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Gentamicin |
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[ Indications/Dosage
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[ Adverse Reactions ] [ Costs
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Description: Gentamicin is an aminoglycoside antibiotic obtained from cultures of Micromonospora purpurea. Gentamicin is most active against aerobic gram-negative rods, but it is also used in combination with other antibiotics to treat Staphylococcus aureus and certain species of streptococcus. Gentamicin and some other aminoglycosides are used in combination with a penicillin for the treatment of endocarditis. Gentamicin is active against certain Mycobacterium species but is not active against any anaerobic bacteria. Gentamicin was approved by the FDA in 1966.
Mechanism of Action: Despite many years of investigation, it is not
clear how gentamicin and other aminoglycosides cause bacterial cell death. It is
known that gentamicin binds irreversibly to one of two aminoglycoside-binding
sites on the 30 S ribosomal subunit, which, in turn, inhibits bacterial protein
synthesis. However, inhibition of bacterial protein synthesis does not
adequately explain gentamicin's bactericidal effects, since other non-aminoglycoside
antibiotics that also inhibit protein synthesis are only bacteriostatic. One
aspect essential to aminoglycoside lethality is the need to achieve
intracellular concentrations in excess of extracellular. Anaerobic bacteria are
not susceptible to aminoglycosides due, at least in part, to a lack of an active
transport mechanism for aminoglycoside uptake.
Against gram-negative aerobic rods, aminoglycosides exhibit
"concentration-dependent killing" and a "post-antibiotic
effect" (PAE). "Concentration-dependent killing" describes the
principle that bactericidal effects increase as the concentration increases. PAE
is where suppression of bacterial growth continues after the antibiotic
concentration falls below the bacterial MIC. The post-antibiotic effect can be
bacteria specific, as well as drug specific. The PAE of aminoglycosides is short
for most gram-postive organisms (< 2 hours) and longer for gram-negative
organisms (2—7 hours), such as E. coli, K. pneumoniae, and Ps. aeruginosa.
Both of these phenomena are being exploited in designing dosage regimens that
employ higher doses administered at longer intervals. A recent study of amikacin
20 mg/kg administered as a single daily dose versus three evenly spaced doses in
granulocytopenic patients revealed less severe nephrotoxicity in the single-dose
group with no difference in efficacy.
Gentamicin is active against Enterobacteriaceae organisms including Escherichia coli, Proteus, Klebsiella, Serratia, Enterobacter, and Citrobacter. In general, Pseudomonas aeruginosa is usually sensitive to gentamicin, although considerable variability in its susceptibility exists. Other pseudomonal species also may be susceptible but are usually less so than Pseudomonas aeruginosa. Staphylococcus aureus is sensitive, while Neisseria and Haemophilus genera are not. Many strains of Streptococcus are sensitive, although gentamicin is usually used in combination with another antibiotic to treat these organisms. Against Enterococcus faecalis, aminoglycosides are used only in combination with a cell-wall active antibiotic such as a penicillin or vancomycin.
Clinical conditions for which gentamicin is useful include urinary tract infections such as pyelonephritis, gynecologic infections, peritonitis, endocarditis, pneumonia, bacteremia and sepsis, respiratory infections including those associated with cystic fibrosis, osteomyelitis, and diabetic foot and other soft-tissue infections. Because aminoglycosides do not penetrate appreciably into the CNS, they are not considered useful in treating meningitis. In all cases, specific organism susceptibility data should be reviewed before selecting an antibiotic for the treatment of gram-negative infections.
Pharmacokinetics: Gentamicin is not absorbed orally, and serum
concentrations are unpredictable after IM injection. Thus, IV infusion over
15—30 minutes is the usual mode of administration. Since penetration into the
CNS is poor, gentamicin also has been given intrathecally or intraventricularly
in conjunction with parenteral therapy for treating CNS infections. Peak serum
concentrations following an intravenous infusion are proportional to the dose; a
peak concentration of 6—8 µg/ml is usually achieved with an IV dose of 2
mg/kg infused over 30 minutes. Gentamicin distributes into extracellular fluid;
the volume of distribution is approximately 0.25—0.3 L/kg. However,
critically-ill patients, and patients with burns, ascites, or heart failure
usually have larger volumes of distribution, often in the range of 0.3—0.4
L/kg. Infants and neonates have volumes of distribution usually between
0.4—0.5 L/kg. Protein binding of gentamicin is negligible.
