Aminoglycosides

Dr. Liaqat Hussain

• AMINOGLYCOSIDES
• The aminoglycosides include streptomycin, neomycin, kanamycin, amikacin,
gentamicin, tobramycin, sisomicin, netilmicin, and others.
• They are used most widely in combination with other agents to treat drug-
resistant organisms; for example, they are used with a β-lactam antibiotic in
serious infections with Gram-negative bacteria,
• with a β-lactam antibiotic or vancomycin for Gram-positive endocarditis, and
with one or more agents for treatment of mycobacterial infections, such as
tuberculosis.
• 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 .
• They are water-soluble, stable in solution, and more active at alkaline than at acid
pH.
• B. Mechanism of Action
• Aminoglycosides are irreversible inhibitors of protein synthesis, but the precise
mechanism for bactericidal activity is unclear.
• The initial event is passive diffusion via porin channels across the outer
membrane.
• 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 those
antibiotics with aminoglycosides.
• Inside the cell, aminoglycosides bind to 30S-subunit ribosomal proteins.
• Protein synthesis is inhibited by aminoglycosides in at least three ways;
• (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 protein;
• (3) breakup of polysomes into nonfunctional monosomes.
• These activities occur more or less simultaneously, and the overall effect is
irreversible and leads to cell death.
• C. Mechanisms of Resistance
• Three principal mechanisms of resistance have been established:
• (1) production of a transferase enzyme that inactivates the aminoglycoside by
adenylylation, acetylation, or phosphorylation. This is the principal type of
resistance encountered clinically.
• (2) There is impaired entry of aminoglycoside into the cell. This may result from
mutation or deletion of a porin protein involved in transport and maintenance of
the electrochemical gradient or from growth conditions under which the oxygen-
dependent transport process 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 GIT tract, and almost
the entire oral dose is excreted in feces after oral administration.
• However, the drugs may be absorbed if ulcerations are present.
• Aminoglycosides are usually administered intravenously as a 30–60 minute
infusion.
• After intramuscular injection, aminoglycosides are well absorbed, giving peak
concentrations in blood within 30–90 minutes.
• 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
• In the presence of active inflammation, 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, the level may reach
30% of that in blood.
• With prolonged therapy, diffusion into pleural or synovial fluid may result in
concentrations 50–90% of that of plasma.
• 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 for at least two reasons.
• Aminoglycosides exhibit concentration dependent killing; that is, higher
concentrations kill a larger proportion of bacteria and kill at a more rapid rate.
They also have a significant post antibiotic effect, such that the antibacterial
activity persists beyond the time during which measurable drug is present.
• The post antibiotic 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 may 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.
• This synergy may be important in certain clinical situations, such as endocarditis.
• Adverse effects from aminoglycosides 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 probably less toxic— than multiple smaller doses.
• Therefore, many authorities recommend that aminoglycosides be administered
as a single daily dose in most clinical situations
• However, the efficacy of once-daily aminoglycoside dosing in combination
therapy of enterococcal and staphylococcal endocarditis in patients with a
prosthetic valve remains to be defined, and administration of lower doses two or
three times daily is still recommended.
• In contrast, limited data do support once-daily dosing in streptococcal
endocarditis.
• The role of once-daily dosing in pregnancy, obesity, and in neonates also is not
well defined.
• Once-daily dosing has potential practical advantages.
• For example, repeated determinations of serum concentrations are unnecessary
unless an 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.
• Aminoglycosides are cleared by the kidney, and excretion is directly proportional to
creatinine clearance.
• To avoid accumulation and toxic levels, once-daily dosing of aminoglycosides is generally
avoided if renal function is impaired.
• E. 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 with 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
• Neomycin, kanamycin, and amikacin are the agents most likely to cause auditory
damage.
• 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, when given promptly, or
neostigmine.
• Hypersensitivity occurs infrequently.
• F. Clinical Uses
• Aminoglycosides are mostly used against aerobic Gram-negative bacteria,
especially when there is concern for drug-resistant pathogens or in critically ill
patients.
• They are almost always used in combination with a β-lactam antibiotic to extend
empiric coverage and to take advantage of the potential synergism between
these two classes of drugs.
• Penicillin-aminoglycoside combinations have also been used to achieve
bactericidal activity in treatment of enterococcal endocarditis and to shorten
duration of therapy for viridans streptococcal endocarditis.
• Due to toxicity, these combinations are used less frequently when alternate
regimens are available.
• For example, in the case of enterococcal endocarditis, studies suggest that the
combination of ampicillin and ceftriaxone is an effective regimen with less risk
for nephrotoxicity.
