2. Aminoglycosides are used for the treatment of
serious infections due to
aerobic gram-negative bacilli.
However, their clinical utility is limited by
serious toxicities. Aminoglycosides are
derived from Streptomyces
4. MECHANISM OF ACTION
• Bactericidal antibiotics.
• All have the same general pattern of action described in two main
steps:
(a) Transport of the aminoglycoside through the bacterial cell wall and
cytoplasmic membrane.
(b) Binding to 30S ribosomes resulting in inhibition of protein
synthesis, where they interfere with assembly of the functional
ribosomal apparatus and/or cause the 30S subunit of the completed
ribosome to misread the genetic code.
5. Antibacterial spectrum
Effective for the majority of aerobic gram negative bacilli, including
those that may be multidrug resistant, such as Pseudomonas
aeruginosa, Klebsiella pneumoniae, and Enterobacter sp.
Aminoglycosides are often combined with a β-lactam antibiotic to
employ a synergistic effect, particularly in the treatment of
Enterococcus faecalis and Enterococcus faecium infective
endocarditis.
6. Resistance
Resistance to aminoglycosides occurs via:
1) efflux pumps,
2) decreased uptake, and/or
3) modification and inactivation by plasmid-associated
synthesis of enzymes. Each of these enzymes has its own
aminoglycoside specificity; therefore, cross-resistance cannot
be presumed.
[Note: Amikacin is less vulnerable to these enzymes than other
antibiotics in this group]
7. Pharmacokinetics
Absorption:
• The highly polar, polycationic structure of the aminoglycosides
prevents adequate absorption after oral administration.
• Therefore, all aminoglycosides (except neomycin) must be given
parenterally to achieve adequate serum levels
• Neomycin is not given parenterally due to severe nephrotoxicity. It is
administered topically for skin infections
• or orally for bowel preparation prior to colorectal surgery.
8. Elimination:
• More than 90% of the
parenteral
aminoglycosides are
excreted unchanged in
the urine
• Accumulation occurs in
patients with renal
dysfunction, and dose
adjustments are require
9. Uses - i
Gentamicin is the cheapest (other than streptomycin) and the first line
aminoglycoside antibiotic.
Preventing and treating respiratory infections in critically ill patients;
those with impaired host defence (receiving anticancer drugs or high-dose
corticosteroids; AIDS), patients in resuscitation wards, with tracheostomy
or on respirators; postoperative pneumonias; patients with implants and
in intensive care units.
• Often combined with a penicillin/cephalosporin or another antibiotic in
these situations.
• It is often added when a combination antibiotic regimen is used
empirically to treat serious infections by extending the spectrum of
coverage.
• Because of low therapeutic index, its use should be restricted to serious
gram-negative bacillary infections.
10. Uses - ii
• Meningitis caused by gram negative bacilli: Because this is a serious
condition, drug combinations including an aminoglycoside are often
used.
• Subacute bacterial endocarditis (SABE): Gentamicin (1 mg/kg 8 hourly
i.m.) is generally combined with penicillin/ampicillin/vancomycin.
• Pseudomonas, Proteus or Klebsiella infections: burns, urinary tract infection,
pneumonia, lung abscesses, osteomyelitis, middle ear infection,
septicaemia, etc., caused mostly by the above bacteria are an important
area of use of gentamicin. It may be combined with piperacillin or a third
generation cephalosporin for serious infections.
12. Adverse effects - i
1. Ototoxicity:
• Ototoxicity (vestibular and auditory) is due to high peak plasma levels and the
duration of treatment.
• The antibiotic accumulates in endolymph and perilymph of the inner ear. Deafness
may be irreversible and can affect developing fetuses.
• Patients simultaneously receiving concomitant ototoxic drugs, such as cisplatin or
loop diuretics, are particularly at risk.
• Vertigo (especially in patients receiving streptomycin) may also occur.
2. Nephrotoxicity:
• Retention of the aminoglycosides by the proximal tubular cells disrupts calcium-
mediated transport processes.
This results in kidney damage ranging from mild, reversible renal impairment to
severe, potentially irreversible, acute tubular necrosis.
