e1-07: Aminoglycosides

Aminoglycosides are a group of bactericidal medications sharing chemical, antimicrobial, pharmacologic, and toxic characteristics. At present, the group includes streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin, paromomycin, spectinomycin, and plazomicin. All these agents inhibit protein synthesis in bacteria by inhibiting the function of the 30S subunit of the bacterial ribosome. Resistance is based on (1) a deficiency of the ribosomal receptor (chromosomal mutant); (2) the enzymatic destruction of the medication (plasmid-mediated transmissible resistance of clinical importance) by acetylation, phosphorylation, or adenylylation; or (3) a lack of permeability to the medication molecule or failure of active transport across cell membranes. Resistance can be chromosomal (eg, streptococci are relatively impermeable to aminoglycosides) or plasmid-mediated (eg, in gram-negative enteric bacteria). Anaerobic bacteria are resistant to aminoglycosides because transport across the cell membrane is an oxygen-dependent energy-requiring process.

All aminoglycosides are potentially ototoxic (cochlear and vestibular) and nephrotoxic, although to different degrees. All can accumulate in kidney disease; therefore, dosage adjustments must be made in patients with kidney dysfunction.

Because of their considerable toxicity and the availability of less toxic agents (eg, cephalosporins, quinolones, carbapenems, beta-lactamase inhibitor combinations), aminoglycosides are used less often than in the past. They are most commonly used in combination with other agents to treat resistant gram-negative organisms or in low doses with beta-lactam medications or vancomycin for their synergistic effect against gram-positive bacterial infection (eg, enterococci, penicillin-resistant viridans streptococci, S aureus and S epidermidis prosthetic heart valve infections). Although aminoglycosides demonstrate in vitro activity against many gram-positive bacteria, they should never be used alone to treat infections caused by these organisms—both because there is minimal clinical experience with such infections and because less toxic alternatives are available. Aminoglycosides are inferior to beta-lactams as monotherapy in the treatment of Pseudomonas infections, particularly in febrile neutropenic patients.

Because of the similarities of the aminoglycosides, a summary of properties is presented briefly.

A. Absorption, Distribution, Metabolism, and Excretion

Aminoglycosides are not absorbed from the gastrointestinal tract. They diffuse poorly into the eye, prostate, bile, central nervous system, and spinal fluid after parenteral injection.

The serum half-life is 2–3 hours in patients with normal kidney function. Excretion is almost entirely by glomerular filtration. Aminoglycosides are removed effectively by hemodialysis or continuous hemofiltration.

B. Dosage and Effect of Impaired Kidney Function

In persons with normal kidney function who have gram-negative infections, the dosage of amikacin and plazomicin is 15 mg/kg/day in a single daily dose; that for gentamicin, tobramycin, or netilmicin is 5–7 mg/kg injected once daily. A single large daily dose of gentamicin, tobramycin, netilmicin, or amikacin is as efficacious as—and no more nephrotoxic than—the originally used dosing every 8–12 hours. When a single large daily dose is given, peak levels are not required. Trough aminoglycoside levels should be undetectable in patients with normal body composition and kidney function receiving once-daily dosing. Some clinicians recommend serum level sampling 12–18 hours after the dose and extending the interval to every 48–72 hours for patients with elevated serum levels. Others have suggested maintaining the dosage interval but decreasing the dose. Patients with kidney disease, volume overload, or obesity have altered antibiotic clearance or volume of distribution. In patients with abnormal kidney function or body composition, once-daily dosing is not recommended and aminoglycoside levels are recommended to guide dosing. In such patients, peak levels greater than 6 mcg/mL are the goal in the treatment of serious gram-negative infection, including pneumonia. When using more frequent dosing (ie, not once daily), troughs of greater than 2 mcg/mL have been associated with an increased incidence of nephrotoxicity. In patients with normal body composition, once-daily dosing regimens should be followed. Reduced gentamicin doses (1 mg/kg every 8 hours) are used synergistically with beta-lactams or vancomycin in the treatment of enterococcal endocarditis. However, synergistic gentamicin dosing of 3 mg/kg every 24 hours (as opposed to 1 mg/kg every 8 hours) is preferred in the treatment of endocarditis due to viridans streptococci. The combination of ampicillin with ceftriaxone offers a less toxic option in the treatment of enterococcal endocarditis.

C. Adverse Effects

All aminoglycosides can cause ototoxicity and nephrotoxicity. Compared with their nephrotoxicity, the ototoxicity is more likely to be irreversible and is cumulative, presenting as hearing loss (cochlear damage), noted first with high-frequency tones, or as vestibular damage, manifested by vertigo and ataxia. Amikacin is likely more cochlear-toxic than gentamicin, tobramycin, or netilmicin. Nephrotoxicity is usually reversible and occurs with similar frequency with gentamicin, tobramycin, amikacin, and netilmicin. The risk of nephrotoxicity exists even with synergistic lower doses in the treatment of serious gram-positive bacterial infection.

