PRESENTATION LAYOUT

❖ Introduction to antimicrobial drugs❖ Classification of antimicrobial drugs❖ Antibacterial drugs:

- Classification- Indications- Side effects

❖ Antibacterial Resistance

❖ Antimicrobial drugs are chemotherapeutic drugs❖ Two categories:

– Antibiotics : Antimicrobial drugs produced by microorganisms

– Synthetic drugs : Antimicrobial drugssynthesized in the lab

❖Have highly selective toxicity to the pathogenic microorganisms in host body

❖Have no or less toxicity to the host❖Low propensity for development of resistance❖Not induce hypersensitivies in the host❖Have rapid and extensive tissue distribution❖Be free of interactions with other drugs❖Be relatively inexpensive

Ideal antimicrobial drug

Where do antibiotics come from

❖ Several species of fungi including Penicillium and Cephalosporium

E.g. penicillin, cephalosporin❖ Species of actinomycetes, Gram +ve filamentous

bacteria❖ Many from species of Streptomyces ❖ Also from Bacillus, Gram +ve spore formers❖ A few from myxobacteria, Gram -ve bacteria❖ New source explored : plants, fish

Sources of some common antibiotics and semisynthetics

❖ Ehrlich (1854–1915) coined the term chemotherapy

❖ 1929 Penicillin discovered by Alexander Fleming❖ 1940 Florey and Chain mass produced penicillin

for war time use, becomes available to the public❖ 1935 Sulfa drugs discovered❖ 1944 Streptomycin discovered by Waksman from

Streptomyces griseus

History of Antimicrobial Therapy

❑ Alexander Fleming was first to characterize penicillin’s activity. He found mold contaminating his culture plates, with clearing of staphylococcal colonies all around the mold. Fleming then isolated penicillin from the mold

❑ Thanks to work by Alexander Fleming

Classification of antimicrobial agent

Chemical structure

Type of organism to

be killed

Antimicrobial agent

Based on chemical structureGroup Examples

Sulfonamide sulfadiazine, dapsone, paraminosalicylic acid

B-lactam penicillins, cephalosporins, monobactams

tetracycline oxytetracycline, doxycycline

aminoglycoside streptomycin, gentamycin, neomycin

Macrolide erythromycin, azithromycin, clarithromycin

polypeptide polymyxin-B, bacitracin

glycopeptide vancomycin

Quinolones ciprofloxacin, ofloxacin, moxifloxacin, gatifloxacin

Azole derivative miconazole, clotrimazole, ketoconazole, fluconazole

nitroimidazole Metronidazole, tinidazole

Antibacterial drugs

❖ Drugs active against bacteria❖ Natural or synthetic ❖ Naturally, obtained from microorganisms which

suppress the growth or kill other microorganisms are k/a antibiotics

❖ Synthetics are made in lab by bioengineering❖ The term antibiotic was first used in 1942

by Selman Waksman

clas

sifi

cati

on Spectrum of activity

Type of action

Mechanism of action

Bacteriostatic

Sulphonamides

Tetracycline

Chloramphenicol

Macrolides

Bactericidal

Penicillins

Aminoglycosides

Cephalosporins

Vancomycin

Type of action

Narrow spectrum

Penicillin G

Streptomycin

Erythromycin

Broad spectrum

Tetracyclin

Chloramphenicol

Cephalosporins

Spectrum of activity

• Inhibit cell wall synthesis

• Cause leakage from cell membranes

• Inhibit protein synthesis

• Inhibit DNA gyrase

• Action as antimetabolite

Mechanism of action

Mechanism of action

Inhibit cell wall synthesis

❖ These are the drugs that interfere with the cell wall synthesis process

❖ These drugs consist β-Lactam rings so called β-lactam antibiotics

❖ Bactericidal in nature

Penicillin

Cephalosporin

Vancomycin

Inhibitor of cell wall synthesis

❖First antibiotic to be used clinically❖Obtained from fungus Penicillium notatum

Structure❖β-lactam is responsible for antimicrobial activity❖Properties like antimicrobial spectrum, stability to

stomach acid and susceptibility to bacterial degradativeenzymes (β-lactamases) depends upon the side chain

❖Also, differ in structure by the side chain

Penicillin

Working of penicillinNAM-NAG-NAM-NAG

Pep Pep

Pep Pep

NAM-NAG-NAM-NAG

Pep side chains are cross linked as the final step in synthesis of peptidoglycan in the presence of penicillin binding protein (PBPs).Penicillin drugs inhibit this process after binding with PBPS.

