Bacterial Disease and Antibiotics Pharmacology exam 1

•Different classifications of bacteria (prokaryotes)

•Gram stain - Gram + (purple) or Gram - (pink) based on membrane constituents

Classification of bacteria in terms of oxygen

aerobic or anaerobic

Classification of bacteria based on shape

•Coccus (pl-cocci) - spherical

•Bacillus (pl-bacilli) - rod-like

•Spirochete (pl- "-s") - spiral

Classification of bacteria based on environment

•intracellular or extracellular

Bacteremia

•bacteria in the blood stream

Sepsis

•bacteremia with toxins causing systemic symptoms/signs

Cell envelope and wall

•Cell Envelope has 2 components that are found in both gram-positive and gram-negative bacteria:

•cytoplasmic membrane

•cell wall

Difference between gram - and gram + in term of cells wall

•The cell wall is much thicker in gram-positive bacteria than it is in gram-negative bacteria

Difference between in terms of outer membrane

The envelope of gram-negatives has an outer membrane not found in other types of bacteria

When do cells wall is synthesized?

synthesized during bacterial replication, and drugs that inhibit cell wall synthesis are more active against rapidly dividing bacteria than they are against bacteria in the resting or stationary phase

When Effectiveness of cell wall inhibitors is usually reduced?

by concurrent administration of bacteriostatic antibiotics that slow the growth of bacteria

•Virulence factors OF BACTERIA

1-PILI

2-Flagella

3-Enzymes

4-CApsule

5-Spores

6-Biofilm

7-Toxins

Pili

•(aka fimbria) - hair-like projections on the bacterial surface

•Adhere to cells

•Invade tissue

•Adhere to other bacteria

Flagella

•rotary, whip-like extension

•Mobility

•Adhesion

Enzymes

•proteins which aid in breeching the cell's defenses

Capsules

•protect the bacteria from immune system

Spores

•dormant and highly resistant (unaffected by heat,

Biofilm

•slimy matrix secreted by bacteria to protect from immune system

Toxins

• poisons cells

Bacterial Toxins

Endotoxin

Exotoxin

Endotoxin (aka lipopolysaccharide)

•part of the cell wall of Gram-bacteria which may be released during growth or antibiotic treatment

•Good news - at low levels, helps stimulate immune reaction

•Bad news - at high levels, cause release of cytokines and activate clotting cascade

Exotoxin

•produced inside bacteria and secreted

•The bad news is there is no good news.

•May damage cell walls

•Or enter cells and change their function

•Examples:

Botulinum toxin

Coagulases

Exfoliative

Enterotoxins

Bacterial Pathogenesis - Evasion

•Necessary to the bacteria so that they may multiply which causes disease

•Mechanisms of evasion

Enzymes

capsules

horizontal

biofilm

•Mechanisms of evasion ( ENZYMES)

•such as proteases which digest plasma proteins

Mechanisms of evasion ( Capsules)

•prevent phagocytosis

Mechanisms of evasion ( Horizontal gene transfer- bug to bug)

•Bacteriophages -viruses

•Plasmids - nonchromosome DNA that move between bacteria by conjugation (fusion with pili)

Mechanisms of evasion ( Biofilm)

•organized extracellular slime of matrix and bacteria+fungi

•Implanted devices, teeth, epithelium

Major mechanisms of bacterial antimicrobial resistance

1- •Enzymatic inactivation or modification of drug

2-•Decreased drug uptake or accumulation

3-•Altered or lack of target receptor site

4-•Circumvention of drug action sequences

What is Enzymatic inactivation or modification of drug?

•Beta-lactamase hydrolysis of beta-lactam ring

•Modification of aminoglycosides by acetylating, adenylating, or phosphorylating enzymes

what •Decreased drug uptake or accumulation?

•Lack of outer membrane permeability (intrinsic or acquired)

•Faulty or lacking antibiotic uptake and transport systems

•Antibiotic efflux system (e.g. tetracycline resistance)

how do bacteria Altered or lack of target receptor site?

•Altered PBP's (beta-lactam resistance)

•Altered ribosomal target (aminoglycoside, macrolides, etc.)

•Altered enzymatic target (sulfa, trimethoprim, rifampin, quinolones)

How do bacteria Circumvention of drug action sequences?

