Aminoglycosides


Figure 72.1 Mechanism of action of aminoglycosides. A, Protein synthesis begins with binding of the 50S and 30S ribosomal subunits to messenger RNA (mRNA), followed by attachment of the first amino acid of the new protein to the 50S subunit. As the ribosome moves down the mRNA strand, additional amino acids are added to the growing peptide chain. When the new protein is complete, it separates from the ribosome, and the ribosomal subunits separate from the mRNA. B, Aminoglycosides bind to the 30S ribosomal subunit and can (1) block initiation, (2) terminate synthesis before the new protein is complete, and (3) cause misreading of the genetic code, which causes synthesis of faulty proteins. 


The aminoglycosides are bactericidal. Cell kill is concentration dependent. Hence the higher the concentration, the more rapidly the infection will clear. Of note, bactericidal activity persists for several hours after serum levels have dropped below the minimal bactericidal concentration, a phenomenon known as the postantibiotic effect.


Bacterial kill appears to result from production of abnormal proteins rather than from simple inhibition of protein synthesis. Studies suggest that abnormal proteins become inserted in the bacterial cell membrane, causing it to leak. The resultant loss of cell contents causes death. Inhibition of protein synthesis per se does not seem the likely cause of bacterial death because complete blockade of protein synthesis by other antibiotics (e.g., tetracyclines, chloramphenicol) is usually bacteriostatic—not bactericidal.




Microbial Resistance


The principal cause for bacterial resistance is production of enzymes that can inactivate aminoglycosides. Among gram-negative bacteria, the genetic information needed to synthesize these enzymes is acquired through transfer of R factors. To date, more than 20 different aminoglycoside-inactivating enzymes have been identified. Because each of the aminoglycosides can be modified by more than one of these enzymes, and because each enzyme can act on more than one aminoglycoside, patterns of bacterial resistance can be complex.


Of all the aminoglycosides, amikacin is least susceptible to inactivation by bacterial enzymes. As a result, resistance to amikacin is uncommon. To minimize emergence of resistant bacteria, amikacin should be reserved for infections that are unresponsive to other aminoglycosides.



Antimicrobial Spectrum


Bactericidal effects of the aminoglycosides are limited almost exclusively to aerobic gram-negative bacilli. Sensitive organisms include Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Proteus mirabilis, and Pseudomonas aeruginosa. Aminoglycosides are inactive against most gram-positive bacteria.


Aminoglycosides cannot kill anaerobes. To produce antibacterial effects, aminoglycosides must be transported across the bacterial cell membrane, a process that is oxygen dependent. Because, by definition, anaerobic organisms live in the absence of oxygen, these microbes cannot take up aminoglycosides and hence are resistant. For the same reason, aminoglycosides are inactive against facultative bacteria when these organisms are living under anaerobic conditions.



Therapeutic Use


Parenteral Therapy


The principal use for parenteral aminoglycosides is treatment of serious infections due to aerobic gram-negative bacilli. Primary target organisms are P. aeruginosa and the Enterobacteriaceae (e.g., E. coli, Klebsiella and Serratia species, P. mirabilis).


One aminoglycoside—gentamicin—is now commonly used in combination with either vancomycin or a beta-lactam antibiotic to treat serious infections with certain gram-positive cocci, specifically Enterococcus species, some streptococci, and Staphylococcus aureus.


The aminoglycosides used most commonly for parenteral therapy are gentamicin, tobramycin, and amikacin. Selection among the three depends in large part on patterns of resistance in a given community or hospital. In settings where resistance to aminoglycosides is uncommon, either gentamicin or tobramycin is usually preferred. Of the two, gentamicin is less expensive and may be selected on this basis. Organisms resistant to both gentamicin and tobramycin are usually sensitive to amikacin. Accordingly, in settings where resistance to gentamicin and tobramycin is common, amikacin may be preferred for initial therapy.



