Aznan Lelo & Zulkarnain Rangkuty

Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran

Universitas Sumatera Utara

22 Oktober 2009, KBK, TROPMED

The tree of antibiotics

Bacterial Targets for Antibiotics

Inhibitors of Cell wall synthesis

bactericidal, time dependent killing

1. Beta-lactams (penicillins,

cephalosporins, carbapenems,

monobactams)monobactams)

2. Cycloserine

3. Glycopeptides (vancomycin,

teicoplanin)

4. Bacitracin

Cell Wall Active Agents

• B-lactams bind to “penicillin binding proteins” (PBP)

-PBP are essential enzymes involved in cell wall

synthesis

-weakened / distorted cell wall leading to cell lysis

and deathand death

• Glycopeptides bind to the terminal D-ala of nascent

cell wall peptides and prevents cross-linking of these

peptide to form mature peptidoglycan

Bacterial cytoplasmic membrane

Structural Features of Bacteria 6

Synthesis of peptidoglycan

Structural Features of Bacteria 7

Antibiotics that inhibit PG synthesis

• Fosfomycin (Monurol) – inhibits formation of PG subunit

• Bacitracin – binds lipid carrier, inhibits externalization of PG subunit (toxic, usually used topically)

Structural Features of Bacteria 8

of PG subunit (toxic, usually used topically)

• Penicillins and cephalosporins (β-lactam antibiotics) -inhibits PG crosslinking

• Vancomycin (glycopeptide antibiotics; Vancocin) –inhibits PG crosslinking

Structure of ββββ-lactam drugs

Penicillins e.g.,

penicillin, cloxacillin,

flucloxacillin, ampicillin, amoxycillin,

carbenicillin, ticarcillin, azlocillin,

mezlocillin, piperacillinmezlocillin, piperacillin

Cephalosporins e.g.,

cephalexin, cefaclor,

cefadrxil, cefuroxime,

cefamandole, cefotaxime,

ceftazidime, cetriaxone

Penicillins

• Penicillin G / V

- good gram positive (not Staph)

-moderate anaerobic activity

• Synthetic penicillins (Ampicillin)

- good gram positive (not Staph)- good gram positive (not Staph)

- moderate gram negative (not Pseudomonas)

• Anti-staphylococcal penicillins

- Cloxacillin

• Anti-pseudomonal penicillins

- Piperacillin

PENICILLIN

• First antibiotic

• Active for coccus gram negative and positive

• Side effects � allergy, anaphylactic shock,

toxic reaction, and local irritation.toxic reaction, and local irritation.

• Excreted by urine

• High resistancy rate

Activity of ß-lactams against common organisms

PenicillinsBenzylpenicillinFlucloxacillinAmoxycillinPiperacillin

Staphylococci++++

E.coli

RR++

Streptococci++++

EnterococciRR++

PseudomonasRRR+

Gram (+)ve Gram (-)ve

Piperacillin

CephalosporinsCephalexinCefuroximeCeftriaxoneCeftazidime

+ ++ + +

++RR

++++

RRRR

RRR+

Urine only+++

CarbapenemsImipenem + + + + +

CEPHALOSPORINS

• Produced by Cephalosporium acremonium

• Inhibit the 3rd step transpeptidase reaction in microbial membrane synthesis.

Type of Cephalosporin :

� 1st Generation (Cefadroxil, Cefazolin, Cephalexin, etc)

� 2nd Generation (Cefaclor, Cefoxitin, Loracarbef, etc)� 2nd Generation (Cefaclor, Cefoxitin, Loracarbef, etc)

� 3rd Generation (Cefixime, Cefoperazone, Cefotaxime, Ceftazidime, Ceftriaxone, etc)

� 4th Generation (Cefepime)Administration : Oral, Intravenous, Intramuscular.

• Cross the placental and blood brain barrier.

• Excretion : kidney and bile.

