Anti- microbials By Dr.Mohamed - PowerPoint Presentation

Slide1

Anti-microbials

By

Dr.Mohamed

Abd

Almoneim

AttiaSlide2

Classifications of antimicrobials

According

to their antimicrobial spectrum

:

*Antibiotics

with narrow spectrum:

Drugs primarily effective against gram-positive organisms e.g. some

penicillins

,

cephalosporins

, macrolides,…….. etc.

Drugs primarily effective against gram-negative organisms e.g. aminoglycosides,

monobactam

,

……...

*Extended spectrum: both gram –

ve

and +

ve

microorganism.

*Broad-spectrum

antimicrobial agents

That affects most gram-positive and most gram-negative organisms and others(protozoa)

e.g

chloramphenicol,

tetracyclines

, broad-spectrum

penicillins

, 3

rd

generation

cephalosporins

………. Slide3

B.Antimicrobial

agents are also classified according to pharmacological effects as either bacteriostatic (inhibitory) or bactericidal (lethal) agents

.

1-Bacterostatic

(stop multiplication of microorganisms)

e.g. sulfonamides, trimethoprim, chloramphenicol,…... Most of bacteriostatic drugs become bactericidal in high concentrations

.

2-Bactericidal

(act primarily by killing microorganism)

e.g. penicillin,

cephalosporins

, aminoglycosides……..Slide4

C.

According to the source and chemistry:

1-Synthetic

Chemotherapeutic Agents:

they act selectively on infective organism such as sulfonamides,

isonicotinic

acid

hydrazide

and the

quinolones.

2-Antibiotics

:

are those compounds produced by microorganisms (bacteria, fungi) that, at high dilutions, are inhibitory or lethal to other microorganisms such as penicillin, tetracycline and chloramphenicol.Slide5

D.

Antimicrobial agents are also classified according to

their Mechanism of action

:



Mechanism of action of antimicrobial agents

Antimicrobials affect microbial cells by one or more of the following:

1-Inhibition

of bacterial cell wall synthesis, so that the cell absorb water and bursts

e.g. B lactam antimicrobials , bacitracin,

cycloserine

,

vancomycin

.

2-Increased

permeability of cell membrane. So that vital metabolites escape

e.g. antifungal (nystatin, amphotericin),

antipseudomonas

(

polymyxin

B,

colistin

).

3-Inhibition

of protein synthesis by an effect on ribosome:

Drugs acting on 30S subunit e.g. aminoglycosides, tetracycline.

Drugs acting on 50S subunit e.g. chloramphenicol, macrolides,

fucidin

,

lincosamides

.

4-Inhibition

of nucleic acid synthesis

e.g. rifampicin, quinolones, metronidazole, antivirals, anticancer.

5-Inhibition

of intermediary metabolism

e.g. sulfonamides, trimethoprim,

pyrimethamine

, methotrexate.

Uses

of antimicrobials

:…………………………………………Slide6



Adverse effects of antimicrobial agents

:

The adverse effects associated with the use of antimicrobial agents include:

1-Hypersensitivity or allergic reactions

: In form of fever, skin rash, arthralgia,

cholestatic

jaundice or hemolysis. More serious reactions are agranulocytosis, bone marrow aplasia or anaphylactic reaction.

2-Resistance

3-Superinfection= (Opportunistic infection): Reactions related to alterations in normal body flora

Administration of broad-spectrum antibiotics if used for long time may alter or kill bacterial flora or have incomplete absorption. So, the bacteria and fungi that are normally inhibited by bacterial flora will multiply leading to superinfection (its early manifestation may by

diarrhoea

). It is caused by staphylococci, Pseudomonas,

proteus

, Candida

albicans

.. etc. Superinfection may be vaginal, oral, pharyngeal or even systemic infection e.g. staphylococcal

enterocolitis

, candidiasis.

