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Aminoglycosides
The aminoglycosides include streptomycin,
neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin,
netilmicin, and others. They are used most widely against
gram-negative enteric bacteria, especially in bacteremia and sepsis, in
combination with vancomycin or a penicillin for endocarditis, and for
treatment of tuberculosis.
General Properties of
Aminoglycosides
Physical and Chemical
Properties
Aminoglycosides have a hexose
ring, either streptidine (in streptomycin) or 2-deoxystreptamine (in
other aminoglycosides), 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.
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
irreversible inhibitors of protein synthesis, but the precise mechanism
for bactericidal activity is not known. 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). 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.
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,
ie, 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.
Pharmacokinetics and Once-Daily
Dosing
Aminoglycosides are absorbed
very poorly from the intact gastrointestinal tract; almost the entire
oral dose is excreted in feces after oral administration. However, the
drugs may be absorbed if ulcerations are present. 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.
Traditionally, aminoglycosides
have been administered in two or three equally divided daily doses for
patients with normal renal function. However, once-daily aminoglycoside
dosing may be preferred in certain 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.
Adverse effects from
aminoglycoside are both time- and concentration-dependent. 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 above 2 mcg/mL 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.
Numerous clinical studies
demonstrate that a single daily dose of aminoglycoside is just as
effective—and no more (and often less) toxic—than multiple smaller doses.
Therefore, many authorities now recommend that aminoglycosides be
administered as a single daily dose in many clinical situations. The efficacy
of once-daily 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 is 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 saves time. And once-a-day dosing lends itself to outpatient
therapy.
Once-daily dosing, however, does
not eliminate responsibility for careful monitoring and dosage adjustment
to minimize toxicity. Selection of the appropriate dose is particularly
critical if renal function is impaired. Aminoglycosides are cleared by
the kidney, and excretion is directly proportional to creatinine
clearance. Rapidly changing renal function, which may occur with acute
renal failure in the patient with septic shock, must be anticipated to
avoid overdose. Provided these pitfalls are avoided, once-daily
aminoglycoside dosing is safe and effective. If the creatinine clearance
is 100 mL/min, gentamicin is given as a 5 mg/kg dose (15 mg/kg for
amikacin) over 30–60 minutes. If the creatinine clearance is 80 mL/min,
the dose is 4 mg/kg (12 mg/kg for amikacin); if creatinine clearance is
50 mL/min, the dose is 3 mg/kg (9 mg/kg for amikacin). If the creatinine
clearance is less than 50 mL/min, a 2 mg/kg gentamicin loading dose is
given, and subsequent doses are adjusted as would normally be done.
Serum concentrations need not be
routinely checked until the second or third day of therapy, depending on
the stability of renal function and the anticipated duration of therapy.
It is probably unnecessary to check peak concentrations because they will
be high. The goal is to administer drug so that concentrations of less
than 1 mcg/mL 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. This is most easily determined either 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 and 6 mcg/mL, the
target trough can be achieved at 18 hours.
Aminoglycosides are highly polar
compounds that do not enter cells readily. They are largely excluded from
the central nervous system and the eye. In the presence of active
inflammation, however, cerebrospinal fluid levels reach 20% of plasma
levels, and in neonatalmeningitis 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.
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.
Dosage adjustments must be made
to prevent accumulation of drug and toxicity in patients with renal
insufficiency. Either the dose of drug is kept constant and the interval
between doses is increased, or the interval is kept constant and the dose
is reduced. Nomograms and formulas have been constructed relating serum
creatinine levels to adjustments in treatment regimens. The simplest
formula divides the dose (calculated on the basis of normal renal
function) by the serum creatinine value (mg/dL). Thus, a 60-kg patient
with normal renal function might receive 300 mg/d of gentamicin (maximum
daily dose of 5 mg/kg), whereas a 60-kg patient with a serum creatinine
of 3 mg/dL would receive 100 mg/d. However, this approach fails to take
into account the age and gender of the patient, both of which
significantly affect creatinine clearance without necessarily being
reflected as a change in serum creatinine. Because aminoglycoside
clearance is directly proportional to the creatinine clearance, a better
method for determining the aminoglycoside dose is to estimate creatinine
clearance using the Cockcroft-Gault formula described in Chapter 60.
