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Micro-organisms can be divided into 4 main groups: bacteria, protozoa, fungi, and viruses. Bacteria are the smallest and most primitive of these microbes, lacking nuclei and existing as single cells or colonies. Viruses are even smaller and simpler, able to replicate only inside host cells. More complex microbes include protozoa, which have true nuclei, and fungi, which resemble primitive plants. An overview of bacterial structure, classification, and important pathogenic species is provided, highlighting bacteria's role in causing infectious disease. The document also discusses how bacteria can become pathogenic and how the human body defends against infection.

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Bacteriology 1 Its only for you Ninaa
.. Hrant Ourgandjian, M.D. Medical Manager
Grouping (Micro-organisms) Micro-organisms can be divided into 4 important groups:  1. Bacteria  2. Protozoa  3. Fungi  4. Viruses
Bacteria  Size: variable depending on the species.  Nucleus: no. Mass of DNA without nuclear membrane, formed by a single chromosome.  Cell wall: yes, formed of liposaccharides and lipoproteins DEFINITIONS
Bacteria Bacteria are small single celled organisms that are not visible to the naked eye and have a very primitive structure.
Microscopic parasites or Protozoan  Kingdom : animal,  Nucleus : true,  Example : Entamoeba histolytica = Ameba Amebiasis
Protozoa Protozoa (eg amoeba) are more complex than bacteria in structure.
Fungi  Kingdom: vegetable,  Size : a few microns,  Nucleus : true.  2 types : yeasts and dermatophytes  Example of yeasts : Candida albicans Mycosis
FUNGI Fungi resemble primitive plants and live on dead organic matter they can exist as single cells (yeast) or as many cells (called mycelium)
Virus  Size: between 20 and 200 millimicrons (visible under the electron microscope),  Nucleus : no. Nucleic acid core (DNA or RNA) contained in an envelope (capsid).  They invade the human, bacterial, plant or animal cells to survive Example : Myxovirus = Flu virus
VIRUSES Viruses are the smallest and simplest of all organisms and can only be seen with powerful electron microscopes. Viruses cannot multiply by themselves and so have to invade host cells to allow multiplication.
Bacterial structure  Constant Elements : Bacterial "nucleus" = chromosomic DNA Cell wall Cytoplasmic membrane Cytoplasm Ribosomes (synthesis of proteins and nutritive reserves of the bacterium)
 Optional elements : Bacterial structure Pili (tissue binding, transmission of plasmids) Plasmid (DNA fragments carrying genes of resistance) Flagella (motility) Capsule (resistance to phagocytosis)
 Characteristics of all bacteria:  All bacteria possess 5 basic components: - Cell wall - Cytoplasmic membrane - Cytoplasm - Ribosomes - Nuclear material  Some bacteria possess: - Flagella - Pili - Capsules
Ribosome
Flagella, and pili
BACTERIOLOGY : Identification of the bacterium ? Metabolism .. .. .. .. .. .. .. .. .. ..
 Bacterial classification Difficulty in classification: Unlike higher organisms, bacteria lack sufficient variations in structure upon which normal classifications can be made. Basic criteria Most of the systems developed to classify bacteria utilise these diagnostic criteria - Shape (morphology) and culture characteristics - Staining – Gram Stain - Culturing and biochemical tests - Growth requirement for oxygen; i.e. aerobic or anaerobic
Shapes of bacteria 1. Identification by shape
Cocci (spheres)
Bacilli (rods)
Vibrio (short curved rods)
Spirochetes (long twisting filaments): syphilis, leptospirosis
GRAM STAIN
Gram staining Gram + Gram - BACTERIOLOGY : 2. Identification staining the cell wall External membrane Peptidoglycane Cytoplasmic membrane Pores PBP Optional capsule
BACTERIOLOGY: 3. Identification by metabolism  METABOLISM Strict aerobe Aero-anaerobe Strict anaerobe (use oxygen to metabolise glucose) (use fermentation to metabolise glucose) .. .. ..
BACTERIOLOGY: Synthesis / Identification Shape Cocci Bacillus Stain Gram + Gram - Bacillus + Bacillus - Cocci + Cocci -
BACTERIOLOGY: Classification of Bacteria  Anaerobes Cocci Bacillus + + - -  Aerobes Cocci Bacillus + + - -
 Genus : Haemophilus Streptococcus  Species : influenzae para influenzae pneumo- b hemolytic group B coccus group A group C group D etc.  Serotypes : a, b, c, d, etc etc. 23F,9, 6,14 etc. (+ of 80 different serotypes) (+ of 80 different serotypes)  The bacterial strain is a colony resulting from a sample and a particular serotype, obtained from sucessive subcultures ("clones"). BACTERIOLOGY: Concept of bacterial strain
Aerobic Pathogens COCCI + • Staphylococcus: – aureus – epidermidis • Streptococcus: – S. pneumoniae – S. group A b hemolytic – S. group B – S. viridans – S. group D = S. foecalis COCCI - • Neisseriae: – meningitidis – gonorrhae • Moraxella catarrhalis
BACILLI + • Corynebacterium diphteriae • Listeria monocytogenes • Haemophilus influenzae • Pseudomonas aeruginosa • Vibrio cholerae • Brucella • Acinetobacter • Helicobacter • Mycobacteria Aerobic Pathogens BACILLI - ENTEROBACTERIA: • Escherichia coli • Proteus • Serratia • Klebsiella • Enterobacter • Citrobacter • Salmonella • Shigella • Yersinia
COCCI + • Peptococcus • Peptostreptococcus COCCI - • Veillonella BACILLI + • Clostridium : – C. difficile – C. botulinum – C. perfringens – C. tetani • Propionobacterium – Corynebacterium acnes BACILLI- • Bacteroides fragilis • fusobacterium Anaerobic Pathogens
Pathogens with intra-cellular development • Mycoplasmae : – Mycoplasma pneumoniae • Chlamydiae : – Chlamydia pneumoniae • Legionella • Rickettsiae Miscellaneous pathogens Spirochaetas • Treponema pallidum • Theptospires • Mycobacterium tuberculosis (KB)
DEFINITIONS  INFECTION = A sequence of repercussions which result in an attack on a living organism by a ± virulent pathogen. Endogen or exogen Infection involves 3 actors : PATHOGEN HOST THERAPY
DEFINITIONS INFECTION 2 types of clinical sign: Typical symptoms Local symptoms The symptoms indicate the illness and the pathogen responsible. An organ is suffering. Experience points to a pathogen.
Streptococcus pneumoniae Gram + Cocci  HABITAT: Commensal (organism that derives food or other benefits from another organism without hurting or helping it (50 % of individual carriers, and more in winter).  PATHOGENIC POWER: Very virulent (capsule), – leader as regards mortality of bacterial origin, – responsible for the majority of cases of acute lobar pneumonia, otitis, adult meningitis, sinusitis
Gr A b hemolytic streptococcus Gram + Cocci  HABITAT: Strictly human bacterium. Commensal  PATHOGENIC POWER: Very virulent (capsule, toxin etc.), responsible for ENT (tonsillitis, otitis etc.) and cutaneous infections (impetigo, erysipelas etc.) COMPLICATIONS: rheumatic fever, glomerulonephritis, endocarditis
Staphylococcus aureus Gram + Cocci  HABITAT: Human, soil, air, water.  PATHOGENIC POWER: Very virulent (capsule, toxins, enzymes, etc.), responsible for cutaneous, osseous, pulmonary and cerebral infections, and for superinfection after severe burns. Responsible for septicemia and endocarditis.
Haemophilus Influenzae Gram - Bacillus  HABITAT: Flora of upper respiratory tract. 75% of children under 5 are healthy carriers.  PATHOGENIC POWER: 35 to 50% of otitis, sinusitis, rhinopharyngitis, superinfection of chronic bronchitis or of viral illnesses. Meningitis and septicemia are due to encapsulated forms (H.i.b.). A vaccine against encapsulated Haemophilus exists. The vaccination must be performed at the age of 3 to 4 months with a booster at 14 or 16 months to be effective.