The most serious form of superinfection if it is caused by

gram+ve

anaerobic organism like

closterdil

difficile resulting in

pseudmembranous

colitis.Slide7



Treatment:

Stop

the causative agent and give drug, which kill the organisms responsible for superinfection e.g. staphylococcal

enterocolitis

, which is treated by

vancomycin

orally, or antifungal nystatin for candidiasis. If it is in the form of

pseudmembranous

colitis, it is treated with

antianaerobic

e.g. metronidazole. In addition you must give symptomatic treatment in form of

adsorbants

and antidiarrheal.

4-Vitamin B complex deficiency may follow the use of antimicrobials

e.g

broad-spectrum antibiotics.

It is due to inhibition of bacterial flora that forms these vitamins.

5-Direct toxic reactions (organ toxicity),

resulting from high doses or drug interactions, on

hemopoietic

system, liver, kidney, GIT, nervous system or CVS.Slide8



Resistance to antimicrobial drugs

Biochemical mechanisms

:

1-Production

of inactivating

enzymes:

e.g.



-lactamases (by staph. and some gram-negative bacilli) inactivate



-lactam antibiotics.

2-Reduced

bacterial permeability to

antibiotics:

e.g

tetracyclines

accumulate by active transport mechanism in susceptible organisms. Resistant strains lack this mechanism.

3-Modification

of the receptor

site:

e.g. Loss or alteration of the receptor protein on 30S ribosome causes resistance to aminoglycosides and 50S ribosome causes resistance to erythromycin.

4-Development

of an alternate metabolic pathway that bypasses the reaction inhibited by the

drugs:

e.g. sulfonamide-resistant bacteria can utilize pre-formed folic acid.Slide9

B.

Genetic basis of acquired resistance

:

Chromosomal resistance:

Extrachromosomal

resistance:

This results from transfer of genetic material from one bacterium to

another.The

genetic material may be in the form of plasmids . The genetic material and plasmids can be transferred by transformation, transduction, conjugation, or translocation.



Prevention of

antimacrobial

resistance:

1-Choice

of proper effective drug.

2-Give

the proper dose for sufficient time to maintain sufficiently high levels of the drug in tissues

3-Drug

combination e.g. in TB

4-Avoid

unnecessary exposure of microorganism to a particularly valuable drug by restricting its use (e.g. rifampicin mainly for TB)Slide10



Combinations of antimicrobials

Clinical values (indications or aims) of antimicrobials combination

:

1-To

obtain better effect (synergism) or to increase the spectrum

e.g.

Sulfamethoxazole

plus trimethoprim to form co-

trimoxazole

.

clavulanic

acid plus amoxicillin as

clavulanic

acid inhibits



-lactamase. Another example is

sulbactam

with ampicillin

Penicillin plus aminoglycoside.

2-To

reduce the toxicity or incidence of adverse

effects.

3-To

prevent or delay the emergence of resistant strains especially in chronic infections as tuberculosis in which two or three agents are used

.

4-In

mixed infections as peritonitis (following colon perforation),

a drug active against anaerobes and gram-positive bacteria (e.g. clindamycin) is combined with one active against gram-negative bacteria coliforms

e.g

aminoglycosides.

5-For

emergency treatment of serious infections before laboratory studies are completed

e.g. in suspected septicemia. Anti-staphylococcus (

nafcillin

) may be combined with a drug active against aerobic gram-negative bacilli (aminoglycosides). Slide11

Results of antimicrobial combinations

:

Combining antimicrobial agents may result in the following:

1-Bactericidal

+ bactericidal results in synergism:

e.g. combined use of penicillin and an aminoglycoside antibiotic (such as gentamicin) on the enterococcus. In this example, inhibition of cell wall synthesis by penicillin permits better penetration of the cell wall by the aminoglycoside and more effective inhibition of protein synthesis than either drug alone.

2-Bacteriostatic

+ bacteriostatic results in addition (summation):

e.g. the use of

tetracyclines

with sulfonamides or chloramphenicol.

