CHEMOTHERAPY

# Chemotherapeutic agent
# Antibiotic # Antimicrobial

Classification of antimicrobials
I. According to mechanism

II. According to antimicrobial activity III.According to cidal and static activities

I-According to the mechanism:

II-According to the antimicrobial activity:

Narrow spectrum Broad spectrum

Wide spectrum

 I-Bacteriostatics:

III-According to the static & cidal activity:

Chloramphenicol Tetracyclins Erythromycin Sulfonamides Trimethoprim Lincomycin

 II-Bactericidals:
Aminoglycosides Cephalosporins Penicillins Quinolones Rifampicin Isoniazid

 Indications of bactericidal agents:

Debilitated patients Agranulocytosis Aplastic anaemia + Immunosuppression Carriers Bacterial endocarditis

Factors affecting the antibacterial activity:

I. Concentration at site of infection II. Bacterial resistance III. Host defense mechanisms IV. Local factors

Factors affecting the antibacterial activity:

I. Concentration at site of infection

1) DOSE

2) PHARMACOKINETICS

Blood CSF barrier to antimicrobials

penetration
Good: in the presence of meningeal inflamation Good: regardless Poor:

Antimicrobials
Pnicillin, vancomycins,3rd G. cephalosporins. Chloramphenicol, rifampicin, sulphonamides. Aminoglycosides, Clindamycin, erythromycin, Cephalosp. 1st&2nd

Route of elimination of antimicrobial

Renal Hepatic Renal & Hepatic

Aminoglycosides Chloramphenicol
Cephalosporins Nitrofurantoin Vancomycin Clindamycin Doxycycline Erythromycin Lincomycin Metronidazole Rifampicin

Most penicillins
Most tetracyclines Quinolones Isoniazide

Factors affecting the antibacterial activity: II. Bacterial resistance MECHANISMS - Genetic Determinants: Mutation, Transduction, Transformation, Conjugation, Transposition. - Biochemical mechanisms:
1. Production of enzymes 2. Alteration of drug uptake 3. Alteration of drug binding sites 4. Development of alternate pathway - Cross Resistace

How to minimize the emergence of resistance ?

1. High level maintainance 2. A.B. Combinations 3. Use restriction of valuable drug

Factors affecting the antibacterial activity:

III. Host defense mechanisms:

How could be affected ?

Immunosuppressants: 1. Ionising radiation 2. Cytotoxic drugs 3. Corticosteroids 4. Chloramphenicol

Immunopotentiators: 1. Levimazole 2. Fungal polysaccharides 3. BCG vaccine

Factors affecting the antibacterial activity:

IV.

Local factors :

Pus, Haematomas, pH, Blood flow, Foreign body

Mention the effect of low pH in abscess, pleural space, CSF & urine on the antimicrobial activity ?

LOW pH :
activity of: 1. Aminoglycosides 2. Erythromycin 3. Clindamycin activity of : 1. Chlortetracycline 2. Nitrofurantoin

What are the causes of failure of antimicrobial therapy ?

Causes of failure of anti-microbial: 1. Wrong route 2. Impaired defense 3. Poor penetration 4. Wrong culture 5. Pus 6. Foreign body 7. Delay 8. Sub optimal dose 9. Sub optimal duration

General adverse reactions: 1. 2. 3. 4. Hypersensitivity reactions Toxic or irritative effects Super infection (opportunistic infection) Organ toxicities

WHAT IS SUPERINFECTION ?

= Opportunistic infection Sites 3 # irritative diarrhoea Common organisms. 3 Predisposing factors: 1. Age< 3 years 2. High dose 3. Prologed therapy 4. Broad spectrum A.B. 5. Combination of A.B. 6. Low defense

General principals of chemotherapy: 1. When necessary 2. Susceptibility test 3. Consideration of Ph.K. & hepatic and renal states 4. Loading dose & cidality in serious infection 5. Continuation 3 days after apparent cure to avoid relapse 6. Adequate dose & duration & combined therapy to avoide emergence of resistance 7. Test of cure 8. Avoid abuse

Beta Lactam Antibiotics

Penicillins, Cephalosporins & Penems

I- Penicillins
O
Amidase

CH3
C CH3
Thiazolidine ring

RCNHCHCH

O=C----- N------CH--COOH

Betalactamase

1. Peptidoglycans Transpeptidase (PBP) Peptidoglycan Polymers

2. Activate cell wall Autolysis

UDP-N acetyl muramic acid

CH2OH O O O--UDP NH C=O UDP

CH3CH
COOH

CH3

UDP

Ala Gly lys

UDP

UDP-N acetylglucosamine
UDP

Cycloserine
UMP

p
p

UDP
p
Glycyl RNAt

Ala Gly Lys

UDP

p
p p p p

Ala
Ala RNAt

Penicillins Cephalosporins

Transpeptidase

Mechanisms of penicillin resistance: 1. B. lactamase production (staph.aurius, E.coli, pseudomonas, proteus, & bacteroids) 2. Lack of penicillin receptors 3. Lack of cell wall formation 4. Impermeability 5. Failure of activation of the autolytic enzymes

Classification:

I-Natural:
A-Pen. G:

II-Semisynthetic

- Benzyl Pen.G 1.Antistaph. 2.Broad S. 3.Extended S. 4.Rev.S - Procaine Pen.GCloxacillin -Ampicillin (Anti-pseudomonas) -Pevmecillinam Dicloxacillin -Amoxicillin Carbenicillin-Mecillinam - Benzathine Pen.G -Oxacillin -Pivamp. -Ticarcillin B-Pen. V:

Flucloxacillin Talamp. -Azlocillin,

Nafcillin Methacillin Bacamp. -Mezlocillin -Piperacillin

I-Natural Pen:
A-Pen. G: - Benzyl Pen.G

- Procaine Pen.G
- Benzathine Pen.G

B-Pen. V:

Explain how
the nature of penicillin can influence its therapeutic use ?