•Hyperproduction of drug targets or competitive substrates (Bactrim resistance)

Killing properties of antibiotics

1-Interval dependent killing (time dependent killing)

2- Concentration dependent killing

Interval dependent killing (time dependent killing)—

•the antibiotic exerts its killing effect as long as the concentration remains above the mic

•Eg: beta-lactams and vancomycin

Concentration dependent killing

The antibiotic continues to exert its killing effect after the concentration has fallen below the bacteria's mic (post antibiotic effect). The higher the peak, the greater the killing effect

Aminoglycosides and fluoroquinolones

The Body Invaders: Friend or Foes?Friends

Commensals

Commensals

•Nonpathogenic microorganisms adapted to grow on body surfaces of the host, forming part of the normal flora

•Body surfaces

•Skin (staph epidermidis, diptheroids)

•Mucous membranes (e. coli, klebsiella)

•Function of commensals

•Digestive aids

•Prevents excessive overgrowth of dangerous bacteria

•Synthesis of essential metabolites

The Body Invaders: Friends or Foes:Frenemies

•Opportunists

•Opportunists

•Microorganisms that do not usually produce disease in healthy individuals, but are involved in human infections when the host'a immunwe system is weakened or compromised

•Transient visitors of the throat

•Strep pneumoniae, Group a strep, neisseria meningitidis, hemophilus influenzae, klebsiella pneumoniae

•Normal residents of the GI tract

•Escherichia coli, klebsiella pneumoniae, citrobacter fruendii, etc.

The Body Invaders: Friends or Foes?Foes

•True pathogens

•True pathogens

•Microorganisms that can produce disease or tissue damage by their mere presence regardless of the condition of the host

•Staphylococcus aureus

•Salmonella typhi, S. enteriditis

•Treponema pallidum

•Mycobacterium tuberculosis

•Shigella

General Antibiotic Principles

Diagnostic

Treatment

•Diagnosis

•Determine the site of infection

•Evaluate host characteristics (age, immunocompromise, comorbidities)

•Determine most likely causative bacteria

•Treatment

•Prophylactic=Prevention

•Empiric=best educated guest ,based on clinical presentation

•Definitive= Targget ,based on cultures and sensitivity

•Minimum inhibitory concentration

•Susceptible

•Intermediate

•Resistant

MBC

•Minimum bactericidal concentration

Bioavailability

•difference between IV and PO routes

Bacteriostatic

prevents growth of bacteria (remain in stationary phase and doesn't replicate)

•Usually by inhibiting protein synthesis (sulphonamides, TCN, macrolides)

•Require the host's immune system to clear the infection

Bactericidal

•actively kills bacteria

•Primarily act on the cell wall (beta-lactams) or cell membrane (daptomycin)

•Necessary in severe (endocarditis), life-threatening (sepsis), or hard to cure infections (osteomyelitis)

How all Abx potentiate the effects of warfarin?

by inhibiting vitamin K producing intestinal flora

Possible lower efficacy of oral contraceptives

Flouroquinolones bind

Cations ( Mg,Ca) in the gut.

Antibiotic Reactions

1- •Hypersensitivity reactions - allergic reactions

2-•Adverse drug reactions - Abx are most common drugs to cause life-threatening immune-mediated reactions

3-•Must avoid any drugs in the same class ( Example : PCN and Beta-lactams)

Staphylococcus aureus

Gram + aerobe

•Most virulent of the staph species

•Produce penicillinases (beta-lactamases)—MSSA: •May still use penicillinase stable beta-lactams: methicillin or cephalosporins

Role of MRSA

Alters the penicillin binding protein (or omits it from chromosomal coding

•Beta-lactams will not work

•Must use antibiotics with a different mechanism of action (ie vancomycin)

Disease associate with staphylococcus aureus

skin and soft tissue infections (abscesses), pneumonia (mostly hospital acquired)

Staphylococcal infections

1-•Furunculosis ("boils")

2-•Carbuncles

3-Bullous impetigo

4-Paronychia

5-Deep tissue infections (•Osteomyelitis

•Bacterial pneumonia

•endocarditis)

what are Diseases caused by staphylococcal toxins?

