1. ANTIBIOTICS Prof. Dr. A. Çağrı BÜKE
Yeditepe University Medical Faculty
Department of Infectious Diseases

2. Sir Alexander Fleming Penicillin He was born at Scotland on 1881
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Sir Alexander Fleming
Penicillin
He was born at Scotland on 1881
He graduated from St. Mary's Medical School, London University
Early in his medical life, Fleming became interested in the natural bacterial action of the blood and in antiseptics
In 1921, he discovered an important bacteriolytic substance which he named “Lysozyme”
In 1928, while working on influenza virus, he observed that mould had developed accidently on a staphylococcus culture plate and that the mould had created a bacteria-free circle around itself.

3. History of antibiotics
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History of antibiotics
The history of antibiotics begun in 1932 when the first sulfonamide was prepared
On February 12, 1941, a 43-year old policeman, Albert Alexander, became the first recipient of the penicillin
Thereafter about substances developed during years

4. General types of antibiotics
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General types of antibiotics
Bactericidal antibiotics; kill bacteria directly
Time dependent
Concentration dependent
Bacteriostatic antibiotics; stop bacteria from growing
Broad spectrum antibacterials; are active against both Gram-positive and Gram-negative organisms
Narrow spectrum antibacterials; have limited activity and are primarily only useful against particular species of microorganisms

5. General types of antibiotics
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General types of antibiotics
Baktericidal
Bacteriostatic
Broad spectrum
Narrow spectrum ?

6. General types of antibiotics
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General types of antibiotics
Baktericidal
Bacteriostatic
Broad spectrum
Narrow spectrum
Penicillin (TD)
Erythromycin
Beta lactams
Glycopeptides
Cephalosporin (TD)
Trimethoprim
Fluoroquinolones
Aminoglycosides
Carbapenemes (TD)
Chloramphenicol
Tetracyclines
Polymixins
Glycopeptides (TD)
Tetracycline
Aminoglycoside (CD)
Sulphonamides
Fluoroquinolon (CD)
Metronidazole (CD)

7. Time vs Concentration dependent killing
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Time vs Concentration dependent killing
The rate and extent of killing increases as the peak drug concentration increases
Bactericidal activity continues as long as the plasma concentration is greater than the MIC
MIC: Minimal inhibitory concentration
Peak /MIC
Time > MIC

8. Mechanisms of antibiotics
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Mechanisms of antibiotics
Topoisomerase II
Metronidazole
Mycolic acid synthesis X
Isoniazid

9. Ç. BÜKE Antibiotics
Antibiotics

10. Ç. BÜKE Antibiotics
Antibiotics
Amox+Clav
Amp+Sulb
Pip+Tazob

11. Antibiotics Ç. BÜKE Antibiotics Amox+Clav Amp+Sulb Pip+Tazob
Ceftaroline 5th

12. Antibiotics Ç. BÜKE Antibiotics Amox+Clav Amp+Sulb Pip+Tazob
Ceftaroline 5th

13. Antibiotics Ç. BÜKE Antibiotics Amox+Clav Amp+Sulb Pip+Tazob
Ceftaroline 5th

14. Antibiotics Ç. BÜKE Antibiotics Amox+Clav Amp+Sulb Pip+Tazob
Ceftaroline 5th

15. Antibiotics Ç. BÜKE Antibiotics Amox+Clav Amp+Sulb Pip+Tazob
Ceftaroline 5th

16. Antibiotics Ç. BÜKE Antibiotics Amox+Clav Amp+Sulb Pip+Tazob
Ceftaroline 5th

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18. No Enterococcal coverage
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They can resist some
potent beta-lactamases
No Enterococcal coverage
Cephradine
Cephalexin
Cefadroxil
Cefaclor
Cefoxitine
Cefonicid
Cephuroxime
Cefotaxim
Cefixime
Cefozopran
Cefpirome

19. Carbapenems It has a broad spectrum of activity
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Carbapenems
It has a broad spectrum of activity
Exept: MRSA, VRE, Acinetobacter spp., Stenotrophomonas spp., and atypicals
Meropenem and imipenem are active against Pseudomonas, but Ertapenem is not
Imipenem is inactivated by human dehydropeptidase I. Cilastatin is an inhibitor of this enzyme
Only IV form is available

20. Fluoroquinolones It has a bactericidal activity
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Fluoroquinolones
It has a bactericidal activity
Excellent absorbtion and bioavailability
Both IV and PO forms are available
They are distributed widely, except CNS penetration