Moraxella catarrhalis Gram - Cocci  HABITAT: Commensal of the respiratory mucus.  PATHOGENIC POWER: Superinfection of chronic bronchitis, otitis, sinusitis
Neisseriae gonorrhoeae Gram - Cocci  HABITAT: Human parasite  PATHOGENIC POWER: Blennorrhagia, salpingitis, pharyngeal gonococci
Salmonella Gram - Bacillus (enterobacteria)  HABITAT: Parasite of the human and animal digestive tract. Contamination by oral route.  PATHOGENIC POWER:  Digestive forms : Toxi-infections (gastro-enteritis)  Septicemic forms : Typhoid (S.typhi) or paratyphoid (S.paratyphi) fever The septicemic forms can become complicated (pulmonary, meningeal, osseous, digestive infections etc
Shigella Gram - Bacillus (enterobacteria)  HABITAT: Human digestive tract. Contamination through food, or water contaminated with fecal matter.  PATHOGENIC POWER: Infectious colitis, gastro-enteritis (children). Bacillary dysentery (army on march).
Escherichia Coli Gram - Bacillus (enterobacteria)  HABITAT: Normally found in human digestive tract.  PATHOGENIC POWER:  Intestinal infections: Infectious diarrhea  Urinary infections: Responsible in up to 90%  Abdominal infections: Peritonitis, salpingitis, cholecystitis  Meningeal infections: Meningitis in infants or elderly patients
Mycoplasma pneumoniae  HABITAT: Micro-organisms without cell wall, intracellular or associated to cells; vegetable, animal, and human parasite.  PATHOGENIC POWER:  Atypical pneumonia : Young adults, particularly in fall and winter.
Intracellular Chlamydia  HABITAT: Strict intracellular parasite of small size.  3 SPECIES: Chlamydia pneumoniae Chlamydia psittaci Chlamydia trachomatis  TREATMENT: Macrolides, fluoroquinolones  Non specific urethritis (50% of cases)  Post-gonococcal urethritis (20 to 60% of cases)  Cervicitis, salpingitis, rectitis  Pneumonias in newborn babies  Conjunctivitis in newborn babies and adults
Intracellular Legionella pneumophila  HABITAT: Bacterium of the environment (lake water, air conditioning). The entry port for the infection is pulmonary.  PATHOGENIC POWER:  Acute pneumonia: pseudo-flu state, dry cough, gastro- intestinal disorders etc. Especially in debilitated subjects of + 50 ans (tabacco, alcohol, immunodepression) Pathology fatal without treatment: 20% of cases
• Specific pathogenic bacterium • Opportunistic pathogenic bacterium .. The different types of pathogenic bacteria
What are the opportunities for a bacterium to become pathogenic ? Migration Immunodepression Antibiotic Physiological change ..
1/ Endogenous infectious illness = rupture of the bacterial ecosystem (saprophyte flora) and proliferation of a bacterial species. 2/ Exogenous infectious illness =  penetration of pathogens within  proliferation the organ  How do they proliferate?  How are they pathogenic?  How do they penetrate? How is bacterial infection or pathogenesis triggered?
1/ How do they proliferate? In favorable environments : • in presence or in absence of oxygen, • in presence of nutrients and space, • humidity, • optimal temperature By mitosis
2/ How are they pathogenic ? Pathogenic power or "Virulence"  2 principal factors of virulence 1. Invasion + or - rapid 2. Toxicity Secretion of sometimes fatal toxins S S S S S S S S S S S SS S S S S S Exotoxins Endotoxins
Other factors of bacterial virulence Bacterium Host Pili Capsule Enzymes - extreme age - weakened general state, - iatrogenic factors , - entry port: wound or surgery.
3/ How do they penetrate ? The entry ports Skin Mucus Respiratory tract Digestive tract
Program of bacterial "excursions"  Surface infection: the pathogens multiply on the surface of mucus,  Infectious site: the pathogens multiply in the tissues close to the entry port,  Targeting of organ: tropism relative to certain organs,  Bacteriemia: passage of pathogens into the blood or the lymph system with no morbid effect,  Septicemia: massive passage of pathogens into the blood Infestation of the whole organism, multiple sites of infection.
How does the human organism defend itself ?  1st line: • Physical resources, • Chemical resources, • Bacteriological resources,  After introduction: • Non specific reaction: inflammatory reaction, • Specific reaction: immune system immune reaction .. .. .. .. .. .. .. .. .. .. .... .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .... .. .. .. .. .. .. .. .. .. ..
1/ A hermetic barrier = the skin Sebaceous gland Sweat Sebum Sweat gland Keratinous cells
2/ A physico-chimique barrier = the mucus Hairs Mucus Lysozyme Transferrine (Igs)
3/ A bacteriological barrier: the saprophyte flora .. .. .. .. .. .. .. .. .. .. .... .. .. .. .. .. .. .. .. .. .. Stop infection .. .. .. .. .. .. .. .. .. .. .... .. .. .. .. .. .. .. .. .. .. Down with pathogens e.g.: Lactobacillus, Doderlein's bacilli in the vagina
Vulvo-vaginal flora • Lactobacilli, • Staphylococcus, • Streptococcus, • Bacteroides, • Peptostreptococcus Skin : Cutaneous flora • Staphylococcus, • Streptococcus, • Corynebacterium, • Fungi. 3/ A bacteriological barrier : the saprophyte flora Oro-pharyngeal flora : Mouth - nose - throat • Staphylococcus, • Streptococcus, • Peptococcus, • Peptostreptococcus, • Fusobacterium, • Bacteroides Intestinal flora • Lactobacilli, • Bifidobacterium, • Bacteroides, • Clostridium, • Colibacille, • Proteus, • Streptococcus, • Staphylococcus, • Yeasts
What if the threshold is crossed ?
1/ The non specific inflammatory reaction 1/ VASODILATATION 2/ PLASMA LEAK . . . . . . 3/ FORMATION OF FIBRINE MESH 4/ PHAGOCYTOSIS
1/ The non specific inflammatory reaction : PHAGOCYTOSIS Two types of phagocytary cells:  Polynuclear  Macrophages 1/ Chemotaxis 2/ Adhesion 3/ Invagination 4/ Digestion
2/ The specific immune reaction LYMPHOCYTES = immunocompetent cells B T Action on contact Circulating antibodies Humoral immunity Cellular immunity
2/ The specific immune reaction Marrow and Thymus lymph vessels and glands blood vessels Production of lymphocytes Transport by During infection the glands swell and become painful (adenopathy).
A- The humoral immune reaction . . . . B B Specific antigen-antibody reaction . . . . . T4 PP PP PP PP Plasmocytes antibodies
A- The humoral immune reaction . . . . B B . . . . T4 Bm Memorization = Immunity acquired The lymphocytes which are not transformed into plasmocytes producing antibodies keep the antigen and the antibody fabrication mode in memory.
