Antibiotic Antimicrobial

8/14/2019 Antibiotic Antimicrobial

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Therapeutics

against infections

By

Dr. Omerel-Adil Abdalla


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Introduction


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In history many scientists to them goes our

gratitude; Fleming , Ehrlich and others


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Antibiotics

andAntimicrobials


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Classification

It is classified according to :A- Origin of production into:-

1. Antibiotic: Chemical produced by a

microorganism.

2. Antimicrobial agent: SyntheticChemical


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Classification

B- Fate of action into:-1. Bacteriostatic:- inhibits growth and

reproduction of bacteria without killing

them .

2.

Bactericidal:- kills bacteria.


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Classification

C- Site of action:-1. Inhibitors of cell wall synthesis and

Membrane active agents.

2. Inhibitors of protein synthesis.

3. Inhibitors of folate metabolism.

4. Inhibitors of DNA synthesis.5. Inhibitors of RNA synthesis.


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Principles and Definitions

Generally, dont combine bacteriostatic andbactericidals.

Which categories to chose?

Bacteriostatic: Duration of treatmentsufficient for host defenses

Bactericidal :Usually antibiotic of choice

No antibiotic is effective against all

microbes.


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Principles and DefinitionsTherapeutic Index: Toxic dose/ Effective dose.

Minimum Inhibitory Concentration (MIC) Lowest

concentration that results in inhibition of visible growth.

Minimum Bactericidal Concentration (MBC) Lowest

concentration that kills 99.9% of the original inoculum


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Inhibitors

ofCell Wall Synthesis
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Lactam Group
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1- Penicillin General Activity: Bactericidal G +ve , G-ve cocci

non- b-lactamase.

Special Usages: in meningitis and endocarditis.

Serious side effects: Rare ; Anaphylaxis, interstitialnephritis, pseudomembranous colitis,encephalopathy.

Contraindications: Hypersensitivity, intrathecalinjection, but save in pregnancy.

Excretions: Renal. Examples:


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Penicillinase -lactamase -sensitive penicillinsBenzylpenicillin (penicillin G, parenteral(

Penicillin V (phenoxymethyl penicillin, oral( Penicillinase-resistant penicillins

Flucloxacillin.

clavulanic acid.

Broad-spectrum penicillins

Amoxicillin.

Combination: Co-amoxiclav (amoxicillin + clavulanicacid(, Ampiclox (amoxicillin + cloxacillin (

Antipseudomonal penicillins

Piperacillin (with tazobactam; Tazocin)

Ticarcillin (plus clavulanic acid)


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2-Cephalosporins

General Activity: Bactericidal, similar to penicillins,broader spectrum , more stable to b-lactamases , notactive against enterococci and L. monocytogenes.

Special Usages:First-generation : active against G +ve cocci ,G-ve

PEcK = (Proteus , Escherichia and Klebsiella) ,

Poor activity against Pseudomonas.

Second-generation: like the first-generation drugs,

in addition H.inf & Neisseria

(HeNPEcK)


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Third-generation :

More G -ve, and able to cross BBB, some are

antipseudomonal , decreased activity against

G +ve especially S. aureus.

Fourth-generation :

G +ve and G -ve ,with good activity against

P.aeruginosa, S. aureus, good activity againstmost

penicillin-resistant strains of streptococci .


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Fifth generation On the horizon

It was only issued an approvable letter in March2008. The FDA is requesting additional

information

Indication : Complicated skin infections including diabetic

foot infections

MRSA

Hospital-acquired pneumonia, including

ventilator associated pneumonia.


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Serious side effect:

Cross-allergenicity with penicillin 10%.

interstitial nephritis.Contraindications:Excretions:RenalExamples: First-generation: Cephalexin. Second-generation: Cefuroxime. Third-generation: Cefotaxime, ceftazidime,

ceftriaxone, cefixime, cefpodoxime . Fourth-generation: Cefepime.

Fifth generation: Ceftobiprole


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3- Monobactams (Aztreonam)

Active against G -ve ; cocci and bacilli , noactivity against G +ve bacteria or anaerobes,

resistant to -lactamase.

