1. MACROLIDES
Macrolide antibiotics contain a many membered lactone ring to which are attached one or more deoxy sugars.
Erythromycin is the most well known member.
Newer members include clarithromycin, and azithromycin.

3. NEWER MACROLIDES Improved acid stability, tissue penetration.
Broader spectrum of activity.

4. ANTIMICROBIAL ACTIVITY
Most active against gram-positive cocci and bacilli.
Mycoplasma, Legionella and Chlamydia.

5. ANTIMICROBIAL ACTIVITY
Mycobacterium avium intracellulare (MAC).
Azithromycin and clarithromycin have enhanced activity vs MAC

6. ABSORPTION
Macrolides are incompletely but adequately absorbed from the GI tract.
Erythromycin base is inactivated by stomach acid.
Made in various acid resistant forms.
Food interferes with absorption.

7. ABSORPTION Erythromycin estolate is absorbed best.
Usually no one preparation offers a significant therapeutic advantage.
The newer macrolides are absorbed more rapidly than erythromycin.

8. DISTRIBUTION Well distributed except into the CNS.
In meningitis enough gets into the CNS to be therapeutically effective.

9. METABOLISM AND EXCRETION
Most of the erythromycin is metabolized.
Erythromycin is concentrated in the liver and excreted in active form in the bile.

10. THERAPEUTIC USES A useful alternative to the penicillins.
Infections caused by pneumococci and group A streptococci with penicillin allergy.
Minor infections caused by penicillin resistant or sensitive Staph. Aureus.
Prophylaxis of rheumatic fever and subacute bacterial endocarditis.

11. MYCOPLASMA PNEUMONIA

12. MYCOPLASMA PNEUMONIA
A macrolide or tetracycline is the drug of choice for Mycoplasma infections.
Reduces the duration of fever and accelerates the clearing of the chest radiographs.

15. CONTRAINDICATIONS
Pregnancy (the estolate)-because of the possibility of hepatotoxicity.
Hepatic dysfunction.

16. DRUG-DRUG INTERACTIONS
Erythromycin (and clarithromycin) inhibit Cytochrome P-450 enzymes.
Azithromycin doesn’t

17. Antifungals,verapamil,
diltiazem
Erythromycin
CytP3A4
Demethylase

18. DRUG-DRUG INTERACTIONS
Drugs that prolong QT interval.

19. COMPARISON OF MACROLIDES
Erythromycin
Clarithromycin
Azithromycin
Effect of food on absorption
Yes No
G.I. intolerance
Prolonged tissue levels
T ½ (h) 2
3-5
10->40
Drug-drug Interactions

20. KETOLIDES (Telithromycin)
Unique structure compared to macrolides, allowing it to be used in resistant respiratory infections.
Differs from erythromycin by substitution of a 3-keto group for the neutral sugar L-cladinose.

21. ANTIBACTERIAL SPECTRUM
Similar antibacterial spectrum to erythromycin but many macrolide-resistant strains are susceptible to ketolides.

22. THERAPEUTIC USES
Respiratory tract infections, including community acquired bacterial pneumonia, acute exacerbations of chronic bronchitis, sinusitis and streptococcal-pharyngitis.

23. CLINDAMYCIN
A lincosamide closely related to lincomycin.

24. ANTIBACTERIAL ACTIVITY
Similar to erythromycin.
Anaerobic bacteria, especially Bacteroides.

25. PHARMACOKINETICS
Absorbed rapidly and nearly completely following oral administration.
Widely distributed throughout the body except for the CNS.

26. Enterohepatic circulation
Clindamycin
Enterohepatic circulation

27. THERAPEUTIC USES

28. Bacteroides fragilis

30. OXAZOLIDINONES New class of synthetic antibacterial agents.
Inhibit protein synthesis by a unique mechanism.

31. LINEZOLID (Zyvox)
The first and one of 2 oxazolidinones presently available.

32. ANTIBACTERIAL ACTIVITY
Wide spectrum of activity vs. gram positive organisms including methicillin- resistant staphylococci, penicillin resistant pneumococci and vancomycin resistant Enterococcus faecalis and E.faecium.
Several anaerobic organisms.