B- The cellular immune reaction . . . . T . . . T4 T Te Te Te Tm Memory T4 lymphocytes T lymphocyte "effectors"
The immune reaction: the T4 T4 T B Humoral immunity Cellular immunity B lymphocyte secreting remote antibody Cytotoxic T lymphocyte Preponderant role of T4
Conclusion Cellular immunity
If the infection is triggered despite the defenses...  What is its origin ? What type of treatment?  viral ? antiviral  parasite ? antiparasite  bacterial ? antibiotics  mycotic ? antifungal  Infections can be mixed: bacteria + fungi.  The infections can be successive: bacterial superinfection of an infection of viral origin
What is bacterial superinfection? "The virus prepares the bacterium's nest." Alteration of healthy cells by the virus Tissue lesions Inflammatory Inflammatory tissue response pathology Disturbance of functions (e.g. cold) + Alteration of defense mechanisms Invasion by bacteria Bacterial superinfection Aggravation of tissue lesions
 Definition: An antibiotic is a substance produced by micro- organisms, or which can be reproduced synthetically, which possesses the property of destroying bacteria or of inhibiting the growth of bacteria. Study of an ANTIBIOTIC
Mechanism of action Process inhibition by antibiotics. Antibacterial agents act by effecting one or more of the following processes taking place inside bacterial cells:  The synthesis of the cell wall.  The functioning of the cell membrane  The synthesis of proteins  The synthesis of nuclear material (DNA)  Metabolic transformations
Study of an antibiotic Chemical Mode Effects Spectrum Indications Pharmacokinetics structure of action & toxicity
 Spectrum of activity This is the range of bacteria that are sensitive to the antibiotic (inhibited or killed) Study of an antibiotic Cocci + Cocci - Bacillus + Bacillus - Cocci + Narrow spectrum Broad spectrum
 Activity : determined in laboratory in a number of ways: Antibiogram Dilution method by diffusion with disks on agar Study of an antibiotic Several antibiotics can be studied at the same time One antibiotic can be studied at a time
 Activity : determined by identifying the MIC and MBC for each common pathogen  MIC = Minimum Inhibiting Concentration the minimum concentration of antibiotic capable of stopping the culture of a given strain in a medium Study of an antibiotic X quantity of germs in the inoculum X quantity of germs after culture
 MBC = Minimum Bactericidal Concentration the minimum antibiotic concentration destroying 99.99 % of a bacteria population after 18 hours of contact at 37° Study of an antibiotic X quantity of germs in the inoculum < 1 pathogen alive out of 10 000
Dilution method: determining the MIC MIC = Minimum Inhibiting Concentration the minimum concentration of antibiotic capable of stopping all culture of a given strain in a medium (37° for 24 hours) MIC Control 0,25 0,50 1 2 4 8 16 32 mg/ml
Dilution method: determining the MBC 4 8 16 32 mg/ml Culture from an MIC tube on agar MBC T1 T2 T3 T4 T1 T2 T3 T4
MBC 1/10 000 = 10 102 105 104 103 106 107 108 109 2 4 6 8 10 12 14 18 8 mg 4 mg 2 mg 1 mg 0,5 mg Control 0,25 mg Number of bacteria / ml Time (hours) Inoculum MBC MIC C o n c. of A B T
Agar diffusion method
Agar diffusion method: THE ANTIBIOGRAM 5 antibiotics tested Inhibition diameter 37° for a period of 18 hours
BACTERIOSTATIC ANTIBIOTIC stop . . B T4 Eradication Stimulation
BACTERICIDAL ANTIBIOTIC
THE ANTIBIOGRAM the laboratory response A B C A: Sensitive B: Moderately sensitive C : Resistant
Study of an antibiotic  Pharmacokinetics : study of the behavior and fate of an antibiotic in the organ from administration to elimination AbsorptionMetabolization Diffusion Elimination
 Pharmacokinetics are dependent on the route of administration Oral Parenteral I.M. I.V.
 Pharmacokinetics Absorption Distribution or Diffusion Elimination Metabolization
 Pharmacokinetics: definitions • absorption: % of the dose of active principle administered passing through the intestinal mucus into the blood. • metabolization: the transformation of the active principle into active or inactive metabolite, principally in the liver. • effect of first hepatic passage: presence of hepatic metabolism. • bioavailability: the result of the previous 2 criteria; the % of the quantity of active principle administered arriving in the blood stream.
Pharmacokinetics : example  administration via oral route of 100 mg of active principle,  absorption = 80 % 80 mg,  metabolization (hepatic first pass) = 20 % into inactive metabolite 16 mg, 64 mg will reach the target Bioavailability will therefore be 64 %
Pharmacokinetics : definitions  distribution or diffusion: passage of the active compound from the blood stream into the tissues (site of the infection ?).  binding to plasma proteins: % of the active compound circulating binding to proteins. Plasma protein TRANSPORTER
Pharmacokinetics: distribution  Passage into the CSF: Not all the products reach the C.N.S.  Passage through the placenta barrier: Harmful effects on fetus ?
Pharmacokinetics: elimination biliary route renal route active form inactive form active form other routes = pulmonary, cutaneous, salivary, lacteous etc.
Pharmacokinetics: The plasma concentration curve Plasma concentration Time Plasma peak C max T max Drug
Pharmacokinetics : The plasma elimination 1/2 life Plasma concentration Time Plasma peak C max T max T / 2 C / 2 1/2 life elimination phase = distribution, metabolization and elimination absorption phase
Pharmacokinetics : Notion of area under the curve Plasma concentratio n Time Plasma peak C max T max MIC The larger the area below the serum concentration curve, the better the impregnation of the organ by the antibiotic
Pharmacokinetics = criteria of choice of an antibiotic  maximum absorption,  tissue diffusion at the site of the infection +++,  intra-cellular diffusion +++,  elimination in non-toxic active form via the kidney or the bile depending on the infection,  long half-life.
Criteria of choice of an antibiotic  Bacteriology  Pharmacokinetics  Type of patient  Side effects  Compliance  Ecology  Economy Major criteria Secondary criteria
Bacteriology 106
1. The B-LACTAMS
Mechanism of action Beta lactam antibiotics inhibit cell wall synthesis by binding to the Penicillin Binding Proteins (PBP’s) on the outer surface of the cytoplasmic membrane. Once they bind to these PBP’s / enzymes, they stop the process of cell wall formation / division or replication (depending on the PBP affected).
Mechanism of bacterial resistance Bacteria can resist the action of beta lactam antibiotics in 3 main ways:  Potential production of beta lactamase enzymes that will hydrolyse (destroy) the beta lactam ring of the antibiotic (mainly a problem with 1st generation penicillins and cephalosporins against gram negative bacteria – the beta lactamase enzymes can be concentrated in the periplasmic space)  Potential for porin channels in gram-negative bacteria to resist entry to some types of beta lactam antibiotics by altering their electrochemical charge  Potential for alteration of the target binding sites (Penicillin binding proteins may change so the antibiotics cannot attach themselves to the site. Alternatively the bacteria may produce alternate PBP's’ that the antibiotic will bind to – the new PBP’s serve as decoys and have no function in cell wall synthesis – this is a significant problem with many gram positive bacteria and some gram negative bacteria)
Examples :  Staphylococcus aureus  Haemophilus influenzae  Moraxella catarrhalis  Escherichia coli Bacterial resistance: a / Production of enzymes : b Lactamases Resistance can be transmitted with plasmids
Bacterial resistance: b/ Impermeability Outer membrane Cytoplasmic membrane Pores too narrow ? Only concerns Gram -
Bacterial resistance: c/ Modification of the target PBP Modification of the PBP -↑ in number MIC ↑ - In structure
1- Betalactams: USE  Penicillins G: - rheumatic fever - gonorrhoea - syphilis  Penicillins V : - strepto tonsillitis  Penicillins M: - skin infections  Penicillins A : - ENT, broncho-pulmonary, urinary  C 1 G : - ENT, broncho-pulmonary  C 2 G : - ENT, broncho-pulmonary, urinary  C 3 G : - ENT, broncho-pulmonary, urinary
2. THE AMINOGLYCOSIDES
Mode of action  Interfere with protein synthesis and may form transient holes in a cell wall to disrupt the permeability function.
Mechanism of bacterial resistance  Bacteria may defend themselves against aminoglycosides by some combination of three mechanisms:  Enzymatic modification: The bacteria has the potential to modify the chemical structure of the aminoglycoside prior to it reaching the ribosomes. The alteration renders the antibiotic useless by a process of ATP-dependent phosphorylation of a hydroxy group or acetylation of an amino group (enzymes break down the structure of the antibiotic)  Alteration in uptake: Potential alterations in the electrochemical charge in the outer membrane will not allow the aminoglycoside to gain entry  Altered ribosomal binding sites: This is the least common method that bacteria may develop resistance. A mutation will alter the binding site so that an aminoglycoside will not recognise the appropriate target area on the ribosome. Examples: Gentamicin, Neomycin, Streptomycin, and Amikacin.
