Protein Synthesis Inhibitors

Question 1

The next class of antibiotics are the protein synthesis inhibitors. What is the general MOA for these patients?

Answer 1

Attacks the 70S ribosome (remember that mammalian cells have 80S ribosome)
–so this forms the basis for the selective toxicity of these drugs against microorganisms without causing major effects on protein synthesis in mammals

Question 2

First up are the tetracyclines (Doxycycline, minocycline, and tetracycline) what are their MOA?

Answer 2

Enter microorganisms in part via passive diffusion and in part via an energy dependent transport that is unique to the bacterial inner cytoplasmic membrane
Once inside the cell, these drugs bind reversibly to the 30S subunit of the bacterial ribosome, preventing binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex
–this prevents addition of amino acids to the growing peptide.

Question 3

What are the three main mechanisms of tetracycline resistance?

Answer 3

1. Impaired influx or increased efflux by an active transport protein pump, thus preventing accumulation of the drug within the bacterial cell
2. Production of proteins that interfere with tetracycline binding to the ribosome
3. Enzymatic inactivation

Question 4

What is the spectrum of activity for the tetracyclines?

Answer 4

Broad spectrum
Bacteriostatic drugs
Aerobic and Anaerobic Gram Positive and Gram Negative

Question 5

Tetracyclines are used in the treatment of what?

Answer 5

Resp Tract 
Sinuses
Middle Ear 
Urinary Tract 
Intestines 
most current use: severe acne and rosacea

Question 6

Tetracyclines are the drug of choice for what?

Answer 6

Chlamydia
Mycoplasma Pneumoniae
Lyme Disease
Cholera
Anthrax (prophylaxis)
Rickettsia (rocky mountain spotted fever, typhus)
(Also recommended for the use in the tx of syphilis in patient who are allergic to penicillin)

Question 7

In combination regimens they have found use in the treatment of what?

Answer 7

Duodenal Ulcer (H. pylori)
Prophylaxis and Tx of Malaria
Tx of plague, tularemia and brucellosis

Question 8

What is the main problem with the use of tetracyclines?

Answer 8

High level of resistance

Question 9

Moving on to the pharmacokinetics of tetracyclines, what are some features?

Answer 9

Oral absorption
Absorption in Upper Small Intestine
Impaired by food (except doxy and mino)
Absorption of all oral tetracyclines is impaired by multivalent cations (Ca2+, Mg 2+, Fe2+) or any dairy products
Widely distributed (except CSF) and cross both the placental barrier and enters the breast milk

Question 10

What are some pharmacokinetic features of doxy?

Answer 10

Lipid soluble and is preferred IV
Good choice for tx of STDs and prostatitis
Excreted in the feces
SID due to their high oral absorption and slow excretion

Question 11

What are some pharmacokinetic features of mino?

Answer 11

Reaches very high concentration in tears and saliva (useful for eradication of the meningococcal carrier state)
SID due to their high oral absorption and slow excretion

Question 12

Finally Adverse Effects with Tetracyclines. Hypersensitivity reactions are uncommon. Most adverse effects are due to direct toxicity of the drug or to alteration in microbial flora. What are the adverse effects?

Answer 12

GI effects: n/v/d (direct irritation of the intestinal tract)
Discoloration and hyperplasia of teeth and stunting of growth: bound to calcium deposited in newly formed bone and teeth in young children. In pregnancy, deposited in the fetal teeth = discoloration and in bone = deformities. AVOIDED IN PREGNANCY AND CHILDREN LESS THAN 8
Hepatotoxicity: impair hepatic function esp during pregnancy
Nephrotoxicity: acute renal failure/damage
Photosensitization: esp with systemic administration
Dizziness and Vertigo: concentrate in the endolymph of the ear

Question 13

Moving on to the next class of Protein Synthesis Inhibitors are the Glycylcyclines (tigecycline). What is the MOA/

Answer 13

Bind to the 30S bacterial ribosome
–but 5 times more tightly than the tetracyclines
Designed to overcome two mechanisms of resistance:
–acquired efflux pumps and/or ribosomal protection

Question 14

What two microorganisms are intrinsically resistant to glycylcyclines?