•Ritter's disease (scalded skin syndrome)

•Toxic shock syndrome

•Staphylococcal food poisoning

Streptococcus •Brown groups

-•Streptococci are grown on sheep's blood agar producing three patterns of hemolysis around the colonies

-•Alpha hemolysis—"incomplete hemolysis"(strep pneumonia -strep viridians)

-•Beta hemolysis—"complete hemolysis"( Strep pyogenes -strep agalactiae)

-Gamma hemolysis—"non-hemolytic

Steptococcal diseases ( •Pharyngitis)

Most common pathogens:

•Viruses

•Strep pyogenes (15%) or other hemolytic strep

•Arcanobacterium hemolyticum

•Neisseria gonorrhea

•Chlamydia pneumoniae

•Epstein-barr virus

Steptococcal diseases(Upper respiratory infections )

•Sinusitis

•Otitis media

Impetigo

•Strep is most common cause

•May see staph aureus as a secondary invader

Streptococcal diseases

Erysipelas

Wound and burn infections

Scarlet fever

Immunologic sequellae

•Rheumatic fever

•Acute glomerulonephritis

Cellulitis

Necrotizing fasciitis

Pneumococcal meningitis

Enterococcus

•Gram +

•E. faecalis***

•E. faceium***

•Opportunistic organisms capable of causing UTI's wound infections, endocarditis

•Normal inhabitants of GI tract

•Able to survive harsh conditions

Enterococcus

Enterococcus typically very resistant to

•Vancomycin resistant enterococcus (VRE)

•Must usually treat synergistically

Anaerobes

•Cannot thrive in the presence of oxygen

•Do not contain enzymes to defend against oxygen—peroxidase, catalase, superoxide dismutase

Gram negative aerobes

Enteric bacilli (Enterobacteriaceae):

•Aka "gram negative rods"

•Large, diverse group of gram negative rods found in nature and as part of the normal flora of man and animals

•Opportunistic pathogens but some are specifically pathogenic (e. coli)

•E.coli is the most prominent of this group followed by klebsiella and proteus

•True pathogens include: salmonella, shigella, e. coli, yersinia

E coli*

•Normal flora

•Most common cause of urinary tract infections

•Causes opportunistic infections

•Diarrheagenic

•Caution: septic shock (lipopolysaccharide)

Klebsiella pneumoniae

•Virulence

•Endotoxin

•Capsule

•Antimicrobial resistance

•Beta lactamase production among others

Diseases

•Pneumonia

•Urinary tract infections

bacteremia

Proteus mirabilis*

•Virulence

•Endotoxin

•Flagella

•Urease production

•Resistance

•Some beta lactamase production

•Disease

•UTI's - cystitis and pyelonephritis

•urolithiasis

Pseudomonas aeruginosa***

•Multiple antibiotic resistance mechanisms—extremely challenging to treat

•Harbored in moist environments—hot tubs, swimming pools

•Common secondary infection with cystic fibrosis

•Diseases

•Pneumonia

•Burn wound infections—typically cause a black/green discoloration

•Endocarditis

•Otitis externa

•Osteomyelitis

UTI's—cystitis and pyelonephritis

•Clostridia-Anaerobes —produce toxins that cause other effects; spore forming

•C. botulinum

•C. tetani

•C. perfringens

•C. difficile***

Type of gram-negative aerobes

Pseudomonas aeruginosa

Proteus mirabilis

Klebsiella pneumoniae

E coli

Enteric bacilli

•Enteric bacilli (Enterobacteriaceae)*

•Aka "gram negative rods"

•Large, diverse group of gram negative rods found in nature and as part of the normal flora of man and animals

•Opportunistic pathogens but some are specifically pathogenic (e. coli)

•E.coli is the most prominent of this group followed by klebsiella and proteus

•True pathogens include: salmonella, shigella, e. coli, yersinia

•E coli*

•Normal flora

•Most common cause of urinary tract infections

•Causes opportunistic infections

•Diarrheagenic

•Caution: septic shock (lipopolysaccharide)