3. THE TETRACYCLINES
TETRACYCLINES: Mode of action On the ribosomes: fraction 30 S Inhibition of protein synthesis bacteriostatic
Mechanism of resistance  There are 3 main resistance mechanisms:  Decreasing the influx into the bacterial cell: The gram-negative bacteria may alter the outer membrane charge to prevent entry to some tetracyclines  Increasing the efflux of the antibiotic out of the cell: Once inside the cell some bacteria have developed mechanisms that act as pumps to export the antibiotic from the cytoplasm before it can exert its mechanism of action  Alteration of the ribosomal binding site: Some bacteria may alter the ribosomal binding site so that the antibiotic will have no target to affect. Examples: Tetracyclines: Doxycycline (Doryx, Vibramycin), Minocycline
TETRACYCLINES: Spectrum Doxycyclin, minocyclin, tetracyclin. Cocci - Gonococcus Miscellaneous Bacillus - Chlamydia, Mycoplasma, Haemophilus, Brucella, Treponema, Borellia, Vibrio cholerae Rickettsia, Leptospires Anaerobes +) P. acnes
TETRACYCLINES : USES  Brucellosis  Acne  STD
4. The QUINOLONES
Mode of action  Interfere with the synthesis of DNA (gyrase and topoisomerase IV)
QUINOLONES : Mode of action On the DNA INHIBITION of DNA synthesis bactericidal the bacterium can no longer multiply, or live.
Mechanism of resistance Bacteria acquire resistance to quinolones by 2 methods:  Spontaneously occurring mutations in chromosomal genes that either alter the target enzymes or DNA  Alteration of the drugs permeation across bacterial cell membranes Examples: Ciprofloxacin (Ciproxin), Moxifloxacin (Avalox), Ofloxacin (Oflocet), Grepafloxacin (new molecule)
Bacterial resistance: Modification of the target of the antibiotic Modification of the DNA
FLUOROQUINOLONES: Spectrum Ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, ofloxacin Cocci + Cocci - Staphylococcus Gonococcus Meningococcus Bacillus - E.coli, Proteus vulgaris Klebsielle (IS), Salmonella Citrobacter (IS), P.mirabilis Campylobacter, Pseudomonas aeruginosa(IS), Serratia (IS). Intracellular, Mycoplasma () Legionella Chlamydia,Rickettsia Haemophilus, S P E C T R U M W I D E
QUINOLONES: USES  1st generation: urinary infections  Fluoroquinolones : » high and low urinary infections, prostatitis » STD caused by Gonococci, Chlamydia, Mycoplasma » Atypical pneumonia caused by Legionella, Chlamydia, Mycoplasma » Digestive infections: salmonellosis, typhoid fever  Aminofluoroquinolones: » pneumopathies, superinfections of chronic bronchitis » acute purulent sinusitis
5. MACROLIDES
Mode of action  Binds to the 50S ribosomal subunit resulting in blockage of transpeptidation. (Binds to ribosome to stop amino acid chains – proteins being produced inside the bacteria).
MACROLIDES : Site of action On the ribosomes: fraction 50 S Inhibition of protein synthesis Dependent on concentration in situ bactericidal bacteriostatic Inhibition of translocase
Mechanism of resistance Bacteria can develop resistance to macrolides in two ways:  Promotion of efflux pumps within the cell to expel the antibiotic prior to exerting the mechanism of action. Some of these bacteria will remain susceptible if higher doses are given.  Alteration in the ribosomal target binding site. Changing the target for the antibiotic so that it has no binding potential. Examples: Erythromycin, Roxithromycin (Rulide) and Clarithromycin
Bacterial resistance: Modification of the target of the antibiotic Ribosomes
MACROLIDES : Spectrum  erythromycin, azithromycin, clarithromycin, dirithromycin Cocci + Cocci - Staphylococcus Meti S Gonococcus Gr A b hemolytic streptococcus Meningococcus Pneumococcus(IS) Moraxella Intracellular Bacillus + Mycoplasma Listeria, diphtheria B. Chlamydia, Legionella Bacillus - Helicobacter, Vibrio cholerae Anaerobes: (+) Clostridium perfringens, P. acnes, Peptostreptococcus., Actinomyces. Protozoan Toxoplasma
6. KETOLIDES: Site of action On the ribosomes: fraction 50 S • Stops protein synthesis, then bacterial lysis 2 components act in synergy: • the first binds to the bacterial ribosome, • the 2nd then binds in turn
KETOLIDES: telithromycin  Cocci + Cocci - Staphylococcus Gonococcus Streptococci Meningococcus Streptococcus D (Enterococcus)(IS) Moraxella Pneumococcus Intracellular Chlamydia, Legionella, Bacillus + Mycoplasma C.diphteriae. , Listeria Anaerobes Bacillus - (-) Bacteroides Haemophilus
KETOLIDES TOXICITY : 0 to + + occasional hepatic toxicity SIDE EFFECTS : + to + + occasional hepatic toxicity RESISTANCE : + to + + + CONTRA-INDICATIONS : + + PHARMACOKINETICS :  BIOAVAILABILITY : 40 to 80%  TISSUE DIFFUSION : very good  ELIMINATION : biliary in active or inactive form
KETOLIDES  ENT: tonsillitis, sinusitis  broncho-pulmonary: typical and atypical pneumonia, bronchitis
7. SULFONAMIDES Mode of action On DNA INHIBITION of synthesis of folic acid bacteriostatic the bacterium no longer multiplies
7. SULFONAMIDES: spectrum Cocci + Bacillus - Streptococcus(IS) E. coli, Proteus, Citrobacter Pneumococcus(IS) Salmonella, Shigella, Staphylococci (IS) Haemophilus, Bacillus + Serratia (IS), Klebsiella (IS) Listeria Enterobacter (IS) Protozoans Miscellaneous Pneumocystis corini Vinbrio cholerae Toxoplasma*
SULFONAMIDES  Trimethoprime + Sulfamethoxazole........
8. NITRO-IMIDAZOLES Mode of action On DNA Attacks the DNA Bactericidal
8. NITRO-IMIDAZOLES : Spectrum  e.g. Metronidazole (Flagyl) Anaerobes Protozoans Bacteroïds Trichomonas vaginalis Fusobacterium Giardia lamblia Clostridium Entamoeba histolitica Peptostreptococcus (IS) Peptococcus (IS) + Helicobacter pylori
Intrinsic and Acquired Resistance  Intrinsic resistance - Intrinsic resistance means that the bacterium has always been resistant to a particular antibiotic or that particular antibiotic has no intrinsic activity against the bacterium. For example, E.coli has intrinsic resistance to Rulide and Chlamydia has intrinsic resistance to Amoxycillin.  Acquired resistance - Acquired resistance means that the bacteria used to be sensitive to a particular antibiotic but it has now developed a mechanism to prevent the antibiotic from killing it. It’s a bit like Charles Darwin’s theory of evolution, in that only those organism that are able to evolve in order to survive will be around in the future. MRSA has acquired resistance to Methicillin, H.flu has acquired resistance to amoxycillin.
Mechanisms of resistance transfer
Which drug to choose ? b Lactams ? Macrolide ? Cocci + ?
Bacteriology 147 Sunsheroosugata@yahoo.com you can find me if you need me

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2010 for ninaa

  • 1.
  • 2.
  • 3.
    Grouping (Micro-organisms) Micro-organisms canbe divided into 4 important groups:  1. Bacteria  2. Protozoa  3. Fungi  4. Viruses
  • 4.
    Bacteria  Size: variabledepending on the species.  Nucleus: no. Mass of DNA without nuclear membrane, formed by a single chromosome.  Cell wall: yes, formed of liposaccharides and lipoproteins DEFINITIONS
  • 5.
    Bacteria Bacteria are smallsingle celled organisms that are not visible to the naked eye and have a very primitive structure.