Gentamicin is not metabolized. Elimination is almost exclusively via glomerular filtration. Minimal amounts are excreted into bile. Thus, elimination half-life varies according to renal function. In adults with normal renal function, the plasma elimination half-life is about 2—3 hours. In patients with impaired renal function, the plasma elimination half-life can be 24 hours or longer. In infants, the plasma elimination half-life ranges from 3—11 hours and is inversely proportional to birth weight and gestational age.
The following organisms are generally considered susceptible to gentamicin in
vitro: Acinetobacter
sp.; Aeromonas sp.; Brucella sp.; Citrobacter sp.; Enterobacter
aerogenes; Enterobacter sp.; Escherichia coli; Francisella
tularensis; Haemophilus influenzae (beta-lactamase negative); Haemophilus
influenzae (beta-lactamase positive); Klebsiella sp.; Morganella
sp.; Proteus mirabilis; Proteus vulgaris; Providencia sp.; Pseudomonas
aeruginosa; Salmonella sp.; Serratia sp.; Shigella sp.;
Staphylococcus aureus (MSSA); Staphylococcus epidermidis; Yersinia
pestis.
NOTE: Synergistic killing of Enterococcus sp. exists between an
aminoglycoside and a cell wall active agent (e.g., penicillin, vancomycin).
Aminoglycosides are not active against Enterococcus sp. when used as
monotherapy.
For the treatment of the following infections due to susceptible organisms:
meningitis, urinary tract infection (UTI), pyelonephritis, bacteremia or
septicemia, neonatal sepsis, lower respiratory tract infections (e.g.
pneumonia), bone and joint infections (e.g. osteomyelitis, infectious
arthritis); endocarditis, gynecologic infections, skin and skin structure
infections (e.g. cellulitis, burn wound infection), intraabdominal infections
(e.g. peritonitis), and empiric anti-infective management of febrile neutropenia:
NOTE: Serum gentamicin concentrations should be used to guide dosage
adjustments. A "dosing" weight should be used to calculate initial
dosages in patients weighing more than their ideal body weight (see above).
Intravenous or Intramuscular dosage:
Adults with normal renal function: Traditional dosing: 3—6 mg/kg/day IV
or IM given in 2—3 divided doses. Lower doses can be used in uncomplicated,
lower urinary tract infections. Higher doses may be required in pneumonia,
gram-negative endocarditis, life-threatening infections, or in infections due to
more resistant organisms (i.e., organisms with a higher gentamicin MIC). Studies
of once daily or "pulse" dosing have typically used doses of 4—7
mg/kg IV. Dosing intervals are often determined using a nomogram and are
frequently based on a random level drawn 8—12 hours after the first dose;
dosing intervals of 24 hr, 36 hr, and in some cases, 48—72 hours, are used.
Children >= 5 years with normal renal function: 2—2.5 mg/kg IV or IM
every 8 hours.
Children and infants < 5 years with normal renal function: 2.5 mg/kg
IV or IM every 8 hours.
Neonates postnatal age > 7 days, weighing > 2000 g: 2.5 mg/kg IV or
IM every 8 hours.
Neonates postnatal age > 7 days, weighing 1200—2000 g: 2.5 mg/kg IV
or IM every 12—18 hours.
Neonates postnatal age < 7 days, weighing > 2000 g: 2.5 mg/kg IV or
IM every 12 hours.
Neonates postnatal age < 7 days, weighing 1200—2000 g: 2.5 mg/kg IV
or IM every 12—18 hours.
Preterm neonates, 0—4 weeks, weighing < 1200 g: 2.5 mg/kg IV or IM
every 18—24 hours.
Preterm neonates weighing < 1000 g: 3.5 mg/kg IV or IM every 24 hours.