Benzyl Pen.:
Is the drug of choice for severe infections As: Pneumonia, endocarditis, meningitis, sepicaemia. Because: 1. Widely distributed except CSF 2. Gm + aerobic cocci Specrum on: S. Pneumoniae, S. Pyogenes S. Viridans Staph. Aurius 3. I.V. & I.M. 4. Rapidly acting

Procaine pen. G:
Indicated in less severe infection & to prevent endocarditis after dental extraction because it: Acts more slowly & longer ( Never I.V. )

Benzathine Pen. G :
Indicated in prophylaxis of : Syphilis, Streptococcal pharyngitis & Rheumatic fever Because: It is very slowly absorbed following deep I.M. injection

What are the advantages of Penicillin V ?

Advantages of Penicillin V:
1. 2. 3. 4. Acid resistant ( given orally ) Less penicillinase sensitive Longer T1/2 + The same spectrum, distribution & fate

II-Semisynthetic Pen
1.Antistaph. (Penicillinase-Resistant Pen)

Cloxacillin Oxacillin

Dicloxacillin Flucloxacillin

Nafcillin

Methacillin

How the penicillins could be Penicillinase resistant ?

Through: 1. Structural modification: ( cloxacillin, oxacillin, dicloxacillin, flucloxacillin ) ( Nafcillin ) ( Methicillin ) 2. + Irriversible B-lactamase inhibitor: Clavulinic acid (+ amoxicillin, + ticarcillin) Sulbactam (+ ampicillin) Lazobactam (+ piperacillin )

What is the advantage of NAFCILLIN ?

The only of the antistaph. Pen. Eliminated by the liver only (NO Nephrotoxicity)

What are the other Antistaph. ?

ANTISTAPH.
1. 2. PENICILLINS Penicillin Penicillinase R. pen. Cloxacillin, dicloxacillin, flucloxacillin. Nafcillin Ampicillin+sulbactam Methicillin BACTRIM 1st GEN. CEPHALOSP. CEFOTAXIME, CEFTAZIDIME (3RD Gen) CLINDAMYCIN PRISINAMYCIN AMINOGLYCOSIDES RIFAMPIN QUINLONES VANCOMYCIN FOSFOMYCIN

II-Semisynthetic
2.Broad S.
-Ampicillin -Amoxicillin -Proampicillin: Pivamp. Talamp. Bacamp.

Compare between Amoxicillin & Ampicillin ?

Amoxicillin Oral - Parenteral 95% intestinal absorption No effect of food Very high urinary conc.

Ampicillin Oral - Parenteral 40 % Decrease absorption High

High & persistant in sputum

No activity on Pen. Resist. Staph. Good activity against salmonella Poor activity against shigella Less diarrhoea

Lower and decrease

No activity Fair-good Good Diarrhoea/rash

What are the advantages of the Proampicillins ?

Advantage of Proampicillins:
Absorption not decreased by food Disadvantage of Proampicillins: Useless in liver disease ( Ampicillin release occurs in the liver )

II-Semisynthetic Pen.
3.Extended S. (Anti-pseudomonas)
Carboxypenicillins:
Carbenicillin, Ticarcillin,

Ureidopenicillins: (More active)

Azlocillin, Mezlocillin,

Piperacillin
( Only Carbenicillin indanyl can be given orally also)

Why called Extended Spectrum ?

 They are broad spectrum + Pseudomonas, but should only be used for pseudomonas and ampicillin resistant proteus. Active against anaerobic gm ve bacilli B-lactamase susceptible Synergistic with aminoglycosides

EFFECT AZLOCILLIN MEZLOCILLIN PIPERACILLIN

Pseudom.

+++

++++

Other Gm -ve

+++

+++

Comare Carbenicillin & Ureidopenicillins groups

CRBENICILLIN gp

UREIDOPENICILLIN gp

Less active on Pseud. & Klebsiella.

More active

Less safe on the kidney

Safer

Use restriction of valuable drug

is an important principal in antimicrobial therapy

Explain Why ?

 To avoid the development of resistance to these valuable drugs. Examples: Rifampicin, Vancomycin Antipseudomonal penicillins

What are the other Antipseudomonas?

Anti-Pseudomonas
Extended Spectrum Penicillins 3rd. Gen. Cephalosporins Carbapenems e.g. Imipenem Monobactams e.g. Aztreonam Aminoglycosides Quinolones 3rd Gen. Polymyxins

II-Semisynthetic Pen.
4.Reversed Spectrum (Amidinopenicillins) (Mre potent agaist gm-ve than gm+ve) But not pseudomonas nor H. influenza. -Pevmecillinam (Prodrug) -Mecillinam

Mecillinam:
Parenteral Antityphoid , UT infection, Shigella

Pivmecillinam:
Oral Prodrug Antityphoid, UT infection, Shigella

List the antityphoid drugs

Antityphoids:
1. Amidinopenicillins (Mecillinam & Pivmecillinam ) 2. 3rd Gen. Cephalosporins: Cefoperazone & Ceftriaxone 3. Ampicillin & Amoxicillin 4. Chloramphenicol 5. Quinolones 6. Septrin

Interactions:
1. Ampicillin decreases the effect of oral contraceptives 2. Ampicillin increases the incidence of allopurinol rashes

3. Ticarcillin and lithium, hypernatraemia

4. Penicillins and probenecid 5. Penicillins and copper reduction test for glucosuria

Uses: A) Treatment:
1. Streptococcal (Pen.G) 10. Salmonella (Amp. &Amox. 2. Pneumococcal (Pen.G) 11. H. influenzae (Amp. &Amox) 3. Staphylococcal 12. Listeria (Amp.) 4. Meningococcal (Pen.G) 13. Pseudomonas 5. Gonococcal (Pen.G) 6. Anaerobic (except B-fragilis) (Pen.G) 7. Actinomycosis (Pen.G) 8. Diphtheria (Pen.G) 9. Anthrax & Clostridial (Pen.G)