  • 6.
    Microscopic parasites or Protozoan Kingdom : animal,  Nucleus : true,  Example : Entamoeba histolytica = Ameba Amebiasis
  • 7.
    Protozoa Protozoa (eg amoeba)are more complex than bacteria in structure.
  • 8.
    Fungi  Kingdom: vegetable, Size : a few microns,  Nucleus : true.  2 types : yeasts and dermatophytes  Example of yeasts : Candida albicans Mycosis
  • 9.
    FUNGI Fungi resemble primitiveplants and live on dead organic matter they can exist as single cells (yeast) or as many cells (called mycelium)
  • 10.
    Virus  Size: between20 and 200 millimicrons (visible under the electron microscope),  Nucleus : no. Nucleic acid core (DNA or RNA) contained in an envelope (capsid).  They invade the human, bacterial, plant or animal cells to survive Example : Myxovirus = Flu virus
  • 11.
    VIRUSES Viruses are thesmallest and simplest of all organisms and can only be seen with powerful electron microscopes. Viruses cannot multiply by themselves and so have to invade host cells to allow multiplication.
  • 12.
    Bacterial structure  ConstantElements : Bacterial "nucleus" = chromosomic DNA Cell wall Cytoplasmic membrane Cytoplasm Ribosomes (synthesis of proteins and nutritive reserves of the bacterium)
  • 13.
     Optional elements: Bacterial structure Pili (tissue binding, transmission of plasmids) Plasmid (DNA fragments carrying genes of resistance) Flagella (motility) Capsule (resistance to phagocytosis)
  • 14.
     Characteristics ofall bacteria:  All bacteria possess 5 basic components: - Cell wall - Cytoplasmic membrane - Cytoplasm - Ribosomes - Nuclear material  Some bacteria possess: - Flagella - Pili - Capsules
  • 16.
  • 17.
  • 18.
    BACTERIOLOGY : Identification ofthe bacterium ? Metabolism .. .. .. .. .. .. .. .. .. ..
  • 19.
     Bacterial classification Difficultyin classification: Unlike higher organisms, bacteria lack sufficient variations in structure upon which normal classifications can be made. Basic criteria Most of the systems developed to classify bacteria utilise these diagnostic criteria - Shape (morphology) and culture characteristics - Staining – Gram Stain - Culturing and biochemical tests - Growth requirement for oxygen; i.e. aerobic or anaerobic
  • 20.
    Shapes of bacteria 1.Identification by shape
  • 21.
  • 22.
  • 23.
  • 24.
  • 25.
  • 27.
    Gram staining Gram +Gram - BACTERIOLOGY : 2. Identification staining the cell wall External membrane Peptidoglycane Cytoplasmic membrane Pores PBP Optional capsule
  • 28.
    BACTERIOLOGY: 3. Identification bymetabolism  METABOLISM Strict aerobe Aero-anaerobe Strict anaerobe (use oxygen to metabolise glucose) (use fermentation to metabolise glucose) .. .. ..
  • 29.
    BACTERIOLOGY: Synthesis / Identification Shape Cocci Bacillus StainGram + Gram - Bacillus + Bacillus - Cocci + Cocci -
  • 30.
    BACTERIOLOGY: Classification of Bacteria Anaerobes Cocci Bacillus + + - -  Aerobes Cocci Bacillus + + - -
  • 31.
     Genus : HaemophilusStreptococcus  Species : influenzae para influenzae pneumo- b hemolytic group B coccus group A group C group D etc.  Serotypes : a, b, c, d, etc etc. 23F,9, 6,14 etc. (+ of 80 different serotypes) (+ of 80 different serotypes)  The bacterial strain is a colony resulting from a sample and a particular serotype, obtained from sucessive subcultures ("clones"). BACTERIOLOGY: Concept of bacterial strain
  • 32.
    Aerobic Pathogens COCCI + •Staphylococcus: – aureus – epidermidis • Streptococcus: – S. pneumoniae – S. group A b hemolytic – S. group B – S. viridans – S. group D = S. foecalis COCCI - • Neisseriae: – meningitidis – gonorrhae • Moraxella catarrhalis
  • 33.
    BACILLI + • Corynebacterium diphteriae •Listeria monocytogenes • Haemophilus influenzae • Pseudomonas aeruginosa • Vibrio cholerae • Brucella • Acinetobacter • Helicobacter • Mycobacteria Aerobic Pathogens BACILLI - ENTEROBACTERIA: • Escherichia coli • Proteus • Serratia • Klebsiella • Enterobacter • Citrobacter • Salmonella • Shigella • Yersinia
  • 34.
    COCCI + • Peptococcus •Peptostreptococcus COCCI - • Veillonella BACILLI + • Clostridium : – C. difficile – C. botulinum – C. perfringens – C. tetani • Propionobacterium – Corynebacterium acnes BACILLI- • Bacteroides fragilis • fusobacterium Anaerobic Pathogens
  • 35.
    Pathogens with intra-cellular development •Mycoplasmae : – Mycoplasma pneumoniae • Chlamydiae : – Chlamydia pneumoniae • Legionella • Rickettsiae Miscellaneous pathogens Spirochaetas • Treponema pallidum • Theptospires • Mycobacterium tuberculosis (KB)
  • 36.
    DEFINITIONS  INFECTION = Asequence of repercussions which result in an attack on a living organism by a ± virulent pathogen. Endogen or exogen Infection involves 3 actors : PATHOGEN HOST THERAPY
  • 37.
    DEFINITIONS INFECTION 2 types ofclinical sign: Typical symptoms Local symptoms The symptoms indicate the illness and the pathogen responsible. An organ is suffering. Experience points to a pathogen.
  • 38.
    Streptococcus pneumoniae Gram +Cocci  HABITAT: Commensal (organism that derives food or other benefits from another organism without hurting or helping it (50 % of individual carriers, and more in winter).  PATHOGENIC POWER: Very virulent (capsule), – leader as regards mortality of bacterial origin, – responsible for the majority of cases of acute lobar pneumonia, otitis, adult meningitis, sinusitis
  • 39.
    Gr A bhemolytic streptococcus Gram + Cocci  HABITAT: Strictly human bacterium. Commensal  PATHOGENIC POWER: Very virulent (capsule, toxin etc.), responsible for ENT (tonsillitis, otitis etc.) and cutaneous infections (impetigo, erysipelas etc.) COMPLICATIONS: rheumatic fever, glomerulonephritis, endocarditis
  • 40.
    Staphylococcus aureus Gram +Cocci  HABITAT: Human, soil, air, water.  PATHOGENIC POWER: Very virulent (capsule, toxins, enzymes, etc.), responsible for cutaneous, osseous, pulmonary and cerebral infections, and for superinfection after severe burns. Responsible for septicemia and endocarditis.
  • 41.
    Haemophilus Influenzae Gram -Bacillus  HABITAT: Flora of upper respiratory tract. 75% of children under 5 are healthy carriers.  PATHOGENIC POWER: 35 to 50% of otitis, sinusitis, rhinopharyngitis, superinfection of chronic bronchitis or of viral illnesses. Meningitis and septicemia are due to encapsulated forms (H.i.b.). A vaccine against encapsulated Haemophilus exists. The vaccination must be performed at the age of 3 to 4 months with a booster at 14 or 16 months to be effective.
  • 42.
    Moraxella catarrhalis Gram -Cocci  HABITAT: Commensal of the respiratory mucus.  PATHOGENIC POWER: Superinfection of chronic bronchitis, otitis, sinusitis
  • 43.
    Neisseriae gonorrhoeae Gram -Cocci  HABITAT: Human parasite  PATHOGENIC POWER: Blennorrhagia, salpingitis, pharyngeal gonococci
  • 44.