In very high doses, usually associated with irrigation of an inflamed peritoneum, aminoglycosides can be neurotoxic, producing a curare-like effect with reversible neuromuscular blockade that results in respiratory paralysis.

The usual dosage of streptomycin is 15–25 mg/kg/day (about 1 g/day) injected in one or two divided doses intramuscularly. If administered over 30–60 minutes, it can also be given intravenously. Streptomycin exhibits all the adverse effects typically associated with the aminoglycosides; however, it has greater vestibular toxicity and probably less nephrotoxicity when compared with gentamicin.

Gram-negative resistance emerges so rapidly and has become so widespread that only a few specific indications for this medication remain: (1) plague and tularemia; (2) endocarditis caused by E faecalis or viridans streptococci (use in conjunction with penicillin or vancomycin) in strains that are susceptible to high levels of streptomycin (ie, 2000 mcg/mL or less)—gentamicin may be substituted for streptomycin in this setting; (3) active tuberculosis when other less toxic medications cannot be used; and (4) acute brucellosis (in combination with tetracycline).

These aminoglycosides are closely related, with similar activity and complete cross-resistance. Systemic use has been abandoned because of ototoxicity and nephrotoxicity.

Neomycin, often combined with bacitracin and polymyxin, is a component of several over-the-counter topical ointments and creams. While the medication mixture covers the most likely encountered staphylococci, streptococci, and gram-negative bacteria, the efficacy of topical application is questionable. Neomycin or kanamycin can give rise to allergic reactions when applied topically to skin or eye.

Paromomycin, closely related to neomycin and kanamycin, is poorly absorbed after oral administration and has been used mainly to treat asymptomatic intestinal amebiasis and, in doses of 25–30 mg/kg/day in three divided doses for 7 days, to treat giardiasis in pregnancy. A dosage of 500 mg orally three or four times daily is marginally effective for cryptosporidiosis.

Amikacin is a semisynthetic derivative of kanamycin. It is relatively resistant to enzymes that inactivate gentamicin and tobramycin. Many gram-negative enteric bacteria, including many gentamicin-resistant strains of Proteus, Enterobacter, and Serratia organisms, are inhibited. After injection of 15 mg/kg/day of amikacin divided every 12 hours, peak levels in serum are 20–30 mcg/mL. Similar to gentamicin and tobramycin, 15 mg/kg/day administered every 24 hours is as effective as and no more toxic than every 12-hour dosing. In addition to therapy for serious gram-negative infections, amikacin is sometimes included with other medications for therapy of M avium complex and M fortuitum complex.

Like all aminoglycosides, amikacin is nephrotoxic and ototoxic (particularly for the auditory portion of the eighth nerve). Medication levels should be monitored in patients with chronic kidney disease.

With doses of 5–7 mg/kg/day of this aminoglycoside, serum levels are sufficient for bactericidal effect against most gram-negative organisms. Enterococci generally are resistant; however, the addition of gentamicin to cell wall active agents, such as penicillin or vancomycin, is associated with increased bactericidal activity against this pathogen. Gentamicin is used in serious infections caused by gram-negative bacteria. The usual dosage is 5–7 mg/kg/day intravenously administered once daily. In endocarditis due to viridans streptococci or E faecalis, gentamicin in lower synergistic doses (3 mg/kg/day) is combined with penicillin or ampicillin. A single daily dose of 3 mg/kg is just as effective as divided daily doses in the synergistic treatment of endocarditis due to viridans streptococci. The combination of ampicillin and ceftriaxone offers a less toxic option in the treatment of enterococcal endocarditis. In kidney disease, the dose should be adjusted as noted above.

Tobramycin closely resembles gentamicin in antibacterial activity, toxicity, and pharmacologic properties and exhibits partial cross-resistance. It is more active than gentamicin against P aeruginosa but much less active than gentamicin when used synergistically with penicillin for enterococcal endocarditis. Dosing is the same as for gentamicin. Tobramycin is also given by aerosol (300 mg twice daily) to patients with cystic fibrosis. This improves pulmonary function and decreases colonization with Pseudomonas without toxicity and with minimal selection for resistant strains.

Netilmicin shares many characteristics with gentamicin and tobramycin and can be given in a similar dosage. It may be less ototoxic and less nephrotoxic than the other aminoglycosides.

Plazomicin is a synthetic aminoglycoside antibiotic that retains activity against aminoglycoside-modifying enzymes that render other aminoglycosides ineffective. Plazomicin has good activity against Enterobacteriaceae, including CRE infections, and variable activity against Pseudomonas and Acinetobacter. Plazomicin is approved for the treatment of complicated urinary tract infections, including pyelonephritis, based on noninferiority to meropenem for the treatment of these infections in clinical studies. However, there is greater interest in the role of plazomicin for CRE infections. In a small randomized study, plazomicin in combination with meropenem or tigecycline resulted in lower rates of composite mortality or disease complications compared to treatment with colistin and meropenem or tigecycline for patients with CRE bloodstream infections.