Uses: B) Prophylaxis 1. Outbreaks of streptococcal infections (Pen.V) 2. Recurrences of rheumatic fever (Benzathine) 3. Gonorrhea & syphilis (Benzathine P) 4. Gonorrheal ophthalmia in neonates (Benzyl) 5. Surgical procedures in patients with valvular heart disease (Procaine P)

Unwanted effects: 1. Hypersensitivity 2. Pain 3. Jarisch-herxheimer reaction 4. Diarrhea- superinfection 5. Nephritis- hepatitis 6. Neurotoxicity 7. Platelet dysfunction (Antipseudomonals) 8. Cation toxicity 9. Rashes (Ampicillins; more with infectious mononucleosis) 10. Agranulocytosis (methicillin, cloxacillin)

N.B.: Incompatibilities of Pen.:

Penicillin G inactivation or precepitation by:acidic solutions, B-complex , chloramphenicol,

tetracyclines, vancomycin and amphoterecin B

Carbenicillin, mezlocillin and piperacillin inactivation by : aminoglycosides

What are the contraindications of Penicillins ?

How can you prevent and treat penicillin hypersensitivity?

Prevention: 1. Never if there is a history. 2. I.D. test: (0.02 ml) 500 u --- 5000 u ----- 50,000 u /ml Treatment: 1. Recumbancy & elevated extrimities 2. Vital signs monitoring 3. Tourniquet & release /15 min 4. Adrenaline 1 ml (1/1000) / 10-20 min (i.m.) & 1 ml / 500 cc dextrose 5 % I.v. infusion 5. H1 blocker 6. Hydrocortisone

II- Cephalosporins & Cephamycins

S R1CNHCHCH O
Dihydrothiazine ring

CH2

O=C

N C

CHCH2 R2

C O OH

Similarities to penicillin:
1. A peptide nucleus (7-amino-cephalosporanoic acid)
2. Inhibition of the transpeptidase of the cell wall. 3. Destroyed by a specific bacterial B-lactamase (cephalosporinase)

What are the cephamycins ?

1st. Gen.
-most gm +ve -some gm-ve

2nd. Gen.
-extended spect.
(+H. infl& proteus)

3rd. Gen.

4th. Gen.

-reversed spect. = 3rd Gen. ( for gm ve)

no CSF bioavailability bioavailability

-no CSF
-t1/2

CSF bioavailability

= 3rd Gen.

2 hrs

t1/2

4 hrs

t1/2

8 hrs

= 3rd Gen.
More resistant

-inactivated by -inactivated by -invariably B-lactamase B-lactamase resistante.g.cefalothin Cefalexin Cefamandole, cefaclor

Cefotaxim, Cefepime, cefoperazone,ceftr iaxone, moxalactam

3rd. Gen. (cont.) cefixime & cefpodoxime are taken orally Cefoperazone & ceftriaxone are of dominant biliary elimination. Moxalactam & ceftazidine are of dominant renal elimination Cefotaxim is of nearly equal renal & biliary elimination Cefotaxim and moxalactam are partialy removed by hemodialysis and not peritoneal dialysis.

Indications:
1st. Gen. : -Prophylactic before surgery -Penicillin resistant infections 2nd. Gen.: -primarily for respiratory & urinary infections 3rd. Gen.: 1-Primarily for gm-ve infections alone or in combination with aminoglycosides 2-Primarily for meningitis Ceftriaxone or Cefotaxim are of choice in adults & children 3-Gonorrhea : Ceftriaxone is of choice 4-Pseudomonas: Ceftazidine + aminoglycoside are of choice 5-Typhoid:Cefoperazone or ceftriaxone is of choice

Adverse effects: 1. Hypersensitivity 2. Nephrotoxicity (especially 1st.Gen.) 3. Thrombophlebitis (with I.v. injection) 4. Bleeding tendency (especially with moxalactam, cefoperazone) 5. Disulfiram-like reaction (with moxalactam & cefoperazone) 6. +ve Coombs reactions (with parenteral high dose) 7. Diarrhea (especially with cefoperazone)

Incompatibilities:

Precipitation by: calcium gluconate or carbonate, erythromycin & tetracyclines

III- OTHER B-LACTAM ANTIBIOTICS

I-Carbapenems:
1) Imipenem: 2)Meropenem:

II-Carbacephems:(Loracarbef)
= second Gen. Cephalosporins

III- Monobactams:
1)Aztreonam: -Synthetic monocyclic B-lactam. -Spectrum of enterobacteria, aerobic gm-ve bacilli (antipseudomonal) -B- lactamase resistant -Parenteral -Induces phlebitis, increase in liver enzymes, thrombocytopenia. 2) New monobactams

Imipenem:
Synthetic Resist B-lactamase Broad spectrum
(Not methicillin-resistant staph.)

Meropenem:
Synthetic Resist B-lactamase Broad spectrum
(Not methicillin-resistant staph.)

Parenteral
- Inactivated by renal dehydropeptidase (so
combined with cilastatin

Parenteral
- Not Inactivated by renal dehydropeptidase Induces G.I. Upsets, Neutropenia

Induces G.I. Upsets, Neutropenia seizures

III- Monobactams:
1)Aztreonam: -Synthetic monocyclic B-lactam. -Spectrum of enterobacteria, aerobic gm-ve bacilli (antipseudomonal) -B- lactamase resistant -Parenteral -Induces phlebitis, increase in liver enzymes, thrombocytopenia. 2) New monobactams

Other antibiotics acting on the cell wall:

1. Vancomycine & Teicoplanin 2. Bacitracine 3. Cycloserine Antibiotics acting on cell membrane: - Polymyxins

UDP

Ala Gly lys

UDP

UDP-N acetylglucosamine
UDP

Cycloserine
UMP

p
p

UDP
p
Glycyl RNAt

Ala Gly Lys

UDP

p
p p p p

Ala
Ala RNAt

Vancomycine: Bactericidal. Crosses the BBB of inflammed meningese Used for: -Methicillin resistant staph. aureus -Serious staph infections( endocarditis, CSF shunt infection, prosthetic valve infection, enterocolitis) -Pseudomembranous colitis ( Clostridium difficile) Nephrotoxic, ototoxic, red neck S., phlebitis. 500 mg/6hrs I.v. & orally for enterocolitis. Precipitated by heparin, penicillin, hydrocortisone, & chloramphenicol.