    Salmonella Gram - Bacillus(enterobacteria)  HABITAT: Parasite of the human and animal digestive tract. Contamination by oral route.  PATHOGENIC POWER:  Digestive forms : Toxi-infections (gastro-enteritis)  Septicemic forms : Typhoid (S.typhi) or paratyphoid (S.paratyphi) fever The septicemic forms can become complicated (pulmonary, meningeal, osseous, digestive infections etc
  • 45.
    Shigella Gram - Bacillus(enterobacteria)  HABITAT: Human digestive tract. Contamination through food, or water contaminated with fecal matter.  PATHOGENIC POWER: Infectious colitis, gastro-enteritis (children). Bacillary dysentery (army on march).
  • 46.
    Escherichia Coli Gram -Bacillus (enterobacteria)  HABITAT: Normally found in human digestive tract.  PATHOGENIC POWER:  Intestinal infections: Infectious diarrhea  Urinary infections: Responsible in up to 90%  Abdominal infections: Peritonitis, salpingitis, cholecystitis  Meningeal infections: Meningitis in infants or elderly patients
  • 47.
    Mycoplasma pneumoniae  HABITAT:Micro-organisms without cell wall, intracellular or associated to cells; vegetable, animal, and human parasite.  PATHOGENIC POWER:  Atypical pneumonia : Young adults, particularly in fall and winter.
  • 48.
    Intracellular Chlamydia  HABITAT: Strictintracellular parasite of small size.  3 SPECIES: Chlamydia pneumoniae Chlamydia psittaci Chlamydia trachomatis  TREATMENT: Macrolides, fluoroquinolones  Non specific urethritis (50% of cases)  Post-gonococcal urethritis (20 to 60% of cases)  Cervicitis, salpingitis, rectitis  Pneumonias in newborn babies  Conjunctivitis in newborn babies and adults
  • 49.
    Intracellular Legionella pneumophila  HABITAT:Bacterium of the environment (lake water, air conditioning). The entry port for the infection is pulmonary.  PATHOGENIC POWER:  Acute pneumonia: pseudo-flu state, dry cough, gastro- intestinal disorders etc. Especially in debilitated subjects of + 50 ans (tabacco, alcohol, immunodepression) Pathology fatal without treatment: 20% of cases
  • 50.
    • Specific pathogenic bacterium •Opportunistic pathogenic bacterium .. The different types of pathogenic bacteria
  • 51.
    What are theopportunities for a bacterium to become pathogenic ? Migration Immunodepression Antibiotic Physiological change ..
  • 52.
    1/ Endogenous infectiousillness = rupture of the bacterial ecosystem (saprophyte flora) and proliferation of a bacterial species. 2/ Exogenous infectious illness =  penetration of pathogens within  proliferation the organ  How do they proliferate?  How are they pathogenic?  How do they penetrate? How is bacterial infection or pathogenesis triggered?
  • 53.
    1/ How dothey proliferate? In favorable environments : • in presence or in absence of oxygen, • in presence of nutrients and space, • humidity, • optimal temperature By mitosis
  • 54.
    2/ How arethey pathogenic ? Pathogenic power or "Virulence"  2 principal factors of virulence 1. Invasion + or - rapid 2. Toxicity Secretion of sometimes fatal toxins S S S S S S S S S S S SS S S S S S Exotoxins Endotoxins
  • 55.
    Other factors ofbacterial virulence Bacterium Host Pili Capsule Enzymes - extreme age - weakened general state, - iatrogenic factors , - entry port: wound or surgery.
  • 56.
    3/ How dothey penetrate ? The entry ports Skin Mucus Respiratory tract Digestive tract
  • 57.
    Program of bacterial "excursions" Surface infection: the pathogens multiply on the surface of mucus,  Infectious site: the pathogens multiply in the tissues close to the entry port,  Targeting of organ: tropism relative to certain organs,  Bacteriemia: passage of pathogens into the blood or the lymph system with no morbid effect,  Septicemia: massive passage of pathogens into the blood Infestation of the whole organism, multiple sites of infection.
  • 58.
    How does thehuman organism defend itself ?  1st line: • Physical resources, • Chemical resources, • Bacteriological resources,  After introduction: • Non specific reaction: inflammatory reaction, • Specific reaction: immune system immune reaction .. .. .. .. .. .. .. .. .. .. .... .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .... .. .. .. .. .. .. .. .. .. ..
  • 59.
    1/ A hermeticbarrier = the skin Sebaceous gland Sweat Sebum Sweat gland Keratinous cells
  • 60.
    2/ A physico-chimiquebarrier = the mucus Hairs Mucus Lysozyme Transferrine (Igs)
  • 61.
    3/ A bacteriologicalbarrier: the saprophyte flora .. .. .. .. .. .. .. .. .. .. .... .. .. .. .. .. .. .. .. .. .. Stop infection .. .. .. .. .. .. .. .. .. .. .... .. .. .. .. .. .. .. .. .. .. Down with pathogens e.g.: Lactobacillus, Doderlein's bacilli in the vagina
  • 62.
    Vulvo-vaginal flora • Lactobacilli, •Staphylococcus, • Streptococcus, • Bacteroides, • Peptostreptococcus Skin : Cutaneous flora • Staphylococcus, • Streptococcus, • Corynebacterium, • Fungi. 3/ A bacteriological barrier : the saprophyte flora Oro-pharyngeal flora : Mouth - nose - throat • Staphylococcus, • Streptococcus, • Peptococcus, • Peptostreptococcus, • Fusobacterium, • Bacteroides Intestinal flora • Lactobacilli, • Bifidobacterium, • Bacteroides, • Clostridium, • Colibacille, • Proteus, • Streptococcus, • Staphylococcus, • Yeasts
  • 63.
    What if thethreshold is crossed ?
  • 64.
    1/ The nonspecific inflammatory reaction 1/ VASODILATATION 2/ PLASMA LEAK . . . . . . 3/ FORMATION OF FIBRINE MESH 4/ PHAGOCYTOSIS
  • 65.
    1/ The nonspecific inflammatory reaction : PHAGOCYTOSIS Two types of phagocytary cells:  Polynuclear  Macrophages 1/ Chemotaxis 2/ Adhesion 3/ Invagination 4/ Digestion
  • 66.
    2/ The specificimmune reaction LYMPHOCYTES = immunocompetent cells B T Action on contact Circulating antibodies Humoral immunity Cellular immunity
  • 67.
    2/ The specificimmune reaction Marrow and Thymus lymph vessels and glands blood vessels Production of lymphocytes Transport by During infection the glands swell and become painful (adenopathy).
  • 68.
    A- The humoralimmune reaction . . . . B B Specific antigen-antibody reaction . . . . . T4 PP PP PP PP Plasmocytes antibodies
  • 69.
    A- The humoralimmune reaction . . . . B B . . . . T4 Bm Memorization = Immunity acquired The lymphocytes which are not transformed into plasmocytes producing antibodies keep the antigen and the antibody fabrication mode in memory.
  • 70.
    B- The cellularimmune reaction . . . . T . . . T4 T Te Te Te Tm Memory T4 lymphocytes T lymphocyte "effectors"
  • 71.
    The immune reaction:the T4 T4 T B Humoral immunity Cellular immunity B lymphocyte secreting remote antibody Cytotoxic T lymphocyte Preponderant role of T4
  • 72.
  • 73.
    If the infectionis triggered despite the defenses...  What is its origin ? What type of treatment?  viral ? antiviral  parasite ? antiparasite  bacterial ? antibiotics  mycotic ? antifungal  Infections can be mixed: bacteria + fungi.  The infections can be successive: bacterial superinfection of an infection of viral origin
  • 74.
    What is bacterial superinfection? "Thevirus prepares the bacterium's nest." Alteration of healthy cells by the virus Tissue lesions Inflammatory Inflammatory tissue response pathology Disturbance of functions (e.g. cold) + Alteration of defense mechanisms Invasion by bacteria Bacterial superinfection Aggravation of tissue lesions
  • 76.
     Definition: An antibioticis a substance produced by micro- organisms, or which can be reproduced synthetically, which possesses the property of destroying bacteria or of inhibiting the growth of bacteria. Study of an ANTIBIOTIC
  • 77.