Pep=peptide linkage

NAM &NAG =N-acetyl muramic acid and N-acety glucosamine

Penicillin

Binds to PBPs

Inhibition of cross linkage

Blockage of peptidoglycan synthesis

Cell dies

Penicillin G

Penicillinase resistant penicillins

Extended spectrum penicillins

-Have side chain of benzyl group-Active against Gram +vebacteria than Gram -ve

-Resistant against penicillinase/β-lactamase producing bacteria

eg. Methicillin, Cloxacillin

❑ The latter two are semisynthetic in nature

-Sensitive against wide range ofbacteria(Gram +ve/-ve)

eg. Ampicillin, Amoxicillin

Types

Coverage of Penicillins

Penicillin GPenicillinase resistant penicillins

Extended spectrum penicillins

Gram Positive cocci:Streptococcus pneumoniaStreptococcus pyogens

Gram Negative cocci:Neisseria gonorrhoeaeNeisseria meningitidis

Gram Positive bacilli:Bacillus anthracisCorynebacteriumClostridia, ListeriaSpirochetes

Penicillinase producing Staphylococcus

Sensitive against all Gram positive as well following Gram negative bacteria- E.coli- Haemophilus- Salmonella- Proteus

o Pneumococcal infectiono Streptococcal infectiono Meningococcal infectiono Tetanuso Gas gangreneo Syphiliso Gonorrhea

o Respiratory tract infectiono Sinusitiso UTIo Bacillary dysenteryo Gonorrheao Enteric fevero Preseptal cellulitis

Penicillin GExtended spectrum penicillins

Indications

❖ Hypersensitivity reaction (rash, itching, urticarial, fever)

❖ Pain at i.m. injection site, thrombophlebitis of injected vein

❖ Oral penicillin can cause nausea, vomiting or diarrhea

❖ Toxicity to the brain: mental confusion, convulsions & coma

Side Effects

Beta-lactamase inhibitors

❖ Some of the bacteria produces β-lactamase enzyme. This enzyme causes hydrolysis of β-lactam ring so that the antibiotic activity of penicillin/ β-lactam drug is destroyed

❖ This can be prevented by two inhibitors i.e. clavulanic acid and sulbactam

❖ These are the enzyme with β-lactam ring but has no antibacterial activity. It combines with the lactamase enzyme and thus prevent the destruction of lactam ring of antibiotic making it potent to show action

Cephalosporins

❖Have similar action to penicillin (bactericidal)❖Semisynthetic antibiotics derived from

cephalosporin-C obtained from fungus Cephalosporium

Cephalosporins

Classification

Cefazolin Cephalexin

Cephradine Cephadroxil

Includes

❖ Exhibits good activity against Gram positive cocci like Staph.sps, Strep. sps & Gram –verods like E.coli, Klebseilla

First Generation

Cefuroxime Cefoxitin

Cefaclor Cefuroxime Axetil

❖ Shows somewhat enhanced activity towards Gram –vebacteria compared to 1st generationCoverage:➢ Coverage of 1st generation &➢ Additional -ve cocci like Neisseria gonorrhoea & -ve

rod H.influenza

Second Generation

Includes

Cefotaxime Ceftriaxone

Ceftizoxime Cefixime

❖ More potent than 2nd generation❖ Shows augmented activity against:➢ Enterobacteria➢ β-lactamases producing bacteria➢ Pseudomonas