• Side Effects : Allergic reaction, anaphylactic reaction with bronchospasme and urticaria, diarrhea, bleeding, etc.

Cephalosporines

Generation Examples Activity

First Generation cefazoline

Cefadroxil

Cephalexin

mainly gram pos, some gram neg

Second

Generation

Cefaclor

Cefprozil

weaker gram pos,

better gram neg

More expensiveAbsorption with food:Generation Cefprozil

Cefuroxime axetil

better gram neg Absorption with food:Ceclor – DecreasedCefzil -- No effectCeftin -- Increased

Third Generation Cefdinir

Cefixine

Cefpodoxine

Ceftriaxone

excellent gram

neg,

some gram pos

Convenient

dosage-once or

twice daily

Fourth generation Cefepime excellent gram

neg,

good gram pos

Vancomycin: Mechanism of Action

• Inhibit peptidoglycan synthesis in bacterial cell wall by

complexing with the D-alanyl-D-alanyl portion of the cell wall

precurser

2L-alaracemase

transpeptidase

-L-ala-D-glu-L-lys-D-ala-D-alacarboxypeptidase

2D-ala

D-ala-D-ala

UDP-L-ala-D-glu-L-lys

UDP-L-ala-D-glu-L-lys-D-ala-D-ala

pentapeptide--

ligase (ddl)

adding enzyme

--L-ala-D-glu-L-lys--D-ala-D-ala

vancomycin

-L-ala-D-glu-L-lys-D-ala-D-alatransglycosidase

-L-ala-D-glu-L-lys-D-ala-D-ala

-L-ala-D-glu-L-lys-D-ala-D-ala

transpeptidase

Cell Wall Active Agents

• B-lactam resistance

1. Production of a B-lactamase (most common)

2. Altered PBP (S.pneumoniae)

3. Novel PBP (MRSA)

4. Altered permeability

• Glycopeptide resistance

- primary concern is Enterococcus / S.aureus

- altered target

- bacteria substitutes D-lac for D-ala

- vancomycin can no longer bind

Beta-lactamase inhibitors

• Clavulanic acid:

- used with amoxycillin (Augmentin®)

- used with ticarcillin (Timentin®)

• Sulbactam:• Sulbactam:

- used with ampicillin (unavailable in UK)

• Tazobactam

- used with piperacillin (Tazocin®)

Inhibitors of protein synthesis

• Ribosomes are the site of protein synthesis

• many classes of antibiotics inhibit protein

synthesis by binding to the ribosome

• binding may be reversible or irreversible• binding may be reversible or irreversible

1. Aminoglycosides

2. Macrolides

3. Tetracyclines

4. Chloramphenicol

5. Fusidic acid

Macrolides

Aminoglycosides - general properties

• Major weapon in treatment of severe sepsis

– Gram negative, rapid bactericidal effect

• Fat insoluble and not absorbed orally• Fat insoluble and not absorbed orally

– Effective by the parenteral route

• Entry into cells depends upon oxygen-dependent

transport (lacked by streptococci & enterococci)

• Toxic to the kidney and inner ear - imperative to

measure levels

Aminoglycosides

Aminoglycoside Comment

Gentamicin First broad spectrum

aminoglycoside

Tobramycin Similar spectrum to gentamicin

Amikacin Semi-synthetic derivative of

kanamycin, active against

Gentamicin-resistant G(-)ve

rods

Neomycin Toxic- used topically

Streptomycin Oldest aminoglycoside –

now used to treat TB

Aminoglycosides - spectrum of activity

DrugGentamicinAmikacinStreptomycin

Staphylococci+++

Klebsiella

+++

Streptococci+++

Enterococci+++

Pseudo

monas

+++

Gram (+)ve Gram (-)ve

E.coli

+++

Proteus

+++

Bacter-

oides

RRR

Entero-

bacter

+++

GentamicinAmikacinStreptomycin

Gram (+)ve wall structure (stain with difficulty)

M. tb

R++

MAI

+++

Macrolides

• Erythromycin

• Azithromycin

• Clarithromycin

Large structures:

CH3

OH

CH3

OHO

H3C

O

OH N(CH3)Large structures:

14- (Erythromycin &

Clarithromycin),

15- (Azithromycin),

or 16-membered

rings.