TEICOPLANIN = Vancomycin
But longer acting

BACITRACIN
A mixture of polypeptide antibiotics
Anti gm +ve especially staph Used topically ( + neomycin + polymyxins ) Nephrotoxic

POLYMYXINS (Colistin ) -Mixture of polypeptide antibiotic -Bactericidal -Interacts with cell memb. Phospholipids -Anti- gm ve & in particular pseudomonas -Used topically in the gut -Nephrotoxic, Neurotoxic, Neuromuscular block

Antibiotics Inhibiting Protein Synthesis

1. Bactericidals: Aminoglycosides

2. Bacteriostatics: - Tetracyclines - Chloramphenicol - Macrolides - Lincomycin - Sodium fusidate

30 S acting: Tetracyclines & Aminoglycosides 50 S acting: Macrolides & Chloramphenicol

1- Aminoglycosides
1. 2. 3. 4. 5. 6. 7. 8. 9. Streptomycin Gentamycin Tobramycin Amikacin Netilmycin Kanamycin Neomycin Paromomycin Spectinomycin

Rapid, concentration dependent bactericidal effect

WHY ?

WHY a single daily dose inspite of a short T1/2 ?

Postantibiotic effect

Why not anaerobics ?

Multiple mechanisms of bacterial resistance

Highly polar.

Serum drug monitoring is important

WHY ?

What are the therapeutic uses ?

Incompatible antibiotic combinations ..

Amphotericin B, Carbenicillin.

Increased toxicity with other antibiotic or drug combinations ..

Nephrotoxicity (+Ceph., vancomycin, amphotericin, furosemide) Ototoxicity (+Loop diuretics, vancomycin) Neuromuscular block (+ NM blockers) Pseudomembranous colitis (+ clindamycin)

Antagonistic combinations..
Synergistic combinations..

What are the contraindications & precautions with aminoglycosides therapy?

Contraindications: 1. Pregnancy 2. Myasthenia gravis

Precautions: 1. Drug combinations 2. Drug incompatibilities 3. Renal insufficiency 4. Narrow safty margin 5. Malabsorption & superinfection

Tetracyclines

Classify tetracyclines ?

 Natural: Short acting t1/2 8hrs tetracyclin HCL, chlortetracycline, oxytetracycline

Intermed.acting t1/2 12hrs : demeclocycline

Hemisynthetic:(long acting t1/2 18 hrs) Minocycline & doxycycline

How tetracycline acts ?

How can bacteria resist ?

Does it work on human cell ?

 30S subunit binding, bacteriostatic

Resistance by an active drug export system

Human cells lack the active transport mechanism

Tetracyclines are wide spectrum antibiotics ; Mention why ?

 Wide spectrum: = gm.+ve : cocci & bacilli, gm- ve :(including cholera, tularemia & bruclla bacilli), =Chlamydia, Mycoplasma, Rickettsiae, Actinomyces, Treponema.

Compare the Ph.K. of

Doxycycline, minocyclie & the other tetracyclines

Tetracyclines

Doxycycline

Minocycline Improved + + CSF Both 16-18 hrs

Decreased abs. By Improved food. Form insoluble chelate with Ca++ +

Distributed by all + CSF except CSF Both renal & Biliary biliary elimination T I/2 6-8 hrs 10-12 hrs 16-18 hrs

Uses of tetracyclines: 1. Ricketsial infections (Rocky Mountain spotted fever, typhus, Q fever) 2. Mycoplasma pneumoniae 3. Chlamydia infections (psitacosis, trachoma, urethritis, lymphogranuloma venereum) 4. Cholera 0.5gm / 6 hrs / 5 days (Drug of choice ) 5. Tularemia 6. Brucellosis 7. Actinomycosis

Adverse effects: 1. G.I. Irritation 2. Superinfecrtion 3. Severe liver damage in pregnancy ( I.v. ) 4. Liver damage with R.F. 5. -ve nitrogen balance 6. Teeth staining & deformity 7. Photosensitisation 8. Fanconi S. 9. Teratogenesis 10. Nephrotoxicity

Drug interactions: Antiacids Iron salts Ca2+

Barbiturates, pheytoins, .. Oral anticoagulants

Contraindications: Renal failure Except Doxycycline Pregnancy, children < 12y

Hepatic disease Hypersensitivity

What are the advantages of doxycycline against other tetracyclines ? 1. Absorption is more rapid & complete, Weaker effect on intestinal flora 2. Better distribution (The most lipid soluble) 3. Excreted primarily in the faces 4. Less incidence of tooth discoloration 5. Insignificant -ve nitrogen balance

Chloramphenicol

How Chloramphenicol acts ?

How can bacteria resist ?
Does it work on human cell ?

 Binds to 50 S ribosomal subunit Bacteriostatic Wide spectrum Inhibits also mitochondrial pr. Synthesis the associated toxicity

Bacterial resistance occurs through:

Acetyl transferase

Chloramphenicol is a wide spectrum antibiotic ; Mention why ?

Wide spectrum bacteriostatic: = gm.+ve : cocci & bacilli, gm- ve :(including H. influenza , tularemia, ) =Chlamydia, Mycoplasma, Rickettsiae,
= Anaerobic bacteria, including B. fragilis.

High bioavailability, Hepatic metabolism & renal elimination

Uses of chloramphenicol: 1. Typhoid & paratyphoid (not for carrier state) 2. H.influenza meningitis & epigottitis 3. Pneumococcal & meningeococcal meningitis 4. Anaerobic infections (B. fragilis) 5. Alternative to tetracyclines in brucellosis, ricketsial diseases, chlamydia, tularemia 6. Intraoccular infections

Adverse effects of chloramphenicol:

1. 2. 3. 4. Pancytopenia, aplastic anaemia, reticulocytopenia Gray baby S. G.I. Upsets, superinfection Haemolysis in G-6-PD deficiency

Incompatibility: Precipitation if added to tetracyclines, vancomycin, hydrocortisone & B-complex Interactions: Chloramphenicol is microsomal enzyme inhibitor (increase oral anticoagulants, hypoglycaemics or phenytoin)

Contraindications: 1. Pregnancy & lactation 2. Neonate 3. Leukopenia, severe anaemias, thrombocytopenia

What are the alternative drugs used for salmonella?