Third Generation

Includes

Cefepime

Cefpirome

❖ Similar to 3rd generation❖ Shows increased resistance to β-lactamase

producing bacteria

Fourth Generation

Includes

❖ Alternative to penicillin allergic patient❖ Respiratory , urinary and soft tissue infection

caused by Gram –ve organism❖ Septicaemia by Gram –ve bacterai❖ Surgical prophylaxis❖ Gonorrhoea❖ Typhoid❖ Preseptal cellulitis & endophthalmitis

Indications

❖ Pain on intramuscular injection

❖ Diarrhoea due to alteration of gut ecology

❖ Hypersensitivity reaction( rashes, asthma, angioedema and urticaria)

❖ Nephrotoxicity

Side effect

Vancomycin

❖ Highly effective against Gram +ve cocci❖ Uses : used for serious infections

❖ Drug of choice for treating:➢ Methicillin resistant staphylococci➢ Penicillin resistant S. pneumoniae

❖ Recommended for topical, intravitreal & subconjunctival therapy for bacterial endophthalmitis

❖ If used with other ototoxic or nephrotoxic drugs can cause impaired renal function and lead to permanent deafness

❖ Contraindicated in hypersensitivity reaction

Side effect

Drugs inhibiting Protein

synthesis

Tetracycline

Chlorem-phenicol

Macrolide

Aminoglycoside

Mechanism of action

Tetracycline

❖ Broad spectrum antibiotics ❖ Have nucleus of four cyclic rings, so named

tetracycline❖ 1st tetracycline to be obtained was

chlortetracycline❖ Bacteriostatic in nature

Class I• Tetracycline• Oxytetracycline

Class II• Methacycline

Class III• Doxycycline• Minocycline

Gram -ve Gram +ve Spirochaetes Chlamydiae

Rickettsiae Entamoeba Mycoplasm

Division of Tetracycline

Coverage of Tetracycline

Atypical pneumonia due to mycoplasma

Cholera

Brucellosis

Plague

Rickettsial infection

To penicillin for tetanus, actinomyces

To ciprofloxan for gonorrhoea

To ceftriaxone for syphilis

To azithromycin for chlamydial infection

Drug of first choice Drug of second choice

Indications

Ocular Use

Trachoma

Conjunctivitis

Ophthalmianeonatorum

❑ Preferred over silver nitrate because it does not cause chemical conjunctivitis.

❖ Epigastric pain, nausea, vomiting and diarrhoea (irritation from mucosa )

❖ Liver toxicity ❖ Renal toxicity❖ Vestibular toxicity (due to drug accumulation in

endolymph)❖ Affect teeth and bone: tetracycline get deposited in

developing teeth and bone hence cause discoloration and ill formation. so contraindicated

❖ Contraindicated in pregnant, lactating woman and child<8yrs

❖ Also contraindicated in pt. with renal dysfunction

Side effects

Chloramphenicol

❖ Broad spectrum

❖ Nitrobenzene substitute

❖ Bacteriostatic in nature

❖ Initially obtained from Streptomyces, now synthesized chemically

❖Though static in nature, its high concn can be cidal too

Active against

Gram +ve cocci & bacilli

Chlamydia

Gram –ve cocci & bacilli

Coverage of chloramphenicol

❖ Because of serious bone marrow toxicity use of this drug has been reduced much

❖ Not used for infection that can be treated by other antibiotics. However, some of its use are:

- Enteric fever- H. Influenza meningitis- Anaerobic infection by fragillis

❖ Has extended ocular use as the topical application is less hazardous than systemic use

❖ Primarily used in oint. as well gtt. form for conjunctivitis, blepharitis etc.

Indications

❖ Chloramphenicol available in ointment and eye drop form

❖ Ointment 1%

❖ Eyedrop 0.5%

Indications

❖ Bone marrow depression▪ Aplastic anaemia, thrombocytopenia

❖ Hypersensitivity reaction▪ Rashes, fever, angioedema

Gray baby syndrome➢ Occurs when high doses=1oomg/kg to neonate as

prophylactic ➢ Baby stops feeding, vomit, abdomen distended,

hypothermic, irregular respiration➢ An ashen gray cyanosis appear with complication of

cardiovascular collapse➢ It occurs due to poor renal development in neonate

which results in accumulation of drug

Side effects

Aminoglycosides

❖ Bactericidal in nature

❖ Includes neomycin, gentamicin, tobramycin, amikacin, streptomycin

❖ good coverage for Gram –ve bacilli like P. aeruginosa, Proteus, Klebseilla, E. coli