33. PHARMACOKINETICS Good oral bioavailability (also given IV).
Metabolized.
No dosage adjustment necessary with impaired renal or hepatic function.

34. THERAPEUTIC USES
MRSA.
Vancomycin resistant E.faecium.

35. Vancomycin resistant enterococcal infections (VRE)
Disproportionately affects patients in the ICU, immunosuppressed hosts, particularly liver and other solid organ recipients and patients with post chemotherapy neutropenia, and patients with intravascular and bladder catheter devices.

36. VRE
Emerged during 1990’s
Enterococci already possess intrinsic and acquired resistance to most other antimicrobials (β-lactams, aminoglys, lincosamides and cotrimoxazole).

37. TREATMENT OF VRE Approved-linezolid and quinopristin/dalfopristin
Available agents which don’t have a specific VRE approval (chloramphenicol, doxycycline, high-dose amoxicillin/sulbactam)

38. PRECAUTIONS SSRI toxicity
Linezolid
Tyramine
MAO
SSRI toxicity
Serotonin
Linezolid

39. STREPTOGRAMINS

40. Quinupristin/Dalfopristin (Synercid)
First streptogramin to be approved in the U.S.
Present in a ratio of 30:70.

41. ANTIBACTERIAL ACTIVITY
Bactericidal vs. susceptible strains of staphylococci and streptococci.
Bacteriostatic vs. Enterococci faecium.

42. ANTIBACTERIAL ACTIVITY
Active vs. a wide range of gram positive bacteria including staphylococci resistant to methicillin, quinolones and vancomycin; pneumococci resistant to penicillin and E.faecium strains resistant to vancomycin.

43. PHARMACOKINETICS
Administered IV (over 1 hr).

44. THERAPEUTIC USES
Vancomycin strains of E.faecium and complicated skin infections caused by Staph.
Serious infections caused by multiple drug-resistant gram-positive organisms.

45. DRUG INTERACTIONS
Inhibits cytochrome CYP3A4.

46. Review-Drugs vs. Gram+ Organisms
Penicillins (G,V and antiStaph)
1st. Generation Cephs.
Macrolides
Vancomycin
Linezolid
Streptogramins

48. DRUG-DRUG INTERACTIONS
Drugs that inhibit CYP3A4 isozymes may increase plasma erythromycin concentrations and increase the risk of ventricular arrhythmias and sudden death (antifungals, verapamil, diltiazem).

49. Serum Concentration After Oral Administration
1.5
Estolate
1.0
Serum Levels mcg/ml
Stearate
0.5
Erythromycin Base
0.5
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
Hours
Serum Concentration After Oral Administration
of Different Erythromycin Preparations

50. VANCOMYCIN Tricyclic glycopeptide antibiotic.
Antibacterial activity-primarily active against gram positive bacteria.

51. MECHANISM OF ACTION Bactericidal.
Inhibits cell wall synthesis (2nd stage of cell wall synthesis).
Binds with high affinity to the D-alanyl-D-alanine terminus of cell wall precursor units, at the crucial site of attachment and thereby inhibits vital peptidoglycan polymerase and transpeptidation reactions.

52. X Vancomycin Glycopeptide Polymrer Glycopeptide Mur NAc Polymer
D-Alanine
Transpeptidase

53. RESISTANCE Increased incidence in recent years.
Due to expression of a unique enzyme that modifies the cell wall precursor so that it no longer binds vancomycin.

54. PHARMACOKINETICS Poorly absorbed after oral administration. Given I.V.
Mainly excreted by the kidney (80-90%).

55. THERAPEUTIC USES
Serious staphylococcal infections such as methicillin resistant staph infections and in penicillin allergy or if the penicillins or cephalosporins can’t be used for other reasons.
Streptococcal endocarditis infections-used with an aminoglycoside .
AAPC.

