AntibioticsDr. Ahmed Omara

DefinitionsAntibiotics (Greek anti, “against”; bios, “life”): are chemical compounds used to kill or inhibit the growth of infectious organisms.

Originally the term antibiotic referred only to organic compounds, produced by bacteria or molds, that are toxic to other microorganisms.

Microbes kill each other with antibiotics

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Antibiotic development 1929-72

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Antibiotics only treat bacterial infections. Antibiotics are useless against viral infections (for example, the common cold) and fungal infections (such as ringworm).

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Selection of Antimicrobial Agent

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Properties Influencing Frequency of Dosing• Concentration dependent killing :e.g. aminoglycosides

Significant ↑ in rate of bacterial killing as the drug concentration ↑

Time-dependent killing e.g. β-lactams, glycopeptides, macrolides, clindamycin & linezoid

Dependent on the % of time that blood concentrations remain above minimum inhibitory concentration (MIC)

• Post-antibiotic effect (PAE): persistent suppression of microbial growth after levels of antibiotic have fallen below MIC

Antibiotics with a long PAE – aminoglycosides and fluroquinolines

• Minimum bacterial concentration (MBC) is the lowest concentration of antibiotic that kills 99.9% of bacteria

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Classifying Antimicrobial Agents• Mode of action• BACTERICIDAL (kills the bug)• BACTERIOSTATIC (stops the bug multiplying)• Spectrum of activity• BROAD (e.g. effective a variety of gram –ve & gram +ve bacteria)• NARROW (e.g. effective only against gram –ve or gram +ve bacteria• Mechanism of action / site of action;• Inhibitors of cell wall synthesis; (β-Lactam, Vancomycin)• Inhibitors of cell metabolism; (Sulfonamides, Trimethoprim)• Inhibitors of protein synthesis; (Tetracyclines, Aminoglycosides, Macrolides, Clindamycin,

Chloramphenicol)• Inhibitors of nucleic acid function or synthesis; (Floroquinolones, Rifampin)• Inhibitors of cell membrane function; (Isoniazid, Amphotericin B) Intoducti

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Spectrum of Activity

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Mechanism of action

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Mechanism of action

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Antimicrobial resistanceIncreasing use of antimicrobials can lead to resistance

Mechanisms of bacterial resistance:

- Mutation (as seen in resistance to anti-tuberculous drugs such as rifampicin)

- Inheritance of “resistance” genes by:

Conjugation via plasmid

Or

Transduction through a bacteriophage.

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Spore formation is NOT a mechanism of resistance

Antimicrobial resistanceMethods of bacterial resistance:

• Altering the antibiotic target, for example

- Changes of bacterial cell wall or membrane by failure of ribosomes to bind erythromycin destruction

- Inactivation of the drug by enzymes, e.g. β-lactamase in penicillin resistance or by acetylation of aminoglycosides

• Prevention of transport of the drug into the microbe

• Use of alternative enzymic pathways that are resistant to the drug, e.g. enzymes resistant to sulphonamide and trimethoprim

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1 .Inhibitors of cell wall synthesis• Interfere with the synthesis of the bacterial cell wall

• Little or NO effect on bacteria that are NOT growing and dividing

Non β-lactam β-lactam group

Vancomycin Penicillins Bacitracin Cephalosporins

Polymixin B Carbapenems Telavancin Monobactams

Daptomycin β-lactam inhibitors+ antibiotic combinations

Cidal

×× Cell wall

Penicillin• Most widely effective and least toxic

• Produced from fungi

• Contain β lactam ring

• Limited use d.t. increased resistance

• Mechanism of action: …….....

Inhibit transpeptidase* i.e cross linking between peptides not occur →

Peptidoglycan of cell wall will NOT be formed.

Susceptible to β lactamase that is present in some bacteria e.g. Staph.

