DR. MABANAG - MACROLIDES, CLINDAMYCIN, CHLORAMPHENICOL, STREPTOGRAMINS & OXAZOLIDINONES Flashcards
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
● 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
discovered in Iloilo City by Dr. Abelardo Aguilar but not given the credit
Streptomyces erythraeus
first brand name of Erythromycin because it was discovered in Iloilo City.
ILOSONE
are semi-synthetic derivatives of erythromycin
CLARITHROMYCIN
AZITHROMYCIN
○ Inhibition of protein synthesis occurs via
binding to the 50S ribosomal RNA
- Activities enhanced at alkaline pH
ERYTHROMYCIN
● 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
● Certain mycobacteria are also susceptible
(non-tuberculous mycobacteria):
○ Mycobacterium kansasii
○ Mycobacterium scrofulaceum
ERYTHROMYCIN
● Gram-negative organisms susceptible strain
○ Neisseria sp
○ Bordatella pertussis
○ Bartonella henselae
○ Bartonella quintana
ERYTHROMYCIN
● Rickettsia species
○ Treponema pallidum
○ Campylobacter species
● Haemophilus influenzae is somewhat less
susceptible
ERYTHROMYCIN
MACROLIDES PHARMACOKINETICS
- DESTROYED BY STOMACH ACIDS
- FOOD INTERFERES WITH ABSORPTION
- NOT REMOVED BY DIALYSIS
- BILE EXCRETION
- CAN CROSS PLACENTA
MACROLIDES ADVERSE REACTIONS
- GI SYMPTOMS
- GI INTOLERANCE
- ACUTE CHOLESTATIC HEPATITIS
- INHIBITS CYP450
= ↑ serum concentration of theophylline, warfarin, cyclosporine, and methylprednisolone so decrease the dose
Inhibits CYP450 system
MACROLIDES
for cardiac rhythm abnormalities
DIGOXIN
● 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
Major metabolite: 14-hydroxyclarithromycin; has antibacterial activity and is eliminated in the urine
CLARITHROMYCIN
● A 15-atom lactone macrolide ring compound derived from erythromycin by addition of a methylated nitrogen into lactone ring
AZITHROMYCIN
do not alter bioavailability but delay absorption and ↓ peak serum concentrations
Al- and Mg3 (Aluminum and magnesium) antacids
Does not inactivate CYP450 compared to
erythromycin and clarithromycin (lesser
drug interactions)
AZITHROMYCIN
Semisynthetic, 14-membered-ring macrolides, differing from erythromycin by substitution by substitution of a 3-keto group for the neutral sugar L-cladinose
KETOLIDES
● 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
causes QT prolongation
Erythromycin, Clarithromycin, Azithromycin, & Ketolides (Telithromycin)
● More widely used
● Chlorine-substituted derivative of Lincomycin
CLINDAMYCIN
** parent compound of clindamycin
LINCOMYCIN
○ 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
- 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
- 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
- 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
- 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
- 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
- T/F. Streptogramins rapidly eradicate susceptible
organisms including Enterococcus faecium
FALSE
- 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
- 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
- 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