The daily dosage of
aminoglycoside is calculated by multiplying the maximum daily dosage by
the ratio of estimated creatinine clearance to normal creatinine
clearance, ie, 120 mL/min, which is a typical value for a 70-kg young
adult male. For a 60-year-old woman weighing 60 kg with a serum
creatinine of 3 mg/dL, the corrected dosage of gentamicin would be
approximately 50 mg/d, half the dose calculated by the simplest formula.
There is considerable individual variation in aminoglycoside serum levels
among patients with similar estimated creatinine clearance values. Therefore,
it is mandatory, especially when using higher dosages for more than a few
days or when renal function is rapidly changing, to measure serum drug
levels to avoid severe toxicity. For a traditional twice- or thrice-daily
dosing regimen, peak serum concentrations should be determined from a
blood sample obtained 30–60 minutes after a dose, and trough
concentrations from a sample obtained just before the next dose.
Adverse Effects
All aminoglycosides are ototoxic
and nephrotoxic. Ototoxicity and nephrotoxicity are more likely to be
encountered when therapy is continued for more than 5 days, at higher
doses, in the elderly, and in the setting of renal insufficiency.
Concurrent use with loop diuretics (eg, furosemide, ethacrynic acid) or
other nephrotoxic antimicrobial agents (eg, vancomycin or amphotericin)
can potentiate nephrotoxicity and should be avoided if possible.
Ototoxicity can manifest either as auditory damage, resulting in tinnitus
and high-frequency hearing loss initially, or as vestibular damage,
evident by vertigo, ataxia, and loss of balance. Nephrotoxicity results
in rising serum creatinine levels or reduced creatinine clearance,
although the earliest indication often is an increase in trough serum
aminoglycoside concentrations. Neomycin, kanamycin, and amikacin are the
most ototoxic agents. Streptomycin and gentamicin are the most
vestibulotoxic. Neomycin, tobramycin, and gentamicin are the most
nephrotoxic.
In very high doses,
aminoglycosides can produce a curare-like effect with neuromuscular
blockade that results in respiratory paralysis. This paralysis is usually
reversible by calcium gluconate (given promptly) or neostigmine.
Hypersensitivity occurs infrequently.
Clinical Uses
Aminoglycosides are mostly used
against gram-negative enteric bacteria, especially when the isolate may
be drug-resistant and when there is suspicion of sepsis. They are almost
always used in combination with a  -lactam antibiotic to extend coverage
to include potential gram-positive pathogens and to take advantage of the
synergism between these two classes of drugs. Penicillin-aminoglycoside
combinations also are used to achieve bactericidal activity in treatment
of enterococcal endocarditis and to shorten duration of therapy for
viridans streptococcal and staphylococcal endocarditis. Which
aminoglycoside and what dose should be used depend on the infection being
treated and the susceptibility of the isolate.
Streptomycin
Streptomycin (Figure 45–1) was
isolated from a strain of Streptomyces griseus. The antimicrobial
activity of streptomycin is typical of that of other aminoglycosides, as
are the mechanisms of resistance. Resistance has emerged in most species,
severely limiting the current usefulness of streptomycin, with the
exceptions listed below. Ribosomal resistance to streptomycin develops
readily, limiting its role as a single agent.
Clinical Uses
Mycobacterial Infections
Streptomycin is mainly used as a
second-line agent for treatment of tuberculosis. The dosage is 0.5–1 g/d
(7.5–15 mg/kg/d for children), which is given intramuscularly or
intravenously. It should be used only in combination with other agents to
prevent emergence of resistance. See Chapter 47 for additional
information regarding the use of streptomycin in mycobacterial
infections.
Nontuberculous Infections
In plague, tularemia, and
sometimes brucellosis, streptomycin, 1 g/d (15 mg/kg/d for children), is
given intramuscularly in combination with an oral tetracycline.