Answer 14

Proteus

P. aeruginosa

Question 15

What is the spectrum of activity and clinical applications for glycylcyclines?

Answer 15

Activity against MRSA, VISA and VRE

• -recommended use is for the tx of complicated skin, soft tissue and intra-abdominal infections
• -licensed for use of community-acquired pneumonia

Question 16

What are some pharmacokinetic features of glycylcyclines?

Answer 16

Only given IV
Wide distribution and tissue and intracellular penetration
Elimination is primarily biliary
No dosage adjustment is needed for renal insufficiency patients

Question 17

What are some adverse effects of glycylcyclines?

Answer 17

Same adverse effects as tetracyclines
–therefor do not give in pregos or kids under 8
Most common adverse effects are n/v

Question 18

Next drug class for protein synthesis inhibitors are the Aminoglycosides. What is the MOA?

Answer 18

Amikacin, Gentamicin, Tobramycin, Streptomycin and Neomycin

• -act irreversibly by inhibiting protein synthesis
• initially cross the outer membrane of the bacteria via passive diffusion before being actively transported across the cell membrane into the cytoplasm
• -once inside these drugs bind to the 30S subunit prior to ribosome formation leading to misreading of the genetic code and inhibition of translocation – cell lysis

Question 19

Aminoglycosides have stability against the development of resistance. Tx-emergent resistance is rare. What three mechanisms does resistance occur?

Answer 19

1. Plasmid-associated synthesis of enzymes that modify and inactivate the drugs by phosphorylation, adenylylation and acetylation
2. The receptor protein on the 30S ribosomal subunit may be deleted or altered due to mutation
3. Decreased accumulation of the drug. Either impaired entry into the cell or increased efflux

Question 20

There are two important pharmacodynamic properties of aminoglycosides. First is the Postantibiotic Effect, what is this?

Answer 20

Postantibiotic Effect (PAE): persistent suppression of bacterial growth that occurs after the drug has been removed. Thought to be due to the drugs strong irreversible binding of the 30S ribosome

Question 21

The second pharmacodynamic property of aminoglycosides is Concentration-dependent killing, what is this?

Answer 21

Ability of higher concentrations of aminoglycosides to induce more rapid and complete killing of the microorganism
–greater efficacy when given as a single large dose than as multiple small doses.
(contrast to time dependent killing like penicillins when in vivo efficacy is directly related to time above MIC and becomes independent of concentration once the MIC has been reached)
Toxicity to these drugs depends on both a critical plasma concentration and on the time that such a level is exceeded.

Question 22

What is the spectrum of activity of aminoglycosides?

Answer 22

Aerobic Gram - microorganisms
Activity against MRSA in vitro
BUT, Not adequate therapy as monotherapy for serious infections caused by MRSA
Synergistic effect has been demonstrated for selected organisms when aminoglycosides are used in combination with other ABX, most often with cell wall inhibitors. (used against strep and staphy)

Question 23

What are the clinical uses of aminoglycosides?

Answer 23

Commonly used in combo with other drugs
–empiric therapy of serious infections such as septicemia, nosocomial resp tract infections, complicated UTIs, complicated intra-abdominal infections, endocarditis, and osteomyelitis caused by aerobic gram negative bacilli

Question 24

What is the drug combination of choice in the empiric treatment of infective endocarditis?

Answer 24

Gentamicin plus either a penicillin or vancomycin

Question 25

What is the most useful drug in treating plague (Yersinia Pestis)?

Answer 25

Streptomycin

Question 26

Oral Neomycin is used for what?

Answer 26

Hepatic Encephalopathy - -second line tx due to risk of serious side effects - lactulose is commonly used as first line tx (acidifying the gut lumen, lactulose traps NH4 in the colon, reducing plasma ammonia concentrations)

Question 27

What are the pharmacokinetics for aminoglycosides?