Neonates receiving ECMO: 2.5 mg/kg IV every 18 hours. Subsequent dosing
should be individualized by monitoring serum drug concentrations. When ECMO is
discontinued, dosage adjustment may be required.
For the management of bronchiectasis in cystic fibrosis patients with
Pseudomonas aeruginosa:
Intravenous dosage:
Adults, adolescents, and children: 3—3.3 mg/kg IV every 8 hours. Dosage
should be adjusted, if necessary, to achieve a peak serum concentration of
8—12 µg/ml and trough concentration < 2 µg/ml.
Nebulized dosage†:
Adults, adolescents, and children >= 6 years: Although no definitive
dosage can be provided, the most recent study of an aminoglycoside in this
setting involved tobramycin 600 mg three times daily for 28 days. In December
1997, tobramycin nebulized solution was approved for this indication at a dose
of 300 mg via inhalation twice daily.
For intraperitoneal administration to treat systemic infections in patients
with no IV access when IM administration is not acceptable:
Intraperitoneal dosage:
Adults and children: 1.5—2 mg/kg per dose intraperitoneally.
For the treatment of peritoneal dialysis-associated peritonitis in patients
with end-stage renal disease:
Intraperitoneal dosage:
Adults and children: Intraperitoneal (IP) gentamicin can administered in
each dialysate exchange bag at a dose of 4—8 mg/L; doses of 6—8 mg/L IP
should be used for documented pseudomonas infections. Higher doses of 12 mg/L IP
per exchange bag have also been used. Alternatively, an IP dose of 20 mg/L can
be administered in one exchange bag per day.
For the treatment of pelvic inflammatory disease (PID) with or without
complications of tubo-ovarian abscess in combination with other antibiotics:
Parenteral dosage:
Adults and adolescents: The CDC recommends gentamicin 2 mg/kg IV or IM
loading dose, followed by an appropriate maintenance dose (e.g., 1.5 mg/kg IV
every 8 hours) in combination with clindamycin IV. Single daily dosing or
"pulse" dosing (e.g., 4—7 mg/kg IV) may be used as an alternative to
traditional gentamicin dosing. Parenteral therapy may be discontinued 24 hours
after a patient improves clinically; therapy should be continued with oral
doxycycline or oral clindamycin to complete a total of 14 days of therapy.
Alternatively, gentamicin 2 mg/kg IV or IM loading dose, followed by an
appropriate maintenance dose (e.g., 1.5 mg/kg IV every 8 hours) in combination
with clindamycin IV and ampicillin IV (i.e., triple therapy) has been
recommended, particularly when PID is complicated by tubo-ovarian abscess.
For intrathecal administration in patients with meningitis due to susceptible
organisms:
Intrathecal dosage (preservative free intrathecal injection):
Adults: 4—8 mg intrathecally once daily in combination with parenteral
therapy.
Children and infants > 3 months: 1—2 mg intrathecally once daily in
combination with parenteral therapy.
Neonates: 1 mg intrathecally once daily in combination with parenteral therapy.
For bacterial endocarditis prophylaxis in high risk patients undergoing
gastrointestinal/genitourinary (excluding esophageal) procedures:
Intravenous or Intramuscular dosage:
Adults and children: 1.5 mg/kg (max: 120 mg) IV or IM with ampicillin 30
minutes prior to the procedure.
•in high risk patients allergic to ampicillin/amoxicillin:
Intravenous or Intramuscular dosage:
Adults and children: 1.5 mg/kg (max: 120 mg) IV or IM with vancomycin 30
minutes prior to surgery or the procedure.
For surgical prophylaxis in patients undergoing GI, biliary, or GU
procedures:
Intravenous or Intramuscular dosage:
Adults: 1.5 mg/kg (max: 80mg) IV or IM with ampicillin or vancomycin 30
minutes prior to surgery or the procedure. Repeat dose in 8 hours.
Children: 2 mg/kg (max: 80mg) IV or IM with ampicillin or vancomycin 30
minutes prior to surgery or the procedure. Repeat in 8 hours. The second dose
should be half the initial dose.
