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FARMAKOLOGI

ANTIBIOTIK
NASRUHAN ARIFIANTO
STIFAR SUNAN GIRI
PONOROGO

inciples of antibacterial therapy

How Can We Inhibit


Bacteria?
Bacteristatic

Inhibits a vital pathway used in the growth


of the bacteria, but does not directly
cause death
Bactericidal

Disrupts bacterial function so much that


death will occur

What Manner Can We Kill?


Time-dependent

Drug
concentration
must
remain
constantly above the minimum inhibitory
concentration (MIC)
-lactams, vancomycin

Concentration-dependent

Drug concentration must reach a certain


concentration, many times based on the
area under the curve (AUC)
Fluoroquinolones
5

What Can We Disrupt?


Cell

Wall
Folic Acid Synthesis
Nucleic Acid Synthesis
Ribosome
Cell Membrane

Cell Wall Inhibitors

hibitors of Cell Wall Synthesis

Fig. 1.1 Simplified scheme of bacterial cell wall synthesis showing site
of action of cell wall-active antibiotics. (Reproduced from Medical
Microbiology, 16th Edition by David Greenwood (2003), with
permission from Elsevier

Cell Wall Agents


-Lactams

Penicillins
Cephalosporins
Monbactams
Carbapenems

Glycopeptides

10

-Lactam Subtypes
All

share a -lactam ring, thereby


having the same mechansim of action
(and explaining the cross-sensitivity
between classes)

Penicillins
Cephalosporins
Monobactams
Carbapenems

11

Penicillin Classifications
Narrow-spectrum

penicillins
Penicillinase-resistant penicillins
Extended-spectrum penicillins

12

Narrow-Spectrum
Penicillins
Penicillin

G (Pfzierpen)-IM, IV, PO

More active
anaerobes

Penicillin

against

Neiserra

and

V (Pen-Vee K, Veetids)-PO

Keep it straight: V is not IV


Good

activity

against

Gram

{+}

cocci
Anaerobic
activity
(except
Bacteroides)
Drug of choice for syphilis, gas

13

Penicillinase-Resistant
Agents
Cloxacillin

(Cloxapen)
Dicloxacillin (Dynapen)
Methacillin (Staphcillin)
Discontinued in US
Nafcillin

(Nafcil)
Oxacillin (Prostaphlin)

14

Extended-spectrum PCNs
Aminopenicillins
Carboxypenicillins
Ureidopenicillins

15

Aminopenicillins
Agents

Ampicillin (Omnipen, Principen)


Amoxicillin (Amoxil, Trimox)
Bacampicillin (Spectrobid)
Broader

spectrum over penicillin

Gram {-} aerobes


Listeria monocytogenes
Proteus mirabilis
E. coli
16

Carboxypenicillins
Agents

Carbenicillin (Geopen)
Ticarcillin (Ticar)
More

coverage
aminopenicillins

than

the

Increased Gram {-} coverage


Peudeomonas aeruginosa
Ticarcillin 2-4 > Carbenicillin

Enterobacter
Carbenicillin

urine

concentrates rapidly in
17

-Lactamase Inhibitors
Chemicals

with no antibacterial
activity
that
irreversibly
inactivate -lactamase
Sulbactam
With ampicillin (Unasyn)

Tazobactam
With pipercillin (Zosyn)

Clavulanate/Clavulanic acid
With amoxicillin (Augmentin)
With ticarcillin (Timentin)
18

Cephalosporins
Spectra

of activity (generation)
Anaerobic activity (Cephamycins)
Anti-pseudomonal activity
Methyltetrazolethiomethyl side-chain
Metabolism/elimination
Cerebrospinal fluid penetrance

19

1st Generation Agents


Cefazolin

(Ancef, Kefzol)
Cefadroxil (Duricef)
Cephalosporin analog of amoxicillin
Cephalexin

(Keflex)

Cephalosporin analog of ampicillin


Cephalothin

(Keflin)
Cephapirin (Cefadyl)
Cephradine (Anspor, Velosef)
20

1st Generation
Cephalosporins
Great

Gram {+} activity


No activity against enterococci or
Listeria monocytogenes
Mainstay of choice for uncomplicated
community acquired infections
PEcK activity
Proteus
E. coli
Klebsiella
21

2nd Generation Agents


Cefaclor

(Ceclor)
Cefamandole (Mandol)
Cefmetazole (Zefazone)
Cefoxitin (Mefoxin)
Cefotetan (Cefotan)
Cefonicid (Monocid)
Cefprozil (Cefzil)
Cefuroxime (Ceftin, Zinacef,
Kefurox)

22

2nd Generation
Cephalosporins
More

Gram {-} activity than 1st


generation agents
Often used for UTIs and URIs
HENPEcK activity

H. influenzae
Enterobacter* (rapid resistance occurs)
Neisseria
Proteus
E. coli
Klebsiella
23

3rd Generation Agents


Cefdinir (Omnicef)
Cefditoren (Spectracef)
Cefixime (Suprax)
Cefoperazone (Cefobid)
Cefotaxime (Claforan)
Cefpodoxime (Vantin)
Ceftazidime (Fortaz, Tazidime)
Ceftibuten (Cedax)
Ceftizoxime (Cefizox)
Ceftriaxone (Rocephin)
24

