DR. MABANAG - MACROLIDES, CLINDAMYCIN, CHLORAMPHENICOL, STREPTOGRAMINS & OXAZOLIDINONES Flashcards by Shiela Micah Gascon

A group of closely related compounds characterized by a long macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy sugars are attached.

MACROLIDES

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● Prototype drug consists of 2 sugar moieties attached to a 14-atom lactone ring
● Obtained in 1952 from Streptomyces erythraeus now called as Saccharopolyspora erythraea

ERYTHROMYCIN

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discovered in Iloilo City by Dr. Abelardo Aguilar but not given the credit

Streptomyces erythraeus

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first brand name of Erythromycin because it was discovered in Iloilo City.

ILOSONE

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are semi-synthetic derivatives of erythromycin

CLARITHROMYCIN
AZITHROMYCIN

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○ Inhibition of protein synthesis occurs via
binding to the 50S ribosomal RNA
- Activities enhanced at alkaline pH

ERYTHROMYCIN

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● Active against susceptible strains of G(+) organisms especially pneumococci, streptococci, and the corynebacteria.
○ Mycoplasma pneumoniae
○ Legionella pneumophila
○ Chlamydia trachomatis
○ Chlamydophila psittaci
○ Chlamydophila pneumoniae
○ H. pylori
○ Listeria monocytogenes

ERYTHROMYCIN

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● Certain mycobacteria are also susceptible
(non-tuberculous mycobacteria):
○ Mycobacterium kansasii
○ Mycobacterium scrofulaceum

ERYTHROMYCIN

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● Gram-negative organisms susceptible strain
○ Neisseria sp
○ Bordatella pertussis
○ Bartonella henselae
○ Bartonella quintana

ERYTHROMYCIN

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● Rickettsia species
○ Treponema pallidum
○ Campylobacter species
● Haemophilus influenzae is somewhat less
susceptible

ERYTHROMYCIN

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MACROLIDES PHARMACOKINETICS

DESTROYED BY STOMACH ACIDS
FOOD INTERFERES WITH ABSORPTION
NOT REMOVED BY DIALYSIS
BILE EXCRETION
CAN CROSS PLACENTA

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MACROLIDES ADVERSE REACTIONS

GI SYMPTOMS
GI INTOLERANCE
ACUTE CHOLESTATIC HEPATITIS
INHIBITS CYP450

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= ↑ serum concentration of theophylline, warfarin, cyclosporine, and methylprednisolone so decrease the dose

Inhibits CYP450 system
MACROLIDES

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for cardiac rhythm abnormalities

DIGOXIN

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● Derived from erythromycin by addition of a methyl group with ↑ stability in oral absorption
● Same mechanism of action and spectrum activity with erythromycin, except: clarithromycin is more active vs Mycobacterium avium complex

CLARITHROMYCIN

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Major metabolite: 14-hydroxyclarithromycin; has antibacterial activity and is eliminated in the urine

CLARITHROMYCIN

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● A 15-atom lactone macrolide ring compound derived from erythromycin by addition of a methylated nitrogen into lactone ring

AZITHROMYCIN

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do not alter bioavailability but delay absorption and ↓ peak serum concentrations

Al- and Mg3 (Aluminum and magnesium) antacids

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Does not inactivate CYP450 compared to
erythromycin and clarithromycin (lesser
drug interactions)

AZITHROMYCIN

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Semisynthetic, 14-membered-ring macrolides, differing from erythromycin by substitution by substitution of a 3-keto group for the neutral sugar L-cladinose

KETOLIDES

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● Active in vitro vs
○ Streptococcus pyogenes
○ S. pneumoniae
○ S. aureus
○ H. influenza
○ Moraxella catarrhalis
○ Mycoplasma spp.
○ L. pneumophila
○ Chlamydia sp.
○ H. pylori
○ Neisseria gonorrhoeae
○ B. fragilis
○ T. gondii
○ Certain nontuberculous bacteria

KETOLIDES

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causes QT prolongation

Erythromycin, Clarithromycin, Azithromycin, & Ketolides (Telithromycin)

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● More widely used
● Chlorine-substituted derivative of Lincomycin

CLINDAMYCIN

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** parent compound of clindamycin

LINCOMYCIN

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○ Interfere with: formation of initiation complexes; aminoacyl translocation reactions ○ 50s binding site

CLINDAMYCIN

○ Susceptible: Streptococci, staphylococci, pneumococci inhibited by clindamycin ○ Resistant: Enterococci and Gram-negative aerobic organisms

CLINDAMYCIN

○ Penetrates well into abscesses - actively taken up and concentrated by phagocytic cells