Cidal

×× Cell wall

×× Cell wall

Treponema pallidum

×× Cell wall

PenicillinExamples Group

*Benzylpenicillin (Acid sensitive = NOT oral) *Phenoxymethylpenicillin

)Acid resistant = Given oral(

Narrow spectrum – penicillinase =)β-lactamase (sensitive

* Methicillin: [ Poor oral availability (only parenteral)]

* Oxacillin: Good oral availability* Cloxacillin* Dicloxacillin

Narrow spectrum – penicillinase =)β-lactamase (resistant

* Ampicillin (Oral)* Amoxicillin (Oral) Broad spectrum – penicillinase (=

β-lactamase) sensitive =)Aminopenicillins(

* Carbenicillin: [Poor oral availability]Active against gram +ve & gram –ve bacteriaActive against Pseudomonas aeruginosa, Klebsiella* Ticarcillin* Mezlocillin* Pipercillin

Extended spectrum – penicillinase (= β-lactamase) sensitive

=)Carboxypenicillins(

×× Cell wall

×× Cell wall

Cephalosporin• Semi-synthetic antibiotics [derived from fungus Cephalosporium ]

• Contain β lactam ring

• Mechanism of action: ……………

Susceptible to β lactamase that is present in some bacteria e.g. Staph

Cidal

Cross-allergies with penicillins are common

×× Cell wall

4 Generations of cephalosporins• 1st generation: Cephalexin, cephalothin, Cephadroxil (mostly GP, some GN)

Poor penetration to BBB

• 2nd generation : Cefaclor, Cefuroxime, Cefoxitin (some GP and some GN, *anaerobes)

• 3rd generation : Cefixime, Cefpodoxime, Ceftriaxone, Cefdinir (good Streptococcal coverage, mostly GN)

and ceftazidime (no GP, mostly GN, Pseudomonas)

Good penetration to BBB

• 4th generation : Cefepime, Cefpirome

(most GP, most GN, Pseudomonas) ×× Cell wall

×× Cell wall

×× Cell wall

×× Cell wall

×× Cell wall

×× Cell wall

Vancomycin• Glycopeptide*

• Spectrum: very good for G +ve

Staph (including MRSA)*

Strept

Bacillus

- Propionobacterium acne

- Cl. Difficile

Indications:*

- Keratitis

- Endophthalmitis (intra-vitreal injection)

Side effect: Ototoxic - Nephrotoxic

MRSA

×× Cell wall

CarbapenemeSpectrum:• Gram +ve except MRSA

• Gram –ve

• Anaerobes

×× Cell wall

Other inhibitors of cell wallBacitracin Polymixin B

G +ve+

NisseriaHemophilusActinomyces

G –ve Hemophilus Enterobacter

E-coliKlebsiella

pseudomonasMechanism of action: They are cyclic peptides that adsorb to negatively

charged lipids in the cell membrane, leading to disorganization of the

membrane and loss of cell function.Conjunctivitis - Blepharitis Used : Conjunctivitis

S.E. : They lack selectivity, which can lead to nephrotoxicity and neurotoxicity

×× Cell wall

Other inhibitors of cell wallBacitracin Polymixin B

G +ve+

NisseriaHemophilusActinomyces

G –ve: • Hemophilus • Enterobacter• E-coli• Klebsiella• pseudomonas

Spectrum

They are cyclic peptides that adsorb to negatively charged lipids in the cell membrane disorganization of the membrane and loss of cell function.

Mechanism of

action

Conjunctivitis - Blepharitis Conjunctivitis UsesThey lack selectivity, which can lead to nephrotoxicity and neurotoxicity

S.E. ×× Cell

wall

2 .PROTEIN SYNTHESIS INHIBITORSInhibit either the 30s or 50s ribosomal subunit

-Aminoglycosides (bactericidal)

–Tetracyclins –Macrolides

– Chloramphenicol Bacteriostatic –Clindamycin

Protein Synthesis Inhibitors• 50S ribosome inhibitors-Macrolides e.g. Erythromycin-Lincosamides e.g. clindamycin, lincomyin• 30S ribosome inhibitors-Aminoglycosides-Tetracyclines

MnemonicsBuy AT 30s & Cell for 50s

1 .AmiNOglycosides• NO protein synthesis [ by inhibition of 30s ribosome]

• NO pregnancy [Teratogenic]

• Negative Organisms killer

• NOt active against anaerobes

• Nephrotoxic - Ototoxic

Scheme

1 .AminoglycosidesSpectrum: effective against gram -ve aerobic bacteria

[Gentamycin & tobramycin kill staph. ]

Distribution: (water soluble = very polar)

Poor penetration to BBB / Cornea

[ Good penetration if inflamed tissue e.g. meningitis]

= NOT used orally but parenteral [may be used in endopthalmitis]

= Used topically for external eye infections e.g. conjunctivitis - keratitis

bactericidal

Penetration into cell requires an oxygen-dependent transport So, anaerobes are resistant

1 .Aminoglycosides• Mechanism of action : 30s ribosome inhibitor

Cause misreading of m-RNA code and affect permeability.