3rd Generation
Cephalosporins
Have

even better Gram {-}


coverage than second generation
agents
Loses more Gram {+} coverage
Extra coverage against Serratia
and Moraxella catarrhalis

25

4th Generation
Cephalosporins
Cefepime

(Maxipime)

Has most of the Gram {-} coverage


with Gram {+} coverage
Anti-pseudomonal activity
No anaerobic activity

26

The Generation
Progression
As

one
moves
up
in
cephalosporin generation, more
Gram {-} activity is seen
Consequently, Gram {+} activity
is
decreased
advancing
in
generation
4th generation has Gram {-}
activity without sacrificing Gram
{+} activity
27

Anti-Pseudomonal
Cephalosporins
3rd

Generation

Cefoperazone
Ceftazidime
4th

Generation

Cefepime
The

3rd generation antipseduomonal agents lose even


more Gram {+} activity than
other 3rd generation agents
28

Cephalosporin Elimination
For

the most part, all are renal with


few exceptions
The zones are hepatic
Cefoperazone
Ceftriaxone

29

CSF penetrance
2nd

Generation

Cefuroxime

Generally not used due to decreased efficacy

3rd

Generation

Cefotaxime

Q6-8 dosing
Agent of choice in neonatal meningitis (along
with ampicillin)

Ceftriaxone

Q12-24 dosing
Agent of choice for adult meningitis
Causes kernicterus in neonates
30

Monobactams
Aztreonam

(Azactam)
Resistant to most Gram {-} lactamases
Activity
Only Gram {-} coverage (spectrum
resembles aminoglycosides)
Excellent
activity
against
P.
aeruginosa
Superb Enterobacteriaceae activity
No Gram {+} or anaerobic activity
31

Carbapenems
More

resistant to hydrolysis from


-lactamases
Very
broad
spectrum
with
coverage of Gram {+} (not
MRSA), Gram {-}, anaerobes, and
Pseudomonas aeruginosa
Higher incidence of seizure than
other -lactam agents
32

Carbapenem Agents
Agents

Ertapenem (Invanz)
Imipenem (Primaxin)
Meropenem (Merrem)
Ertapenem

lacks coverage against


Pseudomonas acinetobacter, two
common nosocomial agents

33

Glycopeptides
Vancomycin

(Vancocin)
Teicoplanin (Targocid)

34

Vancomycin Spectrum
Gram

{+} aerobes

MRSA
Penicillin-resistant

pneumococcus

35

Folic Acid Synthesis


Inhibitors

38

Folic Acid Inhibitors


Sulfas

Inhibit dihydropteroate synthetase, an


enzyme involved in the synthesis of
bacterial folic acid
Trimethoprim

Inhibit
dihydrofolate
reductase,
an
enzyme necessary for thymidine synthesis
Both

are bacteriostatic

39

Folic Acid Inhibitor SE


Rashes

Stevens-Johnson syndrome
Angioedema
Hemolytic

anemia
Nephrotoxicity
Via precipitation of crystals of the inactive
metabolite
Crosses

the placenta

Kernicturus
Should be avoided in pregnancy and in children
under 2 months of age
41

Nucleic Acid
Synthesis Inhibitors

42

Fluoroquinolones
Inhibit

DNA topoisomerase II (DNA

gyrase)
Bacteriostatic
Divided into generations; reverse of
the reverse of cepholosporins (actual
classification varies between sources)
Cephalosporins progress from Gram {+}
to Gram {-} activity, but loses Gram {+}
Fluoroquinolones progress from Gram {-}
to Gram {+} activity, but retains Gram
{-}
43

1st Generation FQs


Nalidixic

Acid (NegGram)
Gram {-} coverage only

Enterobacteraceae
E. Coli
Klebsiella
Proteus

44

2nd Generation FQs


Agents

Cinoxacin (Cinobac)
Enoxacin (Penetrex)
Pulled from market

Lomefloxacin (Maxaquin)
Norfloxacin (Noroxin)
Increased

Gram {-} spectrum

45

Advanced 2nd Generation


FQs
Agents

Ciprofloxacin (Cipro)
Ofloxacin (Floxin)
Has

increased Gram {-} coverage


along with atypicals
Cipro
has
good
Pseudomonas
coverage

46

3rd Generation FQ Agents


Agents

Gatifloxacin (Tequin)
Grepafloxacin (Raxar)
Pulled from market

Levofloxacin (Levaquin)
L-isomer

of Ofloxacin

Sparfloxacin (Zagam)
Temafloxacin (Omniflox)
Pulled from market

Same

coverage as 2nd generation with


moderate Gram {+} activity
Used in community acuquired pneumonia
47

4th Generation FQ Agents


Agents

Alatrofloxacin (Trovan IV)


