Pharmacology - Bacterial Disease and Antibiotics

Bacteremia

bacteria in the blood stream

Sepsis

bacteremia with toxins causing systemic symptoms/signs

What is this referring to

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

• Oxygen requirements – aerobic or anaerobic

• Shape

  • Coccus (pl-cocci) - spherical

  • Bacillus (pl-bacilli) – rod-like

  • Spirochete (pl- “-s”) – spiral

• Environment – intracellular or extracellular

• Atypical

Different classifications of bacteria (prokaryotes)

What cell envelop components are found in both gram-positive and gram-negative bacteria

cytoplasmic membrane and cell wall

What bacteria (gram pos or neg) have a thicker cell wall and outer membrane

gram negative

What maintains bacterial shape and protects it from osmotic lysis if it is placed in a hypotonic medium

Cell wall

________ are more active against rapidly dividing bacteria than they are against bacteria in the resting or stationary phase

Drugs that inhibit cell wall synthesis

What reduces the effectiveness of cell wall inhibitors

concurrent administration of bacteriostatic antibiotics that slow the growth of bacteria

What is – hair-like projections on the bacterial surface

• Adhere to cells

• Invade tissue

• Adhere to other bacteria

Pili (aka fimbria)

What is —- rotary, whip-like extension

• Mobility

• Adhesion

Flagella

What proteins which aid in breeching the cell’s defenses

Enzymes

What – protect the bacteria from immune system

capsule

What – dormant and highly resistant (unaffected by heat,

Spores

What has a – slimy matrix secreted by bacteria to protect from immune system

Biofilm

What poisons cells

Toxins

What is this referring to

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

Endotoxin

What is 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

Exotoxin

What is this referring to

• Enzymes – such as proteases which digest plasma proteins

• Capsules – prevent phagocytosis

• Horizontal gene transfer- bug to bug

  • Bacteriophages –viruses

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

• Biofilm – organized extracellular slime of matrix and bacteria+fungi

  • Implanted devices, teeth, epithelium

Mechanisms of evasion

What is this referring to

• Enzymatic inactivation or modification of drug

• Decreased drug uptake or accumulation

• Altered or lack of target receptor site

• Circumvention of drug action sequences

major mechanism of bacterial antimicrobial resistance

What is this referring

• Beta-lactamase hydrolysis of beta-lactam ring

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

Enzymatic inactivation or modification of drug

What is this referring to

• Lack of outer membrane permeability (intrinsic or acquired)

• Faulty or lacking antibiotic uptake and transport systems

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

Decreased drug uptake or accumulation

What is this referring to

• Altered PBP’s (beta-lactam resistance)

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

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

Altered or lack of target receptor site

What is this referring to

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

Circumvention of drug action sequences

What is it called when the antibiotic exerts its killing effect as long as the concentration remains above the mic

• Ex: beta-lactams and vancomycin

Interval dependent killing (time dependent killing)

What is 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

• Ex: Aminoglycosides and fluoroquinolones

Concentration dependent killing

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

  • Digestive aids

  • Prevents excessive overgrowth of dangerous bacteria

  • Synthesis of essential metabolites

Commensals

Microorganisms that do not usually produce disease in healthy individuals, but are involved in human infections when the host’a immune 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.

Opportunists

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

True pathogens

What does this refer to

• Determine the site of infection

• Evaluate host characteristics (age, immunocompromise, comorbidities)

• Determine most likely causative bacteria

General antibiotic principles for diagnosis

What is this referring to

• Prophylactic

• Empiric

• Definitive

General antibiotic principles for treatment

Prophylactic

prevention

Empiric

best educated guess, based on clinical presentation and probable organism

Definitive

targeted, based on cultures and sensitivities

What is this referring to

• Susceptible

• Intermediate

• Resistant

MIC – Minimum inhibitory concentration (concentration that inhibits visible bacterial growth @ 24 hr.)

MBC (Minimum bactericidal concentration)

concentration that results in 1,000-fold reduction in bacterial density @ 224 hr

Bioavailability

difference between IV and PO routes

What 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

Bacteriostatic

What 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)

Bactericidal

Almost all Abx potentiate (increase the power) of ________ (a vitamin K antagonist anticoagulant) by inhibiting vitamin K producing intestinal flora

Warfarin

What bind cations (Mg, Ca) in the gut (antibiotic interactions)

Flouroquinolones

What interaction can lower efficacy of oral contraceptives

antibiotics (interaction)

What causes allergic reactions

• Rashes, hives

Hypersensitivity reactions

Adverse drug reactions

Abx are most common drugs to cause life-threatening immune-mediated reactions

To prevent antibiotic reactions, one must avoid ______

drugs in the same class (PCN and beta-lactams)