3-Bactericidal

+ bacteriostatic

(antagonism):

e.g

. use of penicillin, with

tetracyclin

in group (A) streptococcal infection. This because the

tetracyclines

inhibit protein synthesis and are bacteriostatic. Penicillin as bactericidal affects cell wall synthesis and requires

that

bacteria be actively multiplying in order to be bactericidal.

 Slide12



Disadvantages of antimicrobial combination

:

1-Antagonism

:

This may occur if a bacteriostatic (tetracycline,

chloramph-enicol

) and a bactericidal (penicillin,

cephalorporins

, aminoglycosides) drugs are used together.

2-Increase

incidence of Adverse effects and cost.

3-Efforts

toward accurate diagnosis may be neglected.

 Slide13



General principles of therapy with antimicrobials

1-Antimicrobials

should only be given when necessary and after antimicrobials susceptibility test whenever possible

.

2-The

pharmacokinetics of the drug should be taken into consideration e.g. the state of hepatic and renal functions of the patient

.

3-In

serious infection it is better to start with a

parentral

loading of a bactericidal agent to avoid emergence of resistant strains by giving adequate dosage for sufficient duration

.

4-Antimicrobials

should be continued for 3 days after apparent cure is achieved to avoid relapse

.

5-Bactericidal

drugs should be used when there is leucopenia or the phagocytic cells can not get to the site of infection e.g. endocarditis

.Slide14



Causes of failure of antimicrobial therapy

Drug:

Inappropriate

choice, in adequate duration or dose, improper route of administration, poor penetration into the site of infection

.

Host (patient):

Poor host defenses,

undrained

pus (presence of dead tissue), retained foreign bodies

.

Pathogens:

drug resistance, superinfection.Slide15

SYNTHETIC ANTIMICROBIALS

The synthetic chemotherapeutic agents available for clinical use include the sulfonamides,

sulfones

, quinolones, p-

aminosalicylic

acid (PAS), trimethoprim,

pyrimethamine

,

nitrofurantoin

, isoniazid and pyrazinamide.

SULFONAMIDES



Chemistry

sulfonamides comprise a large group of compounds that are structural analogous of P-

aminobenzoic

acid (PABA).



Pharmacokinetics



Absorption and distribution

:



Well absorbed and distributed preparations:

the best is

sulphadiazine



Poorly absorbed preparations:

unabsorbed part is excreted in the

faeces

and partly is excreted in milk and bile.



Metabolism and excretion

:

The

sulfonamides are degraded in the liver by acetylation, oxidation and conjugation with a

glucuronic

acid. Both parent compounds and metabolites are excreted in the urine (so, it is useful for the urinary tract infection). The acetylated form is insoluble in acid medium and liable to be precipitated in renal tubules (

Crystalluria

).Slide16



Mechanism of action

The sulfonamides inhibits incorporation of PABA into folic acid and thereby preventing the synthesis of folic acid, a compound essential to bacterial growth. Humans can not synthesize folic acid and must acquire it through their diet; thus, the sulfonamides selectively inhibit microbial growth.



Antibacterial spectrum

They are bacteriostatic chemotherapeutic agents

, effective

against

gram-positive organisms, some gram-negative organisms and chlamydia.

They also are effective against

Toxoplasma

gondii

&

chloroquine

-resistant

Plasmodium falciparum

.Slide17



Therapeutic uses

Systemic uses

: shrinking uses due to……………………?

Local uses:

Prevention of infections in burned patients

e.g

silver sulfadiazine.

Sulfacetamide

is used topically for treatment of ocular infections.



Adverse effects

Mild

e.g. nausea, vomiting, headache, cyanosis and arthritis.

Serious:

1-Crystalluria

:

it is a precipitation of acetylated form or sulfonamide itself in renal tubules leading to renal colic,

haematuria

, oliguria and even anuria

Prevention:

Give excess fluids (at least 2 liters urine/day)

Give alkalinizing agent e.g. citrate, bicarbonate to prevent precipitation (i.e. increase solubility of sulfonamide and its acetylated form).