For the treatment of minor bacterial skin infection, folliculitis,
furunculosis, and paronychia caused by staphylococci, streptococci, Proteus
vulgaris, Escherichia coli, Pseudomonas aeruginosa, and Enterobacter sp.:
Topical dosage:
Adults and children: Apply to the affected skin area 3—4 times a day.
For the treatment of blepharitis, blepharoconjunctivitis, bacterial
conjunctivitis, dacryocystitis, keratitis, keratoconjunctivitis, and acute
meibomianitis caused by coagulase-postive and coagulase-negative staphylococci,
indole-positive and indole-negative Proteus species, Escherichia coli,
Pseudomonas aeruginosa, Klebsiella pneumoniae, Hemophilus influenzae, H.
aegyptius, Moraxella lacunata (Morax-Axenfeld bacillus), Enterobacter aerogenes,
and Neisseria species, including N. gonorrhoeae:
Ophthalmic dosage (ointment):
Adults and children: Apply a thin strip to the conjunctiva ( approx. =
1cm) every 8—12 hours. For severe infections, apply every 3—4 hours.
Ophthalmic dosage (solution):
Adults and children: Instill 1 drop onto the infected eye every 4 hours.
For severe infections, instill every 1 hour.
Patients with renal impairment:
CrCl > 70 ml/min: reduce dose by multiplying maintenance dose by 0.85 and
administer IV every 8—12 hours. Adjust doses based on serum concentrations and
organism MIC.
CrCl 50—69 ml/min: reduce dose by multiplying maintenance dose by 0.85 and
administer IV every 12 hours. Adjust doses based on serum concentrations and
organism MIC.
CrCl 25—49 ml/min: reduce dose by multiplying maintenance dose by 0.85 and
administer IV every 24 hours. Adjust doses based on serum concentrations and
organism MIC.
CrCl <25 ml/min: reduce dose by multiplying maintenance dose by 0.85 and
administer IV doses based on serum concentrations.
Intermittent hemodialysis:
Adults: 1—1.7 mg/kg IV or IM after the initial hemodialysis session.
Subsequent doses should be guided by serum gentamicin concentrations.
Children: 2 mg/kg IV or IM after the initial hemodialysis session.
Subsequent doses should be guided by serum gentamicin concentrations.
†non-FDA-approved indication
NOTE: Dosing of aminoglycosides is highly variable. Factors such as patient
size, renal function, site of infection, and organism susceptibility should all
be considered. In patients who are overweight, the following equation should be
used to determine the appropriate weight for dosage calculations: [(total body
weight - ideal body weight) x 0.4] + ideal body weight. While dosing has
traditionally been based on patient size, recently, importance has been placed
on achieving peak concentrations in several-fold excess of the organism's MIC.
Most urinary tract infections may be adequately treated with lower peak serum
concentrations, however pulmonary infections in general may require much higher
peak serum concentrations to achieve adequate tissue penetration and killing.
Serum trough concentrations of gentamicin should remain below 2 µg/ml to
minimize potential toxicities. Individualization of dosage should be designed to
achieve a peak serum concentrations in several-fold excess of the MIC, achieving
optimal concentration-dependent bacterial activity. As the practice of dosing
based on the organism's MIC becomes more widespread, traditional dosing methods
will no longer be appropriate.
Pulse dose intravenous therapy (often referred to as "single-daily
dosing" or "once-daily dosing") satisfies the goal of producing
serum concentrations that exceed the MIC by several-fold while simultaneously
taking advantage of the PAE in susceptible gram-negative bacteria. This
high-dose, extended interval dosing does not appear to increase the risk of
toxicity and may actually reduce it. High-dose pulse therapy is not advocated in
pregnancy, pediatrics, renal failure, and is usually unnecessary in the
treatment of urinary tract infections.
Ophthalmic administration
•Apply topically to the eye. Solution is not for injection; for ophthalmic use
only.
•Instruct patient on proper instillation of eye ointment or solution (see
Patient Information).
•Do not to touch the tip of the tube or dropper to the eye, fingertips, or
other surface.