56. VANCOMYCIN-TOXICITY

62. TOXICITY Chills, rash and fever. Phlebitis at the site of injection.
Ototoxicity-auditory impairment.
Nephrotoxicity.

64. Erythromycin (Ilosone) can cause cholestatic hepatitis

71. TOXICITY
Red man or red neck syndrome during rapid I.V. infusion

72. DRUG INTERACTIONS
Inhibits cytochrome P450-3A4.

73. MECHANISM OF ACTION Usually bacteriostatic.
Inhibit protein synthesis by binding reversibly to the 50S ribosomal subunit.
Probably inhibits translocation step.

74. 60S
40S
Eucaryotic Ribosome
80S--M.W. 4,200,000
Procaryotic Ribosome
50S
30S
70S--M.W.2,500,000

76. P A aa 50S 30S mRNA template Transferase site Nascent polypeptide
chain
MACROLIDE

77. RESISTANCE Results from multiple mechanisms.
Cross resistance among all the macrolides.

78. ADVERSE REACTIONS
GI upset (nausea, diarrhea, and abdominal pain) is common.
Frequency is less with the newer macrolides

82. CHOLESTATIC HEPATITIS
It is caused primarily by the estolate.
It is probably a hypersensitivity reaction (to estolate ester).

83. QT PROLONGATION AND VENTRICULAR ARRHTHYMIAS
Macrolides prolong cardiac repolarization and are associated with torsades de pointes.

84. His/Purk.
Ventricle R T P
Prolong
QT Interval
Macrolides S Q

85. Torsade de pointes - Polymorphic Ventricular Tachycardia
Prolonged QT

86. MECHANISM OF ACTION Bacteriostatic.
It binds exclusively to the 50S ribosomal subunit and inhibits protein synthesis.
Some cross-resistance with erythromycin

87. Clindamycin,erythromycinand chloramphenicol
50S A
Clindamycin,erythromycinand chloramphenicol
30S

88. ADVERSE REACTIONS Diarrhea and skin rashes are common.
Antibiotic associated pseudomembranous colitis (AAPC).

90. Clindamycin

91. AAPC
Characterized by watery diarrhea, abdominal pain, fever, blood and mucus in stools. It can be fatal.
Results from a toxin secreted by clindamycin resistant strains of Clostridium difficile.
Potentially caused by several antibiotics.

92. AAPC
Results from a toxin secreted by clindamycin resistant strains of Clostridium difficile.
Potentially caused by several antibiotics.

93. Vancomycin and metronidazole

94. AAPC
Vancomycin and metronidazole are effective in treating it.

95. Linezolid

96. MECHANISM OF ACTION
Bacteriostatic and bactericidal.

97. P
50S A
Linezolid
30S

98. MECHANISM OF ACTION
Distorts the tRNA fmet binding site which overlaps both ribosomal subunits, preventing initiation complex formation .
Binding site is unique so cross-resistance doesn’t occur.

99. ADVERSE EFFECTS GI Disturbances and headache are common.
Myelosuppression.
Myelosuppression when used for an extended period of time.

100. Streptogramins

101. P A DALFOPRISTIN aa 50S 30S mRNA template Transferase site
Nascent polypeptide
chain
QUINUPRISTIN
MACROLIDE

102. MECHANISM OF ACTION
Act synergistically to inhibit bacterial protein synthesis.
They bind to separate sites on the 50 S ribosomal subunit and form a ternary complex with the ribosome.

103. MECHANISM OF ACTION
Quinupristin binds at the same site as the macrolides and has a similar effect.
Dalfopristin directly blocks peptide bond formation by inhibiting peptidyl transferase.
Dalfopristin results in a conformational change in the 50S ribosome subunit.

104. Pain, Inflammation

105. ADVERSE EFFECTS GI disturbances (diarrhea and nausea).
Elevated liver enzymes.

106. THERAPEUTIC USES
Disseminated MAC infection in patients with AIDS (azithromycin and clarithromycin).