Answer 27

SID Not absorbed after oral administration (Excluding neomycin which is a topical agent) Well distributed but show poor penetration into the CSF, biliary tree and bronchial secretions 99% of the dose is eliminated unchanged in the urine and doses must be reduced in patients with renal insufficiency

Question 28

Moving on to the adverse effects of aminogylcosides. There are serious toxicities associated with aminoglycosides and therefore not used for minor infections. What are these side effects?

Answer 28

Nephrotoxicity: continued therapy for more than 5 days at higher doses and in patients with renal insufficiency Ototoxicity: therapy is continued for more than 5 days at higher doses and in patients with renal insufficiency. (neomycin, kanamycin and amikacin are the most ototoxic). May be increased by using loop diuretics. Neuromuscular Blockade: patient experiencing such reactions have disease states and or concomitant drug therapy that interfere with neuromuscular transmission. Myasthenia gravis is an absolute contraindication

Question 29

What are contraindications for aminoglycosides?

Answer 29

Pregnancy: due to risk of ototoxicity | Myasthenia gravis

Question 30

The last drug set for this deck of cards are the macrolides (Erythromycin, Clarithromycin, Azithromycin, Telithromycin). What is their MOA and resistance?

Answer 30

MOA: --bind to the 50S subunit of bacterial ribosomes Resistance: (becoming more of a problem) -reduced membrane permeability or active efflux --production of an esterase that results in hydrolyzation of the drugs --modifiction of the ribosomal binding site, either by chromosomal mutation or by a methylase There is complete cross resistance between erythromycin, azithromycin, and clarithromycin for gram + organisms by alteration in ribosomal RNA mechanism.

Question 31

What is the spectrum of activity and clinical applications for a macrolide?

Answer 31

Gram + with some gram - activity Erythromycin not as broad of spectrum and not active against S. Aureus Use: --tx of URI and soft tissue infections (H. influenzae, S. pneumoniae, Staphylococci, Enterococci) --whooping cough (b. pertusis) = erythromycin -also shown activity against legionella, mycoplasma, mycobacteria, rickettsia and chlamydia Common substitute for patients with penicillin allergy

Question 32

What are the pharmacokinetics for macrolides?

Answer 32

Clarithromycin, Azithromycin (can be IV) and Telithromycin: oral absorption, longer serum half lives, and better tissue and intracellular penetration than erythromyxin. Azithromycin, Clarithromycin and Telithromycin: stable gastric pH so better bioavailability Can be taken with or without food except for extended release clarithromycin Telithromycin is the most concentrated in tissue Erythromycin is the safest macrolide in pregnancies

Question 33

Macrolides have a variety of drug interaction, many of them are mediated by inhibition of cytochrome (P450) 3A4. Erythro, Clarithro, and Telithro can all lead to an increase in plasma concentration of drugs that are metabolized via CYP 3A4 (anticoagulants, carbamazepine and theophylline). For the same reason what other drugs should not be used?

Answer 33

Macrolides and statins are not advised due to myopathy Erythro is able to increase plasma levels of digoxin (increasing its bioavailability) Azithromycin does not appear to affect CYP enzymes thus drug interactions are uncommon

Question 34

Finally the adverse effects of Macrolides. The newer macrolides (azithromycin, clarithromycin) are better tolerated than erythromycin. What are these adverse effects?

Answer 34

1. Telithromycin: not used to treat sinusitis or bronchitis. should not be used in myasthenia gravis patients 2. GI irritation: n/v/d/abd pain 3. Hepatic Abnormalities: azithro and erythro have been associated with hepatitis cholestatic jaundice, hepatic necrosis and hepatic failure 4. Long QT syndrome: QT prolongation that can lead to Torsade de Pointes 5. Rare: anaphylaxis, stevens-johnson syndrome and pseudomembranous colitis