Neomycin

❖ Broad spectrum among all the aminoglycoside❖ But, cannot show effectivity against P. aeruginosa❖ Widely used in ophthalmology in the form of drop

and ointment

❖ Ointment 0.5%

❖ Eyedrop 0.5%

Gentamicin

❖ Mainstay in the treatment of serious Gram –vebacilli infection

❖ Frequently used for empiric therapy in presumed Gram –ve bacilli infection

❖ Choice of drug for EOD like corneal ulcer

❖ Ointment 0.3%

❖ Eyedrop 0.3%

Tobramycin

❖ Same coverage as gentamicin

❖ Also effective against Staphylococci

❖ Potent to P.aeruginosa

❖ In ophthalmology preferred for paediatric use

❖ Ointment 0.3%

❖ Eyedrop 0.3%

Amikacin

❖ It is semisynthetic

❖ Preferred in Gram –ve infection resistant to gentamycin and tobramycin

❖ Gram –ve bacillary infection

❖ Septicaemia, abdominal and pelvic sepsis

❖ Bacterial endocarditis

❖ TB

❖ Plague

Indications

❖ Ototoxicity: these drugs get accumulated in the endolymph and perilymph of inner ear and destroy the hair cell in organ of corti

❖ Nephrotoxicity: retention of these drugs in proximal tubular cells disrupts Ca mediated transport system and cause renal damage

❖ Neuromuscular paralysis: these drugs cause decrease in release of Ach

❖ Allergic reaction: Contact dermatitis

Side effects

Macrolides

❖ Bacteriostatic in nature

❖ Protein synthesis inhibitor

❖ Are compounds having a macrocyclic lactone ring to which deoxy sugars are attached

❖ Includes erythromycin, clarithromycin and azithromycin

Erythromycin

❖ First member of this group❖ Effective against many of the same organism as

penicillin G❖ So, used in patient allergic to penicillin❖ For ocular use❖ oral erythromycin are preferred in treatment of

chlamydia infection in children where tetracycline is contraindicated

❖ Also used in treatment of trachoma

❖ Ointment 0.5%

250mg X PO X QID X 3-4 weeks

Azithromycin

❖ Far more active against respiratory infections due to H.influenza and Moraxella catarrhalis

❖ Nowadays preferred in Chlamydial infection too❖ For trachoma single dose of 1 gm

Clarithromycin❖ Same effectivity as erythromycin❖ But effective against Haemophilus influenza and

chlamydia too

❖ Epigastric distress❖ Ototoxicity❖ Cholestatic jaundice

❖ In patient with hepatic dysfunction because of their accumulation in liver as well compromised renal function because their metabolite are excreted from renal

Contraindications

Side effects

Fluoroquinolones

Drug interfering with DNA

Fluoroquinolones

❖ Inhibit bacterial DNA synthesis

❖ Are synthetic fluorinated analogs of quinolones (Nalidixic acid)

❖ Bactericidal in nature

Mechanism of action

❖ Fluoroquinolones block the bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV

❖ Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication

❖ Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division

Classification

Ciprofloxacin Ofloxacin

Pefloxacin Cinafloxacin

Lomefloxacin

Norfloxacin

2nd

Gen

erat

ion

1st Generation

Moxifloxacin Gatifloxacin

Trovafloxacin

Levofloxacin3rd Generation

4th

Gen

erat

ion

Ciprofloxacin

❖ Broad spectrum( most susceptible are aerobic Gram –ve bacilli)