Stop protein synthesis initiation

bactericidal

Better for …….. AntibioticSerratia Gentamycin

Pseudomonas TobramycinPseudomonas +

mycobacteriaAmikacin

T.B + strept viridans StreptomycinAcanthamoeba Neomycin - paraneomycin

Side effects of aminoglycosides*Ototoxicity: (irreversible)

• Affection of cochlear cells : tinnitus – pressure sensation

• Affection of vestibular cells: Nystagmus, vertigo, nausea & vomiting

Nephrotoxicity: Acute tubular necrosis (reversible)

Neuromuscular toxicity: blockage of presynaptic A.Ch release respiratory suppression

Amikacin is less nephrotoxic than gentamycin*

Can be used -with monitoring- in renal failure

Gentamycin

Side effect Route/useCorneal epithelial toxicity Topical gentamicin

(in microbial keratitis)Retinal toxicity* Intra-vitreal gentamicin

NeomycinOne of the most toxic aminoglycosides

• Routes: o Oral: poor penetration [ Used locally in GIT]

e.g. preparation of bowel before surgery or hepatic encephalopathy

o Topical: skin & external earo I.V.: rarely used

• Side effect : Allergy is very common + …………

Neomycin is used in ophthalmology for acanthameoba

TetracyclineHaving a nucleus of four cyclic rings

Spectrum: • G +ve / G –ve

+

• Rickettsia [ Typhus – Q fever ]

• Chalmydia

• Mycoplasma pneumoniae

• Mechanism of action :

Inhibit protein synthesis: by binding to 30s ribosomes

Prevent attachment of aminoacyl-t-RNA to the mRNA ribosome complex.

Bacteriostatic

Tetracycline members• Tetracycline

• Oxytetracycline

• Doxycycline

• Domeclocycline

• Minocycline

Most of them excreted in kidney, so contraindicated if renal failure !!Except, doxycycline (excreted mainly by GIT ! )

Tetracycline: Ophthalmological uses• Anti-collagenase action

TTT of sterile (non-infected) corneal ulcer [corneal melting]

in which stromal necrosis is thought to be d.t. collagenase activity

• Topically for trachomaBut systemic erythromycin is the drug of choice !

Uses: “On empty stomach”

Side effectsChange in dentation: discoloration & dysgenesis [ contraindicated before 8 years ]

d.t. formation of tetracyclin – calcium phosphate complex

MacrolidesMechanism of action : Macrolides bind to 50s ribosome and interfere with translocation

Taken on empty stomach

Specterum

Mostly G +ve and a few G-ve bacteria e.g. Hemophilus,

+ atypical bacteria (Legionella, Chlamydia, Mycoplasma)

[Narrow spectrum antibiotics similar to penicillin]

[Good alternative for patients with penicillin allergy]

bacteriostatic

Poor penetration to BBB & BAB

Erythromycin is bacteriocidal in high dose

MacrolidesErythromycin is highly active against:

• Str. Pyogenes

• Str. Pneumaniae

• N. gonorrhoeae

• C. diphtheriae

Azithromycin [Very long half-life (>24 h)]

Clarithromycin

• Used for H. pylori infection

Specterum & uses of macrolides

CHLORAMPHENICOL Spectrum

• Gram +ve & Gram -ve organisms + anerobes

+ Chalmydia, mycoplasma, Rickettsia

NOT active against Pseudomonas

Mechanism of action

• Binds to 50s ribosome

• Inhibit the transfer of elongated peptide chain to the newly attached aminoacyl -tRNA at ribosome mRNA complex.

bacteriostatic

Lipid soluble, SoGood penetration to BBB & BAB & cornea

Good for topical use & CNS infections

Side effects [Dose dependent]

These side effects are for topical & systemic !!!Restricted for life-threatening infections where no alternative exists

such as Haemophilus influenzae meningitis or typhoid fever

• Bone marrow depression (Reversible)

• Aplastic anemia [idiosyncrasy] (irreversible) (very rare)

• Grey baby syndrome

NOT used at pregnancy & lactation

Clindamycin

Spectrum: G +ve + anaerobes

Mechanism of action: inhibitor of 50s ribosome

Use:

• Anaerobic bacteria e.g Bacteroides fragilis (infections associated with trauma or surgery)