Antityphoids:
1. Amidinopenicillins (Mecillinam & Pivmecillinam ) 2. 3rd Gen. Cephalosporins: Cefoperazone & Ceftriaxone 3. Ampicillin & Amoxicillin 4. Chloramphenicol 5. Quinolones 6. Septrin

Macrolides
Erythromycin, Azithromycin, Clarithromycin, Roxithromycin, Spiramycin

How Macrolides act ?

How can bacteria resist ?

Does it work on human cell ?

 Bind to 50 S ribosomal subunit ( site of chloramphenicol & clindamycin) Wide spectrum Baceriostatic or bactericidal ( depending on the conc. ) They accumulate in the macrophages but have no effect on the immune mechanism.

Bacteria resist through:

1. Decreased drug uptake 2. Plasmid mediated change in 50 S ribosomal subunit 3. Plasmid mediated increased activity of erythromycine esterase

 Erthromycin is partially inactivated by gastric acidity Distributed to all body fluids except CSF Accumulate inside the macrophages Of hepatic metabolism and biliary excretion Pass into milk & through placenta

What are the advantages of the new generation?

1-More acid stable 2-Absorption not affected by the intestinal contents 3- The metabolites are active 4- No hepatotoxicity 5- No drug interactions

Macrolides are wide spectrum antibiotics ; Mention why ?

Wide spectrum : = gm.+ve : cocci ( strept., staph., pneumococci)& bacilli ( diphtheria) gm- ve : cocci ( Neisseria ) & bacilli (including Helicobacter, H. influenza , Legionella ) =Chlamydia, Mycoplasma, Spirchates Toxoplasmosis

Uses of macrolides:
1. 2. 3. 4. 5. 6. Streptococcal & staph infections Prophylaxis of rheumatic fever recurrence Mycoplasma pneumoniae Legionnaires disease (Clarithromycin) Chlamydia Diphtheria, pertussis, syphilis, gonorrhea and tetanus 7. Toxoplasmosis encephalitis & Helicobacter pylori (Clarithromycin & Azithromycin) 8. Branhamella & H. influenza ( Clarithromycin )

Adverse effects: 1. G.I upsets, colic 2. Reversible cholestatic hepatitis 3. Allergy 4. Thrombophlebitis 5. Hypertrophic pyloric stenosis 6. Reversible ototoxicity & cardiac arrhythmias

Incompatibilities: Precipitation if added to cephalosporins

Interactions: Erythromycin inhibits the hepatic microsomal enzymes : So Potentiate: theophyline, oral anticoagulants, phenytoin, carbamazepine, digitoxin.

Contraindications: Pregnancy Hepatic diseases

Lincosamides
(Lincomycin &Clindamycin)

 Mechanism, Kinetics & spectrum : similar to erythromycin for ( staph., strept, most anaerobics ).
G.I. Upsets, Pseudomembranous colitis Hepatotoxicity, B.M. depression, Hypotension with rapid I.v. lincomycin

Poteniate neuromuscular blockers Antagonised by Kaolin & pectin

List the anti- Anaerobics ?

ANTI-ANAEROBICS: -Metronidazole -Imipenem & Meropenem ( Carbapenems )

-Lincomycin & Clindamycin -Chloramphenicol

Quinolones

= Synthetic analogues of nalidixic acid

1st generation: Nalidixic acid 2nd generation: Pipemidic acid 3rd generation: (most are fluorinated) Norfloxacin, pefloxacin, ciprofloxacin, ofloxacin,..)

How Quinolones act ?

How can bacteria resist ?

Does it work on human cell ?

Inhibit DNA gyrase

Quinolones 3rd G. are newly introduced But very frequently used

WHY ?
-Bactericidality -Broad spectrum -Suitable pharmacokinetics

Ouinolones spectrum:
- Most gm ve: E-coli, Klebsiella Proteus Pseudomonas H. influenza Salmonella Shigella Legionella - Gm +ve : Strept., Pneum. & staph.

Quinolones PH.K.:
Rapid abs. Metabolised in the liver & excreted unchanged in urine Appear in urine, stool, bile, bone , prostate & in low conc. In the CSF Long T 1/2

Indicated in: ( norfloxacin, ofloxacin ) - UT infections - Pseudomonal respiratory infection in cystic fibrosis & external ear infection - Prostatitis - Gonorrhoea - Cervicitis - H. influenza & N. meningitis meningitis - GIT infections due to salmonella & shigella ( ciprofloxacin ) - Skin & bone infections

3rd Generation dose:

250-500 mg / 12 hrs / 7-14 ds

Adverse effects of Quinolones: 1. GI upsets 2. Hypersensitivity, photosensitization & haemolysis . 3. Neurological 4. Increase the I. Cranial tension in children 5. Arthropathies of growing bone ( Chondrolytic 6. Interstitial nephritis & crystalluria 7. Inhibit hepatic microsomal enzymes

What are the precautions of quinolones ?

Quinolones Contraindications:
1. Prgnancy & nursing mothers 2. Children under 18 years 3. Epilepsy

Quinolones Interactions:
- Mg & AL. anti acids impair their intestinal absorption - Inhibit the metabolism of : Theophylline Warfarin & Cyclosporins - + NSAIDs cause seizures

Urinary Tract Antiseptics

1. Nitrofurantoin 2. Methenamine mandelate & hippurate 3. Nalidixic acid

Why Only Urinary

Antiseptics ?