21. Ç. BÜKE Antibiotics
Fluoroquinolones
1. gen nalidix acid, pipemidic acid, and oxolinic acid.
2. gen consists of fluoroquinolones owing systemic effect
They spread well in the most tissues and penetrate into cells
Their spectrum is wider than in the former group: gram negative bacteria including Pseudomonas aeruginosa and other less susceptible microbes, staphylococci, chlamydiae, legionellae, and some mycobacteria
Ciprofloxacin, ofloxacin, and pefloxacin

22. Ç. BÜKE Antibiotics
Fluoroquinolones
3. Gen is composed of fluoroquinolones with a very broad spectrum
Gram negative and gram positive bacteria (Levofloxacin, moxifloxacin)
Intracellular pathogens (chlamydiae, mycoplasma), legionellae (Levofloxacin, moxifloxacin)
Majority of mycobacteria, and anaerobes including Bacteroides fragilis (Moxifloxacin)

23. Aminoglycosides Bacterisidals
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Aminoglycosides
Bacterisidals
Most commonly used for serious infections caused by aerobic gram negative rods (including Pseudomonas)
Generally used in combination with beta-lactam or vancomycin (especially for endocarditis)
They cause serious toxicities (nephrotoxicity, ototoxicity, neuromuscular blockade)

24. Aminoglycosides They are not effective against Anaerobes, amikacin
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Aminoglycosides
They are not effective against
Anaerobes,
Spirochetae,
Obligatory intracellular pathogens and
Capsulated pathogens.
Not absorbed from the gastrointestinal tract
Penetration across biological barriers is poor
The bactericidal effect is concentration-dependent
amikacin
gentamicin
kanamycin
neomycin
streptomycin
tobramycin
netilmycin

25. Macrolides Bacteriostatic antibiotics
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Macrolides
Bacteriostatic antibiotics
Reversibly inhibiting protein synthesis on ribosomal level
The drugs are fairly absorbed from the gastrointestinal tract
They penetrate into most tissues and host cells excellently
Macrolides are very safe and non-toxic antibiotics
The drugs are excreted into mucosal fluid, breast milk, bile and urine
Erytromycin, roxitromycin, claritromycin, azitromycin spiramycin, josamycin

26. Glycopeptides Bactericidal drugs
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Glycopeptides
Bactericidal drugs
They inhibits bacterial cell wall synthesis
Not absorbed from the gastrointestinal tract
Penetration across biological barriers is poor
The drugs are excreted almost exclusively by glomerular filtration
For the treatment of serious gram-positive infections, especially MRSA, VRE
Vancomycin
Teicoplanin

27. Oxazolidinones Protein synthesis inhibitors
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Oxazolidinones
Protein synthesis inhibitors
They have bactericidal effects
They are using infections caused by MRSA and VRE
Linezolid (Zyvox), which is available for both intravenous and also has the advantage of having excellent oral bioavailability
Tedizolid, (Sivextro) which is approved for acute skin infections
Cycloserine is a second line drug against tuberculosis

28. Ç. BÜKE Antibiotics
Lipopeptides
Daptomycin has a distinct mechanism of action, disrupting multiple aspects of bacterial cell membrane function
Rapid depolarization, resulting in a loss of membrane potential leading to inhibition of protein, DNA, and RNA synthesis, which results in bacterial cell death
Bactericidal against Gram-positive bacteria only
Approved for right heart endocarditis
MRSA

29. Colistin (Colistimethate)
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Colistin (Colistimethate)
Colistin is a polymixin antibiotic
It has in vitro activity against; Acinetobacter spp. and Pseudomonas spp.
But does NOT have activity; against Proteus, Serratia, Providentia, Burkholderia, Stenotrophomonas, Gram-negative cocci, Gram-positive organisms, or anaerobes
It’s used in the management of infections due to multi-drug resistant Acinetobacter spp. and Pseudomonas spp.
It’s used in combination with other antibiotics
Nephrotoxicity, neuromuscular blockade, neurotoxicity

30. Ç. BÜKE Antibiotics
Fosfomycin
Fosfomycin is a synthetic, broad-spectrum, bactericidal antibiotic
In vitro active against large number of Gram-negative and Gram-positive organisms including E. coli, Klebsiella spp., Proteus spp., Pseudomonas spp., and VRE.
It does not have activity against Acinetobacter spp.
Fosfomycin is available in an oral formulation and its pharmacokinetics allow for one-time dosing
Uncomplicated UTI due to VRE
Salvage therapy for UTI due to Gram-negative organisms

31. Tigecycline It’s a tetracycline derivative, called a glycylcycline
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Tigecycline
It’s a tetracycline derivative, called a glycylcycline
It has in vitro activity against most strains of
Staphylococci and streptococci (including MRSA and VRE)
Anaerobes
Many Gram-negative organisms (except Proteus spp., Pseudomonas aeruginosa)
It’s approved for
Skin and skin-structure infections
Intra-abdominal infections

