There are two main issues that we will talk about:

* mechanisms of drug resistance *Origins of drug resistance

1- mechanisms: a) micro organisms produce enzymes that

destroy the activity of the drug eg:~staphylococcus B-lactamase ~Gram –ve rods

adenylating ,phosphorylating ,and acetylating enzymes ,against aminoglycosides .

INTRODUCTION:

~Gram –ve chloramphinicol acetyl transferase against chloramphinicol .b)Microorganism alters its permeability to the drug eg tetracyclin and polymyxin .Streptococci have natural barrier to aminoglycosides .

acer:acer:

c)Microorganism develops an altered structural target

eg:chromosomal resistance to aminoglycosides “30s ribosomal

subunit’’Erythromycin resistant organisms altere receptors in 50s ribosomal

subunit.Penicillin resistance change in penicillin binding protein “PBP.”

d)Microorganisms develop an altered metabolic pathways that bypass the

reaction inhibited by the drug eg :

Sulfonamides can use the preformed folic acid without need to extracellular PABA.

e)Microorganisms alter an enzyme eg :

Trimethprim resistant bacteria dihydrofolic acid reductease is inhibited.

Origins of the drug resistance

ORIGINS

Non geneticNon genetic GeneticGenetic

chromosomalchromosomal ExtrachromosomalExtrachromosomal

*Active replication of bacteria is required for most antibacterial drug action eg:

Mycobacterim tuberclosis stay many years in the body with slow multiplying.

*Microorganism may lose target structure and so becomes resistant ,eg: penicillin susceptible organisms may have difficiency in L-aminoacids cell wall diff- and so become resistant to cell wall

1Non genetic origin:

Inhibitor drugs (penicillin + cephalosporins).

*microorganisms may infect cells which drug cann’t reach them,eg:

Aminoglycosides salmonella enteric fever

Because salmonellae are intracellular microorganisms and aminoglycosides cannt enter the cell.

Either :a)chromosomal “mutation” :this develops as a result of spontaneous mutation in a locus that controles susceptibility to a given drug

*Chromosomal mutants are most commonly resistant by virtue of changes in a structural receptor of drug ,eg mutation in the gene controlling the structural protein “of streptomycin

2 Genetic origin:

Receptor ) result in streptomycin resistance .b)extrachromosomal “plasmid mediated resistance”: bacteria often contain extrachromosomal gentic elements called plasmids.

*R-factor are a class of plasmids , circular ,double stranded DNA that carry genes for resistance to one –and often several – antimicrobial drug and

heavy metals “Co ,Hg.”

*R-factor composed of two parts:

1 \resistant – transfer factor “RTF” segment of plasmid that responsible for intracellular transfer .and

2 \R-determinant : that carries the resistance genes.

~Dissemintion by bacterial conjugation mainly.

Clinical importance of extrachromosomal resistance:

1 )It occurs in many different species , specially gram –ve rods.

2 )Plasmids frequentely mediate resistance to multiple drugs.

3)plasmids have a high rate of transfer from one cell to another by conjugation .

The mechanisms of resistance:

The plasmid genes control the formation of enzs capable to destory the drugs eg:plasmids determine resistance to penicillins and cephalosporins by carring genes for the fomation B-lactamase

~Genetic material and plasmid can be transferred by transformation ,transduction ,conjugation and transposition.

Transformation:Is the up take of the extra cellular DNA by

bacteria thus ,altering its genotype. This can occur through labrotary manipulation )e.g: in recombinant DNA technology ).Steps:a) DNA must bind to the cell surface.

b) The bound DNA taken up through the cell membrane.

c)the DNA fragment is integrated into the host chromosome or replicates as plasmid.

Transduction:

The genetic transfer occur when a fragment of DNA is carried to the recipient cell by virus “bacteriophage “ e.g :the plasmid carring of the gene for B-lactamase production ,can be transferred from apenicillin –resistant to a susceptible staph aureus.

Conjugation (plasmid- mediated transfer):

It is a unilateral transfer of genetic material between bacteria of the same or different genera occurs during amating )conjugation ) process.This is mediated by afertility factor that result in extension or extrusion of sex pili from the doner )F+) cell to the recipient )F-).

Transposition:

A transfer of short DNA sequences )transposons,transposable element ) occurs between one plasmid and another or between a plasmid and a portion of the bacterial chromosome.

cross resistance:

Microorganisms resistant to a certain drugs may also be resistant to other drugs that share a mechanism of action eg:

~different aminoglycosides are closely related chemically

~macrolides and lincomycins :have a similar mode of action or binding.

Limitation of drug resistance:

1 \by maintainig sufficiently high level of the drug in the tissues to inhibit both the original population and the first step mutants

2\by simultaneously administering two drugs that don’t give cross resistance )each of which delays the emergence of mutants resistant to the other drug eg :Rifampin and isoniazide in treatment of T.B)

3 \by avoiding exposture of microorganism to a particularely valuable drug by limittig its use specially in hospital.

4\health awareness about missuse of antibiotics

Specific mechanisms of resistance

*penicillins and cephalosporins: 1\cleavage by B-lactamases

2\due to change in the PBP3\resistance of N.gonorrhoea to

penicillin is due to poor permeability to the drug.

4\tolerance )decrease of growth but not killing of bacteria)

•*Vancomycin :the resistance is caused by a change in the peptide component of peptidoglycan from D-alanine:D-alanine )normally),to D-alanine :D-lactate )abnormal; no drug bindig )

*Aminoglycosides :three mechanisms:

1 \modification of the drug by plasmid – encoded phosphorylating , adenylating and acetylating

enzymes.

2\chromosomal mutaion

3\Decrease permeability of the bacteria to the drug

MRSA:

)hospitals should be the Mecca of all types of Staphylococcus)

DR\Erick

staphylococcus is one of the most resistant organisms to antimicrobial drugs.

S. Aureus is resistant to methycillin MRSA

The MRSA pt experience the following:

*Depending on the site of body infected

•Surgical wounds infection results in:

-pain

-redness

-swelling of the site and wound drains pus.

*pneumonic pts cough , breathlessness ,chest pain,chills , sweats may presents

SYMPTOMS:

Diagnosis and treatment:

*Culture from the infected site is diagnostic.

*unfortunately limitted A\Bs are effective I.V vancomycin is the most common used for treatment.

Untreated MRSA can result in severe results ,relapse of infection and even death.

MRSA preventionMRSA prevention::

11 \ \covering wounds with bandagescovering wounds with bandages

22\\consulting health provider when consulting health provider when use antibioticsuse antibiotics..

FOR MORE DETAILS:

*Refrences:

1\GOODMAN & GILLMANS pharmacological basis of theraputics

2 \jawetz MEDICAL MICROBIOLOGY

3\ESSENTIALS OF MICROBIOLOGY

WELSY .A.VOLK

Web sites:Web sites:

**www.moreporn.biz\new\index.phpwww.moreporn.biz\new\index.php *www.cdc.gov/drugresistance/community*www.cdc.gov/drugresistance/community

**www.niaid.nih.gov/dmid/antimicrobwww.niaid.nih.gov/dmid/antimicrob

**www.meds.comwww.meds.com

**www.npsf.orgwww.npsf.org

Preppared and Preppared and presented bypresented by::

Dr\Ala Eldin Dr\Ala Eldin SalahSalah

Dr\ Hassan M. Dr\ Hassan M. HassanHassan

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