Oral Therapy


Aminoglycosides are not absorbed from the GI tract, and hence oral therapy is used only for local effects within the intestine. In patients anticipating elective colorectal surgery, oral aminoglycosides have been given prophylactically to suppress bacterial growth in the bowel. One aminoglycoside—paromomycin—is used to treat intestinal amebiasis.



Topical Therapy


Neomycin is available in formulations for application to the eyes, ears, and skin. Topical preparations of gentamicin and tobramycin are used to treat conjunctivitis caused by susceptible gram-negative bacilli.



Pharmacokinetics


All of the aminoglycosides have similar pharmacokinetic profiles. Pharmacokinetic properties of the principal aminoglycosides are shown in Table 72.1.



TABLE 72.1


Dosages and Pharmacokinetics of Systemic Aminoglycosides











































Generic Name Trade Name Total Daily Dose (mg/kg)a,b Half-Life in Adults (hr) Therapeutic (Peak) Levelc,d (mcg/mL) Recommended Trough Levele,f (mcg/mL)
Adults Children Normal Anuric
Amikacin Amikin 15 15 2–3 24–60 15–30 Less than 5–10
Gentamicin Generic only 3–5g 6–7.5g 2 24–60 4–10h Less than 1–2i
Tobramycin Generic only 3–6 6–7.5 2–2.5 24–60 4–10 Less than 1–2i


aThe total daily dose may be administered as one large dose each day or as two or three divided doses given at equally spaced intervals around-the-clock.



bBecause of interpatient variability, standard doses cannot be relied on to produce appropriate serum drug levels, and hence dosage should be adjusted on the basis of serum drug measurements.



cMeasured 30 minutes after IM injection or after completing a 30-minute IV infusion.



dThe peak values presented refer to levels obtained when the total daily dosage is given in divided doses, rather than as a single large daily dose.



eMeasured just before the next dose.



fTo minimize ototoxicity and nephrotoxicity, drug levels should drop below the listed values between doses.



gWhen gentamicin is combined with either vancomycin or a beta-lactam antibiotic to treat certain gram-positive infections, the total daily dose is much lower (e.g., about 1 mg/kg for adults).



hThese peak values apply when gentamicin is used to treat gram-negative infections, not when gentamicin is combined with vancomycin or a beta-lactam antibiotic to treat gram-positive infections.



iFor severe infections, the trough may be higher (e.g., less than 2–4 mcg/mL).



Absorption


Because they are polycations, the aminoglycosides cross membranes poorly. As a result, very little (about 1%) of an oral dose is absorbed. Hence, for treatment of systemic infections, aminoglycosides must be given parenterally (by intramuscular [IM] or intravenous [IV] route). Absorption after application to the intact skin is minimal. However, when used for wound irrigation, aminoglycosides may be absorbed in amounts sufficient to produce systemic toxicity.



Distribution


Distribution of aminoglycosides is limited largely to extracellular fluid. Entry into the cerebrospinal fluid is insufficient to treat meningitis in adults. Aminoglycosides bind tightly to renal tissue, achieving levels in the kidneys up to 50 times higher than levels in serum. These high levels are responsible for nephrotoxicity (see later). Aminoglycosides penetrate readily to the perilymph and endolymph of the inner ears and can thereby cause ototoxicity (see later). Aminoglycosides can cross the placenta and may be toxic to the fetus.



PATIENT-CENTERED CARE ACROSS THE LIFE SPAN


Aminoglycosides






















Life Stage Patient Care Concerns
Infants Aminoglycosides are approved to treat bacterial infections in infants younger than 8 days. Dosing is based on weight and length of gestation.
Children/adolescents Aminoglycosides are safe for use against bacterial infections in children and adolescents.
Pregnant women There is evidence that use of aminoglycosides in pregnancy can harm the fetus. They are classified in U.S. Food and Drug Administration Pregnancy Risk Category D.
Breastfeeding women Gentamycin is probably safe to use in lactation. There is limited information regarding its use.
Older adults Caution must be used regarding decreased renal function in the older adult.

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Apr 8, 2017 | Posted by in PHARMACY | Comments Off on Aminoglycosides
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