32. Ç. BÜKE Antibiotics
Ceftaroline
It has in vitro activity against staphylococci (including MRSA), streptococci and many Gram-negative bacteria
It does not have activity against Acinetobacter spp. and Pseudomonas spp. And Gram negative anaerobes
MRSA pneumoniae
Severe infections when Gram positive and Gram negative coverage is needed
Bacteremia or endocarditis due to MRSA

33. Ceftolozane+tazobactam
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Ceftolozane+tazobactam
It has activity against Gram-negative organisms and some strains of multi-resistant Pseudomonas spp.
It does not have activity against carbapenemase producing Enterobacteriaceae and Staphylococcus spp.
It’s used in the management of infections due to multi-drug resistant Pseudomonas spp.

34. Antibiotic resistance mechanisms
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Antibiotic resistance mechanisms
Changes in the target
Modifyin enzymes
Decreased AB penetration
Efflux

35. Resistance mechanisms to beta lactams
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Resistance mechanisms to beta lactams
Bacteria develop ability to hydrolyze these drugs using β lactamase
Confers resistance to penicillin (penicillinase)
e.g. E. coli, Staphylococcus epidermidis, Pseudomonas aeruginosa, Klebsiella pneumoniae
add β lactamase inhibitor e.g. clavulanic acid, sulbactam, tazobactam

36. Resistance mechanisms to beta lactams
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Resistance mechanisms to beta lactams
Genetic mutation of mecA
Carried by Staphylococcal cassette chromosome (SCCmec) mobile genetic unit
A bacterial gene encoding a penicillin-binding protein (PBP2a)
PBP2a has reduced affinity for antibiotics
confers resistance to methicillin, oxacillin, nafcillin
e.g. MRSA
SCCmec type IV has less genetic elements and is specific to CA-MRSA, making CA-MRSA less multi-drug resistant

37. Resistance mechanisms to beta lactams
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Resistance mechanisms to beta lactams
Altered cell wall permeability
Confers resistance to tetracyclines, quinolones, trimethoprim and β lactam antibiotics
Creation of biofilm barrier
Provides an environment where offending bacteria can multiply safe from the hoste immune system
Salmonella
Staph epidermidis

38. Resistance mechanisms to beta lactams
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Resistance mechanisms to beta lactams
Active efflux pumps
Confers resistance to erythromycin and tetracycline
e.g. msrA gene in Staph
Altered peptidoglycan subunit (altered D-alanyl-D-alanine of NAM/NAG-peptide)
Confers resistance to vancomycin
e.g. vancomycin resistant enterococcus (VRE)

39. Resistance mechanisms to 30 S ribosome sites
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Resistance mechanisms to 30 S ribosome sites
Aminoglycosides
A mutation of ribosomal binding site
Decreased uptake
Enzymatic modification of antibiotic
Tetracyclines
Decreased penetration
An active efflux of antibiotic out of cell
Protection of 30S ribosome

40. Resistance mechanisms to 50 S ribosome sites
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Resistance mechanisms to 50 S ribosome sites
Macrolides
Methylation of 23S ribosomal RNA subunit
Enzymatic cleavage (erythromycin esterase)
An active efflux
Chloramphenicol
Decreased penetration
An active efflux of antibiotic out of cell
Protection of 30S ribosome

41. Resistance mechanisms to fluoroquinolones
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Resistance mechanisms to fluoroquinolones
Mutation in one or more gene of topoisomerase II
gyrA
gyrB
parC
parE
Mutation in quinolone resistance-determining region (QRDR)
Decreased membrane permeability
Efflux pumps

42. Ç. BÜKE Antibiotics
Summary
Antibiotics are only used in the treatment of bacterial infectious diseases
Infections caused by viruses (such as colds, and flu), fungus and parasites cannot be treated with antibiotics
Colonization with bacteria is not indication for antibiotic treatment
Samples (blood, urine, pus…) for microbiological investigation should be taken before the first dose of antibiotics

43. Ç. BÜKE Antibiotics
Summary
In case of microbiological results do not become available for 24 to 72 hours, initial therapy for infection is often empiric and guided by the clinical presentation
Emprical antibiotic treatment should be broad spectrum especially if it’s concidered;
Sepsis
Pneumonia
Endocarditis
Meningitis
Febrile neutropenia

44. Ç. BÜKE Antibiotics
Summary
Definitive antibiotic therapy is given according to microbiological results
Once microbiology results have helped to identify the etiologic pathogen and/or
Antimicrobial susceptibility data are available, every attempt should be made to narrow the antibiotic spectrum
This is a critically important component of antibiotic therapy because it can reduce cost and toxicity and prevent the emergence of antimicrobial resistance in the community

45. Thank you for your attention
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Thank you for your attention