2-Allergic

reactions

e.g. rash, fever, hepatitis, skin and mucous membrane lesions (Erythema multiform). After using long acting sulfonamides in children (Stevens-Johnson syndrome).Slide18

Bone marrow depression leading to aplastic

anaemia

(agranulocytosis).

Haemolytic

anaemia

(idiosyncrasy)

especially in patients with defective glucose-6-phosphate dehydrogenase.

Kernicterus

when given in last 2 weeks of pregnancy or to neonates and infants. It occurs with long acting sulfonamides if used for long time because sulfonamides compete with bilirubin for albumin leading to high free bilirubin concentration in blood.

Superinfection

(with poorly absorbed sulfa).Slide19



Drug interactions

Through displacement from binding sites on plasma proteins of oral hypoglycemic drugs, oral anticoagulants (warfarin), methotrexate.



Preparations of Sulfonamides



Well absorbed from GIT:



Short acting

e.g. Sulfadiazine.



Long acting

e.g

S.

Doxine

.



Poorly absorbed from GIT:

S.

Suxidine

and S.

Thalidine



For local use only

:

S.

Thiazole

for wounds in absence of pus.

Mafenide

for wounds and burns in presence of pus.

S.

Acetamide

: used as eye drops.

Silver

sulphadiazeine

for infected burns, bed sores, etc.

Others:

S.

Salazine

for chronic ulcerative colitis.Slide20

TRIMETHOPRIM

Potent inhibitor of bacterial

dihydro

folate reductase



Pharmacokinetics



Absorption and distribution

:

Trimethoprim is well absorbed from the gastrointestinal tract.

Because the drug is a weak base, so higher concentration will be trapped in acidic prostatic and vaginal fluids. It is also penetrate the cerebrospinal fluid.



Mechanism of action

Trimethoprim competitively inhibits

dihydrofolate

reductase, the enzyme that catalyzes the reduction of

dihydrofolic

acid (folic acid) to

tetrahydrofolic

acid (

folinic

acid) leading to decreased

tetrahydrofolic

acid coenzyme required for purine and pyrimidine synthesis.Slide21



Antibacterial spectrum

Similar to sulfonamide and more potent.

It can be used alone in treatment of acute urinary tract

infection,bacterial

prostatitis (

fluoroquinolones

are preferred) and vaginitis.



Adverse effects

1-Hypersensitivity

to trimethoprim.

2-It

produces the effects of folic acid deficiency which include

megalobastic

anaemia

, leucopenia, and

granulocytopenia

.

Prolonged therapy with full doses can interfere with

haemopoiesis

(only in those with initially low folate stores), so macrocytic

anaemia

is due to interference with conversion of folic to

folinic

acid may occur. Macrocytic

anaemia

can be reversed by

folinic

acid and this will not reverse the antibacterial action of trimethoprim since bacteria cannot utilize pre-formed folic or

folinic

acid because they do not absorb it.

3-Possible

teratogenic risk in pregnancy.



Trimethoprim is contraindicated in pregnancy because it is a folate antagonist.Slide22

SULFONAMIDES COMBINATIONS

:

CO-TRIMOXAZOLE

It is a combination of trimethoprim and S.

methoxazole

:

Either drug alone is bacteriostatic, but in combination co-

trimoxazole

is

bactericidal

(because it inhibits two successive steps of the enzymatic pathway for the synthesis of

folinic

acid), less bacterial resistance develops and bacteria which were not sensitive to sulfonamides become sensitive e.g.

Salmonella, Proteus.

It is effective against

salmonella,

shigella

, staphylococci,

proteus

, E.coli,

haemophilus

, Neisseria (Pseudomonas is usually insensitive). Slide23



Mechanism of action

Sulphamethoxazole

acts on the first step in the folic acid synthesis pathway(see before).

Trimethoprim acts on the second step in the folic acid synthetic pathway(see before). This step occurs in man, but the sensitivity of the enzyme that is inhibited is much greater in bacteria than in man, therefore, the drug is relatively safe.



