent, even when careful patient selection and close monitoring is performed. While rates reported for plazomicin are less than those reported with other aminoglycosides (approximately 3 percent), data are limited to patients primarily with complicated urinary tract infections [37].

In most cases, aminoglycoside nephrotoxicity is reversible.

Aminoglycoside-associated nephrotoxicity is discussed in greater detail elsewhere. (See "Manifestations of and risk factors for aminoglycoside nephrotoxicity" and "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity", section on 'Nephrotoxicity'.)

Ototoxicity — Aminoglycoside-induced ototoxicity may result in either vestibular or cochlear damage. Manifestations of vestibular toxicity include vertigo, disequilibrium, lightheadedness, nausea, vomiting, and ataxia, while the usual symptoms of cochlear toxicity are tinnitus and hearing loss. While ototoxicity can be transient in some cases, it can also be irreversible. In addition to serum drug concentration monitoring, coadministration of agents that may have a protective effect (such as N-acetylcysteine) is a possible preventive strategy in patients receiving long-term aminoglycoside therapy and/or with end-stage kidney disease [38]. (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity", section on 'Prevention of ototoxicity'.)

Aminoglycoside-associated ototoxicity is discussed in greater detail elsewhere. (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity", section on 'Ototoxicity'.)

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.

For patients with myasthenia gravis, we recommend avoiding aminoglycosides altogether, regardless of dosing method.

DRUG INTERACTIONS — The aminoglycosides can interact with a variety of other drugs causing increased toxicity and/or decreased efficacy. Specific interactions may be reviewed using the drug interactions program. This tool can be accessed from the UpToDate search page as well as on individual drug information topics in the section entitled "Drug interactions."

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. (See 'Mechanism of action' above.)

●Aminoglycosides exhibit potent in vitro activity against a wide range of aerobic gram-negative pathogens; Burkholderia cepacia and Stenotrophomonas maltophilia are particular exceptions. Gentamicin usually demonstrates superior in vitro activity to tobramycin against Serratia spp, while tobramycin is usually more potent than gentamicin against Pseudomonas aeruginosa. Plazomicin retains activity against many Enterobacteriaceae isolates resistant to other agents. Aminoglycosides (most notably amikacin and streptomycin) are also active against mycobacteria. (See 'Spectrum of activity' above.)

●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. Enterococci are intrinsically resistant to moderate levels of aminoglycosides. The potential for synergy in combination with a cell wall-active agent remains unless the enterococcus has acquired high-level resistance to aminoglycosides. (See 'Resistance' above.)

●Aminoglycosides are most frequently used in combination with another antibacterial agent for initial empiric therapy of septicemia, nosocomial respiratory tract infections, complicated urinary tract infections, complicated intra-abdominal 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. (See 'Clinical use' above.)

●Combination therapy with gentamicin is also used for the treatment of invasive infections caused by enterococci in the absence of high-level resistance. (See 'Clinical use' above.)

●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. (See 'Clinical use' above.)

●The initial dose and frequency of aminoglycosides depend on method of administration, indication, dosing weight, and renal function. Dosing adjustments should be based upon the results of serum drug concentration monitoring. Certain populations have significant variability in dosing requirements. Dosing and monitoring of parenteral aminoglycosides is discussed in detail elsewhere. (See "Dosing and administration of parenteral aminoglycosides".)

●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. (See 'Mechanism of action' above and 'Pharmacodynamics and kinetics' above.)

●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. (See 'Toxicity' above and "Manifestations of and risk factors for aminoglycoside nephrotoxicity" and "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity".)