• STREPTOMYCIN
• Streptomycin 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, restricting 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
• A. Mycobacterial Infections
• Streptomycin is mainly used as a second-line agent for treatment of tuberculosis.
The dosage is 15 mg/kg/d with a maximum of 1 g/d (20–40 mg/kg/d for
children), and it may be given intramuscularly or intravenously.
• B. Nontuberculous Infections
• In plague, tularemia, and sometimes, brucellosis, streptomycin, 1 g twice daily
(15 mg/kg twice daily 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;
• however, for susceptible strains, gentamicin is used more commonly when an
aminoglycoside is selected as adjunct therapy.
• Streptomycin remains a useful agent for treating gentamicin non-susceptible
enterococcal infections, as some isolates that are resistant to gentamicin (and
therefore resistant to netilmicin, tobramycin, and amikacin) will remain
susceptible to streptomycin.
• Adverse Reactions
• Fever, skin rashes, and other allergic manifestations may result from
hypersensitivity to streptomycin.
• This occurs most frequently with a prolonged course of treatment (eg, for
tuberculosis).
• 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.
• GENTAMICIN
• Gentamicin is a mixture of three closely related constituents, C1, C1A, and C2
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.
• Antimicrobial Activity
• Gentamicin sulfate, 2–10 mcg/mL, inhibits in vitro many strains of staphylococci
and Gram-negative bacteria, including P. aeruginosa and Enterobacteriaceae.
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 some penicillins or vancomycinm
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 during monotherapy
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.
• B. Topical and Ocular 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 in attempts to
prevent intravenous catheter infections.
• The effectiveness of topical preparations for these indications is unclear.
• Topical gentamicin is partly inactivated by purulent exudates.
• Gentamicin can be injected intraocularly for treatment of certain eye infections.
• C. 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 upon drug discontinuation.
• It occurs in 5–25% of patients receiving gentamicin for longer than 3–5 days.
• Ototoxicity, which tends to be irreversible, manifests itself mainly as vestibular
dysfunction.
• Loss of hearing can also occur.
• 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 has an antibacterial spectrum similar to that of gentamicin.
• Although there is some cross resistance between gentamicin and tobramycin.
• A. Intramuscular or Intravenous Administration
• The pharmacokinetic properties of tobramycin are virtually identical with those of
gentamicin.
• The daily dose of tobramycin is 5–7 mg/kg intramuscularly or intravenously,
traditionally divided into three equal amounts and given every 8 hours but now
often given as a single daily dose.
• Tobramycin has almost the same antibacterial spectrum as gentamicin with a few
exceptions.
• Gentamicin is slightly more active against S marcescens, whereas tobramycin is
slightly more active against P aeruginosa; 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.
• B. Inhaled and Ophthalmic Administration
• Tobramycin is formulated in solution (300 mg in 5 mL) for inhalation for
treatment of P 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.
• Tobramycin is also available as 0.3% ophthalmic ointment and drops for the
treatment of superficial eye infections.
• These formulations result in minimal systemic absorption and are unlikely to
cause systemic adverse effects.
• AMIKACIN
• Amikacin is a semisynthetic derivative of kanamycin; it is less toxic than the
parent molecule.
• It is resistant to many enzymes that inactivate gentamicin and tobramycin, and,
therefore, can be used against some microorganisms resistant to the latter drugs.
• Many Gram-negative 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.
• 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,) 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.
• NEOMYCIN, KANAMYCIN, & PAROMOMYCIN
• Neomycin, kanamycin, and paromomycin have similar pharmacologic
• Properties.
• Antimicrobial Activity & Resistance
• Drugs of the neomycin group are active against Gram-positive and Gram-negative
bacteria and some mycobacteria.
• P aeruginosa and streptococci are generally resistant.
• Mechanisms of antibacterial action and resistance are the same as with other
aminoglycosides.
• The former widespread use of these drugs in bowel preparation for elective
surgery contributed to the selection of resistant organisms and some outbreaks
of enterocolitis in hospitals.
• Cross-resistance between kanamycin and neomycin is complete and may result in
amikacin cross-resistance.
• Pharmacokinetics
• Like all aminoglycosides, 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 is generally limited to topical and oral use.
• Paromomycin has been shown to be effective against visceral leishmaniasis.
• Paromomycin can be used for intestinal Entamoeba histolytica infection and is
sometimes used for intestinal infections with other parasites.
• A. Topical Administration
• Solutions containing 1–5 mg/mL neomycin have been 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.
• 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.