4- Carbapenems(Meropenem)

Good activity against G +ve and G ve

cocci , rods, and anaerobes.Resistant to most -lactamase but not

MRSA orClostridium


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Inhibitors of cell wall synthesis

Non Lactam Group

1- Vancomycin General Activity: Bactericidal , active only against

gram-positive bacteria, particularly staphylococci

organisms.

Special Usages: in MRSA, CDID.

Serious side effect: Phlebitis at the site of injection,

Ototoxicity, nephrotoxicity ,"red man" syndrome. Contraindications: Sensitivity.

Excretions: Renal


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2-Cycloserine

It is used almost exclusively to treat

tuberculosis caused by strains of

Mycobacterium tuberculosis resistant to

first-line agents.

Side effect: CNS toxicity, acute psychosis,

and convulsions.


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Inhibitors

ofProtein Synthesis
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1-TetracyclinesGeneral Activity: Bacteriostatic; G +ve , G-ve

including anaerobes. Absorption decreased by milk andminerals.

Special Usages: Rickettsia, Chlamydia, Mycoplasma

and some Spirochetes . Serious side effects: Photosensitivity, teeth

hypoplasia and discoloration in less than 8 years old.

Contraindications: Renal fail., pregnancy, lactationExcretions: RenalExamples: Tetracycllin, Doxycycllin, Demeclocycline


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2-Macrolides General Activity: Bacteriostatic.

Special Usages: Inclusive of Mycoplasma,Chlamydia , Rickettsia, Helicobacter,Pneumococci and Legionella.

Clarythromycin is second line antituberculous. Serious side effects: Chol. hepatitis (erythro) ,

transient h. loss, th.phlebitis. CYP inhibitor(except Azithromycin)

Contraindications: Sensitivity.

Excretions: Mainly Hepatic

Examples: Erythro, Clarithro, Azithro


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3-Aminglycosides General Activity: Bactericidal G-ve aerobic bacilli

Special Usages: Empirical coverage ,especially in

bacteremia and sepsis .

Serious side effects: Ototoxicity. Nephrotoxicity

Contraindications: Hypersensitivity.

Excretions: Renal

Examples: Gentamycin , Amikacin , Neomycin ,Streptomycin


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4- Clindamycin Bacteriostatic

For anaerobic infection caused by bacteroidesand other anaerobes.

Common adverse effects are Clostridiumdifficile induced diarrhea and colitis .


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5- Chloramphenicol It is a bacteriostatic broad-spectrum antibiotic

against both aero and anaero , G+ve and G-ve. Active against Rickettsiae but not Chlamydiae,

H influenzae and N meningitidis. Usedtopically in eye infections.

Side effects: Potential idiosyncratic Bonemarrow toxicity, gray baby syndrome, CYPinh


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Inhibitors

ofFolate metabolism


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Sulphonamides General Activity: Bacteriostatic, broad both G+ve and G

-ve aerobic, Nocardia , Chlamydia trachomatis, and someprotozoa.

Rickettsiae are not inhibited but are stimulated. Special Usages: UTI , Typhoid fever,

Pneumocystis jiroveci, toxoplasma , plasmodia. Serious side effects: bone marrow toxicity, hemolytic

reactions in patients with G-6-PDD,

SJ syndrome , CYP inh.

displace warfarin from the plasma. Contraindications: Hypersensitivity. Excretions: Renal Examples: Septrin (trimethoprim-sulfamethoxazole

mixtures)


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Inhibitorsof

DNA synthesis


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Fluoroquinolones General Activity: Bactericidal Broad but better

against G-ve aerobic bacilli Special Usages: UTI ,Typhoid fever, SBP and

2nd line AntiTB .Absorption delayed by antacidsand H2 block.

Serious side effects: CNS toxicity, QTcprolongation ,Tendinitis ,Photosensitivity, CYPinh.

Contraindications: Hypersensitivity, preg,

childern. Excretions: Renal and hepatic Examples: Cipro, Norfloxacin, levofloxacin,

Nalidixic acid.


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Metronidazole General Activity: Bactericidal, against

anaerobic bacteria and sensitive protozoans Special Usages: Anaerobic infections

(empirical), amibaisis. Serious side effects: GIT Symptoms, metallic

taste, increase alcohol toxicity, peripheralneuropathy.

