Aminoglycosides.pptx

Aminoglycosides

1. Subramaani Parasuraman Faculty of Pharmacy AIMST University Malaysia Aminoglycosides

2. Aminoglycosides Aminoglycosides are natural products or semisynthetic derivatives of highly water-soluble compounds produced by a variety of soil actinomycetes. Streptomycin was the first member discovered in 1944 by Waksman and his colleagues. Amikacin, a derivative of kanamycin, and netilmicin, a derivative of sisomicin , are semisynthetic products.

3. Aminoglycosides Aminoglycosides ( gentamicin, tobramycin, amikacin, netilmicin, kanamycin, streptomycin, paromomycin, and neomycin ) are used primarily to treat infections caused by aerobic gram-negative bacteria. Streptomycin and amikacin are important agents for the treatment of mycobacterial infections, and paromomycin is used orally for intestinal amebiasis. Aminoglycosides are bactericidal inhibitors of protein synthesis.

4. Mechanism of action The aminoglycoside antibiotics are rapidly bactericidal . Bacterial killing is concentration dependent: the higher the concentration, the greater the rate of bacterial killing. Aminoglycosides diffuse through porin channels in the outer membrane of susceptible organisms. Transport of aminoglycosides across the cytoplasmic (inner) membrane depends on a transmembrane electrical gradient coupled to electron transport to drive permeation of these antibiotics. Once inside the bacterial cell, streptomycin binds to 30S ribosomes , but other aminoglycosides bind to additional sites on 50S subunit , as well as to 30S-50S interface.

5. Mechanism of action Aminoglycosides aminoglycosides bind to polysomes and interfere with protein synthesis by causing misreading and premature termination of mRNA translation. Aminoglycoside (represented by red circles) binds to the 30S ribosomal subunit and interferes with initiation of protein synthesis by fixing the 30S-50S ribosomal complex at the start codon (AUG) of mRNA.

6. Antimicrobial Activity Aminoglycosides have concentration-dependent bactericidal activity. The antibacterial activity of gentamicin, tobramycin, and amikacin is directed primarily against aerobic gram-negative bacilli . Aminoglycosides have little activity against anaerobic microorganisms or facultative bacteria under anaerobic conditions. Their action against most gram-positive bacteria is limited, and they should not be used as single agents to treat infections caused by gram-positive bacteria .

7. Antimicrobial Activity Aminoglycosides also exhibit a postantibiotic effect (PAE), which is continued bacterial suppression after drug concentrations fall below the MIC. Susceptibility to aminoglycosides and typical minimal concentrations that will inhibit 90% (MIC90) of clinical isolates for several species

8. Resistance to the Aminoglycosides Bacteria may be resistant to aminoglycosides through inactivation of the drug by microbial enzymes failure of the antibiotic to penetrate intracellularly low affinity of the drug for the bacterial ribosome

9. 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 concentrations. Distribution: Because of their hydrophilicity, aminoglycoside tissue concentrations may be subtherapeutic and penetration into most body fluids is variable. Concentrations achieved in CSF are inadequate.

10. Pharmacokinetics Elimination: More than 90% of the parenteral aminoglycosides are excreted unchanged in the urine . Accumulation occurs in patients with renal dysfunction; thus, dose adjustments are required. Neomycin is primarily excreted unchanged in the feces . Protein binding: Aminoglycosides are reported to have low protein binding.

11. Therapeutic Uses of Aminoglycosides Urinary Tract Infections: Aminoglycosides are well-suitable for treatment of urinary tract infections, less-toxic alternatives are preferred for uncomplicated infections. single intramuscular dose of gentamicin (5 mg/kg) has been effective in uncomplicated infections of the lower urinary tract. A 10- to 14-day course of gentamicin or tobramycin is an alternative for treatment of pyelonephritis if other agents cannot be used.