CH3

O

CH3

O

OH5C2

H3CHO O

OH N(CH3)

CH3

O

OCH3

OCH3

OH

Macrolides - general properties

• Newer macrolides inhibit Mycobacteria,

protozoa (T. gondii, E. histolytica, P.

falciparum), Campylobacter, Helicobacter, falciparum), Campylobacter, Helicobacter,

Borrelia, Neisseria & other genital pathogens

• GI complications, mostly with erythromycin

• Given orally, but absorbtion & bioavailability

variable from one macrolide to another

Macrolides

• Erythromycin is inactivated by gastric acid.

• Erythromycin esters are less susceptible to acid

inactivation and are better absorbed

• It inhibits cytochrome P 450

• Erythromycin and Azithromycin are excreted in • Erythromycin and Azithromycin are excreted in

bile.

• Clarithromycin appear in urine and bile.

• Azithromycin has large Vd – high tissue

distribution – concentrated in neutrophils,

macrophages.

Pharmacokinetic of Macrolides

MACRO-

LIDES

Oral

absorption

Cytochrome

P450

Spectrum Half life

(hours)

Erythro-

mycin

yes Inhibits Penicillin 2

mycin

Clarithro-

mycin

Stable to

acid

Inhibits MAC My,

HP, C,Leg

4

Azithro-

mycin

Stable to

acid

No H.Inf, Chl

MAC

>40

Telithro-

mycin

Stable to

acid

Inhibits Same as

Azithro

10

Macrolides

Adverse effects :

• Epigastric distress - erythromycin

• Cholestatic jaundice (mainly with erythromycin

estolate)

• Ototoxicity – erythromycin at high dose.• Ototoxicity – erythromycin at high dose.

Drug - drug interactions

• Erythromycin, Clarithromycin and Telithromycin

inhibit the cytochrome P450 system and so

potentiate the activity of theophylline and

terfenadine

ClindamycinPharmacodynamic

• Active against gram +ve and anaerobes

• Good activity against bacteroides (including B. fragilis) and Penicillin resistant streptococcus.

• No activity against most gram -ve bacteria

Pharmacokinetic Pharmacokinetic

• Well absorbed orally

• Distribution in most tissues including bone.

• Excretion is mainly biliary and also in urine.

Adverse effects

• Gastrointestinal super-infections – potentially fatal pseudo-membranous colitis by C. difficile.

• Oral Metronidazole and Vancomycin are used for the treatment of the fatal pseudo-membranous colitis.

Linezolid

• the first oxazolidone antibiotic

• Blocks 70S ribosome assembly by binding 50 S

subunit

Linezolid

Anti-bacterial spectrum :

• Gram positive bacteria only

– Penicillin resistant streptococci

– Methicillin and Vancomycin

Pharmacokinetics :

• Orally absorbed

• Well distributed

• Excreted by renal and non-renal routes

staphylococcus

– Vancomycin resistant enterococcus

– Lister monocytogenes, Corynebacterium spp

• Also active against mycobacteria tuberculosis and Clostridium

Adverse effects :

• Nausea and diarrhea

• Thrombocytopenia

• Inhibits MAO, avoid tyramine containing foods

Tetracyclines

OH

R1 R2 R3 R4 Inhibit protein synthesis

by preventing amino-acyl

transfer RNA from

entering the acceptor

Natural e.g.,

chlortetracycline,

oxytetracycline,

tetracycline

Semi-synthetic e.g.,

doxycycline,

minocycline

OH O OH O

CONH2OHentering the acceptor

sites on the ribosome

Tetracyclines – general properties

• Active against many common Gram (+)ve & (-)ve

bacteria, chlamydiae, rickettsiae, coxiellae,

spirochaetes, some mycobacteria, E histolytica, &

plasmodia

• Adiministration : oral, intravenous, intramuscular• Adiministration : oral, intravenous, intramuscular

