Cushman Clindamycin and tetracyclines

Question 1

What is Clindamycin produced from?

Answer 1

Streptomyces lincolnensis

Question 2

Clindamycin MOA

Answer 2

Similar to that of macrolide antibiotics like erythromycin

Inhibits protein synthesis by binding to the bacterial 50S ribosome

Question 3

Clindamycin spectrum

Answer 3

Aerobic Gram (+) cocci: staphylococcus and streptococcus

Anaerobic Gram (-) bacilli including some members of the bacteroides and fusobacterium

It may also be used to treat some bone infections with staphylococcus aureus and topically to treat acne

MRSA

Can be used IV to treat AIDS patients with encephalitis caused by toxoplasma gondii

Question 4

Chlindamycin Metabolism

Answer 4

By CYP450s in the liver to the sulfoxide and the N-demethylated derivative, these metabolites are inactive

Question 5

PK/distribution of clindamycin

Answer 5

90% of the administered dose is absorbed from the GI tract

Penetrates CNS in high concentrations

Mainly excreted in the urine and bile

T1/2: 1.5-5 hours

Dose adjustments may be necessary in hepatic failure

Question 6

Adverse effects of clindamycin

Answer 6

Diarrhea
Pseudomembranous colitis
Nausea
Vomiting
Abdominal cramps
Rash

Question 7

Pseudomembranous colitis

Answer 7

Potentially a lethal condition associated with Clindamycin

May affect 2-10% of patients

Overgrowth of C. diff, which is resistant to Clindamycin, results in the production of a toxin that causes adverse effects ranging from diarrhea to colitis and toxic megacolon

Treatment: 1st line–> metronidazole, 2nd line–>vancomycin

Question 8

How Tetracyclines bind to heavy metals

Answer 8

Chelation. Tetracyclines form stable chelates with polyvalent metal ions such as Ca, Al, Cu, Mg

Question 9

Why should Tetracyclines not be administered with foods that are rich in calcium?

Answer 9

Insoluble calcium chelates are not absorbed from the GI tract

They should not be administered with antacid that contain multivalent metals (TUMS), or with hematinics containing iron

When this cannot be avoided the metals should be administered 1 hour before or 2 hours after tetracycline

Question 10

What is the preferred route of administration for tetracyclines?

Answer 10

Oral since absorption is adequate in the GI tract with the absence of multivalent metals

Question 11

Why should children avoid Tetracyclines during permanent teeth formation?

Answer 11

Tetracyclines chelate calcium during formation of teeth, resulting in permanently brown or gray teeth

Question 12

Epimerization of tetracyclines

Answer 12

The hydrogen on the amine-bearing carbon atom is acidic, resulting in enolization and epimerization.

The epitetracycline product is inactive

Question 13

When can epimerization occur and at what pH?

Answer 13

In solid state as well as in solution

Epimerization is slow in solid state and most rapid in solution at a pH of 4.

Question 14

Dehydration of tetracyclines

Answer 14

The tertiary, benzlyic hydroxyl group at the C-6 has an antiperiplanar relationship with the proton at C-5a, so it is “set-up” for elimination

Question 15

Epianhydrotetracycline toxicity

Answer 15

Toxic to the kidneys and can produce Fanconi-like syndrome (failure of reabsorption mechanism in the proximal convoluted tubules) that can be fatal.

Question 16

Why does minocycline and doxycycline lack this renal toxicity?

Answer 16

Minocycline and Doxycycline lack a C-6 hydroxyl group

Question 17

How do tetracyclines cleave in basic conditions?

Answer 17

Undergo this cleavage in base at pH of 8.5 or above. The lactone product is inactive

Question 18

Tetracycline MOA

Answer 18

Bind to the 30S ribosomal subunit and inhibit bacterial protein synthesis by blocking the attachment of aminoacyl-tRNA to the A site of ribosome

Question 19

Tetracycline indication

Answer 19

BROAD SPECTRUM

Acne
Chlamydia
Rickettsia
Brucellosis
Spirochetal infections
Anthrax
Plague
Tularemia
Legionnaires disease

Question 20

Tetracycline absorption

Answer 20

Food and milk lower oral absorption by 50%

Question 21

Demeclocycline

Answer 21

Contains a secondary hydroxyl group at C-6 instead of the tertiary hydroxyl group

Demeclocycline dehydrates more slowly than tetracycline because the secondary cation intermediate formed from demeclocycline is less stable than the tertiary cation

Question 22

Demeclocycline

Answer 22

Food and milk lower oral absorption by 50%

Question 23

Why does minocycline and doxycycline not undergo dehydration?

Answer 23

They lack a hydroxyl group at C-6

Question 24

PK of Minocycline

Answer 24

90-100% oral bioavailability

The absorption is lowered by 20% when taken with food or milk

Question 25

Minocycline unique toxicities

Answer 25

Vertigo
Ataxia
Nausea

Question 26

Why is Doxycycline the DOC for most physicians?

Answer 26

It has no potential for 4-epihydrotetracycline-mediated toxicity and produces fewer GI symptoms

Question 27

PK of Doxycycline

Answer 27

90-100% oral bioavailability

The absorption is lowered by 20% when taken with food

T1/2= 18-22 hours=once daily dosing

Question 28

Why does Tigecycline have no potential for 4-epianhydrotetracycline toxicity?

Answer 28

Tigecycline lacks a hydroxyl group at C-6 and therefore does not undergo acid-catalyzed dehydration

Question 29

Tigecycline administration

Answer 29

Slow IV infusion

Question 30

Tigecycline Toxicities

Answer 30

Hepatotoxicity (rare)
Pancreatitis
Anaphylactoid reactions

Question 31

Sarecycline

Question 32

Omadacycline indication

Answer 32

IV for skin infections and community-aquired bacterial pneumonia