Topical administration
•Rub cream or ointment gently into cleansed affected area. Care should be
taken to avoid further contamination of the infected skin.
•Treated area may be covered with sterile gauze if desired.
Parenteral administration
•Visually inspect parenteral products for particulate matter and discoloration
prior to administration whenever solution and container permit.
Intravenous infusion:
•If injection for dilution is used, the calculated dose is added to 50—200
ml of D5W or NS.
•Infuse IV over 30 minutes to 2 hours.
Intramuscular injection:
•Use only if IV route is unavailable because IM absorption is erratic.
•Inject deeply into a large muscle mass. Aspirate prior to injection to avoid
injection into a blood vessel.
Intrathecal/intraventricular administration:
•The appropriate dose of the preservative-free injection should be drawn into
a 5—10 ml syringe.
•After puncture is complete and CSF culture specimens obtained, insert the
syringe containing gentamicin into the hub of the spinal needle.
•Allow CSF ( approx. = 10% of estimated CSF total volume) to flow into the
syringe and mix with the drug.
•Inject intrathecally or intraventricularly over 3—5 minutes with the bevel
of the needle directed upward.
Gentamicin should be used cautiously in patients with renal impairment or
dehydration. Gentamicin is eliminated via glomerular filtration and can
accumulate in patients with renal dysfunction. Gentamicin also should be used
cautiously in patients with other types of renal disease since it is nephrotoxic
and can worsen the underlying condition.
Although gentamicin is not absolutely contraindicated during pregnancy, it
should not be considered free from risk. Streptomycin, a related aminoglycoside,
is known to be ototoxic to the fetus. While gentamicin is less ototoxic than
streptomycin, it retains the potential for causing similar toxicity.
Patients should be monitored for ototoxicity or nephrotoxicity if more than
several days of therapy with gentamicin is anticipated (see Adverse Reactions).
Ototoxicity can be manifest as vertigo or high-frequency hearing loss, since
both cochlear and vestibular toxicity occur. Aminoglycosides should be used with
caution in patients with hearing impairment, especially eighth-cranial-nerve
impairment, because of the risk of ototoxicity. Nephrotoxicity can be manifest
as renal insufficiency or acute renal failure. Neonates (age <1 month) and
elderly patients (age >65 years) may be at increased risk.
Aminoglycosides may cause severe neuromuscular weakness lasting hours to days
because of their potential curare-like effect. Aminoglycosides may aggravate
muscle weakness in patients with muscular disorders such as myasthenia gravis,
infant botulism, or parkinsonism.
Patients with aminoglycoside
hypersensitivity should not receive gentamicin. Allergenic reactions
to aminoglycosides are generally uncommon, but hypersensitivity with one agent
may demonstrate cross sensitivity with another aminoglycoside.
Additive nephrotoxicity is possible if gentamicin is used with any of the
following: acyclovir,
amphotericin B, other aminoglycosides, carboplatin, cidofovir, cisplatin,
cyclosporine, and vancomycin. The combination of gentamicin and cidofovir is
contraindicated. Gentamicin should be discontinued 7 days prior to beginning
cidofovir.
Dimenhydrinate and other antiemetics should be used carefully with gentamicin
because they can mask symptoms of ototoxicity (e.g., nausea secondary to
vertigo).
Aminoglycosides can cause neuromuscular blockade when used to irrigate the
abdominal cavity during surgery. It is believed that this problem is less likely
to occur with parenteral aminoglycoside therapy since patients are exposed to
smaller amounts of drug. Nevertheless, patients receiving depolarizing or
nondepolarizing neuromuscular blockers and/or general anesthetics should be
observed for exaggerated effects if they are receiving gentamicin.
Ethacrynic acid and, to a lesser extent, furosemide are ototoxic. Ototoxicity is
additive when administered concomitantly with gentamicin. Bumetanide appears to
be less of a risk.
Certain penicillins, such as carbenicillin and ticarcillin, have been shown to
bind to and inactivate gentamicin in vitro and in vivo. Phlebotomy
samples for assaying gentamicin should be either assayed immediately or frozen
if the patient is also receiving parenteral carbenicillin or ticarcillin.
