Aminoglycosides and Spectinomycin Flashcards
The aminoglycosides include_______________
. They are used most widely in combination with a β-lactam antibiotic in serious infections with gram-negative bacteria, in combination with vancomycin or a β-lactam antibiotic for gram-positive endocarditis, and for treatment of tuberculosis.
streptomycin,
neomycin,
kanamycin,
amikacin,
gentamicin,
tobramycin
, sisomicin
, netilmicin, and others
” MICIN”
A. Physical and Chemical Properties
Aminoglycosides have a hexose ring, either_________________ or __________________-, to which various amino sugars are attached by glycosidic linkages ( Figures 45–1 and 45–2 ). They are water-soluble, stable in solution, and more active at alkaline than at acid pH.
streptidine (in streptomycin)
** 2-deoxystreptamine** (in other aminoglycosides)
B. Mechanism of Action
The mode of action of streptomycin has been studied far more closely than that of other aminoglycosides, but they probably all act similarly. Aminoglycosides are______________________________
The initial event is passive diffusion via porin channels across the outer membrane (see Figure 43–3 ).
Drug is then actively transported across the cell membrane into the cytoplasm by an oxygen-dependent process.
The transmembrane electrochemical gradient supplies the energy for this process, and transport is coupled to a proton pump.
Low extracellular pH and anaerobic conditions inhibit transport by reducing the gradient.
Transport may be enhanced by cell wall-active drugs such as penicillin or vancomycin; this enhancement may be the basis of the synergism of these antibiotics with aminoglycosides. Inside the cell, aminoglycosides bind to specific 30S-subunit ribosomal proteins (S12 in the case of streptomycin)
irreversible inhibitors of protein synthesis, but the precise mechanism for bactericidal activity is not known.
Protein synthesis is inhibited by aminoglycosides in at least three ways ( Figure 45–3 ):
(1) interference with the initiation complex of peptide formation;
(2) misreading of mRNA, which causes incorporation of incorrect amino acids into the peptide and results in a nonfunctional or toxic protein; and
(3) breakup of polysomes into nonfunctional monosomes. These activities occur more or less simultaneously, and the overall effect is irreversible and lethal for the cell.
C. Mechanisms of Resistance Three principal mechanisms have been established:
(1) production of a transferase enzyme or enzymes inactivates the aminoglycoside by adenylylation, acetylation, or phosphorylation. This is the principal type of resistance encountered clinically. (Specific transferase enzymes are discussed below.)
(2) There is impaired entry of aminoglycoside into the cell. This may be genotypic, resulting from mutation or deletion of a porin protein or proteins involved in transport and maintenance of the electrochemical gradient; or phenotypic, eg, resulting from growth conditions under which the oxygen-dependent transport process described above is not functional.
(3) The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of a mutation.
D. Pharmacokinetics and Once-Daily Dosing
Aminoglycosides are absorbed very poorly from the intact gastrointestinal
tract, and almost the entire oral dose is excreted in feces
after oral administration.However, the drugs may be absorbed if______________.
After intramuscular injection, aminoglycosides
are well absorbed, giving peak concentrations in blood
within 30–90 minutes.
Aminoglycosides are usually administered intravenously as a 30- to 60-minute infusion; after a brief distribution phase, this results in serum concentrations that are identical with those following intramuscular injection.
The normal half-life
of aminoglycosides in serum is 2–3 hours, increasing to 24–48
hours in patients with significant impairment of renal function.
Aminoglycosides are only partially and irregularly removed by
hemodialysis—eg, 40–60% for gentamicin—and even less effectively by peritoneal dialysis. Aminoglycosides are highly polar compounds that do not enter cells readily.
They are largely excluded from the central nervous system and the eye.
ulcerations are present
In the presence of ______________ however, cerebrospinal fluid levels reach 20% of plasma levels, and in neonatal meningitis, the levels may be higher.
Intrathecal or intraventricular injection is required for high levels in cerebrospinal fluid. Even after parenteral administration, concentrations of aminoglycosides are not high in most tissues except the renal cortex
. Concentration in most secretions is also modest; in the bile, it may reach 30% of the blood level. With prolonged therapy, diffusion into pleural or synovial fluid may result in concentrations 50–90% of that of plasma.
active inflammation,
Traditionally, aminoglycosides have been administered in two or three equally divided doses per day in patients with normal renal function.
However, administration of the entire daily dose in a single injection may be preferred in many clinical situations.
Aminoglycosides have concentration-dependent killing ; that is, increasing concentrations kill an increasing proportion of bacteria and at a more rapid rate.
They also have a significant postantibiotic effect, such that the antibacterial activity persists beyond the time during which measurable drug is present. The postantibiotic effect of aminoglycosides can last several hours.
Because of these properties, a given total amount of aminoglycoside may have better efficacy when administered as a single large dose than when administered as multiple smaller doses.
When administered with a cell wall-active antibiotic (a β lactam or vancomycin), aminoglycosides exhibit synergistic killing against certain bacteria. The effect of the drugs in combination is greater than the anticipated effect of each individual drug, ie, the killing effect of the combination is more than additive.
Aminoglycosides have
concentration-dependent killing
postantibiotic
effect
synergistic killing
Adverse effects from aminoglycosides are ______________ and _____________
Toxicity is unlikely to occur until a certain threshold concentration is reached, but once that concentration is achieved, the time beyond this threshold becomes critical.
This threshold is not precisely defined, but a trough concentration___________ is predictive of toxicity.
At clinically relevant doses, the total time above this threshold is greater with multiple smaller doses of drug than with a single large dose.
both time- and concentration-dependent. above 2 mcg/mL
Numerous clinical studies demonstrate that a single daily dose
of aminoglycoside is just as effective—and probably less toxic—
than multiple smaller doses.
Therefore, many authorities now
recommend that aminoglycosides be administered as a single daily
dose in many clinical situations.
However, the efficacy of oncedaily
aminoglycoside dosing in combination therapy of enterococcal
and staphylococcal endocarditis remains to be defined, and the
standard low-dose, thrice-daily administration is still recommended.
In contrast, there are limited data supporting once-daily
dosing in streptococcal endocarditis. The role of once-daily dosing
in pregnancy and in neonates also is not well defined.
Once-daily dosing has potential practical advantages.
For example, repeated determinations of serum concentrations are probably unnecessary unless aminoglycoside is given for more than 3 days. A drug administered once a day rather than three times a day is less labor intensive. And once-a-day dosing is more feasible for outpatient therapy.
The goal is to administer
drug so that concentrations of_______________ are present
between 18 and 24 hours after dosing. This provides a sufficient
period of time for washout of drug to occur before the next dose
is given. Appropriate trough levels can be accurately determined
by measuring serum concentrations in samples obtained 2 hours
and 12 hours after dosing and then adjusting the dose based on
the actual clearance of drug or by measuring the concentration in
a sample obtained 8 hours after a dose. If the 8-hour concentration
is between 1.5 mcg/mL and 6 mcg/mL, the target trough can
be achieved at 18 hours.
less than 1 mcg/mL
All aminoglycosides are ____________
ototoxic and nephrotoxic
. Ototoxicity and nephrotoxicity are more likely to be encountered when therapy is continued for _____________at higher doses, in the elderly, and in the setting of renal insufficiency
more than 5 days,
