minoglycosides

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Aminoglycosides (see Table 5: Bacteria and Antibacterial Drugs:

Aminoglycosides ) are bactericidal. They bind to the 30S ribosome, thereby
inhibiting bacterial protein synthesis.

Table 5
Aminoglycosides
Amikacin Some Trade Names
AMIKIN
Click for Drug Monograph

Gentamicin Some Trade Names

GARAMYCIN
Click for Drug Monograph

Neomycin Some Trade Names

NEO-FRADIN
NEO-RX
Click for Drug Monograph
*
Streptomycin Some Trade Names
No US trade name
Click for Drug Monograph

Tobramycin Some Trade Names

NEBCIN
TOBI
TOBREX
Click for Drug Monograph

*Should be used topically or orally

only.

Pharmacology: Aminoglycosides are poorly absorbed orally but are well

absorbed from the peritoneum, pleural cavity, joints (and should never be
instilled in these body cavities), and denuded skin. Aminoglycosides are
distributed well into the ECF except for vitreous humor, CSF, respiratory
secretions, and bile (particularly with biliary obstruction).

Aminoglycosides are excreted by glomerular filtration and have a serum half-life

of 2 to 3 h; the half-life rises exponentially as the GFR falls (eg, in renal
insufficiency or in the elderly). Peak serum levels of at least 10 times the
minimum inhibitory concentration (MIC) are desirable.

When β-lactams, such as piperacillin Some Trade Names

PIPRACIL
Click for Drug Monograph
or ticarcillin Some Trade Names
TICAR

, are used in high doses, the high serum levels of the β-lactam may inactivate the
aminoglycoside in vitro in serum specimens obtained for drug level
determination from patients receiving both drugs, if the serum is not assayed
immediately or frozen. If patients with renal failure are concurrently receiving
both an aminoglycoside and a high-dose β-lactam, the serum aminoglycoside
concentration may be lower because of prolonged interaction in vivo.

Indications: Aminoglycosides are used for serious gram-negative infections,

especially Pseudomonas aeruginosa. They are active against most gram-negative
aerobic bacilli but lack activity against anaerobes and most gram-positive
bacteria, except for most staphylococci; however, some gram-negative bacilli
and methicillin-resistant staphylococci are resistant. Gentamicin Some Trade
Names
GARAMYCIN
Click for Drug Monograph
, tobramycin Some Trade Names
NEBCIN
TOBI
TOBREX
Click for Drug Monograph
, and amikacin Some Trade Names
AMIKIN
Click for Drug Monograph
are active against P. aeruginosa, whereas streptomycin Some Trade Names
No US trade name
Click for Drug Monograph
, neomycin Some Trade Names
NEO-FRADIN
NEO-RX
Click for Drug Monograph
, and kanamycin Some Trade Names
KANTREX
Click for Drug Monograph
are not. Gentamicin Some Trade Names
GARAMYCIN
Click for Drug Monograph
and tobramycin Some Trade Names
NEBCIN
TOBI
TOBREX
Click for Drug Monograph
have similar antimicrobial spectra against gram-negative bacilli, but tobramycin
Some Trade Names
NEBCIN
TOBI
TOBREX
Click for Drug Monograph
is more active against P. aeruginosa , and gentamicin Some Trade Names
GARAMYCIN
Click for Drug Monograph
is more active against Serratia marcescens. Amikacin Some Trade Names
AMIKIN
Click for Drug Monograph
is frequently active against gentamicin Some Trade Names
GARAMYCIN
Click for Drug Monograph
- and tobramycin Some Trade Names
NEBCIN
TOBI
TOBREX
Click for Drug Monograph
-resistant pathogens.

Aminoglycosides are used alone infrequently, typically for plague and tularemia.
They are used with a broad-spectrum β-lactam for severe infection due to a
suspected gram-negative bacillus. However, because of increasing
aminoglycoside resistance, a fluoroquinolone can be substituted for the
aminoglycoside in initial empiric regimens, or the aminoglycoside can be
stopped after 2 to 3 days unless an aminoglycoside-sensitive P. aeruginosa is
identified.