CLINDAMYCIN

○ Skin and soft tissue infections caused by streptococci and staphylococci ○ May be active vs strains of CAMRSA (Community-acquired Methicillin-Resistant Staphylococcus aureus) - may be hospital/community-acquired

CLINDAMYCIN

○ Commonly used in conjugation with Pen G to treat TSS (Toxic Shock Syndrome) or necrotizing fasciitis caused by Group A Streptococcus

CLINDAMYCIN

- Penetrating wounds of the abdomen and the gut - Infections originating in the female genital tract, e.g. septic abortion, pelvic abscesses, or PID (Pelvic Inflammatory Disease); and - Lung and periodontal abscesses

Clindamycin + aminoglycosides or cephalosporin:

effective alternative to TMP-SMX (if the patient is allergic) for moderate to moderately severe Pneumocystis jiroveci (prev. Pneumocystis carinii) pneumonia in AIDS patients

Clindamycin + primaquine

○ Used in combination with pyrimethamine for AIDS-related brain toxoplasmosis

CLINDAMYCIN

Adverse Effects CLINDAMYCIN

○ Diarrhea (and colitis due to Clostridium difficile) ○ Nausea ○ Rashes ○ Impaired liver function ○ Neutropenia (occasional) - decreased WBC

● 50S attacher; reserve drug used for Vancomycin-Resistant MRSA

Streptogramins:Quinupristin-Dalfopristin

Combination of two streptogramins (Ratio 30:70) ○ Quinupristin - streptogramin A OR B? ○ Dalfopristin - streptogramin A OR B?

○ Quinupristin - streptogramin A ○ Dalfopristin - streptogramin B

● Rapid bactericidal for most susceptible organisms ○ Except Enterococcus faecium (slow kill) *NOT faecalis ○ But rapidly skills other susceptible organisms

Streptogramins:Quinupristin-Dalfopristin

○ ↓ dose for hepatic insufficiency - Significantly inhibits CYP3A4 ● CYP3A4 metabolizes warfarin, diazepam, quetiapine, simvastatin, CSA (Cyclosporin A) ● Decrease the dose in patients with liver failure or alcoholism - Dose reduction of CSA may be necessary ○ Reduce dose of immunosuppressants in transplant patients

Streptogramins:Quinupristin-Dalfopristin

● Active vs Gram + cocci ○ Including MDR (multidrug resistant) strains of Streptococci, penicillin-resistant strains of S. pneumoniae, MSSA (Methicillin-Sensitive Staphylococcus aureus), MRSA, and E. faecium ○ Resistance due to modification of the quinupristin binding site (MLS-B type resistance), enzymatic inactivation of dalfopristin, or efflux

Streptogramins:Quinupristin-Dalfopristin

Soluble in alcohol, poorly soluble in H20 ● Inactivated via conjugation with glucuronic acid or by reduction to inactive arylamines

CHLORAMPHENICOL

○ Inhibitor of microbial protein synthesis ○ Bacteriostatic vs most susceptible organisms: - H. influenzae, N. meningitidis, Bacteroides strains (highly susceptible)

CHLORAMPHENICOL

○ Binds reversibly to ribosomal 50S - Inhibits peptide bond formation ○ Broad spectrum

CHLORAMPHENICOL

Active vs rickettsiae, but not Chlamydiae

CHLORAMPHENICOL

- TYPHOID OR ENTERIC FEVER - Rickettsial infections such as typhus and RMSF (Rocky Mountain Spotted Fever) - ALTERNATIVE FOR BETA LACTAMS FOR BACTERIAL MENINGITIS IN PATIENTS WITH MAJOR HYPERSENSITIVITY RXNS TO PENICILLIN

CHLORAMPHENICOL

CHLORAMPHENICOL ADVERSE EFFECTS —-result of alteration of the normal microbial flora

Oral or vaginal candidiasis

CHLORAMPHENICOL ADVERSE EFFECTS Dose-related (>50 mg/kg/d) reversible suppression of RBC production after 1-2 weeks →

APLASTIC ANEMIA

CHLORAMPHENICOL ADVERSE EFFECTS - Newborn infants lack an effective glucuronic acid conjugation mechanism for degradation and detoxification of chloramphenicol

Gray Baby Syndrome

Side effects: Inhibits hepatic microsomal enzymes → prolong serum concentration of phenytoin, tolbutamide, chlorpropamide, warfarin (presence of drug reactions)

chloramphenicol

○ Inhibits protein synthesis by preventing formation of ribosome complex that initiates protein synthesis ○ Unique binding site, located on the 23s (sub member) ribosomal RNA of the 50s subunit, results in no cross-resistance with other drug classes