Klebsiella pneumoniae

Virulence

•Endotoxin

•Capsule

Antimicrobial resistance

•Beta lactamase production among others

Diseases

•Pneumonia

•Urinary tract infections

•bacteremia

Proteus mirabilis

Virulence

•Endotoxin

•Flagella

•Urease production

•Resistance

Some beta lactamase production

Disease

•UTI's - cystitis and pyelonephritis

•urolithiasis

Pseudomonas aeruginosa

•Multiple antibiotic resistance mechanisms—extremely challenging to treat

•Harbored in moist environments—hot tubs, swimming pools

•Common secondary infection with cystic fibrosis

Pseudomonas aeruginosa disease

•Pneumonia

•Burn wound infections—typically cause a black/green discoloration

•Endocarditis

•Otitis externa

•Osteomyelitis

•UTI's—cystitis and pyelonephritis

Extended Spectrum Beta-Lactamase (ESBL)

•A type bacterial resistance due to the production of an enzyme or chemical capable of destroying most beta-lactam antibiotics

ESBL

•Typically seen in gram negative microbes

•Often due to exposure to broad spectrum antibiotics (those covering lots of gram negative organisms)

•Bacteria which produce ESBL's are part of the multi-drug resistant organisms (MDRO's)

Common exhibitors of ESBL:

•E.coli

•Pseudomonas aeruginosa

•Proteus mirabilis

•Klebsiella pneumonia

Antibiotics cell wall inhibtors

Beta-Lactams

•Penicillins

•Cephalosporins

•Carbapenems

Vancomycin

Antibiotics Protein Synthesis Inhibitors

Tetracyclines

Fluoroquinolones

Macrolides

Aminoglycosides

Folate Inhibitors

β-Lactam Drugs : SITES OF DRUG ACTION

β-Lactam Drugs: bind to a group of bacterial enzymes, the PBPs (PCN binding proteins)

•PBPs are responsible for the assembly, maintenance, and regulation of the peptidoglycan portion of the bacterial cell wall- Creates a lattice meshwork that provides structure and stability to the microbe

•Each bacterial species has a set of unique PBPs to which particular β-lactam antibiotics bind with varying affinities

β-Lactam Drugs

Penicillins are grouped according to their antimicrobial activity:

/Narrow-spectrum penicillins include penicillin G & penicillin V

/Penicillinase-resistant penicillins include oxacillin, cloxacillin, dicloxacillin, & nafcillin

-Good treatment option for Methicillin-Sensitive Staph Aureus (MSSA)

-Rarely used unless confirmation of MSSA for step down therapy

/Extended-spectrum penicillins include amoxicillin, ampicillin, piperacillin, and ticarcillin.

-Amoxicillin and Ampicillin are often used for gram positive infections and mild gram-negative infections

-Piperacillin and Ticarcillin have activity against Pseudomonas

Penicillinase resistant penicilins "CONDOM"

Cloxacilin

Oxacilin

Nafcilin

Dicloxacilin

Methicilin

Anti-pseudomonal Penicilin

Piperacilin

Ticarcilin

Carbenicillin

β-Lactam Drugs - adverse effects

•Penicillins are a common cause of drug-induced hypersensitivity reactions.

•True penicillin allergy occurs in only 7% to 23% of patients who give a history of penicillin allergy.

•Hypersensitivity reactions occur when penicillin is degraded to penicilloic acid and other compounds that combine with body proteins to form antigens that elicit antibody formation.

β-Lactam Drugs:adverse effects : An immediate hypersensitivity reaction

which is a type of reaction mediated by Ig E, can lead to urticaria (hives) or anaphylactic shock. Other types of hypersensitivity reactions can lead to serum sickness, interstitial nephritis, hepatitis, and various skin rashes.

•Ampicillin is likely to cause a maculopapular skin rash with certain viral infections, such as mononucleosis (mediated by sensitized lymphocytes). Its incidence in ampicillin-treated patients with mononucleosis is over 90%

β-Lactam Drugs : Penicillin allergy

can be confirmed by the use of commercial preparations of penicillin antigens.

•These preparations contain the major or minor antigenic determinants of penicillin that are formed in the body during penicillin degradation.

•Injected intradermally and cause erythema at the injection site in allergic persons.

•Should be administered by personnel who are prepared to provide treatment for anaphylactic shock in the event that the patient develops a severe hypersensitivity reaction

β-Lactam Drugs others apects

•Except for hypersensitivity reactions, the penicillins are remarkably nontoxic to the human body and produce very few other adverse effects.

•Penicillins can disturb the normal flora of the gut and produce diarrhea and superinfections with penicillin-resistant organisms, such as staphylococci and Clostridium difficile.