Gentamicin Some Trade Names

GARAMYCIN
Click for Drug Monograph
or, less commonly, streptomycin Some Trade Names
No US trade name
Click for Drug Monograph
may be used with other antimicrobials to treat endocarditis due to streptococci or
enterococci. Enterococcal resistance to aminoglycosides has become a common
problem. Because therapy of enterococcal endocarditis requires prolonged use of
a potentially nephrotoxic and ototoxic aminoglycoside combined with a bacterial
cell wall–active drug (eg, penicillin or vancomycin Some Trade Names
VANCOCIN
Click for Drug Monograph
) to achieve bactericidal synergy, the choice of aminoglycoside must be based on
special in vitro susceptibility testing. High-level aminoglycoside susceptibility in
vitro will predict synergy when low-dose aminoglycoside therapy is combined
with a cell wall–active drug. If the strain is susceptible to high-level gentamicin
Some Trade Names
GARAMYCIN
Click for Drug Monograph
and streptomycin Some Trade Names
No US trade name
Click for Drug Monograph
, gentamicin Some Trade Names
GARAMYCIN
Click for Drug Monograph
is preferred because serum levels can be readily determined. High-level
resistance to gentamicin Some Trade Names
GARAMYCIN
Click for Drug Monograph
in vitro does not rule out susceptibility of these enterococcal strains to high
levels of streptomycin Some Trade Names
No US trade name
Click for Drug Monograph
, in which case streptomycin Some Trade Names
No US trade name
Click for Drug Monograph
should be used. There are few therapeutic options available for endocarditis due
to enterococci resistant to high levels of both gentamicin Some Trade Names
GARAMYCIN
Click for Drug Monograph
and streptomycin Some Trade Names
No US trade name
Click for Drug Monograph
, for which no synergistic cell wall–active drug/aminoglycoside combination
exists. Endocarditis due to such strains has been treated with limited success with
prolonged courses of a cell wall–active drug alone or linezolid Some Trade
Names
ZYVOX
Click for Drug Monograph
.

Streptomycin Some Trade Names

No US trade name
Click for Drug Monograph
has limited uses because of resistance. It is used with other antimicrobials for
TB.

Because of toxicity, neomycin Some Trade Names

NEO-FRADIN
NEO-RX
Click for Drug Monograph
and kanamycin Some Trade Names
KANTREX
Click for Drug Monograph
are limited to topical use in small amounts. Neomycin Some Trade Names
NEO-FRADIN
NEO-RX
Click for Drug Monograph
is available for eye, ear, oral, and rectal use and as a bladder irrigant. Oral use as
a topical agent against intestinal flora includes bowel preparation before surgery
and treatment of hepatic coma.

Toxicity: All aminoglycosides produce renal toxicity (often reversible) and

vestibular and auditory toxicity (often irreversible). Symptoms and signs of
vestibular damage are vertigo, nausea, vomiting, nystagmus, and ataxia. Risk
factors for renal, vestibular, and auditory toxicity are large doses, very high
blood levels, frequent doses, longer duration of therapy (particularly > 3 days),
older age, and preexisting renal disease. Other risk factors include
coadministration of vancomycin Some Trade Names
VANCOCIN
Click for Drug Monograph
, cyclosporine Some Trade Names
NEORAL
SANDIMMUNE
Click for Drug Monograph
, amphotericin B Some Trade Names
ABELCET
AMBISOME
AMPHOCIN
AMPHOTEC
Click for Drug Monograph
, or radiocontrast material (for renal toxicity) and preexisting hearing problems
or coadministration of loop diuretics (for auditory toxicity). Patients receiving
aminoglycosides for > 2 wk or those at risk of vestibular and auditory toxicity
should be monitored with serial audiograms. At the 1st sign of toxicity, the drug
is stopped (if possible) or dosing adjusted.

Aminoglycosides can prolong the effect of neuromuscular blockers (eg,

succinylcholine Some Trade Names
ANECTINE
QUELICIN
Click for Drug Monograph
or curare-like drugs) and worsen weakness in diseases affecting neuromuscular
transmission (eg, myasthenia gravis). This particularly occurs with too-rapid
administration or excessively high serum levels. It sometimes resolves more
rapidly with neostigmine Some Trade Names
PROSTIGMIN
Click for Drug Monograph
or IV Ca. Other neurologic effects include paresthesias and peripheral
neuropathy.

Hypersensitivity reactions are uncommon. Large oral doses of neomycin Some

Trade Names
NEO-FRADIN
NEO-RX
Click for Drug Monograph
can produce malabsorption.

