Chapter 83 - Aminoglycosides - Bactericidal Inhibitors

CHAPTER 83

AMINOGLYCOSIDES: BACTERICIDAL INHIBITORS SYNTHESIS

OF

PROTEIN

Narrow-spectrum antibiotics used primarily against aerobic gram-negative bacilli. - not absorbed from the GI tract, therefore, must be administered parenterally

I.

BASIC PHARMACOLOGY

OF

AMINOGLYCOSIDES

- disrupt bacterial protein synthesis by: • inhibition of protein synthesis • premature termination of protein synthesis • production of abnormal proteins - limited almost exclusively to aerobic gram-negative bacilli - - cannot kill anaerobes 1.

Therapeutic Uses a. Parenteral Therapy – used for treatment of serious infections due to aerobic gram-negative bacilli -gentamicin, tobramycin, and amikacin b.

Oral Therapy – used only for local effects within the intestine - suppress bacterial growth in the bowel - treat intestinal amebiasis and tapeworm infestation

c. Topical Therapy – neomycin = available for application to the eyes, ears, and skin - gentamicin = available for application to the skin 2. Pharmacokinetics – very little oral dose absorption, therefore, must be given parenterally - distribution is limited largely to extracellular fluid - entry into CSF is insufficient to treat meningitis - readily penetrate inner ear, causing ototoxicity - may have toxic effects on a fetus - eliminated primarily by the kidneys 3.

Adverse Effects – serious toxicity, especially to the inner ear and kidney - ototoxicity = within the inner ear, causing cellular injury that can impair both hearing and balance - related primarily to excessive trough levels (lowest level between doses, and occurs just prior to administering the next dose) - risk is increased by renal impairment, concurrent use of thacrynic acid, and administration of aminoglycosides in excessive doses or for more than 10 days - patients should be monitored for: • first sign of impending cochlear damage = high pitched tinnitus (ringing in the

ears), for which audiometric testing is needing to detect • first sign of impending vestibular damage = headache (which may last for 1 – 2 days), followed by nausea, unsteadiness, dizziness, and vertigo - special care should be taken to ensure safe trough levels in patients with kidney dysfunction - nephrotoxicity = injured cells of the proximal renal tubules, usually manifests as acute tubular necrosis - symptoms are proteinuria, casts in the urine, production of dilute urine, and elevations in serum creatinine and blood urea nitrogen (BUN) - serum creatinine and BUN should be monitored - significant consequence of renal damage is accumulation of aminoglycosides themselves, which can lead to ototoxicity - neuromuscular blockade – inhibited neuromuscular transmission, causing flaccid paralysis and potentially fatal depression of respiration - risk is increased by concurrent use of neuromuscular blocking agents and general anesthetics - hypersensitivity reactions = rash, pruritus, urticaria - neurologic disorders = optic nerve dysfunction, peripheral neuritis, paresthesias of the face and hands - suprainfections of the bowel and instestinal malabsorption - dermatitis 4.

Drug Interactions - penicillins can inactivate aminoglycosides, therefore they should not be mixed together in the same IV solution - ototoxic drugs - nephrotoxic drugs - skeletal muscle relaxants = to avoid respiratory arrest 5. Dosing Schedules – may be administered in the form of one large dose each day, or as two or three divided doses - common practice is to administer total daily dose all at once, which is safe and effective 6. dosage

Monitoring Serum Drug Levels – provides the best basis for adjusting

- to minimize ototoxicity, trough levels must be sufficiently low (if trough levels remain too high, aminoglycosides can’t diffuse out of the inner ear, hence causing injury) - when once-daily dosing is employed, need to measure trough levels - there is no need to measure peak levels because when the entire daily dose is given at once, high peak levels are guaranteed - when divided doses are employed, need to measure both the peak and trough levels - sample peak levels should be taken 30 minutes after giving an IM injection or after completing a 30-minute IV infusion - sample trough levels depends on the dosing schedule: - divided doses, samples should be taken just prior to the next dose - once-daily doses, two samples are usually drawn (2 and 12 hrs after dosing)

II.

PROPERTIES

OF

INDIVIDUAL AMINOGLYCOSIDES

A.

GENTAMICIN (GARAMYCIN) 1. Therapeutic Uses – used to treat serious infections caused by aerobic gram-negative bacilli - primary targets are pseudomonas aeruginosa - principal advantage is low cost 2.

Adverse Effects and Interactions – toxic to the kidney and inner ear - inactivated by penicillins and should not be mixed in the same IV

solution 3.

Preparations, Dosage, and Administration garamycin – IV and IM administration - desirable to monitor serum levels to adjust dosage (therapeutic levels = 4 – 8 mcg/ml) B. TOBRAMYCIN (NEBCIN, TOBI) - all are similar to gentamicin regarding uses, adverse effects, and interactions - administered parenterally (IV or IM) and as a nebulizer for treatment of cystic fibrosis - can injury inner ear and kidney C.

OTHER AMINOGLYCOSIDES 1. Netilmicin (netromycin)

2. Neomycin – not used parenterally due to increased ototoxicity and nephrotoxicity - employed for topical treatment of infections of the eye, ear and skin

- administered orally to suppress bowel flora prior to surgery of the intestine - oral administration can cause suprainfections of the bowel as well as an intestinal malabsorption syndrome 3. Streptomycin – can be used in combination with other drugs to treat tuberculosis, but newer and safer agents are generally preferred - indicated for uncommon infections to include plague, tularemia, glanders, brucellosis