Lecture 17: Cell Wall Inhibitors

definition of communicable

passes from source to host

most common pathogens

• staphylococcus

• streptococcus

• pseudomonas

• clostridium difficile

• E. coli/salmonella

where on the body are bacterial flora abundant

• skin

• external ocular surface

• nasal mucosal tissue

• oral cavity

• GI pathway

• colon, rectal pathway

• vaginal tissue

gram stain and shape of staph aureus

gram positive

cocci

gram stain and shape of staph epidermidis

gram positive

cocci

gram stain and shape of strep

gram positive

cocci

gram stain and stain of cornyebacterium

gram positive

bacilli

gram stain and shape of haemophilus influenzae

gram negative

coccobacilli

gram stain and shape of pseudomonas aeruginosa

gram negative

bacilli

four most common species causing bacterial keratitis

1. staphylococcus aureus

2. staphylococcus epidermidis

3. streptococcus pneumoniae

4. pseudomonas aeruginosa

common ocular infections optometrists manage

• blepharitis

• hordeolum

• conjunctivitis

• microbial keratitis

• cellulitis

• endophthalmitis

what are the major pathogens responsible for chronic blepharitis

staph epidermidis

staph aureus

what are the most common sources of infection following anterior segment surgery

methicillin-resistant staphylococcus aureus

methicillin-resistant staphylococcus epidermidis

what is strep pneumoniae associated with

• cold climates

• perforates in 7 days

• associated with superficial and deeper skin infections (cellulitis)

what is pseudomonas aeruginosa associated with

• common in hot tubs

• patients on ventilators

• burn patients and contact lens wearers

destroys the cornea within 48 hours

what is the #1 source of nosocomial (hospital) infections

pseudomonas aeruginosa

what should be checked first before treating pediatric conjunctivitis

• check history

• check ears

• check throat

• check temperature

what is the common cause of pediatric conjunctivitis

hemophilus influenzae

what inherit risk factors make neonates at higher risk of conjunctivitis

• decreased tear production

• lack of IgA in tears

• decreased immune function

• absence of lymphoid tissue in conjunctiva

• decreased lysozyme activity

what controllable risk factors make neonates at higher risk for conjunctivitis

• prolonged delivery

• prematurity

• poor prenatal care

• maternal STI

• mechanical ventilation

• poor hygiene conditions

plan of action for neonatal conjunctivitis

always an emergency

treat presumptively as infectious

always culture to rule out neisseria

neonatal conjunctivitis with an onset of 24 hours or less after birth is likely what type

chemical

• previously used silver nitrate drops prophylactically medicines

• erythromycin now more commonly used

neonatal conjunctivitis with an onset between 24-48 hours after birth is likely what type

neisseria gonorrhea is most common within 48 hours

staphylcoccus aureus

neonatal conjunctivitis with an onset between 5 to 14 days after birth is likely what type

chlamydia trachomatis

most common!

neonatal conjunctivitis with an onset between 6 to 14 days after birth is likely what type

herpes simplex virus

what is the most common cause of chronic conjunctivitis in all age groups

chlamydial conjunctivitis

onset in 1-2 weeks post-partum

treatment for chlamydial conjunctivitis

oral erythromycin

azithromycin

potential for conjunctival scarring

what type of conjunctivitis is considered an ocular emergency

neisseria

can invade intact cornea

onset within first 24-48 hours of life

delayed treatment can lead to loss of eye or be potentially fatal

main sign of neisseria conjunctivitis

hyperpurulent conjunctivitis

treatment for neisseria conjunctivitis

oral cephalosporins are the first line antibiotic

which antibiotics target cell wall synthesis

• cycloserine

• vancomycin, teichoplanin

• bacitracin

• penicillins

• cephalosporins

• monobactams

• carbapenems

what antibiotic targets the cell membrane

polymyxins

where do penicillins and cephalosporins act

transpeptidases (PBPs)

where does vancomycin act

D-Ala-D-Ala portion of peptidoglycan precursors

mechanism of action for penicillins and cephalosporins

block cross-linking of peptidoglycan chains, weakening the bacterial cell wall

mechanism of action for vancomycin

binds to the peptide ends, preventing cell wall formation

where does bacitracin act

bactoprenol (lipid carrier)