    Mechanism of action Processinhibition by antibiotics. Antibacterial agents act by effecting one or more of the following processes taking place inside bacterial cells:  The synthesis of the cell wall.  The functioning of the cell membrane  The synthesis of proteins  The synthesis of nuclear material (DNA)  Metabolic transformations
  • 78.
    Study of an antibiotic ChemicalMode Effects Spectrum Indications Pharmacokinetics structure of action & toxicity
  • 80.
     Spectrum ofactivity This is the range of bacteria that are sensitive to the antibiotic (inhibited or killed) Study of an antibiotic Cocci + Cocci - Bacillus + Bacillus - Cocci + Narrow spectrum Broad spectrum
  • 81.
     Activity :determined in laboratory in a number of ways: Antibiogram Dilution method by diffusion with disks on agar Study of an antibiotic Several antibiotics can be studied at the same time One antibiotic can be studied at a time
  • 82.
     Activity :determined by identifying the MIC and MBC for each common pathogen  MIC = Minimum Inhibiting Concentration the minimum concentration of antibiotic capable of stopping the culture of a given strain in a medium Study of an antibiotic X quantity of germs in the inoculum X quantity of germs after culture
  • 83.
     MBC =Minimum Bactericidal Concentration the minimum antibiotic concentration destroying 99.99 % of a bacteria population after 18 hours of contact at 37° Study of an antibiotic X quantity of germs in the inoculum < 1 pathogen alive out of 10 000
  • 84.
    Dilution method: determining theMIC MIC = Minimum Inhibiting Concentration the minimum concentration of antibiotic capable of stopping all culture of a given strain in a medium (37° for 24 hours) MIC Control 0,25 0,50 1 2 4 8 16 32 mg/ml
  • 85.
    Dilution method: determining theMBC 4 8 16 32 mg/ml Culture from an MIC tube on agar MBC T1 T2 T3 T4 T1 T2 T3 T4
  • 86.
    MBC 1/10 000 =10 102 105 104 103 106 107 108 109 2 4 6 8 10 12 14 18 8 mg 4 mg 2 mg 1 mg 0,5 mg Control 0,25 mg Number of bacteria / ml Time (hours) Inoculum MBC MIC C o n c. of A B T
  • 87.
  • 88.
    Agar diffusion method:THE ANTIBIOGRAM 5 antibiotics tested Inhibition diameter 37° for a period of 18 hours
  • 89.
  • 90.
  • 91.
    THE ANTIBIOGRAM the laboratoryresponse A B C A: Sensitive B: Moderately sensitive C : Resistant
  • 92.
    Study of anantibiotic  Pharmacokinetics : study of the behavior and fate of an antibiotic in the organ from administration to elimination AbsorptionMetabolization Diffusion Elimination
  • 93.
     Pharmacokinetics are dependenton the route of administration Oral Parenteral I.M. I.V.
  • 94.
     Pharmacokinetics Absorption Distribution orDiffusion Elimination Metabolization
  • 95.
     Pharmacokinetics: definitions •absorption: % of the dose of active principle administered passing through the intestinal mucus into the blood. • metabolization: the transformation of the active principle into active or inactive metabolite, principally in the liver. • effect of first hepatic passage: presence of hepatic metabolism. • bioavailability: the result of the previous 2 criteria; the % of the quantity of active principle administered arriving in the blood stream.
  • 96.
    Pharmacokinetics : example administration via oral route of 100 mg of active principle,  absorption = 80 % 80 mg,  metabolization (hepatic first pass) = 20 % into inactive metabolite 16 mg, 64 mg will reach the target Bioavailability will therefore be 64 %
  • 97.
    Pharmacokinetics : definitions distribution or diffusion: passage of the active compound from the blood stream into the tissues (site of the infection ?).  binding to plasma proteins: % of the active compound circulating binding to proteins. Plasma protein TRANSPORTER
  • 98.
    Pharmacokinetics: distribution  Passageinto the CSF: Not all the products reach the C.N.S.  Passage through the placenta barrier: Harmful effects on fetus ?
  • 99.
    Pharmacokinetics: elimination biliary routerenal route active form inactive form active form other routes = pulmonary, cutaneous, salivary, lacteous etc.
  • 100.
    Pharmacokinetics: The plasma concentrationcurve Plasma concentration Time Plasma peak C max T max Drug
  • 101.
    Pharmacokinetics : The plasmaelimination 1/2 life Plasma concentration Time Plasma peak C max T max T / 2 C / 2 1/2 life elimination phase = distribution, metabolization and elimination absorption phase
  • 102.
    Pharmacokinetics : Notion ofarea under the curve Plasma concentratio n Time Plasma peak C max T max MIC The larger the area below the serum concentration curve, the better the impregnation of the organ by the antibiotic
  • 103.
    Pharmacokinetics = criteria ofchoice of an antibiotic  maximum absorption,  tissue diffusion at the site of the infection +++,  intra-cellular diffusion +++,  elimination in non-toxic active form via the kidney or the bile depending on the infection,  long half-life.
  • 104.
    Criteria of choiceof an antibiotic  Bacteriology  Pharmacokinetics  Type of patient  Side effects  Compliance  Ecology  Economy Major criteria Secondary criteria
  • 106.
  • 107.
  • 108.
    Mechanism of action Betalactam antibiotics inhibit cell wall synthesis by binding to the Penicillin Binding Proteins (PBP’s) on the outer surface of the cytoplasmic membrane. Once they bind to these PBP’s / enzymes, they stop the process of cell wall formation / division or replication (depending on the PBP affected).
  • 109.
    Mechanism of bacterialresistance Bacteria can resist the action of beta lactam antibiotics in 3 main ways:  Potential production of beta lactamase enzymes that will hydrolyse (destroy) the beta lactam ring of the antibiotic (mainly a problem with 1st generation penicillins and cephalosporins against gram negative bacteria – the beta lactamase enzymes can be concentrated in the periplasmic space)  Potential for porin channels in gram-negative bacteria to resist entry to some types of beta lactam antibiotics by altering their electrochemical charge  Potential for alteration of the target binding sites (Penicillin binding proteins may change so the antibiotics cannot attach themselves to the site. Alternatively the bacteria may produce alternate PBP's’ that the antibiotic will bind to – the new PBP’s serve as decoys and have no function in cell wall synthesis – this is a significant problem with many gram positive bacteria and some gram negative bacteria)
  • 110.
    Examples :  Staphylococcusaureus  Haemophilus influenzae  Moraxella catarrhalis  Escherichia coli Bacterial resistance: a / Production of enzymes : b Lactamases Resistance can be transmitted with plasmids
  • 111.
    Bacterial resistance: b/ Impermeability Outermembrane Cytoplasmic membrane Pores too narrow ? Only concerns Gram -
  • 112.
    Bacterial resistance: c/ Modificationof the target PBP Modification of the PBP -↑ in number MIC ↑ - In structure
  • 113.
    1- Betalactams: USE  PenicillinsG: - rheumatic fever - gonorrhoea - syphilis  Penicillins V : - strepto tonsillitis  Penicillins M: - skin infections  Penicillins A : - ENT, broncho-pulmonary, urinary  C 1 G : - ENT, broncho-pulmonary  C 2 G : - ENT, broncho-pulmonary, urinary  C 3 G : - ENT, broncho-pulmonary, urinary
  • 114.
  • 115.
    Mode of action Interfere with protein synthesis and may form transient holes in a cell wall to disrupt the permeability function.
  • 116.
    Mechanism of bacterialresistance  Bacteria may defend themselves against aminoglycosides by some combination of three mechanisms:  Enzymatic modification: The bacteria has the potential to modify the chemical structure of the aminoglycoside prior to it reaching the ribosomes. The alteration renders the antibiotic useless by a process of ATP-dependent phosphorylation of a hydroxy group or acetylation of an amino group (enzymes break down the structure of the antibiotic)  Alteration in uptake: Potential alterations in the electrochemical charge in the outer membrane will not allow the aminoglycoside to gain entry  Altered ribosomal binding sites: This is the least common method that bacteria may develop resistance. A mutation will alter the binding site so that an aminoglycoside will not recognise the appropriate target area on the ribosome. Examples: Gentamicin, Neomycin, Streptomycin, and Amikacin.
