Antimicrobial agents

Introduction:

Chemotherapy :Describes the use of synthetic chemicals to destroy infective agents.

In recent years the definition of the term has been broadened to include antibiotics which are substances produced by

some microorganisms that kill or inhibit the growth of others.

Choice of an antimicrobial agent:

The choice is depending on patient, infecting organism and drug.

1-Patient factors:

Age -Renal & hepatic function -

Drug allergy -Pregnancy -

2-Organism related considerations:

-Clinical diagnosis -M.O culture.

3-Drug factors:

-Spectrum of activity

-Types of activity (bacteriostatic or bactericidal)

-Route of drug administrations

-Toxicity -Cost

Antibacterial activity

Bacteriostatic Bactericidal

Erythromycin Penicillins
Tetracyclines Cephalosporins
Chloramphinicol Aminoglycosides
Sulfonamides Co-trimexazole
Trimethoprim Quinolones

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- Classification of antibiotics according to the mechanism of action:

Mechanism of action Antibacterial agent

Inhibition of cell wall synthesis Penicillin

Cephalosporin
Monobactam
Vancomycin

Inhibition of protein synthesis Aminoglycosides

Tetracyclines
Erythromycin
Chloramphinicol

Inhibition of - DNA gyrase Quinolons

-DNA polymerase Rifampicin

Inhibition of folic acid metabolism Trimethoprim

Sulfonamides

1- Beta-Lactam antibiotics and other inhibitors of cell wall synthesis

1-Penicillins:

Alexander Fleming reported his discovery of penicillin (1928).

Chemistry:

All penicillins have the basic structure

A ring: thiazolidine is attached to a beta-lactam ring (B ring) that carries a secondary amino group RNH-.

Mechanism of the action: they inhibit cell wall of bacteria and consider as bactericidal agents.

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 Classifications of penicillins

1- Benzyl penicillin (Penicillin G (IV)

Penicillin V(PO)

2- B-lactamase resistant penicillins:

Cloxacillin , dicloxacillin (PO)

Naficillin (IV)

Oxacillin (IV)

3- Extended –spectrum penicillins:

Amoxacillin (PO)

Amoxacillin / potassium clavulanate (PO)

4- Antipseudomonase penicillin

Carbenicillin

Piperacillin (IV)

Ticarcillin (IV)

SE:

1-Hypersensitivity reactions.

2-Broad spectrum penicillins also eradicate normal flora and also results in secondary infections like oral and

vaginal candidiasis.

3-GI upset : Nausea, vomiting, Pseudomembranous colitis (diarrhea).

4- CNS irritation especially in high doses.

5-Neurotoxicity, fits and electrolyte disturbances in patient with impaired renal function treated with anti-

pseudomonas penicillins.

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2- Cephalosporins:

Chemically: 7-aminocephalosporonic acid

Are similar to penicillins : in mechanism of action and toxicity.

-They are classified to four generations according to their spectrum of antimicrobial activity & route of
administration and penetration to CNS.

First generation:( cefadroxil, cephalexin and cefazolin)

They are active against Gr+ bacteria infections, don’t cross BBB.

Second generation: (cefoxitin, cefuroxime)

They are less active against Gr+ bacteria, but have an extended Gr- activity like: Klebsiella and H.influenza.

They are used for : otitis, sinusitis and lower RTI

Third generation (Cefoperazone, cefotaxime, ceftazidime and ceftriaxone):

They are active against Gr- bacterial infections (gonorrhea, meningitis and pneumonia parenteraly

-Ceftazidime are active against P. aeruginosa.

*third generation that can be given orally: Cefixime, Cefpodoxime and Ceftibuten.

Fourth generation: (Cefepime):

More resist to hydrolysis by chromosomal B-lactamase produced by enterobacter , so it is active against

them.

SE:

1-Hypersensitivity & cross allergy with penicillin.

2-Local pain and irritation with IM inj.

3-Superinfection

Other B- lactam drugs:

i)- Monobactam: (Aztreonam)

It has monocyclic beta-lactam ring and resists beta-lactamases. Active against Gr- ve bacteria (pseudomonase)

Dose: 1g tid IV

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SE: skin rash

ii)-Carbapenems:( Imipenem)

-Chemically is related to penicillin

-Active against Gr+ve, Gr-ve & anaerobes.

-Used with Cilastatin (dehydropeptidase inhibitor).

-Drug of choice in treatment enterobacter infections.

Dose: 250-500mg tid IV

SE: NVD, skin rash, reaction at site of inj.

Other inhibitors of bacterial cell wall:

i-Vancomycin:

It is active against Gr+ bacteria

Uses:

1-Sepsis and endocarditis.

