Macrolides, Clindamycin, Streptoramins

Question 1

The macrolides are a group of closely related compounds characterized by a___________ (usually containing 14 or 16 atoms) to which deoxy sugars are attached. c

Answer 1

macrocyclic lactone ring

Question 2

The prototype drug, ____________, which consists of two sugar moieties attached to a 14-atom lactone ring, was obtained in 1952 from Streptomyces erythreus . Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin.

Answer 2

erythromycin

Question 3

ERYTHROMYCIN Chemistry The general structure of ________________ is shown with the macrolide ring and the sugars desosamine and cladinose. It is poorly soluble in water (0.1%) but dissolves readily in organic solvents. Solutions are fairly stable at 4°C but lose activity rapidly at 20°C and at acid pH. Erythromycins are usually dispensed as various esters and salts.

Answer 3

ERYTHROMYCIN

Question 4

Mechanism of Action & Antimicrobial Activity

The antibacterial action of erythromycin and other macrolides may be _________________, particularly at higher concentrations, for susceptible organisms. Activity is enhanced at alkaline pH. Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA. The binding site is near the peptidyltransferase center, and peptide chain elongation (ie, transpeptidation) is prevented by blocking of the polypeptide exit tunnel. As a result, peptidyl-tRNA is dissociated
from the ribosome. Erythromycin also

Answer 4

inhibitory or bactericidal

“ang gamot na confused!”

Question 5

Erythromycin is active against susceptible strains of gram-positive organisms, especially pneumococci, streptococci, staphylococci, and corynebacteria. Mycoplasma pneumoniae , L pneumophila , Chlamydia trachomatis , Chlamydia psittaci, Chlamydia pneumoniae , H pylori , Listeria monocytogenes, and certain mycobacteria (Mycobacterium kansasii, Mycobacterium scrofulaceum) are also susceptible. Gramnegative organisms such as Neisseria sp, Bordetella pertussis, Bartonella henselae, and Bartonella quintana as well as some Rickettsia species, Treponema pallidum , and Campylobacter species are susceptible. Haemophilus influenzae is somewhat less susceptible.

Question 6

Resistance to erythromycin is usually ___________

Answer 6

plasmid-encoded

Question 7

. Three mechanisms have been identified:_______________________________________

Answer 7

(1) reduced permeability of the cell membrane or active efflux;
(2) production (by Enterobacteriaceae) of esterases that hydrolyze macrolides; and (
3) modification of the ribosomal binding site (so-called ribosomal protection) by chromosomal mutation or by a macrolide-inducible or constitutive methylase.

Question 8

_______________are the most important resistance mechanisms in gram-positive

organisms. Cross-resistance is complete between erythromycin and the other macrolides.

Answer 8

Efflux and methylase production

Question 9

Constitutive methylase production also confers resistance to structurally unrelated but mechanistically similar compounds such as clindamycin and streptogramin B (_____________________ which share the same ribosomal binding site

. Because nonmacrolides are poor inducers of the methylase, strains expressing an inducible methylase will appear susceptible in vitro. However, constitutive mutants that are resistant can be selected out and emerge during therapy with clindamycin.

Answer 9

so-called macrolide-lincosamidestreptogramin, or MLS-type B, resistance),

Question 10

Erythromycin base is destroyed by____________________ Food interferes with absorption.

Answer 10

stomach acid and must be administered with enteric coating.

Nmemonics : “ Maarte at confused! “

Kelangn ng Coating

Question 11

Stearates and esters are fairly acid-resistant and somewhat better absorbed. The_________________________is the best-absorbed oral preparation. Oral dosage of 2 g/d results in serum erythromycin base and ester concentrations of approximately 2 mcg/mL.

However, only the base is microbiologically active, and its concentration tends to be similar regardless of the formulation. A 500-mg intravenous dose of erythromycin lactobionate produces serum concentrations of 10 mcg/ mL 1 hour after dosing. The serum half-life is approximately 1.5 hours normally and 5 hours in patients with anuria. Adjustment for renal failure is not necessary.

Erythromycin is not removed by dialysis. Large amounts of an administered dose are excreted in the bile and lost in feces, and only 5% is excreted in the urine.

Absorbed drug is distributed widely except to the brain and cerebrospinal fluid. Erythromycin is taken up by polymorphonuclear leukocytes and macrophages. It traverses the placenta and reaches the fetus.

Answer 11

lauryl salt of the propionyl ester of erythromycin (erythromycin estolate)

Question 12

_________________ is a drug of choice in corynebacterial infections (diphtheria, corynebacterial sepsis, erythrasma); in respiratory, neonatal, ocular, or genital chlamydial infections; and in treatment
of community-acquired pneumonia because its spectrum of activity
includes pneumococcus, M pneumoniae , and L pneumophila.

Answer 12

Erythromycin

“CONFUSED” : inhibitory at bactericidal

“Coating” :

CORYNEBACTERIUM : DOC

Question 13

Erythromycin is also useful as a penicillin substitute in penicillinallergic individuals with infections caused by staphylococci (assuming that the isolate is susceptible), streptococci, or pneumococci.