– Given orally, absorption affected by food

• Effect on dentition (chelates Ca)

• Contraindication : pregnancy, lactating, growing child, liver and renal insufficiency

• Side effects : Allergic, anaphilactic, toxic reaction, diarrhea (GI intolerance common)

Chloramphenicol - general properties

• Nitrobenzene nucleus - Blocks peptidyl transferase,

C

OH

H

CH2OHCO2N

H

NHCOCHCl2

• Nitrobenzene nucleus - Blocks peptidyl transferase, thereby blocking peptide bond synthesis

• Bacteriostatic against G(+)ves, many Gram (-)ves (not P. aeruginosa), leptospires, T. pallidum, chlamydiae, mycoplasmas, rickettsiae, & many anaerobes, (B. fragilis less so)

– Bacteriostatic and bactericid ( in high concentration)

• Second line agent due to marrow effects

Fusidic acid - general properties

• Active against most Gram (+)ves and Gram (-)ve cocci, including MRSA

• Some activity against G.

lamblia, P. falciparumCOOH

lamblia, P. falciparum

• Some activity against Mycobacteria

• Mostly used for staphylococcal infections (osteomyelitis) and topically

• Well absorbed orally

COOH

HHO

H

HHO

OAc

Inhibitors of Nucleic acid synthesis

• Inhibition of synthesis of precursors

Sulphonamides

TrimethoprimTrimethoprim

• Inhibitors of DNA replication

Quinolones

• Inhibitors of RNA polymerase

Rifampicin

Inhibition of synthesis of precursorsDrugs acting on microbial folate synthesis

• Trimethoprim - inhibits folate

required for the synthesis of purines required for the synthesis of purines

and pyrimidines by enzyme inhibition

• Sulphonamides - also inhibit folate

synthesis by enzyme inhibition

Trimethoprim- Sulfamethoxazole

(TMP-SMX)

• Prepared as a fixed 5:1 ratio of SMX to TMP

• MOA - inhibits two steps in the folic acid pathway – optimal antibacterial effects occur at a ratio of 1:20

(TMP:SMX) which is also the peak concentration following

oral and IV administrationoral and IV administration

• Pharmacokinetics:– Oral bioavailability > 90%

– Widely distributed into body tissues and fluids

– Metabolized in liver (Acetylated and glucuronide

conjugated ) - then renally excreted

– SMX: 70% in protein bound• It displaces bilirubin, so it can cause newborn jaundice or make it worse if

used in third trimester.

Mechanism of action ofTMP-SMX

Sulphonamides - general properties

• First chemotherapeutic

• Broad spectrum activity– Restricted in use by resistance

– Side effects � allergy, anaphylactic shock, toxic

reaction, and local irritation.reaction, and local irritation.

• Many interactions with other drugs due to

plasma protein binding

• Principal use has been for treatment of UTIs– Excreted by urine

• Useful in treatment of PCP, Nocardia, &

Toxoplasma gondii

Untoward effects of sulfonamides

• Hematopoietic system:

– Hemolytic anemia (in glucose-6-phosphate dehydrogenase deficient patients);

– aplastic anemia; thrombocytopenia; eosinophylia.

• Urinary tract:

– Occlusions due to precipitates and hypersensitivity reactions.

• Drug interaction:

– Due to the high affinity to plasma proteins.

– These include anticoagulants, hydantoin and hypoglycemic agents of

sulfonylurea group.

• Therefore, the patient must be given sufficient amount of

water to produce 1.2 liter/day of urine (i.e. 3-4 liter of

water/day).