2-Oral vancomycin (0.125-0.25 g/6hrs) used for treatment antibiotics associated with pseudomembranous colitis
caused by clostridium difficile.

SE:

1-Phelibitis at the site of injection.

2-Ototoxicity and nephrotoxicity

3-Red man (red neck) syndrome.

ii)-Teicoplanin:

-Same like vancomycin

-Can be used IM or IV with long duration (once daily)

iii)-Fosofomycin:

-Active against Gr+, Gr- bacteria.

-Used as a single dose (3g ) for treatment UTI in women (safe in pregnancy)

iv)-Bacitracin:

-Toxic systemically.

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-Used topically as an oint. (500u/g) for wound & skin lesions

B-lactamase inhibitors:

Clavulanic acid, sulbactam and tazobactam.

They have weak antibacterial activity. But they are potent inhibitors of many but not all bacterial B-lactamase and can
protect hydrolysable penicillins from inactivation by theses enzymes.

-Ampicillin + sulbactam (Ampictam)

-Piperacillin +tazobactam

-Amoxacillin + clavulanic acid=Co-amoxiclav

( Augmentin)

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Antibiotics that inhibit bacterial protein synthesis:
1- Chloramphenicol:

inhibits bacterial protein synthesis by binding to ribosomes.

-Bacterostatic, broad spectrum antibiotics.

-Active against Gr+ , Gr-, anaerobes and rickettsial infections.

Uses: (dose: 50-100mg/kg/d):

1- Serious rickettsial infections (typhus), Rocky mountain spotted fever.

2- topically for eye infections.

3-Typhoid fever & food poisoning

SE:

1-GI disturbances (NVD, oral or vaginal candidiasis)

2-Bone marrow disturbances (a plastic anemia)

3-Grey-baby syndrome.

4- Hepatic microsomal inhibitors

2-Tetracyclines:

They inhibit bacterial protein synthesis by binding to 30S ribosomes.

Uses (either orally or IV):

1-Tetracyclines are drug of choice for : rickettesial, chlamydial infections and Cholera

2-Tetracycline+ aminoglycosides for plague and brucellosis.

3-Sometimes is used in protozoal infections (Entamoeba and P.falciparm).

4-Acne, pneumonia and UTI.

5-Demeclocycline may inhibit the action of ADH in renal tubules, so can be used in treatment of inappropriate

secretion of ADH.

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SE:

1- Pseudomembranous colitis caused by clostridium difficile and oral or vaginal candidiasis.

2- Affects bone structures (bone deformity and teeth discoloration and development of caries .

3-Liver & kidney toxicity.

4- Local tissue toxicity (IV: venous thrombosis and IM: painful local irritation)

5-Photosensitization (phototoxicity)

6-Vestibular reactions (dizziness, vertigo

C.I : pregnancy, lactation and patients  12 years.

3)-Macrolides:

i)-Erythromycin:

-Bacteriostatic in small doses, bactericidal in large doses.

Uses of erythromycin:

1-Drug of choice for Diphtheria.

2-Treatment pneumonia caused by

Legionella spp. (drug of choice)

3-Prophylaxis against endocarditis during dental procedures in valvular disease.

4- Oral (erythromycin+Neomycin or Kanamycin) for preoperative preparation of colon.

SE:

1-Liver toxicity (cholestatic hepatitis=fever, impaired liver function) especially with estolate salts).

2-Erythromycin is hepatic microsomal inhibitors.

ii)-Clarithromycin:

-Active against M.Leprae & Toxoplasma gondii.

- Used in eradication of H.Pylori.

Dose: 250-500mg twice daily.

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iii)-Azithromycin:

-Highly active against chlamydia & toxoplasmosis.

-Penetrates all tissues except CSF.

-Dose:500mg one tab. for three days (before 1 hour of food).

- It does not have hepatic microsomal inhibiting effect due its 15 atoms structure.

4-Lincosamides:

-Clindamycin is Chlorinated derivative

of lincomycin.

Dose: 150-300mg every 6hrs oral or IV= 600mg tid.

Uses:

1-Clindamycin+Aminoglycosides or cephalosporines for treatment of septic abortion & pelvic abscess.

2-Clindamycin+ primaquine in treatment of pneumonia in AIDS patients.

3-Clindamycin instead of erythromycin for prophylaxis of endocarditis in patient with valvular disease.

4-Locally as solution for acne (Dalacin T)

SE:

1-NVD & impaired liver function.

2-Severe diarrhea due to pseudomembranous colitis.

5-Aminoglycosides:

( not active against anaerobes) including:

-Gentamicin

-Tobramycin -Amikacin

-Sisomicin -Netilmicin

-Kanamycin& neomycin

- Streptomycin

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Uses:

1-Tuberculosis ( streptomycin as second line)

2- Severe infections (Sepsis & pneumonia), especially gentamicin.