Indomethacin has been shown to increase serum aminoglycoside concentrations in
premature infants receiving indomethacin for patent ductus arteriosus. Urine
output decreased and serum creatinine increased in these infants during
indomethacin administration. It is likely that other NSAIDs may cause a similar
interaction with aminoglycosides. Although data regarding these interactions in
adults are not available, serum aminoglycoside concentrations should be
monitored carefully in patients receiving aminoglycosides and indomethacin
concurrently. It is possible that additive nephrotoxicity may occur in patients
who receive aminoglycosides and NSAIDs concomitantly.
Some surfactant-anti-infective mixtures have been shown to affect the in vivo
activity of exogenous pulmonary surfactants when they are administered via
inhalation. Pulmonary surfactants (e.g., beractant, calfactant, poractant alfa,
and colfosceril; cetyl alcohol; tyloxapol) should not be mixed with anti-infectives
that are commonly administered via nebulization such as aminoglycosides,
amphotericin B, ceftazidime, pentamidine, or vancomycin.
Nephrotoxicity is a well-known adverse reaction to gentamicin and other
aminoglycoside antibiotics. Aminoglycoside antibiotics are taken up by lysosomes
in cells lining the proximal tubule, which, in turn, leads to necrosis and/or
fibrosis. With continued exposure, interstitial fibrosis, renal tubular
necrosis, and renal tubular acidosis occur. If aminoglycoside therapy is
discontinued prior to this, renal dysfunction can be reversible. Although it is
commonly believed that maintaining gentamicin serum concentrations within
traditional ranges minimizes the risk of nephrotoxicity, some patients still
experience azotemia.
Worsening of creatinine clearance, hyposthenuria (loss of concentrating
ability), pyuria (increased WBCs), proteinuria, and cylindruria (cells or casts
in the urine) are all manifestations of nephrotoxicity; oliguria occurs rarely.
Various studies have identified risk factors for developing nephrotoxicity from
aminoglycosides: excessive trough serum concentrations, use of other nephrotoxic
agents, total dose or treatment duration, and preexisting renal disease.
Finally, new approaches to clinical dosing of gentamicin can reduce the
incidence of nephrotoxicity. Interstitial nephritis, generally thought to be a
hypersensitivity reaction, has been reported with gentamicin.
Ototoxicity can occur during gentamicin therapy. This can be manifest as
high-frequency hearing loss, tinnitus, vertigo, dizziness, or nausea, since
either cochlear or vestibular toxicity is possible. Although some believe that
peak serum concentrations predict ototoxicity, a firm association has not been
made. Uptake of drug into the inner ear can occur more readily in patients who
develop ototoxicity. Factors that increase risk include total duration of
exposure to aminoglycoside and concomitant use of ototoxic drugs such as
ethacrynic acid. Audiograms should be performed in patients who receive repeated
or prolonged courses of therapy with gentamicin.
Neuromuscular blockade causing myasthenia has occurred with neomycin
intra-abdominal irrigation. Since gentamicin is chemically related to neomycin,
the possibility of this reaction should be considered, although the risk appears
to be low.
Irritation after IM injection of gentamicin has also has been reported. Patients
should be observed for any injection site reaction after IM injection.
Gentamicin has been possibly associated with pseudotumor cerebri (benign
intracranial hypertension). The exact incidence of this adverse effect is
unknown.
Relative Drug Costs
• generic available
• Aminoglycoside (Parenteral) Cost Index: 1
• Antibiotic (Parenteral) Cost Index: 1
Monitoring Parameters
• audiometry: baseline in patients expected to receive prolonged therapy
• serum creatinine/BUN: baseline and periodically during prolonged therapy
• serum aminoglycoside concentrations
Medication Costs
• 80 mg IV q8h: $3.00—3.99/day
• 120 mg IV q8h: $5.00—5.99/day
• 200 mg IV q24h: $1.00—1.49/day
[ Revised 2/7/00 ]
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