  • 117.
  • 118.
    TETRACYCLINES: Mode of action Onthe ribosomes: fraction 30 S Inhibition of protein synthesis bacteriostatic
  • 119.
    Mechanism of resistance There are 3 main resistance mechanisms:  Decreasing the influx into the bacterial cell: The gram-negative bacteria may alter the outer membrane charge to prevent entry to some tetracyclines  Increasing the efflux of the antibiotic out of the cell: Once inside the cell some bacteria have developed mechanisms that act as pumps to export the antibiotic from the cytoplasm before it can exert its mechanism of action  Alteration of the ribosomal binding site: Some bacteria may alter the ribosomal binding site so that the antibiotic will have no target to affect. Examples: Tetracyclines: Doxycycline (Doryx, Vibramycin), Minocycline
  • 120.
    TETRACYCLINES: Spectrum Doxycyclin, minocyclin,tetracyclin. Cocci - Gonococcus Miscellaneous Bacillus - Chlamydia, Mycoplasma, Haemophilus, Brucella, Treponema, Borellia, Vibrio cholerae Rickettsia, Leptospires Anaerobes +) P. acnes
  • 121.
  • 122.
  • 123.
    Mode of action Interfere with the synthesis of DNA (gyrase and topoisomerase IV)
  • 124.
    QUINOLONES : Mode ofaction On the DNA INHIBITION of DNA synthesis bactericidal the bacterium can no longer multiply, or live.
  • 125.
    Mechanism of resistance Bacteriaacquire resistance to quinolones by 2 methods:  Spontaneously occurring mutations in chromosomal genes that either alter the target enzymes or DNA  Alteration of the drugs permeation across bacterial cell membranes Examples: Ciprofloxacin (Ciproxin), Moxifloxacin (Avalox), Ofloxacin (Oflocet), Grepafloxacin (new molecule)
  • 126.
    Bacterial resistance: Modification ofthe target of the antibiotic Modification of the DNA
  • 127.
    FLUOROQUINOLONES: Spectrum Ciprofloxacin, gatifloxacin, gemifloxacin,levofloxacin, moxifloxacin, ofloxacin Cocci + Cocci - Staphylococcus Gonococcus Meningococcus Bacillus - E.coli, Proteus vulgaris Klebsielle (IS), Salmonella Citrobacter (IS), P.mirabilis Campylobacter, Pseudomonas aeruginosa(IS), Serratia (IS). Intracellular, Mycoplasma () Legionella Chlamydia,Rickettsia Haemophilus, S P E C T R U M W I D E
  • 128.
    QUINOLONES: USES  1stgeneration: urinary infections  Fluoroquinolones : » high and low urinary infections, prostatitis » STD caused by Gonococci, Chlamydia, Mycoplasma » Atypical pneumonia caused by Legionella, Chlamydia, Mycoplasma » Digestive infections: salmonellosis, typhoid fever  Aminofluoroquinolones: » pneumopathies, superinfections of chronic bronchitis » acute purulent sinusitis
  • 129.
  • 130.
    Mode of action Binds to the 50S ribosomal subunit resulting in blockage of transpeptidation. (Binds to ribosome to stop amino acid chains – proteins being produced inside the bacteria).
  • 131.
    MACROLIDES : Site ofaction On the ribosomes: fraction 50 S Inhibition of protein synthesis Dependent on concentration in situ bactericidal bacteriostatic Inhibition of translocase
  • 132.
    Mechanism of resistance Bacteriacan develop resistance to macrolides in two ways:  Promotion of efflux pumps within the cell to expel the antibiotic prior to exerting the mechanism of action. Some of these bacteria will remain susceptible if higher doses are given.  Alteration in the ribosomal target binding site. Changing the target for the antibiotic so that it has no binding potential. Examples: Erythromycin, Roxithromycin (Rulide) and Clarithromycin
  • 133.
    Bacterial resistance: Modification ofthe target of the antibiotic Ribosomes
  • 134.
    MACROLIDES : Spectrum  erythromycin,azithromycin, clarithromycin, dirithromycin Cocci + Cocci - Staphylococcus Meti S Gonococcus Gr A b hemolytic streptococcus Meningococcus Pneumococcus(IS) Moraxella Intracellular Bacillus + Mycoplasma Listeria, diphtheria B. Chlamydia, Legionella Bacillus - Helicobacter, Vibrio cholerae Anaerobes: (+) Clostridium perfringens, P. acnes, Peptostreptococcus., Actinomyces. Protozoan Toxoplasma
  • 135.
    6. KETOLIDES: Site ofaction On the ribosomes: fraction 50 S • Stops protein synthesis, then bacterial lysis 2 components act in synergy: • the first binds to the bacterial ribosome, • the 2nd then binds in turn
  • 136.
    KETOLIDES: telithromycin  Cocci +Cocci - Staphylococcus Gonococcus Streptococci Meningococcus Streptococcus D (Enterococcus)(IS) Moraxella Pneumococcus Intracellular Chlamydia, Legionella, Bacillus + Mycoplasma C.diphteriae. , Listeria Anaerobes Bacillus - (-) Bacteroides Haemophilus
  • 137.
    KETOLIDES TOXICITY : 0to + + occasional hepatic toxicity SIDE EFFECTS : + to + + occasional hepatic toxicity RESISTANCE : + to + + + CONTRA-INDICATIONS : + + PHARMACOKINETICS :  BIOAVAILABILITY : 40 to 80%  TISSUE DIFFUSION : very good  ELIMINATION : biliary in active or inactive form
  • 138.
    KETOLIDES  ENT: tonsillitis,sinusitis  broncho-pulmonary: typical and atypical pneumonia, bronchitis
  • 139.
    7. SULFONAMIDES Mode ofaction On DNA INHIBITION of synthesis of folic acid bacteriostatic the bacterium no longer multiplies
  • 140.
    7. SULFONAMIDES: spectrum Cocci+ Bacillus - Streptococcus(IS) E. coli, Proteus, Citrobacter Pneumococcus(IS) Salmonella, Shigella, Staphylococci (IS) Haemophilus, Bacillus + Serratia (IS), Klebsiella (IS) Listeria Enterobacter (IS) Protozoans Miscellaneous Pneumocystis corini Vinbrio cholerae Toxoplasma*
  • 141.
  • 142.
    8. NITRO-IMIDAZOLES Mode ofaction On DNA Attacks the DNA Bactericidal
  • 143.
    8. NITRO-IMIDAZOLES : Spectrum e.g. Metronidazole (Flagyl) Anaerobes Protozoans Bacteroïds Trichomonas vaginalis Fusobacterium Giardia lamblia Clostridium Entamoeba histolitica Peptostreptococcus (IS) Peptococcus (IS) + Helicobacter pylori
  • 144.
    Intrinsic and AcquiredResistance  Intrinsic resistance - Intrinsic resistance means that the bacterium has always been resistant to a particular antibiotic or that particular antibiotic has no intrinsic activity against the bacterium. For example, E.coli has intrinsic resistance to Rulide and Chlamydia has intrinsic resistance to Amoxycillin.  Acquired resistance - Acquired resistance means that the bacteria used to be sensitive to a particular antibiotic but it has now developed a mechanism to prevent the antibiotic from killing it. It’s a bit like Charles Darwin’s theory of evolution, in that only those organism that are able to evolve in order to survive will be around in the future. MRSA has acquired resistance to Methicillin, H.flu has acquired resistance to amoxycillin.
  • 145.
  • 146.
    Which drug tochoose ? b Lactams ? Macrolide ? Cocci + ?
  • 147.