Nitrofurantoin
Broad spectrum Oral Gl. Filtration & tubular secretion urine alkalinization increases U. conc. But decreases efficacy Used for treatment & prophylaxis Induces: GI upsets, neuropathy, megaloblastic anaemia, haemolysis in G6PD, Allergy, pulmonary fibrosis.

Methenamine ( Hexamine )
Is a prodrug ( converted to the active formaldehyde at urine pH of 5.5 ) Broad spectrum Oral, ammonia is generated with degradation Gl. Filtration & tubular secretion Used for treatment & prophylaxis Induces: GI upsets, dysurea, hematuria Contraindicated in hepatic insufficiency

Sulphonamides
= Synthetic analogues of PABA

How bacteria develops resistance against sulphonamides ?

1. Folic acid synthetase alteration 2. Utilization of preformed folic acid 3. Over production of PABA

Preparations:
1)Short acting (4 times/d) (Sulfadiazine, Sulfamerazine)

2)Intermediate acting (2 times/d) (sulfamethoxazole)

3)Long acting (once/d)(sulfadoxine,Sulfamethoxydiazine)

4)Poorly absorbed from GIT:( S.Suxidine,

S.Guandine & S.Salazine)

5)For local use: (S.Thiazole, S.Acetamide)

Sulphonamides PH.K is an important determinant in their therapeutic uses and their adverse effects

Explain ?

Sulphonamides PH.K.:
-Oral -CSF availability -Pl.Pr. Extensive binding -Hepatic acetylation & glucuronidation -Glomerular filtration -Poor solubility of the acetylated form in acid pH of urine.

Sulphonamides spectrum:
Gm ve & +ve bacteria Actinomyces Chlamydia Toxoplasma Pneumocystitis carnii

USES: 1. Acute uncomplicated UT infection 2. Acute Otitis media (Erythromycin + sulfisoxazole) 3. Toxoplasmosis (Sulfadiazine + Pyrimethamine) 4. Chloroquin resistant plasmodium falciparum
5. (Sulfadoxine + Pyrimethamine) Chlamydia infections e.g.Trachoma

6. Ulcerative colitis (Sulfasalazine) 7. Rheumatic fever prophylaxis (Sulfadiazine) 8. Prophylaxis for contacts of meningeococcal meningitis 9. Topical for burns, skin infection (mafenide acetate) & conjunctivitis (sulfacetamide)

Adverse effects: 1. Hypersensitivity 2. Crystalluria 3. Haemopoietic (B.M. depression & haemolysis with G6PD deficiency) 4. Kernicterus 5. GIT upsets Interactions: Potentiate sulfonylureas, Oral anticogulants, Methotrexate , Phenytoin Insoluble urinary precipitate by Methenamine

Contraindications: 1. Pregnancy at term 2. Newborn & infants less than 2 monthes 3. Hypersensitivity 4. Porphyria 5. G6PD deficiency.

What is porphyria ? Mention the precipitating drugs you know?

CP 450

Laevulinic acid synthetase

Porphobilinogen
NEURONAL DEMYLINATION COLIC - MUSCLE PARALYSIS

Porphyria precipitating Drugs

Halothane Barbiturates Carbamazepine Sulphonamides, Rifampicin Oestrogen & progesterone Methyldopa Sulfonylureas

Explain the mechanism of acute haemolysis in G.6.PD deficient patients in using sulphonamides ? Mention the other inducing drugs How these patients could be tested?

glutathione, met HB

reduced glutathione, HB

NADPH
+ Oxydative drug
G6PDehydrogenase

Accelerated oxydation to
NADP

Drugs inducing haemolysis in G6PD deficient patients:

-Antimalarials -Sulfonamides -Nitrofurans -Antipyretics -Vit.K analogs

Explain how the bacteriostatic mechanism of sulphonamides becomes bactericidal ?

PABA
2

Folic acid (dihydrofolic acid)

Folinic acid (tetrahydrofolic acid)

Other S.
2 Trmethoprim

Sulphonamides combinations:
1. Sulphamethoxazole-trimethoprim (Co-trimoxazole)
2. Sulphadoxine-Pyrimethamine (Fansidar: Malaria) 3. Sulphadiazine-Pyrimethamine (Toxoplasmosis) 4. Sulphasoxazole-Erythromycin (Otitis media)

Mention the advantages of Cotrimoxazole

against the individual sulphonamides

Co-Trimoxazole:
Synergistic combination-Bactericidal 80mg trmethoprim-400mg sulphamethoxazole Lower incidence of side effects & resistance Wider spectrum More potent

What are the other important antibacterial combinations?

Mention the indications & disadvantages

1. Ampicillin Aminoglycosides
2. Antipseudomonal penicillins e.g Carbenicillin Aminoglycosides

3. Cephalosporins Aminoglycosides 4. Aminoglycosides- Metronidazole or Clindamycin

Indications:
1. To broaden the spectrum 2. To obtain synergism 3. To delay the emergence of resistance

Disadvantages:
1. 2. 3. 4. 5. Increased risk of adverse effects Increased risk of superinfection Risk of antagonism High cost False sense of security

What is Chemoprophylaxis ?
(Prophylactic Antibiotics) To prevent: 1. Infection before or soon after organism acquisition. 2. Resident organism from infecting a normally sterile site. 3. A dormant pathogenic organism from causing disease

Non surgical: 1. Burn (silver sulpfadizine) 2. Cholera (Tetracycline 250 mg

qid / 5 ds)

3. 4.

Diphtheria (Erythromycin
500 mg qid / 7 ds)

Newborn gonococcal conjunctivitis:

(tetracyclines, Erythrocine)

8 Pneumocystitis carinii pneumonia in leukaemic patients: Co-trimoxazole 2 tab./12 hs + folic acid /3 ds /week. 9. Recurrent rheumatic fever: benzathine pen. 10. Travellers diarrhoea: trimethoprim 200mg /d or doxycyclin 100 mg /d/ 2 ws 11. Recurrent urinary T. infection: Co-trimoxazole one tab./d. 12. Following splenectomy(pneumococci): benzathine pen.