Emergence of erythromycin resistance in strains of group A streptococci and pneumococci (penicillin-non-susceptible pneumococci in particular) has made macrolides less attractive as firstline agents for treatment of pharyngitis, skin and soft tissue infections, and pneumonia.

_____________ has been recommended as prophylaxis against endocarditis during dental procedures in individuals with valvular heart disease, although clindamycin, which is better tolerated, has largely replaced it. Although erythromycin estolate is the best-absorbed salt, it imposes the greatest risk of adverse reactions. Therefore, the stearate or succinate salt may be preferred.

Answer 13

Erythromycin

Question 14

_____________, is the most common reason for discontinuing erythromycin and substituting another antibiotic.

Answer 14

Gastrointestinal intolerance, which is due to a direct stimulation of gut motility

Question 15

_______________, can produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction. Most patients recover from this, but hepatitis recurs if the drug is readministered. Other allergic reactions include fever, eosinophilia, and rashes.

Answer 15

Erythromycins, particularly the estolate

Question 16

Erythromycin metabolites inhibit cytochrome P450 enzymes and, thus, increase the serum concentrations of numerous drugs, including_________________

Answer 16

** theophylline, warfarin, cyclosporine, and **methylprednisolone.

Question 17

Erythromycin increases serum concentrations of ______________ by increasing its bioavailability.

Answer 17

oral digoxin

Question 18

___________ is derived from erythromycin by addition of a methyl group and has improved acid stability and oral absorption compared with erythromycin.

Its mechanism of action is the same as that of erythromycin.

Answer 18

Clarithromycin

Question 19

_________________ are similar with respect to antibacterial activity except that clarithromycin is more active against Mycobacterium avium complex (see Chapter 47 ). Clarithromycin also has activity against Mycobacterium leprae , Toxoplasma gondii, and H influenzae . Erythromycin-resistant streptococci and staphylococci are also resistant to clarithromycin.

Answer 19

Clarithromycin and erythromycin

Question 20

A 500-mg dose of clarithromycin produces serum concentrations of 2–3 mcg/mL.

The longer half-life of clarithromycin (6 hours) compared with erythromycin permits twice-daily dosing.

The recommended dosage is 250–500 mg twice daily or 1000 mg of the extended-release formulation once daily.

Clarithromycin penetrates most tissues well, with concentrations equal to or exceeding serum concentrations. Clarithromycin is metabolized in the liver.

The major metabolite is 14-hydroxyclarithromycin, which also has antibacterial activity. Portions of active drug and this major metabolite are eliminated in the urine, and dosage reduction (eg, a 500-mg loading dose, then 250 mg once or twice daily) is recommended for patients with creatinine clearances less than 30 mL/min.

Clarithromycin has drug interactions similar to those described for erythromycin. The advantages of clarithromycin compared with erythromycin ________________-

Answer 20

are lower incidence of gastrointestinal intolerance and less frequent dosing.

Question 21

What are the advantages of azithromycin over clinda and erythromycin?

Answer 21

it doesnt inhit cytochrome p450

The drug is slowly released from tissues (tissue half-life of
2–4 days) to produce an elimination half-life approaching 3 days.
These unique properties permit once-daily dosing and shortening of
the duration of treatment in many cases.

azithromycin penetrates into most tissues
(except cerebrospinal fluid) and phagocytic cells extremely well, with
tissue concentrations exceeding serum concentrations by 10- to
100-fold.

COPD!!!!

Question 22

Ketolides are semisynthetic 14-membered-ring macrolides, differing from erythromycin by substitution of a 3-keto group for the neutral sugar l-cladinose. Telithromycin is approved for limited clinical use. It is active in vitro against Streptococcus pyogenes, S pneumoniae, S aureus, H influenzae, Moraxella catarrhalis , Mycoplasma sp, L pneumophila, Chlamydia sp, H pylori, Neisseria gonorrhoeae, B fragilis, T gondii, and certain nontuberculosis mycobacteria. Many macrolide-resistant strains are susceptible to ketolides because the structural modification of these compounds renders them poor substrates for efflux pump-mediated resistance, and they bind to ribosomes of some bacterial species with higher affinity than macrolides.

Question 23

___________________- is a chlorine-substituted derivative of lincomycin , an antibiotic that is elaborated by Streptomyces lincolnensis.

Answer 23

Clindamycin

Question 24

Clindamycin, like erythromycin,_______________ The binding site for clindamycin on the __________________ of the bacterial ribosome is identical with that for erythromycin. Streptococci, staphylococci, and pneumococci are inhibited by clindamycin, 0.5–5 mcg/mL. Enterococci and gramnegative aerobic organisms are resistant. Bacteroides sp and other anaerobes, both gram-positive and gram-negative, are usually susceptible.

Answer 24

inhibits protein synthesis by interfering with the formation of initiation complexes and with aminoacyl translocation reactions.

50S subunit

Question 25

Resistance to clindamycin, which generally confers crossresistance to macrolides, is due to

Answer 25

(1) mutation of the ribosomal receptor site;
(2) modification of the receptor by a constitutively expressed methylase (see section on erythromycin resistance, above); and (3) enzymatic inactivation of clindamycin. Gram-negative aerobic species are intrinsically resistant because of poor permeability of the outer membrane.