Penicillin plus streptomycin is
effective for enterococcal endocarditis and 2-week therapy of viridans
streptococcal endocarditis. Gentamicin has largely replaced streptomycin
for these indications. Streptomycin remains a useful agent for treating
enterococcal infections, however, because approximately 15% of
enterococcal isolates that are resistant to gentamicin (and therefore to
netilmicin, tobramycin, and amikacin) will be susceptible to
streptomycin.
Adverse Reactions
Fever, skin rashes, and other
allergic manifestations may result from hypersensitivity to streptomycin.
This occurs most frequently with prolonged contact with the drug either
in patients who receive a prolonged course of treatment (eg, for
tuberculosis) or in medical personnel who handle the drug.
Desensitization is occasionally successful.
Pain at the injection site is
common but usually not severe. The most serious toxic effect with
streptomycin is disturbance of vestibular function—vertigo and loss of
balance. The frequency and severity of this disturbance are in proportion
to the age of the patient, the blood levels of the drug, and the duration
of administration. Vestibular dysfunction may follow a few weeks of
unusually high blood levels (eg, in individuals with impaired renal
function) or months of relatively low blood levels. Vestibular toxicity
tends to be irreversible. Streptomycin given during pregnancy can cause
deafness in the newborn and therefore is relatively contraindicated.
Gentamicin
Gentamicin is an aminoglycoside
(Figure 45–2) isolated from Micromonospora purpurea. It is
effective against both gram-positive and gram-negative organisms, and
many of its properties resemble those of other aminoglycosides. Sisomicin
is very similar to the C1a component of gentamicin.
Antimicrobial Activity
Gentamicin sulfate, 2–10 mcg/mL,
inhibits in vitro many strains of staphylococci and coliforms and other
gram-negative bacteria. It is active alone, but also as a synergistic
companion with -lactam antibiotics, against
pseudomonas, proteus, enterobacter, klebsiella, serratia,
stenotrophomonas, and other gram-negative rods that may be resistant to
multiple other antibiotics. Like all aminoglycosides, it has no activity
against anaerobes.
Resistance
Streptococci and enterococci are
relatively resistant to gentamicin owing to failure of the drug to
penetrate into the cell. However, gentamicin in combination with vancomycin
or a penicillin produces a potent bactericidal effect, which in part is
due to enhanced uptake of drug that occurs with inhibition of cell wall
synthesis. Resistance to gentamicin rapidly emerges in staphylococci
owing to selection of permeability mutants. Ribosomal resistance is rare.
Among gram-negative bacteria, resistance is most commonly due to
plasmid-encoded aminoglycoside-modifying enzymes. Gram-negative bacteria
that are gentamicin-resistant usually are susceptible to amikacin, which
is much more resistant to modifying enzyme activity. The enterococcal
enzyme that modifies gentamicin is a bifunctional enzyme that also
inactivates amikacin, netilmicin, and tobramycin, but not streptomycin;
the latter is modified by a different enzyme. This is why some
gentamicin-resistant enterococci are susceptible to streptomycin.
Clinical Uses
Intramuscular or Intravenous
Administration
Gentamicin is used mainly in
severe infections (eg, sepsis and pneumonia) caused by gram-negative
bacteria that are likely to be resistant to other drugs, especially
pseudomonas, enterobacter, serratia, proteus, acinetobacter, and
klebsiella. It usually is used in combination with a second agent,
because an aminoglycoside alone may not be effective for infections
outside the urinary tract. For example, gentamicin should not be used as
a single agent to treat staphylococcal infections because resistance
develops rapidly. Aminoglycosides should not be used for single-agent
therapy of pneumonia because penetration of infected lung tissue is poor
and local conditions of low pH and low oxygen tension contribute to poor
activity. Gentamicin 5–6 mg/kg/d traditionally is given intravenously in
three equal doses, but once-daily administration is just as effective for
some organisms and less toxic.
Serum gentamicin concentrations
and renal function should be monitored if gentamicin is administered for
more than a few days or if renal function is changing (eg, in sepsis,
which often is complicated by acute renal failure). For patients receiving
dosing every 8 hours, target peak concentrations are 5–10 mcg/mL, and
trough concentrations should be less than 1–2 mcg/mL. Trough
concentrations above 2 mcg/mL indicate accumulation of drug and are
associated with toxicity; in this case, the dose should be lowered or the
interval extended to achieve the target range.