Inhibitors of DNA replication

• Quinolones (eg ciprofloxacin - a fluoroquinolone) large family of synthetic agents that affect DNA gyrase synthetic agents that affect DNA gyrase

• DNA gyrase required to supercoil bacterial DNA (it is also important in DNA repair) – bacteria unable to ‘pack’ DNA into cell

Quinolones

• These are synthetic anti-microbials.

• The member of this group –

– Old quinolon (unfluorinated quinolone; first

generation)generation)

– Fluoroquinolones

• Bactericidal and concentration dependent.

• Long post-antibiotic effect on enterobacteriacea

FLUOROQUINOLONES

• Fluoroquinolones (ciprofloxacin, norfloxacin, levofloxacin, moxifloxacin)

- bactericidal, concentration dependent

- bind to 2 essential enzymes required for DNA

replication

- DNA gyrase and topoisomerase IV- DNA gyrase and topoisomerase IV

- gram pos and gram neg

- atypical bacteria, some have anaerobic activity

• Farmakokinetic : well absorbed by oral administration

�widely distributed�Excreted by urine

• Clinical use : UTI, RTI, STD, arthritis, bone infection

• Side effects : Nausea, vomite, headache.

FluoroquinolonesGeneration Examples Spectrum

First

generation

Nalidixic acid,

Pipemidic acid

gram -ve only ;

U T I

Second

generation

Ciprofloxacin,

Norfloxacin,

Ofloxacin

gram –ve, gram +ve,

atypical like

mycoplasma and Ofloxacin mycoplasma and

chlamydia

Third

generation

Sparfloxacin,

Moxifloxacin,

Gatifloxacin

gram –ve, gram +ve

S. pneumoniae,

atypical, anaerobes

Fourth

generation

Trovafloxacin gram +ve and many

anaerobes.

Mechanism of action Quinolones

Fluoroquinolones

Pharmacokinetics :

• Orally well absorbed, metabolism in liver

• FQ chelate Ca, Mg, Fe and Zn

• High tissue penetration – bone, lungs and • High tissue penetration – bone, lungs and phagocytes exceeds that in plasma

• Excreted primarily in urine –(Trovafloxacin and Sparfloxacin are predominantly eliminated by non – renal route)

Fluoroquinolones

Adverse effects :

• CNS : dizziness, confusion, seizures threshold

is decreased.

• Cartilage damage • Cartilage damage – Quinolones are not recommended for

prepuberal children and pregnant woman due to possible arthropathy in children

• Liver failure – Trovafloxacin

• QT prolonged – Sparfloxacin and Moxifloxacin

• Phototoxicity – Sparfloxacin

Fluoroquinolones

Drug interaction

• Plasma concentrations of theophylline,

Warfarin, Caffeine are increased by FQ due to

inhibition of metabolism of these drugsinhibition of metabolism of these drugs

• FQ enhance the CNS toxicity of Caffeine and

seizures are reported.

Inhibitors of RNA polymerase

that affect bacterial DNA and RNA

• Rifamycins (eg rifampacin) specific

inhibitors of bacterial DNA-dependent

RNA polymerase – blocks mRNARNA polymerase – blocks mRNA

• Metronidazole (a nitroimidazole)

When reduced it can react with DNA,

oxidizing it and causing strand breaks

METRONIDAZOLE

• Active for the anaerob

• Well oral absorption

• Effect on CNS

• Drug of choice for � paracytic infection (G. • Drug of choice for � paracytic infection (G.

lamblia), amoeba, and bacterial vaginosis.

Characteristics of a good antibiotic

• Kills or inhibits the growth of bacteria at low concentrations

• Broad spectrum

• Minimal side effects

– Due to direct effects of antibiotic itself

Structural Features of Bacteria 52

– Due to direct effects of antibiotic itself

– Due to effects on the normal microflora of the body

• Appropriate pharmacokinetic properties

– Must get to the site of infection in high concentrations

– Distribution influences mode of administration (oral, injected)