LINEZOLID (OXAZOLIDINONES)

○ Resistance caused by mutation of the Linezolid binding site on 23s ribosomal RNA

LINEZOLID

○ Active vs: - G (+) organisms including Staphylococci, Streptococci, Enterococci - G (+) anaerobic cocci, and - G (+) rods: corynebacteria, Nocardia sp., Listeria monocytogenes

LINEZOLID

○ Primarily a bacteriostatic agent but is bactericidal against Streptococci ○ Active vs Mycobacterium tuberculosis; for MDR TB [Multidrug-resistant Tuberculosis] - second line or last line treatment only

LINEZOLID

● Remember: It is only a reserve drug. Use it only when Vancomycin and other drugs are not effective. ● Sometimes, this drug is considered as one of the last line treatments for MRSA and MDR TB.

LINEZOLID

○ HCAP (Health Care-associated Pneumonia) or CAP [Community-acquired pneumonia] ○ VRE (Vancomycin-Resistant Enterococcus) faecium

LINEZOLID

○ Off-label uses: treatment of MDR TB; nocardia infections

LINEZOLID

LINEZOLID ADVERSE EFFECTS

- HEMATOLOGIC - THROMBOCYTOPENIA - ANEMIA& NEUTROPENIA

LINEZOLID ADVERSE EFFECT usually seen in patients co-administered with serotonergic drugs most frequently selective serotonin uptake inhibitor antidepressant agents

SEROTONIN SYNDROME

● Active moiety of prodrug tedizolid phosphate - high potency against Gram (+) bacteria, MRSA

TEDIZOLID

● Potential Advantages (vs Linezolid) ○ ↑ potency vs staphylococci ○ ↓ risk of bone marrow suppression ○ ↓ risk of serotonergic activity ○ ↑ protein-bound (70-90% - higher protein binding) > Linezolid (31%)

TEDIZOLID

1.This drug penetrates well in abscesses and is used in combination with Penicillin G to treat Toxic Shock Syndrome. A. Clindamycin B. Erythromycin C. Streptogramins D. Linezolid E. Azithromycin

A. Clindamycin

2. What is the clinical use of Clindamycin? A. Penetrating wounds of the abdomen and gut B. Skin and soft tissue infections C. Abscesses D. Infections originating in the female genital tract E. All of the above

E. All of the above

3. What is the main route of excretion for erythromycin where the majority of it gets excreted? A. Urine B. Bile C. Dialysis D. Stomach acids E. CSF

B. BILE

4. Which drug has the same mechanism of action as Erythromycin but is more tolerated in the gastrointestinal tract? A. Azithromycin B. Clindamycin C. Clarithromycin D. Azithromycin E. Linezolid

C. Clarithromycin

5. Which statement about the pharmacokinetics of Azithromycin is NOT TRUE? A. It does not inactivate CYP450 enzymes, therefore free of the drug interactions that occur with erythromycin and clarithromycin B. Rapidly absorbed and well tolerated orally C. Slowly released from tissues with a tissue half-life of 2-4 days D. Penetrates well into most tissues including the CSF and phagocytic cells

D. Penetrates well into most tissues including the CSF and phagocytic cells

6. The following are adverse effects of Chloramphenicol, except A. Gray Baby Syndrome in newborn infants B. Oral or vaginal candidiasis C. Aplastic anemia D. Nausea, vomiting, and diarrhea E. None of the above

E. None of the above

7. T/F. Streptogramins rapidly eradicate susceptible organisms including Enterococcus faecium

FALSE

8. What is the unique binding site of Linezolid? A. 28S Ribosomal RNA B. 26S Ribosomal RNA C. 23S Ribosomal RNA D. 16S Ribosomal RNA

C. 23S Ribosomal RNA

9. What newer generation Oxazolidinone has a lower risk of serotonergic activity thereby preventing the risk for the development of Serotonergic Syndrome? A. Linezolid B. Chloramphenicol C. Tedizolid D. Cycloserine

C. Tedizolid

10. The following statements are true regarding the clinical use of Chloramphenicol, except A. Used for the treatment of rickettsial infections B. Used for the treatment of typhoid fever in the Philippines C. Used for the treatment of bacterial meningitis D. Used for the treatment of chlamydial infections

D. Used for the treatment of chlamydial infections

DR. MABANAG - MACROLIDES, CLINDAMYCIN, CHLORAMPHENICOL, STREPTOGRAMINS & OXAZOLIDINONES Flashcards

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