What is this referring to

Gram + aerobe

• Most virulent of the staph species

• Produce penicillinases (beta-lactamases)—MSSA

  • May still use penicillinase stable beta-lactams: methicillin or cephalosporins

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

Staphylococcus aureus

What is the following

• Furunculosis (“boils”)

  • Pyogenic suppurative lesion

  • Infection of the hair follicle or seat gland

  • Stye

• Carbuncles

• Bullous impetigo

• Paronychia

• Deep tissue infections

  • Osteomyelitis

  • Bacterial pneumonia

  • endocarditis

Staphylococcal infections

What is the following

• Ritter’s disease (scalded skin syndrome)

• Toxic shock syndrome

• Staphylococcal food poisoning

Diseases caused by staphylococcal toxins

What is this referring to

• —”incomplete hemolysis”

  • Strep pneumoniae: usually ”diplococcus” – has polysaccharide capsules

  • Strep viridans: grows in chains; usually commensal

    • Doesn’t usually cause infection but if it does mouth and nasopharynx usually involved

Alpha hemolysis

What is this referring to

• —”complete hemolysis”

  • Strep pyogenes

  • Strep agalactiae

Beta hemolysis

What is this referring to “non-hemolytic”

Gamma hemolysis

What are grown on sheep’s blood agar producing three patterns of hemolysis around the colonies

Streptococci (brown groups)

What is this referring to

• Most common pathogens

  • Viruses

  • Strep pyogenes (15%) or other hemolytic strep

  • Arcanobacterium hemolyticum

  • Neisseria gonorrhea

  • Chlamydia pneumoniae

  • Epstein-barr virus

Pharyngitis (streptococcal diseases)

What is this referring to

• Upper respiratory infections

  • Sinusitis

  • Otitis media

• Impetigo

  • Strep is most common cause

  • May see staph aureus as a secondary invader

• Erysipelas

• Wound and burn infections

• Scarlet fever

• Immunologic sequellae

  • Rheumatic fever

  • Acute glomerulonephritis

• Cellulitis

• Necrotizing fasciitis

• Pneumococcal meningitis

Streptococcal diseases

What is this referring to

• Gram +

  • E. faecalis***

  • E. faceium***

• Normal inhabitants of GI tract

• Able to survive harsh conditions

• Typically very resistant

  • Vancomycin resistant enterococcus (VRE)

  • Must usually treat synergistically

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

Enterococcus

What is this referring to

• Cannot thrive in the presence of oxygen

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

Anaerobes

What is this referring to

• Anaerobe that produces toxins that cause other effects; spore forming

  • C. botulinum

  • C. tetani

  • C. perfringens

  • C. difficile***

Clostridia

What is this referring to

• Aka “gram negative rods”, aerobes

• 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

Enteric bacilli (Enterobacteriaceae)

What is this referring to

• Normal flora

• Gram negative aerobe

• Most common cause of urinary tract infections

• Causes opportunistic infections

• Diarrheagenic

• Caution: septic shock (lipopolysaccharide)

E. coli

What is this referring to

• Gram negative aerobes

• Virulence

  • Endotoxin

  • Flagella

  • Urease production

• Resistance

  • Some beta lactamase production

• Disease

  • UTI’s – cystitis and pyelonephritis

  • urolithiasis

Proteus mirabilis

What is this referring to

• 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

Pseudomonas aeruginosa

What is this referring to

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

  • 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

        • Also known to be producers of Carbapenemases (KPC)

        • Can be extremely resistant microbes

Extended Spectrum Beta-Lactamase (ESBL)

What is this referring to

• Beta-Lactams

  • Penicillins

  • Cephalosporins

  • Carbapenems

• Vancomycin

Cell Wall Inhibitors (antibiotics)

What is this referring to

• Tetracyclines

• Fluoroquinolones

• Macrolides

• Aminoglycosides

• Folate Inhibitors

Protein Synthesis Inhibitors (Antibiotics)

What binds to a group of bacterial enzymes, the PBPs (PCN binding proteins)

• inhibit cross-linking of peptidoglycan

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

B-Lactam Drugs

What is 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

Penicillin Binding Proteins (PBPs)

What includes penicillin G and penicillin V

Narrow-spectrum penicillins

What includes oxacillin, cloxacillin, dicloxacillin, & nafcillin

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

• Rarely used unless confirmation of MSSA for step down therapy

Penicillinase-resistant penicillins

What includes 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

Extended-spectrum penicillins

What are adverse effects of B-Lactam Drugs

• 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

What is this referring to

Penicillin (beta lactam ring plus a thiazolidine ring)

What is this referring to

Penicilloic Acid

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

Ampicillin

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.

B-Lactam Drugs Adverse Effects

What can be confirmed by the use of commercial preparations of ____ antigens.

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

Penicillin allergy

What is this referring to

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

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

Penicillin

Penicillin in association with C. difficile superinfections can cause

Pseudomembranous collitis

What is this referring to

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

• Is the only oral B-Lactamase 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.