Contraindications: Hypersensitivity, preg.

Excretions: Renal and hepatic Examples:


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Nitrofurantoin General Activity: Bacteriostatic.

Special Usages: UTI Serious side effects: GIT Symptoms,

pneumonitis, CNS demyelination, haemolysisin G6PDD

Contraindications: Hypersensitivity, preg. Excretions: Renal . Examples:


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Inhibitorsof

RNA synthesis


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Rifampin General Activity: Bactericidal against G+ve and

G-ve cocci, some enteric bacteria,mycobacteria, and chlamydia. Special Usages: Tuberculosis, leprosy,

brucelosis, osteomyelitis, meningococcal

carriage Serious side effects: orange discoloration,

cholestatic jaundice and hepatitis, CYP inducer Contraindications: Hypersensitivity. Excretions: hepatic Examples: Rifampicin,rifabutin


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Drug Interactions! Cytochrome P450 isoforms(CYPs 1A2, 2C9, 2C19, 2D6, and

3A4).

Levels increased by (Metabolism inhibited by)

Macrolides (Erythromycin) , Azoles (Fluconazole,

Itraconazole), Protease inhibitors, Ciprofloxacin Levels decreased by (Metabolism induced by)

Rifampin.

Oral Contraceptives

Decreased with rifampin & nafcillin +/- others .

Drugs affected by CYP 450

Many like; Statins, Cyclosporine, Benzodiazepines,

Theophylline, Anticonvulsants, oral hypoglycemics


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What Anti Microbial to choose?1. Pharmacokinetic factors: Sufficient antibiotic must penetrate to the site of the

infection. (Difficult sites include the brain, eye andprostate and abscesses).

Knowledge of the standard pharmacokinetic

considerations of absorption, distribution,

metabolism and excretion. Interacting medications. Resistance trends. Allergies, organ dysfunction. Formularies and cost


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2. Disease related:

Local epidemiology of the organisms. Exposure history, risk factors for

specific microbes.

weight, height.


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Three ways antibiotics used

1-Prophylaxis

Medical.

Procedural (surgery).

2-Empiric (usually up to 72 hours) Diagnosis of infection made based on S/S,

Likely pathogens suspected but specific

pathogen not yet known.3- Definitive

Microbiologic or serologic diagnosis .


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How long to treat?

Not well defined!Usually 7 to 14 days!

Longer for Endocarditis, Osteomyelitis,

Endometritis until afebrile 24-48 hrs

Progress note & set endpoint!

Prolonged unnecessary therapy increasesrisk of resistance and adverse effects


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Critical Thinking Exercises 1

A nurse asks you why it is important to determineif the patient is allergic to penicillin before giving

cephalosporin

The most correct answer is that persons

allergic to penicillin .

A. are allergic to most antibiotics.

B. respond poorly to antibiotic therapy.

C. require higher doses of other antibiotics.D. have a higher cross allergy to the cephalosporin.

E. Interaction between old pencillin doses and new cephalosporin.


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Antibiotic Resistance

Introduction Alexander Fleming recognized the potential

danger of antibiotic resistance.

In 1945, he warned that misuse of penicillin couldlead to the selection and propagation of mutant

forms of bacteria resistant to the drug.

The first penicillin-resistant bacteria appearedseveral years later. Their mutant gene encoded for

a penicillin-destroying enzyme penicillinase.


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Intensive care units seem to have

particularly high incidences of resistantmicrobes.


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Mechanisms of resistance1. Bacteria become resistant through Adaptations (product of selection). Acquisition and transmission of antibiotic

resistance (horizontal gene transfer).

2. Decreased transport of the antibiotic into the cell3. Production of enzymes that destroy the inhibitory

capacity of the antibiotic.

4. Modification of the antibiotic binding site so that the

drug no longer binds to the target.5. Production of alternate molecules that can replace

those disrupted by the antibiotic.


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Preventing the use of antibiotics

Verify diagnosis & need for antibioticsConsider other (non-infectious) causes of

symptoms.

Remember: antibiotics dont work against

viruses.

Vaccinate at risk patients.Wash your hands!, also stethoscopes.

Documents

Antibiotic Antimicrobial