• B. Oral Administration
• In preparation for elective bowel surgery, 1 g of neomycin may be 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 encephalopathy, coliform flora can be suppressed by giving 1 g every 6–8
hours together with reduced protein intake, thus reducing ammonia production. Use of
neomycin for hepatic encephalopathy has been largely supplanted by lactulose and
• PLAZOMICIN
• Plazomicin is a new aminoglycoside under development and is expected to
undergo review by the U.S. Food and Drug Administration in 2017.
• It has been studied in phase II clinical trials for treatment of urinary tract
infections; phase III clinical trials are underway for treatment of carbapenem-
resistant Enterobacteriaceae.
• It appears to have similarly potent in vitro activity against Enterobacteriaceae and
displays two- to four-fold lower MICs against nonfermenting Gram-negative bacilli
(eg, P aeruginosa) when compared with gentamicin, tobramycin, and amikacin. It
has activity similar to gentamicin against staphylococci.
• Due to limited clinical experience, it is unclear whether the toxicity profile will be
similar to other aminoglycosides; however, no ototoxicity or nephrotoxicity has
been observed in early trials.
• Spectinomycin
• is an aminocyclitol antibiotic that is structurally related to aminoglycosides.
• It lacks amino sugars and glycosidic bonds.
• Spectinomycin is active in vitro against many Gram-positive and Gram-negative
organisms, but it is used almost solely as an alternative treatment for drug-
resistant gonorrhea or gonorrhea in penicillin-allergic patients.
• The majority of gonococcal isolates are inhibited by 6 mcg/mL of spectinomycin.
Strains of gonococci may be resistant to spectinomycin, but there is no cross-
resistance with other drugs used in gonorrhea.
• Notably, it is not recommended for treatment of pharyngeal gonococcal
infections due to high failure rates regardless of in vitro susceptibility.
• There is pain at the injection site and, occasionally, fever and nausea.
• Nephrotoxicity and anemia have been observed rarely.
• A 31-year-old man has gonorrhea. He has no drug allergies, but a few years ago
acute hemolysis followed use of an antimalarial drug. The physician is concerned
that the patient has an accompanying urethritis caused by C trachomatis,
although no cultures or enzyme tests have been performed. Which of the
following drugs will be reliably effective against both gonococci and C trachomatis
and safe to use in this patient?
• (A) Cefixime
• (B) Ciprofloxacin
• (C) Spectinomycin
• (D) Sulfamethoxazole-trimethoprim
• (E) None of the above
• Cefixime in a single oral dose is effective in gonorrhea
• (Chapter 43), but it has no activity against organisms causing
• nongonococcal urethritis. Spectinomycin (Chapter 45) is
• active against most gonococci, but does not eradicate a urogenital
• chlamydial infection. Although ciprofloxacin might
• be effective in both gonorrhea and chlamydial urethritis, it
• is no longer recommended for treatment of gonorrhea in the
• United States, since resistance is now common. This patient
• could be treated by single oral doses of cefixime plus azithromycin
• (not listed). Sulfamethoxazole or TMP-SMZ would
• not be useful and may cause acute hemolysis in this patient.
• The answer is E.
• A 40-year-old man complains of periodic bouts of diarrhea with lower abdominal
cramping and intermittent rectal bleeding. Seen in the clinic, he appears well
nourished, with blood pressure in the normal range. Examination reveals
moderate abdominal pain and tenderness. His current medications are limited to
loperamide for his diarrhea. Sigmoidoscopy reveals mucosal edema, friability, and
some pus. Laboratory findings include mild anemia and decreased serum
albumin. Microbiologic examination via stool cultures and mucosal biopsies do
not reveal any evidence for bacterial, amebic, or cytomegalovirus involvement.
The most appropriate drug to use in this patient is
• (A) Ampicillin
• (B) Doxycycline
• (C) Norfloxacin
• (D) Sulfasalazine
• (E) Trimethoprim-sulfamethoxazole
• In the absence of any evidence pointing toward a definite
• microbial cause for the colitis in this patient, a drug that
• decreases inflammation is indicated. Sulfasalazine has significant
• anti-inflammatory action, and its oral use results
• in symptomatic improvement in 50–75% of patients suffering
• from ulcerative colitis. The drug is also used for
• its anti-inflammatory effects in rheumatoid arthritis. The
• answer is D.
• A 5-d course of treatment for community-acquired pneumonia
• would be effective in this patient with little risk of drug interactions. if the drug
prescribed were
• (A) Azithromycin
• (B) Clindamycin
• (C) Doxycycline
• (D) Erythromycin
• (E) Vancomycin