5. H.influenza or meningeococcal meningitis: rifampin 600 mg

bid /4 ds, 20mg/kg/d.

6. Bacterial endocarditis: 2gm

pen.V one hour before minor procedure & 1 gm 6 hrs after

7.

Malaria: chloroquin
500mg/w.. &/6 ws after return

Surgical : 1. Clean surgery: -Prothetic valve, open heart, peripheral V. surgery -Orthopedic surgery -Neurosurgery Cloxacillin 2gm iv or vancomycin 2gm iv +gentamicin 1.5 mg/kg iv.

2.Clean contaminated surgery: -Oral, ear, nose, throat: Clindamycin 600 mg iv -Upper GIT : Amoxicillin 1 gm iv +gentamicin 1.5 mg /kg iv. -Colorectal: Gentamycin 1.5 mg/kg iv +metronidazole 500 mg iv (or clindamycin 600 mg iv) 3. Contaminated: ,, ,, Before & for 10 ds after

SPECIAL CHEMOTHERAPY

ANTIMYCOBACTERIAL AGENTS

I- ANTITUBERCULOSIS

Tubercle Bacilli
Inactive intracellularly (most bacilli) Easy developement of A.B. resistance.

Therapy speciality
Combination Long duration High risk of adverse effects Poor compliance

ANTI-TB CATEGORIES
I- 1ST LINE DRUGS: (more effective & less toxic) Isoniazid Ethambutol Rifampin Pyrazinamide Streptomycin
II- 2nd LINE DRUGS: Capreomycin Cycloserine P.A.S Rifabutin

Ethionamide Thiocetazon Fluroquinolone(Ciprofloxacin)

ISONIAZID Cidal Inh. Mycolic A. synthesis Intra & Extr Hepatotoxic Neuropathy Hep. Met. & Renal Clear. ---

RIFAMPIN Cidal + other bact. Inh. RNA synthesis Intra & Extr Hepatotoxic rarely renal --Hep. Met. & Clearance ---

ETHAMB. Static Inh. RNA synthesis Intra &Extr --Neuropathy Renal Elim. Hyperurica.

PYRAZIN. Cidal

Inh. Mycolic A. synthesis Intra mainly Hepatotoxic ---

Hepatic Met. & Renal Clear

Hyperurica.

ISONIAZID
Rapid acetylators are liable for hepatotoxicity Slow acetylators are liable for neurotoxicity (INH competes for pyridoxine)
Systemic lupus, H. anaemia in Gl-6-PD def.

For treatment & prophylaxis

RIFAMPIN
Indicated also for: pharyngeal carrier of Neisseria meningitides bid/2ds Prophylaxis for H.influenza meningitides bid/4ds Staph. & leprosy. Hepatotoxicity, flue like S., proteinuria, enzyme induction.

ETHAMBUTOL

The least toxic (used in pregnancy +INH)

PYRAZINAMIDE

CSF bioavailability with inflamed meninges only

STREPTOMYCIN
Bactericidal Only on extracellular bacilli Not given during pregnancy

P.A.S.

PABA competition Bacteriostatic Blood dyscriasis

Regimen of Therapy
Initial intensive course / 2 monthes isoniazid + rifampicin + Pyrazinamide + ethambutol Continuation Phase / 4 16 monthes isoniazid + rifampicin + ethambutol

Precaution in pregnancy

Indications of glucocorticoids :
1. 2. 3. 4. 5. TB meningitis Milliary TB TB of suprarenals Massive pleural & pericardial effusion Large lymph nodes & hypersensitivity

II- ANTILEPROSY
Dapson (bacteriostatic) + Clofazimine (bactericidal)

+ Rifampin (bactericidal)

PROTOZOAL DISEASES
AMOEBIASIS BALANTIDIUM COLI GIARDIASIS TRICHOMONIASIS MALARIA

M, E, DE

M, Ch,
E, DE

M, E,DE

D, I
M, D, I, P, ER

D, I

AMOEBIASIS

ANTIAMOEBICS
Tissue & Luminal antiamoebics: Nitroimidazoles (metronidazole, tinidazole,) Tissue antiamoebics: 1. Chloroquine (liver only) 2. Emetine 3. & Dehydroemetine Luminal antiamoebics: 1. Dichloroacetamides (Diloxanide & Etofamide) 2. Halogenated hydroxy quinolines (Iodoquinol & Clioquinol) 3. Antibiotics Direct: Paromomycin & Erythromycin Indirect: tetracyclines)

METRONIDAZOLE

Ferredoxin Metronidazole activated metronidazole

oxidoreductase

multiple DNA break

USES:
Amoebiasis: except cysts 750 mg TDS (6 tab.) l 7 days for adults 40 mg l kg l d (3 doses) l 7 days for enfants Giardiasis: 250 mg TDS / 5 days for adults 5 mg / kg TDS /5 days Urogenital trichomoniasis Balantidiasis Anaerobic infections 40 mg / kg / d (3doses)/ 10 days

ADVERSE EFFECTS
Nausea, dry mouth, metalic taste headache, dark and red brown urine. Infrequently; vomiting, stomatitis, diarrhoea, insomnia & weakness. Rarely; urethral burning, vertigo, parasthesia, ataxia, encephalopathy & leukopenia. Disulfiram effect Phlebitis (I.v. use) Mutagenicity & carcinogenicity.

CONTRAINDICATIONS & CAUTIONS

Prolonged use & multiple courses Pregnancy & lactation + Oral anticoagulants ( decrease coumarine metabolism)

Emetine & Dehydroemetine

No effect on lumenal trophozoite or cyst G.I. Toxicity Cardiotoxic Skeletal M. toxicity Dehydroemetine is more safe

Diloxanide
Affects amoeba before encystment Protect against cyst reactivation No effect on tissue invasive amoeba No serious adverse effects Contraindicated in pregnancy & children < 2 years old

Iodoquinol
Affects amoeba before encystment Protect against cyst reactivation No effect on tissue invasive amoeba Effective against Giardiasis & Balantidiasis G.I. Upsets, Iodine content intolerance Useless for traveller or non specific diarrhea Contraindicated in renal, hepatic & thyroid diseases

Asymptomatic Diloxanide

Iodoquinol (or Paromomycin) I(or P)+ Tetracycline

Followed by choroquine

Mild to Moderate Dysentry

D +Metronidazol.