Topical Administration
Creams, ointments, and solutions
containing 0.1–0.3% gentamicin sulfate have been used for the
treatment of infected burns, wounds, or skin lesions and the prevention
of intravenous catheter infections. Topical gentamicin is partly
inactivated by purulent exudates. Ten mg can be injected
subconjunctivally for treatment of ocular infections.
Intrathecal Administration
Meningitis caused by
gram-negative bacteria has been treated by the intrathecal injection of
gentamicin sulfate, 1–10 mg/d. However, neither intrathecal nor
intraventricular gentamicin was beneficial in neonates with meningitis,
and intraventricular gentamicin was toxic, raising questions about the
usefulness of this form of therapy. Moreover, the availability of
third-generation cephalosporins for gram-negative meningitis has rendered
this therapy obsolete in most cases.
Adverse Reactions
Nephrotoxicity is usually
reversible and mild. It occurs in 5–25% of patients receiving gentamicin
for longer than 3–5 days. Such toxicity requires, at the very least,
adjustment of the dosing regimen and should prompt reconsideration of the
need for the drug, particularly if there is a less toxic alternative
agent. Measurement of gentamicin serum levels is essential. Ototoxicity,
which tends to be irreversible, manifests itself mainly as vestibular
dysfunction. Loss of hearing can also occur. The incidence of ototoxicity
is in part genetically determined, having been linked to point mutations
in mitochondrial DNA, and occurs in 1–5% for patients receiving
gentamicin for more than 5 days. Hypersensitivity reactions to gentamicin
are uncommon.
Tobramycin
This aminoglycoside (Figure
45–2) has an antibacterial spectrum similar to that of gentamicin.
Although there is some cross-resistance between gentamicin and
tobramycin, it is unpredictable in individual strains. Separate
laboratory susceptibility tests are therefore necessary.
The pharmacokinetic properties
of tobramycin are virtually identical with those of gentamicin. The daily
dose of tobramycin is 5–6 mg/kg intramuscularly or intravenously,
traditionally divided into three equal amounts and given every 8 hours.
Monitoring blood levels in renal insufficiency is an essential guide to
proper dosing.
Tobramycin has almost the same
antibacterial spectrum as gentamicin with a few exceptions. Gentamicin is
slightly more active against serratia, whereas tobramycin is slightly
more active against pseudomonas; Enterococcus faecalis is
susceptible to both gentamicin and tobramycin, but E faecium is
resistant to tobramycin. Gentamicin and tobramycin are otherwise
interchangeable clinically.
Like other aminoglycosides,
tobramycin is ototoxic and nephrotoxic. Nephrotoxicity of tobramycin may
be slightly less than that of gentamicin, but the difference is
clinically inconsequential.
Tobramycin is also formulated in
solution (300 mg in 5 mL) for inhalation for treatment of Pseudomonas
aeruginosa lower respiratory tract infections complicating cystic
fibrosis. The drug is recommended as a 300-mg dose regardless of the
patient's age or weight for administration twice daily in repeated cycles
of 28 days on therapy, followed by 28 days off therapy. Serum concentrations
1 hour after inhalation average 1 mcg/mL; consequently, nephrotoxicity
and ototoxicity rarely occur. Caution should be used when administering
tobramycin to patients with preexisting renal, vestibular, or hearing
disorders.
Amikacin
Amikacin is a semisynthetic
derivative of kanamycin; it is less toxic than the parent molecule
(Figure 45–2). It is resistant to many enzymes that inactivate gentamicin
and tobramycin, and it therefore can be used against some microorganisms
resistant to the latter drugs. Many gram-negative enteric bacteria,
including many strains of proteus, pseudomonas, enterobacter, and
serratia, are inhibited by 1–20 mcg/mL amikacin in vitro. After injection
of 500 mg of amikacin every 12 hours (15 mg/kg/d) intramuscularly, peak
levels in serum are 10–30 mcg/mL.
Strains of multidrug-resistant Mycobacterium
tuberculosis, including streptomycin-resistant strains, are usually
susceptible to amikacin. Kanamycin-resistant strains may be
cross-resistant to amikacin. The dosage of amikacin for tuberculosis is
7.5–15 mg/kg/d as a once-daily or two to three times weekly injection and
always in combination with other drugs to which the isolate is
susceptible.