mechanism of action for bacitracin

prevents recycling of the lipid carrier needed to transport cell wall building blocks

where does polymyxin B act

bacterial cell membrane

mechanism of action of polymyxin B

damages the cell membrane, causing leakage of cell contents

characteristics of gram positive cell wall

1. thick peptidoglycan layer

2. no outer phospholipid membrane bi-layer

characteristics of gram-negative cell wall

1. outer phospholipid membrane bi-layer

2. has small pores that allow molecules to enter bacteria

3. thin peptidoglycan layer below the outer membrane

what beta-lactams are bacterial cell wall inhibitors

• penicillins

• cephalosporins

• carbapenems

• monobactams

components of peptidoglycan

1. N-acetylglucosamine (NAG)

2. N-acetylmuramic acid (NAM)

3. short peptide chains

steps for the synthesis of peptidoglycan

1. monosaccharides with 5 amino acid peptide chain are prepared in cytoplasm

2. lipid carrier, bactoprenol, moves disaccharide-peptide chain across the cytoplasmic membrane

3. transpeptidases and PBP crosslink peptides together to grow the peptidoglycan chain

mechanism of vancomycin

peptide drug that binds to peptide chain, preventing transpeptidases from binding

mechanism of beta lactam antibiotics

inhibits transpeptidases which links disaccharide chains

mechanism of bacitracin

blocks lipid carrier (bactoprenol) from being recycled back to the other side of the membrane

why are cell wall inhibitors selectively toxic to bacteria

1. human cells lack peptidoglycan cell walls

2. bacteria require peptidoglycan for structural strength

3. cell wall inhibitors disrupt bacterial wall formation

4. beta-lactams work best on actively growing bacteria

pencillin classes

1. penicillins G and V

2. antistaphylcoccal penicillin

3. aminopenicillins/extended spectrum

4. antipseudomonal penicillin

which drugs are antistaphylococcal penicillins

• methicillin

• dicloxacillin

• nafcillin

• oxacillin

which drugs are aminopenicillins/extended spectrum

• ampicillin

• amoxicillin

which drugs are antipseudomonal penicillin

• ticarillin

• piperacillin

• carbenicillin

mechanism of action of penicillin

1. irreversibly binds to PCPs (transpeptidases), inhibiting cross-linking of peptidoglycan in bacterial cell wall

2. triggers activation of bacterial autolysins, which degrade the cell wall and lead to cell lysis

action of beta-lactamase/penicillinase

enzymes produced by bacteria that break down beta-lactam ring of antibiotics

one mechanism used by bacteria to generate resistance against antibiotics

action of transpeptidase/penicillinase binding proteins

enzymes produced by bacteria used to cross-link the peptidoglycan chains in the bacterial cell wall

what bacteria have cell walls that are easily traversed by penicillin

gram positive

what type of bacteria have a barrier to water soluble penicillins

gram negative

outer phospholipid membrane surrounding cell wall create barrier

porins will allow smaller penicillins to enter

how do penicillin R groups influence gram negative activity

alters drug’s size, charge, and hydrophilicity which affects it ability to pass through outer membrane porins

action of beta-lactamase inhibitors

• prevent degradation of penicillin by bacterial beta-lactamase or penicillinase

• minor anti-bacterial activity

• potentiates the activity of the antibiotic

three bacterial beta-lactamase inhibitors

1. clavulanic acid

2. sulbactam

3. tazobactam

what antibiotics are not broken down by bacteria beta-lactamases

1. methicillin

2. dicloxacillin

3. nafcillin

4. oxacillin

these are beta-lactamase resistant anti-staphylococcal penicillins

what bacteria are beta-lactamase resistant anti-staphylococcal penicillins effective and not effective against

used against staph resistant to other beta-lactams

bulky side chains cannot enter porins so they are not effective against gram (-) bacteria

ocular uses of beta-lactamase resistant anti-staphylococcal penicillins

oral dicloxacillin used for:

• internal hordeolum

• blepharitis

• oculoplastic procedures

IV nafcillin and cephalosporin used for:

• orbital cellulitis

when are penicillins considered as a treatment for hordeola

if warm compresses do not provide resolution

if preseptal cellulitis is noted

dicloxacillin 250 mg QID PO x10D

hordeola are often associated with what type of bacteria

staph aureus infections

what is the most commonly prescribed antibiotic

amoxicillin

what is amoxicillin commonly used to treat

• H. pylori ulcers

• preseptal cellulitis

• dacryocystitis

what is augmentin a combination of

amoxicillin and beta-lactamase inhibitor clavulanic acid

what is augmentin used to treat

• internal hordeolum

• preseptal cellulitis

• dacryocystitis

• pediatric hemophilus

benefits of extended-spectrum penicillin

• effective against penicillinase producers - clavulanate blockes penicillinase

• bacteriocidal

• low GI side effects

• safe in pregnancy

• cheap

two main types of antipseudomonal penicillins

• piperacillin: available alone or with beta-lactamase inhibitor tazobactam

• ticarcillin: available alone or with beta-lactamase inhibitor clavulanic acid

adverse effects of penicillins as a whole

hypersensitivity can lead to life-threatening anaphylaxis

associated with stevens-johnson syndrome

but generally safe in pregnancy

pathophysiology of stevens-johnson syndrome

• type IV (delayed) hypersensitivity reaction

• drug binds to proteins in keratinocytes

• keratinocytes present these drug-associated antigens on MHC I

• CD*+ cytotoxic T cells recognize these keratinocytes as abnormal

• T cells induce keratinocyte apoptosis

• widespread keratinocyte death causes epidermal necrosis and skin detachment

adverse effects of penicillins

• very high therapeutic index

• hypersensitivity

• diarrhea and C. difficile

• renal and neurotoxicity

• reduced platelet aggregation

what penicillin has excellent resistance to bacteria beta-lactamase but no gram negative coverage

dicloxacillin

what penicillin has less GI upset, better absorption, but is not effective against beta-lactamase producing bacteria

amoxicillin

what penicillin has excellent resistance to bacterial beta-lactamase

augument

are penicillins effective against MRSA

no

what is the DOC to treat syphilis

penicillin G

who should you be careful prescribing cephalosporins to

patients with penicillin allergies

what beta-lactams are good for UTIs

cephalosporins because there are high levels in the urine

rank generations of cephalosporins for most activity against gram (+) to least activity

1st > 2nd > 3rd

rank generations of cephalosporins for most activity against gram (-) to least activity

3rd > 2nd > 1st

efficacy of 1st gen cephalosporins

most gram (+) organisms

efficacy of 2nd gen cephalosporins

expanded efficacy against many gram (-) but less gram (+) activity

efficacy of 3rd gen cephalosporins

declining gram (+) spectrum but increased gram (-) efficacy

what are 4th gen cephalosporins useful for

wide spectrum and pseudomonas

what are 5th generation cephalosporins useful for

MRSA

1st generation cephalosporin agents

1. cefazolin

2. cefadroxil

3. cephalexin

what is cefazolin used to treat

• endophthalmitis

• corneal ulcers

• penetrating eye injury

what is cephalexin used to treat

• soft tissue infections

• external hordeolum

• lid trauma

• dacryoadenitis

• dacryocystitis

• respiratory, urinary, and skin infections

2nd generation cephalosporin agents

1. cefuroxime

2. cefoxitin

3. cefaclor

4. cefprozil

5. cefotetan

what are 2nd gen cephalosporins used to treat

• otitis media

• skin infections

• respiratory tract infections

3rd gen cephalosporin agents

1. cefixime

2. ceftriaxone

3. cefotaxime

4. ceftazidime

5. ceftibuten

6. cefpodoxime

what are 3rd gen cephalosporins used to treat

• respiratory tract infections

• urinary tract infections

• meningitis

• ceftazidime → treat pseudomonas aeruginosa

• ceftriaxone → gonorrhea treatment

4th gen cephalosporin agent

cefepime

what is cefepime (4th gen) effective against

• pseudomonas

• enterobacter

• E. coli

• K. pneumonia

• P. mirabilis

5th gen cephalosporin agents

1. ceftaroline

2. ceftobiprole

what are 5th gen cephalosporins active against

MRSA (methicillin-resistant S. aureus

penicillin-resistant streptococci

not active against pseudomonas