Limited market availability d/t toxicity

Gemifloxacin (Factive)
Moxifloxacin (Avelox)
Trovafloxacin (Trovan PO)
Limited market availability d/t toxicity

Same

as 3rd generation with anaerobic


coverage
48

FQ Side Effects
Complexes

with cations
Photosensitivity
CYP450 interactions
Renal elimination
QT prolongationTorsades de Pointes
Hepatic failure (Trovan)
Tendon rupture
Do not give if <18yo
49

Ribosomal Inhibitors

51

Inhibitors of Protein Synthesis

Inhibitors
Tetracyclines:

Bind to amino acyl t-RNA portion of the


mRNA-ribosome complex
Bacteriostatic
Aminoglycosides

Bind to the separated 30s subunit causing


misreading
Bacteriocidal

55

Tetracyclines
Demeclocycline

(Declomycin)
Doxycycline (Vibramycin)
Minocycline (Minocin)
Tetracycline (Sumycin)

56

Tetracycline Spectrum
Gram

{+} Bacilli
Gram {-} Rods
Gram {-} Bacilli
H. influenzae, Vibrio cholera
Spirochetes

Borrelia burgdorferi
pallidum (syphilis)

(Lyme

dz),

treponema

Chlamydia
Rickettsia

rickettsii

(Rocky

Mt.

Spotted

Fever)
57

Tetracycline SE
Chelates

with cations

Decreased absorption with dairy, calcium


Deposition on calcified tissues
GI

upset
Phototoxicity
Demeclocycline
Never used as an antibiotic because it can
induce nephrogenic diabetes insipidus
Used in treatment of SIADH
58

Aminoglycocides
Amikacin

(Amikin)
Gentamicin (Garamycin)
Netilmycin (Netromycin)
Neomycin (Mycifradin)
Kanamycin (Kantrex)
Streptomycin
Tobramycin (Nebcin)

60

Aminoglycocide Spectrum

Gram {-} Bacteria


Pseudomonas aeruginosa
Vibrio cholerae
Yersinia pestis (PLAGUE! )
Enterobacter aerogenes
E. coli
Klebsiella pneumoneae
Proteus
Serratia
61

Aminoglycocide SE
Highly

polar (cationic) molecules,


usually prevents GI absorption
Renally eliminated
Ototoxicity
Nephrotoxicity
Neomycin-used

topically, orally for

hepatic failure
Streptomycin-used in TB
62

Macrolides
Azalides:

Azithromycin (Zithromax)
Ketolides:

Telithromycin (Ketek)
Macrolides:

Clarithromycin (Biaxin)
Dirithromycin (Dynabac)
Erythromycin (Ery-Tab)

64

Macrolide Spectrum
Chlamydia

(Erythro drug of
choice in pregnancy)
Mycoplasma pneumoniae
Ureaplasma urealyticum
Legionella

pneumophila
Treponema pallidum (Syphillis)
Gram (+) cocci
Gram (+) bacilli
65

Macrolide Spectrum
Clarithro>erythro

Chlamydia, Legionella, Ureaplasma


H. flu
Azithro<erythro

Staph, Strep
Azithro>erythro

H. flu, moraxella catarrhalis (why


used for pneumonia)

66

Macrolide SE
Erythro

destroyed by gastric acid

Enteric coated or esterified forms


Azithro

concentrates in
neutrophils, macrophages,
fibroblasts
Erythro Azithro=hepatic;
clarithro=renal
SE:
NVD, cholestatic jaundice (estolate
salt-erythro), Erythro & clarithro go
through CYP450
67

Lincomycins
Clindamycin

(Cleocin)
Lincomycin (Lincocin)

70

Lincomycin Spectrum
Gram

{+} aerobes
Gram {+} anaerobes
Gram {-} anaerobes
NO gram {-} aerobic coverage
Think of these as 2nd-line
penicillins

71

Lincomycin SE
Rash
Neutropenia
Thrombocytopenia
Erythema

multiforme (rare)
Pseudomembranous colitis

72

Chloramphenicol
Broad

spectrum against Gram


{+}, Gram {-}, and anaerobes.
Can be extremely toxic
Dose-related revesible anemia
Hemolytic anemia in G6PD
deficiency
Dose-independent aplastic anemia
Grey baby syndrome caused by
drug accumulation leading to
cyanosis, cardiovascular collapse
and eventual death
73

Cell Membrane
Inhibitors

74

Cell Membrane Inhibitors


Daptomycin

(Cubicin)
Unique mechanism of action that it
binds to bacterial membranes and
causes a rapid depolarization of
membrane potential which leads to
inhibition of protein, DNA, and RNA
synthesis
Used in antibiotic resistant MRSA,
VRE, and linezolid-resistant strains
Can cause myalgias

75

PUSAT INFORMASI OBAT (PIO)


PC. IKATAN APOTEKER INDONESIA (IAI)
PONOROGO
NASRUHAN ARIFIANTO, S.Farm., M.Farm.Klin.,
Apt.
WA : 081331443337
BBM : 233D670E

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