Like all aminoglycosides,
amikacin is nephrotoxic and ototoxic (particularly for the auditory
portion of the eighth nerve). Serum concentrations should be monitored.
Target peak serum concentrations for an every-12-hours dosing regimen are
20–40 mcg/mL, and troughs should be maintained between 4 and 8 mcg/mL.
Netilmicin
Netilmicin shares many characteristics
with gentamicin and tobramycin. However, the addition of an ethyl group
to the 1-amino position of the 2-deoxystreptamine ring (ring II, Figure
45–2) sterically protects the netilmicin molecule from enzymatic
degradation at the 3-amino (ring II) and 2-hydroxyl (ring III) positions.
Consequently, netilmicin may be active against some gentamicin-resistant
and tobramycin-resistant bacteria.
The dosage (5–7 mg/kg/d) and the
routes of administration are the same as for gentamicin. Netilmicin is
completely interchangeable with gentamicin or tobramycin but is no longer
available in the USA.
Neomycin & Kanamycin
Neomycin and kanamycin are
closely related. Paromomycin is also a member of this group. All
have similar properties.
Antimicrobial Activity & Resistance
Drugs of the neomycin group are
active against gram-positive and gram-negative bacteria and some
mycobacteria. Pseudomonas and streptococci are generally resistant.
Mechanisms of antibacterial action and resistance are the same as with
other aminoglycosides. The widespread use of these drugs in bowel
preparation for elective surgery has resulted in the selection of
resistant organisms and some outbreaks of enterocolitis in hospitals.
Cross-resistance between kanamycin and neomycin is complete.
Pharmacokinetics
Drugs of the neomycin group are
poorly absorbed from the gastrointestinal tract. After oral
administration, the intestinal flora is suppressed or modified, and the
drug is excreted in the feces. Excretion of any absorbed drug is mainly
through glomerular filtration into the urine.
Clinical Uses
Neomycin and kanamycin are now
limited to topical and oral use. Neomycin is too toxic for parenteral
use. With the advent of more potent and less toxic aminoglycosides,
parenteral administration of kanamycin has also been largely abandoned.
Paromomycin has recently been shown to be effective against visceral
leishmaniasis when given parenterally (see Chapter 52), and this serious
infection may represent an important new use for this drug.
Topical Administration
Solutions containing 1–5 mg/mL
are used on infected surfaces or injected into joints, the pleural
cavity, tissue spaces, or abscess cavities where infection is present.
The total amount of drug given in this fashion must be limited to 15
mg/kg/d because at higher doses enough drug may be absorbed to produce
systemic toxicity. Whether topical application for active infection adds
anything to appropriate systemic therapy is questionable. Ointments,
often formulated as a neomycin-polymyxin-bacitracin combination, can be
applied to infected skin lesions or in the nares for suppression of
staphylococci but they are largely ineffective.
Oral Administration
In preparation for elective
bowel surgery, 1 g of neomycin is given orally every 6–8 hours for 1–2 days,
often combined with 1 g of erythromycin base. This reduces the aerobic
bowel flora with little effect on anaerobes. In hepatic coma, coliform
flora can be suppressed by giving 1 g every 6–8 hours together with
reduced protein intake, thus reducing ammonia intoxication. Use of
neomycin for hepatic coma has been almost entirely supplanted by
lactulose, which is much less toxic. Use of paromomycin is discussed in
Chapter 52.
Adverse Reactions
All members of the neomycin
group have significant nephrotoxicity and ototoxicity. Auditory function
is affected more than vestibular function. Deafness has occurred,
especially in adults with impaired renal function and prolonged elevation
of drug levels.
The sudden absorption of
postoperatively instilled kanamycin from the peritoneal cavity (3–5 g)
has resulted in curare-like neuromuscular blockade and respiratory
arrest. Calcium gluconate and neostigmine can act as antidotes.
Although hypersensitivity is not
common, prolonged application of neomycin-containing ointments to skin
and eyes has resulted in severe allergic reactions.
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