Question 26

It penetrates well into abscesses and is actively taken up and concentrated by phagocytic cells.

Clindamycin is metabolized by the liver, and both active drug and active metabolites are excreted in bile and urine.

The half-life is about 2.5 hours in normal individuals, increasing to 6 hours in patients with anuria.

No dosage adjustment is required for renal failure

.

Question 27

Clinical Uses Clindamycin is indicated for the ____________________. It is often active against community-acquired strains of methicillin-resistant S aureus , an increasingly common cause of skin and soft tissue infections. Clindamycin is also indicated for treatment of anaerobic infections caused by Bacteroides sp and other anaerobes that often participate in mixed infections.

Clindamycin, sometimes in combination with an aminoglycoside or cephalosporin, is used to treat penetrating wounds of the abdomen and the gut; infections originating in the female genital tract, eg, septic abortion, pelvic abscesses, or pelvic inflammatory disease; and lung abscesses.

Clindamycin is now recommended rather than erythromycin for prophylaxis of endocarditis in patients with valvular heart disease who are undergoing certain dental procedures and have significant penicillin allergies.

Answer 27

treatment of skin and soft-tissue infections caused by streptococci and staphylococci

Question 28

________________ is an effective alternative to trimethoprim-sulfamethoxazole for moderate to moderately severe Pneumocystis jiroveci pneumonia in AIDS patients. It is also used in combination with pyrimethamine for AIDS-related toxoplasmosis of the brain.

Answer 28

Clindamycin plus primaquine

Question 29

Common adverse effects are

diarrhea, nausea, and skin rashes.

Impaired liver function (with or without jaundice) and neutropenia sometimes occur.

Administration of clindamycin is a ___________________

Answer 29

risk factor for diarrhea and colitis due to C difficile .

Question 30

STREPTOGRAMINS Mechanism of Action & Antibacterial Activity _________________ is a combination of two streptogramins— quinupristin, a streptogramin B, and dalfopristin, a streptogramin A—in a 30:70 ratio. The streptogramins share the same ribosomal binding site as the macrolides and clindamycin and thus inhibit protein synthesis in an identical manner. It is rapidly bactericidal for most susceptible organisms except Enterococcus faecium , which is killed slowly. Quinupristin-dalfopristin is active against gram-positive cocci, including multidrug-resistant strains of streptococci,
penicillin-resistant strains of S pneumoniae , methicillinsusceptible
and -resistant strains of staphylococci, and E faecium
(but not Enterococcus faecalis ). Resistance is due to modification of
the quinupristin binding site (MLS-B type resistance), enzymatic
inactivation of dalfopristin, or efflux.

Answer 30

Quinupristin-dalfopristin

Question 31

Quinupristin-dalfopristin is approved for treatment of infections caused by staphylococci or by vancomycin-resistant strains of E faecium , but not E faecalis , which is intrinsically resistant, probably because of an efflux-type resistance mechanism. The principal toxicities are infusion-related events, such as ____________

Answer 31

pain at the infusion site, and an arthralgia-myalgia syndrome.

Question 32

____________is a member of the oxazolidinones, a new class of synthetic antimicrobials. It is active against gram-positive organisms including staphylococci, streptococci, enterococci, gram-positive anaerobic cocci, and gram-positive rods such as corynebacteria, Nocardia sp, and L monocytogenes

. It is primarily a bacteriostatic agent but is bactericidal against streptococci. It is also active against Mycobacterium tuberculosis .

Answer 32

Linezolid

Question 33

Linezolid inhibits protein synthesis by preventing formation of
the ribosome complex that initiates protein synthesis.

Its unique
binding site, _______________
results in no cross-resistance with other drug classes. Resistance is
caused by mutation of the linezolid binding site on 23S ribosomal
RNA.

Question 34

Linezolid is approved for _____________infections; nosocomial pneumonia; community-acquired pneumonia; and both complicated and uncomplicated skin and soft tissue infections caused by susceptible gram-positive bacteria. Off-label uses of linezolid include treatment of multidrug-resistant tuberculosis and Nocardia infections.

Answer 34

vancomycin-resistant E faecium

Question 35

The principal toxicity of linezolid is ______________; the effects are reversible and generally mild.

_____________ is the most common manifestation (seen in approximately 3% of treatment courses), particularly when the drug is administered for longer than 2 weeks.

Anemia and neutropenia may also occur, most commonly in patients with a predisposition to or underlying bone marrow suppression.

Answer 35

hematologic

**Thrombocytopenia **

Question 36

Cases of______________ and ____________ have been reported with prolonged courses of linezolid. These side effects are thought to be related to linezolid-induced inhibition of mitochondrial protein synthesis. There are case reports of serotonin syndrome occurring when linezolid is coadministered with serotonergic drugs, most frequently selective serotonin reuptake inhibitor antidepressants. The FDA issued a warning regarding the use of the drug with serotonergic agents in 2011.

Answer 36

optic and peripheral neuropathy

lactic acidosis