•Pseudomembranous colitis can occur in association with C. difficile superinfections.

Shouldnt give antibodies to person with mononucleosis

True

What effet of penicillin in the normal gut

disturb-produce diarrhea and superinfections with penicillin-resistant organisms, such as staphylococci and Clostridium difficile.

such as Pseudomembranous colitis can occur in association with C. difficile superinfections

β-Lactamase Inhibitors

-•Clavulanic acid - has little IF ANY antimicrobial effects itself but is used on beta-lactamase producing microbes to tie up enzymes (serve as surrogate substrates)

•Claulanic acid/Clavulanate is the only oral inhibitor

•Effective on H. influenza, N. gonorrheae, E. coli, Salmonella, Shigella, Staphylococcus, Klebsiella, Bacteroides fragilis, and Legionella.

Does not inhibits beta-lactamases from Enterobacter, Serratia, Morganella, Citrobacter, Pseudomonas, & Acinetobacter

-•Sulbactam - used with ampicillin (Unasyn)=Parental

-•Tazobactam - used with piperacillin (Zosyn) and ticarcillin (Timentin)= Parental

β-Lactam Drugs: Cephalosporins

•One of the largest and most widely used groups of antibiotics; four generations ; semisynthetic drugs

•First-generations are primarily active against gram-positive cocci and a few gram-negative bacilli.

•Subsequent generations have increased activity against gram-negative bacilli and less activity against some species of gram-positive cocci.

Cephalosporins

•First-generation cephalosporins (Keflex), have good activity against most streptococci and methicillin-sensitive staphylococci; also a few gram-negative enteric bacilli, including E. coli and Klebsiella pneumoniae

•Second-generation cephalosporins (Ceclor, Cefzil, Ceftin) have similar activity against gram-positive cocci with increased activity against gram-negative bacilli.

•Third-generation cephalosporins (Rocephin, Vantin) have greater activity against a wider range of gram-negative organisms, including enteric gram-negative bacilli (Enterobacteriaceae), H. influenzae, and M. catarrhalis

•Cefepime (Maxipime) has been called a fourth-generation cephalosporin because it is active against many gram-negative bacilli, including Citrobacter freundii and Enterobacter cloacae, that are resistant to other cephalosporins

Cephalosporins 1st- 5th generation

1st generation—UTI, mild skin or soft tissue infections, otitis media, upper and lower respiratory tract infections

2nd generation—Sinusitis, otitis media, lower respiratory tract infections

3rd generation—Meningitis, febrile neutropenia, community acquired pneumonia

4th generation—Meningitis, febrile neutropenia, pneumonia, nosocomial infections

5TH generation—RESISTANT INFECTIONS

1st generation

•Cefadroxil (Duracef) - oral

•Cefazolin (Ancef)**- IV

•Cephalexin (Keflex)**- oral

•Cephapirin - IV

•Cephradine - oral

2nd generation

•Cefaclor (Ceclor)**- oral

•Cefamandole (Mandol)- IV

•Cefotetan (Cefotan)- IV

•Cefoxitin (Mefoxin)- IV

•Cefprozil (Cefzil)- oral

•Cefuroxime (Ceftin)**- oral, IV

•Cefmetazole - IV

3rd generation

•Cefdinir (Omnicef)**- oral

•Cefditoren (Spectracef)**-oral

•Cefixime (Suprax)- oral

•Cefotaxime (Claforen)- IV

•Cefpodoxime (Vantin)- oral

•Ceftazidime (Fortaz)**- IV

•Ceftizoxime (Cefizox)- IV

•Ceftriaxone (Rocephin)- IV

•Cefoperazone (Cefobid) - IV

•Ceftibuten (Cedax) - oral

4th generation

Cefepime (Maxipime)**, Cefluprenam, cefozopran, cefpirome

•Gram-positive: similar activity against Gram + organisms as 1st generation cephsGram-negative: have a greater resistance to beta-lactamases than 3rd generation cephs. Many can cross the BBB and are effective in meningitis. Effective against pseudomonas aeruginosa

5th GENERATION

ceftobiprole (Zeftera)

• Advantage is activity against MRSA, pseudomonas and Enterococci

Ceftaroline (Teflaro)

•Broad spectrum coverage against gram+ and gram - esp. MRSA & VRSA