D +Metronidazol.

I(or P)+ Tetracycline +

E.Or dehydroEmetine
Hepatic Abscess Amoeboma D + Metronidazol
Followed by choroquine I(or P)+

Followed by choroquine E.Or dehydroEmetine Followed by choroquine I(or P)+ D + Metronidazol

E or dehydroEmetine

Toxoplasmosis Pyrimethamine + Sulfadiazine Or Clindamycine

Spiramycine (during pregnancy)

Leishmaniasis

- Pentavalent antimonials: Of choice Induces toxic pancreatitis, frequent failure due to development of resistance Amphotericin B

CHEMOTHERAPY OF MALARIA

liver Schizonts Hypnozoite

Human

Blood

Merozoite

Trophozoite

Sporozoite

Schizonts Gametocytes Zygote

Mosquito
Oocyste

TYPES OF TREATMENT OF MALARIA

I. Anti-sporozoite ( True causal prophylaxis):No drug II. Anti-exoerythrocytic form (causal prophylaxis): - primaquine, pyrimethamine, proguanil III. Anti-erythrocytic form(suppressive prophylaxis & Clinical cure): Chloroquine, quinine, mephloquine, pyrimethamine & proguanil. IV. Radical cure: Primaquine. V. Anti-gametocytic form (antitransmission):primaquine, pyrimethamine, proguanil

liver Schizonts Hypnozoite

Human Merozoite

Blood Trophozoite

Sporozoite

Schizonts Gametocytes

II.

Anti-exoerythrocytic form (causal prophylaxis):

(Proguanil, pyrimethamine & Primaquin)

To Kill the merozoite coming from the liver before invading RBCs

liver Schizonts Hypnozoite

Human

Blood

Merozoite

Trophozoite

Sporozoite

Schizonts Gametocytes

III-Suppressive or clinical cure OF THE ACUTE ATTACK

(ANTIERYTHROCYTIC)(= radical cure in P. Falciparum; Has no hypnozoites

1- Chloroquine 2- Mefloquine 3- Pyrimethamine & proguanil 4- Combinations: -Fansidar (Pyrimethamine + Sulphadoxine) -Fansimaf ( + + Mefloquine)

liver Schizonts Hypnozoite

Human Merozoite

Blood Trophozoite

Sporozoite

Schizonts Gametocytes (only in P. Ovale & P. Vivax)

IV- Antirelapse:
(Radical cure) :
Primaquin

+ II =

RADICAL CURE

Human 5. Anti-gametocytic form (antitransmission):primaquine, pyrimethamine, proguanil

Blood

Merozoite

Trophozoite

Schizonts Gametocytes

Mosquito
Oocyste

Zygote

CHLOROQUINE

Blocks the enzymatic synthesis of parasite DNA & RNA Forms a complex with its DNA Inhibits HB digestion by increasing the PH of its acidic vacules

Chloroquine kinetics: Good GI absorption Widely distributed in the tissues Concentrated in RBCs especially the parasitized 500 times concentrated in the liver as blood Concentrated in melanin containing cells The drug & its metabolites are of slow renal elimination . T is 6-7 days

Chloroquine uses: Acute attack of malaria & Malaria chemoprophylaxis ().5 gm once /week Extraintestinal amoebiasis Giardiasis Rheumatoid arthritis & LE

Chloroquine S.E. In doses of malaria & amoebiasis: Dizziness, headache, itching, blured vision Inhigher doses: Corneal deposits, optic atrophy, bone marrow depression I.V. : hypotension & ECG changes

Chloroquine C.I. 1. Retinal & visual field changes 2. Porphyria & psoriasis (it may precipitate an attack) 3. Pregnancy

PRIMAQUINE
Acts on liver schizonts and hypnozoits & gametocytes. As oxidant agents interrupts mitochondria function. Orally absorbed, rapidly metabolised & of short t1/2 .

Primaquine uses:
Radical cure of p. vivax & ovale 15 mg /d/15 ds During the last 2 weeks of terminal prophylaxis As gameticidal for all types of malaria

Primaquine S.E.:
Haemolysis with gl.-6-ph dehydrogenase deficiency, due to decrease of NADPH by the oxidant activity. G.I. Upsets,

metHB.(Cyanosis)

MEFLOQUINE
Acts on the erythrocytic form Used for the acute attack of mild to moderate multiresistant p. falciparum ( fansimaf ) Chemoprophylaxis once / week Induces G.I. Upsets, psychosis, visual alteration

QUININE
Act againest erythrocytic forms of all p. malaria Used for the chloroquine resistant P. falciparum Not for chemoprophylaxis Of analgesic, antipyretic, oxytocic & sk. M. relax. Highly Toxic: Cinchonism, G.I. Upsets, Arrhythmias, neurotoxicity, Black water fever.

ANTI-FOLATES
Pyrimethamine & Proguanil- Sulphadoxine & sulphones.

Pyrimethamine & proguanil act on the Erythrocytic stage Both prevent transmission Pyrimethamine is Contained in Fansidar & Fansimaf Fansimaf is used for : chloroquine resistant malaria & Chemoprophylaxis

All types of malaria:

Acute attack: Chemoprophylaxis: (during exposure & 4 ws afterwards) CHLOROQUIN CHLOROQUINE 0.5gm/w 1 gm 6 hours 0.5 gm/d/2ds Or primaquine 26 mg/d/14 ds MEFLOQUINE 0.25 gm/w

Chloroquine Resistant P. Falciparum:

Acute attack: Quinine / 7ds Chemoprophylaxis: Mefloquin / a week

+ one of the following:

1. Doxycycline / 7 ds or 2. Fansidar once or 3. Clindamycin / 3ds or