• MRSA

• Toxoplasma

Side effects: pseudo-membraneous colitis d.t. overgrowth of cl. Difficile

Bacteriostatic

TTT of pseudomembraneous colitis: oral vancomycin or metronidazole

Inhibitors of nucleic acid function or synthesis

• Floroquinolone• Rifampin• Metronidazole

QuinolonesAnalogues of nalidixic acid

Mostly fluorinated = Fluoroquinolones (except nalidixic acid) to activity

Spectrum:

• G –ve

• Some G +ve ( heamophilus, pseudomonas, Enterobacteria, staph)

• Chalamydia

• Rickettsia

• Mycoplasma

Bacteriocidal

QuinolonesMechanism of action:

Inhibitors of DNA Gyrase (= Topoisomerase II) [a bacterial enzyme that winds and unwinds DNA (required for supercoiling the bacterial genome)] inhibition of DNA synthesis and transcription

Bacteriocidal

Generations of Quinolones

• 4th generation has enhanced activity against G +ve

Examples GenerationNalidixic acid 1st generationCiprofloxacin

OfloxacinNorfloxacin

2nd generation

Levofloxacin 3rd generationGatifloxacinMoxifloxacinBesifloxacinTravofloxacin

4th generation

Ophthalmic uses• Conjunctivitis

• Keratitis

• Prophylaxis in penetrating trauma

Oral ciprofloxacin produce high levels in vitreous as they are with intravitreous therapy.

So, It is used as part of endophthalmitis protocols.

Uses

Side effects

Cartilage damage in children is experimental finding بيرضعوا .. واللي للحوامل ممنوع بس يحصل خايفين يعني

MetronidazoleSpectrum

• Anaerobes (e.g. bacteroides)

• Protozoa:

Amoeba (drug of choice)

Trichomonas vaginalis (drug of choice)

Giardia (drug of choice)

Mechanism of action:

Inhibition of microbial DNA synthesis [by forming toxic metabolites]

USE in ophthalmology: Orbital cellulitis in combination with cefuroxime.

Good penetration (Can pass BBB)

NOT in

pregnancy

Disulifram reaction

Inhibitors of cell metabolism

• Sulfonamides• Trimethoprim

SulfonamidesMechanism of action:

Inhibition of folic acid synthesis

Example:

Sulfacetamide

Spectrum:

G +ve / G –ve

+

Toxoplasmosis

Chalamydia

Actinomyces

Pneumocystits

Bacteriostatic

Trimethoprim

• Has similar activity to sulphonamides

• Give synergistic effect in combination with sulphonamides

(= Cotrimoxazole)

UsesRarely used now d.t. resistancy

• Conjunctivitis

• Blepharitis

• Toxoplasmosis

Side effects• Hypersensitivity (Steven Jhonson syndrome)*

• Nephrotoxicity

• Haemopoeitic disturbances

• Transient myopia*

Cotrimoxazole(sulfamethoxazole plus trimethoprim)

Anti – T.B. drugs

Anti-mycobacterials

optic neuritis

The Top Ten Rule1. All cell wall inhibitors are Beta-lactams (penicllins, cephalosporins etc) except vancomycin.2. All penicllins are water soluble except nafcillin.3. All protein synthesis inhibitors are bacteriostatic, except for the aminoglycosides4. All cocci are gram positive, except Neisseria spp.5. All bacilli are gram negative, except anthrax, tetanus, botulism and diphtheria bugs6. All spirochaetes are gram negative

The Top Ten Rule7. Tetracylcines and macrolides are used for intracellular bacteria8. Beware pregnant women and tetracylcines, aminoglycosides, fluoroquinolones and sulfonamides.9. Antibitoics beginning with 'C' are particularly associated with pseudomembranous colitis i.e. Cephalosporins, Clindamycin and Ciprofloxacin.10. While the penicillins are the most famous for causing allergies, a significant proportion of people with penicillin allergies may also react to cephalosporins. These should therefore also be avoided.

Antibiotics for Selected Bacteria

Use of prophylactic antibiotic in patient with cardiac murmur

Needed with:• DCR

• Orbital floor fracture

As they are associated with septicemia d.t. the amount of bleeding & high load of bacterial commensals in sinus & nasal cavity

NOT needed with:

• Cataract operation

• Trabeculectomy

• Ptreygium operation

As they are relatively clean procedure