13. Adverse effects - ii
3. Neuromuscular paralysis:
• Associated with rapid increase in concentrations (for example, high
doses infused over a short period) or concurrent administration with
neuromuscular blockers.
• Patients with myasthenia gravis are particularly at risk.
• Prompt administration of calcium gluconate or neostigmine can
reverse the block that causes neuromuscular paralysis.
4. Allergic reactions:
• Contact dermatitis is a common reaction to topically applied
neomycin.
14. PRECAUTIONS AND INTERACTIONS
1. Avoid aminoglycosides during pregnancy: risk of foetal
ototoxicity.
2. Avoid concurrent use of other nephrotoxic drugs, e.g. NSAIDs,
amphotericin B, vancomycin, cyclosporine and cisplatin.
3. Cautious use of other potentially ototoxic drugs like vancomycin,
minocycline
4. Cautious use in patients >60 years age and in those with kidney
damage.
5. Cautious use of muscle relaxants in patients receiving an
aminoglycoside.
6. Do not mix aminoglycoside with any drug in the same
syringe/infusion bottle.
17. Mechanism of action
•The macrolides bind irreversibly to a site on the 50S
subunit of the bacterial ribosome, thus inhibiting
translocation steps of protein Synthesis.
•They may also interfere with other steps, such as
transpeptidation.
•Considered to be bacteriostatic, but may be
bactericidal at higher doses.
18. Antibacterial spectrum - i
1. Erythromycin: Effective against same organisms as penicillin G.
Therefore, it may be used in patients with penicillin allergy.
Streptococcal pharyngitis, tonsillitis, mastoiditis and
community acquired respiratory infections caused by
pneumococci and H.influenzae respond equally well to
erythromycin.
It is an alternative drug for prophylaxis of rheumatic fever
and SABE.
19. Antibacterial spectrum - ii
Diphtheria: Acute stage as well as for carriers—7 day
treatment is recommended.
Tetanus: as an adjuvant to antitoxin, toxoid therapy.
Syphilis and gonorrhoea: only if other alternative
drugs, including tetracyclines als cannot be used.
Leptospirosis: In patients allergic to penicillins.
20. Antibacterial spectrum - iii
2. Clarithromycin: Clarithromycin has activity
similar to erythromycin, but also effective against
H. influenzae.
Its activity against intracellular pathogens, such
as Chlamydia, Legionella, Moraxella,
Ureaplasma species and Helicobacter pylori, is
higher than that of erythromycin.
21. Antibacterial spectrum - iii
3. Azithromycin: Less active against streptococci and staphylococci than
erythromycin, but more active against respiratory infections due to H. influenzae
and Moraxella catarrhalis.
Azithromycin is the preferred therapy for urethritis caused by Chlamydia
trachomatis.
Mycobacterium avium is preferentially treated with a macrolide-containing
regimen, including clarithromycin or azithromycin.
The other indications are pharyngitis, tonsillitis, sinusitis, otitis media,
pneumonias, acute exacerbations of chronic bronchitis, streptococcal and some
staphylococcal skin and soft tissue infections.
Multidrug resistant typhoid fever in patients allergic to cephalosporins; and in
toxoplasmosis.
22. Pharmacokinetics - i
•Erythromycin is destroyed by gastric acid. Thus,
either enteric-coated tablets or esterified forms of the
antibiotic are administered.
•All are adequately absorbed upon oral administration
Clarithromycin, azithromycin, and telithromycin are
stable in stomach acid and are readily absorbed.
•Food interferes with the absorption of erythromycin
and azithromycin but can increase that of
clarithromycin.
• Erythromycin and azithromycin are available in IV
formulations
23. Pharmacokinetics - ii
Excretion:
• Erythromycin and azithromycin are primarily
concentrated and excreted in the bile as active drugs.
•Partial reabsorption occurs through the enterohepatic
circulation.
•Clarithromycin and its metabolites are eliminated by
the kidney as well as the liver. The dosage of this drug
should be adjusted in patients with renal impairment.