12. Therapeutic Uses of Aminoglycosides Pneumonia: Community-acquired pneumonia are susceptible to broad-spectrum β-lactam antibiotics, macrolides, or a fluoroquinolone, and usually it is not necessary to add an aminoglycoside. Aminoglycosides are ineffective for the treatment of pneumonia due to anaerobes. Aminoglycoside in combination with a β-lactam antibiotic is recommended as standard empiric therapy to treat hospital-acquired pneumonia caused by aerobic multidrug-resistant gram-negative bacilli.

13. Therapeutic Uses of Aminoglycosides Meningitis: Third-generation cephalosporins, especially cefotaxime and ceftriaxone, has reduced the need for treatment with aminoglycosides in most cases of meningitis, except for infections caused by gram-negative organisms resistant to β-lactam antibiotics. If an aminoglycoside is necessary, direct instillation into the CNS is likely to achieve therapeutic levels than intravenous administration.

14. Therapeutic Uses of Aminoglycosides Peritonitis: Patients who develop peritonitis as a result of peritoneal dialysis may be treated with aminoglycoside (gentamicin, netilmicin, or tobramycin or amikacin). Sepsis: An aminoglycoside in an empirical regimen is commonly recommended for the febrile patient with neutropenia and for sepsis when P. aeruginosa is a potential pathogen. Tularemia ( also known as “rabbit fever” ): Streptomycin (or gentamicin) is the drug of choice for the treatment of tularemia .

15. Therapeutic Uses of Aminoglycosides Bacterial Endocarditis: “Synergistic” or low-dose gentamicin (3 mg/kg/d) in combination with a penicillin or vancomycin has been recommended in certain circumstances for treatment of bacterial endocarditis due to certain gram-positive organisms. For this indication, the administration of gentamicin may be given as a consolidated once-daily dose . Penicillin and gentamicin in combination are effective as a shortcourse (i.e., 2-week) regimen. In cases of enterococcal endocarditis, concomitant administration of penicillin (or ampicillin) and gentamicin (given as divided doses) for 4–6 weeks is recommended as standard therapy.

16. Therapeutic Uses of Aminoglycosides Plague A 10-day treatment course of streptomycin or gentamicin is recommended for severe forms of plague. Mycobacterial Infections Streptomycin is a second-line agent for the treatment of active tuberculosis Amikacin is another alternative agent for infections due to drug-resistant Mycobacterium tuberculosis

17. Therapeutic Uses of Aminoglycosides Cystic Fibrosis Aminoglycosides (tobramycin) are frequently used as therapy during acute exacerbations of cystic fibrosis. Topical Applications Aminoglycosides, especially neomycin and paromomycin, may be employed as topical agents in skin and mucous membrane infections.

18. Therapeutic Uses of Individual Aminoglycosides

19. Adverse effects Therapeutic drug monitoring of gentamicin, tobramycin, and amikacin plasma concentrations is imperative to ensure appropriateness of dosing and to minimize dose-related toxicities. The elderly are particularly susceptible to nephrotoxicity and ototoxicity. Ototoxicity: Ototoxicity (vestibular and auditory) is directly related to high peak plasma concentrations and the duration of treatment. Nephrotoxicity (kidney damage ranging from mild, reversible renal impairment to severe, potentially irreversible acute tubular necrosis) Neuromuscular paralysis (associated with a rapid increase in concentration) Allergic reactions (dermatitis is a common reaction to topically applied neomycin)

20. Precautions and Interactions Avoid aminoglycosides during pregnancy due to risk of foetal ototoxicity. Avoid concurrent use of other nephrotoxic drugs, e.g. NSAIDs, amphotericin B, vancomycin, cyclosporine and cisplatin. Cautious use of other potentially ototoxic drugs like vancomycin, minocycline and furosemide. Cautious use in patients >60 years age and in those with kidney damage. Do not mix aminoglycoside with any drug in the same syringe/infusion bottle.

21. Ref: https://tmedweb.tulane.edu/pharmwiki/doku.php/aminoglycosides ; last assessed on 04/05/2022