Uses of Co-

trimoxazole

1-Respiratory

infection due to H.

influenza,pneumonia

due to

pneumocystitis

carinii

(opportunistic infection in patients with AIDS)

2-Urinary

tract infection and prostatitis

3-Salmonella

infection e.g. enteric fever

4-Shigellosis

5-Gonococcal

urethritis.

6-Toxoplasmosis

.



Adverse effects

Like sulfonamides and trimethoprim (see before) Slide24



OTHER SULFONAMIDES COMBINATIONS

1-Sulfadoxine

+

pyrimethamine

"

Fansidar

" (for treatment of

chloroquine

-resistant malaria which is caused by Plasmodium falciparum:

2-Sulfadiazine

(or

trisulfapyrimidine

) +

pyrimethamine

for treatment of toxoplasmosis (drug of choice).

3-Silver

S.diazine

is applied to infected skin lesions e.g. burn.

 Slide25

QUINOLONES



Members

1-First

generation:

Nalidixic

acid.

2-Second

generation:

Pipemidic

acid.

3-Third

generation: Most are fluorinated. They include ciprofloxacin ,

ofloxacin

, etc… (Fluorination was found to produce compounds with greater antibacterial activity, achieving clinically useful drug levels in the blood and tissues).

4-Fourth

generation: e.g.

moxifloxacin

,

trovafloxacin

.



Spectrum

Gram-negative organisms, e.g. E.coli, Proteus,

Klebsiella

,

Shigella

, Salmonella, coliform bacteria, Neisseria,

Pseudomonus

, and H. Influenza.

Less active on gram-positive bacteria.

Not active on anaerobes.

Fourth generation: they are like third generation with enhanced gram-positive and

antianaerobes

activity.Slide26

Members

Fluoroquinolones

2

nd

generation

1

st

generation

3

rd

generation

4

th

generation

Nalidixic

acid

Pipemidic

acid

Ciprofloxacin

Levofloxacin

Norfloxacin

Ofloxacin

Trovafloxacin

Moxifloxacin

Spectrum:

More active on

G -

ve

(

E.coli

,

Shigella

, Proteus

)

active

onG-ve

&

lessactive

onGm .

Active onG -ve, G+ve, &Pseudomonas

G -ve, G+ve,Pseudomonas &anaerobes

Excretion

Renal

Renal

Renal & biliary

Renal & biliarySlide27



Mechanism of action

They inhibit DNA synthesis by inhibition of DNA

gyrase

needed for the synthesis of bacterial DNA.



Pharmacokinetics

They are readily absorbed from GIT, diffuse into tissues including prostate.

They are metabolized in the liver.

Excretion is renal and biliary (3

rd

and 4

th

generations).

Antacids (Mg & Al antacids) &

sucralfate

decrease their GIT absorption. Slide28



Therapeutic uses

1-GIT

infection caused by salmonella (enteric fever),

shigella

, E.coli.

2-Urinary

tract infections , genital tract infection

e.g

gonorrhea and prostatitis.

3-Third

generation can be used in severe systemic infections.

4-Ciprofloxacin

is also used in treatment of meningitis (due to H. influenza, N. meningitides), respiratory tract infections.

5-Treatment

of skin infections, gonorrhea and

septicaemia

.

6-Treatment

of bone infection

e.g

osteomyelitis and

Septicemia.Slide29



Adverse effects

1-GI upset (nausea, vomiting, abdominal pain), and pseudomembranous colitis.

2-Hypersensitivity reactions and

photosensitization.

3-Neurological Adverse effects (headache, drowsiness, vertigo, and seizures).

4-Fluoroquinolones should not be used in children up to 17 years as it causes

arthropathies

in experimental animals, also it is avoided in pregnancy and lactation.

5-Interstitial nephritis and

crystalluria

.

6-Decrease metabolism of theophylline, warfarin and

sulphonylureas

leading to increase in their blood levels.