Clavulanic acid/Clavulanate

What B-Lactamase Inhibitor is used with ampicillin (Unasyn)

• parenteral

Sulbactam

What B-Lactamase Inhibitor is used with piperacillin (Zosyn) and ticarcillin (Timentin)

• parenteral

Tazobactam

What is this referring to

• 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 (B-Lactam Drugs)

What have good activity against most streptococci and methicillin-sensitive staphylococci; also a few gram-negative enteric bacilli, including E. coli and Klebsiella pneumoniae

What has similar activity against gram-positive cocci with increased activity against gram-negative bacilli.

Second-generation cephalosporins (Ceclor, Cefzil, Ceftin)

What has a greater activity against a wider range of gram-negative organisms, including enteric gram-negative bacilli (Enterobacteriaceae), H. influenzae, and M. catarrhalis

Third-generation cephalosporins (Rocephin, Vantin)

What is active against many gram-negative bacilli, including Citrobacter freundii and Enterobacter cloacae, that are resistant to other cephalosporins

Cefepime (Maxipime) has been called a fourth-generation cephalosporin

What generation of cephalosporins is used for UTI, mild skin or soft tissue infections, otitis media, upper and lower respiratory tract infections

1st generation cepahlosporins

What generation of cephalosporins is used for Sinusitis, otitis media, lower respiratory tract infections

2nd generation cephalosporins

What generation of cephalosporins is used for Meningitis, febrile neutropenia, community acquired pneumonia

3rd generation cephalosporins

What generation of cephalosporins is used for Meningitis, febrile neutropenia, pneumonia, nosocomial infections

4th generation cephalosporins

What generation of cephalosporins is used for resistant infections

5th generation

What generation of cephalosporins does this belong to

• Cefadroxil (Duracef) - oral

• Cefazolin (Ancef)**- IV

• Cephalexin (Keflex)**- oral

• Cephapirin – IV

• Cephradine - oral

1st generation cepahlosporins

What generation of cephalosporins does this belong to

• Cefaclor (Ceclor)**- oral

• Cefamandole (Mandol)- IV

• Cefotetan (Cefotan)- IV

• Cefoxitin (Mefoxin)- IV

• Cefprozil (Cefzil)- oral

• Cefuroxime (Ceftin)**- oral, IV

• Cefmetazole - IV

2nd generation cepahlosporins

What generation of cephalosporins does this belong to

• 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

3rd generation cepahlosporins

What generation of cephalosporins does this belong to

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

  • Gram-positive: similar activity against Gram + organisms as 1st generation cephs

  • Gram-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

4th generation cepahlosporins

What generation of cephalosporins does this belong to

• ceftobiprole (Zeftera)

  • Advantage is activity against MRSA, pseudomonas and Enterococci

• Ceftaroline (Teflaro)

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

5th generation cepahlosporins

What does this refer to

• Although can elicit hypersensitivity reactions, the incidence of this is lower than for penicillins.

• ________ exhibit some cross-sensitivity with penicillins, and about 5% of persons allergic to penicillin will also be allergic to cephalosporins.

• Persons who have had a mild hypersensitivity reaction to penicillin usually do not cross-react to a _______; a severe hypersensitivity reaction to penicillin (e.g., an anaphylactic reaction) has a greater risk of cross-reacting and should usually not be given a _________.

Cephalosporins

What does this refer to

• Aztreonam (Azactam) is a monocyclic β-lactam (monobactam) antibiotic.

• Active against many aerobic gram-negative bacilli, including strains of Enterobacter, Citrobacter, Klebsiella, and Proteus species as well as P. aeruginosa.

• IV for very serious infections

• Aztreonam can cause hypersensitivity reactions and thrombophlebitis.

• Only rarely shows cross-sensitivity with penicillins and cephalosporins, and can usually be used in persons allergic to other β-lactam antibiotics

Monobactam (B-Lactam Drugs)

What does this refer to

• ________ is a monocyclic β-lactam (monobactam) antibiotic.

• ________ can cause hypersensitivity reactions and thrombophlebitis.

Aztreonam

What does this refer to

• Bactericidal to a wide range of gram-positive and gram-negatives , including many aerobic and anaerobic gram-negative bacilli

• Resistant to most beta-lactamases and are the drugs of choice for infections caused by ESBLs- extended spectrum beta-lactamases

• Covers Streptococcus, Staphylococcus, Enterococcus, Listeria, Gram negatives, and anaerobes; All cover Pseudomonas except Ertapenem

Carbapenems

What B-Lactam drugs can cause seizures

Imipenem

What is the Drug of Choice for the treatment for respirator-associated and/or aspiration nosocomial pneumonia in the ICU (DOC for Enterobacter & Serratia)

Meropenem