Administration: Aminoglycosides are usually given IV. Intravitreous injection is

required to treat endophthalmitis. Intraventricular injection is often required to
achieve adequate intraventricular levels for treatment of meningitis. Because
toxicity depends more on the duration of therapeutic levels than peak levels and
because drug efficacy is concentration-dependent rather than time-dependent,
frequent doses are avoided. Once/day IV dosing is preferred for most indications
except enterococcal endocarditis. IV aminoglycosides are given slowly (30 min
for divided daily dosing or 30 to 45 min for once/day dosing). Once-daily dosing
of gentamicin Some Trade Names
GARAMYCIN
Click for Drug Monograph
or tobramycin Some Trade Names
NEBCIN
TOBI
TOBREX
Click for Drug Monograph
is 5 to 7 mg/kg q 24 h; the higher dose is used initially in critically ill patients,
who are likely to have expanded volumes of distribution, to achieve targeted
peak serum levels of 16 to 24 μg/mL and thereby facilitate concentration-
dependent bactericidal activity. Peak serum levels should be determined after the
1st dose in critically ill patients. Peak and trough levels are measured after the
2nd or 3rd dose when the daily aminoglycoside dose is divided and the duration
of therapy is > 3 days. Dosing is adjusted to ensure a therapeutic peak serum
level and nontoxic trough level (see Table 6: Bacteria and Antibacterial Drugs:
Dosing for Aminoglycosides in Adults ). Trough levels should be undetectable
at 18 to 24 h after the 1st dose with once-daily dosing and between 1 and 2
mg/mL with multiple daily dosing of gentamicin Some Trade Names
GARAMYCIN
Click for Drug Monograph
or tobramycin Some Trade Names
NEBCIN
TOBI
TOBREX
Click for Drug Monograph
. The peak concentration is the level 60 min after an IM injection or 30 min after
the end of a 30-min IV infusion. Assuming clinical response and continued
normal renal function, the once-daily dose can be reduced after the 1st few days
of therapy to 5 mg/kg. Troughs are measured within 30 min before the next dose.
Serum creatinine is measured q 2 to 3 days, and if stable, serum aminoglycoside
levels need not be repeated.

Table 6
Dosing for Aminoglycosides in Adults
1. Choose loading dose in mg/kg (ideal weight) for
peak serum levels in range from below for desired
aminoglycosides. Dose is based on lean body
weight plus 50% of adipose mass in obese patients
and total body weight in edematous patients.
Aminoglycoside Usual Loading Doses Expected Peak Serum Target
Levels Serum
Trough
Levels
Tobramycin Some 1.5–2.0 mg/kg 4–10 μg/mL <2
Trade Names μg/mL
NEBCIN
TOBI
TOBREX
Click for Drug
Monograph
, gentamicin Some
Trade Names
GARAMYCIN
Click for Drug
Monograph

Amikacin Some 5.0–7.5 mg/kg 15–30 μg/mL <5

Trade Names μg/mL
AMIKIN
Click for Drug
Monograph

2. Choose maintenance dose (as percentage of

chosen loading dose) to continue peak serum levels
indicated above according to desired interval and
the patient's corrected creatinine clearance.
Calculate corrected creatinine clearance C(c)cr as
follows:
Percentage of Loading Dose Required for Dosage Interval Selected
C(c)cr (mL/min) 8 h (%) 12 h (%) 24 h (%)
90 84 — —
70 76 88 —
50 65 79 —
30 48 63 86
20 37 50 75
15 31 42 67
10 24 34 56
5 16 23 41
0 8 11 21
C(c)cr male = (140 − age)wt in kg/70 × serum creatinine.
C(c)cr female = 0.85 × C(c)cr male.
Dosing for patients with C(c)cr ≤ 90 mL/min should be assisted by measured
serum levels.
Modified from Sarubbi FA Jr, Hull JH: Amikacin Some Trade Names
AMIKIN
Click for Drug Monograph
serum concentrations: Prediction of levels and dosage guidelines. Annals of
Internal Medicine 89:612–618, 1978.

In patients with renal insufficiency, the loading dose is the usual dose based on
body weight in patients with normal renal function; usually the dosing interval is
increased rather than the dose amount decreased. Nomograms calculate
maintenance doses based on serum creatinine or creatinine clearance values (see
Table 6: Bacteria and Antibacterial Drugs: Dosing for Aminoglycosides in
Adults ), but they are not precise, and measurement of blood levels is preferred.
Spectinomycin

Spectinomycin Some Trade Names

TROBICIN

is a bacteriostatic antibiotic chemically related to the aminoglycosides.

Spectinomycin Some Trade Names
TROBICIN

binds to the 30S subunit of the ribosome, thus inhibiting bacterial protein
synthesis. Its activity is restricted to gonococci. Spectinomycin Some Trade
Names
TROBICIN

is excreted by glomerular filtration.

Spectinomycin Some Trade Names

TROBICIN

is given for gonococcal urethritis, cervicitis, and proctitis but is not effective in
gonococcal pharyngitis. It is reserved for patients who cannot be treated with
ceftriaxone Some Trade Names
ROCEPHIN
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, cefpodoxime Some Trade Names
VANTIN
Click for Drug Monograph
, cefixime Some Trade Names
SUPRAX
Click for Drug Monograph
, or a fluoroquinolone.

Adverse effects, including hypersensitivity reactions and fever, are rare.