*Gentamicin+pencillinG in treatment of endocarditis .

*Gentamicin topically (creams, oint.,sol.) in treatment wound infection.

*Gentamicin intrathecally in meningitis.

SE of aminoglycosides:

1-Nephrotoxicity (neomycin, gentamicin, tobramycin).

2-Ototoxicity(more than 5-days)

i)-Auditory toxicity= tinnitus +loss of hearing (neomycin, tobramycin, gentamicin)

ii)-Vestibular toxicity= vertigo & ataxia especially with streptomycin & gentamicin and this effect is increasing with loop
diuretics combination.

3-Hypersensitivity(streptomycin).

4-Neuromuscular blockade (curare-like effect) which lead to respiratory paralysis in high doses.

Sulfonamides, Trimethoprim & Quinolones:

1)-Antifolate Drugs:

-Like structure of PABA.

-More soluble in alkaline pH.

MOA:

They compete with PABA for enzyme :Dihydropteroate synthase.

-They are active against most m.o except Rickettesial infections.

Classification & uses

a)- Oral absorbable agents:

1- Sulfisoxazole & Sulfamethoxazole are used in UTI.

2-Sulfadiazine+Pyrimethamine combination is the first choice in treatment Toxoplasmosis.

3-Sulfadoxine+Pyrimethamine combination (Fansidar®) is used in treatment malaria as second choice.

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b)- Oral non-absorbable agents:

-Sulfasalazine( Salicylazosulfapyridine) which is used in ulcerative colitis. This agent is splitting by intestinal microflora

to sulfapyridine+ 5-aminosalicylate which has antiinflammatory effect for ulcerative colitis.

-Olsalazine (more safer than Sulfasalazine)

c)-Topical agents:

1-Sodium sulfacetamide ophthalmic solution or ointment for bacterial conjunctivitis & adjunctive therapy for

trachoma.

2- Mefenide acetate:

is used topically to prevent bacterial colonization and infection of burn wounds.

-Silver sulfadiazine is preferred, because is less toxic.

SE:

1)-Cross allergic between all sulfonamides.

2)-NVD, fever, exfoliative dermatitis, photosensitivity, hepatitis and arthritis.

3)-UT disturbances: sulfonamides may precipitate in acidic &neutral media which stimulate crystalluria & hematouria

(non-absorbable sulfonamides).

4)-Megaloblastic anemia.

C.I: pregnant women. It causes Kernicterus in newborn

Trimethoprim+Sulfamethoxazole combination:

-Bactericidal if combined together.

-They are used orally or IV.

-Trimethoprim conc. In prostate & vaginal fluids.

Uses:

1-100mg twice daily for UTI.

2-This combination in treatment of: Pneumonia, Shigellosis, Salmonella, UT infections and Prostatitis.

3-IV combination in treatment severe P.carinii especially in AIDS patient.

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SE:

1-Megaloblastic anemia.

2-NV, renal damage &CNS disturbances

Quinolones
MOA:

inhibit DNA gyrase (Topoisomerse II, IV).

-They are synthetic fluorinated analogs of Nalidixic acid.

-They are bactericidal agents against many types of m.o.

Classification of quinolones:

Generation Action ‫ اﻟﻤﺜﺎل‬Example

Frist generation Moderate G- activity Nalidixic acid
Secon generation Ciprofloxacin,norfloxacin
and ofloxacin
Third generation Gatifloxacin,levofloxacin
Moxifloxacin and
sparfloxacin
Fourth generation Trovafloxacin

Uses

1-Treatment UTI caused by Pseudomonas.

2-Treatment bacterial diarrhea caused by: Shigella, Salmonella, Toxigenic E.coli

3- Infections of soft tissues, bones, joints, RTI caused by legionella as second choice.

4-Ciprofloxacin is effective in T.B and meningitis. It is drug of choice for typhoid.

SE:

1-NVD 2-Headache & insomnia

3-Fluoroquinolines may damage growing cartilage and cause arthropathy in children & tendonitis in adults.

**C.I in pregnancy & lactating mothers, Patients <18 years old). And with theophylline.

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Rationale for combination antimicrobial therapy:

1-To provide broad spectrum therapy in seriously ill patients. For example a patient with sepsis
of unknown origin may require coverage for Gr+ and Gr-ve bacterial infections.

2-To treat polymicrobial infections (both aerobic and nonaerobic. (Aminoglycoside + penicillin)

3-To decrease the emergence of resistant strains.

Like tuberculosis

4-To decrease dose-related toxicity by using reduced doses of one or more component.

5-To obtain enhanced inhibition or killing

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