❖ Rapid in action❖ Relatively long post-antibiotic effect❖ Low frequency of mutational resistance❖ Active against many β-lactam and aminoglycoside

resistant bacteria

Widen use due to

From first to fourth generation -ve +ve coverage

Ofloxacin❖ Active against gram negative ❖ Also shows more potency against gram +ve cocci +

chlamydia, mycoplasma too

Moxifloxacin❖ Active against gram –ve bacilli, gram +ve cocci, β-

lactam and macrolide resistant ones and anaerobic bacteria

➢ Prophylaxis and treatment of urinary tract infection➢ Bacillary desentry➢ Enteric fever➢ Diarrhoea due to E.coli➢ Gonorrhoea➢ Septicaemia➢ Respiratory infection

Indications

Generic name Trade name indication

Ciprofloxacin(0.3%)

Ciloxan Conjuctivitis, keratitis

Ofloxacin (0.3%) Exocin Conjuctivitis,keratitis

Levofloxacin Quixin Conjuctivitis

Ophthalmic use

Topical ophthalmic drops can be used for children from one year old

GI upset most common nausea, vomiting, diarrhoea

Hypersensitivity reaction rash, photosensitivity

CNS disturbances dizziness, headache, confusion

❖ Tendinitis in children (damage growing cartilage). Ophthalmic drops do not show such toxicity. Hence is safer to use

❖ Contraindicated in patient with known hypersensitivity to these drugs

Side effects

❖ Bacteriostatic

❖ Binds and blocks enzymes mainly pteridinesynthetase, dihydrofolate reductase responsible for folic acid synthesis

❖ Folic acid enzymes are nessary for the synthesis of amino acids, hence necessary for bacterial protein

Metabolic inhibitors

Sulfonamides

Mode of action - These antimicrobials are analogues of para-aminobenzoic acid (PABA) and competitively inhibit formation of dihydropteroic acid

Spectrum of activity - Broad range activity against Gram +veand Gram -ve bacteria; used primarily in urinary tract and Nocardia infections

Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains

p-aminobenzoic acid + Pteridine

Dihydropteroic acid

Dihydrofolic acid

Tetrahydrofolic acid

Pteridine synthetase

Dihydrofolate synthetase

Dihydrofolate reductase

Thymidine

Purines

Methionine

Trimethoprim

Sulfonamides

Ocular infections Antibacterial drugs Route of administration

Blepharitis chloramphenicol, Topical

Meibomianitis Tetracycline Oral

Conjunctivitis :

Acute mucopurulent

Hyper acuteChlamydial

Gentamycin ,ciprofloxacin, ofloxacin,tobramycincefriaxonetetracycline ,erythromycin

Topical

ParenteralOral

Hordeolum cloxacillin, dicloxacillin Topical

Dacryocystitis Amoxicillin ,erythromycin Oral , topical

Keratitis Gentamycin & cepazolin ,ciprofloxacin

Topical

Endopthalmitis Vanomycin & amikacin Intravitreal

Preseptal cellulitis Ampicillin, cloxacillin, cefaclor oral

Antibacterial Drugs of choice for initial treatment of ocular infection

❖A variety of mutations can lead to antibiotic resistance❖Mechanisms of antibiotic resistance➢ Enzymatic destruction of drug➢ Prevention of penetration of drug➢ Alteration of drug's target site➢ Rapid ejection of the drug

❖Resistance genes are often on plasmids or transposons that can be transferred between bacteria

Antibiotic Resistance

Mechanism of Resistance

In cell wall synthesis inhibitor

➢Penicillinases: break the beta lactam ring structure ( staphylococci)

➢Structural changes in PBP: S.aureus, S. pneumococci

➢Change in porin structure: concerns the Gram Negative organism

In protein synthesis inhibitor

➢ A mutation of ribosomal binding site➢ Enzymatic modification of antibiotic➢ An active efflux of antibiotic out of cell

In nucleic acid synthesis inhibitor

➢ An alteration of alpha subunit of DNA gyrase (chromosomal)

➢ Beta subunit of RNA polymerase (chromosomal) is altered

oTextbook of microbiology by Ananthanarayan & Paniker

o Essentials of Medical Pharmacology KD Tripathi

o Basic & Clinical Pharmacology by Bertram G. Katzung

o Ophthalmic Drugs by Graham Hopkins and Richard Pearson

o Internet

https://healthkura.com

References