24. Adverse effects
1. Gastric distress and motility: Most common adverse effect of the macrolides
and may lead to poor patient compliances especially erythromycin. Azithromycin
and clarithromycin seem to be better tolerated.
• Higher doses of erythromycin lead to smooth muscle contractions that result in
the movement of gastric contents to the duodenum, an adverse effect sometimes
used therapeutically for the treatment of gastroparesis or postoperative ileus.
2. Cholestatic jaundice
3. Ototoxicity: Transient deafness has been associated with erythromycin, especially
at high dosages. Azithromycin has also been associated with irreversible
sensorineural hearing loss.
4. Hypersensitivity: Rashes and fever are infrequent.
25. Contraindications:
Patients with hepatic dysfunction should be treated
cautiously with erythromycin, telithromycin, or
azithromycin, because these drugs accumulate in the
liver. Severe hepatotoxicity with telithromycin has
limited its use, given the availability of alternative
therapies.
Macrolides may prolong the QTc interval and should
be used with caution in those patients with
proarrhythmic conditions or concomitant use of
proarrhythmic agents.
26. Drug interactions:
• Erythromycin, telithromycin, and clarithromycin inhibit the
hepatic metabolism of a number of drugs, which can lead
to toxic accumulation of these compounds.
• An interaction with digoxin may occur. In this case, the
antibiotic eliminates a species of intestinal flora that
ordinarily inactivates digoxin, thus leading to greater
reabsorption of the drug from the enterohepatic
circulation.
29. Clindamycin:
MOA
This potent lincosamide antibiotic is similar in mechanism of action
(inhibits protein synthesis by binding to 50S ribosome) and
spectrum of activity to erythromycin.
Spectrum of activity
Clindamycin inhibits most gram positive cocci (including most
species of streptococci, penicillinase producing Staph.
pharmacokinetics
Oral absorption of clindamycin is good. It penetrates into most
skeletal and soft tissues, but not in brain and CSF; accumulates in
neutrophils and macrophages.
30. use of clindamycin:
Restricted to anaerobic and mixed infections, especially those involving
Bact. fragilis causing abdominal, pelvic and lung abscesses. It is a first line
drug for these conditions, and is generally combined with an
aminoglycoside or a cephalosporin.
Metronidazole and chloramphenicol are the alternatives to clindamycin
for covering the anaerobes. Skin and soft tissue infections in patients
allergic to penicillins can be treated with clindamycin.
Anaerobic streptococcal and Cl. Perfringens infections, especially those
involving bone and joints respond well.
31. Uses of clindamycin - ii
prophylaxis of endocarditis in penicillin allergic patients with
valvular defects who undergo dental surgery, as well as to prevent
surgical site infection in colorectal/pelvic surgery.
In AIDS patients, it has been combined with pyrimethamine for
toxoplasmosis and with primaquine or Pneumocystis jiroveci
pneumonia.
It is an alternative to doxycycline for supplementing
quinine/artesunate in treating multidrug resistant falciparum
malaria.
Topically it is used for infected acne vulgaris.
33. Vancomycin:
MOA
Acts by inhibiting bacterial cell wall synthesis
Toxicity:
Systemic toxicity of vancomycin is
high. It can cause plasma concentration-dependent nerve deafness
which may be permanent.
Kidney damage is also dose-related. Other oto and nephrotoxic
drugs like aminoglycosides must be very carefully administered
34. Uses:
Given orally (125–500 mg 6 hourly), it is the second choice
drug to metronidazole for antibiotic associated
pseudomembranous enterocolitis caused by C. difficile.
Staphylococcal enterocolitis is another indication of oral
vancomycin.
It is an alternative drug for serious skin, soft tissue and
skeletal infections in which gram-positive bacteria are
mostly causative.
35. Uses:
For empirical therapy of bacterial meningitis, i.v. vancomycin is
usually combined with i.v. ceftriaxone/cefotaxime.
It is also used in dialysis patients and those undergoing cancer
chemotherapy.
Vancomycin is the preferred surgical prophylactic in MRSA
prevalent areas and in penicillin allergic patients.
Penicillin-resistant pneumococcal infections and infection
caused by diphtheroids respond very well to vancomycin.
